WO2007091950A1 - Benzimidazoles et imidazopyridines utiles dans le traitement de maladies ou de troubles associés au récepteur cannabinoïde 2 (cb2) tels que la douleur - Google Patents

Benzimidazoles et imidazopyridines utiles dans le traitement de maladies ou de troubles associés au récepteur cannabinoïde 2 (cb2) tels que la douleur Download PDF

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Publication number
WO2007091950A1
WO2007091950A1 PCT/SE2007/000110 SE2007000110W WO2007091950A1 WO 2007091950 A1 WO2007091950 A1 WO 2007091950A1 SE 2007000110 W SE2007000110 W SE 2007000110W WO 2007091950 A1 WO2007091950 A1 WO 2007091950A1
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alkyl
arylalkyl
aryl
haloalkyl
heteroaryl
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PCT/SE2007/000110
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English (en)
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Daniel PAGÉ
Hua Yang
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Astrazeneca Ab
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Publication of WO2007091950A1 publication Critical patent/WO2007091950A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/14—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 three or more hetero rings
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • Benzimidazoles and imidazopyridines useful in the treatment of diseases or disorders associated with cannabinoid receptor 2 (CB2) such as pain.
  • the present invention relates to novel benzimidazoles and imidazopyridines, and pharmaceutical compositions containing the same.
  • the present invention relates to the use of such compounds and compositions, and to therapeutic methods for the treatment and/or prevention of diseases and disorders associated with cannabinoid receptor 2 (CB2).
  • CBD2 cannabinoid receptor 2
  • the present invention further relates to processes for the preparation of such novel compounds.
  • cannabinoid receptor 1 CBl
  • CB2 cannabinoid receptor 2
  • CB2 receptor is an interesting target for the discovery of novel analgesics which would be expected to be devoid of CBl mediated side-effects associated with conventional cannabinoid agonists, e.g., tetrahydrocannabinol (THC).
  • cannabinoid agonists e.g., tetrahydrocannabinol (THC).
  • selective CB2 agonists/antagonists may be expected to reduce pain without the psychoactive side effects and the commonly perceived abuse potential of centrally acting cannabimimetic (CBl) or opiate drugs.
  • CBl centrally acting cannabimimetic
  • analgesics that have been identified and are existing in the prior art have many disadvantages among which are poor pharmacokinetics and loss of analgesic activity when administered by systemic routes.
  • CB2 agonists/antagonists can be used as a new approach to the treatment of pain, in particular neuropathic pain.
  • Neuropathathic pain includes, but it not limited to, hyperalgesic conditions such as pain caused by primary lesion or dysfunction in the nervous system and is associated with a variety of etiologies including trauma, infection, diabetes, immune deficiencies, ischemic disorders, and toxic neuropathies. Aproximately 26 million patients are affected worldwide and the lifestyle of this cohort can be severely impeded, a problem compounded by the lack of efficacy and frequent incidence of side effects associated with current treatment options.
  • CB2 antagonists could be used as anti-inflammatory agents and immunosupressants.
  • R 1 is Ci-8 alkyl, Ci -J haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 R ⁇ ;
  • R 7 , R 8 , R 9 and R 10 are each, independently, H, halo, CN, NO 2 , OH, Ci -4 alkyl, Ci -4 haloalkyl, Ci -4 alkoxy, or Ci -4 haloalkoxy;
  • D 1 Is CR 5 Or N;
  • R a and R a are each, independently, H, Ci -8 alkyl, Ci-S haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the Ci -8 alkyl, Ci -8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 OH, CM alkoxy, Ci -4 haloalkoxy, amino, halo, Ci -8 alkyl, Ci -8 haloalkyl, aryl,
  • R b and R b are each, independently, H, Ci -8 alkyl, Ci -8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the Ci -8 alkyl, Ci -8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 OH, Ci -4 alkoxy, Ci -4 haloalkoxy, amino, halo, Ci -8 alkyl, Ci -8 haloalkyl, Ci -8
  • R c and R d are each, independently, H, Ci-io alkyl, Ci -8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the Ci-io alkyl, Ci -8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 OH, Ci -4 alkoxy, Ci -4 haloalkoxy, amino, halo, Ci -8 alkyl, Ci -8 haloalkyl, Ci
  • R 0' and R d> are each, independently, H, C W c alkyl, Ci -8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the CM O alkyl, Ci -8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 OH, Ci -4 alkoxy, Ci -4 haloalkoxy, amino, halo, Ci -8 alkyl, Ci -8 haloalkyl,
  • X is Ci- 6 alkylenyl, C 2 - 6 alkenylenyl or C 2 -6 alkynylenyl, each optionally substituted by
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R s , R 8 , R 10 , R 16 , and m have any of the meanings as defined hereinwith.
  • R 17 and R 18 are each, independently, H, halo, OH, CN, Ci_6 haloalkyl, Ci_6 alkyl, or alkoxy;
  • R 1 , R 2 , R 3 , R 4 and R 5 have any of the meanings as defined hereinwith.
  • compositions comprising a compound of any of the formulas described herein, or a pharmaceutically acceptable salt, tautomer or in vzv ⁇ -hydrolysable precursor thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention further provides methods of modulating activity of CB2 comprising contacting CB2 with a compound of any of the formulas described herein, or a pharmaceutically acceptable salt, tautomer or in vzV ⁇ -hydrolysable precursor thereof, or any composition comprising the same.
  • the present invention further provides methods of treating a CB2 mediated disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of any of the formulas described herein, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, or any composition comprising the same.
  • the present invention further provides methods of treating pain such as acute pain, chronic pain, neuropathic pain, inflammatory pain, acute and chronic neuropathic pain, or acute and chronic inflammatory pain in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of any of the formulas described herein, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, or any composition comprising the same.
  • the present invention further provides a compound of any of the formulas described herein, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, described herein for use as a medicament.
  • the present invention further provides a compound of any of the formulas described herein, or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof, described herein for the manufacture of a medicament.
  • the present invention further provides synthetic methods of making a compound of any of the formulas described herein, or or a pharmaceutically acceptable salt, tautomer or in vzvo-hydrolysable precursor thereof.
  • R 1 is Ci- ⁇ alkyl, Ci -8 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subset thereof, each optionally substituted by 1, 2, 3, 4 or 5 R 11 ;
  • R 7 , R 8 , R 9 and R 10 are each, independently, H, halo, CN, NO 2 , OH, Ci -4 alkyl, C 1-4 haloalkyl, Ci -4 alkoxy, or Ci- 4 haloalkoxy, or any subset thereof;
  • R a and R a are each, independently, H, C 1-S alkyl, Ci-S haloalkyl, C 2- s alkenyl, C 2- 8 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subset thereof, wherein the Ci -8 alkyl, Ci -S haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 OH, Ci -4 alkoxy, Ci -4 haloalkoxy, amino, halo, Ci -8 alkyl, Ci-S hal
  • R b and R b' are each, independently, H, Ci -8 alkyl, Ci -8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subset thereof, wherein the Ci -8 alkyl, Ci -8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 OH, Ci -4 alkoxy, Ci -4 haloalkoxy, amino, halo, Ci -8 alkyl, Ci -8 halo
  • R 0 and R d are each, independently, H, C MO alkyl, Ci -8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subset thereof, wherein the Cwo alkyl, Ci -S haloalkyl, C 2 - 8 alkenyl, C 2-S alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 OH, C 1 .
  • R c' and R d are each, independently, H, C 1-1 O alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subset thereof, wherein the Q -1O alkyl, Ci -8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 OH, Ci -4 alkoxy, Q -4 haloalkoxy, amino, halo, Ci -8 alkyl, Ci -8
  • R 1 is Q -8 alkyl, Cj -8 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subset thereof, each optionally substituted by 1, 2 or 3 substituents independently selected from halo, Ci -4 alkyl, Cj -4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OH, Cj.
  • R 1 is Cj -8 alkyl, Cj -8 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subset thereof, each optionally substituted by 1, 2 or 3 substituents independently selected from halo, Cj -4 alkyl, Cj -4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OH, Ci -4 alkoxy, Cj -4 haloalkoxy, amino, Cj -4 alkylamino and C 2-8 dialkylamino, or any subset thereof.
  • R 1 is Cj -8 alkyl, Cj -8 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subset thereof, each optionally substituted by 1 or 2 substituents independently selected from halo, C x-4 alkyl, Cj -4 haloalkyl, CN, NO 2 , Cj -4 alkoxy, Cj -4 haloalkoxy and C 2-8 dialkylamino, or any subset thereof.
  • R 1 is Ci-S alkyl, Ci -8 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subset thereof. In some further embodiments, R 1 is C 3 ..8 alkyl, C3. 8 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subset thereof.
  • R 1 is -CH 2 -R 20 and R 20 is Ci -7 alkyl, Ci -7 haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyloalkyl, or any subset thereof.
  • R 2 , R 4 and R 5 are each, independently, H, Ci -4 alkoxy, Ci -4 haloalkoxy, halo, Ci -8 alkyl or Ci -8 haloalkyl, or any subset thereof. In some further embodiments, R 2 , R 4 and R 5 are each, independently, H, Ci -4 alkoxy, C x-4 haloalkoxy, halo, Ci -4 alkyl or Ci -4 haloalkyl, or any subset thereof. In yet further embodiments, R 2 , R 4 and R 5 are each, independently, H.
  • R 7 , R 8 , R 9 and R 10 are each, independently, H, halo, Ci -4 alkyl, C 1 . 4 haloalkyl, Ci -4 alkoxy or Ci -4 haloalkoxy, or any subset thereof.
  • R 7 , R 8 , R 9 and R 10 are each, independently, H, halo, or Ci -4 alkyl, or any subset thereof. In some further embodiments, R 7 , R , R 9 and R 10 are each H.
  • D 1 is CR 5 . In some other embodiments, D 1 is N.
  • X 1 is Q.6 alkylenyl, C 2- 6 alkenylenyl or C 2- 6 alkynylenyl, or any subset thereof, each optionally substituted by 1, 2, 3, 4, 5, or 6 R 16 .
  • X 1 is Ci- ⁇ alkylenyl optionally substituted by 1, 2, 3, 4, 5, or 6 R 1 . In some further embodiments, X 1 is Ci-6 alkylenyl. In some further embodiments, X 1 is (CH 2 X and t is 1, 2 or 3. In yet further embodiments, X is CH 2 .
  • R 16 is each, independently, halo, OH, CN, Q- ⁇ haloalkyl, Ci- alkyl, or Ci- ⁇ alkoxy, or any subset thereof.
  • n is 0 or 1. In some further embodiments, m is 0.
  • the : compounds of the ] invention have formula H:
  • X 1 is Ci -6 alkylenyl, C 2-6 alkenylenyl or C 2-6 alkynylenyl, or any subset thereof, each optionally substituted by 1, 2, 3, 4, 5, or 6 R 16 .
  • X 1 is C 1 . 6 alkylenyl, C 2-6 alkenylenyl or C 2-6 alkynylenyl, or any subset thereof.
  • the compounds of the invention have formula III:
  • R 17 and R 18 are each, independently, H, halo, OH, CN, Ci -6 haloalkyl, Ci -6 alkyl, or Ci -6 alkoxy, or any subset thereof.
  • R 1 is 0 3 . 3 alkyl, C 3 - 8 haloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subset thereof, each optionally substituted by 1, 2 or 3 substituents independently selected from halo, Ci -4 alkyl, Ci -4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OH, Ci -4 alkoxy, Ci -4 haloalkoxy, amino, Ci -4 alkylamino and C 2- S dialkylamino, or any subset thereof.
  • R 1 is -CH 2 -R 21 and R 21 is C 2-7 alkyl, C 2-7 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, or any subset thereof, each optionally substituted by 1, 2 or 3 substituents independently selected from halo, C M alkyl, Ci -4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN 5 NO 2 , OH, C M alkoxy, Ci -4 haloalkoxy, amino, Ci -4 alkylamino and C 2-8 dialkylamino, or any subset thereof.
  • R 2 , R 4 and R 5 are each, independently, H, Ci -4 alkoxy, Ci -4 haloalkoxy, halo, Ci -4 alkyl or Ci -4 haloalkyl, or any subset thereof. In some further embodiments, R 2 , R 4 and R 5 are each, independently, H.
  • the present invention provides the following compounds :2-(2,3- dihydro-l-benzofuran-5-yhnethyl)-l-(3-methylbutyl)-N,N-bis(2,2,2-trifluoro-ethyl)-lH- benzimidazole-5-carboxamide;N-[2-(2,3-dihydro-l-benzofuran-5-yknethyl)-l-(3-methylbutyl)- lH-benzimidazol-5-yl]-N,3-dimemylbutanamide; N-[2-(2,3-dihydro-l-benzofuran-5-ylmethyl)- l-(3-methylbutyl)-lH-benzimidazol-5-yl]-N-methylacetamide; N-[2-(2,3-dihydro-l-benzofuran-yhnethyl)-l-(3-methylbutyl)-N,N-bis(2,2,2-triflu
  • Compounds of the present invention also include pharmaceutically acceptable salts, tautomers and in vzVo-hydrolysable precursors of the compounds of any of the formulas described herein.
  • Compounds of the invention further include hydrates, solvates, and hydrated or solvated salts.
  • substitution means that substitution is optional and therefore it is possible for the designated atom or moiety to be unsubstituted. In the event a substitution is desired then such substitution means that any number of hydrogens on the designated atom or moiety can be replaced with a selection from the indicated group, provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group (i.e., CH 3 ) is optionally substituted, then 3 hydrogens on the carbon atom can be replaced.
  • a methyl group i.e., CH 3
  • a variety of compounds in the present invention may exist in particular stereoisomeric forms.
  • the present invention takes into account all such compounds, including cis- and trans isomers, R- and S- enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • the compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms.
  • optically active forms such as by resolution of racemic forms or by synthesis from optically active starting materials.
  • separation of the racemic material can be achieved by methods known in the art.
  • Cis and trans isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all stereoisomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
  • the compounds of the present invention may exist in different geometric isomers.
  • phenyl substituted by methyl can be phenyl substituted by methyl at ortho-, meta-, or para-position.
  • n-membered where n is an integer typically describes the number of ring- forming atoms in a moiety where the number of ring-forming atoms is n.
  • furanyl is an example of 5-membered heteroaryl
  • pyridinyl i.e., pyridyl
  • piperdinyl is an example of a 6-membered heterocycloalkyl.
  • alkyl As used herein, “alkyl”, “alkylenyl” or “alkylene” used alone or as a suffix or prefix, is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having from 1 to 12 carbon atoms or if a specified number of carbon atoms is provided then that specific number would be intended.
  • C 1 ⁇ alkyl denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.
  • Cu alkyl whether a terminal substituent or an alkylene (or alkylenyl) group linking two substituents, is understood to specifically include both branched and straight-chain methyl, ethyl, and propyl.
  • alkylenyl refers to a divalent linking alkyl group.
  • alkenyl refers to an alkyl group having one or more double carbon-carbon bonds.
  • Example alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like.
  • alkenylenyl refers to a divalent linking alkenyl group.
  • alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds.
  • Example alkynyl groups include ethynyl, propynyl, and the like.
  • alkynylenyl refers to a divalent linking alkynyl group.
  • aromatic refers to hydrocarbyl groups having one or more polyunsaturated carbon rings or unsaturated heterocylic rings (can be mono- or poly-cyclic) having aromatic characters, (e.g., 4n + 2 delocalized electrons) and comprising up to about 14 carbon atoms.
  • aryl refers to an aromatic ring structure made up of from 5 to 20 ring-forming carbon atoms. Ring structures containing 5, 6, 7 and 8 carbon atoms would be single-ring aromatic groups, for example, phenyl. Ring structures containing 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 would be a polycyclic moiety in which at least one carbon is common to any two adjoining rings therein (for example, the rings are "fused rings"), for example naphthyl.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls or cycloalkynyls.
  • ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively.
  • the names 1,2-dimethylbenzene and ortfio-dimethylbenzene are synonymous.
  • cycloalkyl refers to a non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups, having the specified number of carbon atoms (wherein the ring comprises 3 to 20 ring-forming carbon atoms). Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused or bridged rings) groups.
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane (i.e., indanyl), cyclopentene, cyclohexane, and the like.
  • cycloalkyl further includes saturated ring groups, having the specified number of carbon atoms. These may include fused or bridged polycyclic systems. Suitable cycloalkyls have from 3 to 10 carbon atoms in their ring structure; suitable cycloalkyls can also have 3, 4, 5, and 6 carbons in the ring structure. For example, " €3. 6 cycloalkyl” denotes such groups as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • heterocyclyl or “heterocyclic” or “heterocycle” refers to a ring-containing monovalent and divalent structures having one or more heteroatoms, independently selected from N, O and S, as part of the ring structure and comprising from 3 to 20 ring-forming atoms (i.e. a 3-20 membered ring), more preferably 3-10 ring-forming atoms (i.e. a 3-10 membered ring).
  • the number of ring-forming atoms in heterocyclyl are given in ranges herein.
  • Cs-io heterocyclyl refers to a ring strcture comprising from 5 to 10 ring-forming atoms (i.e.
  • heterocyclic groups may be saturated or partially saturated or unsaturated, containing one or more double bonds, and heterocyclic groups may contain more than one ring as in the case of polycyclic systems.
  • the heterocyclic rings described herein may be substituted on carbon or on a heteroatom atom if the resulting compound is stable. If specifically noted, nitrogen in the heterocyclyl may optionally be quaternized. It is understood that when the total number of S and O atoms in the heterocyclyl exceeds 1, then these heteroatoms are not adjacent to one another.
  • heterocyclyls include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H, 6H- 1, 5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1, 2,5-thiadiazinyl, acridinyl, azabicyclo, azetidine, azepane, aziridine, azocinyl, benzimidazolyl, benzodioxol, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl
  • heteroaryl refers to an aromatic heterocycle (wherein the ring comprises 3 to 20 ring-forming atoms) having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl (i.e., pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (i.e.
  • the heteroaryl group contains 3 to about 14, 4 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heteroaryl group has 1 heteroatom.
  • halo or halogen refers to fluoro, chloro, bromo, and iodo.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include, but are not limited to, CF3, C 2 Fs, CH 2 CF 3 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.
  • alkoxy refers to an -O-alkyl group.
  • Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • alkylthio or “thioalkoxy” represent an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
  • haloalkoxy refers to an -O-haloalkyl group.
  • An example haloalkoxy group is OCF 3 .
  • aryloxy refers to -O-aryl.
  • An example heteroaryloxy is phenoxy.
  • arylalkyl refers to Ci -1O alkyl substituted by aryl and "cycloalkylalkyl” refers to C] -1 O alkyl substituted by cycloalkyl.
  • An example arylalkyl group is benzyl.
  • heteroarylalkyl refers to Cno alkyl substituted by heteroaryl and “heterocycloalkylalkyl” refers to Cno alkyl substituted by heterocycloalkyl.
  • amino refers to NH 2 .
  • alkylamino refers to an amino group substituted by an alkyl group.
  • dialkylamino refers to an amino group substituted by two alkyl groups.
  • R is Cno alkyl, Q.io haloalkyl, C 3 - 1 0 cycloalkyl, aryl, heteroaryl, arylalkyl or heteroaryalkyl.
  • An example of acyl group is acetyl group.
  • Counteririon is used to represent a small, negatively or positively charged species such as, for example, chloride (Cl “ ), bromide (Br “ ), hydroxide (OH “ ), acetate (CH 3 COO “ ), sulfate (SO 4 2” ), tosylate (CHa-phenyl-SCV), benezensulfo ⁇ ate (phenyl-SCV), sodium ion (Na + ), potassium (K + ), ammonium (NH 4 + ), and the like.
  • R is represented by but not limited to hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 3 rd ed.; Wiley: New York, 1999).
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof (i.e., also include counterions).
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, phosphoric, and the like; and the salts prepared from organic acids such as lactic, maleic, citric, benzoic, methanesulfonic, and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile can be used.
  • in vivo hydrolysable precursors means an in vivo hydroysable (or cleavable) ester of a compound of any of the formulas described herein that contains a carboxy or a hydroxy group.
  • amino acid esters Q-g alkoxymethyl esters like methoxymethyl; Ci. 6 alkanoyloxymethyl esters like pivaloyloxymethyl; C 3 .. 8 cycloalkoxycarbonyloxy Ci. ⁇ alkyl esters like 1-cyclohexylcarbonyloxyethyl, acetoxymethoxy, or phosphoramidic cyclic esters.
  • tautomer means other structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom. For example, keto-enol tautomerism where the resulting compound has the porperties of both a ketone and an unsturated alchol.
  • 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.
  • compounds of the present invention include the compounds of any of the formulas described herein, and pharmaceutically acceptable salts, tautomers and in vz ' v ⁇ -hydrolysable precursors thereof.
  • Compounds of the present invention further include hydrates and solvates.
  • Some of the compounds of the present invention are capable of forming salts with various inorganic and organic acids and bases and such salts are also within the scope of this invention.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, phosphoric, and the like; and the salts prepared from organic acids such as lactic, maleic, citric, benzoic, methanesulfonic, trifluoroacetate and the like.
  • Compounds having acidic groups can form salts with alkaline or alkaline earth metals such as Na, K, Mg and Ca, and with organic amines such as triethylamine and Tris (2-hydroxyethyl)amine. Salts can be formed between compounds with basic groups, e.g. amines, with inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as acetic acid, citric acid, benzoic acid, fumaric acid, or tartaric acid. Compounds having both acidic and basic groups can form internal salts.
  • alkaline or alkaline earth metals such as Na, K, Mg and Ca
  • organic amines such as triethylamine and Tris (2-hydroxyethyl)amine. Salts can be formed between compounds with basic groups, e.g. amines, with inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as acetic acid, citric acid, be
  • Acid addition salts may be formed with a wide variety of acids, both inorganic and organic.
  • Examples of acid addition salts include salts formed with hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic, toluenesulphonic, methanesulphonic, ethanesulphonic, naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids.
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 Ri + , NHR3 "1" , NR 4 + ).
  • Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolarnine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CHs) 4 + .
  • the compounds may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of the invention.
  • Compounds containing an amine function may also form N-oxides.
  • a reference herein to a compound that contains an amine function also includes the N-oxide.
  • N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemisti ⁇ , by Jerry March, 4 th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with r ⁇ -chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
  • MCPBA r ⁇ -chloroperoxybenzoic acid
  • Esters can be formed between hydroxyl or carboxylic acid groups present in the compound and an appropriate carboxylic acid or alcohol reaction partner, using techniques well known in the art.
  • esters are compounds containing the group C(O)OR, wherein R is an ester substituent, for example, a Cn alkyl group, a C 3-2O heterocyclyl group, or a C5. 20 aryl group, preferably a Cn alkyl group.
  • R is an acyloxy substituent, for example, a Ci -7 alkyl group, a C 3-2 o heterocyclyl group, or a C5.20 aryl group, such as a Cn alkyl group.
  • prodrugs which are prodrugs of the compounds are convertible in vivo or in vitro into one of the parent compounds. Typically, at least one of the biological activities of compound will be reduced in the prodrug form of the compound, and can be activated by conversion of the prodrug to release the compound or a metabolite of it.
  • some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.).
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • Other derivatives include coupling partners of the compounds in which the compounds is linked to a coupling partner, e.g. by being chemically coupled to the compound or physically associated with it.
  • Examples of coupling partners include a label or reporter molecule, a supporting substrate, a carrier or transport molecule, an effector, a drug, an antibody or an inhibitor.
  • Coupling partners can be covalently linked to compounds of the invention via an appropriate functional group on the compound such as a hydroxyl group, a carboxyl group or an amino group.
  • Other derivatives include formulating the compounds with liposomes.
  • novel compounds of the present invention can be prepared in a variety of ways known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C NMR), infrared spectroscopy (IR), spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • HPLC high performance liquid chromatograpy
  • Preparation of compounds can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein by reference in its entirety.
  • Other references and descriptions of suitable reactions are described in textbooks of organic chemistry, for example, "Advanced Organic Chemistry", March, 4 th ed. McGraw Hill (1992) or, "Organic Synthesis", Smith, McGraw Hill, (1994).
  • the reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • the compounds of the invention can be prepared, for example, using the reaction pathways and techniques described below.
  • the novel compounds of the present invention can be synthesized starting from a benzene or pyridine derivative 1-1 which has a fluro and a nitro substituted on the adjacent positions.
  • the compound 1-1 can undergo nucleophilic aromatic substitution to provide the compound 1-2 by replacing the fluorine with an amine R 1 NHa.
  • the necleophilic aromatic substitution can be carried out in a suitable organic solvent such as a polar organic solvent (e.g., an alcohol such as ethanol or isopropanol) and in the presence of a suitable base such as a tertiary amine (.g., triethylamine (Et 3 N or TEA), diisopropylethylamine (iP ⁇ NEt or DIPEA) and/or dimethylaminopyridine (DMAP)).
  • a suitable organic solvent such as a polar organic solvent (e.g., an alcohol such as ethanol or isopropanol)
  • a suitable base such as a tertiary amine (.g., triethylamine (Et 3 N or TEA), diisopropylethylamine (iP ⁇ NEt or DIPEA) and/or dimethylaminopyridine (DMAP)
  • a suitable organic solvent such as a polar organic solvent (e.g., an alcohol such
  • the coupling of the amine compound 1-3 to an acid compound 1-4 can be carried out by a conventional amide bond formation method such as using a coupling reagent.
  • a coupling reagent can be used to facilitate the coupling reaction of amide bond formation.
  • Those ordinary skilled in the art will readily recognize such coupling reagents.
  • suitable coupling reagents include benzotriazole-contaning coupling reagents such as N-hydoxybenzotriazole (HOBt), benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexaftuorophosphate (HBTU); an azabenzotriazole-containing reagent such as O-(7- Azabenzotriazole-l-yl)-N, N,N'NMetramemyluroniumhexafluorophosphate (HATU); and dicarboimides such as l-Ethyl-3-(3-dimemylarmnopropyl)-carbodiimide (EDC), and dicyclohexyl carbodimide (DCC).
  • HOBt N-hy
  • the coupling reaction can be carried out in a suitable organic solvent.
  • suitable organic solvent include polar orgranic solvent such as an alcohol (such as methanol, ethanol or isopropanol), or tetrahydrofuran (THF).
  • polar orgranic solvent such as an alcohol (such as methanol, ethanol or isopropanol), or tetrahydrofuran (THF).
  • aprotic solvent Some suitable organic solvent include polar aprotic organic solvent such as N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) or methylene chloride.
  • DMF N,N-dimethylformamide
  • THF tetrahydrofuran
  • DMSO dimethyl sulfoxide
  • methylene chloride methylene chloride
  • Suitable bases include organic bases such as tertiary amines (e.g., triethylamine (Et 3 N or TEA), diisopropylethylamine (iPr 2 NEt or DIPEA) and/or dimethylaminopyridine (DMAP)).
  • tertiary amines e.g., triethylamine (Et 3 N or TEA), diisopropylethylamine (iPr 2 NEt or DIPEA) and/or dimethylaminopyridine (DMAP)
  • the reaction mixture is heated to an elevated temperature (i.e., above the room temperature).
  • the reaction mixture is heated to a temperature of about 4O 0 C, about 50 0 C, about 60 0 C, about 7O 0 C, about 80 0 C, about 90 0 C, about 100 0 C, about 110 0 C, about 120 0 C, about 130 0 C 5 about 140 0 C, about 15O 0 C, about 160 0 C.
  • the reaction progress can be monitored by conventional methods such as TLC or NMR.
  • the acid 1-4 can be converted to a more reactive species (same as compound 2-3 in Scheme 2 and the decription thereof) such as an ester, a mixed anhydride or acid chloride, and the species 1 can be separated.
  • the species can further react with the amine compound 1-3 to form the amide 1-5 under suitable conditions.
  • Cylization of compound 1-5 can be carried out by suitable methods such as under acidic conditions and at an elevated temperature (e.g., at about 70 0 C, about 80 0 C, about 90 0 C or about 100 0 C) to provide the compound 1-6.
  • suitable acids include HCl, sulfuric acid or an organic sulfonic acid (such as p-tolunesulfonic acid).
  • a compound 2-6 (wherein R la can be Ci -7 alkyl, Ci -7 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, each of which can be optionally substituted by 1, 2, 3, 4 or 5 subsit ⁇ ents such as halo, Ci -4 alkyl, Ci -4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , Q- 4 alkoxy, Ci -4 haloalkoxy, C 2- S dialkylamino, and the like) can be synthesized from a benzene or pyridine derivative 2-1 which has a fluro and a nitro substituted on the adjacent positions.
  • the amino group of the compound 2-2 can be introduced through nucleophilic aromatic substitution by replacing the fluorine with an amino group in the presence of an ammonia producing source as ammonium hydroxide (at an elevated temperature).
  • the coupling the amine compound 2-2 to an acid compound or a more reactive acid derivative 2-3 (wherein Y is OH, it is an acid compound, wherein Y is Cl, it is an acid chloride).
  • Y is OH (i.e., 2-3 is an acid compound)
  • a conventional coupling reaction of amide bond formation can be carried out (similar to the methods described in Scheme 1).
  • a more reactive species 2-3 are used.
  • the species can be an acid halide such as an acid chloride (wherein Y is halo such as Cl), an ester (wherein Y can be -O-CM alkyl such as ethoxy, p-nitrophenoxy, 2,4,5-trichlorophenoxy), an acylated N-hydroxysuccinimide derivative (wherein Y is succinimidohydroxy, i.e., pyrrolidin-2,5-dion-l-ylhydroxy) or a mixed anhydride b-4 (wherein Y is an acyl-O- group such as acetyl-O-).
  • an acid halide such as an acid chloride (wherein Y is halo such as Cl)
  • an ester wherein Y can be -O-CM alkyl such as ethoxy, p-nitrophenoxy, 2,4,5-trichlorophenoxy
  • acylated N-hydroxysuccinimide derivative wherein Y is succinimidohydroxy, i.e
  • the nitro group of the compound 2-4 can be reduced to the amino group of 2-5 by hydrogenation such as catalytic hydrogenation (e.g., Pd/C as the catalyst).
  • the amine compound 2-5 can be reacted with an aldehyde R la CHO under reductive animation condition (using a reducing reagent such as BH3 or BH3 "pyridine complex) to afford the secondary amine 2-6.
  • Cylization of compound 2-6 can be carried out under acidic conditions at an elevated temperature (e.g., at about 70°C, about 8O 0 C, about 90 0 C or about 100 0 C) to provide the compound 2-7.
  • Suitable acids include HCl, sulfuric acid or an organic sulfonic acid (such as ⁇ -tolunesulfonic acid).
  • an amide 3-3 (wherein R c can be H, Ci -4 alkyl or the like; and R a can be Ci -4 alkyl or the like) can be hydrolyzed to the amine 3-4 under suitable conditions for cleaving amide bonds (e.g., under reflux in an alcohol such as ethanol and in the presence of an acid such as HCl).
  • a CN group can be hydrolyzed to afford an amide group, or it can be reduced to be an aldehyde; a carboxylic acid can be converted to an amide; a carboxylic acid can be converted to an ester, which in turn can be reduced to an alcohol, which in turn can be further modified.
  • an OH ' group can be converted into a better leaving group such as mesylate, which in turn is suitable for nucleophilic substitution, such as by CN.
  • a compound of formula I (such as compound 1-6 of Scheme 1) having a substituent which contains a functional group can be converted to another compound of formula I having a different substituent group.
  • reacting refers to the bringing together of designated chemical reactants such that a chemical transformation takes place generating a compound different from any initially introduced into the system. Reacting can take place in the presence or absence of solvent.
  • Compounds of the invention exhibit a high degree of potency and selectivity for individual cannabinoid receptor 2 (CB2) groups. Accordingly, compounds of the invention can modulate activity of CB2.
  • modulate is meant to refer to an ability to increase or decrease activity of an enzyme or receptor (therefore a modulating compound can be an agonist, antagonists, or inverse agonist). Accordingly, compounds of the invention can be used in methods of modulating CB2 by contacting the CB2 with any one or more of the compounds or compositions described herein. In some embodiments, compounds of the present invention can act as inhibitors (antagonists and/or inverse agonists) of CB2.
  • the compounds of the invention can be used to modulate activity of CB2 in a mammal (including humams and laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice) in need of modulation of the receptor by administering a modulating amount of a compound of the invention.
  • the compounds of the invention can bind to CB2 receptors by displacement of a CB2 agonist or antoagonist such as WIN55212-2 (See, Compton et al., J. Pharmacol. Exp. Ther., 1992, 263, 1118). Accordingly, the compounds of the invention can be used to modulate activities of CB2.
  • GTPy[ 35 S] assay was used to evaluate the affinity of the compounds of the invention to CB2 and/or CBl. The affinity of a CB2 agonist/antangoist can be measured by KJ:
  • K 1 l+([Agonist used]/EC 50 Agonist) [0126] See, Cheng and Pnisoff (Biochem. Pharmacol. 1973, 22, 3099).
  • the compounds of the invention can selectively bind to CB2 over CBl.
  • the affinity of the compounds of the present invention to CB2 is greater than that to CBl.
  • the relative affinity of the the compounds of the present invention is measured by the ratio of CBl-Kj / CB2-Kj. In some embodiments, the ratio is greater than about 5, about 7, about 10, about 50, about 100, about 300, about 500, about 800, or about 1000.
  • CB2 mediated diseases and/or disorders include diseases/disorders and conditions associated with excitatory activation of CB2.
  • Example disorders can also include any disorder, condition or disease that is directly or indirectly linked to expression or activity of the receptor (CB2).
  • a CB2-associated disease/disorder can also include any disorder, condition or disease that can be prevented, ameliorated, or cured by modulating (such as inhibiting) CB2 activity.
  • CB2 associated diseases/disorders include pain such as acute pain, chronic pain, neuropathic pain, inflammatory pain, acute and chronic neuropathic pain, and acute and chronic inflammatory pain.
  • diseases/disorder may be selected from the group comprising mechanical hyperalgesia associated with nerve injury, and neuropathic pain.
  • Neuropathic pain includes hyperalgesic conditions such as pain caused by primary lesion or dysfunction in the nervous system and is associated with a variety of etiologies including trauma, infection, diabetes, immune deficiencies, ischemic disorders, and toxic neuropathies.
  • CB2 antagonists could also be used as anti-inflammatory agents and immunosupressants.
  • the present invention relates to the use of the compounds of formula I, II and III as herein described, or compositions comprising the same, in therapy. In some embodiments, the present invention relates to the use of the compounds of formula I, II and Ell as herein described, for treatment of CB2 mediated disorders. [0131] In some further embodiments, the present invention relates to the use of the compounds of formula I, II and III as herein described, or compositions comprising the same, for treatment of pain such as acute pain, chronic pain, neuropathic pain, inflammatory pain, acute and chronic neuropathic pain, and acute and chronic inflammatory pain.
  • pain such as acute pain, chronic pain, neuropathic pain, inflammatory pain, acute and chronic neuropathic pain, and acute and chronic inflammatory pain.
  • the present invention relates to the use of the compounds of formula I, II and III as herein described, in the manufacture of a medicament for treatment of CB2 mediated disorders and for treatment of pain such as acute pain, chronic pain, neuropathic pain, inflammatory pain, acute and chronic neuropathic pain, and acute and chronic inflammatory pain, and any other disorder mentioned above.
  • the present invention relates to a method of treatment of CB2 mediated disorders such as pain (e.g. acute pain, chronic pain, neuropathic pain, inflammatory pain, acute and chronic neuropathic pain, and acute and chronic inflammatory pain), comprising administrering to a mammal, including a human, a therapeutically effective amount of the compounds of formula I, II and III as herein described.
  • the mammal will be in need of such treatment.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the compounds of formula I, II and III as herein described, for use in treatment of CB2 mediated disorders and for treatment of pain such as acute pain, chronic pain, neuropathic pain, inflammatory pain, acute and chronic neuropathic pain, and acute and chronic inflammatory pain.
  • the mammal or human being treated with a compound of the present invention has been diagnosed with a particular disease or disorder, such as those described herein. In these cases, the mammal or human being treated is in need of such treatment. Diagnosis, however, need not be previously performed.
  • disorder means any disorder, condition and disease that is directly or indirectly linked to the expression or activity of CB2. In some embodiments, the disorders are associated with CB2 activity.
  • inhibitor and “antagonist” mean a compound that by any means, partly or completely, blocks the transduction pathway leading to the production of a response by the ligand.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in a mammal.
  • the cell is a pancreatic cell, a hepatocyte or neuron.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" the CB2 with a compound of the invention includes the administration of a compound of the present invention to a mammal, such as a human, having CB2, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the CB2.
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: preventing the disorder; for example, preventing a disorder, condition or disease in a mammal who may be predisposed to the disorder, condition or disease but does not yet experience or display the pathology or symptomatology of the disorder; inhibiting the disorder; for example, inhibiting a disorder, condition or disease in a mammal who is experiencing or displaying the pathology or symptomatology of the disorder, condition or disease (i.e., arresting further development of the pathology and/or symptomatology); and ameliorating the disorder; for example, ameliorating a disorder, condition or disease in a mammal who is experiencing or displaying the pathology or symptomatology of the disorder, condition or disease (i.e., reversing the pathology and
  • the compounds of Formula I can be administered in the form of pharmaceutical compositions.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery (e.g. suppository)), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral.
  • topical including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery (e.g. suppository)
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal
  • Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically .dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration.
  • Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of adminisfration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral adminstration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the age, weight and sex of the patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose- response curves derived from in vitro or animal model test systems. Thus, the skilled artisan can readily determine the amount of compound and optional additives, vehicles, and/or carrier in compositions and to be administered in methods of the invention.
  • the compounds of the invention can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent of value in treating one or more disorder or disease conditions referred to herein.
  • Another aspect of the present invention relates to labeled compounds of the invention (radio-labeled, fluorescent-labeled, etc.) that would be useful not only in radio-imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the enzyme in tissue samples, including human, and for identifying ligands by inhibition binding of a labeled compound.
  • the present invention includes enzyme assays that contain such labeled compounds.
  • the present invention further includes isotopically-labeled compounds of the invention.
  • An “isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 1, 124 I, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro receptor labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 1 , 131 1, 35 S or will generally be most useful. For radio-imaging applications 11 C, 18 F, 125 1, 123 1, 124 1, 131 I, 75 Br, 76 Br or 77 Br will generally be most useful.
  • a "radio-labeled compound” is a compound that has incorporated at least one radionuclide.
  • the radionuclide is selected from the group consisting of 3 H, 14 C, 125 1 , 35 S and 82 Br.
  • the labeled compounds of the present invention contain a fluorescent lable.
  • a labeled compound of the invention can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • a test compound which is labeled can be evaluated for its ability to bind a CB2 by monitering its concentration variation when contacting with the CB2, through tracking the labeling.
  • a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to CB2 (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the CB2 directly correlates to its binding affinity.
  • the standard compound is labled and test compounds are unlabeled. Accordingly, the concentration of the labled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.
  • Step 3 2 ⁇ (2,3-dihydro-l ⁇ benzofuran-5-ylmethyl)-l-(3-rnethylbutyl)-N,N-bis(2,2,2-trifluoro- ethyI)-lH-benzimidazole-5-carboxamide
  • Dichloromethane was added to the resulting residue.
  • the residue is partially soluble in dichloromethane.
  • an aqueous NaHCC> 3 solution were added, the residue became soluble.
  • the organic layer was washed once with a saturated aqueous NaHC ⁇ 3 solution, once with brine and dried over anhydrous Na 2 SO 4 .
  • Dichloromethane was removed at reduce pressure.
  • the resulting residue was insoluble in dichloroethane so acetic acid was added. A few drops of concentrated HCl were added too.
  • the mixture was stirred at 80 °C for 3 hours. Complete consumption of the starting material was confirmed by LC-MS. Solvents (dichloroethane and acetic acid) were removed under reduced pressure.
  • Example 8 iV-[2-(2,3-dihydro-l-benzofuran-5-ylmethyl)-l-(3-methylbutyl)-lH- benzimidazol-5-yl]-iV-methyl- ⁇ p -phenylurea
  • Example 14 iV- ⁇ 2-(2,3-dihydro-l-benzofuran-5-ylmethyl)-l-(3-methylbutyl)-lH- benzimidazol-5-yl]-iV,2,2-trimetb.ylpropanamide
  • Dichloromethane was added to the resulting residue. The organic layer was washed once with a saturated aqueous NaHCOs solution, once with brine and dried over anhydrous Na 2 SO 4 . Dichloromethane was removed under reduce pressure. The resulting residue was dissolved in dichloroethane (3 mL) and a few drops of concentrated HCl were added. The mixture was stirred at 80 °C for 2 hours. Complete consumption of the starting material was confirmed by LC-MS. Dichloromethane was added. The organic layer was washed once with a 2M aqueous NaOH solution, once with brine and dried over anhydrous Na 2 SO 4 . Dichloromethane was removed under reduced pressure.
  • Step 1 tert-butyl 2-[( ⁇ 4 ⁇ [(diethylamino)carbonyl]-2-nitrophenyl ⁇ amino)methyl]-piperidine-l- carboxylate
  • Step 4 l-(cyclohexylmethyl)-2-(2, 3-dihydro-l ⁇ benzofuran-5-y ⁇ methyl)-N,N-diethy ⁇ -lH- benzimidazole-5-carboxamide
  • Step 1 methyl ⁇ 3-amino-4-[(cydohexylmethy ⁇ )amino]phenyl ⁇ carbamate
  • Example 28 l-(cyclohexylmethyl)-2-(2,3-dihydro-l-benzofuran-5-ylmethyl)-iV-methyl-liy- benzimidazol-5-amine
  • Triethylamine 15 ⁇ L
  • benzenesulfonyl chloride 10 ⁇ L
  • a catalytic amount of DMAP were added.
  • the mixture was stirred at room temperature for a few hours. Complete consumption of the starting material was confirmed by LC-MS.
  • Dichloromethane was added to the reaction mixture.
  • the organic layer was washed once with a saturated aqueous ⁇ a ⁇ C ⁇ 3 solution, once with brine and dried over anhydrous MgSO 4 .
  • Dichloromethane was removed under reduced pressure.
  • the resulting residue was purified by column chromatography on silica gel (EtOAc/hexanes, 50:50 to 80:20). The product was dissolved in methanol and TFA (1.3 equiv) was added.
  • compositions may be obtained by conventional procedures well known in the pharmaceutical art.
  • GTPy[ 35 S] binding assay [0223] The reversal of WIN55212-2-induced stimulation of GTP ⁇ [ 35 S] binding was used to assay the antagonist properties of the compounds.
  • Membranes prepared from HEK-293S cells expressing human CB2 receptor were combined with approximately 0.13 riM GTPy[ 35 S], 3 nM of WIN55212-2, and 3 ⁇ M of the inverse agonist compounds.
  • the assay was performed in 50 mM Hepes, 20 mM NaOH, pH 7.4, 5 mM MgC12, 100 mM NaCl, 1 mM EDTA, 0.1% BSA and 15 ⁇ M GDP.
  • Ki l+([Agonist used]/EC 50 Agonist).

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Abstract

La présente invention concerne des benzimidazoles et des imidazopyridines nouveaux présentant la structure de formule I ci-dessous et leurs sels, leurs tautomères ou leurs précurseurs hydrolysables in vivo pharmaceutiquement acceptables, des compositions et des procédés d'utilisation de ceux-ci. Ces nouveaux composés permettent de traiter des troubles associés au CB2.
PCT/SE2007/000110 2006-02-07 2007-02-06 Benzimidazoles et imidazopyridines utiles dans le traitement de maladies ou de troubles associés au récepteur cannabinoïde 2 (cb2) tels que la douleur WO2007091950A1 (fr)

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WO2012090179A2 (fr) 2010-12-30 2012-07-05 Lupin Limited Dérivés d'isoquinoline en tant que modulateurs des récepteurs cannabinoïdes
WO2012090177A2 (fr) 2010-12-30 2012-07-05 Lupin Limited Modulateurs des récepteurs cannabinoïdes
WO2013005168A2 (fr) 2011-07-05 2013-01-10 Lupin Limited Modulateurs des récepteurs de cannabinoïdes
US8865912B2 (en) 2010-10-06 2014-10-21 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
WO2016000230A1 (fr) * 2014-07-03 2016-01-07 上海医药工业研究院 Procédé de préparation d'un intermédiaire d'étexilate de dabigatran et composé intermédiaire
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9156797B2 (en) 2010-10-06 2015-10-13 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US10314845B2 (en) 2010-10-06 2019-06-11 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US10660898B2 (en) 2010-10-06 2020-05-26 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US8865912B2 (en) 2010-10-06 2014-10-21 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9872860B2 (en) 2010-10-06 2018-01-23 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
US9062003B2 (en) 2010-10-06 2015-06-23 Glaxosmithkline Llc Benzimidazole derivatives as PI3 kinase inhibitors
WO2012090179A2 (fr) 2010-12-30 2012-07-05 Lupin Limited Dérivés d'isoquinoline en tant que modulateurs des récepteurs cannabinoïdes
WO2012090177A2 (fr) 2010-12-30 2012-07-05 Lupin Limited Modulateurs des récepteurs cannabinoïdes
US9006442B2 (en) 2011-07-05 2015-04-14 Lupin Limited Cannabinoid receptor modulators
WO2013005168A2 (fr) 2011-07-05 2013-01-10 Lupin Limited Modulateurs des récepteurs de cannabinoïdes
WO2016000230A1 (fr) * 2014-07-03 2016-01-07 上海医药工业研究院 Procédé de préparation d'un intermédiaire d'étexilate de dabigatran et composé intermédiaire
US10112901B2 (en) 2014-07-03 2018-10-30 Shanghai Institute Of Pharmaceutical Industry Method for preparing dabigatran etexilate intermediate, and intermediate compound
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors

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