WO2010039186A2 - Compounds useful as faah modulators and uses thereof - Google Patents

Compounds useful as faah modulators and uses thereof Download PDF

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Publication number
WO2010039186A2
WO2010039186A2 PCT/US2009/005270 US2009005270W WO2010039186A2 WO 2010039186 A2 WO2010039186 A2 WO 2010039186A2 US 2009005270 W US2009005270 W US 2009005270W WO 2010039186 A2 WO2010039186 A2 WO 2010039186A2
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substituted
unsubstituted
disease
disorders
compound according
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PCT/US2009/005270
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French (fr)
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WO2010039186A3 (en
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Carl Kaub
Sumithra Gowlugari
John Kincaid
Russell James Johnson
Donogh John Roger O'mahony
Maria De Los Angeles Estiarte-Martinez
Matthew Duncton
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Renovis, Inc.
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Publication of WO2010039186A3 publication Critical patent/WO2010039186A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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]

Definitions

  • This invention relates to novel compounds that are capable of modulating FAAH (fatty acid amide hydrolase) activity, and to pharmaceutical compositions containing such compounds.
  • the invention further relates to preparation of such compounds.
  • This invention also relates to methods for preventing and/or treating conditions that are causally related to aberrant FAAH activity or can be alleviated by modulating FAAH activity, such as pain, sleep disorders, anxiety and depression disorders, weight and eating disorders, Parkinson's disease, addiction, spasticity, inflammatory disorders, glaucoma or other disorders.
  • Fatty acid amide hydrolase is an integral membrane protein that degrades fatty acid primary amides and ethanolamides. Furthermore, FAAH has been shown to be important for the hydrolysis of the fatty acid amide (FAA) class of endogenous, lipid signaling molecules. FAAH has been shown to be relevant to the in vivo degradation of anandamide (AEA), oleamide, N-palmitoyl ethanolamide (PEA), N-oleoyl ethanolamide (OEA) and N-acyl taurines. These molecules act through a number of pathways and regulate diverse physiological behaviors including anxiety, pain, satiety, cognition and sleep (M. K. McKinney and B. J. Cravatt, (2005) Annu.
  • AEA anandamide
  • PEA N-palmitoyl ethanolamide
  • OEA N-oleoyl ethanolamide
  • N-acyl taurines N-acyl taurines.
  • compounds, pharmaceutical compositions and methods provided are used to treat, prevent or ameliorate a range of conditions in mammals such as, but not limited to, pain of various genesis or etiology, for example acute, chronic, inflammatory and neuropathic pain, dental pain, dysmenorrhea and headache (such as migraine, cluster headache and tension headache), hi some embodiments, the compounds, pharmaceutical compositions and methods provided are useful for the treatment of inflammatory pain and associated hyperalgesia and allodynia. In some embodiments, the compounds, pharmaceutical compositions and methods provided are useful for the treatment of neuropathic pain and associated hyperalgesis and allodynia (e.g.
  • the compounds, pharmaceutical compositions and methods provided are useful as anti-inflammatory agents for the treatment of arthritis, and as agents to treat Parkinson's Disease, Alzheimer's Disease, asthma, myocardial infarction, neurodegenerative disorders, spasticity, inflammatory bowel disease and autoirrTiune disorders, fever, atherosclerosis and cardiovascular diseases, renal disorders, obesity, eating disorders, emesis, cancer, memory disorders, schizophrenia, epilepsy, sleeping disorders, cognitive disorders, depression, anxiety, blood pressure, addiction, glaucoma and lipid disorders.
  • X is NR 1 R 2 ; or X is N-containing 3-1 1 membered mono or fused heterocycloalkyl, joined to the core group via ring N;
  • R 1 is selected from a substituted or unsubstituted cycloalkyl; or R 1 is substituted or unsubstituted aryl or heteroaryl;
  • R 2 is selected from hydrogen, and substituted or unsubstituted C ,-C 6 alkyl;
  • R 3 is selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
  • each R 4 is independently selected from H, C r C 6 alkyl, substituted Ci-C 6 alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubsti
  • R 3 is heteroaryl; and the heteroaryl is other than substituted or unsubstituted 1 ,4,5,6-tetrahydro-6-oxo-3-pyridazinyl.
  • the invention excludes compounds wherein R 3 is substituted or unsubstituted l,4,5,6-tetrahydro-6-oxo-3- pyridazinyl or substituted or unsubstituted
  • compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent.
  • the pharmaceutical composition can comprise one or more of the compounds described herein.
  • the pharmaceutical compositions of the invention can comprise a compound in combination with one or more other compounds and/or compositions having a like therapeutic effect.
  • compositions and treatment methods disclosed herein can be pharmaceutically acceptable as prepared and used.
  • methods are provided for preventing, treating or ameliorating a condition from among those listed herein, and particularly, such condition as may be associated with, e.g., arthritis, asthma, myocardial infarction, lipid disorders, cognitive disorders, anxiety, schizophrenia, depression, memory dysfunctions such as Alzheimers disease, inflammatory bowel disease and autoimmune disorders, which method comprises administering to a mammal in need thereof an amount of one or more of the compounds as provided herein, or pharmaceutical composition thereof, effective to prevent, treat or ameliorate the condition.
  • methods are provided for preventing, treating or ameliorating a variety of disease states, including the diseases associated with pain, sleep disorders, anxiety and depression disorders, weight and eating disorders, addiction, spasticity, and glaucoma, by administration of a compound such as those provided herein.
  • a neurodegenerative disease or disorder can, for example, be Parkinson's disease, Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in neuroinflammation such as, for example, encephalitis; centrally-mediated neuropsychiatric diseases and disorders such as, for example, depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction such as, for example urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders such as, for example, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflammation such as, for example rheumatoid
  • the methods comprise administering an effective condition-treating or condition-preventing amount of one or more of the compounds as provided herein, or pharmaceutical composition thereof, to a mammal in need thereof.
  • the present invention extends to the use of any of the compounds of the invention for the preparation of medicaments that may be administered for such treatments, as well as to such compounds for the treatments disclosed and specified.
  • methods are provided for synthesizing the compounds described herein, with representative synthetic protocols and pathways described below.
  • a still further object of the invention is to provide pharmaceutical compositions that are effective in the treatment or prevention of a variety of disease states, including the diseases associated with pain, sleep disorders, anxiety and depression disorders, weight and eating disorders, addiction, spasticity, intraocular pressure or other disorders.
  • a still further object of the invention is to provide a method for the treatment of the disease states recited above, by the administration of a therapeutically effective amount of the compounds of the invention, and/or the pharmaceutical compositions of the invention.
  • a yet further object of the invention is to provide formulations for the treatment of the diseases as aforesaid, by the combination of at least one of the compounds of the invention, a pharmaceutical composition of the invention, combinations thereof with other compounds and compositions having a like therapeutic effect.
  • analogue means one analogue or more than one analogue.
  • 'Acyl' or 'Alkanoyl' refers to a radical -C(O)R 20 , where R 20 is hydrogen, C,-C 8 alkyl, C 3 -
  • Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzyl carbonyl.
  • 'acyl' groups are -C(O)H, -C(O)-C 1 -C 8 alkyl, -C(O)-(CH 2 MC 6 -C 10 aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), -C(O)-(CH 2 X(C 3 -C 10 cycloalkyl), and -C(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
  • 'Substituted Acyl' or 'Substituted Alkanoyl' refers to a radical -C(O)R 21 , wherein R 21 is independently • C 1 -C 8 alkyl, substituted with halo or hydroxy; or
  • 'Acylamino' refers to a radical -NR 22 C(O)R 23 , where R 22 is hydrogen, C 1 -C 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 ar yl > arylalkyl, 5-10 memberd heteroaryl or heteroarylalkyl and R 23 is hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 - C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, as defined herein.
  • Exemplary 'acylamino' include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino.
  • Particular exemplary 'acylamino' groups are -NR 24 C(O)-C 1 -C 8 alkyl, -NR 24 C(O)-(CH 2 ),(C 6 -C 10 aryl), -NR 24 C(O)-(CH 2 ),(5-10 membered heteroaryl), -NR 24 C(O)-(CH 2 ) t (C 3 -C 10 cycloalkyl), and -NR 24 C(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, and each R 24 independently represents H or Ci-C 8 alkyl.
  • R 25 is independently
  • R 26 is independently
  • 'Acyloxy' refers to a radical -OC(O)R 27 , where R 27 is hydrogen, CpC 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C] 0 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein.
  • Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl.
  • Exemplary 'acyP groups are -C(O)H, -C(O)-CpC 8 alkyl, -C(O)-(CH 2 MC 6 -C 10 aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), -C(O)-(CH 2 MC 3 -C 10 cycloalkyl), and -C(O)-(CH 2 ),(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
  • 'Substituted Acyloxy' refers to a radical -OC(O)R 28 , wherein R 28 is independently
  • alkoxy' refers to the group -OR 29 where R 29 is Ci-C 8 alkyl.
  • Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1 ,2-dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • Substituted alkoxy' refers to an alkoxy group substituted with one or more of those groups recited in the definition of "substituted” herein, and particularly refers to an alkoxy group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -Ci 0 aryl, aryloxy, carboxyl, cyano, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl- S(O) 2 -.
  • Exemplary 'substituted alkoxy' groups are -O-(CH 2 ),(C 6 -Ci 0 aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -O-(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and -O-(CH 2 ),(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC 4 alkyl, halo, unsubstituted C]-C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted CpC 4 haloalkoxy or hydroxy.
  • Particular exemplary 'substituted alkoxy' groups are OCF 3 , OCH 2 CF 3 , OCH 2 Ph, OCH 2 -cyclopropyl, OCH 2 CH 2 OH, and OCH 2 CH 2 NMe 2 .
  • Alkoxycarbonyl' refers to a radical -C(O)-OR 30 where R 30 represents an C 1 -C 8 alkyl, C 3 -
  • alkoxycarbonyl groups are C(O)O-Ci -C 8 alkyl, -C(O)O- (CH 2 ),(C 6 -C,o aryl), -C(O)O-(CH 2 ) t (5-10 membered heteroaryl), -C(O)O-(CH 2 ),(C 3 -C, 0 cycloalkyl), and - C(O)O-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 1 to 4.
  • 'Substituted Alkoxycarbonyl' refers to a radical -C(O)-OR 31 where R 31 represents:
  • 'AryloxycarbonyP refers to a radical -C(O)-OR 32 where R 32 represents an C 6 -Ci 0 aryl, as defined herein.
  • R 32 represents an C 6 -Ci 0 aryl, as defined herein.
  • exemplary "aryloxycarbonyl” groups is -C(O)O-(C 6 -Ci 0 aryl).
  • Aryloxycarbonyl' refers to a radical -C(O)-OR 33 where R 33 represents • C 6 -C) 0 aryl > substituted with unsubstituted Ci-C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted CpC 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted C]-C 4 haloalkoxy or hydroxyl.
  • ⁇ eteroaryloxycarbonyF refers to a radical -C(O)-OR 34 where R 34 represents a 5-10 membered heteroaryl, as defined herein.
  • An exemplary "aryloxycarbonyl" group is -C(O)O-(5-10 membered heteroaryl).
  • 'Substituted HeteroaryloxycarbonyP refers to a radical -C(O)-OR 35 where R 35 represents:
  • heteroaryl substituted with unsubstituted C r C 4 alkyl, halo, unsubstituted C r C 4 alkoxy, unsubstituted C r C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted CpC 4 haloalkoxy or hydroxyl.
  • 'Alkoxycarbonylamino' refers to the group -NR 36 C(O)OR 37 , where R 35 is hydrogen, C 1 -
  • 'Alkyl' means straight or branched aliphatic hydrocarbon having 1 to 20 carbon atoms.
  • Particular alkyl has 1 to 12 carbon atoms. More particular is lower alkyl which has 1 to 6 carbon atoms. A further particular group has 1 to 4 carbon atoms.
  • Exemplary straight chained groups include methyl, ethyl, n-propyl, and n-butyl. Branched means that one or more lower alkyl groups such as methyl, ethyl, propyl or butyl is attached to a linear alkyl chain, exemplary branched chain groups include isopropyl, iso- butyl, t-butyl and isoamyl.
  • Substituted alkyl' refers to an alkyl group as defined above substituted with one or more of those groups recited in the definition of "substituted” herein, and particularly refers to an alkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of acyl, acylamino, acyloxy (- O-acyl or -OC(O)R 20 ), alkoxy, alkoxycarbonyl, alkoxycarbonylamino (-NR -alkoxycarbonyl or -NH- C(O)-OR 27 ), amino, substituted amino, aminocarbonyl (carbamoyl or amido or -C(O)-NR 2 ), aminocarbonylamino (-NR -C(O)-NR 2 ), aminocarbonyloxy (-0-C(O)-NR 2 ), aminosulfonyl,
  • 'substituted alkyl' refers to a Ci-C 8 alkyl group substituted with halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR ' SO 2 R “ , -SO 2 NR R ' , -C(O)R “ , -C(O)OR “ , -OC(O)R “ , -NR “ C(O)R “ , - C(O)NR 1 R “ , -NR ' R ' , or -(CR “ R ⁇ ) 1n OR “” ; wherein each R " is independently selected from H, C,-C 8 alkyl, -(CH 2 MC 6 -Ci 0 aryl), -(CH 2 ),(5-10 membered heteroaryl), -(CH 2 ) t (C 3 -C, 0 cycloalkyl), and -(CH 2 ),(4-10
  • alkylene' refers to divalent saturated alkene radical groups having 1 to 11 carbon atoms and more particularly 1 to 6 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., - CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like.
  • Substituted alkylene' refers to those groups recited in the definition of "substituted” herein, and particularly refers to an alkylene group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, amino-carbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O)
  • alkenyl' refers to monovalent olefinically unsaturated hydrocarbyl groups preferably having 2 to 11 carbon atoms, particularly, from 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation.
  • Substituted alkenyl' refers to those groups recited in the definition of "substituted” herein, and particularly refers to an alkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O
  • Alkenylene' refers to divalent olefinically unsaturated hydrocarbyl groups particularly having up to about 1 1 carbon atoms and more particularly 2 to 6 carbon atoms which can be straight- chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation.
  • Alkynyl' refers to acetylenically or alkynically unsaturated hydrocarbyl groups particularly having 2 to 1 1 carbon atoms, and more particularly 2 to 6 carbon atoms which can be straight- chained or branched and having at least 1 and particularly from 1 to 2 sites of alkynyl unsaturation.
  • alkynyl groups include acetylenic, ethynyl (-C ⁇ CH), propargyl (- CH 2 C ⁇ CH), and the like.
  • Substituted alkynyl' refers to those groups recited in the definition of "substituted” herein, and particularly refers to an alkynyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, a ll Oxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)
  • 'Amino' refers to the radical -NH 2 .
  • 'Substituted amino' refers to an amino group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to the group -N(R 38 ) 2 where each
  • R 38 is independently selected from:
  • Ci-C 8 alkyl substituted with halo or hydroxy
  • -N(R 38 ) 2 is an amino group.
  • exemplary 'substituted amino' groups are -NR 39 -C,-C 8 alkyl, -NR 39 -(CH 2 ) t (C 6 -C l0 aryl), -NR 39 -(CH 2 ) t (5-10 membered heteroaryl), -NR 39 - (CH 2 MC 3 -Ci O cycloalkyl), and -NR 39 -(CH 2 ),(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R 39 independently represents H or C 1 -C 8 alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl,
  • substituted amino includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino as defined below.
  • 'Alkylamino' refers to the group -NHR 40 , wherein R 40 is Ci-C 8 alkyl.
  • Substituted Alkylamino' refers to the group -NHR 41 , wherein R 41 is C r C 8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Alkylarylamino' refers to the group -NR 42 R 43 , wherein R 42 is aryl and R 43 is CpC 8 alkyl.
  • Substituted Alkylarylamino' refers to the group -NR 44 R 45 , wherein R 44 is aryl and R 45 is
  • Ci-C 8 alkyl and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C 3 - Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci -C 4 alkyl, halo, cyano, unsubstituted Ci-C 4 alkoxy, unsubstituted CpC 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Q-C 4 haloalkoxy or hydroxy.
  • 'Arylamino' means a radical -NHR 46 where R 46 is selected from C 6 -C, 0 aryl and 5-10 membered heteroaryl as defined herein.
  • Substituted Arylamino' refers to the group -NHR 47 , wherein R 47 is independently selected from C 6 -Ci 0 aryl and 5-10 membered heteroaryl; and any aryl or heteroaryl groups present, may themselves be substituted by unsubstituted CpC 4 alkyl, halo, cyano, unsubstituted Ci -C 4 alkoxy, unsubstituted CpC 4 haloalkyl, unsubstituted CpC 4 hydroxyalkyl, or unsubstituted CpC 4 haloalkoxy or hydroxy.
  • 'Dialkylamino' refers to the group -NR 48 R 49 , wherein each of R 48 and R 49 are independently selected from CpCg alkyl.
  • Substituted Dialkylamino ' refers to the group -NR 50 R 5 ' , wherein each of R 59 and R 5 ' are independently selected from CpCg alkyl; and at least one of the alkyl groups is independently substituted with halo, hydroxy, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC 4 alkyl, halo, unsubstituted CpC 4 alkoxy, unsubstituted Cp 4 haloalkyl, unsubstituted C ⁇ -C 4 hydroxyalkyl, or unsubstituted CpC 4 haloalk
  • 'Diarylamino' refers to the group -NR 52 R 53 , wherein each of R 52 and R 53 are independently selected from C 6 -Ci 0 aryl.
  • 'AminosulfonyF or 'Sulfonamide' refers to the radical -S(O 2 )NH 2 .
  • Substituted aminosulfonyl or “substituted sulfonamide” refers to a radical such as -
  • each R 548 is independently selected from:
  • Ci-C 4 hydroxyalkyl or unsubstituted C r C 4 haloalkoxy or hydroxy.
  • 'Aralkyl' or 'arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups, as defined above. Particular aralkyl or arylalkyl groups are alkyl groups substituted with one aryl group.
  • 'Substituted Aralkyl' or 'substituted arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups; and at least one of the aryl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, cyano, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci -C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted C t -C 4 haloalkoxy or hydroxy.
  • 'Aryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • aryl refers to an aromatic ring structure, mono-cyclic or poly-cyclic that includes from 5 to 12 ring members, more usually
  • aryl group is a monocyclic ring system it preferentially contains 6 carbon atoms.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene.
  • Particularly aryl groups include phenyl
  • 'Substituted Aryl' refers to an aryl group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to an aryl group that may optionally be substituted with 1 or more substituents, for instance from 1 to 5 substituents, particularly 1 to 3 substituents, in particular 1 substituent.
  • 'Substituted Aryl' refers to an aryl group substituted with one or more of groups selected from halo, C r C 8 alkyl, Ci-C 8 haloalkyl, cyano, hydroxy, Q-C 8 alkoxy, and amino.
  • R 56 and R 57 may be hydrogen and at least one of R 56 and R 57 is each independently selected from Ci-C 8 alkyl, Q-C 8 haloalkyl, 4-10 membered heterocycloalkyl, alkanoyl, Ci-C 8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , NR 58 SOR 59 NR 58 SO 2 R 59 , COOalkyl, COOaryl, CONR 58 R 59 , CONR 58 OR 59 , NR 58 R 59 , SO 2 NR 58 R 59 , S-alkyl, SOalkyl, SO 2 alkyl, Saryl, SOaryl, SO 2 aryl; or R 56 and R 57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heterocycloalkyl, alkano
  • R 60 and R 61 are independently hydrogen, Q-C 8 alkyl, Q-C 4 haloalkyl, C 3 -Q 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C) 0 aryl, substituted aryl, 5-10 membered heteroaryl.
  • 'Fused Aryl' refers to an aryl having two of its ring carbon in common with a second aryl ring or with an aliphatic ring.
  • Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein.
  • Arylalkyloxy refers to an -O-alkylaryl radical where alkylaryl is as defined herein; and any aryl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, cyano, unsubstituted CpC 4 alkoxy, unsubstituted Cp 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • 'Azido' refers to the radical -N 3 .
  • Carbamoyl or amido' refers to the radical -C(O)NH 2 .
  • Ci-C 8 alkyl C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • Exemplary 'Substituted Carbamoyl' groups are -C(O) NR 64 Oi-C 8 alkyl, -C(O)NR 64 -(CH 2 ) t (C 6 -Ci 0 aryl),
  • each R 64 independently represents H or C]-C 8 alkyl and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C r C 4 alkyl, halo, unsubstituted C r C 4 alkoxy, unsubstituted
  • Ci-C 4 haloalkyl unsubstituted CpC 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • Carboxy' refers to the radical -C(O)OH.
  • 'Cycloalkyl' refers to cyclic non-aromatic hydrocarbyl groups having from 3 to 10 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
  • 'Substituted cycloalkyl' refers to a cycloalkyl group as defined above substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to a cycloalkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent
  • 'Halo' or 'halogen' refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, cycloalkenyl, e.g. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • Heteroaryl' means an aromatic ring structure, mono-cyclic or polycyclic, that includes one or more heteroatoms and 5 to 12 ring members, more usually 5 to 10 ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups.
  • Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
  • bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole and imidazoimidazole.
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, isoindolone, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine, triazolopyrimidine, benzodioxole and pyrazolopyridine groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.
  • heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
  • Examples of representative heteroaryls include the following: wherein each Y is selected from carbonyl, N, NR 65 , O and S; and R 65 is independently hydrogen, C]-Cg alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, and 5-10 membered heteroaryl.
  • Examples of representative aryl having hetero atoms containing substitution include the following:
  • each W is selected from C(R 66 ) 2 , NR 66 , O and S; and each Y is selected from carbonyl, NR 66 , O and S; and R 66 is independently hydrogen, CpC 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, and 5-10 membered heteroaryl.
  • heterocycloalkyl refers to a 4-10 membered, stable heterocyclic non-aromatic ring and/or including rings containing one or more heteroatoms independently selected from N, O and S, fused thereto.
  • a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • heterocyclic rings include, but are not limited to, morpholine, piperidine (e.g. 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.
  • thiomorpholine and its S-oxide and S,S-dioxide particularly thiomorpholine
  • Still further examples include azetidine, piperidone, piperazone, and N-alkyl piperidines such as N-methyl piperidine.
  • heterocycloalkyl groups are shown in the following illustrative examples: wherein each W is selected from CR 67 , C(R 67 ) 2 , NR 67 , O and S; and each Y is selected from NR 67 , O and
  • R 67 is independently hydrogen, C r C 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl,
  • heterocycloalkyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl ,-S(O)-aryl, -S(O) 2 -alkyl, and -S(O) 2 - aryl.
  • Substituting groups include carbonyl or thiocarbonyl which provide
  • 'Nitro' refers to the radical -NO 2 .
  • 'Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • NO 2 , N 2 , -N 3 , -S(O) 2 O " , -S(O) 2 OH, -S(O) 2 R 68 , -OS(O 2 )O " , -OS(O) 2 R 68 , -P(O)(O ) 2 , -P(O)(OR 68 )(O ),
  • substituted groups are substituted with one or more substituents, particularly with 1 to 3 substituents, in particular with one substituent group.
  • the substituent group or groups are selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR 72 SO 2 R 73 , -SO 2 NR 73 R 72 , -C(O)R 73 , -C(O)OR 73 ,
  • each R 73 is independently selected from H, C 1 -C 8 alkyl, -(CH 2 ),(C 6 -C, 0 aryl), -(CH 2 ),(5-10 membered heteroaryl), -(CH 2 ) t (C 3 -Cio cycloalkyl), and -(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4; and
  • any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present may themselves be substituted by unsubstituted Q-C 4 alkyl, halo, unsubstituted CpC 4 alkoxy, unsubstituted Q- C 4 haloalkyl, unsubstituted CpC 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • Each R independently represents H or Ci-C 6 alkyl.
  • Substituted sulfanyl refers to the group -SR 74 , wherein R 74 is selected from:
  • Ci-C 8 alkyl C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 5 -Ci 0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • Exemplary 'substituted sulfanyl' groups are -S-(CpC 8 alkyl) and -S-(C 3 -Ci 0 cycloalkyl),
  • (CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC 4 alkyl, halo, unsubstituted CpC 4 alkoxy, unsubstituted CpC 4 haloalkyl, unsubstituted CpC 4 hydroxyalkyl, or unsubstituted CpC 4 haloalkoxy or hydroxy.
  • the term 'substituted sulfanyl' includes the groups
  • 'Alkylthio' or 'Alkylsulfanyl' refers to a radical -SR 75 where R 75 is a CpC 8 alkyl or group as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio and butylthio.
  • 'Substituted Alkylthio'or 'substituted alkylsulfanyl' refers to the group -SR 76 where R 76 is a CpC 8 alkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Cycloalkylthio' or 'Cycloalkylsulfanyl' refers to a radical -SR 77 where R 77 is a C 3 -C , 0 cycloalkyl or group as defined herein.
  • Representative examples include, but are not limited to, cyclopropylthio, cyclohexylthio, and cyclopentylthio.
  • 'Substituted cycloalkylthio' or 'substituted cycloalkylsulfanyl' refers to the group -SR 78 where R 78 is a C 3 -Ci 0 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Arylthio' or 'Arylsulfanyl' refers to a radical -SR 79 where R 79 is a C 6 -Ci 0 aryl group as defined herein.
  • 'Heteroarylthio' or 'Heteroarylsulfanyl' refers to a radical -SR 80 where R 80 is a 5-10 membered heteroaryl group as defined herein.
  • 'Substituted sulfinyl' refers to the group -S(O)R 81 , wherein R 81 is selected from:
  • Exemplary 'substituted sulfinyl' groups are -S(O)-(C,-C 8 alkyl) and -S(O)-(C 3 -Ci 0 cycloalkyl), -S(O)-(CH 2 MC 6 -C 10 aryl), -S(O)-(CH 2 ),(5-10 membered heteroaryl), -S(O)-(CH 2 X(C 3 -C 10 cycloalkyl), and -S(O)-(CH 2 ),(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl
  • substituted sulfinyl includes the groups 'alkylsulfinyP, 'substituted alkylsulfinyP, 'cycloalkylsulfinyl', 'substituted cycloalkylsulf ⁇ nyP,
  • 'AlkylsulfinyP refers to a radical -S(O)R 82 where R 82 is a C 1 -C 8 alkyl group as defined herein.
  • Representative examples include, but are not limited to, methylsulf ⁇ nyl, ethylsulfinyl, propylsulfinyl and butylsulfinyl.
  • Substituted AlkylsulfinyP refers to a radical -S(O)R 83 where R 83 is a C 1 -C 8 alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Cycloalkylsulfinyl' refers to a radical -S(O)R 84 where R 84 is a C 3 -C 10 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylsulfinyl, cyclohexylsulfinyl, and cyclopentylsulfinyl. Exemplary 'cycloalkylsulfinyl' groups are S(O)-C 3 -Ci 0 cycloalkyl.
  • cycloalkylsulfinyl refers to the group -S(O)R 85 where R 85 is a C 3 -C 10 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Arylsulfinyl' refers to a radical -S(O)R 86 where R 86 is a C 6 -C 10 aryl group as defined herein.
  • Heteroarylsulfinyl' refers to a radical -S(O)R 87 where R 87 is a 5-10 membered heteroaryl group as defined herein.
  • Substituted sulfonyP refers to the group -S(O) 2 R 88 , wherein R 88 is selected from:
  • Exemplary 'substituted sulfonyP groups are -S(O) 2 -(Ci-C 8 alkyl) and -S(O) 2 -(C 3 -Ci 0 cycloalkyl), -S(O) 2 -(CH 2 ) t (C 6 -C, 0 aryl), -S(O) 2 -(CH 2 ) t (5-10 membered heteroaryl), -S(O) 2 -(CH 2 ) t (C 3 -C, 0 cycloalkyl), and -S(O) 2 -(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C r C 4 alkyl, halo, unsubstituted C r C
  • substituted sulfonyl includes the groups alkylsulfonyl, substituted alkylsulfonyl, cycloalkylsulfonyl, substituted cycloalkylsulfonyl, arylsulfonyl and heteroarylsulfonyl.
  • Alkylsulfonyl refers to a radical -S(O) 2 R 89 where R 89 is an C r C 8 alkyl group as defined herein.
  • Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl and butylsulfonyl.
  • Substituted Alkylsulfonyl' refers to a radical -S(O) 2 R 90 where R 90 is an C 1 -C 8 alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Cycloalkylsulfonyl' refers to a radical -S(O) 2 R 91 where R 91 is a C 3 -Ci 0 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylsulfonyl, cyclohexylsulfonyl, and cyclopentylsulfonyl.
  • cycloalkylsulfonyl refers to the group -S(O) 2 R 92 where R 92 is a C 3 -Ci 0 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Arylsulfonyl' refers to a radical -S(O) 2 R 93 where R 93 is an C 6 -Ci 0 aryl gr° u P a s defined herein.
  • Heteroarylsulfonyl refers to a radical -S(O) 2 R 94 where R 94 is an 5-10 membered heteroaryl group as defined herein.
  • 'Sulfo' or 'sulfonic acid' refers to a radical such as -SO 3 H.
  • 'Substituted sulfo' or 'sulfonic acid ester' refers to the group -S(O) 2 OR 95 , wherein R 95 is selected from:
  • Ci-C 8 alkyl C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • Exemplary 'Substituted sulfo' or 'sulfonic acid ester' groups are -S(O) 2 -O-(Ci-C 8 alkyl) and -S(O) 2 -O-(C 3 -C 10 cycloalkyl), -S(O) 2 -O-(CH 2 ) t (C 6 -C, 0 aryl), -S(O) 2 -O-(CH 2 ) t (5-10 membered heteroaryl), -S(O) 2 -O-(CH 2 ) t (C 3 -C, 0 cycloalkyl), and -S(O) 2 -O-(CH 2 ),(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C 4
  • [001171 'Thiol' refers to the group -SH.
  • 'Aminocarbonylamino' refers to the group -NR 96 C(O)NR 96 R 96 where each R 96 is independently hydrogen Q-C 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl, as defined herein; or where two R 96 groups, when attached to the same N, are joined to form an alkylene group.
  • 'Bicycloaryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent bicycloaromatic ring system.
  • Typical bicycloaryl groups include, but are not limited to, groups derived from indane, indene, naphthalene, tetrahydronaphthalene, and the like. Particularly, an aryl group comprises from 8 to 11 carbon atoms.
  • 'BicycloheteroaryP refers to a monovalent bicycloheteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent bicycloheteroaromatic ring system.
  • Typical bicycloheteroaryl groups include, but are not limited to, groups derived from benzofuran, benzimidazole, benzindazole, benzdioxane, chromene, chromane, cinnoline, phthalazine, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, benzothiazole, benzoxazole, naphthyridine, benzoxadiazole, pteridine, purine, benzopyran, benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quinolizine, quinoxaline, benzomorphan, tetrahydroisoquinoline, tetrahydroquinoline, and the like.
  • the bicycloheteroaryl group is between 9-11 membered bicycloheteroaryl, with 5-10 membered heteroaryl being particularly preferred.
  • Particular bicycloheteroaryl groups are those derived from benzothiophene, benzofuran, benzothiazole, indole, quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane.
  • 'Cycloalkylalkyl refers to a radical in which a cycloalkyl group is substituted for a hydrogen atom of an alkyl group.
  • Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.
  • ⁇ eterocycloalkylalkyl' refers to a radical in which a heterocycloalkyl group is substituted for a hydrogen atom of an alkyl group.
  • Typical heterocycloalkylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.
  • 'Cycloalkenyl' refers to cyclic hydrocarbyl groups having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefinic unsaturation.
  • Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.
  • cycloalkenyl refers to those groups recited in the definition of "substituted” herein, and particularly refers to a cycloalkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S
  • Cycloalkenyl refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation located to impart aromaticity to the cycloalkenyl ring.
  • ⁇ thynyl' refers to -(C ⁇ C)-.
  • 'Hydrogen bond donor' group refers to a group containg O-H, or N-H functionality.
  • Examples of 'hydrogen bond donor' groups include -OH, -NH 2 , and -NH-R 97 and wherein R 97 is alkyl, acyl, cycloalkyl, aryl, or heteroaryl.
  • 'Dihydroxyphosphoryl' refers to the radical -PO(OH) 2 .
  • substituted herein, and particularly refers to a dihydroxyphosphoryl radical wherein one or both of the hydroxyl groups are substituted. Suitable substituents are described in detail below.
  • 'Aminohydroxyphosphoryl' refers to the radical -PO(OH)NH 2 .
  • substituted herein, and particularly refers to an aminohydroxyphosphoryl wherein the amino group is substituted with one or two substituents. Suitable substituents are described in detail below. In certain embodiments, the hydroxyl group can also be substituted.
  • Heterocycloalkyl' group means a 4 to 7 membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2-pyrrolidinyl and 3- pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • 'Pharmaceutically acceptable means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • 'Pharmaceutically acceptable salt' refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulf
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • 'Pharmaceutically acceptable vehicle refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • 'Prodrugs' refers to compounds, including derivatives of the compounds of the invention,which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • 'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • 'Solvate' encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • 'Subject' includes humans.
  • the terms 'human', 'patient' and 'subject' are used interchangeably herein.
  • 'Therapeutically effective amount means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • “therapeutically effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • [00145J 'Preventing' or 'prevention' refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
  • 'prophylaxis' is related to 'prevention', and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • 'Treating' or 'treatment' of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • "treating" or "treatment” relates to slowing the progression of the disease.
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
  • Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particular prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • acyloxy alkyl esters or ((alkoxycarbonyl)oxy
  • alkoxycarbonyl alkoxycarbonyl
  • Ci Ci to C 8 alkyl, C 2 -C 8 alkenyl, aryl, C 7 -Ci 2 substituted aryl, and C 7 -C] 2 arylalkyl esters of the compounds of the invention.
  • the term 'isotopic variant' refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound.
  • an 'isotopic variant' of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • non-radioactive isotopes such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • the following atoms, where present may vary, so that for example, any hydrogen may be 2 HZD, any carbon may be 13 C, or any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • compounds may be prepared that are substituted with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Stereoisomers that are not mirror images of one another are termed 'diastereomers' and those that are non-superimposable mirror images of each other are termed 'enantiomers'.
  • a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a 'racemic mixture'.
  • 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electror° and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an "S" form of the compound is substantially free from the "R” form of the compound and is, thus, in enantiomeric excess of the "R” form.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • the term "enantiomerically pure R- compound” refers to at least about 80% by weight R-compound and at most about 20% by weight S- compound, at least about 90% by weight R-compound and at most about 10% by weight S-compound, at least about 95% by weight R-compound and at most about 5% by weight S-compound, at least about 99% by weight R-compound and at most about 1% by weight S-compound, at least about 99.9% by weight R- compound or at most about 0.1% by weight S-compound.
  • the weights are based upon total weight of compound.
  • the term “enantiomerically pure S- compound” or “S-compound” refers to at least about 80% by weight S-compound and at most about 20% by weight R-compound, at least about 90% by weight S-compound and at most about 10% by weight R- compound, at least about 95% by weight S-compound and at most about 5% by weight R-compound, at least about 99% by weight S-compound and at most about 1% by weight R-compound or at least about 99.9% by weight S-compound and at most about 0.1% by weight R-compound.
  • the weights are based upon total weight of compound.
  • an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure R- compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R- compound.
  • the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S- compound, by total weight of the compound.
  • a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound.
  • the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier.
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • the present invention provides compounds useful for preventing and/or treating a broad range of conditions, among them, pain, sleep disorders, anxiety and depression disorders, weight and eating disorders, Parkinson's disease, addiction, spasticity, inflammatory disorders, glaucoma or other disorders. [00164] In one aspect, the present invention provides compounds according to formula I:
  • X is NR 1 R 2 ; or X is N-containing 3-1 1 membered mono or fused heterocycloalkyl, joined to the core group via ring N;
  • R 1 is selected from a substituted or unsubstituted cycloalkyl; or R 1 is substituted or unsubstituted aryl or heteroaryl;
  • R 2 is selected from hydrogen, and substituted or unsubstituted Ci-C 6 alkyl
  • R 3 is selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl
  • each R 4 is independently selected from H, C
  • R 3 is heteroaryl; and the heteroaryl is other than substituted or unsubstituted 1 ,4,5,6-tetrahydro-6-oxo-3-pyridazinyl.
  • the invention excludes compounds where R 3 is substituted or unsubstituted l ,4,5,6-tetrahydro-6-oxo-3- pyridazinyl or substituted or unsubstituted
  • R 2 is H.
  • n is 1 or 2; and R 4 is independently selected from halo, Ci-C 6 alkyl, haloC,-C 6 alkyl, cyano, hydroxy, alkoxy and sulfonyl.
  • n is 1 or 2; and R 4 is independently selected from Me, Cl, F, OMe, CF 3 and CN.
  • n 3; and R 4 is
  • R 1 and R 3 are as in formula I.
  • R 1 is substituted or unsubstituted cyclohexyl, cycloheptyl, cyclopentyl, cyclopropyl, or cyclobutyl.
  • R 1 is substituted or unsubstituted cyclohexyl.
  • R 1 is unsubstituted cyclohexyl.
  • R 1 is substituted or unsubstituted phenyl.
  • R 1 is substituted or unsubstituted heteroaryl.
  • R 1 is substituted or unsubstituted pyridyl, quinolinyl, isoquinolinyl, substituted or unsubstituted benzodioxole, substituted or unsubstituted benzodioxane, substituted or unsubstituted benzofuran, substituted or unsubstituted benzothiophene, and substituted or unsubstituted benzodioxepine.
  • R 1 is phenyl, substituted with one or more substituents independently selected from halo, Ci-C 6 alkyl, haloC
  • R 1 is pyridyl, substituted with one or more substituents independently selected from halo, Ci-C 6 alkyl, haloCi-C 6 alkyl, C 3 -C 8 cycloalkyl, amino, cyano, hydroxy, alkoxy and sulfonyl.
  • R 1 is pyridyl, substituted with one or more substituents independently selected from Me, Et, Ph, Cl, F, Br, CN, OH,
  • R 1 is unsubstituted phenyl.
  • the compound is according to formula HIb:
  • Cy is azetidin-1- yl, pyrrolidin-1 -yl, piperidin-1 -yl, piperazin-1-yl, morpholin-1 -yl, dihydroindol-1-yl, dihydroisoindol-1- yl, tetrahydroquinolin-1-yl, or tetrahydroisoquinolinyl.
  • R 3 is substituted or unsubstituted phenyl.
  • R 3 is substituted or unsubstituted heteroaryl.
  • R 3 is substituted or unsubstituted pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted benzoxazinyl, substituted or unsubstituted benzodioxole, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothiophenyl, and substituted or unsubstituted benzodioxepinyl.
  • R 3 is substituted or unsubstituted indolyl, substituted or unsubstituted indolinyl, substituted or unsubstituted N- methlylindol-5-yl, or substituted or unsubstituted N-methylindolin-5-yl imidazopyridinyl.
  • R 3 is phenyl, substituted with one or more substituents independently selected from halo, C r C 6 alkyl, haloC r C 6 alkyl,
  • R 3 is phenyl, substituted with one or more substituents independently selected from halo, C r C 6 alkyl, haloC
  • R 3 is phenyl, substituted with one or more substituents independently selected from cyano, alkoxy and sulfonyl.
  • R 3 is phenyl, substituted with amino.
  • R 3 is phenyl, substituted with one or more substituents independently selected from hydroxyl.
  • R 3 is phenyl, substituted with one or more substituents independently selected from Me, Et, Ph, Cl, F, Br, CN, OH,
  • R 3 is 4- substituted phenyl; and the substitution is selected from halo, C
  • R 3 is 4- substituted phenyl; and the substitution is selected from OMe, Cl and F.
  • R 3 is 3,4- disubstituted phenyl; and the substitution is independently selected from halo, Ci-C ⁇ alkyl, Ci-C 6 alkoxy, and haloCi-C 6 alkyl.
  • R 3 is 3,4- disubstituted phenyl; and the substitution is independently selected from OMe, Cl and F.
  • R 3 is pyridyl, substituted with one or more substituents independently selected from halo, Ci-C 6 alkyl, haloCi-C 6 alkyl,
  • R 3 is pyridyl, substituted with one or more substituents independently selected from Me, Et, Ph, Cl, F, Br, CN, OH,
  • R 3 is unsubstituted phenyl.
  • R 3 is
  • Z is CR 3c or N;
  • R 3a is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl;
  • R 3b is selected from H and substituted or unsubstituted alkyl;
  • R 3c is selected from H, halo, and substituted or unsubstituted alkyl.
  • R 3 is as described above; and R 3b is H or alkyl. [00205] hi one particular embodiment, R 3 is as described above; and R 3b is H, Me, or Et. [00206] In one particular embodiment, R 3 is as described above; and Z is CR 3c ; and R 3c is H, Cl,
  • R 3 is as described above; and Z is N.
  • the compound is according to formula IVa, IVb, IVc, or IVd:
  • R 3a is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.
  • the compound is according to formula Va, Vb, Vc, or Vd:
  • R 3a is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.
  • the compound is according to formula Via, VIb, VIc, or VId:
  • R 3a is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.
  • R 3a is H.
  • R 3a is H
  • R 3a is cyclopropyl, cyclobutyl, cyclohexyl, or cyclopentyl.
  • R 3a is oxetan-3-yl.
  • R 3 is substituted or unsubstituted benzodioxepinyl.
  • R 3 is indolyl or indolinyl, unsubstituted or substituted with halo, Ci-C 6 alkyl, or haloCi-Qalkyl.
  • R 3 is N- methlylindol-5-yl or N-methylindolin-5-yl.
  • R 3 is imidazopyridinyl, unsubstituted or substituted with halo, Ci-C ⁇ alkyl, or haloCi-Qalkyl.
  • R 3 is imidazo[l,2-a]pyridine-6-yl, unsubstituted or substituted with halo, Ci-C ⁇ alkyl, or haloCi-C ⁇ alkyl.
  • R 3 is a phenyl
  • R 3 is a substituted phenyl.
  • R 3 is a mono-substituted phenyl.
  • R 3 is a di-substituted phenyl.
  • R 3 is a substituted phenyl where the substituent on the phenyl is selected from halo, amido, Ci-C 6 alkyl, alkoxy, sulfonyl, sulfonamidyl, haloalkyl and trihaloalkyl.
  • the substitution on the R 3 phenyl is selected from Cl, F, CF 3 , Me, t-Bu, OMe,
  • the substitution on the R 3 phenyl is selected from Cl, Me, t-Bu and SO 2 Me.
  • R 3 is a substituted phenyl
  • one or more substituents are on the phenyl at the 2 (ortho), 3 (meta) and/or 4 (para) position relative to the carbon attached to the nitrogen atom in the fused heterocyclic scaffold in formula I.
  • R 3 is a substituted phenyl, where a substituent is on the phenyl at the 2 (ortho), 3 (meta) and/or 4 (para) position.
  • the substitution on the R 3 phenyl is at the 2 or 4 position. In the most preferred embodiments, the substitution on the R 3 phenyl is at the 4 position.
  • R 3 are selected from
  • n' is selected from 1-5 and each of R 5 is independently selected from hydrogen, substituted or unsubstituted C,-C 6 alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfo, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfony
  • subscript n' is 1 , 2 or 3.
  • subscript n' is 1 or 2.
  • each R 5 is independently selected from Me, Et, Pr, iso-Pr, Ph, Cl,
  • each R 5 is independently selected from Me, Et, Pr, iso-Pr, Ph, Cl,
  • the compound is selected from the compounds listed in Table 1.
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • the present invention provides prodrugs and derivatives of the compounds according to the formulae above.
  • Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo.
  • Such examples include, but are not limited to, choline ester derivatives and the like, and N-alkylmorpholinyl esters and the like.
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • the compounds of this invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the pharmaceutical composition may comprise a compound of the invention in combination with one or more compounds or compositions of like therapeutic utility and effect.
  • the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of 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.
  • compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • the compounds of this invention are preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • 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.
  • Typical unit dr° ⁇ ge forms include pref ⁇ lled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the furansulfonic acid compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin
  • Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable carriers known in the art.
  • the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
  • the compounds of this invention can also be administered by a transdermal device.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press.
  • a compound of the invention may be admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule).
  • a compound of the invention (125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (1 1 :89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color are diluted with water and added with stirring. Sufficient water may then added to produce a total volume of 5 mL.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press.
  • a compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.
  • the present compounds are used as therapeutic agents for the treatment of conditions in mammals. Accordingly, the compounds and pharmaceutical compositions of this invention find use as therapeutics for preventing and/or treating neurodegenerative, autoimmune and inflammatory conditions in mammals including humans.
  • this invention provides a method of treating a mammal susceptible to or afflicted with a condition associated with arthritis, asthma, myocardial infarction, inflammatory bowel disease and autoimmune disorders, which method comprises administering an effective amount of one or more of the pharmaceutical compositions just described.
  • this invention provides methods of treating a mammal susceptible to or afflicted with neurodegenerative diseases and disorders such as, for example Parkinson's disease, Alzheimer's disease and multiple sclerosis; sleep disorders, anxiety and depression disorders, weight and eating disorders, addiction, spasticity, and glaucoma; diseases and disorders which are mediated by or result in neuro ; "flammation such as, for example encephalitis; centrally-mediated neuropsychiatric diseases and disorders such as, for example depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction such as, for example urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders such as, for example, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in neuro ; "flammation
  • this invention provides a method of treating a mammal susceptible to or afflicted with a condition that gives rise to pain responses or that relates to imbalances in the maintenance of basal activity of sensory nerves.
  • the present compounds have use as analgesics for the treatment of pain of various geneses or etiology, for example acute, inflammatory pain (such as pain associated with osteoarthritis and rheumatoid arthritis); various neuropathic pain syndromes (such as post-herpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillian Barre syndrome, fibromyalgia, phantom limb pain, post-mastectomy pain, peripheral neuropathy, HIV neuropathy, and chemotherapy-induced and other iatrogenic neuropathies); visceral pain, (such as that associated with gastroesophageal reflex disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and various gy
  • the present compounds for use as a pharmaceutical especially in the treatment or prevention of the aforementioned conditions and diseases.
  • Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
  • the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • the compounds of this invention When used to prevent the onset of a neurodegenerative, autoimmune or inflammatory condition, the compounds of this invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • the compounds of this invention can be administered as the sole active agent or they can be administered in combination with other agents, including other active amines and derivatives.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. See, e.g., Synthetic Schemes, below. 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. [00267] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
  • the compounds of this invention may be prepared by the reaction of a chloro derivative with an appropriately substituted amine and the product isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography or HPLC. The following schemes are presented with details as to the preparation of representative fused heterocyclics that have been listed hereinabove.
  • the compounds of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
  • reaction mixture was heated under microwave irradiation at 150 0 C for 20 mins. After allowing to cool to room temperature, the mixture was purified directly by preparative high-performance liquid chromatography [acetonitrile:water buffered to pH 10 with eluent used in a gradient system] to give the title compound (7.7 mg, 26%) as a solid.
  • the compound was prepared using general procedure A'. After completion of the reaction, the mixture was diluted with EtOAc (5 mL) and washed with brine (5 mL). The aqueous layer was back-extracted with EtOAc (2 mL) and the combined organics were washed with brine (2 x 5 mL), dried (Na 2 SO 4 ), filtered and evaporated. The crude product was dissolved in DMSO (450 ⁇ L) and purified by reverse-phase HPLC (40-95% acetonitrile: water gradient buffered with 10 mM diethylamine in the aqueous to pH 10). The combined pure fractions were concentrated under vacuum to afford the title compound as a solid (13.5 mg, 65%).
  • NRR' is X; and X is N-containing heterocycloalkyl.
  • a microwave vial was charged with 5-bromo-benzooxazole-2-thiol (400 mg, 1.74 mmol), isoindoline (590 ⁇ L, 5.2 mmol), and acetonitrile (5.0 mL). The mixture was purged with nitrogen then heated in a microwave at 190 0 C for 30 min (LCMS indicates product, a thioamide (H 2 S reacted with ACN and the resulting amide reacted with isoindoline) and a debrominated version of the desired product).
  • the compound was synthesized using General Procedure E'. After the reaction, the mixture was diluted with EtOAc (5 mL) and washed with brine (5 mL). Solid precipitated from the mixture and was filtered (the filter cake was primarily product). The aqueous layer was back extracted with EtOAc (about 2 mL) and the combined organics were washed with brine (2 x 5 mL), dried (Na 2 SO,)), filtered and evaporated. The filtered solids were dissoved in DMSO (1200 ⁇ L) and purified by reverse phase HPLC (acetonitrile in water gradient buffered to pHIO with 10 mM Et 2 NH in water). The low solubility of the compound caused the product to streak.
  • Human cell line T84 human colon epithelial cells
  • HEK293-TRex cells stably transfected with hFAAH in the pCDNA5-Tet-off vector
  • medium containing DMEM 10% FBS penicillin/streptomycin, glutamax, 200 ⁇ g/ml hygromycin and 0.5 ⁇ g/ml blasticidin.
  • Cell collection is done 24h after induction with doxycycline by first washing the cells with cold PBS and then incubating them with Versene before centrifugation. Cell pellets are then stored at -80 0 C until needed.
  • the cell pellets are thawed on ice at room temperature and resuspended in homogenization buffer (50 mM HEPES (pH 7.4), 1 mM EDTA, 1 ⁇ M Pepstatin A, 100 ⁇ M Leupeptin, 0.1 mg/mL aprotinin).
  • Cell suspensions are then homogenized on ice using the Polytron 1200C at setting 6 for three 30-second intervals with 30-second rests. The suspension is centrifuged at lOOOg for 10 minutes at 4°C and the supernatant is collected and further centrifuged at 24000rpm for 30 minutes at 4°C using an ultracentrifuge.
  • Pellets are resuspended by adding in cold microsomal buffer (50 mM HEPES (pH 7.4) and 1 mM EDTA) and sheared through a 23-gauge needle five times, keeping the suspension on ice. Protein concentrations are determined using the BCA assay and aliquoted preparations are stored at -80 0 C until needed.
  • cold microsomal buffer 50 mM HEPES (pH 7.4) and 1 mM EDTA
  • Compound potency against hFAAH is determined using an enzymatic assay with a fluorescence readout. Briefly, experiments are carried out in a 96-well plate format (Corning Costar, # 3370) with a total well volume of 160 ⁇ L with components added in the following order: assay buffer (50 mM HEPES (pH 7.4), 1 mM EDTA, 1.4 mg/mL BSA), compound solutions (7 different concentrations per compound in duplicate), microsomal enzyme preparation (10 ⁇ g per well) and substrate [AA-AMC (arachadonyl 7-amino 4-methyl coumarin amide), 2 ⁇ M]. After a brief shaking, a kinetic read of the plate is obtained using a Tecan Safire II in kinetic mode for 275 cycles with excitation and emission wavelengths of 355 and 460nm, respectively. Raw data is then processed and analyzed using Assay
  • Compound potency against hFAAH is determined using an enzymatic assay with a radiometric readout. Briefly, experiments are carried out in 1.5mL vials with a total well volume of 200 ⁇ L with components added in the following order: assay buffer (50 mM HEPES (pH 7.4), 1 mM EDTA, 1 mg/mL BSA), compound solutions (6 different concentrations per compound in triplicate), microsomal enzyme preparation (10 ⁇ g per well) and substrate (AEA with 3 H-AEA tracer, 1 ⁇ M).
  • assay buffer 50 mM HEPES (pH 7.4), 1 mM EDTA, 1 mg/mL BSA
  • compound solutions 6 different concentrations per compound in triplicate
  • microsomal enzyme preparation (10 ⁇ g per well
  • substrate AEA with 3 H-AEA tracer, 1 ⁇ M
  • CCI Chronic Constriction Injury Model
  • the CCI model is performed according to the method described by Bennett and Xie,
  • the L4 and L5 spinal nerves may need to be separated to fully expose the L5 spinal nerve for ligation using extra caution not to damage the L4 nerve during this process. Animals that exhibit L4 nerve damage as evidenced by paw drop post-anesthesia are not included in studies. Once the L5 spinal nerve is exposed, the nerve is ligated with 6-0 silk. Alternatively, the spinal nerve is cut distal to the ligation site. If a more complete neuropathy is required, then the L6 spinal nerve may also be ligated using the procedure described above. Sham operated animals are treated identically with the exception that the nerves will not be ligated/transected.
  • Test compounds are administered at various times prior to intraplantar administration of formalin.
  • a dilute solution of formalin 50 ⁇ L of 2.5% formaldehyde/saline) is administered s.c. into the plantar surface of the left hind paw under light restraint.
  • animals are placed on a mesh stand inside a clear observation chamber large enough to allow for free movement of the animals during the study. Behaviors are scored using manual scoring or automated scoring.
  • Manual scoring Using a three channel timer, the observer records the time (t in seconds) of decreased weight-bearing (ti), paw lifting (t 2 ), and licking/biting/shaking (t 3 ).
  • CFA Complete Freund's Adjuvant Model
  • the colonic reaction threshold is defined as the pressure inducing the first abdominal contraction. Abdominal contraction indicative of visceral pain correlates with hunching, hump-backed position, licking of the lower abdomen, repeated waves of contraction of the ipsilateral oblique musculature with inward turning of the ipsilateral hindlimb, stretching, squashing of the lower abdomen against the floor (Wesselman, Neurosci. Lett., 246:13-16, 1998). Acetic Acid WrithingTest:
  • a 0.6% solution of acetic acid (10 ml/kg) is administered i.p. to rats and the number of abdominal constrictions over 30 min are counted.
  • the paw is touched with 1 of a series of 8 von Frey hairs (Stoelting, Wood Dale, IL) with logarithmically incremental stiffness (0.4, 0.6, 1.4, 2, 4, 6, 8, and 15 g).
  • Each von Frey hair is presented perpendicularly to the plantar surface with sufficient force to cause slight buckling against the paw and held for approximately 6-8 s.
  • Stimulation is presented at intervals of several seconds, allowing for apparent resolution of any behavioral responses to previous stimuli. A positive response will be noted if the paw is sharply withdrawn. Flinching immediately upon removal of the hair will also be considered a positive response. Ambulation will be considered an ambiguous response and in such cases, the stimulus will be repeated.
  • Paw withdrawal latencies are defined as the time it takes for the animal to remove its paw from the heat source. To ensure that no tissue damage occurs, all tests will have a 20 sec cutoff even when the animal does not withdraw its paw away from the heat stimulation. The test consists of 3 measurements of the same paw, with a minimum 5 minute intervals between each determination. To minimize distress, thermal testing is conducted no more than 3 times per day. Cold testing:
  • acetone drop test is conducted no more than 5 times over the course of a study (including the pre-surgery baseline test) and no more than once per day (Kotinen et al., Pain 80:341-346, 1999).
  • the animals are assessed for response to noxious mechanical stimuli by determining paw withdrawal threshold (PWT), as described below, prior to surgery (baseline), then immediately prior to and at various time points after being administered with a compound of this invention (30 mg/kg) in the left rear paw of the animal. Additionally, other animals may also be assessed for thermal or mechanical hyperalgesia, as described below.
  • PWT paw withdrawal threshold
  • the plantar test can be used to assess thermal hyperalgesia.
  • hind paw withdrawal latencies to a noxious thermal stimulus are determined using a plantar test apparatus (commercially available from Ugo Basile of Italy) following the technique described by Hargreaves et ai, Pain 32: 77-88, 1988.
  • the maximum exposure time is set at 32 seconds to avoid tissue damage and any directed paw withdrawal from the heat source is taken as the end point.
  • Three latencies are determined at each time point and averaged. Only the affected (ipsilateral) paw is tested. An increase latency of paw withdrawal demonstrates reversal of hyperalgesia.
  • the paw pressure assay can be used to assess mechanical hyperalgesia.
  • hind paw withdrawal thresholds (PWT) to a noxious mechanical stimulus are determined using an analgesymeter (Model 7200, commercially available from Ugo Basile of Italy) as described in Stein et al., Pharmacol. Biochem. Behav. 31 :451-455, 1988.
  • the maximum weight that can be applied to the hind paw is set at 250 g and the end point is taken as complete withdrawal of the paw.
  • PWT is determined once for each rat at each time point and only the affected (ipsilateral) paw is tested.

Abstract

Compounds are disclosed that have formula I: wherein X, R1, R2, R3, R4 and n are as defined herein. The compounds and pharmaceutical compositions thereof are useful for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, anxiety, depression, inflammation, cognitive disorders, weight and eating disorders, Parkinson's disease, Alzheimer's disease, spasticity, addiction, glaucoma, and others.

Description

COMPOUNDS USEFUL AS FAAH MODULATORS AND USES THEREOF
FIELD OF THE INVENTION
[0001] This invention relates to novel compounds that are capable of modulating FAAH (fatty acid amide hydrolase) activity, and to pharmaceutical compositions containing such compounds. The invention further relates to preparation of such compounds. This invention also relates to methods for preventing and/or treating conditions that are causally related to aberrant FAAH activity or can be alleviated by modulating FAAH activity, such as pain, sleep disorders, anxiety and depression disorders, weight and eating disorders, Parkinson's disease, addiction, spasticity, inflammatory disorders, glaucoma or other disorders.
BACKGROUND OF THE INVENTION
[0002] Fatty acid amide hydrolase (FAAH) is an integral membrane protein that degrades fatty acid primary amides and ethanolamides. Furthermore, FAAH has been shown to be important for the hydrolysis of the fatty acid amide (FAA) class of endogenous, lipid signaling molecules. FAAH has been shown to be relevant to the in vivo degradation of anandamide (AEA), oleamide, N-palmitoyl ethanolamide (PEA), N-oleoyl ethanolamide (OEA) and N-acyl taurines. These molecules act through a number of pathways and regulate diverse physiological behaviors including anxiety, pain, satiety, cognition and sleep (M. K. McKinney and B. J. Cravatt, (2005) Annu. Rev. Biochem. 74, 411-432). [0003] The distribution of FAAH in the CNS suggests that it degrades neuromodulating fatty acid amides at their sites of action and is intimately involved in their regulation (E. A. Thomas, et al., (1997) J. Neurosci. Res. 50, 1047-1052). The creation of the FAAH KO (knockout) mouse confirmed that degradation of anandamide (AEA), oleamide, N-palmitoyl ethanolamide (PEA), N-oleoyl ethanolamide (OEA) and N-acyl taurines is regulated by FAAH in mice brains, as elevated levels of these molecules were observed in the absence of FAAH (B. F. Cravatt, et al., (2001), Proc. Natl. Acad. Sci. USA 98, 9371-9376; A. H. Lichtman, et al., (2002), J. Pharmacol. Exp. Ther. 302, 73-79; and A. Saghatelian, et al., (2004), Biochem. 43, 14332-14339).
[0004] As a number of small molecule inhibitors of FAAH have also been identified (M. Mor, et al., (2004), J. Med Chem. 47, 4998-5008; and D. L. Boger, et al., (2005) J. Med. Chem. 48, 1849-1856) both genetic (FAAH KO) and chemical tools were available to study the effect of FAAH inhibition in vivo. Additionally, some preliminary evidence exists regarding the existence of endogenous substances capable of activating FAAH (M. Maccarrone, et al., (2004) MoI. Hum. Reprod. 10, 215-221), this suggests that FAAH activation may be possible in vivo. Based on the fact that anandamide is both a CBl receptor and a CB2 receptor agonist, amongst other biological roles, most of the investigations conducted focused on areas known to be affected by the activity of these two receptors. Interestingly, FAAH inhibition did not produce the side effects common to all CBl receptor agonists: catalepsy, hypothermia, hypomotility and hyperphagia. The consequences of FAAH inhibition by a small molecule inhibitor were tested in animal models of anxiety and depression (S. Kathuria, et al., (2003), Nat. Med. 9, 76-81 ; and G. Gobbi, et al., (2005) Proc. Natl. Acad. ScL USA 102, 18620-18625). Results indicated that FAAH inhibition led to increased levels of anandamide in the brain and concurrent anxiolytic and anti-depressant effects. [0005] Several studies using both FAAH KO mice and small molecules inhibitors also demonstrated that FAAH inhibition led to analgesia in multiple animal models of pain (L. Chang, et al., (2006) Br. J. Pharmacol. 148, 102-1 13; A. Jayamanne, et al., (2005) Br. J. Pharmacol. 147, 281-288; M. D. Jhaveri, et al., (2006) J. Neurosci. 26, 13318-13327; and B. F. Cravatt, et al., (2001), Proc. Natl. Acad. Sci. USA 98, 9371-9376). Furthermore, a FAAH inhibitor was found to possess anti-inflammatory activity as it reduced carrageenan-induced hind paw inflammation in pentobarbital treated mice (S. Holt, et al., (2005) Br. J. Pharmacol. 146, 467-476). Recently, a link between FAAH inhibition and a potential treatment for Parkinson's disease was established (A. C. Kreitzer and R. C. Malenka, (2007) Nature, 445, 643-647). Endocannabinoids were revealed to play a role in the indirect pathway eCB-LTD (Long Term Depression) that is hypothesized to be absent in patients afflicted with the disease. Co-administration of a dopamine D2 receptor agonist and a FAAH inhibitor markedly reduced the motor deficits observed in two animal models of Parkinson's disease. These data clearly demonstrate that FAAH activity can be modulated by small molecules in vivo and that modulation of FAAH activity in vivo has clear potential therapeutic effects for several indications such as anxiety, depression, pain, Parkinson's disease and inflammation (M. K. McKinney and B. J. Cravatt, (2005) Annu. Rev. Biochem. 74, 41 1-432). [0006] Accordingly, a need therefore exists for the development of agents, i.e. compounds, that are effective as modulators of FAAH activity, and it is toward the fulfillment of that need, that the present invention is directed.
SUMMARY OF THE INVENTION
[0007] Compounds, and pharmaceutical compositions thereof, having potency and selectivity in the prevention and treatment of conditions that have been associated with neurological and inflammatory disorders and dysfunctions are described herein.
[0008] In particular, compounds, pharmaceutical compositions and methods provided are used to treat, prevent or ameliorate a range of conditions in mammals such as, but not limited to, pain of various genesis or etiology, for example acute, chronic, inflammatory and neuropathic pain, dental pain, dysmenorrhea and headache (such as migraine, cluster headache and tension headache), hi some embodiments, the compounds, pharmaceutical compositions and methods provided are useful for the treatment of inflammatory pain and associated hyperalgesia and allodynia. In some embodiments, the compounds, pharmaceutical compositions and methods provided are useful for the treatment of neuropathic pain and associated hyperalgesis and allodynia (e.g. trigeminal or herpetic neuralgia, diabetic neuropathy, causalgia, sympathetically maintained pain and deafferentation syndromes such as brachial plexus avulsion). In some embodiments, the compounds, pharmaceutical compositions and methods provided are useful as anti-inflammatory agents for the treatment of arthritis, and as agents to treat Parkinson's Disease, Alzheimer's Disease, asthma, myocardial infarction, neurodegenerative disorders, spasticity, inflammatory bowel disease and autoirrTiune disorders, fever, atherosclerosis and cardiovascular diseases, renal disorders, obesity, eating disorders, emesis, cancer, memory disorders, schizophrenia, epilepsy, sleeping disorders, cognitive disorders, depression, anxiety, blood pressure, addiction, glaucoma and lipid disorders.
[0009] Accordingly, in one aspect, compounds are provided that have formula I:
Figure imgf000004_0001
(R4)n
I wherein
X is NR1R2; or X is N-containing 3-1 1 membered mono or fused heterocycloalkyl, joined to the core group via ring N;
R1 is selected from a substituted or unsubstituted cycloalkyl; or R1 is substituted or unsubstituted aryl or heteroaryl;
R2 is selected from hydrogen, and substituted or unsubstituted C ,-C6 alkyl; R3 is selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; each R4 is independently selected from H, CrC6alkyl, substituted Ci-C6alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfo, sulfonic acid ester, substituted or unsubstituted dihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituor unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol; and n is 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof; provided that i) when X is heterocycloalkyl, R3 is other than unsubstituted phenyl or unsubstituted pyridyl; and ii) the compound is other than a) N-cyclohexyl-5-(3,7-dimethylimidazo[l ,2-a]pyridin-2-yl)-2-Benzoxazolamine
Figure imgf000004_0002
b) 4-[5-[4-(trifluoromethyl)phenyl]-2-benzoxazolyl]-l ,4-diazabicyclo[3.2.2]nonane;
Figure imgf000005_0001
c) 4-[5-(3-methylphenyl)-2-benzoxazolyl]- 1 ,4-Diazabicyclo[3.2.2]nonane
Figure imgf000005_0002
d) 2,4-dihydro-2-phenyl-5-[(5-phenyl-2-benzoxazolyl)amino]-3H-pyrazol-3-one
Figure imgf000005_0003
e) 5-phenyl-N-[2-[3-(trifluoromethyl)phenoxy]-3-pyridinyl]-2-benzoxazolamine
Figure imgf000005_0004
f) N-[2-[2-(l,l-dimethylethyl)phenoxy]-3-pyridinyl]-5-phenyl-2-benzoxazolamine
Figure imgf000005_0005
[0010] In one embodiment with respect to formula I, R3 is heteroaryl; and the heteroaryl is other than substituted or unsubstituted 1 ,4,5,6-tetrahydro-6-oxo-3-pyridazinyl. For the sake of clarity, the invention excludes compounds wherein R3 is substituted or unsubstituted l,4,5,6-tetrahydro-6-oxo-3- pyridazinyl or substituted or unsubstituted
Figure imgf000005_0006
[0011] In another aspect, pharmaceutical compositions are provided comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent. The pharmaceutical composition can comprise one or more of the compounds described herein. In a further embodiment, the pharmaceutical compositions of the invention can comprise a compound in combination with one or more other compounds and/or compositions having a like therapeutic effect.
[0012] It will be understood that compounds of the present invention useful in the pharmaceutical compositions and treatment methods disclosed herein, can be pharmaceutically acceptable as prepared and used. [0013] In another aspect, methods are provided for preventing, treating or ameliorating a condition from among those listed herein, and particularly, such condition as may be associated with, e.g., arthritis, asthma, myocardial infarction, lipid disorders, cognitive disorders, anxiety, schizophrenia, depression, memory dysfunctions such as Alzheimers disease, inflammatory bowel disease and autoimmune disorders, which method comprises administering to a mammal in need thereof an amount of one or more of the compounds as provided herein, or pharmaceutical composition thereof, effective to prevent, treat or ameliorate the condition.
[0014] In yet another aspect, methods are provided for preventing, treating or ameliorating a variety of disease states, including the diseases associated with pain, sleep disorders, anxiety and depression disorders, weight and eating disorders, addiction, spasticity, and glaucoma, by administration of a compound such as those provided herein.
[0015] In a further aspect, methods are provided for preventing, treating or ameliorating a neurodegenerative disease or disorder in a mammal. A neurodegenerative disease or disorder can, for example, be Parkinson's disease, Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in neuroinflammation such as, for example, encephalitis; centrally-mediated neuropsychiatric diseases and disorders such as, for example, depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction such as, for example urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders such as, for example, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflammation such as, for example rheumatoid arthritis and osteoarthritis, myocardial infarction, various autoimmune diseases and disorders; itch / pruritus such as, for example, psoriasis; obesity; lipid disorders; cancer; and renal disorders For example, the compounds of the invention might be used in conjunction with a dopamine D2 receptor agonist to treat Parkinson's disease, in accordance with the recent findings of Malenka (A. C. Kreitzer and R. C. Malenka, (2007) Nature, 445, 643-647), that FAAH inhibition in conjunction with dopamine administration promises an effective treatment of the disease. Typically, the methods comprise administering an effective condition-treating or condition-preventing amount of one or more of the compounds as provided herein, or pharmaceutical composition thereof, to a mammal in need thereof.
[0016] In addition to the methods of treatment set forth above, the present invention extends to the use of any of the compounds of the invention for the preparation of medicaments that may be administered for such treatments, as well as to such compounds for the treatments disclosed and specified. [0017] In additional aspects, methods are provided for synthesizing the compounds described herein, with representative synthetic protocols and pathways described below. [0018] Accordingly, it is a principal object of the invention to provide a novel series of compounds, which can modify any aberrant activity of FAAH and thus may have the ability to treat certain of the conditions in which FAAH is believed to play a role. [0019] A still further object of the invention is to provide pharmaceutical compositions that are effective in the treatment or prevention of a variety of disease states, including the diseases associated with pain, sleep disorders, anxiety and depression disorders, weight and eating disorders, addiction, spasticity, intraocular pressure or other disorders.
[0020] A still further object of the invention is to provide a method for the treatment of the disease states recited above, by the administration of a therapeutically effective amount of the compounds of the invention, and/or the pharmaceutical compositions of the invention.
[0021] A yet further object of the invention is to provide formulations for the treatment of the diseases as aforesaid, by the combination of at least one of the compounds of the invention, a pharmaceutical composition of the invention, combinations thereof with other compounds and compositions having a like therapeutic effect.
[0022] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0023] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.
[0024] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term "substituted" is to be defined as set out below. It should be further understood that the terms "groups" and "radicals" can be considered interchangeable when used herein.
[0025] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example "an analogue" means one analogue or more than one analogue.
[0026] 'Acyl' or 'Alkanoyl' refers to a radical -C(O)R20, where R20 is hydrogen, C,-C8 alkyl, C3-
Cio cycloalkyl, C3-Ci0 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzyl carbonyl. Exemplary
'acyl' groups are -C(O)H, -C(O)-C1-C8 alkyl, -C(O)-(CH2MC6-C10 aryl), -C(O)-(CH2)t(5-10 membered heteroaryl), -C(O)-(CH2X(C3-C10 cycloalkyl), and -C(O)-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
[0027] 'Substituted Acyl' or 'Substituted Alkanoyl' refers to a radical -C(O)R21, wherein R21 is independently • C1-C8 alkyl, substituted with halo or hydroxy; or
• C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[0028] 'Acylamino' refers to a radical -NR22C(O)R23, where R22 is hydrogen, C1-C8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl> arylalkyl, 5-10 memberd heteroaryl or heteroarylalkyl and R23 is hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6- C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, as defined herein. Exemplary 'acylamino' include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino. Particular exemplary 'acylamino' groups are -NR24C(O)-C1-C8 alkyl, -NR24C(O)-(CH2),(C6-C10 aryl), -NR24C(O)-(CH2),(5-10 membered heteroaryl), -NR24C(O)-(CH2)t(C3-C10 cycloalkyl), and -NR24C(O)-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, and each R24 independently represents H or Ci-C8 alkyl.
[0029] 'Substituted Acylamino' refers to a radical -NR25C(O)R26, wherein:
R25 is independently
• H, CpC8 alkyl, substituted with halo or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Cj0 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted Ci-C4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; and
R26 is independently
• H, C1-C8 alkyl, substituted with halo or hydroxy; or
• C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl> arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl; provided at least one of R25 and R26 is other than H.
[0030] 'Acyloxy' refers to a radical -OC(O)R27, where R27 is hydrogen, CpC8 alkyl, C3-C10 cycloalkyl, C3-C]0 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. Exemplary 'acyP groups are -C(O)H, -C(O)-CpC8 alkyl, -C(O)-(CH2MC6-C10 aryl), -C(O)-(CH2)t(5-10 membered heteroaryl), -C(O)-(CH2MC3-C10 cycloalkyl), and -C(O)-(CH2),(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4. [0031] 'Substituted Acyloxy' refers to a radical -OC(O)R28, wherein R28 is independently
• CpC8 alkyl, substituted with halo or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl. arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted Ci -C4 alkyl, halo, unsubstituted CrC4 alkoxy, unsubstituted Ci-C4 haloalkyl, unsubstituted CrC4 hydroxyalkyl, or unsubstituted Q -C4 haloalkoxy or hydroxy.
[0032] 'Alkoxy' refers to the group -OR29 where R29 is Ci-C8 alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1 ,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
[0033] 'Substituted alkoxy' refers to an alkoxy group substituted with one or more of those groups recited in the definition of "substituted" herein, and particularly refers to an alkoxy group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C6-Ci0 aryl, aryloxy, carboxyl, cyano, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl- S(O)2-. Exemplary 'substituted alkoxy' groups are -O-(CH2),(C6-Ci0 aryl), -O-(CH2)t(5-10 membered heteroaryl), -O-(CH2)t(C3-Ci0 cycloalkyl), and -O-(CH2),(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC4 alkyl, halo, unsubstituted C]-C4 alkoxy, unsubstituted Ci-C4 haloalkyl, unsubstituted Ci-C4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy. Particular exemplary 'substituted alkoxy' groups are OCF3, OCH2CF3, OCH2Ph, OCH2-cyclopropyl, OCH2CH2OH, and OCH2CH2NMe2.
[0034] 'Alkoxycarbonyl' refers to a radical -C(O)-OR30 where R30 represents an C1-C8 alkyl, C3-
Cio cycloalkyl, C3-Ci0 cycloalkylalkyl, 4-10 membered heterocycloalkylalkyl, aralkyl, or 5-10 membered heteroarylalkyl as defined herein. Exemplary "alkoxycarbonyl" groups are C(O)O-Ci -C8 alkyl, -C(O)O- (CH2),(C6-C,o aryl), -C(O)O-(CH2)t(5-10 membered heteroaryl), -C(O)O-(CH2),(C3-C,0 cycloalkyl), and - C(O)O-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 1 to 4. [0035] 'Substituted Alkoxycarbonyl' refers to a radical -C(O)-OR31 where R31 represents:
• Ci-C8 alkyl, C3-Ci0 cycloalkyl, C3-Ci0 cycloalkylalkyl, or 4-10 membered heterocycloalkylalkyl, each of which is substituted with halo, substituted or unsubstituted amino, or hydroxy; or
• C6-Ci0 aralkyl, or 5-10 membered heteroarylalkyl, each of which is substituted with unsubstituted Ci-C4 alkyl, halo, unsubstituted Ci-C4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CrC4 hydroxyalkyl, or unsubstituted CrC4 haloalkoxy or hydroxyl.
[0036] 'AryloxycarbonyP refers to a radical -C(O)-OR32 where R32 represents an C6-Ci0 aryl, as defined herein. Exemplary "aryloxycarbonyl" groups is -C(O)O-(C6-Ci0 aryl).
[0037] 'Substituted Aryloxycarbonyl' refers to a radical -C(O)-OR33 where R33 represents • C6-C)0 aryl> substituted with unsubstituted Ci-C4 alkyl, halo, unsubstituted Ci-C4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted Ci-C4 hydroxyalkyl, or unsubstituted C]-C4 haloalkoxy or hydroxyl.
[0038] ΗeteroaryloxycarbonyF refers to a radical -C(O)-OR34 where R34 represents a 5-10 membered heteroaryl, as defined herein. An exemplary "aryloxycarbonyl" group is -C(O)O-(5-10 membered heteroaryl). [0039] 'Substituted HeteroaryloxycarbonyP refers to a radical -C(O)-OR35 where R35 represents:
• 5-10 membered heteroaryl, substituted with unsubstituted CrC4 alkyl, halo, unsubstituted Cr C4 alkoxy, unsubstituted CrC4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxyl.
[0040] 'Alkoxycarbonylamino' refers to the group -NR36C(O)OR37, where R35 is hydrogen, C1-
C8 alkyl, C3-C10 cycloalkyl, C3-Ci0 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5- 10 membered heteroaryl or heteroarylalkyl as defined herein, and R37 is Ci-C8 alkyl, C3-C10 cycloalkyl, C3-Ci0 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein.
[0041] 'Alkyl' means straight or branched aliphatic hydrocarbon having 1 to 20 carbon atoms.
Particular alkyl has 1 to 12 carbon atoms. More particular is lower alkyl which has 1 to 6 carbon atoms. A further particular group has 1 to 4 carbon atoms. Exemplary straight chained groups include methyl, ethyl, n-propyl, and n-butyl. Branched means that one or more lower alkyl groups such as methyl, ethyl, propyl or butyl is attached to a linear alkyl chain, exemplary branched chain groups include isopropyl, iso- butyl, t-butyl and isoamyl.
[0042] 'Substituted alkyl' refers to an alkyl group as defined above substituted with one or more of those groups recited in the definition of "substituted" herein, and particularly refers to an alkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of acyl, acylamino, acyloxy (- O-acyl or -OC(O)R20), alkoxy, alkoxycarbonyl, alkoxycarbonylamino (-NR -alkoxycarbonyl or -NH- C(O)-OR27), amino, substituted amino, aminocarbonyl (carbamoyl or amido or -C(O)-NR 2), aminocarbonylamino (-NR -C(O)-NR 2), aminocarbonyloxy (-0-C(O)-NR 2), aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, heteroaryl, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl,-S(O)-aryl, -S(O)2-alkyl, and -S(O)2-aryl. In a particular embodiment 'substituted alkyl' refers to a Ci-C8 alkyl group substituted with halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR 'SO2R", -SO2NR R ', -C(O)R", -C(O)OR", -OC(O)R", -NR "C(O)R ", - C(O)NR1R", -NR 'R ', or -(CR "R^)1nOR ""; wherein each R" is independently selected from H, C,-C8 alkyl, -(CH2MC6-Ci0 aryl), -(CH2),(5-10 membered heteroaryl), -(CH2)t(C3-C,0 cycloalkyl), and -(CH2),(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C4 alkyl, halo, unsubstituted Ci-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted Ci-C4 haloalkoxy or hydroxy. Each of R and R independently represents H or Ci-C8 alkyl.
[0043] 'Alkylene' refers to divalent saturated alkene radical groups having 1 to 11 carbon atoms and more particularly 1 to 6 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the propylene isomers (e.g., - CH2CH2CH2- and -CH(CH3)CH2-) and the like.
[0044] 'Substituted alkylene' refers to those groups recited in the definition of "substituted" herein, and particularly refers to an alkylene group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, amino-carbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-.
[0045] 'Alkenyl' refers to monovalent olefinically unsaturated hydrocarbyl groups preferably having 2 to 11 carbon atoms, particularly, from 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CH=CH2), w-propenyl (- CH2CH=CH2), isopropenyl (-C(CH3)=CH2), vinyl and substituted vinyl, and the like. [0046] 'Substituted alkenyl' refers to those groups recited in the definition of "substituted" herein, and particularly refers to an alkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-. [0047] ' Alkenylene' refers to divalent olefinically unsaturated hydrocarbyl groups particularly having up to about 1 1 carbon atoms and more particularly 2 to 6 carbon atoms which can be straight- chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. This term is exemplified by groups such as ethenylene (-CH=CH-), the propenylene isomers (e.g., - CH=CHCH2- and -C(CH3)=CH- and -CH=C(CH3)-) and the like.
[0048] 'Alkynyl' refers to acetylenically or alkynically unsaturated hydrocarbyl groups particularly having 2 to 1 1 carbon atoms, and more particularly 2 to 6 carbon atoms which can be straight- chained or branched and having at least 1 and particularly from 1 to 2 sites of alkynyl unsaturation. Particular non-limiting examples of alkynyl groups include acetylenic, ethynyl (-C≡CH), propargyl (- CH2C≡CH), and the like.
[0049] 'Substituted alkynyl' refers to those groups recited in the definition of "substituted" herein, and particularly refers to an alkynyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, allOxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-.
[0050] 'Amino' refers to the radical -NH2.
[0051] 'Substituted amino' refers to an amino group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to the group -N(R38)2 where each
R38 is independently selected from:
• hydrogen, Ci-Cs alkyl, C6-Qo aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C3-C10 cycloalkyl; or
• Ci-C8 alkyl, substituted with halo or hydroxy; or
• -(CH2MC6-C10 aryl), -(CH2)t(5-10 membered heteroaryl), -(CH2)^C3-C10 cycloalkyl) or - (CH2)t(4-10 membered heterocycloalkyl) wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C]-C4 haloalkoxy or hydroxy; or
• both R38 groups are joined to form an alkylene group.
When both R38 groups are hydrogen, -N(R38)2 is an amino group. Exemplary 'substituted amino' groups are -NR39-C,-C8 alkyl, -NR39-(CH2)t(C6-Cl0 aryl), -NR39-(CH2)t(5-10 membered heteroaryl), -NR39- (CH2MC3-CiO cycloalkyl), and -NR39-(CH2),(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R39 independently represents H or C1-C8 alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C]-C4 hydroxyalkyl, or unsubstituted Ci-C4 haloalkoxy or hydroxy. For the avoidance of doubt the term "substituted amino" includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino as defined below.
[0052] 'Alkylamino' refers to the group -NHR40, wherein R40 is Ci-C8 alkyl.
[0053] 'Substituted Alkylamino' refers to the group -NHR41, wherein R41 is CrC8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted Ci-C4 alkoxy, unsubstituted Ci-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.
[0054] 'Alkylarylamino' refers to the group -NR42R43, wherein R42 is aryl and R43 is CpC8 alkyl.
[0055] 'Substituted Alkylarylamino' refers to the group -NR44R45, wherein R44 is aryl and R45 is
Ci-C8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C3- Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci -C4 alkyl, halo, cyano, unsubstituted Ci-C4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted Ci-C4 hydroxyalkyl, or unsubstituted Q-C4 haloalkoxy or hydroxy.
[0056] 'Arylamino' means a radical -NHR46 where R46 is selected from C6-C,0 aryl and 5-10 membered heteroaryl as defined herein.
[0057] 'Substituted Arylamino' refers to the group -NHR47, wherein R47 is independently selected from C6-Ci0 aryl and 5-10 membered heteroaryl; and any aryl or heteroaryl groups present, may themselves be substituted by unsubstituted CpC4 alkyl, halo, cyano, unsubstituted Ci -C4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy.
[0058] 'Dialkylamino' refers to the group -NR48R49, wherein each of R48 and R49 are independently selected from CpCg alkyl.
[0059] ' Substituted Dialkylamino ' refers to the group -NR50R5 ' , wherein each of R59 and R5 ' are independently selected from CpCg alkyl; and at least one of the alkyl groups is independently substituted with halo, hydroxy, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted Cp4 haloalkyl, unsubstituted C\-C4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy.
[0060] 'Diarylamino' refers to the group -NR52R53, wherein each of R52 and R53 are independently selected from C6-Ci0 aryl.
[0061] 'AminosulfonyF or 'Sulfonamide' refers to the radical -S(O2)NH2.
[0062] 'Substituted aminosulfonyl" or "substituted sulfonamide" refers to a radical such as -
S(O2)N(R54)2 wherein each R548 is independently selected from:
• H, CpC8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• CpC8 alkyl substituted with halo or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C]0 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy; provided that at least one R54 is other than H.
[0063] Exemplary 'substituted aminosulfonyl' or 'substituted sulfonamide' groups are -
S(O2)N(R55)-C,-C8 alkyl, -S(O2)N(R55)-(CH2)t(C6-C,0 aryl), -S(O2)N(R55)-(CH2)t(5-10 membered heteroaryl), -S(O2)N(R55)-(CH2)t(C3-C,0 cycloalkyl), and -S(O2)N(R55)-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4; each R55 independently represents H or CpCg alkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted C]-C4 haloalkyl, unsubstituted
Ci-C4 hydroxyalkyl, or unsubstituted CrC4 haloalkoxy or hydroxy.
[0064] 'Aralkyl' or 'arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups, as defined above. Particular aralkyl or arylalkyl groups are alkyl groups substituted with one aryl group.
[0065] 'Substituted Aralkyl' or 'substituted arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups; and at least one of the aryl groups present, may themselves be substituted by unsubstituted Ci-C4 alkyl, halo, cyano, unsubstituted Ci-C4 alkoxy, unsubstituted Ci -C4 haloalkyl, unsubstituted Ci-C4 hydroxyalkyl, or unsubstituted Ct-C4 haloalkoxy or hydroxy.
[0066] 'Aryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, mono-cyclic or poly-cyclic that includes from 5 to 12 ring members, more usually
6 to 10. Where the aryl group is a monocyclic ring system it preferentially contains 6 carbon atoms.
Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
[0067] 'Substituted Aryl' refers to an aryl group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to an aryl group that may optionally be substituted with 1 or more substituents, for instance from 1 to 5 substituents, particularly 1 to 3 substituents, in particular 1 substituent. Particularly, 'Substituted Aryl' refers to an aryl group substituted with one or more of groups selected from halo, CrC8 alkyl, Ci-C8 haloalkyl, cyano, hydroxy, Q-C8 alkoxy, and amino.
[0068] Examples of representative substituted aryls include the following
Figure imgf000014_0001
[0069] In these formulae one of R56 and R57 may be hydrogen and at least one of R56 and R57 is each independently selected from Ci-C8 alkyl, Q-C8 haloalkyl, 4-10 membered heterocycloalkyl, alkanoyl, Ci-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59 NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R56 and R57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O or S. R60 and R61 are independently hydrogen, Q-C8 alkyl, Q-C4 haloalkyl, C3-Q0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C)0 aryl, substituted aryl, 5-10 membered heteroaryl. [0070] 'Fused Aryl' refers to an aryl having two of its ring carbon in common with a second aryl ring or with an aliphatic ring.
[0071] 'Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein.
[0072] 'Substituted Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein; and any aryl groups present, may themselves be substituted by unsubstituted Ci-C4 alkyl, halo, cyano, unsubstituted CpC4 alkoxy, unsubstituted Cp4 haloalkyl, unsubstituted Ci-C4 hydroxyalkyl, or unsubstituted Ci-C4 haloalkoxy or hydroxy.
[0073] 'Azido' refers to the radical -N3.
[0074] 'Carbamoyl or amido' refers to the radical -C(O)NH2.
[0075] 'Substituted Carbamoyl or substituted amido' refers to the radical -C(O)N(R62)2 wherein each R62 is independently
• H, Ci-C8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• Ci-C8 alkyl substituted with halo or hydroxy; or
• C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C]-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted Q-C4 haloalkyl, unsubstituted C]-C4 hydroxyalkyl, or unsubstituted Ci-C4 haloalkoxy or hydroxy; provided that at least one R62 is other than H.
Exemplary 'Substituted Carbamoyl' groups are -C(O) NR64Oi-C8 alkyl, -C(O)NR64-(CH2)t(C6-Ci0 aryl),
-C(O)N64-(CH2)t(5-10 membered heteroaryl), -C(O)NR64-(CH2),(C3-C10 cycloalkyl), and -C(O)NR64-
(CH2),(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R64 independently represents H or C]-C8 alkyl and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CrC4 alkyl, halo, unsubstituted CrC4 alkoxy, unsubstituted
Ci-C4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted Ci-C4 haloalkoxy or hydroxy.
[0076] 'Carboxy' refers to the radical -C(O)OH.
[0077] 'Cycloalkyl' refers to cyclic non-aromatic hydrocarbyl groups having from 3 to 10 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
[0078] 'Substituted cycloalkyl' refers to a cycloalkyl group as defined above substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to a cycloalkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent
[0079] 'Cyano' refers to the radical -CN.
[0080] 'Halo' or 'halogen' refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
[0081] 'Hetero' when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, cycloalkenyl, e.g. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms. [0082] 'Heteroaryl' means an aromatic ring structure, mono-cyclic or polycyclic, that includes one or more heteroatoms and 5 to 12 ring members, more usually 5 to 10 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five. Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups. Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine. Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole and imidazoimidazole. Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, isoindolone, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine, triazolopyrimidine, benzodioxole and pyrazolopyridine groups. Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups. Particular heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine. [0083) Examples of representative heteroaryls include the following:
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000017_0003
wherein each Y is selected from carbonyl, N, NR65, O and S; and R65 is independently hydrogen, C]-Cg alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, and 5-10 membered heteroaryl. [0084] Examples of representative aryl having hetero atoms containing substitution include the following:
Figure imgf000017_0004
wherein each W is selected from C(R66)2, NR66, O and S; and each Y is selected from carbonyl, NR66, O and S; and R66 is independently hydrogen, CpC8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, and 5-10 membered heteroaryl.
[0085] As used herein, the term 'heterocycloalkyl' refers to a 4-10 membered, stable heterocyclic non-aromatic ring and/or including rings containing one or more heteroatoms independently selected from N, O and S, fused thereto. A fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, morpholine, piperidine (e.g. 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1- pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Further examples include thiomorpholine and its S-oxide and S,S-dioxide (particularly thiomorpholine). Still further examples include azetidine, piperidone, piperazone, and N-alkyl piperidines such as N-methyl piperidine. Particular examples of heterocycloalkyl groups are shown in the following illustrative examples:
Figure imgf000018_0001
wherein each W is selected from CR67, C(R67)2, NR67, O and S; and each Y is selected from NR67, O and
S; and R67 is independently hydrogen, CrC8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl,
C6-Ci0 aryl, 5-10 membered heteroaryl, These heterocycloalkyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl ,-S(O)-aryl, -S(O)2-alkyl, and -S(O)2- aryl. Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.
[0086] 'Hydroxy' refers to the radical -OH.
[0087] 'Nitro' refers to the radical -NO2.
[0088] 'Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). Typical substituents may be selected from the group consisting of: halogen, -R68, -O\ =O, -OR68, -SR68, -S", =S, -NR68R69, =NR68, -CCl3, -CF3, -CN, -OCN, -SCN, -NO, -
NO2, =N2, -N3, -S(O)2O", -S(O)2OH, -S(O)2R68, -OS(O2)O", -OS(O)2R68, -P(O)(O )2, -P(O)(OR68)(O ),
-OP(O)(OR68XOR69), -C(O)R68, -C(S)R68, -C(O)OR68, -C(O)NR68R69, -C(O)O-, -C(S)OR68, -
NR70C(O)NR68R69, -NR70C(S)NR68R69, -NR71C(NR70)NR68R69 and -C(NR70)NR68R69; wherein each R68, R69, R70 and R7' are independently:
• hydrogen, C]-Cg alkyl, C6-Ci0 aryl, arylalkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, heteroarylalkyl; or
• C)-C8 alkyl substituted with halo or hydroxy; or
• C6-CiO aryl' 5-10 membered heteroaryl, C6-CiO cycloalkyl or 4-10 membered heterocycloalkyl each of which is substituted by unsubstituted CrC4 alkyl, halo, unsubstituted Q-C4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted Ci-C4 haloalkoxy or hydroxy.
In a particular embodiment, substituted groups are substituted with one or more substituents, particularly with 1 to 3 substituents, in particular with one substituent group.
[0089] In a further particular embodiment the substituent group or groups are selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR72SO2R73, -SO2NR73R72, -C(O)R73, -C(O)OR73,
-OC(O)R73, -NR72C(O)R73, -C(O)NR73R72, -NR73P72, -(CR72R72)mOR72, wherein, each R73 is independently selected from H, C1-C8 alkyl, -(CH2),(C6-C,0 aryl), -(CH2),(5-10 membered heteroaryl), -(CH2)t(C3-Cio cycloalkyl), and -(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4; and
• any alkyl groups present, may themselves be substituted by halo or hydroxy; and
• any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Q-C4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted Q- C4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Each R independently represents H or Ci-C6alkyl.
[0090] 'Substituted sulfanyl' refers to the group -SR74, wherein R74 is selected from:
• Ci-C8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C5-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• CpC8 alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or
• C3-C]0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted Ci-C4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted Ci -C4 haloalkyl, unsubstituted Ci -C4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy.
[0091] Exemplary 'substituted sulfanyl' groups are -S-(CpC8 alkyl) and -S-(C3-Ci0 cycloalkyl),
-S-(CH2)t(C6-Cio aryl), -S-(CH2)t(5-10 membered heteroaryl), -S-(CH2)t(C3-C,o cycloalkyl), and -S-
(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC4 alkyl, halo, unsubstituted CpC4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy. The term 'substituted sulfanyl' includes the groups
'alkylsulfanyP or 'alkylthio', 'substituted alkylthio' or 'substituted alkylsulfanyl' , 'cycloalkylsulfanyl' or
' cycloalkyl thio', 'substituted cycloalkylsulfanyl' or 'substituted cycloalkylthio', 'arylsulfanyl' or
'arylthio' and 'heteroarylsulfanyl' or 'heteroarylthio' as defined below.
[0092] 'Alkylthio' or 'Alkylsulfanyl' refers to a radical -SR75 where R75 is a CpC8 alkyl or group as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio and butylthio.
[0093] 'Substituted Alkylthio'or 'substituted alkylsulfanyl' refers to the group -SR76 where R76 is a CpC8 alkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
[0094] 'Cycloalkylthio' or 'Cycloalkylsulfanyl' refers to a radical -SR77 where R77 is a C3-C ,0 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylthio, cyclohexylthio, and cyclopentylthio.
[0095] 'Substituted cycloalkylthio' or 'substituted cycloalkylsulfanyl' refers to the group -SR78 where R78 is a C3-Ci0 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
[0096] 'Arylthio' or 'Arylsulfanyl' refers to a radical -SR79 where R79 is a C6-Ci0 aryl group as defined herein.
[0097] 'Heteroarylthio' or 'Heteroarylsulfanyl' refers to a radical -SR80 where R80 is a 5-10 membered heteroaryl group as defined herein. [0098] 'Substituted sulfinyl' refers to the group -S(O)R81, wherein R81 is selected from:
• CpC8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• Ci-C8 alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted Cj-C4 alkyl, halo, unsubstituted Ci-C4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted CpC4 hydroxyalkyl, or unsubstituted CpC4 haloalkoxy or hydroxy.
[0099] Exemplary 'substituted sulfinyl' groups are -S(O)-(C,-C8 alkyl) and -S(O)-(C3-Ci0 cycloalkyl), -S(O)-(CH2MC6-C10 aryl), -S(O)-(CH2),(5-10 membered heteroaryl), -S(O)-(CH2X(C3-C10 cycloalkyl), and -S(O)-(CH2),(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted
C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. The term substituted sulfinyl includes the groups 'alkylsulfinyP, 'substituted alkylsulfinyP, 'cycloalkylsulfinyl', 'substituted cycloalkylsulfϊnyP,
'arylsulfinyl' and 'heteroarylsulfinyl' as defined herein.
[00100] 'AlkylsulfinyP refers to a radical -S(O)R82 where R82 is a C1-C8 alkyl group as defined herein. Representative examples include, but are not limited to, methylsulfϊnyl, ethylsulfinyl, propylsulfinyl and butylsulfinyl.
[00101] 'Substituted AlkylsulfinyP refers to a radical -S(O)R83 where R83 is a C1-C8 alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.
[00102] 'Cycloalkylsulfinyl' refers to a radical -S(O)R84 where R84 is a C3-C10 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylsulfinyl, cyclohexylsulfinyl, and cyclopentylsulfinyl. Exemplary 'cycloalkylsulfinyl' groups are S(O)-C3-Ci0 cycloalkyl.
[00103] 'Substituted cycloalkylsulfinyl' refers to the group -S(O)R85 where R85 is a C3-C10 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
[00104] 'Arylsulfinyl' refers to a radical -S(O)R86 where R86 is a C6-C10 aryl group as defined herein.
[00105] 'Heteroarylsulfinyl' refers to a radical -S(O)R87 where R87 is a 5-10 membered heteroaryl group as defined herein.
[00106] 'Substituted sulfonyP refers to the group -S(O)2R88, wherein R88 is selected from:
• CpC8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• CpCg alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or
• C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl. aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C]-C4 alkoxy, unsubstituted Q-C4 haloalkyl, unsubstituted Ci-C4 hydroxyalkyl, or unsubstituted C)-C4 haloalkoxy or hydroxy.
[00107] Exemplary 'substituted sulfonyP groups are -S(O)2-(Ci-C8 alkyl) and -S(O)2-(C3-Ci0 cycloalkyl), -S(O)2-(CH2)t(C6-C,0 aryl), -S(O)2-(CH2)t(5-10 membered heteroaryl), -S(O)2-(CH2)t(C3-C,0 cycloalkyl), and -S(O)2-(CH2)t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CrC4 alkyl, halo, unsubstituted CrC4 alkoxy, unsubstituted Ci-C4 haloalkyl, unsubstituted Ci-C4 hydroxyalkyl, or unsubstituted Ci -C4 haloalkoxy or hydroxy. The term substituted sulfonyl includes the groups alkylsulfonyl, substituted alkylsulfonyl, cycloalkylsulfonyl, substituted cycloalkylsulfonyl, arylsulfonyl and heteroarylsulfonyl.
[00108] 'Alkylsulfonyl' refers to a radical -S(O)2R89 where R89 is an CrC8 alkyl group as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl and butylsulfonyl.
[00109] ' Substituted Alkylsulfonyl' refers to a radical -S(O)2R90 where R90 is an C1-C8 alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy. [00110] 'Cycloalkylsulfonyl' refers to a radical -S(O)2R91 where R91 is a C3-Ci0 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylsulfonyl, cyclohexylsulfonyl, and cyclopentylsulfonyl.
[00111] 'Substituted cycloalkylsulfonyl' refers to the group -S(O)2R92 where R92 is a C3-Ci0 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy. [00112] 'Arylsulfonyl' refers to a radical -S(O)2R93 where R93 is an C6-Ci0 aryl gr°uP as defined herein.
[00113] 'Heteroarylsulfonyl' refers to a radical -S(O)2R94 where R94 is an 5-10 membered heteroaryl group as defined herein.
[00114] 'Sulfo' or 'sulfonic acid' refers to a radical such as -SO3H.
[00115] 'Substituted sulfo' or 'sulfonic acid ester' refers to the group -S(O)2OR95, wherein R95 is selected from:
• Ci-C8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
• Ci-C8 alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or
• C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted CrC4 alkyl, halo, unsubstituted Ci-C4 alkoxy, unsubstituted CpC4 haloalkyl, unsubstituted Ci-C4 hydroxyalkyl, or unsubstituted Ci -C4 haloalkoxy or hydroxy.
[00116] Exemplary 'Substituted sulfo' or 'sulfonic acid ester' groups are -S(O)2-O-(Ci-C8 alkyl) and -S(O)2-O-(C3-C10 cycloalkyl), -S(O)2-O-(CH2)t(C6-C,0 aryl), -S(O)2-O-(CH2)t(5-10 membered heteroaryl), -S(O)2-O-(CH2)t(C3-C,0 cycloalkyl), and -S(O)2-O-(CH2),(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C4 alkyl, halo, unsubstituted Ci-C4 alkoxy, unsubstituted Ci-C4 haloalkyl, unsubstituted Ci -C4 hydroxyalkyl, or unsubstituted CrC4 haloalkoxy or hydroxy.
[001171 'Thiol' refers to the group -SH.
[00118] 'Aminocarbonylamino' refers to the group -NR96C(O)NR96R96 where each R96 is independently hydrogen Q-C8 alkyl, C3-Ci0 cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl, as defined herein; or where two R96 groups, when attached to the same N, are joined to form an alkylene group.
[00119] 'Bicycloaryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent bicycloaromatic ring system. Typical bicycloaryl groups include, but are not limited to, groups derived from indane, indene, naphthalene, tetrahydronaphthalene, and the like. Particularly, an aryl group comprises from 8 to 11 carbon atoms. [00120] 'BicycloheteroaryP refers to a monovalent bicycloheteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent bicycloheteroaromatic ring system. Typical bicycloheteroaryl groups include, but are not limited to, groups derived from benzofuran, benzimidazole, benzindazole, benzdioxane, chromene, chromane, cinnoline, phthalazine, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, benzothiazole, benzoxazole, naphthyridine, benzoxadiazole, pteridine, purine, benzopyran, benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quinolizine, quinoxaline, benzomorphan, tetrahydroisoquinoline, tetrahydroquinoline, and the like. Preferably, the bicycloheteroaryl group is between 9-11 membered bicycloheteroaryl, with 5-10 membered heteroaryl being particularly preferred. Particular bicycloheteroaryl groups are those derived from benzothiophene, benzofuran, benzothiazole, indole, quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane.
[00121] 'Compounds of the present invention', and equivalent expressions, are meant to embrace the compounds as hereinbefore described, in particular compounds according to any of the formulae herein recited and/or described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
[00122] 'Cycloalkylalkyl' refers to a radical in which a cycloalkyl group is substituted for a hydrogen atom of an alkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.
[00123] Ηeterocycloalkylalkyl' refers to a radical in which a heterocycloalkyl group is substituted for a hydrogen atom of an alkyl group. Typical heterocycloalkylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like. [00124] 'Cycloalkenyl' refers to cyclic hydrocarbyl groups having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefinic unsaturation. Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.
[00125] 'Substituted cycloalkenyl' refers to those groups recited in the definition of "substituted" herein, and particularly refers to a cycloalkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-.
[00126] 'Fused Cycloalkenyl' refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation located to impart aromaticity to the cycloalkenyl ring.
[00127] Εthenyl" refers to substituted or unsubstituted -(C=C)-.
[00128] 'Ethylene' refers to substituted or unsubstituted -(C-C)-.
[00129] Εthynyl' refers to -(C≡C)-.
[00130] 'Hydrogen bond donor' group refers to a group containg O-H, or N-H functionality.
Examples of 'hydrogen bond donor' groups include -OH, -NH2, and -NH-R97 and wherein R97 is alkyl, acyl, cycloalkyl, aryl, or heteroaryl.
[00131] 'Dihydroxyphosphoryl' refers to the radical -PO(OH)2.
[00132] 'Substituted dihydroxyphosphoryl' refers to those groups recited in the definition of
"substituted" herein, and particularly refers to a dihydroxyphosphoryl radical wherein one or both of the hydroxyl groups are substituted. Suitable substituents are described in detail below.
[00133] 'Aminohydroxyphosphoryl' refers to the radical -PO(OH)NH2.
[00134] 'Substituted aminohydroxyphosphoryl' refers to those groups recited in the definition of
"substituted" herein, and particularly refers to an aminohydroxyphosphoryl wherein the amino group is substituted with one or two substituents. Suitable substituents are described in detail below. In certain embodiments, the hydroxyl group can also be substituted.
[00135] 'Nitrogen-Containing Heterocycloalkyl' group means a 4 to 7 membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2-pyrrolidinyl and 3- pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.
[00136] 'Thioketo' refers to the group =S.
[00137] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically fea^'ble heterocyclic ring, whether it is aromatic or non aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
[00138] 'Pharmaceutically acceptable' means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
[00139] 'Pharmaceutically acceptable salt' refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
[00140] 'Pharmaceutically acceptable vehicle' refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
[00141] 'Prodrugs' refers to compounds, including derivatives of the compounds of the invention,which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. [00142] 'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. 'Solvate' encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
[00143] 'Subject' includes humans. The terms 'human', 'patient' and 'subject' are used interchangeably herein.
[00144] 'Therapeutically effective amount' means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The
"therapeutically effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
[00145J 'Preventing' or 'prevention' refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
[00146] The term 'prophylaxis' is related to 'prevention', and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
[00147] 'Treating' or 'treatment' of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.
[00148] 'Compounds of the present invention', and equivalent expressions, are meant to embrace compounds of the Formula(e) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, where the context so permits.
Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
[00149] When ranges are referred to herein, for example but without limitation, CpC8 alkyl, the citation of a range should be considered a representation of each member of said range.
[00150] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalia" organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21 -24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly the Ci to C8 alkyl, C2-C8 alkenyl, aryl, C7-Ci2 substituted aryl, and C7-C]2 arylalkyl esters of the compounds of the invention.
[00151] As used herein, the term 'isotopic variant' refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an 'isotopic variant' of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be 2HZD, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting isotopes, such as 11C, 18F, 15O and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
[00152] All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention.
[00153] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed 'isomers'. Isomers that differ in the arrangement of their atoms in space are termed 'stereoisomers'.
[00154] Stereoisomers that are not mirror images of one another are termed 'diastereomers' and those that are non-superimposable mirror images of each other are termed 'enantiomers'. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a 'racemic mixture'.
[00155] 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electror° and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
[00156) Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
[00157] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an "S" form of the compound is substantially free from the "R" form of the compound and is, thus, in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound. [00158] As used herein and unless otherwise indicated, the term "enantiomerically pure R- compound" refers to at least about 80% by weight R-compound and at most about 20% by weight S- compound, at least about 90% by weight R-compound and at most about 10% by weight S-compound, at least about 95% by weight R-compound and at most about 5% by weight S-compound, at least about 99% by weight R-compound and at most about 1% by weight S-compound, at least about 99.9% by weight R- compound or at most about 0.1% by weight S-compound. In certain embodiments, the weights are based upon total weight of compound.
[00159] As used herein and unless otherwise indicated, the term "enantiomerically pure S- compound" or "S-compound" refers to at least about 80% by weight S-compound and at most about 20% by weight R-compound, at least about 90% by weight S-compound and at most about 10% by weight R- compound, at least about 95% by weight S-compound and at most about 5% by weight R-compound, at least about 99% by weight S-compound and at most about 1% by weight R-compound or at least about 99.9% by weight S-compound and at most about 0.1% by weight R-compound. In certain embodiments, the weights are based upon total weight of compound.
[00160] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R- compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R- compound. In certain embodiments, the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S- compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain errMdiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.
[00161] The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof. [00162] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
THE COMPOUNDS
[00163] In certain aspects, the present invention provides compounds useful for preventing and/or treating a broad range of conditions, among them, pain, sleep disorders, anxiety and depression disorders, weight and eating disorders, Parkinson's disease, addiction, spasticity, inflammatory disorders, glaucoma or other disorders. [00164] In one aspect, the present invention provides compounds according to formula I:
Figure imgf000028_0001
I wherein
X is NR1R2; or X is N-containing 3-1 1 membered mono or fused heterocycloalkyl, joined to the core group via ring N;
R1 is selected from a substituted or unsubstituted cycloalkyl; or R1 is substituted or unsubstituted aryl or heteroaryl;
R2 is selected from hydrogen, and substituted or unsubstituted Ci-C6 alkyl; R3 is selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; each R4 is independently selected from H, C|-C6alkyl, substituted C|-C6alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfo, sulfonic acid ester, substituted or unsubstituted dihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituor unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol; and n is 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof; provided that i) when X is heterocycloalkyl, R3 is other than unsubstituted phenyl or unsubstituted pyridyl; and ii) the compound is other than a) N-cyclohexyl-5-(3,7-dimethylimidazo[l ,2-a]pyridin-2-yl)-2-Benzoxazolamine
Figure imgf000029_0001
b) 4-[5-[4-(trifluoromethyl)phenyl]-2-benzoxazolyl]-l ,4-diazabicyclo[3.2.2]nonane
Figure imgf000029_0002
c) 4-[5-(3-methylphenyl)-2-benzoxazolyl]- 1 ,4-Diazabicyclo[3.2.2]nonane
Figure imgf000029_0003
d) 2,4-dihydro-2-phenyl-5-[(5-phenyl-2-benzoxazolyl)amino]-3H-pyrazol-3-one
Figure imgf000029_0004
e) 5-phenyl-N-[2-[3-(trifluoromethyl)phenoxy]-3-pyridinyl]-2-benzoxazolamine
Figure imgf000029_0005
f) N-[2-[2-(l , 1 -dimethylethyl)phenoxy]-3-pyridinyl]-5-phenyl-2-benzoxazolamine
Figure imgf000029_0006
[00165] In one embodiment with respect to formula I, R3 is heteroaryl; and the heteroaryl is other than substituted or unsubstituted 1 ,4,5,6-tetrahydro-6-oxo-3-pyridazinyl. For the sake of clarity, the invention excludes compounds where R3 is substituted or unsubstituted l ,4,5,6-tetrahydro-6-oxo-3- pyridazinyl or substituted or unsubstituted
Figure imgf000029_0007
[00166] In one particular embodiment, witu ^espect to compounds of formula I, R2 is H. [00167] In one particular embodiment, with respect to compounds of formula I, n is 1 or 2; and R4 is independently selected from halo, Ci-C6alkyl, haloC,-C6alkyl, cyano, hydroxy, alkoxy and sulfonyl.
[00168] In one particular embodiment, with respect to compounds of formula I, n is 1 or 2; and R4 is independently selected from Me, Cl, F, OMe, CF3 and CN.
[00169] In one particular embodiment, with respect to compounds of formula I, n is 3; and R4 is
H.
[00170] In one particular embodiment, with respect to compounds of formula I, the compound is according to formula II
Figure imgf000030_0001
wherein R1 and R3 are as in formula I.
[00171] In one particular embodiment, with respect to compounds of formulae I-II, R1 is substituted or unsubstituted cyclohexyl, cycloheptyl, cyclopentyl, cyclopropyl, or cyclobutyl. [00172] In one particular embodiment, with respect to compounds of formulae I-II, R1 is substituted or unsubstituted cyclohexyl.
[00173] In one particular embodiment, with respect to compounds of formulae I-II, R1 is unsubstituted cyclohexyl.
[00174] In one particular embodiment, with respect to compounds of formulae I-II, R1 is substituted or unsubstituted phenyl.
[00175] In one particular embodiment, with respect to compounds of formulae I-II, R1 is substituted or unsubstituted heteroaryl.
[00176] In one particular embodiment, with respect to compounds of formulae I-II, R1 is substituted or unsubstituted pyridyl, quinolinyl, isoquinolinyl, substituted or unsubstituted benzodioxole, substituted or unsubstituted benzodioxane, substituted or unsubstituted benzofuran, substituted or unsubstituted benzothiophene, and substituted or unsubstituted benzodioxepine.
[00177] In one particular embodiment, with respect to compounds of formulae I-II, R1 is phenyl, substituted with one or more substituents independently selected from halo, Ci-C6alkyl, haloC|-C6alkyl, C3-C8cycloalkyl, amino, cyano, hydroxy, alkoxy and sulfonyl.
[00178] In one particular embodiment, with respect to compounds of formulae I-II, R1 is phenyl, substituted with one or more substituents independently selected from Me, Et, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CF3, CHF2, OCF3, i-Pr, i-Bu, t-Bu, SMe, CH=CH-CO2H, SOMe, SO2Me, SO3H, and SO3Me.
[00179] In one particular embodiment, with respect to compounds of formulae I-II, R1 is pyridyl, substituted with one or more substituents independently selected from halo, Ci-C6alkyl, haloCi-C6alkyl, C3-C8cycloalkyl, amino, cyano, hydroxy, alkoxy and sulfonyl. [00180] In one particular embodiment, with respect to compounds of formulae I-II, R1 is pyridyl, substituted with one or more substituents independently selected from Me, Et, Ph, Cl, F, Br, CN, OH,
OMe, OEt, OPh, COPh, CF3, CHF2, OCF3, i-Pr, i-Bu, t-Bu, SMe, CH=CH-CO2H, SOMe, SO2Me, SO3H, and SO3Me.
100181] In one particular embodiment, with respect to compounds of formulae I-II, R1 is unsubstituted phenyl.
[00182] In one particular embodiment, with respect to compounds of formula I, the compound is according to formula Ilia
Figure imgf000031_0001
Ilia wherein R3 is as in formula I.
[00183] In one particular embodiment, with respect to compounds of formula I, the compound is according to formula HIb:
Figure imgf000031_0002
wherein R is as in formula I.
[00184] In one particular embodiment, with respect to compounds of formula I, the compound is according to formula IV
Figure imgf000031_0003
IV wherein R3 is as in formula I; and Cy is 3-1 1 membered mono or fused heterocycloalkyl. [00185] In one particular embodiment, with respect to compounds of formula IV, Cy is azetidin-1- yl, pyrrolidin-1 -yl, piperidin-1 -yl, piperazin-1-yl, morpholin-1 -yl, dihydroindol-1-yl, dihydroisoindol-1- yl, tetrahydroquinolin-1-yl, or tetrahydroisoquinolinyl.
[00186] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is substituted or unsubstituted phenyl.
[00187] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is substituted or unsubstituted heteroaryl. [00188] hi one particular embodiment, with respect to compounds of formulae I-IV, R3 is substituted or unsubstituted pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted benzoxazinyl, substituted or unsubstituted benzodioxole, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothiophenyl, and substituted or unsubstituted benzodioxepinyl.
[00189] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is substituted or unsubstituted indolyl, substituted or unsubstituted indolinyl, substituted or unsubstituted N- methlylindol-5-yl, or substituted or unsubstituted N-methylindolin-5-yl imidazopyridinyl.
[00190] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is phenyl, substituted with one or more substituents independently selected from halo, CrC6alkyl, haloCrC6alkyl,
C3-C8cycloalkyl, amino, cyano, hydroxy, alkoxy and sulfonyl.
[00191] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is phenyl, substituted with one or more substituents independently selected from halo, CrC6alkyl, haloC|-C6alkyl.
[00192] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is phenyl, substituted with one or more substituents independently selected from cyano, alkoxy and sulfonyl.
[00193] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is phenyl, substituted with amino.
[00194] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is phenyl, substituted with one or more substituents independently selected from hydroxyl.
[00195] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is phenyl, substituted with one or more substituents independently selected from Me, Et, Ph, Cl, F, Br, CN, OH,
OMe, OEt, OPh, COPh, CF3, CHF2, OCF3, i-Pr, i-Bu, t-Bu, SMe, CH=CH-CO2H, SOMe, SO2Me, SO3H, and SO3Me.
[00196] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is 4- substituted phenyl; and the substitution is selected from halo, C|-C6alkyl, Q-Cgalkoxy, and haloCp
C6alkyl.
[00197] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is 4- substituted phenyl; and the substitution is selected from OMe, Cl and F.
[00198] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is 3,4- disubstituted phenyl; and the substitution is independently selected from halo, Ci-Cόalkyl, Ci-C6alkoxy, and haloCi-C6alkyl.
[00199] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is 3,4- disubstituted phenyl; and the substitution is independently selected from OMe, Cl and F.
[00200] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is pyridyl, substituted with one or more substituents independently selected from halo, Ci-C6alkyl, haloCi-C6alkyl,
C3-C8cycloalkyl, amino, cyano, hydroxy, alkoxy and sulfonyl.
[00201] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is pyridyl, substituted with one or more substituents independently selected from Me, Et, Ph, Cl, F, Br, CN, OH,
OMe, OEt, OPh, COPh, CF3, CHF2, OCF3, i-Pr, i-Bu, t-Bu, SMe, CH=CH-CO2H, SOMe, SO2Me, SO3H, and SO3Me. [00202] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is unsubstituted phenyl.
[00203] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is
Figure imgf000033_0001
Figure imgf000033_0002
wherein Z is CR3c or N; R3a is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl; R3b is selected from H and substituted or unsubstituted alkyl; R3c is selected from H, halo, and substituted or unsubstituted alkyl.
[00204] hi one particular embodiment, R3 is as described above; and R3b is H or alkyl. [00205] hi one particular embodiment, R3 is as described above; and R3b is H, Me, or Et. [00206] In one particular embodiment, R3 is as described above; and Z is CR3c; and R3c is H, Cl,
F, or Me.
[00207] In one particular embodiment, R3 is as described above; and Z is N.
[00208] In one particular embodiment, with respect to compounds of formula I, the compound is according to formula IVa, IVb, IVc, or IVd:
Figure imgf000033_0003
IVa IVb
Figure imgf000033_0004
IVc IVd and wherein X is as in formula I; R3a is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.
[00209] hi one particular embodiment, with respect to compounds of formula I, the compound is according to formula Va, Vb, Vc, or Vd:
Figure imgf000034_0001
Vb
Va
Figure imgf000034_0002
Vd
Vc and wherein X is as in formula I; R3a is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.
[00210] In one particular embodiment, with respect to compounds of formula I, the compound is according to formula Via, VIb, VIc, or VId:
Figure imgf000034_0003
VIb
Via
Figure imgf000034_0004
VId
VIc and wherein X is as in formula I; R3a is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.
[00211] In one particular embodiment, with respect to compounds of formula FVa-VId, R3a is H.
[00212] In one particular embodiment, with respect to compounds of formula FVa-VId, R3a is H,
Me, Et, or i-Pr.
[00213] In one particular embodiment, with respect to compounds of formula FVa-VId, R3a is cyclopropyl, cyclobutyl, cyclohexyl, or cyclopentyl.
[00214] In one particular embodiment, with respect to compounds of formula IVa-VId, R3a is oxetan-3-yl.
[00215] In one particular embodiment, with respect to compounds of formula I, FV, FVa-VId, X is:
Figure imgf000035_0001
Figure imgf000035_0002
[00216] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is substituted or unsubstituted benzodioxepinyl.
[00217] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is indolyl or indolinyl, unsubstituted or substituted with halo, Ci-C6alkyl, or haloCi-Qalkyl.
[00218] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is N- methlylindol-5-yl or N-methylindolin-5-yl.
[00219] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is imidazopyridinyl, unsubstituted or substituted with halo, Ci-Cβalkyl, or haloCi-Qalkyl.
[00220] In one particular embodiment, with respect to compounds of formulae I-IV, R3 is imidazo[l,2-a]pyridine-6-yl, unsubstituted or substituted with halo, Ci-Cβalkyl, or haloCi-Cβalkyl.
[00221] In some embodiments, R3 is a phenyl.
[00222] In certain embodiments, R3 is a substituted phenyl.
[00223] In some embodiments, R3 is a mono-substituted phenyl.
[00224] In other embodiments, R3 is a di-substituted phenyl.
[00225] In certain embodiments, R3 is a substituted phenyl where the substituent on the phenyl is selected from halo, amido, Ci-C6alkyl, alkoxy, sulfonyl, sulfonamidyl, haloalkyl and trihaloalkyl. In preferred embodiments, the substitution on the R3 phenyl is selected from Cl, F, CF3, Me, t-Bu, OMe,
SO2R2 , NR2 R2', and SO2NR2 R2'. In another embodiment, the substitution on the R3 phenyl is selected from Cl, Me, t-Bu and SO2Me.
[00226] In embodiments where R3 is a substituted phenyl, one or more substituents are on the phenyl at the 2 (ortho), 3 (meta) and/or 4 (para) position relative to the carbon attached to the nitrogen atom in the fused heterocyclic scaffold in formula I. In certain embodiments, R3 is a substituted phenyl, where a substituent is on the phenyl at the 2 (ortho), 3 (meta) and/or 4 (para) position. In more preferred embodiments, the substitution on the R3 phenyl is at the 2 or 4 position. In the most preferred embodiments, the substitution on the R3 phenyl is at the 4 position.
[00227] In some embodiments, R3 are selected from
Figure imgf000035_0003
wherein subscript n' is selected from 1-5 and each of R5 is independently selected from hydrogen, substituted or unsubstituted C,-C6alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfo, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfonic acid ester, substituted or unsubstituted dihydroxyphosphoryl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol.
[00228] In some embodiments, subscript n' is 1 , 2 or 3.
[00229] In some embodiments, subscript n' is 1 or 2.
[00230] In some embodiments, each R5 is independently selected from Me, Et, Pr, iso-Pr, Ph, Cl,
F, Br, CN, OH, OMe, OEt, OPh, COPh, CO2Me, CH2-N-morpholino, CH2-N-(4-Me-piperidino), CONH2,
CF3, CHF2, OCF3, OCHF2, t-Bu, SMe, CH=CH-CO2H, SOMe, SO2Me, SO2CF3, SO2NH2, SO3H, SO3Me, and pyridyl.
[00231] In some embodiments, each R5 is independently selected from Me, Et, Pr, iso-Pr, Ph, Cl,
F, CN, OH, OMe, OEt, OPh, CF3, CHF2, OCF3, OCHF2, t-Bu, SO2Me, SO2CF3, and SO3Me.
[00232] With regard to compounds of formula I, in certain embodiments, the compound is selected from the compounds listed in Table 1.
[00233] With regard to compounds of formula I, in certain embodiments, the compound is selected from:
Cyclohexyl-(5-phenyl-benzooxazol-2-yl)-amine;
Cyclohexyl-(5-furan-3-yl-benzooxazol-2-yl)-amine;
Cyclohexyl-[5-(2,3-dihydro-benzofuran-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(2-fluoro-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(2-methoxy-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-(5-p-tolyl-benzooxazol-2-yl)-amine;
Phenyl-(5-pyrimidin-5-yl-benzooxazol-2-yl)-amine;
Phenyl-(5-p-tolyl-benzooxazol-2-yl)-amine;
[5-(2-Methoxy-phenyl)-benzooxazol-2-yl]-phenyl-amine;
Cyclohexyl-fS-β-dimethylamino-phenyO-benzooxazol^-ylJ-amine;
Cyclohexyl-(5 -pyrimidin-5 -yl-benzooxazol-2-yl)-amine;
Cyclohexyl-[5-(4-trifluoromethoxy-phenyl)-benzooxazol-2-yl]-amine;
3-(2-Cyclohexylamino-benzooxazol-5-yl)-benzamide;
[5-(2-Fluoro-phenyl)-benzooxazol-2-yl]-phenyl-amine;
[5-(4-Fluoro-phenyl)-benzooxazol-2-yl]-phenyl-amine;
Cyclohexyl-[5-(2,3-dihydro-benzo[l ,4]di — in-6-yl)-benzooxazol-2-yl]-amine; [5-(4-Methoxy-phenyl)-benzooxazol-2-yl]-phenyl-amine;
Phenyl-[5-(3-trifluoromethyl-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(3-trifluoromethyl-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(4-methanesulfonyl-phenyl)-benzooxazol-2-yl]-amine;
3-(2-Phenylamino-benzooxazol-5-yl)-benzamide;
[5-(3-Dimethylamino-phenyl)-benzooxazol-2-yl]-phenyl-amine;
Phenyl-[5-(4-trifluoromethoxy-phenyl)-benzooxazol-2-yl]-amine;
Phenyl-(5-pyridin-3-yl-benzooxazol-2-yl)-amine;
4-(2-Phenylamino-benzooxazol-5-yl)-phenol;
[5-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-benzooxazol-2-yl]-phenyl-amine;
[5-( 1 -Methyl- 1 H-indol-5 -yl)-benzooxazol-2-yl] -phenyl -amine;
4-(2-Phenylamino-benzooxazol-5-yl)-benzoic acid;
(5-Benzo[l ,3]dioxol-5-yl-benzooxazol-2-yl)-phenyl-amine;
[5-(6-Moφholin-4-yl-pyridin-3-yl)-benzooxazol-2-yl]-phenyl-amine;
[5-(4-Dimethylaminomethyl-phenyl)-benzooxazol-2-yl]-phenyl-amine;
(5-Benzofuran-5-yl-benzooxazol-2-yl)-phenyl-amine;
[5-(l-Methyl-2,3-dihydro-lH-indol-5-yl)-benzooxazol-2-yl]-phenyl-amine;
[5-(4-Methyl-3,4-dihydro-2H-benzo[l ,4]oxazin-7-yl)-benzooxazol-2-yl]-phenyl-amine;
5-(2-Phenylamino-benzooxazol-5-yl)-l ,3-dihydro-indol-2-one;
[5-(3-Methoxy-phenyl)-benzooxazol-2-yl]-phenyl-amine;
[5-(3,4-Dimethoxy-phenyl)-benzooxazol-2-yl]-phenyl-amine;
[5-(2,4-Dimethoxy-phenyl)-benzooxazol-2-yl]-phenyl-amine;
[5 -(3 -Fluoro-4-methoxy-phenyl)-benzooxazol-2-yl] -phenyl -amine;
[5-(2-Methoxy-pyrimidin-5-yl)-benzooxazol-2-yl]-phenyl-amine;
[5-(4-Isopropoxy-phenyl)-benzooxazol-2-yl]-phenyl-amine;
[5-(3,4-Dihydro-2H-benzo[b][l ,4]dioxepin-7-yl)-benzooxazol-2-yl]-phenyl-amine;
[5-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-benzooxazol-2-yl]-phenyl-amine;
[5-(4-Methoxymethyl-phenyl)-benzooxazol-2-yl]-phenyl-amine;
[4-(2-Phenylamino-benzooxazol-5-yl)-phenyl]-methanol;
[2-(2-Phenylamino-benzooxazol-5-yl)-phenyl]-methanol;
[5-(4-Dimethylamino-phenyl)-benzooxazol-2-yl]-phenyl-amine;
4-(2-Phenylamino-benzooxazol-5-yl)-benzonitrile;
3-(2-Phenylamino-benzooxazol-5-yl)-benzoic acid;
[5-(lH-Indol-5-yl)-benzooxazol-2-yl]-phenyl-amine;
N-[4-(2-Phenylamino-benzooxazol-5-yl)-phenyl]-acetamide;
Phenyl-(5-pyridin-4-yl-benzooxazol-2-yl)-amine;
Phenyl-(5-quinoxalin-6-yl-benzooxazol-2-yl)-amine;
(5-Imidazo[ 1 ,2-a]pyridin-6-yl-benzooxazol-2-yl)-phenyl-amine;
[5-(6-Methoxy-pyridin-3-yl)-benzooxazol "• -yl] -phenyl-amine; 3-[4-(2-Cyclohexylamino-benzooxazol-5-yl)-phenyl]- 1 ,1 -dimethyl -urea;
[4-(2-Cyclohexylamino-benzooxazol-5-yl)-phenyl]-carbamic acid methyl ester;
Cyclohexyl-[5-(4-methoxy-3-methyl-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(4-methoxy-2-methyl-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(l-methyl-lH-indazol-5-yl)-berizooxazol-2-yl]-amine;
N-[4-(2-Cyclohexylamino-benzooxazol-5-yl)-phenyl]-methanesulfonamide;
[5-(4-Amino-phenyl)-benzooxazol-2-yl]-cyclohexyl-amine;
[5-(l-Ethyl-lH-indol-5-yl)-benzooxazol-2-yl]-phenyl-amine;
[5-(l -Isobutyl-1 H-indol-5-yl)-benzooxazol-2-yl]-phenyl-amine;
{5-[l-(2-Methoxy-ethyl)-lH-indol-5-yl]-benzooxazol-2-yl} -phenyl-amine;
{5-[l-(2-Dimethylamino-ethyl)-lH-indol-5-yl]-benzooxazol-2-yl} -phenyl-amine;
2-[5-(2-Phenylamino-benzooxazol-5-yl)-indol-l-yl]-acetamide;
[5-(l-Oxetan-3-yl-lH-indol-5-yl)-benzooxazol-2-yl]-phenyl-amine;
[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-pyridin-2-yl-amine;
[5-( 1 -Methyl- 1 H-indol-5 -yl)-benzooxazol-2-yl] -pyridin-3 -yl -amine;
[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-pyridin-4-yl-amine;
5-( 1 -Methyl- 1 H-indol-5 -yl)-2-piperidin- 1 -yl-benzooxazole;
Methyl-[5-(l-methyl-lH-indol-5-yl)-benzooxazol-2-yl]-phenyl-amine;
Indan-2-yl-[5 -( 1 -methyl- 1 H-indol-5 -yl)-benzooxazol-2-yl] -amine;
[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-pyridazin-3-yl-amine;
5-(l -Methyl-lH-indol-5-yl)-2-(4-methyl-piperazin-l-yl)-benzooxazole;
5-( 1 -Methyl- 1 H-indol-5 -yl)-2-moφholin-4-yl-benzooxazole;
Cyclobutyl-[5-(l-methyl-lH-indol-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(4-fluoro-3-methoxy-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(2-fluoro-4-methoxy-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(3,5-difluoro-4-methoxy-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5 -(3 ,5 -dimethoxy-phenyl)-benzooxazol-2-yl] -amine;
Cyclohexyl-[5-(3,4,5-trimethoxy-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(2-methoxy-pyridin-4-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-fS-CS-methoxy-pyridin^-yO-benzooxazol^-ylJ-amine;
Cyclohexyl-[5-(6-methoxy-pyridin-2-yl)-benzooxazol-2-yl]-amine;
5-(2-Cyclohexylamino-benzooxazol-5-yl)-2-methoxy-benzonitrile;
5-(2-Cyclohexylamino-benzooxazol-5-yl)-lH-pyridin-2-one;
5-(2-Cyclohexylamino-benzooxazol-5-yl)-l -methyl-lH-pyridin-2-one;
[3-(2-Cyclohexylamino-benzooxazol-5-yl)-phenyl]-methanol;
4-(2-Cyclohexylamino-benzooxazol-5-yl)-benzamide; l-[5-(2-Cyclohexylamino-benzooxazol-5-yl)-2,3-dihydro-indol-l-yl]-ethanone;
6-(2-Cyclohexylamino-benzooxazol-5-yl)-3,4-dihydro-lH-quinolin-2-one;
5-(2-Cyclohexylamino-benzooxazol-5-yl) ' -methyl- l,3-dihydro-indol-2-one; Cyclohexyl-[5-(l -methyl-1 H-indol-6-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(2-methyl-lH-benzoimidazol-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(2-methyl-2H-indazol-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(7-methyl-lH-indazol-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(2-methyl-2H-indazol-4-yl)-benzooxazol-2-yl]-amine;
Cyclopentyl-[5-(l -methyl-1 H-indol-5-yl)-benzooxazol-2-yl]-amine;
Indan- 1 -yl-[5 -( 1 -methyl-1 H-indol-5 -yl)-benzooxazol-2-yl] -amine;
2-(4,4-Difluoro-piperidin-l-yl)-5-(l -methyl-1 H-indol-5-yl)-benzooxazole;
2-((2S,6R)-2,6-Dimethyl-moφholin-4-yl)-5-(l-methyl-lH-indol-5-yl)-benzooxazole;
2-((2S,6S)-2,6-Dimethyl-moφholin-4-yl)-5-(l -methyl- lH-indol-5-yl)-benzooxazole;
2-(4-Methoxy-piperidin- 1 -yl)-5 -( 1 -methyl-1 H-indol-5 -yl)-benzooxazole;
5-(l-Methyl-lH-indol-5-yl)-2-(4-trifluoromethyl-piperidin-l -yl)-benzooxazole;
5-( 1 -Methyl- 1 H-indol-5-yl)-2-( 1 -oxo-1 $l%4&-thiomoφholin-4-yl)-benzooxazole;
Cyclohexyl-[5-(lH-indol-6-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(2-methyl-lH-indol-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(lH-pyrrolo[2,3-b]pyridin-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(l -methyl-1 H-benzoimidazol-5-yl)-benzooxazol-2-yl]-amine;
[5-(lH-Benzoimidazol-5-yl)-benzooxazol-2-yl]-cyclohexyl-amine;
Cyclohexyl-fS-OH-indazol-S-y^-benzooxazol^-ylj-amine;
Cyclohexyl-[5 -( 1 -methyl-1 H-indazol-4-yl)-benzooxazol-2-yl] -amine;
Cyclohexyl-fS-P-methyl-lH-indazol-S-y^-benzooxazol^-yll-amine;
Cyclohexyl-[5-(2-methyl-2H-indazol-6-yl)-benzooxazol-2-yl]-amine;
5-(2-Cyclohexylamino-benzooxazol-5-yl)-2-hydroxy-benzonitrile;
(5-Benzothiazol-5-yl-benzooxazol-2-yl)-cyclohexyl-amine;
Cyclohexyl-(5-quinolin-6-yl-benzooxazol-2-yl)-amine;
6-(2-Cyclohexylamino-benzooxazol-5-yl)-3-methyl-3,4-dihydro-lH-quinazolin-2-one;
6-(2-Cyclohexylamino-benzooxazol-5-yl)- 1 ,4-dihydro-benzo[d] [ 1 ,3]oxazin-2-one;
[5-(l -Methyl-1 H-indol-5-yl)-benzooxazol-2-yl]-(4-trifluoromethyl-phenyl)-amine;
(4-Fluoro-phenyl)-[5-(l -methyl-1 H-indol-5-yl)-benzooxazol-2-yl]-amine;
(4-Methoxy-phenyl)-[5-(l -methyl-1 H-indol-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(3-methyl-[l ,2,4]triazolo[4,3-a]pyridin-6-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-{5-[4-(l -methoxy-ethyl)-phenyl]-benzooxazol-2-yl} -amine;
Cyclohexyl-[5-(3-methoxymethyl-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(l-ethyl-lH-indol-5-yl)-benzooxazol-2-yl]-arnine;
Cyclohexyl-{5-[l -(2-methoxy-ethyl)-lH-indol-5-yl]-benzooxazol-2-yl} -amine;
2-[5-(2-Cyclohexylamino-benzooxazol-5-yl)-indol-l-yl]-acetamide;
Cyclohexyl-fS-Cl -oxetan-S-yl-lH-indol-S-yO-benzooxazol^-ylj-amine;
Cyclohexyl-[5-(lH-pyrrolo[3,2-b]pyridin-6-yl)-benzooxazol-2-yl]-amine;
[5-(l -Methyl-1 H-indol-5-yl)-benzooxazol ^ yl]-(lH-pyrazol-3-yl)-amine; 2-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-l,2,3,4-tetrahydro-isoquinoline;
Cycloheptyl-[5 -( 1 -methyl- 1 H-indol-5 -yl)-benzooxazol-2-yl] -amine;
2-Azepan-l -yl-5-( 1 -methyl- 1 H-indol-5 -yl)-benzooxazole;
2-Azetidin- 1 -yl-5-( 1 -methyl- 1 H-indol-5 -yl)-benzooxazole;
Cyclohexyl-[5 -( 1 -methyl- 1 H-indol-5-yl)-benzooxazol-2-yl] -amine;
5 -( 1 -Methyl- 1 H-indol-5-yl)-2-pyrrolidin- 1 -yl-benzooxazole;
2-(l,3-Dihydro-isoindol-2-yl)-5-(l-methyl-lH-indol-5-yl)-benzooxazole;
2-(2,3-Dihydro-indol-l -yl)-5-(l-methyl-lH-indol-5-yl)-benzooxazole;
Cyclohexyl-ethyl-[5-(l-methyl-lH-indol-5-yl)-benzooxazol-2-yl]-amine;
[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-piperidin-l-yl-amine;
Cyclohexyl-fS-O-methoxy^-methoxymethyl-phenyO-benzooxazol^-ylJ-amine;
Cyclohexyl-[5-(3-ethoxy-4-ethoxymethyl-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-methyl-[5-(l-methyl-lH-indol-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-(2-methoxy-ethyl)-[5-(l-methyl-lH-indol-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(4-ethoxymethyl-3-methoxy-phenyl)-benzooxazol-2-yl]-amine;
2-Methyl-5-[5-(l-methyl-lH-indol-5-yl)-benzooxazol-2-yl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3- c]pyridine;
2-(Hexahydro-cyclopenta[c]pyrrol-2-yl)-5 -( 1 -methyl- 1 H-indol-5 -yl)-benzooxazole;
Cyclohexyl-[5-(3-ethoxy-4-methoxy-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(4-methoxy-3-methoxymethyl-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(3-ethoxymethyl-4-methoxy-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(4-ethoxy-3-ethoxymethyl-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(3,4-diethoxy-phenyl)-benzooxazol-2-yl]-amine;
2-(l ,3-Dihydro-isoindol-2-yl)-5-imidazo[l,2-a]pyridin-6-yl-benzooxazole;
5-(3,4-Dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-(l,3-dihydro-isoindol-2-yl)-benzooxazole;
2-( 1 ,3 -Dihydro-isoindol-2-yl)-5 -( 1 -methyl- 1 H-indazol-5 -yl)-benzooxazole;
2-(5,7-Dihydro-pyrrolo[3,4-b]pyridin-6-yl)-5-(l-methyl-lH-indol-5-yl)-benzooxazole;
7-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-5,6,7,8-tetrahydro-imidazo[l ,2-a]pyrazine;
2-(3 ,4-Dihydro- 1 H-pyrrolo[ 1 ,2-a]pyrazin-2-yl)-5 -( 1 -methyl- 1 H-indol-5 -yl)-benzooxazole;
2-(l,3-Dihydro-isoindol-2-yl)-5-(4-methoxymethyl-phenyl)-benzooxazole;
2-(l ,3-Dihydro-isoindol-2-yl)-5-(l-methyl-lH-indazol-4-yl)-benzooxazole;
2-(l,3-Dihydro-isoindol-2-yl)-5-(l-ethyl-lH-indol-5-yl)-benzooxazole;
2-(l,3-Dihydro-isoindol-2-yl)-5-(3-methoxy-phenyl)-benzooxazole;
2-(l ,3-Dihydro-isoindol-2-yl)-5-(3-methoxy-4-methoxymethyl-phenyl)-benzooxazole;
2-(l ,3-Dihydro-isoindol-2-yl)-5-(2-methoxy-pyridin-4-yl)-benzooxazole;
7-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-5,6,7,8-tetrahydro-imidazo[l,5-a]pyrazine;
6-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
7-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-5,6,7,8-tetrahydro-[l,7]naphthyridine;
2-(Hexahydro-pyrrolo[l ,2-a]pyrazin-2-yl) c (1 -methyl-lH-indol-5-yl)-benzooxazole; 2-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-l,2,3,4-tetrahydro-[2,7]naphthyridine;
(4,4-Difluoro-cyclohexyl)-[5 -( 1 -methyl- 1 H-indol-5 -yl)-benzooxazol-2-yl] -amine;
2-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-5-(l-methyl-lH-indol-5-yl)-benzooxazole;
S-fS-Cl-Methyl-lH-indol-S-yO-benzooxazol^-ylJ^^^J-tetrahydro-thiazolofS^-cJpyridine;
2-Methyl-5-[5-(l-methyl-lH-indol-5-yl)-benzooxazol-2-yl]-4,5,6,7-tetrahydro-oxazolo[5,4- cjpyridine;
5-[2-(l ,3-Dihydro-isoindol-2-yl)-benzooxazol-5-yl]-2-hydroxy-benzonitrile;
6-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-5,6,7,8-tetrahydro-[l,6]naphthyridine;
7-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-5,6,7,8-tetrahydro-[l,2,4]triazolo[l ,5- a]pyrazine;
2-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-l,2,3,4-tetrahydro-[2,6]naphthyridine;
2-(4-Isopropyl-piperazin- 1 -yl)-5 -( 1 -methyl- 1 H-indol-5 -yl)-benzooxazole;
2,2,2-Trifluoro- 1 - {4-[5 -( 1 -methyl- 1 H-indol-5 -yl)-benzooxazol-2-yl] -piperazin- 1 -yl } -ethanone;
2-(l,3-Dihydro-pyrrolo[3,4-c]pyridin-2-yl)-5-(l-methyl-lH-indol-5-yl)-benzooxazole;
5-(l-Methyl-lH-indol-5-yl)-2-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-benzooxazole;
7-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- a]pyrazine;
5-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-4,5,6,7-tetrahydro-[l,2,3]triazolo[l,5- a]pyrazine;
2-( 1 ,3-Dihydro-isoindol-2-yl)-5 -( 1 -oxetan-3 -yl- 1 H-indol-5 -yl)-benzooxazole;
2-(l,3-Dihydro-isoindol-2-yl)-5-(3-ethoxy-4-ethoxymethyl-phenyl)-benzooxazole;
Methyl-[5-(l-methyl-lH-indol-5-yl)-benzooxazol-2-yl]-amine;
5-( 1 -Methyl- 1 H-indol-5-yl)-2-(4-phenyl-piperazin- 1 -yl)-benzooxazole;
5 -( 1 -Methyl- 1 H-indol-5 -yl)-2 -piperazin- 1 -yl-benzooxazole; l-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-l,2,3,4-tetrahydro-quinoline;
2-(8-Aza-spiro[4.5]dec-8-yl)-5-(l-methyl-lH-indol-5-yl)-benzooxazole;
2-{5-[2-(l,3-Dihydro-isoindol-2-yl)-benzooxazol-5-yl]-indol-l-yl}-acetamide;
2-(2-Aza-spiro[4.4]non-2-yl)-5-(l-methyl-lH-indol-5-yl)-benzooxazole;
[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-[l,3,4]thiadiazol-2-yl-amine;
5-(l-Methyl-lH-indol-5-yl)-2-[4-(2,2,2-trifluoro-ethyl)-piperazin-l-yl]-benzooxazole;
3-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-3-aza-spiro[5.5]undecane;
(4,5-Dimethyl-thiazol-2-yl)-[5-(l -methyl-lH-indol-5-yl)-benzooxazol-2-yl]-amine;
2-(2,3-Dihydro-pyrrolo[2,3-b]pyridin-l-yl)-5-(l-methyl-lH-indol-5-yl)-benzooxazole;
2-(4,4-Dimethyl-piperidin- 1 -yl)-5 -( 1 -methyl- 1 H-indol-5 -yl)-benzooxazole;
5-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-4,5,6,7-tetrahydro-pyrazolo[l ,5-a]pyrazine;
[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-thiophen-2-yl-amine;
5-(l-Methyl-lH-indol-5-yl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-benzooxazole;
6-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-2-trifluoromethyl-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidine; and 3-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-2,3,4,5-tetrahydro-lH-benzo[d]azepine; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof.
[00234] With regard to compounds of formula I, in certain embodiments, the compound is selected from:
2-(l,3-Dihydro-isoindol-2-yl)-5-(l-methyl-lH-indazol-5-yl)-benzooxazole;
2-(l,3-Dihydro-isoindol-2-yl)-5-(l-ethyl-lH-indol-5-yl)-benzooxazole;
2-(l,3-Dihydro-isoindol-2-yl)-5-(l -methyl-lH-indazol-4-yl)-benzooxazole;
2-(l ,3-Dihydro-isoindol-2-yl)-5-(l-oxetan-3-yl-lH-indol-5-yl)-benzooxazole;
2-(l,3-Dihydro-isoindol-2-yl)-5-(2-methoxy-pyridin-4-yl)-benzooxazole;
2-(l,3-Dihydro-isoindol-2-yl)-5-(4-methoxymethyl-phenyl)-benzooxazole;
[5-(l-Ethyl-lH-indol-5-yl)-benzooxazol-2-yl]-phenyl-amine;
2-(l,3-Dihydro-isoindol-2-yl)-5-(l-methyl-lH-indol-5-yl)-benzooxazole;
2-( 1 ,3 -Dihydro-isoindol-2-yl)-5 -(3 -methoxy-4-methoxymethyl-phenyl)-benzooxazole;
2-(l,3-Dihydro-isoindol-2-yl)-5-imidazo[l,2-a]pyridin-6-yl-benzooxazole;
2-(2,3-Dihydro-indol-l -yl)-5-(l-methyl-lH-indol-5-yl)-benzooxazole;
2-{5-[2-(l,3-Dihydro-isoindol-2-yl)-benzooxazol-5-yl]-indol-l-yl}-acetamide;
2-(l ,3-Dihydro-isoindol-2-yl)-5-(3-methoxy-phenyl)-benzooxazole;
5-(3,4-Dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-2-(l,3-dihydro-isoindol-2-yl)-benzooxazole;
2-(3 ,4-Dihydro- 1 H-pyrrolo[ 1 ,2-a]pyrazin-2-yl)-5 -( 1 -methyl- 1 H-indol-5-yl)-benzooxazole;
[5-(l-Oxetan-3-yl-lH-indol-5-yl)-benzooxazol-2-yl]-phenyl-amine;
Cyclohexyl-[5 -( 1 H-indazol-5 -yl)-benzooxazol-2-yl] -amine;
[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-phenyl-amine;
Cyclohexyl-fS-Cl-methyl-lH-indazol^-y^-benzooxazol^-y^-amine;
5-(2-Cyclohexylamino-benzooxazol-5-yl)-2-hydroxy-benzonitrile;
2-[5-(l-Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-l,2,3,4-tetrahydro-isoquinoline;
[5-(lH-Indol-5-yl)-benzooxazol-2-yl]-phenyl-amine;
Cyclohexyl-[5 -( 1 -methyl- 1 H-indazol-5 -yl)-benzooxazol-2-yl] -amine;
5-( 1 -Methyl- 1 H-indol-5-yl)-2-(4-phenyl-piperazin- 1 -yl)-benzooxazole;
Methyl-[5 -( 1 -methyl- 1 H-indol-5 -yl)-benzooxazol-2-yl] -phenyl-amine;
[5-(3,4-Dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-benzooxazol-2-yl]-phenyl-amine;
Cyclohexyl-[5-(3-methyl-lH-indazol-5-yl)-benzooxazol-2-yl]-amine;
2-(2,3-Dihydro-pyrrolo[2,3-b]pyridin-l-yl)-5-(l-methyl-lH-indol-5-yl)-benzooxazole;
Cyclohexyl-fS-CT-methyl-lH-indazol-S-yO-benzooxazol^-ylJ-amine;
2-[5-(2-Phenylamino-benzooxazol-5-yl)-indol-l -yl]-acetamide; and
(4-Fluoro-phenyl)-[5-(l -methyl-lH-indol-5-yl)-benzooxazol-2-yl]-amine; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof. [00235] With regard to compounds of formula I, in certain embodiments, the compound is selected from:
Cyclohexyl-[5 -(2,3 -dihydro-benzofuran-5 -yl)-benzooxazol-2-yl] -amine;
[4-(2-Cyclohexylamino-benzooxazol-5-yl)-phenyl]-carbamic acid methyl ester;
Cyclohexyl-[5-(4-methoxy-3-methyl-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(l-methyl-lH-indazol-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(3,5-dimethoxy-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(2-methoxy-pyridin-4-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5 -( 1 -methyl- 1 H-indol-6-yl)-benzooxazol-2-yl] -amine;
Cyclohexyl-[5-(2-methyl-2H-indazol-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-^-CT-methyl-lH-indazol-S-yO-beiizooxazol^-ylJ-amine;
Cyclohexyl-[5-(lH-indol-6-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(2-methyl-lH-indol-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(lH-pyrrolo[2,3-b]pyridin-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(lH-indazol-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(l-methyl-lH-indazol-4-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(3-methyl-lH-indazol-5-yl)-benzooxazol-2-yl]-amine;
(5-Benzo[d]isoxazol-5-yl-benzooxazol-2-yl)-cyclohexyl-amine;
Cyclohexyl-(5-quinolin-6-yl-benzooxazol-2-yl)-amine;
6-(2-Cyclohexylamino-benzooxazol-5-yl)-3-methyl-3,4-dihydro-lH-quinazolin-2-one;
Cyclohexyl-[5-(l-ethyl-lH-indol-5-yl)-benzooxazol-2-yl]-amine;
2-[5-(2-Cyclohexylamino-benzooxazol-5-yl)-indol-l-yl]-acetamide;
Cyclohexyl-[5 -( 1 -oxetan-3 -yl- 1 H-indol-5-yl)-benzooxazol-2-yl] -amine;
Cyclohexyl-[5-(lH-pyrrolo[3,2-b]pyridin-6-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(l -methyl-lH-indol-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-ethyl-fS-Cl-methyl-lH-indol-S-yO-benzooxazol^-ylJ-amine;
Cyclohexyl-[5-(3-methoxy-4-methoxymethyl-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(3-ethoxy-4-ethoxymethyl-phenyl)-benzooxazol-2-yl]-amine;
Cyclohexyl-methyl-[5-(l-methyl-lH-indol-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-(2-methoxy-ethyl)-[5-(l-methyl-lH-indol-5-yl)-benzooxazol-2-yl]-amine;
Cyclohexyl-[5-(4-ethoxymethyl-3-methoxy-phenyl)-benzooxazol-2-yl]-amine;
2-[5-(l -Methyl-lH-indol-5-yl)-benzooxazol-2-yl]-l ,2,3,4-tetrahydro-isoquinoline;
2-( 1 ,3 -Dihydro-isoindol-2-yl)-5 -( 1 -methyl- 1 H-indol-5 -yl)-benzooxazole; and
2-(2,3-Dihydro-indol-l-yl)-5-(l -methyl-lH-indol-5-yl)-benzooxazole; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof.
[00236] Additional embodiments within the scope of the present invention are set forth in non-limiting fashion elsewhere herein and in the examples. It should be understood that these examples are for illustrative purposes only and are not to be "onstrued as limiting this invention in any manner. [00237] In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, and N-alkylmorpholinyl esters and the like. [00238) Certain compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Preferred are the Ci to C8 Ci-C6alkyl, C2-Cg alkenyl, aryl, C7-C12 substituted aryl, and C7-Ci2 arylalkyl esters of the compounds of the invention.
PHARMACEUTICAL COMPOSITIONS
[00239] When employed as pharmaceuticals, the compounds of this invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. In certain embodiments, the pharmaceutical composition may comprise a compound of the invention in combination with one or more compounds or compositions of like therapeutic utility and effect. [00240] Generally, the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of 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.
[00241] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, the compounds of this invention are preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
[00242] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "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. Typical unit dr°αge forms include prefϊlled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
In such compositions, the furansulfonic acid compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form. [00243] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
[00244] Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable carriers known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
[00245] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention. [00246] The compounds of this invention can also be administered by a transdermal device.
Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
[00247] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's The Science and Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins, which is incorporated herein by reference. [00248] The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
[00249] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.
Formulation 1 - Tablets [00250] A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press.
Formulation 2 - Capsules
[00251] A compound of the invention may be admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule).
Formulation 3 - Liquid
[00252] A compound of the invention (125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (1 1 :89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water may then added to produce a total volume of 5 mL.
Formulation 4 - Tablets
[00253] A compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press.
Formulation 5 - Injection
[00254] A compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
Formulation 6 - Topical
[00255] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.
METHODS OF TREATMENT
[00256] The present compounds are used as therapeutic agents for the treatment of conditions in mammals. Accordingly, the compounds and pharmaceutical compositions of this invention find use as therapeutics for preventing and/or treating neurodegenerative, autoimmune and inflammatory conditions in mammals including humans.
[00257] In a method of treatment aspect, this invention provides a method of treating a mammal susceptible to or afflicted with a condition associated with arthritis, asthma, myocardial infarction, inflammatory bowel disease and autoimmune disorders, which method comprises administering an effective amount of one or more of the pharmaceutical compositions just described. [00258] In additional method of treatment aspects, this invention provides methods of treating a mammal susceptible to or afflicted with neurodegenerative diseases and disorders such as, for example Parkinson's disease, Alzheimer's disease and multiple sclerosis; sleep disorders, anxiety and depression disorders, weight and eating disorders, addiction, spasticity, and glaucoma; diseases and disorders which are mediated by or result in neuro;"flammation such as, for example encephalitis; centrally-mediated neuropsychiatric diseases and disorders such as, for example depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction such as, for example urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders such as, for example, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflammation such as, for example rheumatoid arthritis and osteoarthritis, myocardial infarction, various autoimmune diseases and disorders; itch / pruritus such as, for example psoriasis; obesity; lipid disorders; cancer; and renal disorders method comprises administering an effective condition-treating or condition-preventing amount of one or more of the pharmaceutical compositions just described.
[00259] In yet further method of treatment aspects, this invention provides a method of treating a mammal susceptible to or afflicted with a condition that gives rise to pain responses or that relates to imbalances in the maintenance of basal activity of sensory nerves. The present compounds have use as analgesics for the treatment of pain of various geneses or etiology, for example acute, inflammatory pain (such as pain associated with osteoarthritis and rheumatoid arthritis); various neuropathic pain syndromes (such as post-herpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillian Barre syndrome, fibromyalgia, phantom limb pain, post-mastectomy pain, peripheral neuropathy, HIV neuropathy, and chemotherapy-induced and other iatrogenic neuropathies); visceral pain, (such as that associated with gastroesophageal reflex disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and various gynecological and urological disorders), dental pain and headache (such as migraine, cluster headache and tension headache).
[00260] As a further aspect of the invention there is provided the present compounds for use as a pharmaceutical especially in the treatment or prevention of the aforementioned conditions and diseases. We also provide the use of the present compounds in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases.
[00261] Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient. [00262] For the prevention and/or treatment of long-term conditions, such as neurodegenerative and autoimmune conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg. [00263] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses. [00264] When used to prevent the onset of a neurodegenerative, autoimmune or inflammatory condition, the compounds of this invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
[00265] The compounds of this invention can be administered as the sole active agent or they can be administered in combination with other agents, including other active amines and derivatives.
GENERAL SYNTHETIC PROCEDURES
[00266] The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. See, e.g., Synthetic Schemes, below. 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. [00267] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. [00268] The compounds of this invention, for example, may be prepared by the reaction of a chloro derivative with an appropriately substituted amine and the product isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography or HPLC. The following schemes are presented with details as to the preparation of representative fused heterocyclics that have been listed hereinabove. The compounds of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
[00269] Various naphthyridines can be prepared using a general procedures or synthetic schemes described below. The following scheme specifically depicts the preparation of Compound 1, below. [00270] The syntheses of representative compounds of this invention are carried out in accordance with the methods set forth above and using the appropriate reagents, starting materials, and purification methods known to those skilled in the art.
Experimental
Representative Synthetic Scheme 1
Figure imgf000049_0001
wherein ArI is R3 and R3 is as described herein.
Preparation of Intermediate 1-1 5-Chlorobenzo[«floxazole-2-thiol (l-l):
[00271] To a stirred solution of 2-amino-4-chlorophenol (20.0 g, 139.3 mmol) in EtOH (500 mL) was added KOH (18.36 g, 327.3 mmol) followed by CS2 (126.7 mL, 1318 mmol) and refluxed for 4 h. Volatiles were removed and the residue was diluted with water ( 100 mL) and acidified with 2 M HCl (50 mL) and extracted with CH2Cl2 (2 x 250 mL). The organic phase was dried over anhydrous Na2Sθ4 and concentrated under reduced pressure to give 23.5 g (91%) of 1-1 as brown solid. 1H NMR (400 MHz, MeOD) δ 7.35-7.33 (m, IH), 7.25-7.22 (m, 2H), 3.31-3.30 (m, IH); MS: ESI m/∑ 186 [M + H]+.
Preparation of Intermediate 1-2 5-Chloro-N-phenylbenzo[</loxazol-2-ainine (1-2)
[00272] To the suspension of 18 (9.40 g, 50.64 mmol) in toluene (120 mL) was added aniline
(11.5 mL, 126.6 mmol) and refluxed for 48 h. The solvent was evaporated and residue was purified by silica gel column chromatography (gradient: hexanes to 30% ethyl acetate in hexanes) to afford 1-2 as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J= 8.0 Hz, 2H), 7.46-7.40 (m, 3H), 7.25 (s, 2H), 7.17-7.09 (m, 2H); MS: ESI m/z 245 [M + H]+.
General Synthesis of N-phenylbenzo[d]oxazol-2-amines (1-3) (Scheme 1)
Method A
Microwave-assisted Suzuki coupling with boronic acids or boronic esters 5-(l-Methyl-lH-indol-5-yl)-7V-phenylbenzo[</]oxazol-2-amine (Compound 27)
Figure imgf000049_0002
[00273] In a 5mL microwave vial, 5-chloro-N-phenylbenzo[cT]oxazol-2-amine (1-2) (7.00 mg,
0.029 mmol), 1 -methyl- lH-indol-5-yl boronic acid (7.5 mg, 0.043 mmol), Cs2CO3 (37.3 mg, 0.11 mmol), Bu4NI (1.27 mg, 0.0034 mmol) and dihydrogen dichlorobis(di-tert-butyl phoshinito-/rP)palladate (2-) (0.4 mg, 0.0009 mmol) were dissolved in H2O (0.09 mL) and DMF (0.4 mL). The reaction mixture was heated under microwave irradiation at 150 °C for 20 mins. After allowing it to cool to room temperature, the mixture was purified directly by preparative high-performance liquid chromatography to give the title compound (3 mg, 29%) as a solid. 5-(Benzo[</] [l,3]dioxol-5-yl)-Λ'-phenylbenzo[</]oxazol-2-amine (Compound 29)
Figure imgf000050_0001
[00274] The compound was synthesized using Method A. After completion of the reaction and cooling, the mixture was diluted with EtOAc (5 mL) and washed with brine (5 mL). The aqueous layer was extracted with EtOAc (2 mL) and the combined organic extracts were washed with brine (3 x 5 mL), dried (Na2SO4), filtered and concentrated under vacuum. Purification by preparative HPLC (MeCN:H2O buffered to pH 10 with 10 mM Et2NH) gave the desired product (3.8 mg, 40%) as a solid. 1H NMR (400 MHz; CDCl3) 7.61-7.66 (m, 3H), 7.43 (t with fine str, J = 8.0 Hz, 2H), 7.36 (d, J= 8.3 Hz, IH), 7.28 (dd, J= 1.8 Hz, J= 8.3 Hz, 1 H), 7.13 (t with fine str, J= 7.4 Hz, IH), 7.04-7.10 (m, 2H), 6.89 (d, J= 7.9 Hz, IH), 1.59 (br s, NH and H2O, IH). LC/MS: 3.59 min on 6.5 min run; ESI m/z 331.3 [M+H].
[5-(3,4-Dihydro-2H-benzo[b] [l,4]dioxepin-7-yl)-benzooxazol-2-yl]-phenyl-amine (Compound 42)
Figure imgf000050_0002
[00275] The compound was synthesized using Method A. After completion of the reaction and cooling, the mixture was diluted with EtOAc (5 mL) and washed with brine (5 mL). The aqueous layer was extracted with EtOAc (2 mL) and the combined organic extracts were washed with brine (2 x 5 mL), dried (Na2SO4), filtered and concentrated under vacuum. Purification by preparative HPLC (10-95% MeCNiH2O buffered to pH 10 with 10 mM Et2NH) gave the desired product.
5-(4-Methoxymethyl-phenyl)-benzooxazol-2-yl]-phenyl-amine (Compound 44)
Figure imgf000050_0003
[00276] The compound was synthesized using Method A. After completion of the reaction and cooling, the mixture was diluted with EtOAc (5 mL) and washed with brine (5 mL). The aqueous layer was extracted with EtOAc (2 mL) and the combined organic extracts were washed with brine (2 x 5 mL), dried (Na2SO4), filtered and concentrated under vacuum. Purification by preparative HPLC (10-95% MeCNiH2O buffered to pH 10 with 10 mM Et2NH) gave the desired product.
5-(lH-indol-5-yl)-N-phenylbenzo[rf]oxazol-2-amine (Compound 50)
Figure imgf000051_0001
[00277] The compound was synthesized using Method A. After completion of the reaction and cooling, the mixture was diluted with EtOAc (5 mL) and washed with brine (5 mL). The aqueous layer was extracted with EtOAc (2 mL) and the combined organic extracts were washed with brine (2 x 5 mL), dried (Na2SO4), filtered and concentrated under vacuum. Purification by preparative HPLC (10-95% MeCN:H2O buffered to pH 10 with 10 mM Et2NH) gave the desired product. ESI m/z 326.5 [M+H].
Representative Synthetic Scheme 2
Suzuki reaction
Figure imgf000051_0003
Figure imgf000051_0002
1-2 2-1 1-3 wherein ArI is R and R is as described herein.
Preparation of Intermediate 2-1
7V-phenyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[</]oxazol-2-amine (2-1). [00278] A 4 mL vial was charged with bis(dibenzylideneacetone)palladium(0) (12 mg, 0.020 mmol) and tricyclohexylphosphine (13 mg, 0.045 mmol). The system was evacuated then was charged with 1 ,4-dioxane (1.2 mL, 15 mmol) and purged with nitrogen. The resulting mixture was stirred at room temperature for 50 minutes then a mixture of bis(pinacolato)diboron (55 mg, 0.22 mmol), 5-chloro-N- phenylbenzo[d]oxazol-2-amine (50 mg, 0.20 mmol), and potassium acetate (30 mg, 0.31 mmol) were added and the mixture was heated at 80 0C for 41 hours. After cooling to room temperature, the mixture was diluted with DCM (5 mL) then washed with a mixture of water (2 mL) and brine (5 mL). The aqueous layer was back extracted with DCM (5 mL) and the combined organics were dried (Na2SO4), filtered and evaporated. The residue was purified by silica gel column chromatography (hexanes to 25% EtOAc in hexanes) to obtain an off white solid (22 mg, 32% yield). 1H NMR (400 MHz, CDCl3) δ 7.95 (s, IH), 7.58-7.66 (m, 3H), 7.40 (dd, J= 7.5 Hz, J= 8.5 Hz, 2H), 7.35 (d, J= 8.0 Hz, IH), 7.26 (s, IH), 7.12 (t with fine str., J= 7.4 Hz, IH), 1.36 (s, 12 H) MS: ESI m/z 337 [M+H]+.
General Synthesis of N-phenylbenzo[</]oxazol-2-amines (1-3) (Scheme 2)
Method B
Suzuki coupling with arylhalides or arlytriflates 5-(6-Methoxypyridin-3-yl)-7V-phenylbenzo [d\ oxazol-2-amine (Compound 55)
Figure imgf000052_0001
[00279] To a 0.5-2 niL microwave vial was added N-phenyl-5-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)benzo[(/]oxazol-2-amine (11 mg, 0.033 mmol), cesium carbonate (53 mg, 0.16 mmol), tetra-N-butylammonium iodide (1.2 mg, 0.0033 mmol), dihydrogen dichlorobis(di-tert-butyl phoshinito- £P)palladate (2-) (1.6 mg, 0.0033 mmol), water (150 μL, 8.3 mmol), N,N-dimethylformamide (600 μL, 8 mmol), and 5-bromo-2-methoxypyridine (8.5 uL, 0.065 mmol). The system was purged with nitrogen then heated under microwave irradiation at 150 °C for 20 minutes. After cooling to room temperature, the mixture was diluted with EtOAc (5 mL) and washed with brine (5 mL). The aqueous layer was back extracted with EtOAc (2 mL) and the combined organics were washed with brine (2 x 5 mL), dried (Na2SO4), filtered and evaporated. The residue was purified by preparative HPLC [acetonitrile:water buffered to pH 10 with 10 mM diethylamine in water] to afford the title compound (3.66 mg, 35%) as a solid. 1H NMR (400 MHz, J6-DMSO) 10.69 (S, IH), 8.51 (d with fine str., J = 1.5 Hz, IH), 8.05 (dd, J = 2.6 Hz, J= 8.6 Hz, IH), 7.78 (dd, J= 1.0 Hz, J= 8.6 Hz, 2H), 7.74 (d, J= 1.6 Hz, IH), 7.57 (d, J= 8.3 Hz, IH), 7.35-7.43 (m, 3H), 7.05 (t with fine str., J= 7.4 Hz, IH), 6.91 (d with fine str., J = 8.6 Hz, IH), 3.90 (s, 3H). ESI m/z 318.3 [M+H].
5-(l-Ethyl-l//-indol-5-yl)-./V-phenylbenzo[</]oxazol-2-amine (Compound 63)
Figure imgf000052_0002
[00280] The compound was synthesized using Method B. After completion of the reaction and cooling, the product was precipitated from the mixture by slow addition Of H2O (2 mL). The emerging solid was filtered and the filter cake purified by preparative HPLC [20-98% acetonitrile:water buffered to pH 10 with 10 mM diethylamine in water] to afford the title compound. ESI m/z 354.5 [M+H].
2-(5-(2-(Phenylamino)benzo [d] oxazol-5-yl)-lH-indol-l-yl)acetamide (Compound 67)
Figure imgf000052_0003
[00281] The compound was synthesized using Method B. After completion of the reaction and cooling, the product was precipitated from the mixture by slow addition of H2O (2 mL). The emerging solid was filtered and the filter cake purified by preparative HPLC [40-95% acetonitrile:water buffered to pH 10 with 10 mM diethylamine in water] to afford the title compound. ESI m/z 383.7 [M+H].
5-(l-(Oxetaii-3-yl)-lH-indol-5-yl)-./V-phenylbeiizo[</]oxazol-2-amine (Compound 68)
Figure imgf000053_0001
[00282] The compound was synthesized using Method B. After completion of the reaction and cooling, the product was precipitated from the mixture by slow addition of H2O (2 mL). The emerging solid was filtered and the filter cake purified by preparative HPLC [acetonitrile: water buffered to pH 10 with 10 mM diethylamine in water] to afford the title compound.
Representative Synthetic Scheme 3
2-A
Figure imgf000053_0002
mino-4-chIorophenol 18'
Suzuki reaction
Figure imgf000053_0003
Preparation of 5-chlorobenzo[</]oxazole-2-thiol (18')
[00283] To a stirred solution of 2-amino-4-chlorophenol (20.0 g, 139.3 mmol) in EtOH (500 mL) was added KOH (18.36 g, 327.3 mmol) followed by CS2 (126.7 mL, 1318 mmol) and refluxed for 4 h. Volatiles were removed and the residue was diluted with water (100 mL) and acidified with 2 M HCl (50 mL) and extracted with CH2Cl2 (2 x 250 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 23.5 g (91%) of 18' as brown solid. 1H NMR (400 MHz, MeOD) δ 7.35-7.33 (m, IH), 7.25-7.22 (m, 2H), 3.31-3.30 (m, IH); MS: ESI m/z 186 [M + H]+.
Preparation of 5-chloro-7V-cycIohexylbenzo[d]oxazol-2-amine (19')
[00284] To the suspension of 18' (9.40 g, 50.64 mmol) in toluene (120 mL) was added cyclohexylamine (11.5 mL, 101 mmol) and refluxed for 48 h. The solvent was evaporated and residue was purified by silica gel column chromatography (gradient: hexanes to 30% ethyl acetate in hexanes) to afford 19' (7.00 g, 74%) as a light orange solid. 1H NMR (400 MHz, CDCl3) δ 7.31 (s, IH), 7.13 (d, J = 12 Hz, IH), 6.99-6.97 (m, IH), 5.08 (bs, IH), 3.78-3.70 (m, IH), 2.14-2.1 1 (m, 2H), 1.81-1.76(m, 2H),
1.65-1.57 (m, 2H), 1.49-1.31 (m, 2H), 1.29-1.28 (m, 2H); MS: ESI m/z 251 [M + H]+.
General Procedure A' - microwave-assisted Suzuki coupling with boronic acids or boronic esters. Preparation of yV-cyclohexyl-5-(2,3-dihydrobenzo[Λ] [l,4]dioxin-6-yl)benzo[</]oxazol-2-aniine (Compound 16)
Figure imgf000054_0001
[00285] In a 5mL microwave vial, 5-chloro-N-cyclohexylbenzo[t/]oxazol-2-amine (20 mg, 0.08 mmol), dihydrobenzo[Z>][l,4]dioxin-6-yl boronic acd (21.5 mg, 0.12 mmol), CS2CO3 (100 mg, 0.3 mmol), Bu4NI (4 mg, 0.01 mmol) and dihydrogen dichlorobis(di-tert-butyl phosphino-AP)palladate (2-) (1 mg, 0.002 mmol) were dissolved in H2O (0.2 mL) and DMF (1 mL). The reaction mixture was heated under microwave irradiation at 150 0C for 20 mins. After allowing to cool to room temperature, the mixture was purified directly by preparative high-performance liquid chromatography [acetonitrile:water buffered to pH 10 with eluent used in a gradient system] to give the title compound (7.7 mg, 26%) as a solid.
Preparation of ./V-cyclohexyl-5-(l-methyl-l//-indazol-5-yl)benzo[</]oxazol-2-amine (Compound 60)
Figure imgf000054_0002
[00286] The compound was prepared using general procedure A'. After completion of the reaction, the mixture was diluted with EtOAc (5 mL) and washed with brine (5 mL). The aqueous layer was back-extracted with EtOAc (2 mL) and the combined organics were washed with brine (2 x 5 mL), dried (Na2SO4), filtered and evaporated. The crude product was dissolved in DMSO (450 μL) and purified by reverse-phase HPLC (40-95% acetonitrile: water gradient buffered with 10 mM diethylamine in the aqueous to pH 10). The combined pure fractions were concentrated under vacuum to afford the title compound as a solid (13.5 mg, 65%). LC/MS: 3.69 min on 6.5 min run; m/z = 346.9 (M + H)+. 1H NMR (400 MHz; J6-DMSO) 8.07 (s, IH), 7.96 (app t, J = 1.2 Hz, IH), 7.92 (d, J= 7.8 Hz, IH), 7.71-7.68 (m, 2H), 7.52 (d, J= 1.7 Hz, IH), 7.39 (d, J= 8.2 Hz, IH), 7.26 (dd, J= 8.2, 1.8 Hz, IH), 4.07 (s, 3H), 3.64- 3.50 (m, IH), 2.05-1.92 (m, 2H), 1.81-1.68 (m, 2H), 1.65-1.55 (m, IH), 1.40-1.25 (m, 4H), 1.25-1.10 (m, IH).
Representative Synthetic Scheme 4
Figure imgf000055_0001
Preparation of ΛLcyclohexyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[(/]oxazol-2-amine
[00287] A 100 mL flask was charged with bis(dibenzylideneacetone)palladium(0) (0.325 g, 0.565 mmol) and tricyclohexylphosphine (0.400 g, 1.43 mmol), sealed, evacuated and purged with nitrogen. The mixture was charged with 1 ,4-dioxane (43 mL) and stirred at room temperature for 30 minutes to obtain a clear deep red solution. A mixture of bis(pinacolato)diboron (2.02 g, 7.98 mmol), 5-chloro-N- cyclohexylbenzo[t/]oxazol-2-amine (2.00 g, 7.98 mmol), and potassium acetate (1.17 g, 12.0 mmol) were added and the mixture was heated at 80 0C for 65 hours. The reaction was quenched with water (1 mL) then filtered through celite and the filter cake was washed with EtOAc (2 x 75 mL) and water (75 mL). Volatiles were removed in vacuo and the residue was dissolved in EtOAc (150 mL) and washed with water (50 mL) followed by brine (50 mL), dried (Νa2SO4), filtered and evaporated. The product was purified by silica gel chromatography (0 to 30% EtOAc in hexanes) to obtain the product (1.44 g, 53%) as a solid; m/z = 343.1 (M + H)+. 1H NMR (400 MHz; CDCl3) δ 7.79 (s, IH), 7.52 (dd, J= 8.0, 1.0 Hz, IH), 7.23 (d, J = 7.9 Hz, IH), 4.95 (br. d, J= 6.5 Hz, IH), 3.82-3.69 (m, IH), 2.17-2.07 (m, 2H), 1.82-1.72 (m, 2H), 1.69-1.60 (m, IH), 1.51-1.16 (m, 5H), 1.34 (s, 12 H).
General Procedure B' - microwave-assisted Suzuki coupling with halies or "pseudo-halides". Preparation of cyclohexyl-[5-(l-ethyl-lH-indol-5-yl)-benzoxazol-2-yl]-amine (Compound 128)
Figure imgf000055_0002
[00288] To a 5 mL microwave vial was added 5-bromo-l-ethyl-lH-indole (13 mg, 0.06 mmol) and POPd (1.5 mg, 0.003 mmol). A solution of N-cyclohexyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)benzo[d]oxazol-2-amine (10 mg, 0.03 mmol) and tetra-N-butylammonium iodide (1.1 mg, 0.003 mmol) in N,N-dimethylformamide (600 μL), followed by a solution of cesium carbonate (38 mg, 0.12 mmol) in water (150 μL). The system was sealed and purged with nitrogen then irradiated in the microwave for 20 min at 150 0C. LC/MS indicates complete reaction. The product was precipitated out of solution with water (about 2 mL) and buffered to near neutral pΗ with 1 M NaH2PO4 (200 μL). After sitting over the weekend to fully precipiate, the solution was filtered and the residue was dissolved in DMSO (400 μL) and filtered. The vial was rinsed with DMSO (2 x 200 μL) and purified by reverse phase HPLC (acetonitrile: water gradient buffered with 10 mM diethyl amine in aqueous to pH 10). The product contains about 15% of an impurity. The fractions were evaporated and the residue purified by additional prep HPLC with a less steep gradient. The first couple of fractions were cleaned and the later fractions still contained some impurity. The impure fractions were purified one more time using this purification method. All clean fractions were combined and concentrated under vacuum to afford the title compound as a solid (4.2 mg, 40%). LC/MS: 3.73 min on 6.5 min run time; m/z = 360.4 (M + H)+; 1H NMR (400 MHz; 4-DMSO) 7.88 (br d, J= 7.8 Hz, IH), 7.76 (d, J= 1.5 Hz, IH), 7.53 (d, J= 8.6 Hz, IH), 7.46 (d, J = 1.7 Hz, IH), 7.43-7.38 (m, 2H), 7.36 (d, J= 8.2 Hz, IH), 7.22 (dd, J= 8.2, 1.8 Hz, IH), 6.47 (d with fin str, J= 3.0 Hz, IH), 4.23 (q, J= 7.2 Hz, 2H), 3.63-3.51 (m, IH), 2.04-1.94 (m, 2H), 1.80-1.68 (m, 2H), 1.64-1.56 (m, IH), 1.39 (t, J= 7.2 Hz, 3H), 1.41-1.25 (m, 4H), 1.25-1.11 (m, IH).
Representative Synthetic Scheme 5
Figure imgf000056_0001
2-Amino-4-bromophenol 20' 21'
Figure imgf000056_0002
wherein NRR' is X; and X is N-containing heterocycloalkyl.
Preparation 2-Amino-4-(l-methyl-lH-indol-5-yl)-phenol (20')
[00289] In a 250 mL flask, 2-Amino-4-bromo-phenol (3.22 g, 17.1 mmol), 1 -methyl- lH-indol-5- ylboronic acid (4.5 g, 26 mmol), Potassium carbonate (9.48 g, 68.6 mmol) and
Bis(triphenylphosphine)palladium(II) chloride (602 mg, 0.857 mmol) were added and the flask was degassed using vacuum/N2. The reaction was dissolved in degassed 1,4-Dioxane (30 mL,
400 mmol) and the flask was filed with N2 using vacuum (x2). The reaction mixture was heated for 16 hr at 1 100C. The reaction was concentrated in vacuo, neutralized to pΗ 6 with NaH2PO4 and concentrated in vacuo. The residue was purified by column chromatography (Hex:EtOAc, 20-60%) to yield the title product (1.07 g, 26 %) as a brown solid. MS: ESI m/z 239 [M + H].
Preparation of 5-(l-Methyl-l//-indol-5-yl)-benzoxazole-2-thiol (21')
[00290] To a solution of 2-amino-4-(l-methyl-lH-indol-5-yl)-phenol (700 mg, 3 mmol) in ethanol
(10 mL, 200 mmol), Potassium hydroxide (412.0 mg, 7.344 mmol) was added. The reaction mixture was soluble after 2 min and became dark brown. Then, carbon disulfide (1.590 mL, 26.44 mmol) was added and the reaction mixture was heated to reflux for 6h. The reaction mixture was concentrated in vacuo and the residue was dissolved in water and acidified with 12 M of hydrogen chloride in water (0.7344 rriL,
8.813 mmol). The precipitate formed was filtered and washed with water to yield the title product (750 mg, 91%) as a grey solid that was used without further purification into the next step. MS: ESI m/z 281 [M + H].
General Procedure C: 2-(l,3-Dihydro-isoindol-2-yl)-5-(l-methyl-lH-indol-5-yl)-benzoxazole (Compound 140)
Figure imgf000057_0001
[00291] A microwave vial was charged with 5-(l-methyl-lH-indol-5-yl)-benzoxazole-2 -thiol (20 mg, 0.07 mmol), isoindoline (26 mg, 0.21 mmol), and acetonitrile (0.2 mL). The mixture was heated in the microwave at 190 0C for 1 hr. The crude mixture was dissolved in DMSO, filtered and purified by preparative ΗPLC to yield the title product (4 mg) as a solid. LC-MS: 3.92 min; ESI m/z 366.3 [M+Η]. 1H-NMR (400 MHZ; 4-DMSO) 7.80 (d, J = 1.2 Hz, IH), 7.58 (d, J= 1.5 Hz, IH), 7.50 (d, J= 8.3 Hz, 2H), 7.47-7.43 (m, 3H), 7.38-7.35 (m, 3H), 7.31 (dd, J= 8.3, 1.8 Hz, IH), 6.47 (dd, J= 3.0, 0.6 Hz, IH), 4.97 (s, 4H), 3.82 (s, 3H).
2-(2,3-Dihydroindol-l-yl)-5-(l-methyl-lH-indol-5-yl)-benzoxazole (Compound 141)
Figure imgf000057_0002
[00292] The compound was synthesized according to General Procedure C to give the product (2 mg) as a solid. 1H-NMR (400 MHZ; </6-DMSO) 8.03 (d, J= 7.9 Hz, IH), 7.83 (s, IH), 7.71 (d, J= 1.7 Hz, IH), 7.61 (d, J= 8.3 Hz, 2H), 7.52 (d, J= 8.5 Hz, IH), 7.48 (dd, J= 8.4, 1.6 Hz, IH), 7.42 (dd, J= 8.3, 1.8 Hz, IH), 7.36 (d, J= 3.0 Hz, IH), 7.33-7.28 (m, 2H), 7.02 (t, J= 7.4 Hz, IH), 4.33 (t, J= 8.4 Hz, 2H), 3.82 (s, 3H). LC-MS: 4.15 min; ESI m/z 366.4 [M+H].
l-[5-(l-Methyl-lH-indol-5-yl)-benzoxazol-2-yl]-l,2,3,4-tetrahydro-quinoline (Compound 192)
Figure imgf000057_0003
[00293] The compound was synthesized according to General Procedure C except 1 ,4-dioxane
(0.2 mL) was used as solvent and the reaction was heated at 190 0C for 2 hr. The product was also purified twice by preparative ΗPLC to give the product (0.9 mg) as an oil. 1H-NMR (400 MHZ; db- DMSO) 8.04 (d, J= 8.2 Hz, IH), 7.81 (d, J= 1.2 Hz, IH), 7.67 (d, J= 1.6 Hz, IH), 7.54 (d, J= 8.3 Hz,
IH), 7.51 (d, J= 8.6 Hz, IH), 7.47 (dd, J= 8.4, 1.6 Hz, IH), 7.40 (dd, J= 8.3, 1.8 Hz, IH), 7.35 (d, J = 3.0 Hz, IH), 7.27 (bt, J= 8.8, IH), 7.21 (d, J= 7.4 Hz, IH), 7.06 (bt, J= 8.4 Hz, IH), 6.47 (d, J= 3.0 Hz, IH), 4.04 (t, J= 6.0 Hz, 2H), 3.82 (s, 3H), 3.50 (s, 2H), 2.831 (t, J= 6.1 Hz, 2H). LC-MS: 4.19 min; ESI m/z 380.1 [M+H].
Representative Synthetic Scheme 6
Figure imgf000058_0002
2-Amino-4-bromophenol
Suzuki reaction
Figure imgf000058_0001
5-Bromo-2-(l,3-dihydro-isoindol-2-yl)-benzoxazole
[00294] A microwave vial was charged with 5-bromo-benzooxazole-2-thiol (400 mg, 1.74 mmol), isoindoline (590 μL, 5.2 mmol), and acetonitrile (5.0 mL). The mixture was purged with nitrogen then heated in a microwave at 190 0C for 30 min (LCMS indicates product, a thioamide (H2S reacted with ACN and the resulting amide reacted with isoindoline) and a debrominated version of the desired product). After allowing to cool, the crude product was presorbed directly onto silica gel (6 g) and the mixture was purified by column chromatography on silica gel (4Og Isco cartridge) using hexane to DCM as eluent to give a solid (494 mg; contains about 85% desired product, 10% thioamide and 5% debromination by product). This material was presorbed onto silica gel (4g) and purifed by column chromatography (40g Isco cartridge) using hexanes to DCM as eluent to give the product (394 mg, 72%) as a solid. 1H NMR (400 MHz, CDCl3) 7.54 (br. d, J= 1.0 Hz, IH), 7.36 (s, 4H), 7.18 (d, J= 8.4 Hz, IH), 7.16 (dd, J= 1.7 Hz, J = 8.4 Hz, IH), 5.02 (s, 4H). LC/MS: 1.47 min on 2 min run; ESI m/z 315.3 [M+H].
General procedure D': 2-(l,3-Dihydro-isoindol-2-yl)-5-imidazo[l,2-α]pyridin-6-yl-benzoxazole (Compound 156)
Figure imgf000058_0003
[00295] A microwave vial was charged with 5-Bromo-2-(l,3-dihydro-isoindol-2-yl)-benzoxazole
(15 mg, 0.05 mmol), imidazo[l ,2-a]pyridin-6-ylboronic acid (15 mg, 0.1 mmol), POPd (2.4 mg, 0.005 mmol), tetra-N-butylammonium iodide (2.1 mg, 0.006 mmol) and Cs2CO3 (62 mg, 0.2 mmol). N,N- Dimethylformamide (0.7 mL) and water (0.18 mL) was added and the mixture was placed under an atmosphere of nitrogen (air was evacuated x 2). The mixture was heated in the microwave at 150 0C for 20 min. The crude mixture was dissolved in DMSO, filtered and purified by preparative HPLC to yield the title product (7 mg) as a solid. This product was repurified by preparative HPLC to yield the title product (2.5 mg) as a solid. 1H-NMR (300 MHz; Of6-DMSO) 8.90 (s, IH), 8.54 (s, IH), 7.90 (s, IH), 7.66 (d, J = 1.2 Hz, IH), 7.64 (d, J = 8.4 Hz, IH), 7.61-7.57 (m, 3H), 7.46-7.44 (m, 2H), 7.38-7.34 (m, 3H), 4.98 (s, 2H). LC-MS: 2.03 min; ESI m/z 353.1 [M+H].
5-(3,4-Dihydro-2H-l,5-benzodioxepin-7-yl)-2-(l,3-dihydro-isoindol-2-yl)-benzoxazole (Compound
157)
Figure imgf000059_0001
[00296] The compound was synthesized using General procedure D' using 3,4-dihydro-2H- benzo[Z?][l,4]dioxepin-7-ylboronic acid (18 mg, 0.1 mmol) to yield the title product (1.3 mg) as a solid. 1H-NMR (400 MHz; ^5-DMSO) 7.53 (d, J= 1.6 Hz, IH), 7.49 (d, J = 8.3 Hz, IH), 7.45-7.42 (m, 2H), 7.38-7.35 (m, 2H), 7.26-7.22 (m, 3H), 7.04-7.02 (m, IH), 4.96 (s, 2H), 4.19-4.14 (m, 4H), 1.33-1.30 (m, 2H). LC-MS: 3.91 min; ESI m/z 385.3 [M+H].
2-(l,3-Dihydro-isoindol-2-yl)-5-(3-methoxy-phenyl)-benzoxazoIe (Compound 165)
Figure imgf000059_0002
[00297] The compound was synthesized using General procedure D' using 3-methoxyphenyl boronic acid (7.7 mg, 0.05 mmol) to yield the title product (7.2 mg, 82%) as a solid. 1H-NMR (400 MHz; ύ?6-DMSO) 7.61 (d, J= 1.7 Hz, IH), 7.53 (d, J= 8.3 Hz, IH), 7.48-7.42 (m, 2H), 7.40-7.34 (m, 3H), 7.33 (dd, J = 1.9 Hz, J= 8.3 Hz, IH), 7.23 (d with fine sir., J= 6.8 Hz, IH), 7.19 (app t, J= 2.0 Hz, IH), 6.92 (ddd, J= 0.7 Hz, J= 2.5 Hz, J= 8.2 Hz, IH), 4.97 (s, 4H), 3.83 (s, 3H). LC/MS: 3.90 min on 6.5 min run; ESI m/z 343.1 [M+H].
Representative Synthetic Scheme 7
Figure imgf000059_0003
2-(l,3-Dihydro-isoindol-2-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-benzoxazole
[00298] To a mixture of 5-bromo-2-(l ,3-dihydro-isoindol-2-yl)-benzoxazole (200 mg, 0.63 mmol), bis(pinacolato)diboron (242 mg, 0.953 mmol), KOAc (31 1 mg, 3.17 mmol), and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with DCM (1 :1) (51.8 mg, 0.0634 mmol) under nitrogen was added N,N-dimethylformamide (1.3 mL). The mixture was heated under nitrogen at 80 0C overnight. LC/MS at 15 hours indicates complete reaction (about 4:1 boronic ester to boronic acid, but no SM). The mixture was diluted with EtOAc (20 mL) and washed with brine (20 mL). The aqueous was back extracted with EtOAc (5 mL) and the combined organics washed with brine (2 x 20 mL), dried (Na2SO4), filtered and concentrated under vacuum. The crude product was presorbed onto silica gel (1.3g) and purified by column chromatography on silica gel (12g Isco cartridge) using hexane to EtOAc as eluent (product elutes with about 20-25% EtOAc) to obtain the desired product (206 mg, 90%) as a solid. 1HNMR (400 MHz; CDCl3) 7.87 (br s, IH), 7.54 (d, J = 8.0 Hz, IH), 7.35 (br s, 4H), 7.31 (d, J = 8.0 Hz, IH), 5.03 (s, 4H), 1.39 (s, 12 H). LC/MS: 1.53 min on 2 min run; ESI m/z 363.2 [M+H].
2-(l,3-Dihydro-isoindol-2-yl)-5-(l-methyl-lH-indazol-4-yl)-benzoxazole (Compound 158)
Figure imgf000060_0001
[00299] The compound was synthesized using General Procedure E' (see below) to give the desired product (2.54 mg, 31%) as a solid. 1H NMR (400 MHz; ^6-DMSO) 8.12 (d, J= 0.9 Hz, IH), 7.66- 7.59 (m, 3H), 7.52-7.43 (m, 3H), 7.41-7.34 (m, 3H), 7.27 (d, J= 6.5 Hz, IH), 4.99 (s, 4H), 4.10 (s, 3H). LC/MS: 3.67 min on 6.5 min run; ESI m/z 367.3 [M+H].
2-(l ,3-Dihydro-isoindol-2-yl)-5-(4-methoxymethyl-phenyl)-benzoxazole (Compound 162)
Figure imgf000060_0002
[00300] The compound was synthesized using General Procedure E' (see below) to give the desired product (6.08 mg, 67%) as a solid. 1H NMR (400 MHz; </6-DMSO) 7.66 (d with fine str, J= 8.2 Hz, 2H), 7.60 (d, J= 1.7 Hz, IH), 7.53 (d, J= 8.3 Hz, IH), 7.48-7.42 (m, 2H), 7.40 (d, J= 8.3 Hz, 2H), 7.38-7.34 (m, 2H), 7.32 (dd, J= 1.9 Hz, J= 8.3 Hz, IH), 4.97 (s, 4H), 4.45 (s, 2H), 3.32 (s, 3H). LC/MS: 3.85 min on 6.5 min run; ESI m/z 357.1 [M+H].
2-(l,3-Dihydro-isoindol-2-yl)-5-(l-ethyl-lH-indol-5-yl)-benzoxazole (Compound 164)
Figure imgf000060_0003
[00301] The compound was synthesized using General Procedure E' (see below) to give the desired product (1.9 mg, 22%) as a solid. 1H NMR (400 MHz; ^6-DMSO) 7.80 (d, J= 1.3 Hz, IH), 7.58 (d, J= 1.7 Hz, IH), 7.55 (d, J = 8.6 Hz, IH), 7.51 (d, J= 8.3 Hz, IH), 7.48-7.40 (m, 4H), 7.40-7.34 (m, 2H), 7.31 (dd, J = 1.8 Hz, J= 8.3 Hz, IH), 6.48 (dd, J= 0.6 Hz, J= 3.1 Hz, IH), 4.98 (s, 4H), 4.24 (q, J =
7.2 Hz, 2H), 1.38 (t, J= 7.2 Hz, 3H). LC/MS: 4.08 min on 6.5 min run; ESI m/z 380.0 [M+H].
General Procedure E': 2-(l,3-Dihydro-isoindol-2-yl)-5-(3-methoxy-4-methoxymethyl-phenyl)- benzoxazole (Compound 166)
Figure imgf000061_0001
[00302] To a small microwave vial was added 4-bromo-2-methoxy-l-methoxymethylbenzene
(100 mg, 0.044 mmol) and POPd (1.1 mg, 0.0022 mmol). A solution of 2-(l ,3-dihydro-isoindol-2-yl)-5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-benzoxazole (8.0 mg, 0.022 mmol) and tetra-N- butylammonium iodide (0.82 mg, 0.0022 mmol) in N,Ν-dimethylformamide (600 μL) followed by a solution of CS2CO3 (29 mg, 0.088 mmol) in Water (150 μL). The system was sealed and purged with nitrogen then heated in the microwave for 20 min at 150 0C. LC/MS indicates complete reaction. The reaction was diluted with EtOAc (5 mL) and washed with brine (5 mL). The aqueous layer was back extracted with EtOAc (about 2 mL) and the combined organics were washed with brine (2 x 5 mL), dried (Na2SO4), filtered and evaporated. The crude product was dissoved in DMSO (450 μL) and purified by reverse phase HPLC (acetonitrile in water gradient buffered to pHIO with 10 mM Et2NH in water) to obtain a the desired product (1.14 mg, 13%) as a solid. 1H NMR (400 MHz; ώi-MeOH) 7.55 (d, J= 1.7 Hz, IH), 7.47-7.40 (m, 3H), 7.40-7.33 (m, 4H), 7.21-7.17 (m, 2H), 5.02 (s, 4H), 4.53 (s, 2H), 3.93 (s, 3H), 3.41 (s, 3 H). LC/MS: 3.88 min on 6.5 min run; ESI m/z 387.2 [M+H].
2-(l,3-Dihydro-isoindol-2-yl)-5-(2-methoxy-pyridin-4-yl)-benzoxazole (Compound 167)
Figure imgf000061_0002
[00303] The compound was synthesized using General Procedure E' to give the desired product
(2.4 mg, 32%) as a solid. 1H NMR (400 MHz; </6-DMSO) 8.21 (d, J= 5.4 Hz, IH), 7.75 (d, J= 1.8 Hz, IH), 7.58 (d, J= 8.3 Hz, IH), 7.48-7.42 (m, 3H), 7.40-7.32 (m, 3H), 7.12 (d, J= 1.0 Hz, IH), 4.98 (s, 4H), 3.90 (s, 3H). LC/MS: 3.59 min on 6.5 min run; ESI m/z 344.3 [M+H].
5-[2-(l,3-Dihydro-isoindoI-2-yl)-benzoxazol-5-yl]-2-hydroxy-benzonitrile (Compound 177)
Figure imgf000061_0003
[00304] The compound was synthesized using General Procedure E' using 5-bromo- benzo[J]isoxazole (8.7 mg) as a starting material to give the desired product (2.28 mg, 22%) as a solid. 1H NMR (400 MHz; </6-DMSO) 1 1.17 (v br s, IH), 7.88 (d, J= 2.4 Hz, IH), 7.80 (dd, J= 2.4 Hz, J= 8.7 Hz,
IH), 7.58 (d, J= 1.8 Hz, IH), 7.51 (d, J= 8.3 Hz, IH), 7.47-7.41 (m, 2H), 7.39-7.33 (m, 2H), 7.28 (dd, J = 1.9 Hz, J= 8.3 Hz, IH), 7.07 (d, J= 8.7 Hz, IH), 4.97 (s, 4H). LC/MS: 3.39 min on 6.5 min run; ESI m/z 354.0 [M+H].
2-(l,3-Dihydro-isoindoI-2-yl)-5-(l-oxetan-3-yl-lH-indol-5-yl)-benzoxazole (Compound 187)
Figure imgf000062_0001
[00305] The compound was synthesized using General Procedure E' to give the desired product
(4.97 mg, 63%) as a solid. 1H NMR (400 MHz; ^6-DMSO) 7.84 (d, J= 1.6 Hz, IH), 7.78 (d, J= 3.2 Hz, IH), 7.65 (d, J= 8.7 Hz, IH), 7.59 (d, J= 1.8 Hz, IH), 7.52 (d, J= 8.3 Hz, IH), 7.50-7.42 (m, 3H), 7.40- 7.34 (m, 2H), 7.32 (dd, J= 1.8 Hz, J= 8.3 Hz, IH), 6.61 (d, J= 3.2 Hz, IH), 5.80 (app quint, J= 7.0 Hz, IH), 5.07 (app t, J= 7.3 Hz, 2H), 4.98 (s, 4H), 4.96 (app t, J= 6.6 Hz, 2H). LC/MS: 3.75 min on 6.5 min run; ESI m/z 408.2 [M+H].
2-(l,3-Dihydro-isoindol-2-yl)-5-(3-ethoxy-4-ethoxymethyl-phenyl)-benzoxazole (Compound 188)
Figure imgf000062_0002
[00306] The compound was synthesized using General Procedure E' to give the desired product
(2.99 mg, 37%) as a solid. 1H NMR (400 MHz; ^6-DMSO) 7.63 (d, J= 1.7 Hz, IH), 7.53 (d, J= 8.3 Hz, IH), 7.48-7.42 (m, 2H), 7.39-7.31 (m, 4H), 7.24-7.20 (m, 2H), 4.97 (s, 4H), 4.48 (s, 2H), 4.17 (q, J = 6.9 Hz, 2H), 3.54 (q, J= 7.0 Hz, 2H), 1.37 (t, J= 6.9 Hz, 3H), 1.18 (t, J= 7.0 Hz, 3H). LC/MS: 4.25 min on 6.5 min run; ESI m/z 415.3 [M+H].
2-{5-[2-(l,3-Dihydro-isoindol-2-yl)-benzoxazoI-5-yl]-indol-l-yl}-acetamide (Compound 194)
Figure imgf000062_0003
[00307] The compound was synthesized using General Procedure E'. After the reaction, the mixture was diluted with EtOAc (5 mL) and washed with brine (5 mL). Solid precipitated from the mixture and was filtered (the filter cake was primarily product). The aqueous layer was back extracted with EtOAc (about 2 mL) and the combined organics were washed with brine (2 x 5 mL), dried (Na2SO,)), filtered and evaporated. The filtered solids were dissoved in DMSO (1200 μL) and purified by reverse phase HPLC (acetonitrile in water gradient buffered to pHIO with 10 mM Et2NH in water). The low solubility of the compound caused the product to streak. Collected the waste after the product peak (mostly product). The collected waste was evaporated and purified by preparative HPLC as descibed above. The organics from the workup contained a small amount of product and was purified by preparative HPLC as descibed above. The appropriate clean fractions were combined to obtain the desired product (0.86 mg, 9%) as a solid. 1H NMR (400 MHz; ^6-DMSO) 7.80 (s, IH), 7.58 (d, J= 1.7 Hz, IH), 7.54 (br s, IH), 7.51 (d, J= 8.3 Hz, IH), 7.48-7.39 (m, 4H), 7.39-7.33 (m, 3H), 7.31 (dd, J= 1.8 Hz, J = 8.3 Hz, IH), 7.26 (br s, IH), 6.49 (d, J= 3.1 Hz, IH), 4.98 (s, 4H), 4.82 (s, 2H). LC/MS: 3.16 min on 6.5 min run; ESI m/z 409.2 [M+H].
ASSAYS hFAAH Microsome Collection Procedure
[00308] Human cell line T84 (human colon epithelial cells), which expresses endogenous hFAAH, or HEK293-TRex cells (Invitrogen) stably transfected with hFAAH in the pCDNA5-Tet-off vector are cultured in medium containing DMEM, 10% FBS penicillin/streptomycin, glutamax, 200μg/ml hygromycin and 0.5μg/ml blasticidin. Cell collection is done 24h after induction with doxycycline by first washing the cells with cold PBS and then incubating them with Versene before centrifugation. Cell pellets are then stored at -800C until needed. For homogenization, the cell pellets are thawed on ice at room temperature and resuspended in homogenization buffer (50 mM HEPES (pH 7.4), 1 mM EDTA, 1 μM Pepstatin A, 100 μM Leupeptin, 0.1 mg/mL aprotinin). Cell suspensions are then homogenized on ice using the Polytron 1200C at setting 6 for three 30-second intervals with 30-second rests. The suspension is centrifuged at lOOOg for 10 minutes at 4°C and the supernatant is collected and further centrifuged at 24000rpm for 30 minutes at 4°C using an ultracentrifuge. Pellets are resuspended by adding in cold microsomal buffer (50 mM HEPES (pH 7.4) and 1 mM EDTA) and sheared through a 23-gauge needle five times, keeping the suspension on ice. Protein concentrations are determined using the BCA assay and aliquoted preparations are stored at -800C until needed.
Compound IC50 determination Fluorimetric assay with hFAAH microsomes
[00309) Compound potency against hFAAH is determined using an enzymatic assay with a fluorescence readout. Briefly, experiments are carried out in a 96-well plate format (Corning Costar, # 3370) with a total well volume of 160 μL with components added in the following order: assay buffer (50 mM HEPES (pH 7.4), 1 mM EDTA, 1.4 mg/mL BSA), compound solutions (7 different concentrations per compound in duplicate), microsomal enzyme preparation (10 μg per well) and substrate [AA-AMC (arachadonyl 7-amino 4-methyl coumarin amide), 2 μM]. After a brief shaking, a kinetic read of the plate is obtained using a Tecan Safire II in kinetic mode for 275 cycles with excitation and emission wavelengths of 355 and 460nm, respectively. Raw data is then processed and analyzed using Assay
Explorer and GraphPad Prism. Radioactive assay with hFAAH microsomes
[00310] Compound potency against hFAAH is determined using an enzymatic assay with a radiometric readout. Briefly, experiments are carried out in 1.5mL vials with a total well volume of 200 μL with components added in the following order: assay buffer (50 mM HEPES (pH 7.4), 1 mM EDTA, 1 mg/mL BSA), compound solutions (6 different concentrations per compound in triplicate), microsomal enzyme preparation (10 μg per well) and substrate (AEA with 3H-AEA tracer, 1 μM). After a 30 minute incubation, 400 μL of CH3OH/CHCL3 1/1 (v/v) solution is added to each tube, reactions are vortexed and centrifuged before extracting 300 μL of the aqueous layer, mixing it with 5 mL of scintillation fluid before counting the amount of radioactivity present in a liquid scintillation counter. Raw data is then processed and analyzed using GraphPad Prism.
[00311] In alternative FAAH assays, 14C- anandamide may be utilized or anandamide
[ethanolamine-l-3H] and incubated with microsomes or cell membranes from liver cells or cell lines. The reaction can be monitored by differential absorption of the substrate and its products to charcoal (L. Boldrup, et al., (2004) J. Biochem. Biophys. Methods 60, 171-177; S. Wilson, et al., (2003) Anal. Biochem. 318, 270-275). A fluorescent assay utilizing substrate decanoyl 7-amino-4-methyl coumarin (D-AMC), that is cleaved to the fluorescent molecule 7-amino-4-methyl coumarin (AMC) has also been described (K. L. Kage, et al., (2006) J. Neurosci. Methods (2006) Nov 1 [E pub ahead of print: doi: 10.1016/i.ineumeth.2006.10.0061).
Neuropathic pain models
Chronic Constriction Injury Model (CCI or Bennett model):
[00312] The CCI model is performed according to the method described by Bennett and Xie,
Pain, 33:87-107, 1988. Briefly, under isoflurane anesthesia, the right sciatic nerve is exposed at mid- thigh level via blunt dissection through the biceps femoris. Proximal to the bifurcation of the sciatic nerve, about 7mm of nerve is freed of adhering tissue and 4 loose ligatures of 4.0 chromic gut are tied around the nerve. Spacing between ligatures is approximately lmm. The wound is closed in layers, and the skin closed with staples or non-silk sutures. Sham operated animals are treated identically with the exception that the sciatic nerve will not be ligated. Mechanical allodynia, cold allodynia, or thermal hyperalgesia testing occur 7-21 days post surgery. Spinal Nerve Transection (SNT or Chung model):
[00313] The SNT model will be performed according to the method described by Kim and Chung,
Pain 50:355-363, 1992. Under isoflurane anesthesia, a longitudinal incision is made at the lower lumbar and sacral levels, exposing paraspinal muscles on the left side. The location of the incision is determined by the position of the L5 spinous process. The paraspinal muscles are isolated and removed from the level of the L4 spinous process to the sacrum. This opens up the space ventrolateral to the articular processes, dorsal to the L6 transverse process, and medial to the ileum. Remaining connective tissues and muscles are removed. Under a dissecting microscope, the L6 transverse process, which covers the L5 spinal nerve, is removed. Due to their close proximity, the L4 and L5 spinal nerves may need to be separated to fully expose the L5 spinal nerve for ligation using extra caution not to damage the L4 nerve during this process. Animals that exhibit L4 nerve damage as evidenced by paw drop post-anesthesia are not included in studies. Once the L5 spinal nerve is exposed, the nerve is ligated with 6-0 silk. Alternatively, the spinal nerve is cut distal to the ligation site. If a more complete neuropathy is required, then the L6 spinal nerve may also be ligated using the procedure described above. Sham operated animals are treated identically with the exception that the nerves will not be ligated/transected. Following spinal nerve ligation, hemostasis is confirmed, the muscles are sutured in layers, and the skin is closed with staples or non-silk sutures. Mechanical allodynia, cold allodynia, or thermal hyperalgesia testing occur 7- 21 days post surgery.
Chemotherapy-induced painful neuropathy:
[00314] Chemotherapy neuropathy is induced by i.p. administration of 1 mg/kg Taxol administered once/day on 4 alternating days (total dose = 4 mg/kg) (Polomano et al., Pain, 94:293-304, 2001). Mechanical allodynia, cold allodynia, or thermal hyperalgesia testing occur 9-30 days post day 1 of Taxol administration.
Inflammatory pain models Formalin model:
[00315] Test compounds are administered at various times prior to intraplantar administration of formalin. A dilute solution of formalin (50 μL of 2.5% formaldehyde/saline) is administered s.c. into the plantar surface of the left hind paw under light restraint. Immediately following injection, animals are placed on a mesh stand inside a clear observation chamber large enough to allow for free movement of the animals during the study. Behaviors are scored using manual scoring or automated scoring. [00316] Manual scoring: Using a three channel timer, the observer records the time (t in seconds) of decreased weight-bearing (ti), paw lifting (t2), and licking/biting/shaking (t3). Results are weighted according to the method of Dubuisson and Dennis, Pain, 4:161-174, 1977, using the formula ti+2t2+3t3/l 80 where 180 s is the evaluation time for each increment. Behaviors are acquired in alternating 3 min increments starting at time = 0 min (i.e. 0-3 min, 6-9 min etc.) and ending at 60 min. [00317] Automated scoring: A small metal band weighing 0.5 g is placed on the left paw.
Formalin is administered and the animal placed unrestrained inside an observation chamber over an electromagnetic detector system (Automated Nociception Analyzer, University of California, San Diego). The number of paw flinches is electronically recorded. Complete Freund's Adjuvant Model (CFA):
[00318] Animals receive an s.c. injection of 100 μL complete Freund's adjuvant containing
100 μg Mycobacterium tuberculosis strain H37Ra into the plantar surface of the right hind paw under isoflurane anesthesia. Swelling and inflammation are visible within 1 h after administration. Mechanical allodynia or thermal hyperalgesia testing start 24 h post CFA administration. Carageenan: [00319] Animals receive a subcutaneous injection of 100 μL of either 2% carrageenan or saline
(controls) into the plantar surface of the right hind paw under isoflurane anesthesia. Swelling and inflammation are visible within Ih after administration. Mechanical allodynia or thermal hyperalgesia testing start 3-24 h post carageenan administration (Hargreaves et al., Pain, 32:77-88, 1988).
Visceral pain models Colo-rectal Distension (CRD):
[00320] Prior to induction of the model, animals are deprived of food but allowed access to water ad libitum for 16h prior to the induction of the model. A 5 cm latex balloon is attached to a barostat system composed of a flow meter and pressure control program by a length of tubing. Under isoflurane anesthesia, the balloon is inserted into the distal colon via the anus at a distance of 5 cm from the anus and taped to the base of the tail. Post-anesthesia, the animal is placed unrestrained into a clean polypropylene cage and allowed to acclimate for 30 mins. The balloon is progressively inflated from 0-75 mmHg in 5 mm increments every 30 s. The colonic reaction threshold is defined as the pressure inducing the first abdominal contraction. Abdominal contraction indicative of visceral pain correlates with hunching, hump-backed position, licking of the lower abdomen, repeated waves of contraction of the ipsilateral oblique musculature with inward turning of the ipsilateral hindlimb, stretching, squashing of the lower abdomen against the floor (Wesselman, Neurosci. Lett., 246:13-16, 1998). Acetic Acid WrithingTest:
[00321] A 0.6% solution of acetic acid (10 ml/kg) is administered i.p. to rats and the number of abdominal constrictions over 30 min are counted.
Behavioral Testing Mechanical testing:
[00322] Mechanical allodynia testing is performed using the up-down method of Dixon, Ann. Rev.
Pharmacol. Toxicol. 20:441-462, 1980, modified for mechanical thresholds by Chaplan et al., J. Neurosci. Methods 53:55-63, 1994. Testing is performed during the day portion of the circadian cycle (7:00-19:00). Animals are placed in separate plastic enclosures with a mesh bottom which allowed for full access to the paws. For all tests, animals are acclimated to the apparatus for at least 15 min prior to testing or until cage exploration and major grooming activities have ceased. The area tested will be the mid-plantar hind paw. The paw is touched with 1 of a series of 8 von Frey hairs (Stoelting, Wood Dale, IL) with logarithmically incremental stiffness (0.4, 0.6, 1.4, 2, 4, 6, 8, and 15 g). Each von Frey hair is presented perpendicularly to the plantar surface with sufficient force to cause slight buckling against the paw and held for approximately 6-8 s. Stimulation is presented at intervals of several seconds, allowing for apparent resolution of any behavioral responses to previous stimuli. A positive response will be noted if the paw is sharply withdrawn. Flinching immediately upon removal of the hair will also be considered a positive response. Ambulation will be considered an ambiguous response and in such cases, the stimulus will be repeated.
[00323] To determine the 50% withdrawal threshold, testing will be initiated with the 2 g fiber
(the middle fiber in the series). Fibers will be presented in a consecutive fashion whether ascending or descending. In the absence of a paw withdrawal response to the initially selected fiber, the next highest fiber is presented. In the event of a paw withdrawal, the next weaker fiber is presented. The optimal threshold calculation by this method requires 6 responses in the immediate vicinity of the 50% withdrawal threshold. Counting of the critical 6 data points will not begin until the response threshold is first crossed at which time the 2 responses straddling the threshold will be designated as the first 2 responses of the series of 6. Four additional responses to the continued presentation of the fibers constituted the remaining 4 responses.
[00324] In cases where continuous positive or negative responses are observed to the exhaustion of the fiber set, values of 15 g and 0.25 g are assigned, respectively.
[00325] The range of fibers tested in this paradigm have not been shown to cause tissue damage although prolonged stimulation over short time intervals may result in sensitization and/or habituation, scenarios which would lead to decreased or increased thresholds, respectively. Therefore, there is a minimum 1 h interval between testing sessions with no more than 4 testing sessions per day. For testing intervals, animals are returned to their cages following all testing sessions. Testing sessions will last no longer than 1 h. No two testing sessions will occur on consecutive hours. To minimize distress, mechanical allodynia testing is conducted no more than 4 times per day. Thermal testing:
[00326] To measure heat thermal hyperalgesia, an Ugo Basile radiant heat source (I.R. intensity of
40) will be provided by a light bulb focused onto the plantar surface of the paw (Hargreaves et al., Pain 32:77-88, 1988). Paw withdrawal latencies are defined as the time it takes for the animal to remove its paw from the heat source. To ensure that no tissue damage occurs, all tests will have a 20 sec cutoff even when the animal does not withdraw its paw away from the heat stimulation. The test consists of 3 measurements of the same paw, with a minimum 5 minute intervals between each determination. To minimize distress, thermal testing is conducted no more than 3 times per day. Cold testing:
[00327] To measure cold allodynia, a drop of acetone is applied to the plantar surface of the paw through the underside of the grating on which the animals are standing using a 50 μL Hamilton syringe. The process is performed 5 times with a 3 min interval between each time. Vigorous shaking will be recorded as a positive response. The acetone drop test is conducted no more than 5 times over the course of a study (including the pre-surgery baseline test) and no more than once per day (Kotinen et al., Pain 80:341-346, 1999).
Neuropathic Pain Measurements using Chung Model
[00328] Under pentobarbital anesthesia (60 mg/kg, i.p.), rats are placed in a prone position on a flat, sterile surface. A midline incision from L4-S2 is made and the left paraspinal muscles are separated from the spinous processes. The L5 and L6 spinal nerves are tightly ligated with a 4-0 silicon-treated silk suture, according to the method described by Kim and Chung, Pain, 50:355-363, 1992. The L4 spinal nerve is carefully preserved from being surgically injured. The skin is closed with wound clips and animals are returned to their home cages. Rats exhibiting prolonged postoperative neurological deficits or poor grooming are excluded from the experiments. The animals are assessed for response to noxious mechanical stimuli by determining paw withdrawal threshold (PWT), as described below, prior to surgery (baseline), then immediately prior to and at various time points after being administered with a compound of this invention (30 mg/kg) in the left rear paw of the animal. Additionally, other animals may also be assessed for thermal or mechanical hyperalgesia, as described below.
[00329] Assessment of Tactile Allodynia: To assess tactile allodynia, rats are placed in clear,
Plexiglas compartments with a wire mesh floor and allowed to habituate for a period of at least 15 minutes. After habituation, a series of von Frey monofilaments are presented to the plantar surface of the left (operated) foot of each rat. The series of von Frey monofilaments consists of six monofilaments of increasing diameter, with the smallest diameter fiber presented first. Five trials are conducted with each filament with each trial separated by approximately 2 minutes. Each presentation lasts for a period of 4-8 seconds or until a nociceptive withdrawal behavior is observed. Flinching, paw withdrawal or licking of the paw are considered nociceptive behavioral responses.
[00330] Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia: The plantar test can be used to assess thermal hyperalgesia. For this test, hind paw withdrawal latencies to a noxious thermal stimulus are determined using a plantar test apparatus (commercially available from Ugo Basile of Italy) following the technique described by Hargreaves et ai, Pain 32: 77-88, 1988. The maximum exposure time is set at 32 seconds to avoid tissue damage and any directed paw withdrawal from the heat source is taken as the end point. Three latencies are determined at each time point and averaged. Only the affected (ipsilateral) paw is tested. An increase latency of paw withdrawal demonstrates reversal of hyperalgesia.
[00331] Response to Mechanical Stimuli as an Assessment of Mechanical Hyperalgesia: The paw pressure assay can be used to assess mechanical hyperalgesia. For this assay, hind paw withdrawal thresholds (PWT) to a noxious mechanical stimulus are determined using an analgesymeter (Model 7200, commercially available from Ugo Basile of Italy) as described in Stein et al., Pharmacol. Biochem. Behav. 31 :451-455, 1988. The maximum weight that can be applied to the hind paw is set at 250 g and the end point is taken as complete withdrawal of the paw. PWT is determined once for each rat at each time point and only the affected (ipsilateral) paw is tested.
Activity of Exemplary Compounds of the Invention
[00332] The following compounds have been or can be prepared according to the methods of the invention. An enzymatic (fluorescence based) assay is performed as described above. The IC50 data for some of the representative compounds are given in Table 1 below. In Table 1, for the compounds where IC50 was not determined, the % Inhibition data is given and the data is expressed as follows:
++++ % Inhibition >75% at 1 μM
+++ % Inhibition 51 -75% at 1 μM
++ % Inhibition 25-50% at 1 μM
+ % Inhibition <25% at 1 μM le 1: IC50 Data for Exemplary Compounds of Invention
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
[00334] From the foregoing description, various modifications and changes in the compositions and methods of this invention will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein.
[00335) All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. [00336] At least some of the chemical names of compounds of the invention as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by Open Eye Software, Inc. and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control.
[00337] Chemical structures shown herein were prepared using ISIS® /DRAW. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. Where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral structure are encompassed by the structure.

Claims

WHAT IS CLAIMED IS:
1. A compound having a formula:
Figure imgf000093_0001
wherein
X is NR1R2; or X is N-containing 3-11 membered mono or fused heterocycloalkyl, joined to the core group via ring N;
R1 is selected from a substituted or unsubstituted cycloalkyl; or R1 is substituted or unsubstituted aryl or heteroaryl;
R2 is selected from hydrogen, and substituted or unsubstituted CpC6 alkyl;
R3 is selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; each R4 is independently selected from H, Ci-C6alkyl, substituted Ci-Cβalkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted sulfonyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfo, sulfonic acid ester, substituted or unsubstituted dihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituor unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thiol; and n is 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof; provided that i) when X is heterocycloalkyl, R3 is other than unsubstituted phenyl or unsubstituted pyridyl; and ii) the compound is other than a) N-cyclohexyl-5-(3,7-dimethylimidazo[l ,2-a]pyridin-2-yl)-2-Benzoxazolamine
Figure imgf000093_0002
b) 4-[5-[4-(trifluoromethyl)phenyl]-2-benzoxazolyl]-l ,4-diazabicyclo[3.2.2]nonane
Figure imgf000094_0001
c) 4-[5-(3-methylphenyl)-2-benzoxazolyl]-l,4-diazabicyclo[3.2.2]nonane
Figure imgf000094_0002
d) 2,4-dihydro-2-phenyl-5-[(5-phenyl-2-benzoxazolyl)amino]-3H-pyrazol-3-one
V f ^ H^"
e) 5-phenyl-N-[2-[3-(trifluoromethyl)phenoxy]-3-pyridinyl]-2-benzoxazolamine
Figure imgf000094_0003
f) N-[2-[2-(l ,l-dimethylethyl)phenoxy]-3-pyridinyl]-5-phenyl-2-benzoxazolamine
Figure imgf000094_0004
2. A compound according to Claim 1 wherein X is NR1R2; and R2 is H.
3. A compound according to Claim 1 wherein n is 1 or 2; and R4 is independently selected from halo, Ci-C6alkyl, haloCi-Qalkyl, cyano, hydroxy, alkoxy and sulfonyl.
4. A compound according to Claim 1 wherein n is 3; and R4 is H.
5. A compound according to claim 1 wherein the compound is according to formula II
Figure imgf000094_0005
wherein R1 and R3 are as in claim 1.
6. A compound according to any one of Claims 1 -5 wherein R1 is substituted or unsubstituted cyclohexyl, cycloheptyl, cyclopentyl, cyclopropyl, or cyclobutyl.
7. A compound according to any one of Claims 1-5 wherein R1 is substituted or unsubstituted cyclohexyl.
A compound according to any one of Claims 1-5 wherein R1 is unsubstituted cyclohexyl.
9. A compound according to any one of Claims 1-5 wherein R1 is substituted or unsubstituted phenyl.
10. A compound according to any one of Claims 1-5 wherein R1 is substituted or unsubstituted heteroaryl.
1 1. A compound according to any one of Claims 1-5 wherein R1 is substituted or unsubstituted pyridyl, quinolinyl, isoquinolinyl, substituted or unsubstituted benzodioxole, substituted or unsubstituted benzodioxane, substituted or unsubstituted benzofuran, substituted or unsubstituted benzothiophene, and substituted or unsubstituted benzodioxepine.
12. A compound according to any one of Claims 1-5 wherein R1 is phenyl, or pyridyl, substituted with one or more substituents independently selected from halo, Ci-C6alkyl, haloCi-C6alkyl,
C3-C8cycloalkyl, amino, cyano, hydroxy, alkoxy and sulfonyl.
13. A compound according to any one of Claims 1-5 wherein R1 is phenyl, or pyridyl, substituted with one or more substituents independently selected from Me, Et, Ph, Cl, F, Br, CN, OH,
OMe, OEt, OPh, COPh, CF3, CHF2, OCF3, i-Pr, i-Bu, t-Bu, SMe, CH=CH-CO2H, SOMe,
SO2Me, SO3H, and SO3Me.
14. A compound according to any one of Claims 1-5 wherein R1 is unsubstituted phenyl.
15. A compound according to claim 1 wherein the compound is according to formula Ilia
Figure imgf000095_0001
Ilia wherein R3 is as in claim 1.
16. A compound according to claim 1 wherein the compound is according to formula IHb
Figure imgf000095_0002
wherein R3 is as in claim 1.
17. A compound according to claim 1 wherein the compound is according to formula IV
Figure imgf000095_0003
IV wherein R3 is as in claim 1; and Cy is 3-11 membered mono or fused heterocycloalkyl.
18. A compound according to claim 17, wherein Cy is azetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1 - yl, piperazin-1-yl, morpholin-1-yl, dihydroindol-1-yl, dihydroisoindol-1 -yl, tetrahydroquinolin-1-yl, or tetrahydroisoquinolinyl.
19. A compound according to any one of Claims 1-17 wherein R3 is substituted or unsubstituted phenyl.
20. A compound according to any one of Claims 1-17 wherein R3 is substituted or unsubstituted heteroaryl.
21. A compound according to any one of Claims 1-17 wherein R3 is substituted or unsubstituted pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted benzoxazinyl, substituted or unsubstituted benzodioxole, substituted or unsubstituted benzodioxanyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indolyl, substituted or unsubstituted indolinyl, substituted or unsubstituted N-methlylindol-5-yl, substituted or unsubstituted N-methylindolin-5-yl imidazopyridinyl, and substituted or unsubstituted benzodioxepinyl.
22. A compound according to any one of Claims 1-17 wherein R3 is phenyl, substituted with one or more substituents independently selected from halo, Cj-Cβalkyl, haloCi-C6alkyl, C3- Cgcycloalkyl, amino, cyano, hydroxy, alkoxy and sulfonyl.
23. A compound according to any one of Claims 1-17 wherein R3 is phenyl, substituted with one or more substituents independently selected from Me, Et, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CF3, CHF2, OCF3, i-Pr, i-Bu, t-Bu, SMe, CH=CH-CO2H, SOMe, SO2Me, SO3H, and SO3Me.
24. A compound according to any one of Claims 1 -17 wherein R3 is pyridyl, substituted with one or more substituents independently selected from halo, Ci-Cδalkyl, haloCi-C6alkyl, C3- Cgcycloalkyl, amino, cyano, hydroxy, alkoxy and sulfonyl.
25. A compound according to any one of Claims 1-17 wherein R3 is pyridyl, substituted with one or more substituents independently selected from Me, Et, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CF3, CHF2, OCF3, i-Pr, i-Bu, t-Bu, SMe, CH=CH-CO2H, SOMe, SO2Me, SO3H, and SO3Me.
26. A compound according to any one of Claims 1 -17 wherein R3 is
Figure imgf000097_0001
Figure imgf000097_0002
wherein Z is CR3c or N; R3a is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl; R3b is selected from H and substituted or unsubstituted alkyl; R3c is selected from H, halo, and substituted or unsubstituted alkyl.
27. A compound according to claim 26, wherein R3b is H or alkyl.
28. A compound according to claim 26, wherein R3b is H, Me, or Et.
29. A compound according to claim 26, wherein Z is CR3c; and R3c is H, Cl, F, or Me.
30. A compound according to claim 26, wherein Z is N.
31. A compound according to claim 1 wherein the compound is according to formula IVa, IVb,
IVc, or IVd:
Figure imgf000097_0003
IVa IVb
Figure imgf000097_0004
IVc IVd and wherein X is as in claim 1 ; R3a is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.
32. A compound according to claim 1 wherein the compound is according to formula Va, Vb, Vc, or Vd:
Figure imgf000098_0001
Vb
Va
Figure imgf000098_0002
Vd
Vc and wherein X is as in claim 1 ; R3a is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.
33. A compound according to claim 1 wherein the compound is according to formula Via, VIb, VIc, or VId:
Figure imgf000098_0003
VIb
Via
Figure imgf000098_0004
VId
VIc and wherein X is as in claim 1 ; R3a is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.
34. A compound according to any one of Claims 26-33 wherein R3a is H.
35. A compound according to any one of Claims 26-33 wherein R3a is H, Me, Et, or i-Pr.
36. A compound according to any one of Claims 26-33 wherein R3a is cyclopropyl, cyclobutyl, cyclohexyl, or cyclopentyl.
37. A compound according to any one of Claims 26-33 wherein R3a is oxetan-3-yl.
38. A compound according to any one of Claims 26-37 wherein X is:
Figure imgf000099_0001
Figure imgf000099_0002
39. A compound according to claim 1 wherein the compound is selected from the compounds exemplified in Table 1 ; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof.
40. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of any of claims 1-39.
41. The pharmaceutical composition of claim 40, wherein the carrier is a parenteral carrier.
42. The pharmaceutical composition of claim 40, wherein the carrier is an oral carrier.
43. The pharmaceutical composition of claim 40, wherein the carrier is a topical carrier.
44. A method for preventing, treating or ameliorating in a mammal a disease or condition associated with the aberrant behavior of FAAH in vivo or which can be alleviated by modulating FAAH activity, which comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound according to any of claims 1-39 or a pharmaceutical composition according to any of claims 40-43.
45. The method of claim 34, wherein the disease or condition is selected from: pain including acute, inflammatory and neuropathic pain, chronic pain, dental pain and headache including migraine, cluster headache and tension headache, Parkinson's disease, Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in inflammation, arthritis, rheumatoid arthritis and osteoarthritis, and inflammatory bowel disease; diseases and disorders which are mediated by or result in neuroinflammation, encephalitis; centrally-mediated neuropsychiatric diseases and disorders, depression mania, bipolar disease, anxiety, schizophrenia, weight and eating disorders, sleep disorders and cognition disorders; neurological and neurodegenerative diseases and disorders; epilepsy and seizure disorders; addiction, spasticity, glaucoma, respiratory and airway disease and disorders, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; myocardial infarction, autoimmune diseases and disorders, itch / pruritus, psoriasis; obesity; lipid disorders; cancer; and renal disorders.
46. The method of claim 45, wherein the disease or condition is Parkinson's disease.
47. The method of claim 45, wherein the disease or condition is Alzheimer's disease.
48. The method of claim 45, wherein the disease or condition is pain.
49. The method of claim 45, wherein the disease or condition is neuropathic pain.
50. The method of claim 45, wherein the disease or condition is an autoimmune disease.
51. The method of claim 45, wherein the disease or condition is an inflammatory disease or condition.
52. The method of claim 45, wherein the disease or condition is a neurological or neurodegenerative disease or condition.
53. A compound according to any one of claims 1-39, or a pharmaceutically acceptable salt or solvate thereof, for use as a pharmaceutical.
54. A compound according to any one of claims 1-39, or a pharmaceutically acceptable salt or solvate thereof, for use as a pharmaceutical in the treatment or prevention of a disease or condition selected from: pain including acute, inflammatory and neuropathic pain, chronic pain, dental pain and headache including migraine, cluster headache and tension headache; Parkinson's disease, Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in inflammation, arthritis, rheumatoid arthritis and osteoarthritis; diseases and disorders which are mediated by or result in neuroinflammation, encephalitis; centrally-mediated neuropsychiatric diseases and disorders, depression mania, bipolar disease, anxiety, schizophrenia, weight and eating disorders, sleep disorders and cognition disorders; neurological and neurodegenerative diseases and disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction, urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; addiction, spasticity, glaucoma, respiratory and airway disease and disorders, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; myocardial infarction; autoimmune diseases and disorders, itch / pruritus, psoriasis; obesity; lipid disorders; cancer; and renal disorders.
55. Use of a compound according to any of claims 1-39, in the manufacture of a medicament for the treatment or prevention of a disease or condition selected from: pain including acute, inflammatory and neuropathic pain, chronic pain, dental pain and headache including migraine, cluster headache and tension headache; Parkinson's disease, Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in inflammation, arthritis, rheumatoid arthritis and osteoarthritis; diseases and disorders which are mediated by or result in neuroinflammation, encephalitis; centrally-mediated neuropsychiatric diseases and disorders, depression mania, bipolar disease, anxiety, schizophrenia, weight and eating disorders, sleep disorders and cognition disorders; neurological and neurodegenerative diseases and disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction, urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; addiction, spasticity, glaucoma, respiratory and airway disease and disorders, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; myocardial infarction; autoimmune diseases and disorders, itch / pruritus, psoriasis; obesity; lipid disorders; cancer; and renal disorders.
56. A combination of a compound as defined in any one of Claims 1-39, and another pharmacologically active agent.
57. The combination of claim 56, wherein said combination is useful for the treatment of Parkinson's disease.
58. The combination of claims 56 or 57, wherein the said another pharmacologically active agent comprises a dopamine D2 receptor agonist.
59. The combination of claims 56 or 57, wherein the said another pharmacologically active agent comprises dopamine.
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