WO2009011904A1 - Composés utiles comme modulateurs de la faah et utilisation de ceux-ci - Google Patents

Composés utiles comme modulateurs de la faah et utilisation de ceux-ci Download PDF

Info

Publication number
WO2009011904A1
WO2009011904A1 PCT/US2008/008783 US2008008783W WO2009011904A1 WO 2009011904 A1 WO2009011904 A1 WO 2009011904A1 US 2008008783 W US2008008783 W US 2008008783W WO 2009011904 A1 WO2009011904 A1 WO 2009011904A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
quinolin
tetrahydro
naphthyridin
Prior art date
Application number
PCT/US2008/008783
Other languages
English (en)
Inventor
Michael G. Kelly
John Kincaid
Sumithra Gowlugari
Carl Kaub
Original Assignee
Renovis, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Renovis, Inc. filed Critical Renovis, Inc.
Publication of WO2009011904A1 publication Critical patent/WO2009011904A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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, hypertension, or other disorders.
  • Fatty acid amide hydrolase is an integral membrane protein that degrades fatty acid primary amides and ethanolamides, a 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.
  • 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 autoimmune disorders, fever, atherosclerosis and cardiovascular diseases, renal disorders, bone disorders, obesity, eating disorders, nausea, emesis, cancer, memory disorders, schizophrenia, epilepsy, sleeping disorders, cognitive disorders, depression, anxiety, high blood pressure, addiction, glaucoma and lipid disorders.
  • each A, B, and Y are independently CR 2a R 2b ;
  • W and Z are independently CR 4 ;
  • X is -SO 2 -, -CO-, -SO 2 NR 20 -, or -CONH-; nl is 0 or 1 ;
  • L 1 is a single bond or substituted or unsubstituted Ci-C 5 alkylene; provided that when nl is 0, Ll is substituted or unsubstituted Ci -C 5 alkylene;
  • R 1 is selected from a substituted or unsubstituted aryl or heteroaryl; each of R 2a , R 2b , and R 2c is independently selected from hydrogen, and substituted or unsubstituted C 1 -C 6 alkyl;
  • R 3 is selected from substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted C 3 -
  • R 4 is independently selected from H, Ci-C 6 alkyl, substituted Ci-C ⁇ alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, substituted arylalkyl, substituted sulfanyl, substituted sulfinyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfo, sulfonic acid ester, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted C 3 -C 8 cycloalkyl,
  • 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.
  • compounds of the present invention useful in the pharmaceutical compositions and treatment methods disclosed herein can be pharmaceutically acceptable as prepared and used.
  • methods 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 the 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 1 -C 8 alkyl, C 3 -
  • Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl.
  • 'acyl' groups are -C(O)H, -C(O)-C 1 -C 8 alkyl, -C(O)-(CHj) 1 (C 6 -C 10 aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), -C(O)-(CH 2 ) t (C 3 -C 10 cycloalkyl), and -C(O)-(CH 2 ),(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
  • 'Substituted AcyF or 'Substituted AlkanoyP refers to a radical -C(O)R 21 , wherein R 21 is independently
  • 'Acylamino' refers to a radical -NR 22 C(O)R 23 , where R 22 is hydrogen, Q-C 8 alkyl, C 3 -Q 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C) 0 ar yl > arylalkyl, 5-10 memberd heteroaryl or heteroarylalkyl and R 23 is hydrogen, Ci-C 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 - Cio 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 ) t (C 6 -Q 0 aryl), -NR 24 C(O)-(CH 2 ) t (5-10 membered heteroaryl), -NR 24 C(O)-(CH 2 MC 3 -Q 0 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 CpCg 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 -Ci 0 cycloalkyl, C 3 -Ci 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)-(CHj) 1 (C 6 -Q 0 aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), -C(0)-(CH 2 ) t (C 3 -Cio cycloalkyl), and -C(O)-(CH 2 ),(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
  • [0029J '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 -C) 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 -C, 0 aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -O-(CH 2 ),(C 3 -Ci 0 cycloalkyl), and -O-(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 Ci-C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
  • 'AlkoxycarbonyP refers to a radical -C(O)-OR 30 where R 30 represents an C,-C 8 alkyl, C 3 -
  • alkoxycarbonyl groups are C(O)O-Ci-C 8 alkyl, -C(O)O- (CH 2 ),(C 6 -Cio aryl), -C(O)O-(CH 2 ) t (5-10 membered heteroaryl), -C(O)O-(CH 2 ) t (C 3 -C, 0 cycloalkyl), and - C(O)O-(CH 2 ),(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:
  • aryloxycarbonyl is -C(O)O-(C 6 -C 10 aryl).
  • 'Substituted Aryloxycarbonyl' refers to a radical -C(O)-OR 33 where R 33 represents
  • HeteroaryloxycarbonyP 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 Heteroaryloxycarbonyl' refers to a radical -C(O)-OR 35 where R 35 represents:
  • Alkoxycarbonylamino refers to the group -NR 36 C(O)OR 37 , where R 36 is hydrogen, C,-
  • R 37 is Ci-Cg alkyl, C 3 -Ci 0 cycloalkyl, C 3 -Ci 0 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein.
  • '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 C)-C 8 alkyl group substituted with halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NfT SO 2 R " , -SO 2 NR R.
  • each R is independently selected from H, C,-C 8 alkyl, -(CH 2 ) t (C 6 -C,o aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 ) t (C 3 -C, 0 cycloalkyl).
  • 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 Q-C 4 alkoxy, unsubstiruted CpC 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • R and R independently represents H or Ci-C 8 alkyl.
  • 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 olef ⁇ nically 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
  • Alkynyl refers to acetylenically or alkynically unsaturated hydrocarbyl groups particularly having 2 to 11 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.
  • 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, 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)-, alkynyl group
  • '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
  • R 38 groups When both R 38 groups are hydrogen, -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, o aryl), -NR 39 -(CH 2 ) t (5-10 membered heteroaryl), -NR 39 -
  • each R 39 independently represents H or CpC 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
  • 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 C 1 -C 8 alkyl;
  • Substituted Alkylamino' refers to the group -NHR 4 ', wherein R 41 is C 1 -C 8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C 3 -C 10 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, unsubstituted Ci-C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted
  • Alkylarylamino' refers to the group -NR 42 R 43 , wherein R 42 is aryl and R 43 is C ,-C 8 alkyl-
  • 'Substituted Alkylarylamino' refers to the group -NR 44 R 45 , wherein R 44 is aryl and R 45 is
  • Ci-Cg alkyl and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C 3 - Cio 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 CpC 4 hydroxyalkyl, or unsubstituted C r C 4 haloalkoxy or hydroxy.
  • 'Arylamino' means a radical -NHR 46 where R 46 is selected from C 6 -Ci 0 aryl
  • Substituted Arylamino' refers to the group -NHR 47 , wherein R 47 is independently selected from C 6 -Ci 0 aryl an d 5-10 membered heteroaryl; and any aryl or heteroaryl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, cyano, unsubstituted C]-C 4 alkoxy, unsubstituted Q-C 4 haloalkyl, unsubstituted Q-C 4 hydroxyalkyl, or unsubstituted C r C 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 Ci-C 8 alkyl.
  • 'Substituted Dialkylamino' refers to the group -NR 50 R 51 , wherein each of R 59 and R 51 are independently selected from Ci-C 8 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 Ci-C 4 alkoxy, unsubstituted Cp 4 haloalkyl, unsubstituted CpC 4 hydroxyalkyl, or unsubstituted CpC 4 haloalkoxy or hydroxy.
  • '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.
  • aminosulfonyl 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 Ci-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 Q-C 4 alkyl, halo, cyano, unsubstituted C r C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted C r C 4 hydroxyalkyl, or unsubstituted Ci-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, Ci-C 8 alkyl, Ci-C 8 haloalkyl, cyano, hydroxy, C r 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 C 1 -C 8 alkyl, Ci-C 8 haloalkyl, 4-10 membered heterocycloalkyl, alkanoyl, CpC 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
  • R 60 , and R 61 are independently hydrogen, CpC 8 alkyl, Ci-C 4 haloalkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 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 Ci-C 4 alkoxy, unsubstituted C r4 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 .
  • 'Substituted Carbamoyl or substituted amido' refers to the radical -C(O)N(R 62 ) 2 wherein each R 62 is independently
  • Exemplary 'Substituted Carbamoyl' groups are -C(O) alkyl, -C(0)NR 64 -(CH 2 ) t (C 6 -C 1 o aryl),
  • each R 64 independently represents H or CpC 8 alkyl 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.
  • 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, CpC 8 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:
  • 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 S; and R 67 is independently hydrogen, Ci-C 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, Cg-Ci 0 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
  • '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).
  • Typical substituents may be selected from the group consisting of:
  • 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 6S )(O ), -OP(O)(OR 68 XOR 69 ), -C(O)R 68 , -C(S)R 68 , -C(O)OR 68 , -C(O)NR 68 R 69 , -C(O)O ' , -C(S)OR 68 , -
  • substituted groups are substituted with one or more substituents, particularly with 1 to 3 substituents, in particular with one substituent group.
  • 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 , -OC(O)R 73 , - NR 72 C(O)R 73 , -C(O)NR 73 R 72 , -NR 73 R 72 , -(CR 72 R 72 ) m OR 72 , wherein, each R 73 is independently selected from H, C 1 -C 8 alkyl, -(CH 2 MC 6 -C, 0 aryl), -(CH 2 ),(5-10 membered heteroaryl), -(CH 2 ) t (C 3 -C,o cycloalkyl), and -(CH 2 ),(4-10 membered heterocycloalkyl), wherein
  • any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present may themselves be substituted by unsubstituted CpC 4 alkyl, halo, unsubstituted CpC 4 alkoxy, unsubstituted Cp C 4 haloalkyl, unsubstituted CpC 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • Each R independently represents H or CpC 6 alkyl.
  • Substituted sulfanyl refers to the group -SR 74 , wherein R 74 is selected from:
  • Exemplary 'substituted sulfanyl' groups are -S-(CpC 8 alkyl) and -S-(C 3 -C, 0 cycloalkyl),
  • any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present may themselves be substituted by unsubstituted CpC 4 alkyl, halo, unsubstituted CpC 4 alkoxy, unsubstituted C 1 -C 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 10 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 -C 10 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:
  • 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 sulfinyl' groups are -S(O)-(CpC 8 alkyl) and -S(O)-(C 3 -C 10 cycloalkyl), -S(O)-(CH 2 MC 6 -C 10 aryl), -S(O)-(CH 2 ),(5-10 membered heteroaryl), -S(O)-(CH 2 ) t (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 CpC 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted CpC 4 haloalkyl, unsub
  • substituted sulfinyl includes the groups 'alkylsulfinyP, 'substituted alkylsulfinyP, 'cycloalkylsulfinyP, 'substituted cycloalkylsulfinyl',
  • Alkylsulfinyl refers to a radical -S(O)R 82 where R 82 is a CpC 8 alkyl group as defined herein.
  • Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl and butylsulfinyl.
  • Substituted Alkylsulfinyl 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, cyclohexylsulf ⁇ nyl, 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 -Ci 0 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, o 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 sulfonyl' refers to the group -S(O) 2 R 88 , wherein R 88 is selected from:
  • Exemplary 'substituted sulfonyF 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 10 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 Ci-C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy
  • 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 Ci-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,-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 -C 10 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylsulfonyl, cyclohexylsulfonyl, and cyclopentylsulfonyl.
  • 'Substituted cycloalkylsulfonyl' refers to the group -S(O) 2 R 92 where R 92 is a C 3 -C, 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 -C, 0 aryl group as 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 -Ci 0 cycloalkyl), -S(O) 2 -O-(CHj) 1 (C 6 -C 10 aryl), -S(O) 2 -O-(CH 2 ) t (5-10 membered heteroaryl), -S(O) 2 -O-(CH 2 X(C 3 -C 10 cycloalkyl), and -S(O) 2 -O-(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 Cj-C 4 alkyl,
  • '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 Ci-C 8 alkyl, C 3 -C] 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.
  • 'BicycloaryP 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.
  • 'BicycloheteroaryF 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.
  • 'CycloalkylalkyP 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.
  • Heterocycloalkylalkyl 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, morpholinyl ethyl, 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.
  • 'Ethylene' refers to substituted or unsubstituted -(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. [00131] '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.
  • '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.
  • 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.
  • 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.
  • '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.
  • '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
  • 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 ⁇ electrons and an atom (usually H).
  • 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.
  • 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.
  • R R
  • S S
  • 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 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.
  • each A, B, and Y are independently CR 2a R 2b ;
  • W and Z are independently CR 4 ;
  • X is -SO 2 -, -CO-, -SO 2 NR 21 S or -CONH-; nl is 0 or 1 ;
  • L 1 is a single bond or substituted or unsubstituted C 1 -C 5 alkylene; provided that when nl is 0, Ll is substituted or unsubstituted Ci -C 5 alkylene;
  • R 1 is selected from a substituted or unsubstituted aryl or heteroaryl; each of R 2a , R 2b , and R 2c is independently selected from hydrogen, and substituted or unsubstituted CpC 6 alkyl;
  • R 3 is selected from substituted or unsubstituted C r C 6 alkyl, substituted or unsubstituted C 3 -
  • R 4 is independently selected from H, Ci-C 6 alkyl, substituted Ci-C ⁇ alkyi, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, substituted arylalkyl, substituted sulfanyl, substituted sulfinyl, substituted sulfonyl, substituted or unsubstituted aminosulfonyl, sulfo, sulfonic acid ester, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstiruted C 3 -Cgcycloalkyl,
  • A is CR 2a R 2b .
  • A is CHR 2b .
  • A is CH 2 .
  • each of B and Y is independently CR 2a R 2b . In another embodiment, each of B and Y is independently CHR 2b . [00167] In one particular embodiment, with respect to compounds of formula I, B is CH 2 .
  • Y is CH 2 .
  • each of B and Y is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • R 1 is substituted or unsubstituted aryl.
  • R 1 is substituted or unsubstituted phenyl.
  • R 1 is substituted or unsubstituted heteroaryl.
  • R 1 is substituted or unsubstituted pyridyl.
  • R 1 is substituted or unsubstituted quinoline.
  • R 1 is substituted or unsubstituted isoquinoline.
  • Rl is selected from substituted or unsubstituted benzodioxole, substituted or unsubstituted benzodioxane, substituted or unsubstituted benzofuran, substituted or unsubstituted benzothiophene, and substituted or unsubstituted benzodioxepine.
  • R 1 is substituted or unsubstituted quinolin-3-yl.
  • R 1 is unsubstituted quinolin-3-yl.
  • R 1 is unsubstituted phenyl. In another embodiment, R 1 is unsubstituted pyridyl. [00180] In one particular embodiment, with respect to compounds of formula I, R 1 is phenyl, pyridyl or quinolin-3-yl, substituted with one or more substituents independently selected from halo, C r C 6 alkyl, haloCi-C 6 alkyl, C 3 -C 8 cycloalkyl, amino, aryl, heteroaryl, cyano, hydroxy, alkoxy and substituted sulfonyl.
  • n is O. In another embodiment, n is 1.
  • L 1 is a single bond.
  • L 1 is a Ci-C 5 alkylene group.
  • L 1 is -CH 2 -, -
  • W is CR 4 and R 4 is H, substituted or unsubstituted Ci-C 6 alkyl, or halo.
  • W is CR 4 and R 4 is H, Me, CF 3 , Cl or F.
  • Z is CR 4 and R 4 is
  • Z is CR 4 and R 4 is
  • each of W and Z is independently CH.
  • the compound is according to formula Ha, lib, Hc, Hd, He, Hf, Hg, Hh, Hi, or Hj:
  • the compound is according to formula Ha, lib, Hc, or Hd.
  • the compound is according to formula Hf, Hg, or Hh.
  • the compound is according to formula Hi, or Hj.
  • R 2c is H. In another embodiment, R 2c is Me, Et, n-Pr, i-Pr, or n-Bu.
  • R 3 is Me, Et, n-Pr, i-Pr, or n-Bu; and R 3 is Me, Et, n-Pr, i-Pr, or n-Bu.
  • each of R 2c and R 3 is independently Me, or Et.
  • each of R 2c and R 3 is Et. [00198]
  • R 3 is substituted or unsubstituted C
  • R 3 is unsubstituted C r C 6 alkyl.
  • R 3 is Me, Et, n-Pr, i-Pr, n-Bu, t-Bu, 1-methylpropyl, 2-methylpropyl, 2,2-dimethylpropyl, or CF 3 .
  • R 3 is C r
  • R 3 is Ci-C 6 alkyl, substituted with Cl, F or OH.
  • R 3 is CH 2 OH.
  • R 3 is CH 2 Ph.
  • R 3 is CH 2 -(2-Cl-Ph). In yet another particular embodiment, R 3 is CH 2 -
  • R 3 is C 3 -
  • C 8 cycloalkyl unsubstituted or substituted with one or more substituents independently selected from halo, hydroxyl, C r C 6 alkyl, alkoxy and haloalkyl.
  • R 3 is unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 3 is unsubstituted cyclobutyl.
  • R 3 is unsubstituted cyclopentyl.
  • R 3 is unsubstituted cyclohexyl.
  • R 3 is unsubstituted cyclobutyl.
  • R 3 is unsubstituted cyclohexyl.
  • R 3 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, substituted with one or more substituents independently selected from halo, hydroxyl, C r C 6 alkyl, alkoxy and haloalkyl.
  • R 3 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, substituted with one or more substituents independently selected from Me, Et, Cl, F, CN, OH, OMe, OEt, CF 3 , CHF 2 , OCF 3 , i-Pr, i-Bu, and t-Bu.
  • R 3 is substituted or unsubstituted heterocycloalkyl.
  • R 3 is unsubstituted pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl.
  • R 3 is pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, substituted with one or more substituents independently selected from halo, hydroxyl, C
  • R 3 is pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, substituted with one or more substituents independently selected from Me, Et, Cl, F, CN, OH, OMe, OEt, CF 3 , CHF 2 , OCF 3 , i-Pr, i-Bu, and t-Bu.
  • R 3 is pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, substituted with Me.
  • R 3 is pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, unsubstituted or substituted with Me.
  • R 3 is substituted or unsubstituted aryl or heteroaryl.
  • R 3 is phenyl, unsubstituted or substituted with one or more substituents independently selected from halo, hydroxyl, amino, cyano, sulfo, substituted sulfanyl, substituted sulfinyl, substituted sulfonyl, amido, carboxy, Q-C 6 alkoxycarbonyl, Ci-C 6 alkyl, substituted C
  • R 3 is monosubstituted phenyl.
  • R 3 is disubstituted phenyl.
  • R 3 is Ph, 2 -Cl-
  • R 3 is Ph substituted with substituted or unsubstituted amino. In another particular embodiment, R 3 is Ph substituted with NH 2 .
  • R 3 is Ph, 2-Cl-Ph, 2-F-Ph, 4-Cl-Ph, 4-F-Ph, 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-OH-Ph, or 2-OH-Ph. In another particular embodiment, R 3 is 4-OH-Ph.
  • R 3 is Ph substituted with Cl.
  • R 3 is 2-Cl-Ph, 3-Cl-Ph, or 4-Cl-Ph.
  • R 3 is 2-Cl.
  • R 3 is Ph substituted with F.
  • R 3 is 2-F-Ph, 3-F-Ph, or 4-F-Ph.
  • R 3 is 2-F.
  • R 3 is Ph substituted with OCF 3 .
  • R 3 is 3-OCF 3 -Ph.
  • R 3 is 2-OCF 3 -Ph.
  • R 3 is Ph substituted with CF 3 .
  • R 3 is 3-CF 3 -Ph.
  • R 3 is 2-CF 3 -Ph or 4-CF 3 -Ph.
  • R 3 is 2,4- difluorophenyl.
  • R 3 is Ph substituted with NO 2 .
  • R 3 is 2-NO 2 -Ph, 3-NO 2 -Ph, or 4-NO 2 -Ph.
  • R 3 is 2-NO 2 Ph.
  • R 3 is 2,4-di-NO 2 Ph.
  • R 3 is pyridyl, unsubstituted or substituted with one or more substituents independently selected from halo, hydroxyl, amino, cyano, sulfo, substituted sulfanyl, substituted sulfinyl, substituted sulfonyl, amido, carboxy, CpCe alkoxycarbonyl, C r C 6 alkyl, substituted C r C 6 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and sulfonamide.
  • R 3 is unsubstituted pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, benzoxazinyl, benzdioxolanyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thienyl, thiazolyl, oxadiazolyl, or thiadiazolyl.
  • R 3 is unsubstituted indolyl, indazolyl, thiadiazolyl, or furanyl.
  • R 3 is pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, benzoxazinyl, benzdioxolanyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thienyl, thiazolyl, oxadiazolyl, or thiadiazolyl, substituted with one or more substituents independently selected from halo, hydroxyl, amino, cyano, sulfo, substituted sulfonyl, substituted sulfanyl, amido, carboxy, C r C 6 alkoxycarbonyl, C r C 6 alkyl, substituted C
  • R 3 is unsubstituted thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, or oxadiazolyl.
  • R 3 is thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, or oxadiazolyl, substituted with one or more substituents independently selected from Me, Et, Cl, CF 3 , CO 2 Me, CO 2 Et, and NHAc.
  • R 3 is Ph, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl, or oxadiazolyl, substituted with 5- membered heteroaryl.
  • the 5-membered heteroaryl is selected from pyrrolyl, thiopheny, oxazolyl, pyrazolyl, thiazolyl, and thiadiazolyl.
  • the 5- membered heteroaryl substituted with halo or Ci-C 6 alkyl.
  • the 5- membered heteroaryl is selected from pyrrolyl, thiopheny, oxazolyl, pyrazolyl, thiazolyl, and thiadiazolyl, substituted with one or more substituents independently selected from Me, Et, Cl, and CF 3 .
  • R 3 is thiophenyl, methylthiophenyl, furanyl, methylfuranyl, pyrazolyl, or methylpyrazolyl.
  • R 3 is thiadiazolyl substituted with Me, Et, Cl, or CF 3 .
  • R 3 is thiadiazolyl substituted with Cl. In one particular embodiment, R 3 is 1,2,4-thiadiazolyl.
  • R 3 is oxadiazolyl substituted with Me, Et, Cl, CO 2 Et, or CF 3 . hi another particular embodiment, R 3 is oxadiazolyl substituted with CO 2 Et. hi one particular embodiment, R 3 is 1,2,4-oxadiazolyl.
  • R 3 is furanyl, unsubstitured or substituted with Me, Et, Cl, or CF 3 .
  • R 3 is unsubstituted furanyl. In yet another particular embodiment, R 3 is furanyl substituted with Cl. [00244] In one particular embodiment, with respect to compounds of formula I-IIj, R 3 is thiophenyl, unsubstitured or substituted with Me, Et, Cl, CO 2 Et, or CF 3 . hi another particular embodiment, R 3 is unsubstituted thiophenyl. In yet another particular embodiment, R 3 is thiophenyl substituted with Cl or CO 2 Et,.
  • R 3 is oxazoyl or thiazolyl, unsubstitured or substituted with Me, Et, Cl, or CF 3 .
  • R 3 is unsubstituted thiazolyl.
  • R 3 is thiazoyl substituted with Me or Cl.
  • R 3 is thiazoyl or oxazolyl substituted with dimethyl.
  • R 3 is pyrazolyl substituted with Me, Et, Cl, CO 2 Et, or CF 3 .
  • R 3 is pyrazolyl substituted with CO 2 Et or Me.
  • R 3 is thiophenyl, methylthiophenyl, furanyl, methylfuranyl, pyrazolyl, or methylpyrazolyl, substituted with one or more substituents independently selected from Me, Et, Cl, CF 3 , CO 2 Me, CO 2 Et, and NHAc.
  • R 3 is a phenyl, hi certain embodiments, 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, SO 2 R 2 , NR 2 R 2 , and SO 2 NR 2 R 2 .
  • 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 (orth ⁇ ), 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 phenyl is at the 2 or 4 position.
  • 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 H, Ci-C 6 alkyl, substituted C
  • 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 compound #s 7, 10, 22, 25, 29, 35, 36, 55, 69, 75, 81, 82, 84, 97, 105, 107, 1 14, 121, 123,
  • the compound is selected from compound #s 7, 22, 35, 36, 97, and 144.
  • the compound is selected from compound #s 10, 25, and 82.
  • the compound is selected from compound #s 55, 69, 81, 84, 123, 127, 129, 147, 162, 183, 239, 281, and 309.
  • the compound is selected from compound #s 105, 107, 1 14, 175, 188, 203, 204, 228, 270, and 322.
  • the compound is selected from compound #s 75, 260, 271, and 274
  • 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, N-alkylmorpholinyl esters and the like.
  • 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,
  • 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.
  • Ci to C 8 or Ci-C ⁇ alkyl C 2 -C 8 alkenyl, aryl, substituted aryl, and arylalkyl esters of the compounds of the invention.
  • 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 dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions, hi 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.
  • 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.
  • the compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • a compound of the invention is 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 is 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 (11 :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 is dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
  • Formulation 6 Topical [00286] Stearyl alcohol (250 g) and a white petrolatum (250 g) are melted at about 75 0 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) is added and the resulting mixture is stirred until it congeals.
  • 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) is added and the resulting mixture is 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. Thus, and as stated earlier, the present invention includes within its scope, and extends to, the recited methods of treatment, as well as to the compounds for such methods, and for the preparation of medicaments useful for such methods.
  • this invention provides a method of treating a mammal susceptible to or afflicted with a condition associated with arthritis, asthma, dermatitis, 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 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
  • 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 gyn
  • 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. 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.
  • 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 Scheme, 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. [00298] 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 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.
  • the compounds of the present invention may be prepared by a variety of processes well known for the preparation of compounds of this type, for example reaction schemes, and general procedures as described below.
  • R is -(X) n i-L'-R 3 ; nl is 0; and X, L 1 and R 3 are as described herein.
  • R is -(X) nI -L -R ; nl is 0; and X, L and R are as described herein.
  • Azepane-1-sulfonyl chloride (7.51 mg, 0.0380 mmol) was added dropwise and the mixture was allowed to stir at room tmeperature for 30 minutes.
  • the combined pure fractions were reduced invacuo to afford the title compound as an off white solid.
  • R is -(X) nI -L -R ; nl is O; and X, L and R are as described herein.
  • 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 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.

Landscapes

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

Abstract

L'invention concerne des composés de formule (I) : dans laquelle A, B, L1, X, W, Y, R1, R3, et n sont tels que définis. Les composés et les compositions pharmaceutiques de ceux-ci sont utiles pour la prévention et le traitement d'un grand nombre d'états chez les mammifères, y compris chez les humains, et qui comprennent, sans s'y limiter, la douleur, l'anxiété, la dépression, l'inflammation, les troubles cognitifs, les troubles du poids et de l'alimentation, la maladie de Parkinson, la maladie d'Alzheimer, la spasticité, l'addiction, le glaucome, entre autres.
PCT/US2008/008783 2007-07-19 2008-07-18 Composés utiles comme modulateurs de la faah et utilisation de ceux-ci WO2009011904A1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US95066807P 2007-07-19 2007-07-19
US60/950,668 2007-07-19
US818807P 2007-12-19 2007-12-19
US818707P 2007-12-19 2007-12-19
US820007P 2007-12-19 2007-12-19
US61/008,187 2007-12-19
US61/008,200 2007-12-19
US61/008,188 2007-12-19
US6157808P 2008-06-13 2008-06-13
US61/061,578 2008-06-13

Publications (1)

Publication Number Publication Date
WO2009011904A1 true WO2009011904A1 (fr) 2009-01-22

Family

ID=40259944

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/008783 WO2009011904A1 (fr) 2007-07-19 2008-07-18 Composés utiles comme modulateurs de la faah et utilisation de ceux-ci

Country Status (1)

Country Link
WO (1) WO2009011904A1 (fr)

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010039186A2 (fr) * 2008-09-23 2010-04-08 Renovis, Inc. Composés utiles en tant que modulateurs de la faah et leurs utilisations
WO2010059610A1 (fr) * 2008-11-19 2010-05-27 Renovis, Inc. Composés 6, 7 -dihydro- 5h- pyrrolo [3, 4-d] pyrimidin-4-yl] -quinolin-3 -ylamine s'utilisant comme modulateurs de la faah et utilisations desdits composés
WO2010135360A1 (fr) * 2009-05-18 2010-11-25 Infinity Pharmaceuticals, Inc. Isoxazolines en tant qu'inhibiteurs de l'hydrolase des amides d'acides gras
WO2011085216A2 (fr) 2010-01-08 2011-07-14 Ironwood Pharmaceuticals, Inc. Utilisation d'inhibiteurs de faah pour traiter la maladie de parkinson et le syndrome des jambes sans repos
WO2011123719A2 (fr) 2010-03-31 2011-10-06 Ironwood Pharmaceuticals, Inc. Utilisation d'inhibiteurs de faah pour le traitement des douleurs abdominales, viscérales et pelviennes
US8329675B2 (en) 2006-10-10 2012-12-11 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
WO2013134518A1 (fr) * 2012-03-09 2013-09-12 Amgen Inc. Inhibiteurs sulfamides des canaux de sodium
US8546564B2 (en) 2009-04-07 2013-10-01 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
JP2014506930A (ja) * 2011-02-28 2014-03-20 アレイ バイオファーマ、インコーポレイテッド セリン／トレオニンキナーゼインヒビター
US8765735B2 (en) 2009-05-18 2014-07-01 Infinity Pharmaceuticals, Inc. Isoxazolines as inhibitors of fatty acid amide hydrolase
US8802119B2 (en) 2009-04-07 2014-08-12 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
US8927551B2 (en) 2009-05-18 2015-01-06 Infinity Pharmaceuticals, Inc. Isoxazolines as inhibitors of fatty acid amide hydrolase
US8957049B2 (en) 2008-04-09 2015-02-17 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
US9034849B2 (en) 2010-02-03 2015-05-19 Infinity Pharmaceuticals, Inc. Fatty acid amide hydrolase inhibitors
US9062116B2 (en) 2009-04-23 2015-06-23 Infinity Pharmaceuticals, Inc. Anti-fatty acid amide hydrolase-2 antibodies and uses thereof
US9149465B2 (en) 2009-05-18 2015-10-06 Infinity Pharmaceuticals, Inc. Isoxazolines as inhibitors of fatty acid amide hydrolase
WO2019037861A1 (fr) * 2017-08-24 2019-02-28 Asceneuron S.A. Inhibiteurs de glycosidases annelés
US10336775B2 (en) 2014-08-28 2019-07-02 Asceneuron Sa Glycosidase inhibitors
WO2019146739A1 (fr) 2018-01-26 2019-08-01 塩野義製薬株式会社 Composé cyclique condensé présentant un antagonisme au récepteur d3 de la dopamine
US10556902B2 (en) 2016-02-25 2020-02-11 Asceneuron Sa Glycosidase inhibitors
US10696668B2 (en) 2016-02-25 2020-06-30 Asceneuron Sa Acid addition salts of piperazine derivatives
US10870660B2 (en) 2016-07-28 2020-12-22 Shionogi & Co., Ltd. Nitrogen-containing condensed ring compounds having dopamine D3 antagonistic effect
US11213525B2 (en) 2017-08-24 2022-01-04 Asceneuron Sa Linear glycosidase inhibitors
US11261183B2 (en) 2016-02-25 2022-03-01 Asceneuron Sa Sulfoximine glycosidase inhibitors
US11612599B2 (en) 2016-02-25 2023-03-28 Asceneuron Sa Glycosidase inhibitors
US11731972B2 (en) 2018-08-22 2023-08-22 Asceneuron Sa Spiro compounds as glycosidase inhibitors
US11795165B2 (en) 2018-08-22 2023-10-24 Asceneuron Sa Tetrahydro-benzoazepine glycosidase inhibitors
US12016852B2 (en) 2018-08-22 2024-06-25 Asceneuron Sa Pyrrolidine glycosidase inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6936619B2 (en) * 2002-03-14 2005-08-30 Pfizer, Inc. Quinazolinone compounds useful in therapy
US20070123531A1 (en) * 2003-05-02 2007-05-31 Elan Pharmaceuticals, Inc. 4-Bromo-5-(2-chloro-benzoylamino)-1h-pyrazole-3-carboxylic acid (phenyl) amide derivatives and related compounds as bradykinin b1 receptor antagonists for the treatment of inflammatory diseases
US20070161834A1 (en) * 2004-01-30 2007-07-12 Japan Science And Technology Agency Method of catalytic reaction using micro-reactor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6936619B2 (en) * 2002-03-14 2005-08-30 Pfizer, Inc. Quinazolinone compounds useful in therapy
US20070123531A1 (en) * 2003-05-02 2007-05-31 Elan Pharmaceuticals, Inc. 4-Bromo-5-(2-chloro-benzoylamino)-1h-pyrazole-3-carboxylic acid (phenyl) amide derivatives and related compounds as bradykinin b1 receptor antagonists for the treatment of inflammatory diseases
US20070161834A1 (en) * 2004-01-30 2007-07-12 Japan Science And Technology Agency Method of catalytic reaction using micro-reactor

Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8329675B2 (en) 2006-10-10 2012-12-11 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
US9108989B2 (en) 2006-10-10 2015-08-18 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
US8629125B2 (en) 2006-10-10 2014-01-14 Infinty Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
US8349814B2 (en) 2006-10-10 2013-01-08 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
US8957049B2 (en) 2008-04-09 2015-02-17 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
WO2010039186A3 (fr) * 2008-09-23 2010-11-18 Renovis, Inc. Composés utiles en tant que modulateurs de la faah et leurs utilisations
WO2010039186A2 (fr) * 2008-09-23 2010-04-08 Renovis, Inc. Composés utiles en tant que modulateurs de la faah et leurs utilisations
WO2010059610A1 (fr) * 2008-11-19 2010-05-27 Renovis, Inc. Composés 6, 7 -dihydro- 5h- pyrrolo [3, 4-d] pyrimidin-4-yl] -quinolin-3 -ylamine s'utilisant comme modulateurs de la faah et utilisations desdits composés
JP2012509332A (ja) * 2008-11-19 2012-04-19 レノビス， インコーポレイテッド Ｆａａｈ調整因子として有用な６，７−ジヒドロ−５ｈ−ピロロ［３，４−ｄ］ピリミジン−４−イル］キノリン−３−イルアミン化合物およびその使用
US8802119B2 (en) 2009-04-07 2014-08-12 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
US8546564B2 (en) 2009-04-07 2013-10-01 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
US8802064B2 (en) 2009-04-07 2014-08-12 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
US9062116B2 (en) 2009-04-23 2015-06-23 Infinity Pharmaceuticals, Inc. Anti-fatty acid amide hydrolase-2 antibodies and uses thereof
JP2012527467A (ja) * 2009-05-18 2012-11-08 インフイニトイ プハルマセウトイカルス インコーポレイテッド 脂肪酸アミドヒドロラーゼ阻害薬としてのイソオキサゾリン
CN102459202A (zh) * 2009-05-18 2012-05-16 无限药品股份有限公司 作为脂肪酸酰胺水解酶的抑制剂的异噁唑啉
US9149465B2 (en) 2009-05-18 2015-10-06 Infinity Pharmaceuticals, Inc. Isoxazolines as inhibitors of fatty acid amide hydrolase
WO2010135360A1 (fr) * 2009-05-18 2010-11-25 Infinity Pharmaceuticals, Inc. Isoxazolines en tant qu'inhibiteurs de l'hydrolase des amides d'acides gras
US8765735B2 (en) 2009-05-18 2014-07-01 Infinity Pharmaceuticals, Inc. Isoxazolines as inhibitors of fatty acid amide hydrolase
CN102459202B (zh) * 2009-05-18 2015-11-25 无限药品股份有限公司 作为脂肪酸酰胺水解酶的抑制剂的异噁唑啉
US8927551B2 (en) 2009-05-18 2015-01-06 Infinity Pharmaceuticals, Inc. Isoxazolines as inhibitors of fatty acid amide hydrolase
RU2539595C2 (ru) * 2009-05-18 2015-01-20 Инфинити Фармасьютикалз, Инк. Изоксазолины в качестве ингибиторов амидгидролазы жирных кислот
WO2011085216A2 (fr) 2010-01-08 2011-07-14 Ironwood Pharmaceuticals, Inc. Utilisation d'inhibiteurs de faah pour traiter la maladie de parkinson et le syndrome des jambes sans repos
US9034849B2 (en) 2010-02-03 2015-05-19 Infinity Pharmaceuticals, Inc. Fatty acid amide hydrolase inhibitors
US9951089B2 (en) 2010-02-03 2018-04-24 Infinity Pharmaceuticals, Inc. Methods of treating a fatty acid amide hydrolase-mediated condition
WO2011123719A2 (fr) 2010-03-31 2011-10-06 Ironwood Pharmaceuticals, Inc. Utilisation d'inhibiteurs de faah pour le traitement des douleurs abdominales, viscérales et pelviennes
WO2011123719A3 (fr) * 2010-03-31 2011-12-15 Ironwood Pharmaceuticals, Inc. Utilisation d'inhibiteurs de faah pour le traitement des douleurs abdominales, viscérales et pelviennes
JP2014506930A (ja) * 2011-02-28 2014-03-20 アレイ バイオファーマ、インコーポレイテッド セリン／トレオニンキナーゼインヒビター
WO2013134518A1 (fr) * 2012-03-09 2013-09-12 Amgen Inc. Inhibiteurs sulfamides des canaux de sodium
US9051311B2 (en) 2012-03-09 2015-06-09 Amgen Inc. Sulfamide sodium channel inhibitors
US11046712B2 (en) 2014-08-28 2021-06-29 Asceneuron Sa Glycosidase inhibitors
US10336775B2 (en) 2014-08-28 2019-07-02 Asceneuron Sa Glycosidase inhibitors
US11591327B2 (en) 2016-02-25 2023-02-28 Asceneuron Sa Acid addition salts of piperazine derivatives
US11612599B2 (en) 2016-02-25 2023-03-28 Asceneuron Sa Glycosidase inhibitors
US10696668B2 (en) 2016-02-25 2020-06-30 Asceneuron Sa Acid addition salts of piperazine derivatives
US10556902B2 (en) 2016-02-25 2020-02-11 Asceneuron Sa Glycosidase inhibitors
US11261183B2 (en) 2016-02-25 2022-03-01 Asceneuron Sa Sulfoximine glycosidase inhibitors
US10995090B2 (en) 2016-02-25 2021-05-04 Asceneuron Sa Substituted dihydrobenzofuran glycosidase inhibitors
US10870660B2 (en) 2016-07-28 2020-12-22 Shionogi & Co., Ltd. Nitrogen-containing condensed ring compounds having dopamine D3 antagonistic effect
US11345716B2 (en) 2016-07-28 2022-05-31 Shionogi & Co., Ltd. Nitrogen-containing condensed ring compounds having dopamine D3 antagonistic effect
US11897899B2 (en) 2016-07-28 2024-02-13 Shionogi & Co., Ltd. Nitrogen-containing condensed ring compounds having dopamine D3 antagonistic effect
US11213525B2 (en) 2017-08-24 2022-01-04 Asceneuron Sa Linear glycosidase inhibitors
US11458140B2 (en) 2017-08-24 2022-10-04 Asceneuron Sa Annulated glycosidase inhibitors
WO2019037861A1 (fr) * 2017-08-24 2019-02-28 Asceneuron S.A. Inhibiteurs de glycosidases annelés
WO2019146739A1 (fr) 2018-01-26 2019-08-01 塩野義製薬株式会社 Composé cyclique condensé présentant un antagonisme au récepteur d3 de la dopamine
US11578084B2 (en) 2018-01-26 2023-02-14 Shionogi & Co., Ltd. Condensed ring compounds having dopamine D3 receptor antagonistic effect
KR20200112910A (ko) 2018-01-26 2020-10-05 시오노기 앤드 컴파니, 리미티드 도파민 d3 수용체 길항 작용을 갖는 축환 화합물
US11731972B2 (en) 2018-08-22 2023-08-22 Asceneuron Sa Spiro compounds as glycosidase inhibitors
US11795165B2 (en) 2018-08-22 2023-10-24 Asceneuron Sa Tetrahydro-benzoazepine glycosidase inhibitors
US12016852B2 (en) 2018-08-22 2024-06-25 Asceneuron Sa Pyrrolidine glycosidase inhibitors

Similar Documents

Publication Publication Date Title
WO2009011904A1 (fr) Composés utiles comme modulateurs de la faah et utilisation de ceux-ci
WO2010039186A2 (fr) Composés utiles en tant que modulateurs de la faah et leurs utilisations
AU2016214132B2 (en) Autotaxin inhibitory compounds
WO2010130638A1 (fr) Composés sulfamides, compositions pharmaceutiques et leurs utilisations
CA2642130C (fr) Derives de benzylamine selectifs et leur utilite en tant qu'inhibiteurs de la proteine de transfert de l'ester de cholesterol
NZ749202A (en) Modulators of the beta-3 adrenergic receptor useful for the treatment or prevention of disorders related thereto
BRPI0619782A2 (pt) uso de pirrol [2,3-b] piridinas para preparar um medicamento para tratar dor
US20110053982A1 (en) Ether benzylidene piperidine 5-membered aryl carboxamide compounds useful as faah inhibitors
WO2010033168A2 (fr) Composés amides, compositions et utilisations des composés et compositions
EP2888242B1 (fr) 4-pyridones substituées et leur utilisation comme inhibiteurs de l'activité de l'élastase neutrophile
BRPI0713590A2 (pt) derivados de pirrol com atividade de modulador de receptor de crth2
TW201121962A (en) Compounds which selectively modulate the CB2 receptor
EP2276736A1 (fr) Composés aryl carboxamides à 5 éléments de 4-[3-(aryloxy)benzylidèn]-3-méthyl pipéridine utiles comme inhibiteurs de la faah
US20110144159A1 (en) Ether benzylidene piperidine aryl carboxamide compounds useful as faah inhibitors
AU2018223982A1 (en) 1, 4, 6-trisubstituted-2-alkyl-1H-benzo[d]imidazole derivatives as dihydroorotate oxygenase inhibitors
CN113454082A (zh) 咪唑并吡啶基化合物及其用于治疗神经退行性疾病的用途
EP3487849A1 (fr) Composés de sulfonylcycloalkyl carboxamide en tant que modulateurs de trpa1
BRPI0619422A2 (pt) derivados de cromona úteis como antagonistas de receptores vr1
CA2719789A1 (fr) Composes de 4-benzylidene-3-methylpiperidine-aryl-carboxamide utiles comme inhibiteurs de faah
WO2018015410A1 (fr) Composés de proline bicycliques
JP5539376B2 (ja) Ｆａａｈ調整因子として有用な６，７−ジヒドロ−５ｈ−ピロロ［３，４−ｄ］ピリミジン−４−イル］キノリン−３−イルアミン化合物およびその使用
CA2875628C (fr) Derives d'imidazo-oxydiazole et d'imidazo-thiadiazole
JP2018087173A (ja) 悪性脳腫瘍治療薬
WO2014072325A1 (fr) Composés [3-hétéroaryl-2-trifluorométhyl-propyl]-pipéridin-1-yle ou -morpholin-4-yle en tant qu'antagonistes de trpa1 pour le traitement de maladies respiratoires
CN118159535A (zh) 小分子sting拮抗剂

Legal Events

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

Ref document number: 08794571

Country of ref document: EP

Kind code of ref document: A1

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08794571

Country of ref document: EP

Kind code of ref document: A1