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  • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/69—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
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  • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/70—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a saturated carbon skeleton containing rings
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Definitions

• heterocyclic compounds and pharmaceutical compositions comprising such compounds.
• methods for preventing and/or treating conditions in mammals such as (but not limited to) arthritis, Parkinson's disease, Alzheimer's disease, asthma, myocardial infarction, pain syndromes (acute and chronic or neuropathic), neurodegenerative disorders, schizophrenia, cognitive disorders, anxiety, depression, inflammatory bowel disease and autoimmune disorders, and promoting neuroprotection, using the compounds and pharmaceutical compositions provided herein.
• WO 06/119504 describes fused heterocyclic compounds as P2X 3 and P2X 2/3 modulators for use in the treatment of various diseases.
• WO04/56774 describes certain substituted biphenyl-4-carboxylic acid arylamide analogues having possible application as receptor modulators.
• WO 08/119,773 describes amide derivatives as inhibitors of aspartyl proteases and their use in the treatment of Alzheimer's disease.
• WO 09/058,298 and WO 09/058,299 describe benzamide derivatives as P2X 3 receptor antagonists for treatment of pain.
• WO 05/065195 describes certain phenylamides and pyridylamides as ⁇ -secretase inhibitors.
• WO 02/070469 describes certain substituted sulfonylalkylcarboxamides as selective pde3b inhibitors
• WO 04/039753 describes certain benzoic acids and related compounds as EP1 receptor antagonists for the treatment of prostaglandin mediated diseases.
• WO03/104230 describes certain bicyclic pyrimidine derivatives
• US Published Application Serial No. 20030092908 and WO02/087513 describe fused heterocyclic PDE7 inhibitors.
• U.S. Pat. Nos. 3,424,760 and 3,424,761 both describe a series of 3-ureidopyrrolidines that are said to exhibit analgesic, central nervous system, and pyschopharmacologic activities. These patents specifically disclose the compounds 1-(1-phenyl-3-pyrrolidinyl)-3-phenyl urea and 1-(1-phenyl-3-pyrrolidinyl)-3-(4-methoxyphenyl)urea respectively.
• International Patent Applications, Publication Numbers WO 01/62737 and WO 00/69849 disclose a series of pyrazole derivatives which are stated to be useful in the treatment of disorders and diseases associated with the NPY receptor subtype Y5, such as obesity.
• WO 01/62737 specifically discloses the compound 5-amino-N-isoquinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide.
• WO 00/69849 specifically discloses the compounds 5-methyl-N-quinolin-8-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide, 5-methyl-N-quinolin-7-yl-1-[3-trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide, 5-methyl-N-quinolin-3-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide, N-isoquinolin-5-yl-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide, 5-methyl-N-quinolin-5-yl-1-[3-(trifluoromethyl)
• German Patent Application Number 2502588 describes a series of piperazine derivatives. This application specifically discloses the compound N-[3-[2-(diethylamino)ethyl]-1,2-dihydro-4-methyl-2-oxo-7-quinolinyl]-4-phenyl-1-piperazinecarboxamide.
• Fused heterocylic compounds, and pharmaceutical compositions thereof, having potency and selectivity in the prevention and treatment of conditions that have been associated with neurological and inflammatory disorders and dysfunctions are provided herein.
• compounds, pharmaceutical compositions and methods provided are useful 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 and headache (such as migraine, cluster headache and tension headache).
• compounds, pharmaceutical compositions and methods provided are useful for the treatment of inflammatory pain and associated hyperalgesia and allodynia.
• compounds, pharmaceutical compositions and methods provided are useful for the treatment of neuropathic pain and associated hyperalgesia and allodynia (e.g.
• 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, inflammatory bowel disease and autoimmune disorders, renal disorders, obesity, eating disorders, cancer, schizophrenia, epilepsy, sleeping disorders, cognitive disorders, depression, anxiety, blood pressure, and lipid disorders.
• R 1 is selected from substituted or unsubstituted aryl, or heteroaryl;
• R 1 is selected from substituted or unsubstituted 4-7 membered heterocycloalkyl.
• R 1 is selected from substituted or unsubstituted alkyl.
• R 1 is selected from substituted or unsubstituted cycloalkyl.
• one of A, B, and W is N; and the rest are independently selected from CR 4 .
• each A, B, and W is independently selected from CR 4 .
• each A, B, and W is CH.
• the compound is according to formula 2:
• compositions comprising a fused heterocyclic compound provided herein, and a pharmaceutical carrier, excipient or diluent.
• the pharmaceutical composition can comprise one or more of the compounds described herein.
• 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 for preventing, treating or ameliorating a condition that gives rise to pain responses or that relates to imbalances in the maintenance of basal activity of sensory nerves in a mammal.
• the compounds provided herein 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-masectomy pain, peripheral neuropathy, HIV neuropathy, and chemotherapy-induced and other iatrogenic neuropathies); visceral pain, (such as that associated with gastroesophageal reflex disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and various gynecological and urological disorders), dental
• a neurodegenerative disease or disorder can, for example, be Parkinson's disease, Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in neuroinflammation such as, for example, encephalitis; centrally-mediated neuropsychiatric diseases and disorders such as, for example, depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction such as, for example urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders such as, for example, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflammation such as, for example rheumatoid arthritis and osteoarthritis
• 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.
• provided are methods of making enantiomerically pure compounds according to formula 1 by asymmetric synthesis.
• provided are methods of making enantiomerically pure compounds according to formula 1 by chiral resolution.
• a still further object of this 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 the central nervous system, cardiovascular conditions, chronic pulmonary obstructive disease COPD), inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, and other diseases where an inflammatory component is present.
• diseases associated with the central nervous system including the diseases associated with the central nervous system, cardiovascular conditions, chronic pulmonary obstructive disease COPD), inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, and other diseases where an inflammatory component is present.
• 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 -C 10 cycloalkyl, C 3 -C 10 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.
• acyl groups are —C(O)H, —C(O)—C 1 -C 8 alkyl, —C(O)—(CH 2 ) t (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 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
• Substituted Acyl or ‘Substituted Alkanoyl’ refers to a radical —C(O)R 21 , wherein R 21 is independently
• Acylamino refers to a radical —NR 22 C(O)R 23 , where R 22 is hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl and R 23 is hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, as defined herein.
• 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 -C 10 aryl), —NR 24 C(O)—(CH 2 ) t (5-10 membered heteroaryl), —NR 24 C(O)—(CH 2 ) t (C 3 -C 10 cycloalkyl), and —NR 24 C(O)—(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, and each R 24 independently represents H or C 1 -C 8 alkyl.
• Substituted Acylamino refers to a radical —NR 25 C(O)R 26 , wherein:
• R 25 is independently
• R 26 is independently
• R 25 and R 26 is other than H.
• Acyloxy refers to a radical —OC(O)R 27 , where R 27 is hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 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.
• acyl groups are —C(O)H, —C(O)—C 1 -C 8 alkyl, —C(O)—(CH 2 ) t (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 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
• Substituted Acyloxy refers to a radical —OC(O)R 28 , wherein R 28 is independently
• Alkoxy refers to the group —OR 29 where R 29 is C 1 -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 10 aryl, aryloxy, carboxyl, cyano, C 3 -C 10 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 ) t (C 6 -C 10 aryl), —O—(CH 2 ) t (5-10 membered heteroaryl), —O—(CH 2 ) t (C 3 -C 10 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 C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
• Particular exemplary ‘substituted alkoxy’ groups are OCF 3 , OCH 2 CF 3 , OCH 2 Ph, OCH 2 -cyclopropyl, OCH 2 CH 2 OH, and OCH 2 CH 2 NMe 2 .
• Alkoxycarbonyl refers to a radical —C(O)—OR 30 where R 30 represents an C 1 -C s alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, 4-10 membered heterocycloalkylalkyl, aralkyl, or 5-10 membered heteroarylalkyl as defined herein.
• alkoxycarbonyl groups are C(O)O—C 1 -C 8 alkyl, —C(O)O—(CH 2 ) t (C 6 -C 10 aryl), —C(O)O—(CH 2 ) t (5-10 membered heteroaryl), —C(O)O—(CH 2 ) t (C 3 -C 10 cycloalkyl), and —C(O)O—(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 1 to 4.
• Substituted Alkoxycarbonyl refers to a radical —C(O)—OR 31 where R 31 represents:
• Aryloxycarbonyl refers to a radical —C(O)—OR 32 where R 32 represents an C 6 -C 10 aryl, as defined herein.
• exemplary “aryloxycarbonyl” groups is —C(O)O—(C 6 -C 10 aryl).
• Substituted Aryloxycarbonyl refers to a radical —C(O)—OR 33 where R 33 represents
• Heteroaryloxycarbonyl 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 32 , where R 36 is hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein, and R 37 is C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 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 (—O—C(O)—NR′′ 2 ), aminosulfonyl,
• substituted alkyl refers to a C 1 -C s alkyl group substituted with halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR′′′SO 2 R′′, —SO 2 NR′′R′′′, —C(O)R′′, —C(O)OR′′, —OC(O)R′′, —NR′′′C(O)R′′, —C(O)NR′′R′′′, —NR′′R′′′, or —(CR′′′R′′′′) m OR′′′; wherein each R′′ is independently selected from H, C 1 -C 8 alkyl, —(CH 2 ) t (C 6 -C 10 aryl), —(CH 2 ) t (5-10 membered heteroaryl), —(CH 2 ) t (C 3 -C 10 cycloalkyl), and —(CH 2 ) t (4-10 membere
• 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) 2 —.
• Alkenyl refers to monovalent olefinically unsaturated hydrocarbyl groups preferably having 2 to 11 carbon atoms, particularly, from 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation.
• Particular alkenyl groups include ethenyl (—CH ⁇ CH 2 ), n-propenyl (—CH 2 CH ⁇ CH 2 ), isopropenyl (—C(CH 3 ) ⁇ CH 2 ), vinyl and substituted vinyl, and the like.
• Substituted alkenyl refers to those groups recited in the definition of “substituted” herein, and particularly refers to an alkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)
• Alkenylene refers to divalent olefinically unsaturated hydrocarbyl groups particularly having up to about 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 olefinic unsaturation. This term is exemplified by groups such as ethenylene (—CH ⁇ CH—), the propenylene isomers (e.g., —CH ⁇ CHCH 2 — and —C(CH 3 ) ⁇ CH— and —CH ⁇ C(CH 3 )—) and the like.
• 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.
• alkynyl groups include acetylenic, ethynyl (—C ⁇ CH), propargyl (—CH 2 C ⁇ CH), and the like.
• Substituted alkynyl refers to those groups recited in the definition of “substituted” herein, and particularly refers to an alkynyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S
• Amino refers to the radical —NH 2 .
• Substituted amino refers to an amino group substituted with one or more of those groups recited in the definition of ‘substituted’ herein, and particularly refers to the group —N(R 38 ) 2 where each R 38 is independently selected from:
• Alkylamino refers to the group —NHR 40 , wherein R 40 is C 1 -C 8 alkyl.
• Substituted Alkylamino refers to the group —NHR 41 , 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 -C 10 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
• Alkylarylamino refers to the group —NR 42 R 43 , wherein R 42 is aryl and R 43 is C 1 -C 8 alkyl.
• Substituted Alkylarylamino refers to the group —NR 44 R 45 , wherein R 44 is aryl and R 45 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 -C 10 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, cyano, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4
• Arylamino means a radical —NHR 46 where R 46 is selected from C 6 -C 10 aryl and 5-10 membered heteroaryl as defined herein.
• Substituted Arylamino refers to the group —NHR 47 , wherein R 47 is independently selected from C 6 -C 10 aryl and 5-10 membered heteroaryl; and any aryl or heteroaryl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, cyano, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -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 C 1 -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 C 1 -C 8 alkyl; and at least one of the alkyl groups is independently substituted with halo, hydroxy, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1-4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 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 -C 10 aryl.
• aminosulfonyl or ‘Sulfonamide’ refers to the radical —S(O 2 )NH 2 .
• Substituted aminosulfonyl or ‘substituted sulfonamide’ refers to a radical such as —S(O 2 )N(R 54 ) 2 wherein each R 548 is independently selected from:
• Exemplary ‘substituted aminosulfonyl’ or ‘substituted sulfonamide’ groups are —S(O 2 )N(R 55 )—C 1 -C 8 alkyl, —S(O 2 )N(R 55 )—(CH 2 ) t (C 6 -C 10 aryl), —S(O 2 )N(R 55 )—(CH 2 ) t (5-10 membered heteroaryl), —S(O 2 )N(R 55 )—(CH 2 ) t (C 3 -C 10 cycloalkyl), and —S(O 2 )N(R 55 )—(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4; each R 55 independently represents H or C 1 -C 8 alkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by
• 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 C 1 -C 4 alkyl, halo, cyano, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -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 6 to 10. Where the aryl group is a monocyclic ring system it preferentially contains 6 carbon atoms.
• Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene, 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. Particularly, ‘Substituted Aryl’ refers to an aryl group substituted with one or more of groups selected from halo, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, cyano, hydroxy, C 1 -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, C 1 -C 8 haloalkyl, 4-10 membered heterocycloalkyl, alkanoyl, C 1 -C 8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , NR 58 SOR 59 NR 58 SO 2 R 59 , COOalkyl, COOaryl, CONR 58 R 59 , CONR 58 OR 59 , NR 58 R 59 , SO 2 NR 58 R 59 , S-alkyl, SOalkyl, SO 2 alkyl, Saryl, SOaryl, SO 2 aryl; or R 56 and R 57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or
• R 60 and R 61 are independently hydrogen, C 1 -C 8 alkyl, C 1 -C 4 haloalkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 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.
• Substituted Arylalkyloxy refers to an —O-alkylaryl radical where alkylaryl is as defined herein; and any aryl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, cyano, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1-4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy.
• 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
• 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
• Cyano refers to the radical —CN.
• 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.
• Particular heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
• heteroaryls examples include the following:
• each Y is selected from carbonyl, N, NR 65 , O and S; and R 65 is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 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, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 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, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl,
• These heterocycloalkyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy,
• Hydrophilicity refers to the radical —OH.
• Niro 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:
• 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 ) t (C 6 -C 10 aryl), —(CH 2 ) t (5-10 membered heteroaryl), —(CH 2 ) t (C 3 -C 10 cycloalkyl), and —(CH 2 ) t (4-10 membered heterocycloalkyl),
• Substituted sulfanyl refers to the group —SR 74 , wherein R 74 is selected from:
• Exemplary ‘substituted sulfanyl’ groups are —S—(C 1 -C 8 alkyl) and —S—(C 3 -C 10 cycloalkyl), —S—(CH 2 ) t (C 6 -C 10 aryl), —S—(CH 2 ) t (5-10 membered heteroaryl), —S—(CH 2 ) t (C 3 -C 10 cycloalkyl), and —S—(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 haloalkyl, unsubstituted C 1 -C 4
• substituted sulfanyl includes the groups ‘alkylsulfanyl’ or ‘alkylthio’, ‘substituted alkylthio’ or ‘substituted alkylsulfanyl’, ‘cycloalkylsulfanyl’ or ‘cycloalkylthio’, ‘substituted cycloalkylsulfanyl’ or ‘substituted cycloalkylthio’, ‘arylsulfanyl’ or ‘arylthio’ and ‘heteroarylsulfanyl’ or ‘heteroarylthio’ as defined below.
• Alkylthio or ‘Alkylsulfanyl’ refers to a radical —SR 75 where R 75 is a C 1 -C 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 C 1 -C 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 -C 10 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:
• Exemplary ‘substituted sulfinyl’ groups are —S(O)—(C 1 -C 8 alkyl) and —S(O)—(C 3 -C 10 cycloalkyl), —S(O)—(CH 2 ) t (C 6 -C 10 aryl), —S(O)—(CH 2 ) t (5-10 membered heteroaryl), —S(O)—(CH 2 ) t (C 3 -C 10 cycloalkyl), and —S(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 C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4
• substituted sulfinyl includes the groups ‘alkylsulfinyl’, ‘substituted alkylsulfinyl’, ‘cycloalkylsulfinyl’, ‘substituted cycloalkylsulfinyl’, ‘arylsulfinyl’ and ‘heteroarylsulfinyl’ as defined herein.
• Alkylsulfinyl refers to a radical —S(O)R 82 where R 82 is a C 1 -C 8 alkyl group as defined herein. Representative examples include, but are not limited to, 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, cyclohexylsulfinyl, and cyclopentylsulfinyl. Exemplary ‘cycloalkylsulfinyl’ groups are S(O)—C 3 -C 10 cycloalkyl.
• Substituted cycloalkylsulfinyl refers to the group —S(O)R 85 where R 85 is a C 3 -C 10 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
• Arylsulfinyl refers to a radical —S(O)R 86 where R 86 is a C 6 -C 10 aryl group as defined herein.
• Heteroarylsulfinyl refers to a radical —S(O)R 87 where R 87 is a 5-10 membered heteroaryl group as defined herein.
• Substituted sulfonyl refers to the group —S(O) 2 R 88 , wherein R 88 is selected from:
• Exemplary ‘substituted sulfonyl’ groups are —S(O) 2 —(C 1 -C 8 alkyl) and —S(O) 2 —(C 3 -C 10 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 10 cycloalkyl), and —S(O) 2 —(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, un
• substituted sulfonyl includes the groups alkylsulfonyl, substituted alkylsulfonyl, cycloalkylsulfonyl, substituted cycloalkylsulfonyl, arylsulfonyl and heteroarylsulfonyl.
• Alkylsulfonyl refers to a radical —S(O) 2 R 89 where R 89 is an C 1 -C 8 alkyl group as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl and butylsulfonyl.
• Substituted Alkylsulfonyl refers to a radical —S(O) 2 R 90 where R 90 is an C 1 -C 8 alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.
• Cycloalkylsulfonyl refers to a radical —S(O) 2 R 91 where R 90 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 10 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 10 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:
• Exemplary ‘Substituted sulfo’ or ‘sulfonic acid ester’ groups are —S(O) 2 —O—(C 1 -C 8 alkyl) and —S(O) 2 —O—(C 3 -C 10 cycloalkyl), —S(O) 2 —O—(CH 2 ) t (C 6 -C 10 aryl), —S(O) 2 —O—(CH 2 ) t (5-10 membered heteroaryl), —S(O) 2 —O—(CH 2 ) t (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 C 1 -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 C 1 -C 3 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -C 10 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl, as defined herein; or where two R 96 groups, when attached to the same N, are joined to form an alkylene group.
• Bicycloaryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent bicycloaromatic ring system.
• Typical bicycloaryl groups include, but are not limited to, groups derived from indane, indene, naphthalene, tetrahydronaphthalene, and the like. Particularly, an aryl group comprises from 8 to 11 carbon atoms.
• Bicycloheteroaryl 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
• the bicycloheteroaryl group is between 9-11 membered bicycloheteroaryl, with 5-10 membered heteroaryl being particularly preferred.
• Particular bicycloheteroaryl groups are those derived from benzothiophene, benzofuran, benzothiazole, indole, quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane.
• Cycloalkylalkyl refers to a radical in which a cycloalkyl group is substituted for a hydrogen atom of an alkyl group.
• Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.
• 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, morpholinylethyl, and the like.
• Cycloalkenyl refers to cyclic hydrocarbyl groups having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefinic unsaturation.
• Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.
• Substituted cycloalkenyl refers to those groups recited in the definition of “substituted” herein, and particularly refers to a cycloalkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—,
• Fused Cycloalkenyl refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation located to impart aromaticity to the cycloalkenyl ring.
• Ethenyl refers to substituted or unsubstituted —(C ⁇ C)—.
• Ethylene refers to substituted or unsubstituted —(C—C)—.
• ‘Hydrogen bond donor’ group refers to a group containing 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 dihydroxyphosphoryl refers to those groups recited in the definition of “substituted” herein, and particularly refers to a dihydroxyphosphoryl radical wherein one or both of the hydroxyl groups are substituted. Suitable substituents are described in detail below.
• Aminohydroxyphosphoryl refers to the radical —PO(OH)NH 2 .
• Substituted aminohydroxyphosphoryl refers to those groups recited in the definition of “substituted” herein, and particularly refers to an aminohydroxyphosphoryl wherein the amino group is substituted with one or two substituents. Suitable substituents are described in detail below. In certain embodiments, the hydroxyl group can also be substituted.
• ‘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.
• Thioketo refers to the group ⁇ S.
• 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-toluenesulfonic acid
• 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.
• the “therapeutically effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
• Preventing 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). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.
• 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.
• double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
• 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 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’.
• enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
• An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or ( ⁇ )-isomers respectively).
• a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.
• 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). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
• 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. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
• provided herein are compounds useful for preventing and/or treating a broad range of conditions, among them, arthritis, Parkinson's disease, Alzheimer's disease, stroke, uveitis, asthma, myocardial infarction, the treatment and prophylaxis of pain syndromes (acute and chronic or neuropathic), traumatic brain injury, acute spinal cord injury, neurodegenerative disorders, alopecia (hair loss), inflammatory bowel disease and autoimmune disorders or conditions in mammals.
• R 1 is selected from substituted or unsubstituted 4-7 membered heterocycloalkyl.
• R 1 is selected from substituted or unsubstituted alkyl.
• R 1 is selected from substituted or unsubstituted cycloalkyl.
• R 4 is other than hydroxy, alkoxy, aryloxy, or heteroaryloxy.
• the invention does not include compounds wherein R 4 is hydroxy, alkoxy, aryloxy, or heteroaryloxy.
• one of A, B, and W is N; and the rest are independently selected from CR 4 .
• each A, B, and W is independently selected from CR 4 .
• each A, B, and W is CH.
• R 1 is selected from substituted or unsubstituted 4-7 membered heterocycloalkyl
• the compound is according to formula 2:
• L is selected from —CH 2 —, —CHMe-, —CMe 2 -, —(CH 2 ) 2 —, —CMe 2 -CH 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —CH(CH 3 )CH 2 —, —(CH 2 ) 2 SCH 2 —, —(CH 2 ) 2 —SO 2 CH 2 —, —CH(CH 2 CH 3 )CH 2 OCH 2 —, —CH 2 CHF—, —CH 2 CF 2 —, —CH 2 CH(OH)—, —CH(CH 2 OH)—, —CH(CH 2 CH 2 OH)—, and —CH 2 CO—.
• L is selected from —CH 2 —, —CHMe-, —CMe 2 -, —(CH 2 ) 2 —, —CMe 2 -CH 2 —)—, —CH(CH 2 OH)—, —CH(CH 2 CH 2 OH)—, and —(CH 2 ) 3 —.
• L is selected from —CH 2 —, —(CH 2 ) 2 —, —CHMe-, and —C(Me)H—CH 2 —.
• each R 4a , and R 4b is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsub
• L is selected from —CH 2 —, —CHMe-, —CMe 2 -, —(CH 2 ) 2 —, —CMe 2 -CH 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —CH(CH 3 )CH 2 —, —(CH 2 ) 2 SCH 2 —, —(CH 2 ) 2 —SO 2 CH 2 —, —CH(CH 2 CH 3 ) CH 2 OCH 2 —, —CH 2 CHF—, —CH 2 CF 2 —, —CH 2 CH(OH)—, —CH(CH 2 OH)—, —CH(CH 2 CH 2 OH)—, and —CH 2 CO—.
• L is selected from —CH 2 —, —CHMe-, —(CH 2 ) 2 —, —CMe 2 -CH 2 —)—, —CH(CH 2 OH)—, —CH(CH 2 CH 2 OH)—, and —(CH 2 ) 3 —.
• L is selected from —CH 2 —, and —CHMe-.
• R 3 is substituted or unsubstituted azetidine, pyrrolidine, piperidinyl, morpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, or azepinyl.
• R 3 is azetidine, pyrrolidine, piperidinyl, morpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, or azepinyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo.
• R 3 is azetidine, pyrrolidine, piperidinyl, morpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, or azepinyl, substituted with oxo.
• R 3 is
• R 3a is independently selected from hydrogen, or substituted or unsubstituted alkyl.
• the compound is according to formula 3aa, 4aa, 5aa, 6aa, 7aa, or 8aa:
• m′ is 1, 2 or 3.
• the compound is according to formula 9aa, 10aa, 11aa, 12aa, 13aa, or 14aa:
• R 3a is H or alkyl.
• R 3a is H, Me, Et, or i-Pr.
• X′ is CR 4a .
• X′ is N.
• X′ is CR 4a ; and R 4a is independently H, C 1 -C 4 alkyl, halo C 1 -C 4 alkyl, CN, NO 2 , or halo.
• X′ is CR 4a ; and R 4a is H, Me, CF 3 , Cl, F, CN or NO 2 .
• X′ is CR 4a ; and R 4a is Cl or CN.
• R 4b is H, C 1 -C 4 alkyl or halo C 1 -C 4 alkyl or halo.
• R 4b is H, Me, CF 3 , Cl or F.
• each of R 2a and R 2b is hydrogen.
• one of R 2a and R 2b is methyl, hydroxymethyl or hydroxyethyl.
• each of R 2a and R 2b is methyl.
• R 2a and R 2b join together to form a cycloalkyl ring.
• R 2a and R 2b join together to form a cyclopropyl ring.
• R 2a is selected from Me, Et, n-Pr, t-Bu, CF 3 , CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 OAc, CH 2 (CH 2 ) 2 OH, CH 2 CH 2 NHMe, CH 2 NMe 2 , CH 2 CH 2 NMe 2 , CH 2 CONH 2 , CH 2 CONMe 2 , CH 2 COOH, CH 2 CH 2 COOH, CH 2 (CH 2 ) 2 COOH, CH 2 OMe, and CH 2 CH 2 OMe; and R 2b is H.
• R 2a is selected from CH 2 NR 2′ R 2′′ , CH 2 CH 2 NR 2′ R 2′′ , CH 2 CH 2 CH 2 NR 2′ R 2′′ and wherein R 2′ and R 2′′ can join together to form a heterocyclic ring; and R 2b is H.
• R 2a is selected from cyclopropyl, cyclobutyl or cyclohexyl; and R 2b is H.
• R 2a is CH 2 OH or CH 2 CH 2 OH; and R 2b is H.
• R 1 is substituted or unsubstituted alkyl.
• R 1 is Me, Et, i-Pr, or t-Bu.
• R 1 is substituted or unsubstituted aryl or heteroaryl.
• R 1 is substituted or unsubstituted bicycloaryl, bicycloalkyl, or bicycloheteroaryl.
• R 1 is substituted or unsubstituted phenyl.
• R 1 is substituted or unsubstituted pyridyl, pyrimidinyl or pyrazinyl.
• R 1 is selected from substituted or unsubstituted quinolinyl, isoquinolinyl, methylenedioxyphenyl, imidazopyridyl, benzoxazolyl, and indolyl.
• R 1 is
• each R 5b is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted
• R 1 is as described above and the subscript n2 is 1, 2 or 3.
• R 1 is as described above and the subscript n2 is 1 or 2.
• R 1 is
• each R 5b is independently selected from H, alkyl, halo, cyano, alkoxy, and haloalkyl.
• R 1 is as described above and each R 5b is independently selected from H, Me, Et, Pr, iso-Pr, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CO 2 Me, CH 2 —N-morpholino, CH 2 —N-(4-Me-piperidino), NH 2 , CONH 2 , CF 3 , CHF 2 , OCF 3 , OCHF 2 , t-Bu, SMe, CH ⁇ CH—CO 2 H, SOMe, SO 2 Me, SO 2 CF 3 , SO 2 NH2, SO 3 H, SO 3 Me, cyclopropyl, triazolyl, morpholinyl, and pyridyl.
• each R 5b is independently selected from H, Cl, F, Me, or CF 3 .
• the compound is selected from the group consisting of
• R 3 is substituted or unsubstituted 6-10 membered aryl.
• R 3 is substituted or unsubstituted 6-10 membered heteroaryl.
• the invention does not include 5 membered heteroaryls, for example pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl and the like.
• R 3 is substituted or unsubstituted bicycloaryl, bicycloalkyl, or bicycloheteroaryl.
• R 3 is substituted or unsubstituted phenyl.
• R 3 is substituted or unsubstituted pyridyl, pyrazinyl or unsubstituted pyrimidinyl.
• R 3 is selected from substituted or unsubstituted quinolinyl, isoquinolinyl, methylenedioxyphenyl, imidazopyridyl, benzoxazolyl, and indolyl.
• R 3 is
• R 1 is unsubstituted heterocycloalkyl.
• R 1 substituted heterocycloalkyl
• R 1 is heterocycloalkyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo.
• R 1 is heterocycloalkyl, substituted with one or more groups selected from alkyl, halo, haloalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo.
• R 1 is selected from substituted or unsubstituted aryl, and heteroaryl; or
• R 1 is selected from substituted or unsubstituted aryl, and heteroaryl; or
• R 1 is substituted or unsubstituted cycloalkyl
• the compound is according to formulae 6, 7, 8, 9, 10, or 11:
• n2 0.
• n2 is 1.
• each R 4a is independently H, C 1 -C 4 alkyl, halo C 1 -C 4 alkyl, CN, NO 2 , or halo.
• each R 4a is H, Me, CF 3 , Cl, F, CN or NO 2 .
• R 4a is Cl or CN.
• R 4b is H, C 1 -C 4 alkyl or halo C 1 -C 4 alkyl or halo.
• R 4b is H, Me, CF 3 , Cl or F.
• subscript n1 is 1, 2 or 3.
• subscript n1 is 1 or 2.
• subscript n1 is 1.
• each R 5a is independently selected from H, alkyl, halo, cyano, alkoxy, and haloalkyl.
• each R 5a is independently selected from H, Me, Et, Pr, iso-Pr, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CO 2 Me, CH 2 —N-morpholino, CH 2 —N-(4-Me-piperidino), NH 2 , CONH 2 , CF 3 , CHF 2 , OCF 3 , OCHF 2 , t-Bu, SMe, CH ⁇ CH—CO 2 H, SOMe, SO 2 Me, SO 2 CF 3 , SO 2 NH 2 , SO 3 H, SO 3 Me, cyclopropyl, triazolyl, morpholinyl, and pyridyl.
• each R 5a is independently selected from H, Cl, F, Me, or CF 3 .
• each R 5a is H.
• R 1 is selected from substituted or unsubstituted aryl, and heteroaryl.
• R 1 is selected from alkyl, and hydroxyalkyl; or R 1 is heterocycloalkyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo.
• R 1 is heterocycloalkyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo.
• R 1 is other than aryl or heteroaryl.
• R 1 is unsubstituted aryl or heteroaryl.
• R 1 is selected from substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.
• R 1 is substituted or unsubstituted alkyl.
• R 1 is alkyl
• R 1 is hydroxyalkyl
• R 1 is unsubstituted heterocycloalkyl.
• R 1 is heterocycloalkyl, unsubstituted or substituted with one or more groups selected from alkyl, haloalkyl, and oxo.
• R 1 is heterocycloalkyl, substituted with one or more groups selected from alkoxyalkyl, aminoalkyl, and dialkylaminoalkyl, alkylsulfonylalkyl, and oxo.
• R 1 is heterocycloalkyl, substituted with alkylsulfonylalkyl.
• each of R 2a and R 2b is independently selected from hydrogen, C 2 -C 4 alkyl, hydroxyalkyl, and halo. In another embodiment, each of R 2a and R 2b is independently selected from hydrogen, C 2 -C 4 alkyl, and hydroxyalkyl.
• R 2a and R 2b join together to form a cycloalkyl or heterocycloalkyl ring of 3-7 atoms.
• R 2a and R 2b join together to form a cycloalkyl ring of 3-7 atoms.
• R 2a and R 2b join together to form a cyclopropyl ring.
• n2 is 1; and R 1 is unsubstituted heterocycloalkyl.
• n2 is 1; and R 1 substituted heterocycloalkyl.
• the subscript n2 is 1; and R 1 is heterocycloalkyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo.
• R 1 is heterocycloalkyl, substituted with one or more groups selected from alkyl, halo, haloalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo.
• R 1 is selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and azepinyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo.
• R 1 is selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and azepinyl, substituted with oxo.
• R 1 is selected from morpholinyl, and 1,1-dioxo-thiomorpholinyl.
• the subscript n2 is 1; and R 1 is selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and azepinyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo.
• the subscript n2 is 1; and R 1 is selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and azepinyl, unsubstituted or substituted with alkyl.
• n2 is 1; and R 1 is selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and azepinyl, substituted with oxo.
• n2 is 1; and R 1 is selected from morpholinyl, and 1,1-dioxo-thiomorpholinyl.
• R 3 is unsubstituted N containing heterocycloalkyl; and the heterocycloalkyl is attached to the core group via the N.
• R 3 is N containing heterocycloalkyl, substituted with one or more groups selected from alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo; and the heterocycloalkyl is attached to the core group via the N.
• R 3 is N containing heterocycloalkyl, substituted with one or more groups selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo.
• R 3 is N containing heterocycloalkyl, substituted with hydroxyalkyl.
• R 3 is N containing heterocycloalkyl, substituted with oxo.
• R 3 is unsubstituted azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, or azepinyl.
• R 3 is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, or azepinyl, unsubstituted or substituted with one or more groups selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo.
• R 3 is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, or azepinyl, substituted with one or more groups selected from hydroxyalkyl, and oxo.
• R 3 is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, or azepinyl, substituted with oxo.
• R 3 is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, or azepinyl, substituted with hydroxyalkyl.
• R 3 is
• the compound is according to formula 12, 13, 14, 15, 16, or 17:
• the subscript m′ is 1, 2 or 3.
• the compound is according to formulae 18, 19, 20, 21, 22, or 23:
• each of R 2a and R 2b is independently selected from hydrogen, C 1 -C 4 alkyl, and halo. In another embodiment, each of R 2a and R 2b is independently selected from hydrogen, and C 1 -C 4 alkyl.
• R 2a and R 2b join together to form a cycloalkyl or heterocycloalkyl ring of 3-7 atoms.
• R 2a and R 2b join together to form a cycloalkyl ring of 3-7 atoms.
• each of R 2a and R 2b is hydrogen.
• one of R 2a and R 2b is hydrogen.
• one of R 2a and R 2b is methyl, hydroxymethyl or hydroxyethyl.
• each of R 2a and R 2b is methyl.
• R 2a and R 2b join together to form a cycloalkyl ring.
• R 2a and R 2b join together to form a cyclopropyl ring.
• R 2a is selected from Me, Et, n-Pr, t-Bu, CF 3 , CH 2 OH, CH 2 CH 2 OH, CH 2 (CH 2 ) 2 OH, CH 2 CH 2 NHMe, CH 2 NMe 2 , CH 2 CH 2 NMe 2 , CH 2 OMe, and CH 2 CH 2 OMe; and R 2b is H.
• R 2a is selected from Me, Et, n-Pr, t-Bu; and R 2b is H.
• R 2a is selected from CH 2 OH, CH 2 CH 2 OH, CH 2 (CH 2 ) 2 OH, CH 2 OMe, and CH 2 CH 2 OMe; and R 2b is H.
• R 2a is selected from CF 3 , and CH 2 CF 3 ; and R 2b is H.
• R 2a is selected from CH 2 NR 2′ R 2′′ , CH 2 CH 2 NR 2′ R 2′′ , CH 2 CH 2 CH 2 NR 2′ R 2′′ and wherein R 2′ and R 2′′ can join together to form a heterocyclic ring; and R 2b is H.
• R 2a is selected from cyclopropyl, cyclobutyl or cyclohexyl; and R 2b is H.
• R 2a is CH 2 OH or CH 2 CH 2 OH; and R 2b is H.
• n2 is 1.
• R 3a is H or alkyl.
• R 3a is H, Me, Et, or i-Pr.
• X′ is CR 4a .
• X′ is N.
• X′ is CR 4a ; and R 4a is independently H, C 1 -C 4 alkyl, halo C 1 -C 4 alkyl, CN, NO 2 , or halo.
• X′ is CR 4a ; and R 4a is H, Me, CF 3 , Cl, F, CN or NO 2 .
• X′ is CR 4a ; and R 4a is Cl or CN.
• R 4b is H, C 1 -C 4 alkyl or halo C 1 -C 4 alkyl or halo.
• R 4b is H, Me, CF 3 , Cl or F.
• R 1 is other than aryl or heteroaryl.
• R 1 is aryl or heteroaryl.
• R 1 is selected from substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.
• R 1 is substituted or unsubstituted alkyl.
• R 1 is hydroxyalkyl
• R 1 is alkyl
• R 1 is Et, i-Pr, or t-Bu.
• R 1 is substituted or unsubstituted cycloalkyl.
• R 1 is substituted or unsubstituted heterocycloalkyl.
• R 1 is selected from substituted or unsubstituted pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, and azepinyl.
• R 1 is selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and azepinyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo.
• R 1 is selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and azepinyl, substituted with oxo.
• R 1 is selected from morpholinyl, and 1,1-dioxo-thiomorpholinyl.
• n2 is 1; and R 1 is selected from substituted or unsubstituted pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, and azepinyl.
• n2 is 1; and R 1 is selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and azepinyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo.
• n2 is 1; and R 1 is selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and azepinyl, substituted with oxo.
• n2 is 1; and R 1 is selected from morpholinyl, and 1,1-dioxo-thiomorpholinyl.
• R 1 is selected from substituted or unsubstituted bicycloaryl, bicycloalkyl, or bicycloheteroaryl.
• R 1 is selected from substituted or unsubstituted pyridyl, pyrazinyl or unsubstituted pyrimidinyl.
• R 1 is selected from substituted or unsubstituted quinolinyl, isoquinolinyl, methylenedioxyphenyl, imidazopyridyl, benzoxazolyl, and indolyl.
• R1 is
• n3 is 1, 2 or 3.
• n3 is 1 or 2.
• R 1 is
• each R 5b is independently selected from H, alkyl, halo, cyano, alkoxy, and haloalkyl.
• each R 5b is independently selected from H, Me, Et, Pr, iso-Pr, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CO 2 Me, CH 2 —N-morpholino, CH 2 —N-(4-Me-piperidino), NH 2 , CONH 2 , CF 3 , CHF 2 , OCF 3 , OCHF 2 , t-Bu, SMe, CH ⁇ CH—CO 2 H, SOMe, SO 2 Me, SO 2 CF 3 , SO 2 NH 2 , SO 3 H, SO 3 Me, cyclopropyl, triazolyl, morpholinyl, and pyridyl.
• each R 5b is independently selected from H, Cl, F, Me, or CF 3 .
• the compound is according to formulae 3a, 4a, or 5a:
• the compound is according to formulae 6a, 7a, 8a, 9a, 10a, or 11a:
• the compound is according to formula 12a, 13a, 14a, 15a, 16a, or 17a:
• the compound is according to formulae 18a, 19a, 20a, 21a, 22a, or 23a:
• R 1 is selected from substituted or unsubstituted pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, and azepinyl.
• nd R 1 is selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and azepinyl, unsubstituted or substituted with one or more groups selected from alkyl, halo, haloalkyl, alkoxyalkyl, aminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, and oxo.
• R 1 is selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and azepinyl, substituted with oxo.
• R 1 is selected from morpholinyl, and 1,1-dioxo-thiomorpholinyl.
• R 3a is H or alkyl.
• R 3 a is H, Me, Et, or i-Pr.
• X′ is CR 4a .
• X′ is N.
• X′ is CR 4a ; and R 4a is independently H, C 1 -C 4 alkyl, halo C 1 -C 4 alkyl, CN, NO 2 , or halo.
• X′ is CR 4a ; and R 4a is H, Me, CF 3 , Cl, F, CN or NO 2 .
• X′ is CR 4a ; and R 4a is Cl or CN.
• R 4b is H, C 1 -C 4 alkyl or halo C 1 -C 4 alkyl or halo.
• R 4b is H, Me, CF 3 , Cl or F.
• each of R 2a and R 2b is hydrogen.
• each of R 2a and R 2b is hydrogen.
• one of R 2a and R 2b is methyl, hydroxymethyl or hydroxyethyl.
• each of R 2a and R 2b is methyl.
• R 2a and R 2b join together to form a cycloalkyl ring.
• R 2a and R 2b join together to form a cyclopropyl ring.
• R 2a is selected from Me, Et, n-Pr, t-Bu, CF 3 , CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 OAc, CH 2 (CH 2 ) 2 OH, CH 2 CH 2 NHMe, CH 2 NMe 2 , CH 2 CH 2 NMe 2 , CH 2 CONH 2 , CH 2 CONMe 2 , CH 2 COOH, CH 2 CH 2 COOH, CH 2 (CH 2 ) 2 COOH, CH 2 OMe, and CH 2 CH 2 OMe; and R 2b is H.
• R 2a is selected from CH 2 NR 2′ R 2′′ , CH 2 CH 2 NR 2′ R 2′′ , CH 2 CH 2 CH 2 NR 2′ R 2′′ and wherein R 2′ and R 2′′ can join together to form a heterocyclic ring; and R 2b is H.
• R 2a is selected from cyclopropyl, cyclobutyl or cyclohexyl; and R 2b is H.
• R 2a is CH 2 OH or CH 2 CH 2 OH; and R 2b is H.
• R 1 is Me. E t , i-Pr, or t-Bu.
• R 1 is substituted or unsubstituted aryl or heteroaryl.
• the compound is according to formula 3b, 4b, 5b, 6b, 7b, or 8b:
• the subscript m′ is 1, 2 or 3.
• the compound is according to formula 9b, 10b, 11b, 12b, 13b, or 14b:
• R 3a is H or alkyl.
• R 3a is H, Me, Et, or i-Pr.
• the compound is according to formula 3c, 4c, or 5c:
• the compound is according to formula 6c, 7c, 8c, 9c, 10c or 11c:
• X′ is CR 4a .
• X′ is N.
• X′ is CR 4a ; and R 4a is independently H, C 1 -C 4 alkyl, halo C 1 -C 4 alkyl, CN, NO 2 , or halo.
• X′ is CR 4a ; and R 4a is H, Me, CF 3 , Cl, F, CN or NO 2 .
• X′ is CR 4a ; and R 4a is Cl or CN.
• R 4b is H, C 1 -C 4 alkyl or halo C 1 -C 4 alkyl or halo.
• R 4b is H, Me, CF 3 , Cl or F.
• each of R 2a and R 2b is hydrogen.
• one of R 2a and R 2b is methyl, hydroxymethyl or hydroxyethyl.
• each of R 2a and R 2b is methyl.
• R 2a and R 2b join together to form a cycloalkyl ring.
• R 2a and R 2b join together to form a cyclopropyl ring.
• R 2a is selected from Me, Et, n-Pr, t-Bu, CF 3 , CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 OAc, CH 2 (CH 2 ) 2 OH, CH 2 CH 2 NHMe, CH 2 NMe 2 , CH 2 CH 2 NMe 2 , CH 2 CONH 2 , CH 2 CONMe 2 , CH 2 COOH, CH 2 CH 2 COOH, CH 2 (CH 2 ) 2 COOH, CH 2 OMe, and CH 2 CH 2 OMe; and R 2b is H.
• R 2a is selected from CH 2 NR 2′ R 2′′ , CH 2 CH 2 NR 2′ R 2′′ , CH 2 CH 2 CH 2 NR 2′ R 2′′ and wherein R 2′ and R 2′′ can join together to form a heterocyclic ring; and R 2b is H.
• R 2a is selected from cyclopropyl, cyclobutyl or cyclohexyl; and R 2b is H.
• R 2a is CH 2 OH or CH 2 CH 2 OH; and R 2b is H.
• R 1 is substituted or unsubstituted bicycloaryl, bicycloalkyl, or bicycloheteroaryl.
• R 1 is substituted or unsubstituted phenyl.
• R 1 is substituted or unsubstituted pyridyl, pyrimidinyl or pyrazinyl.
• R 1 is selected from substituted or unsubstituted quinolinyl, isoquinolinyl, methylenedioxyphenyl, imidazopyridyl, benzoxazolyl, and indolyl.
• R 1 is
• R 1 is as described above and the subscript n3 is 1, 2 or 3.
• R 1 is as described above and the subscript n3 is 1 or 2.
• R 1 is
• each R 5b is independently selected from H, alkyl, halo, cyano, alkoxy, and haloalkyl.
• R 1 is as described above and each R 5b is independently selected from H, Me, Et, Pr, iso-Pr, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CO 2 Me, CH 2 —N-morpholino, CH 2 —N-(4-Me-piperidino), NH 2 , CONH 2 , CF 3 , CHF 2 , OCF 3 , OCHF 2 , t-Bu, SMe, CH ⁇ CH—CO 2 H, SOMe, SO 2 Me, SO 2 CF 3 , SO 2 NH 2 , SO 3 H, SO 3 Me, cyclopropyl, triazolyl, morpholinyl, and pyridyl.
• each R 5b is independently selected from H, Cl, F, Me, or CF 3 .
• n2 is 0; and R 1 is substituted or unsubstituted aryl or heteroaryl.
• the subscript n2 is 0; and R 1 is substituted or unsubstituted bicycloaryl, bicycloalkyl, or bicycloheteroaryl.
• n2 is 0; and R 1 is substituted or unsubstituted phenyl.
• n2 is 0; and R 1 is substituted or unsubstituted pyridyl, pyrimidinyl or pyrazinyl.
• the subscript n2 is 0; and R 1 is selected from substituted or unsubstituted quinolinyl, isoquinolinyl, methylenedioxyphenyl, imidazopyridyl, benzoxazolyl, and indolyl.
• the subscript n2 is 0; and R 1 is as described above and the subscript n3 is 1, 2 or 3.
• the subscript n2 is 0; and R 1 is as described above and the subscript n3 is 1 or 2.
• each R 5b is independently selected from H, alkyl, halo, cyano, alkoxy, and haloalkyl.
• n2 is 0; and R 1 is as described above and each R 5b is independently selected from H, Me, Et, Pr, iso-Pr, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CO 2 Me, CH 2 —N-morpholino, CH 2 —N-(4-Me-piperidino), NH 2 , CONH 2 , CF 3 , CHF 2 , OCF 3 , OCHF 2 , t-Bu, SMe, CH ⁇ CH—CO 2 H, SOMe, SO 2 Me, SO 2 CF 3 , SO 2 NH 2 , SO 3 H, SO 3 Me, cyclopropyl, triazolyl, morpholinyl, and pyridyl.
• each R 5b is independently selected from H, Cl, F, Me, or CF 3 .
• R 1 is substituted or unsubstituted heterocycloalkyl
• said heterocycloalkyl is other than morpholino or piperidine; even more preferably R 1 is other than substituted or unsubstituted heterocycloalkyl.
• the compound is selected from the compounds exemplified in Table 1; or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer or isotopic variant thereof.
• the compound is selected from:
• prodrugs and derivatives of the compounds according to the formulae above are derivatives of the compounds provided herein, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds provided herein, 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.
• 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 provided herein are preferred prodrugs.
• double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
• double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
• Preferred are the C 1 to C 8 alkyl, C 2 -C 8 alkenyl, aryl, C 7 -C 12 substituted aryl, and C 7 -C 12 arylalkyl esters of the compounds provided herein.
• compositions When employed as pharmaceuticals, the compounds provided herein 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 compounds provided herein are administered in a therapeutically 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 provided herein 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 provided herein 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.
• 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
• 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 provided herein.
• 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 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 may be added as a lubricant.
• the mixture is formed into 240-270 mg tablets (80-90 mg of active amide compound per tablet) in a tablet press.
• a compound of the invention may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio.
• the mixture may be filled into 250 mg capsules (125 mg of active amide compound per capsule).
• a compound of the invention (125 mg), sucrose (1.75 g) and xanthan gum (4 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 is 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 amide compound) in a tablet press.
• a compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/ml.
• Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75° C. and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) 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 provided herein find use as therapeutics for preventing and/or treating neurodegenerative, autoimmune and inflammatory conditions in mammals including humans and non-human mammals.
• 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 to the use of such compounds for the preparation of medicaments useful for such methods.
• a method of treating a mammal susceptible to or afflicted with a condition associated with arthritis, asthma, myocardial infarction, inflammatory bowel disease and autoimmune disorders comprises administering an effective amount of one or more of the pharmaceutical compositions just described.
• 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-masectomy pain, peripheral neuropathy, HIV neuropathy, and chemotherapy-induced and other iatrogenic neuropathies); visceral pain, (such as that associated with gastroesophageal reflex disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, and various gynecological and
• neurodegenerative diseases and disorders such as, for example Parkinson's disease, Alzheimer's disease and multiple sclerosis; diseases and disorders which are mediated by or result in neuroinflammation such as, for example encephalitis; centrally-mediated neuropsychiatric diseases and disorders such as, for example depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction such as, for example urinary incontinence, urinary hesitancy, rectal hypersensitivity, fecal incontinence, benign prostatic hypertrophy and inflammatory bowel disease; respiratory and airway disease and disorders such as, for example, allergic rhinitis, asthma and reactive airway disease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflammation such as, for example rheumatoid arthritis and osteoarthritis, myocardial infar
• 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.
• each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, 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 provided herein When used to prevent the onset of a neurodegenerative, autoimmune or inflammatory condition, the compounds provided herein 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 provided herein can be administered as the sole active agent or they can be administered in combination with other agents, including other active amines and derivatives. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.
• the compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. See, e.g., FIG. 1 and Synthetic Schemes 1-10 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.
• protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
• the choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis , Second Edition, Wiley, New York, 1991, and references cited therein.
• the compounds provided herein 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 provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
• the enantiomerically pure compounds provided herein may be prepared according to any techniques known to those of skill in the art. For instance, they may be prepared by chiral or asymmetric synthesis from a suitable optically pure precursor or obtained from a racemate by any conventional technique, for example, by chromatographic resolution using a chiral column, TLC or by the preparation of diastereoisomers, separation thereof and regeneration of the desired enantiomer. See, e.g., “Enantiomers, Racemates and Resolutions,” by J. Jacques, A. Collet, and S. H. Wilen, (Wiley-Interscience, New York, 1981); S. H. Wilen, A. Collet, and J. Jacques, Tetrahedron, 2725 (1977); E.
• an enantiomerically pure compound of formula 1 may be obtained by reaction of the racemate with a suitable optically active acid or base.
• suitable acids or bases include those described in Bighley et al., 1995 , Salt Forms of Drugs and Adsorption, in Encyclopedia of Pharmaceutical Technology , vol. 13, Swarbrick & Boylan, eds., Marcel Dekker, New York; ten Hoeve & H. Wynberg, 1985 , Journal of Organic Chemistry 50:4508-4514; Dale & Mosher, 1973 , J. Am. Chem. Soc. 95:512; and CRC Handbook of Optical Resolution via Diastereomeric Salt Formation , the contents of which are hereby incorporated by reference in their entireties.
• Enantiomerically pure compounds can also be recovered either from the crystallized diastereomer or from the mother liquor, depending on the solubility properties of the particular acid resolving agent employed and the particular acid enantiomer used.
• the identity and optical purity of the particular compound so recovered can be determined by polarimetry or other analytical methods known in the art.
• the diasteroisomers can then be separated, for example, by chromatography or fractional crystallization, and the desired enantiomer regenerated by treatment with an appropriate base or acid.
• the other enantiomer may be obtained from the racemate in a similar manner or worked up from the liquors of the first separation.
• enantiomerically pure compound can be separated from racemic compound by chiral chromatography.
• Various chiral columns and eluents for use in the separation of the enantiomers are available and suitable conditions for the separation can be empirically determined by methods known to one of skill in the art.
• Exemplary chiral columns available for use in the separation of the enantiomers provided herein include, but are not limited to CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.
• a pressure vial was charged with 3-bromo-5-iodo-benzoic acid (7.60 g, 23.2 mmol), p-tolylboronic acid (3.16 g, 23.2 mmol), tetrakis(triphenylphosphine)palladium(0) (1.34 g, 1.16 mmol), cesium carbonate (8.33 g, 25.6 mmol), toluene (99.0 mL, 930 mmol), ethanol (27.1 mL, 465 mmol) and water (12.6 mL, 697 mmol) and the reaction stirred at 85° C. over nights. The reaction mixture was filtered over celite and the solvent removed to get the crude product as a brown solid.
• a microwave vial was charged with methyl 3-bromo-5-iodobenzoate (2.00 g, 5.87 mmol), 5-methyl-2-(tributylstannyl)pyridine (2.24 g, 5.87 mmol), tetrakis(triphenylphosphine)palladium(0) (339 mg, 0.29 mmol) and 1,4-dioxane (30 mL).
• the reaction mixture was subjected to microwave irradiation at 120° C. for 1 hour.
• the reaction was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to afford the product as a white solid.
• a microwave vial was charged with methyl 3-bromo-5-(5-methylpyridin-2-yl)benzoate (100 mg, 0.33 mmol), morpholin-3-one (42 mg, 0.41 mmol), palladium acetate (4 mg), cesium carbonate (169 mg, 0.52 mmol), xantphos (3 mg), and 1,4-dioxane (1 mL).
• the reaction mixture was subjected to microwave irradiation at 110° C. for 15 min.
• the reaction mixture was filtered and the filterate was concentrated under reduced pressure.
• the resultant residue was purified by preparative HPLC to get the product as a yellow solid.
• reaction mixture was subjected to microwave irradiation at 150° C. for 10 mins. After cooling, the reaction mixture was extracted with ethylacetate. The organic layer was washed with brine, dried, and concentrated under reduced pressure to give the residue which was purified by silica gel column to yield the title compound.
• reaction mixture was subjected to microwave irradiation at 150° C. for 10 mins. After cooling, the reaction mixture was extracted with ethylacetate. The organic layer was washed with brine, dried, and concentrated under reduced pressure to afford the residue which was purified by silica gel column to yield the title compound.
• a microwave vial was charged with methyl 3-bromo-5-iodobenzoate (2.00 g, 5.87 mmol), 5-methyl-2-(tributylstannyl)pyridine (2.24 g, 5.87 mmol), tetrakis(triphenylphosphine)palladium(0) (340 mg, 0.30 mmol) and 1,4-dioxane (30 mL).
• the reaction mixture was subjected to microwave irradiation at 120° C. for 1 hour. After cooling, the mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to afford the product as a white solid.
• Compounds provided herein can be evaluated using cell-based assays, such as calcium influx or electrophysiological assays, using biochemical assays, such as binding assays to P2X 2 and P2X 3 receptors, or can be evaluated in animal models of pain or urinary function. Examples of assays are described below.
• the purinergic receptors P2X 2 and P2X 3 are expressed in a variety of tissues including various sensory and sympathetic ganglia, such as the dorsal root (DRG), nodose (ND), trigeminal (TG), and superior cervical ganglia (SCG) and also in smooth muscle cells (Burnstock, Trends Pharmacol. Sci. 27:166-76, 2006). In several regions, P2X 2 and P2X 3 receptors are coexpressed and functional studies have demonstrated the presence of heteromeric P2X 2/3 receptors whose properties differ from those of either homomeric receptor.
• DDG dorsal root
• ND nodose
• TG trigeminal
• SCG superior cervical ganglia
• chimeric P2X 2/3 receptors containing the N-terminal cytoplasmic domain of P2X 2 fused to the first transmembrane domain of P2X 3 have been described; these chimeric channels retain the pharmacological profile of homomeric P2X 3 receptors, while gaining the non-desensitizing phenotype of the homomeric P2X 2 receptor (Neelands et al., Br. J. Pharmacol. 140:202-10, 2003).
• the non-desensitizing behavior of the chimeric receptor is especially useful for screening.
• ligand-gated non-selective cation channels whose activity can be characterized by using electrophysiological methods, or by measuring calcium ion influx using calcium-sensitive fluorescent dyes.
• Applications of agonists such as ATP, or an ATP analog such as ⁇ , ⁇ -Methyleneadenosine 5′-triphosphate ( ⁇ MeATP, Sigma-Aldrich) causes channel opening, resulting in current flow and calcium influx (Bianchi et al., Eur. J. Pharmacol. 376:127-38, 1999).
• the compounds provided herein can be tested for antagonist activity at P2X 3 and P2X 2/3 receptors by measuring their ability to affect channel opening by ATP, ⁇ MeATP, or other agonists.
• Functional tests of receptor activity include but are not limited to: (i) calcium ion influx measured by fluorescence of a calcium-sensitive dye and; (ii) ion flux resulting from channel opening measured by electrophysiological methods. These methods can be used to evaluate channel function when the relevant receptor is heterologously expressed in mammalian or amphibian cells. These methods can also be used to evaluate compounds provided herein in rodent primary neurons and other mammalian primary cells and cell lines that normally express the receptor of interest.
• Compounds can further be evaluated for their ability to bind P2X 3 and P2X 2/3 receptors using biochemical approaches.
• Compounds can also be evaluated for their ability to modify sensory and autonomic nervous system signaling where the receptors are known to have a role (e.g., urinary bladder afferent signaling, sensory nerve pain sensation).
• a role e.g., urinary bladder afferent signaling, sensory nerve pain sensation.
• compounds provided herein can be tested in vivo in relevant animal models known to one skilled in the art, such as, for example, models of neuropathic, inflammatory, or visceral pain, or models of urinary incontinence.
• Human P2X 3 (Accession no. NM — 002559), P2X 2 (Accession no. NM — 170682) and Rat P2X 3 (Accession no. NM — 031075) and P2X 2 (Accession no. NM — 053656) are cloned into a mammalian expression vector (e.g., pcDNA5/TO or pcDNA3 Invitrogen).
• the human P2X 2/3 chimera clone is created as described by Neelands et al, and then cloned into an expression vector as above.
• Receptors are expressed in cells (e.g., HEK293 or 1321N1 (obtained from the ECACC)) via transient transfection using standard lipid mediated transfection, or by creation of stable transfectants for each receptor.
• the P2X 3 expression vector is stably transfected into a cell line already stably expressing P2X 2 .
• P2X 2/3 heteromer function is isolated using pharmacological methods. Cell lines are maintained in DMEM+5% Glutamax, the appropriate level of selective antibiotic, and 10% heat inactivated FBS.
• Functional activity of compounds at the P2X receptor is determined by measuring their ability to inhibit agonist-induced calcium influx. Compounds are tested for antagonist activity against the P2X 2/3 chimera, the P2X 3 homomer, or the P2X 2/3 heteromer. At the start of each screening day, the agonist EC 50 is determined. Compound % inhibition or IC50s are subsequently determined using a pre-determined agonist concentration (EC 50-90 depending on cell line) as a stimulus. The agonists used are ⁇ MeATP, ATP, or other ATP analogs. Compounds may be tested at concentrations ranging from 1 pM to 10 ⁇ M.
• cells expressing the appropriate receptor are seeded onto 96 or 384 well plates 18-24 hours prior to assay.
• cells are loaded with calcium-sensitive fluorescent dye (e.g., Fluo-4 no wash reagent-Invitrogen cat# F36206, or the BDTM PBX Calcium Assay Kit-BD cat# 640175) in Hank's Buffered Salt Solution (HBSS) with up to 10 mM supplemental CaCl 2 . Plates are incubated at 37° C. and then equilibrated at room temperature.
• Antagonism of agonist-induced calcium influx is measured using a fluorescent imaging plate reader (e.g. FLIPR TETRA , Molecular Devices, Sunnyvale, Calif.).
• the assay comprises two stages: a pre-treatment phase followed by a treatment phase.
• Compounds may be tested as follows: For the pre-treatment phase, 50 ⁇ L of 3 ⁇ concentration of test compound in HBSS is added to cells containing 100 ⁇ L of dye loading media to achieve a final concentration of 1 ⁇ test compound.
• For the treatment phase at a set interval after pre-treatment (1-30 minutes), 50 ⁇ L of 1 ⁇ test compound plus 4 ⁇ agonist solution is added, resulting in a final concentration of 1 ⁇ compound and 1 ⁇ agonist. Fluorescence is measured at 0.1-3 second intervals—with an excitation wavelength of 494 nM and an emission wavelength of 515 nM. Responses are measured as (peak fluorescence after agonist addition) minus (baseline fluorescence prior to treatment). Percent inhibition is calculated as follows:
• Percentage ⁇ ⁇ inhibition 1 - ( Compound ⁇ ⁇ Response - Control ⁇ ⁇ Resonse ) ( Agonist ⁇ ⁇ Response - Control ⁇ ⁇ Response ) ⁇ 100
• IC 50 values are determined by analyzing dose response data in a 4 parameter logistic fit using GraphPad Prizm.
• Whole cell recordings are made using the Multiclamp700A patch-clamp amplifier and Clampex acquisition program (Molecular Devices Corporation).
• Whole-cell recordings are obtained from 1321N1 or HEK cells stably or transiently transfected with P2X 3 and/or P2X 2 expression vectors. Solutions are either applied for periods of 1 to 3s by a gravity flow, 8-valve delivery system, or for periods of milliseconds using the quick-change Dynaflow perfusion system (Cellectricon Inc.).
• the internal pipette solution may include 140 mM Cesium-Chloride, 10 mM EGTA, and 5 mM Hepes at pH 7.2; normal external solution is 140 mM NaCl, 5 mM KCl, 1 mM CaCl 2 , 2 mM MgCl 2 , 25 mM Hepes, and 10 mM glucose.
• Concentration-response curves are obtained by recording currents in response to brief applications of agonist at 1-3 min intervals where regular external solution is perfused during the intervals. To obtain inhibition curves, antagonists are pre-applied to the cells for a defined time period before a short application of the agonist+ antagonist.
• the periods of antagonist pre-application and agonist+ antagonist applications are constant for the entire test concentration series.
• Agonist evoked currents are measured in cells that are voltage clamped at ⁇ 60 or ⁇ 80 millivolts.
• IC 50 values are determined by analyzing dose response data in a 4 parameter logistic fit using GraphPad Prizm or Origin.
• Xenopus oocytes are isolated by enzymatic dissociation using collagenase (Worthington, 2 mg/ml). Oocytes are then individually injected with P2X 3 , P2X 2 , or a combination of P2X 2 and P2X 3 mRNA. Each oocyte receives ⁇ 64 nl of RNA solution in water at a concentration of ⁇ 0.01 ⁇ g/ ⁇ l. Injected oocytes are stored in standard oocyte incubation solution, ND96, containing (in mM) 96 NaCl, 2 KCl, 1 MgCl 2 , 1-5 CaCl 2 and 50 ⁇ g/ml Gentamicin at 16° C.
• Agonist-induced-current caused by P2X channel opening is observed in oocytes 1-5 days after injection.
• 8 oocytes are placed in the recording chambers. Each oocyte is impaled by 2 glass electrodes having resistances of 0.5 to 1 MOhm when filled with a 3 M KCl solution. Electrode advancement and oocyte impalement are under software control (OPUSXPRESS 1.1, Molecular devices Corporation). The solutions are prepared in 96 well plates and robotically pipetted into the oocyte recording chambers by an 8 channel pipettor. Inhibition by antagonists is determined by calculating % current remaining when oocytes are stimulated with agonist in the presence of test compound compared to the peak current in the presence of agonist alone.
• the sequence of solution application to the oocyte is as follows: a specific concentration (e.g., EC 50 , EC 80 , or EC 90 ) of the agonist is added first to elicit the maximal response. After the pulse, oocytes are washed for several minutes with ND96. The test compound is then added at a particular concentration, followed by the compound at the same concentration along with the agonist. Concentrations for the compounds may range from 0.3 to 10,000 nM. IC 50 values are determined by analyzing dose response data using a 4 parameter logistic fit using GraphPad Prizm or Origin software.
• oocytes are impaled manually with 2 electrodes and agonist evoked current are measured using an Oocyte clamp amplifier (Warner Instrument Corp.) and Clampex (Molecular Devices Corporation) acquisition software. Solutions are delivered using gravity flow and applied as above. The agonist induced current is measured in the absence and presence of antagonist. Antagonists are tested in a concentration series to obtain an inhibition curve as described above.
• P2X 3 and/or P2X 2/3 activation will be tested for activity against other P2X receptors to determine their selectivity for specific P2X family members.
• the list of receptors to be assayed includes, but is not restricted to P2X1, P2X 2 , P2X4, P2X5, P2X6, and P2X7.
• the types of assay used for selectivity determination may include: 1) Agonist-induced Calcium influx in cells heterologously expressing the relevant receptor, 2) Electrophysiological determination of receptor inhibition in either mammalian cells or Xenopus oocytes heterologously expressing the receptor of interest. Methods and data analysis are similar to those described above for P2X 3 and P2X 2/3 .
• Radioligand experiments are done to determine the affinity of test compounds for P2X 3 homomeric and P2X 2/3 heteromeric receptors. These studies also provide valuable insights into the mechanism of action of antagonism.
• the general methodologies used for radioligand binding experiments for P2X 3 and P2X 2/3 receptors are described by Jarvis et al., J. Pharmacol. Exp. Ther. 10:407-16, 2004.
• cell membranes are prepared from cells transiently or stably expressing P2X 3 or P2X 2/3 receptors. Cells are grown to confluence, washed, isolated, and stored as pellets at ⁇ 80° C. until use. Some studies may require the addition of Apyrase or hexokinase (Sigma-Aldrich) during membrane preparation to minimize ATP-mediated receptor desensitization during membrane preparation. Membranes are prepared by resuspending the cell pellet in homogenization buffer, homogenizing, and centrifuging to obtain a membrane pellet. Total protein concentrations are determined using standard methods.
• Displacement binding studies are conducted using procedures adapted from Jarvis et al. Under optimized conditions, ligand competition experiments are conducted using radioligand ([3H]A-317491, Abbott), or other high affinity radioligands and a range of different concentrations of test compounds in binding buffer. Ligand saturation studies are conducted using a range of concentrations of radioligand. All binding reactions are terminated by rapid filtration through a glass fiber filter. Membranes are washed, incubated in scintillant, and counted in a scintillation counter. IC 50 values are determined using a four-parameter logistic Hill equation.
• Caco-2 permeability is measured according to the method described in Yee, Pharm. Res. 14:763-6, 1997. Caco-2 cells are grown on filter supports (Falcon HTS multiwell insert system) for 14 days. Culture medium is removed from both the apical and basolateral compartments and the monolayers are preincubated with pre-warmed 0.3 ml apical buffer and 1.0 ml basolateral buffer for 0.75 hour at 37° C. in a shaker water bath at 50 cycles/min.
• the apical buffer consists of Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 mM MES Biological Buffer, 1.25 mM CaCl 2 and 0.5 in M MgCl 2 (pH 6.5).
• the basolateral buffer consists of Hanks Balanced Salt Solution, 25 mM D-glucose monohydrate, 20 mM HEPES Biological Buffer, 1.25 mM CaCl 2 and 0.5 mM MgCl 2 (pH 7.4).
• test compound solution (10 ⁇ M) in buffer is added to the apical compartment.
• the inserts are moved to wells containing fresh basolateral buffer and incubated for 1 hr. Drug concentration in the buffer is measured by LC/MS analysis.
• Flux rate (F, mass/time) is calculated from the slope of cumulative appearance of substrate on the receiver side and apparent permeability coefficient (Papp) is calculated from the following equation:
• Cell paste of HEK-293 cells expressing the HERG product can be suspended in 10-fold volume of 50 mM Tris buffer adjusted at pH 7.5 at 25° C. with 2 M HCl containing 1 mM MgCl 2 , 10 mM KCl.
• the cells are homogenized using a Polytron homogenizer (at the maximum power for 20 seconds) and centrifuged at 48,000 g for 20 minutes at 4° C.
• the pellet is resuspended, homogenized and centrifuged once more in the same manner.
• the resultant supernatant is discarded and the final pellet was resuspended (10-fold volume of 50 mM Tris buffer) and homogenized at the maximum power for 20 seconds.
• the membrane homogenate is aliquoted and stored at ⁇ 80° C. until use. An aliquot is used for protein concentration determination using a Protein Assay Rapid Kit and ARVO SX plate reader (Wallac). All the manipulation, stock solution and equipment are kept on ice at all time. For saturation assays, experiments are conducted in a total volume of 200 ⁇ l. Saturation is determined by incubating 20 ⁇ l of [ 3 H]-dofetilide and 160 ⁇ l of membrane homogenates (20-30 ⁇ g protein per well) for 60 min at room temperature in the absence or presence of 10 ⁇ M dofetilide at final concentrations (20 ⁇ l) for total or nonspecific binding, respectively.
• compounds are diluted in 96 well polypropylene plates as 4-point dilutions in semi-log format. All dilutions are performed in DMSO first and then transferred into 50 mM Tris buffer (pH 7.5 at 25° C.) containing 1 mM MgCl 2 , 10 mM KCl so that the final DMSO concentration became equal to 1%.
• Compounds are dispensed in triplicate in assay plates (4 ⁇ l). Total binding and nonspecific binding wells are set up in 6 wells as vehicle and 10 ⁇ M dofetilide at final concentration, respectively. The radioligand was prepared at 5.6 ⁇ final concentration and this solution is added to each well (36 ⁇ l).
• the assay is initiated by addition of YSi poly-L-lysine Scintillation Proximity Assay (SPA) beads (50 ⁇ l, 1 mg/well) and membranes (110 ⁇ A, 20 ⁇ g/well). Incubation is continued for 60 min at room temperature. Plates are incubated for a further 3 hours at room temperature for beads to settle. Receptor-bound radioactivity is quantified by counting WALLAC MICROBETA plate counter.
• SPA YSi poly-L-lysine Scintillation Proximity Assay
• HEK 293 cells which stably express the HERG potassium channel are used for electrophysiological study.
• the methodology for stable transfection of this channel in HEK cells can be found elsewhere (Zhou et al., Biophys. J. 74:230-41, 1998).
• MEM Minimum Essential Medium
• FCS Fetal Calf Serum
• HERG currents are studied using standard patch clamp techniques in the whole-cell mode.
• the cells are superfused with a standard external solution of the following composition (mM); NaCl, 130; KCl, 4; CaCl 2 , 2; MgCl 2 , 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH.
• Whole-cell recordings are made using a patch clamp amplifier and patch pipettes which have a resistance of 1-3 MOhm when filled with the standard internal solution of the following composition (mho); KCl, 130; MgATP, 5; MgCl 2 , 1.0; HEPES, 10; EGTA 5, pH 7.2 with KOH.
• the voltage protocol is applied to a cell continuously throughout the experiment every 4 seconds (0.25 Hz).
• the amplitude of the peak current elicited around ⁇ 40 mV during the ramp is measured.
• vehicle (0.5% DMSO in the standard external solution) is applied for 10-20 min by a peristalic pump.
• the test compound of either 0.3, 1, 3, or 10 mM is applied for a 10 min period.
• the 10 min period included the time which supplying solution was passing through the tube from solution reservoir to the recording chamber via the pump.
• Exposing time of cells to the compound solution was more than 5 min after the drug concentration in the chamber well reached the attempting concentration. There is a subsequent wash period of a 10-20 min to assess reversibility. Finally, the cells is exposed to high dose of dofetilide (5 mM), a specific IKr blocker, to evaluate the insensitive endogenous current.
• dofetilide 5 mM
• Test compounds (1 ⁇ M) are incubated with 3.3 mM MgCl 2 and 0.78 mg/mL HLM (HL101) in 100 mM potassium phosphate buffer (pH 7.4) at 37° C. on the 96-deep well plate.
• the reaction mixture is split into two groups, a non-P450 and a P450 group.
• NADPH is only added to the reaction mixture of the P450 group.
• An aliquot of samples of P450 group is collected at 0, 10, 30, and 60 min time point, where 0 min time point indicated the time when NADPH was added into the reaction mixture of P450 group.
• An aliquot of samples of non-P450 group is collected at ⁇ 10 and 65 min time point.
• Half-life ln 2 /k.
• P2X 3 , P2X 2/3 antagonists may be tested in various animal models of human diseases, including models of neuropathic, inflammatory, and visceral pain, and models of bladder function. P2X 3 antagonists may be administered prior to or post-induction of the model depending upon the specific model and the compound PK characteristics.
• the route of administration may include intraperitoneal, (i.p.), subcutaneous (s.c.), oral (p.o.), intravenous (i.v.), intrathecal (i.t.), or intraplantar.
• the endpoints for these studies may include mechanical allodynia, thermal hyperalgesia, cold allodynia, decreased formalin-induced pain responses, decreased writhing and contractions or altered bladder mechanosensation as appropriate for the model as described below.
• Test compounds are administered at various times prior to intraplantar administration of formalin.
• a dilute solution of formalin (25-50 ⁇ L of 1-2.5% formaldehyde/saline) is administered s.c. into the plantar surface of the left hind paw under light restraint.
• animals are placed on a mesh stand inside a clear observation chamber large enough to allow for free movement of the animals during the study. Behaviors are scored using manual scoring or automated scoring.
• Automated scoring A small metal band weighing 0.5 g is placed on the left paw. Formalin is administered and the animal placed unrestrained inside an observation chamber over an electromagnetic detector system (Automated Nociception Analyzer, University of California, San Diego). The number of paw flinches is electronically recorded.
• Rats are administered up to 1 ⁇ Mol ⁇ meATP, ATP, adenosine, or PBS in a volume up to 100 ⁇ L subcutaneously into the dorsal surface of the hindpaw.
• animals are placed on a stand inside a clear observation chamber large enough to allow for free movement of the animals.
• the duration of flinching and licking are recorded over a 20 minute interval to evaluate nocifensive behavior. Responses are measured using the either the manual or automated methods described above for the Formalin test. Additional behavioral testing may include assessment of mechanical allodynia and thermal hyperalgesia.
• compounds are administered prior to agonist injection.
• CFA Complete Freund's Adjuvant Model
• Animals receive an s.c. injection of 100 ⁇ L complete Freund's adjuvant containing 100 ⁇ g Mycobacterium tuberculosis strain H37Ra into the plantar surface of the right hind paw under isoflurane anesthesia. Swelling and inflammation are visible within 1 h after administration. Nociceptive testing may begin 24 h post CFA administration. Compounds are generally administered 0.5-12 hrs before testing.
• CCI Chronic Constriction Injury Model
• the CCI model is performed according to the method described by Bennett and Xie, Pain, 33:87-107, 1988. Briefly, under isoflurane anesthesia, the right sciatic nerve is exposed at mid-thigh level via blunt dissection through the biceps femoris. Proximal to the bifurcation of the sciatic nerve, about 7 mm of nerve is freed of adhering tissue and 4 loose ligatures of 4.0 chromic gut are tied around the nerve. Spacing between ligatures is approximately 1 mm. The wound is closed in layers, and the skin closed with staples or non-silk sutures. Sham operated animals are treated identically with the exception that the sciatic nerve will not be ligated. Nociceptive testing can be done 7-21 days post surgery. Compounds are generally administered 0.5-12 hrs before testing.
• rats Under anesthesia, rats are placed in a prone position on a flat, sterile surface. A midline incision from L4-S2 is made and the left paraspinal muscles are separated from the spinous processes.
• the L5 and L6 spinal nerves are tightly ligated with a 4-0 silicon-treated silk suture, according to the method described by Kim and Chung, Pain, 50:355-363, 1992.
• the L4 spinal nerve is carefully preserved from being surgically injured.
• the skin is closed with wound clips and animals are returned to their home cages. Rats exhibiting prolonged postoperative neurological deficits or poor grooming are excluded from the experiments.
• the animals are assessed for nociceptive responses prior to surgery (baseline), then at various timepoints after administration of test compounds. Nociceptive testing can be done 7-21 days post surgery. Compounds are generally administered 0.5-12 hrs before testing.
• Hind paw withdrawal latencies to a noxious thermal stimulus are determined using a plantar test apparatus (Ugo Basile) following the technique described by Hargreaves et al., Pain 32: 77-88, 1988.
• the radiant heat sourced is focused onto the plantar surface of the ipsilateral paw, and the paw withdrawal latency is determined.
• An increase latency of paw withdrawal demonstrates reversal of hyperalgesia.
• the paw pressure assay can be used to assess mechanical hyperalgesia.
• hind paw withdrawal thresholds (PWT) to a noxious mechanical stimulus are determined using an analgesymeter (Ugo Basile) as described in Stein et al., Pharmacol. Biochem. Behav. 31:451-455, 1988.
• the maximum weight that can be applied to the hind paw is set at 250 g and the end point is taken as complete withdrawal of the paw.
• PWT is determined once for each rat at each time point.
• Cold allodynia To measure cold allodynia, a drop of acetone is applied to the plantar surface of the paw through the underside of the grating on which the animals are standing using a 50 Hamilton syringe. The process is performed 5 times with a 3 min interval between each time. Vigorous shaking will be recorded as a positive response, and the time spent shaking is recorded.
• cold allodynia may be tested using the cold water bath method in which animals are placed into a cold water bath with water at a depth of 1.5-2.0 cm and at a temperature of 3-4 degrees centigrade and the number of paw lifts counted.
• a 5 cm latex balloon is attached to a barostat system composed of a flow meter and pressure control program by a length of tubing. Under isoflurane anesthesia, the balloon is inserted into the distal colon via the anus at a distance of 5 cm from the anus and taped to the base of the tail. Post-anesthesia, the animal is placed unrestrained into a clean polypropylene cage and allowed to acclimate for 30 mins. The balloon is progressively inflated from 0-75 mmHg in 5 mm increments every 30 s.
• the colonic reaction threshold is defined as the pressure inducing the first abdominal contraction. Abdominal contraction indicative of visceral pain correlates with hunching, hump-backed position, licking of the lower abdomen, repeated waves of contraction of the ipsilateral oblique musculature with inward turning of the ipsilateral hindlimb, stretching, squashing of the lower abdomen against the floor (Wesselman, Neurosci. Lett., 246:73-76, 1998). Alternatively, electrodes may be placed into the external oblique musculature for eletromyographic recordings of abdominal contractions. In this case, EMG activity is quantified during colonic balloon inflation. Compounds are generally administered 0.5-12 hrs before testing.
• a 0.6% solution of acetic acid (10 ml/kg) is administered i.p. to rats and the number of abdominal constrictions within 30 min are counted.
• Compounds are generally administered 0.5-12 hrs before testing.
• test compounds will be examined for their ability to modulate afferent signaling from the urinary bladder.
• Compounds are evaluated in the urinary bladder/pelvic nerve preparation described by Vlaskovska et al., J. Neuroscience, 21:5670-7, 2001, and Cockayne et al., J. Physiol. 567:621-39, 2005. Briefly, the whole urinary tract attached to the lower vertebrae and surrounding tissues is isolated en bloc and superfused in a recording chamber with oxygenated (5% CO 2 and 95% O 2 ) Krebs solution. The bladder is catheterized through the urethra for intraluminal infusion.
• a second double lumen catheter is inserted into the bladder to measure intraluminal pressure and to drain the bladder.
• the pelvic nerve exiting the vertebrae is dissected and impaled with a suction glass electrode. Nerve activity is measured using standard electrophysiological methods. Following a 60 min stabilization period, repeated ramp distensions are performed until the afferent response stabilizes. This stabilized afferent response was used for comparing mechanosensitivity of bladder afferents between different treatment groups.
• Female Sprague dawley rats are anesthetized, tracheotomized, and cannulated in the carotid artery and femoral vein.
• the urinary bladder is accessed via an abdominal incision, and the ureters ligated and transected. For fluid infusion and pressure measurements, the urinary bladder is cannulated.
• the bladder is infused with saline until stable volume-induced bladder contractions are elicited. Once stable threshold volumes and contraction frequencies are obtained, the animal is dosed with compound and contraction frequency is measured.
• Each cystometrogram consists of slowly filling the bladder with normal saline via the transurethral catheter, and then recording the pressure associated with filling via a pressure transducer. Contractions greater than a predetermined threshold value are interpreted as micturition contractions. For each cystometrogram, the volume at which active contractions occurred (micturition threshold) and the number of contractions per cystometrogram are recorded. The effects of compounds are then determined.
• Cystometrograms may also be obtained in animals cystitis models in which bladders are irritated by injection of cyclophosphamide (150 mg/kg, i.p.) 24 hrs prior to cystometry, or by infusion of up to 1% acetic acid during cystometry.

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