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1. (WO2010072597) DIHYDROPYRIDONE AMIDES AS P2X7 MODULATORS
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DIHYDROPYRIDONE AMIDES AS P2X7 MODULATORS

This invention pertains to compounds useful for treatment of diseases associated with P2X purinergic receptors, and more particularly to P2X7 modulators usable for treatment of autoimmune and inflammatory diseases.

P2X purinergic receptors are ATP-activiated ionotropic receptors having seven subtypes. The P2X7 receptor subtype (also known as the P2Z receptor) is a ligand-gated ion channel found on mast cells, peripheral macrophages, lymphocytes, erythrocytes, fibroblasts and epidermal langerhans cells. Activation of P2X7 receptor on such immune system cells results in release of interleukin-lbeta. (Solle et al, J. Biol. Chemistry 276,125-132, (2001)). The P2X7 receptor is also found on microglia, Schwann cells and astrocytes within the central nervous system (Donnelly-Roberts et al., Br. J. Pharmacol. 151, 571-579 (2007)). Antagonists of P2X7 have been showned to block P2X7 -mediated IL-lbeta release and P2X7 -mediated cation flux (Stokes et al., Br. J. Pharmacol. 149, 880-887 (2006)). Mice lacking the P2X7 receptor show a lack of inflammatory and neuropathic hypersensitivity to mechanical and thermal stimuli (Chessell et al., Pain 114, 386-396 (2005)). P2X7 is thus believed to have a role in inflammatory responses (Ferrari et al., J. Immunol. 176, 3877-3883 (2006)) and in the onset and persistence of chronic pain (Honore et al., J. Pharmacol. Ex. Ther. 319, 1376-1385 (2006b)). Modulators of the P2X7 receptor thus may have utility in the treatment of disease states such as rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, glomerulonephritis, irritable bowel disease, diabetes and Crohn's disease. P2X7 modulators may also be useful for treatment of pain, including chronic pain, neuropathic pain, and pain associated inflammatory processes and degenerative conditions.

There is accordingly a need for compounds that act as modulators of P2X receptors, including antagonists of P2X7 receptor, as well as a need for methods of treating diseases, conditions and disorders mediated by P2X7 The present invention satisfies these needs as well as others. The invention provides compounds of the formula I:


or pharmaceutically acceptable salts thereof, wherein: m is 0 or 1 ; n is 0 or 1 ;

R1 is optionally substituted heteroaryl R2 is: optionally substituted aryl; optionally substituted heteroaryl; C3_6cycloalkyl; or Ci_6alkyl; R3 is: hydrogen; Ci-ealkyl; alkylcarbonylalkyl; or alkoxyc arbonylalkyl ; R4 and R5 each independently is: hydrogen; or Ci-βalkyl; and Ra is: hydrogen; Ci_6alkyl; hydroxy-Ci_6alkyl; Ci-6alkoxy-Ci-6alkyl.

The invention also provides and pharmaceutical compositions comprising the compounds, methods of using the compounds, and methods of preparing the compounds.

Definitions

Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an," and "the" include plural referents unless the context clearly dictates otherwise.

"Alkyl" means the monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. "Lower alkyl" refers to an alkyl group of one to six carbon atoms, i.e. Ci-Cδalkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

"Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.

"Alkynyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.

"Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.

"Alkoxy" and "alkyloxy", which may be used interchangeably, mean a moiety of the formula

-OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

"Alkoxyalkyl" means a moiety of the formula Ra-O-Rb-, where Ra is alkyl and Rb is alkylene as defined herein. Exemplary alkoxyalkyl groups include, by way of example, 2-methoxyethyl, 3-methoxypropyl, l-methyl-2-methoxyethyl, l-(2-methoxyethyl)-3-methoxypropyl, and l-(2-methoxyethyl)-3-methoxypropyl. "Alkoxyalkoxy' means a group of the formula -O-R-R' wherein R is alkylene and R' is alkoxy as defined herein.

"Alkylcarbonyl" means a moiety of the formula -C(O)-R, wherein R is alkyl as defined herein.

- A - "Alkoxycarbonyl" means a group of the formula -C(O)-R wherein R is alkoxy as defined herein.

"Alkylcarbonylalkyl" means a group of the formula -R-C(O)-R wherein R is alkylene and R' is alkyl as defined herein. "Alkoxycarbonylalkyl" means a group of the formula -R-C(O)-R wherein R is alkylene and R' is alkoxy as defined herein.

"Alkoxycarbonylalkoxy"means a group of the formula -0-R-C(O)-R' wherein R is alkylene and R' is alkoxy as defined herein.

"Hydroxycarbonylalkoxy" means a group of the formula -0-R-C(O)-OH wherein R is alkylene as defined herein.

"Alkylaminocarbonylalkoxy" means a group of the formula -0-R-C(O)-NHR' wherein R is alkylene and R' is alkyl as defined herein.

"Dialkylaminocarbonylalkoxy" means a group of the formula -0-R-C(0)-NR'R" wherein R is alkylene and R' and R" are alkyl as defined herein. "Alkylaminoalkoxy" means a group of the formula -0-R-NHR' wherein R is alkylene and R' is alkyl as defined herein.

"Dialkylaminoalkoxy" means a group of the formula -0-R-NR'R' wherein R is alkylene and

R' and R" are alkyl as defined herein.

"Alkylsulfonyl" means a moiety of the formula - SO2-R, wherein R is alkyl as defined herein. "Alkylsulfonylalkyl means a moiety of the formula -R'-Sθ2-R" where where R' is alkylene and R" is alkyl as defined herein.

"Alkylsulfonylalkoxy" means a group of the formula -O-R-SO2-R' wherein R is alkylene and R' is alkyl as defined herein.

"Amino means a moiety of the formula -NRR' wherein R and R' each independently is hyrdogen or alkyl as defined herein. "Amino thus includes "alkylamino (where one of R and

R' is alkyl and the other is hydrogen) and "dialkylamino (where R and R' are both alkyl.

"Aminocarbonyl" means a group of the formula -C(O)-R wherein R is amino as defined herein.

"Alkoxyamino" means a moiety of the formula -NR-OR' wherein R is hydrogen or alkyl and R' is alkyl as defined herein.

"Alkylsulfanyl" means a moiety of the formula -SR wherein R is alkyl as defined herein.

"Alkoxy hydroxyalkyl" and "hydroxy alkoxyalkyl", which may be used interchangeably, means an alkyl as defined herein that is substituted at least once with hydroxy and at least once with alkoxy. "Alkoxy hydroxyalkyl" and "hydroxy alkoxyalkyl" thus encompass, for example, 2-hydroxy-3-methoxy-propan-l-yl and the like.

"Aminoalkyl" means a group -R-R' wherein R' is amino and R is alkylene as defined herein.

"Aminoalkyl" includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of "aminoalkyl" may be substituted once or twice with alkyl to provide "alkylaminoalkyl" and "dialkylaminoalkyl" respectively. "Alkylaminoalkyl" includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like. "Dialkylaminoalkyl" includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, and the like. "Aminoalkoxy" means a group -OR-R' wherein R' is amino and R is alkylene as defined herein.

"Alkylsulfonylamido" means a moiety of the formula -NR1SO2-R wherein R is alkyl and R' is hydrogen or alkyl.

"Aminocarbonyloxyalkyl" or "carbamylalkyl" means a group of the formula -R-O-C(O)-NR'R" wherein R is alkylene and R', R" each independently is hydrogen or alkyl as defined herein.

"Anunocarbonylalkyl" means a group of the formula -R-C(OVNR1R" wherein R is alkylene and R\ R" each independently is hydrogen or alkyl as defined herein,

"Alkynylalkoxy" means a group of the formula -0-R-R' wherein R is alkylene and R' is alkynyl as defined herein.

"Aryl" means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring. The aryl group can be optionally substituted as defined herein.

Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof, each being optionally substituted. "Arylalkyl" and "Aralkyl", which may be used interchangeably, mean a radical-RaRb where

Ra is an alkylene group and Rb is an aryl group as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like are examples of arylalkyl.

"Arylsulfonyl means a group of the formula -SO2-R wherein R is aryl as defined herein.

"Aryloxy" means a group of the formula -O-R wherein R is aryl as defined herein. "Aralkyloxy" means a group of the formula -O-R-R" wherein R is alkylene and R' is aryl as defined herein. "Carboxy" or "hydroxycarbonyl", which may be used interchangeably, means a group of the formula -C(O)-OH.

"Cyanoalkyl" " means a moiety of the formula -R'-R", where R' is alkylene as defined herein and R" is cyano or nitrile. "Cycloalkyl" means a monovalent saturated carbocyclic moiety consisting of mono- or bicyclic rings. Preferred cycloalkyl are unsubstituted or substituted with alkyl. Cycloalkyl can optionally be substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino, unless otherwise specifically indicated. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated (cycloalkenyl) derivatives thereof.

"Cycloalkylalkyl" means a moiety of the formula -R'-R", where R' is alkylene and R" is cycloalkyl as defined herein.

"Cycloalkylalkoxy" means a group of the formula -O-R-R' wherein R is alkylene and R' is cycloalkyl as defined herein. "Heteroaryl" means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like, including partially hydrogenated derivatives thereof, each optionally substituted.

Heteroarylalkyl" or "heteroaralkyl" means a group of the formula -R-R' wherein R is alkylene and R' is heteroaryl as defined herein.

"Heteroarylsulfonyl means a group of the formula -SO2-R wherein R is heteroaryl as defined herein. "Heteroaryloxy" means a group of the formula -O-R wherein R is heteroaryl as defined herein.

"Heteroaralkyloxy" means a group of the formula -0-R-R" wherein R is alkylene and R' is heteroaryl as defined herein.

The terms "halo", "halogen" and "halide", which may be used interchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

"Haloalkyl" means alkyl as defined herein in which one or more hydrogen has been replaced with same or different halogen. Exemplary haloalkyls include -CH2Cl,

-CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3), and the like.

"Haloalkoxy" means a moiety of the formula -OR, wherein R is a haloalkyl moiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.

"Heterocycloamino" means a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

"Heterocyclyl" means a monovalent saturated moiety, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl, benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl, tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like.

"Heterocyclylalkyl" means a moiety of the formula -R-R' wherein R is alkylene and R' is heterocyclyl as defined herein.

"Heterocyclyloxy" means a moiety of the formula -OR wherein R is heterocyclyl as defined herein.

"Heterocyclylalkoxy" means a moiety of the formula -OR-R' wherein R is alkylene and R' is heterocyclyl as defined herein.

"Hydroxyalkoxy" means a moiety of the formula -OR wherein R is hydro xyalkyl as defined herein. "Hydroxyalkylamino" means a moiety of the formula -NR-R' wherein R is hydrogen or alkyl and R' is hydroxyalkyl as defined herein.

"Hydroxyalkylamino alkyl" means a moiety of the formula -R-NR'-R" wherein R is alkylene, R' is hydrogen or alkyl, and R" is hydroxyalkyl as defined herein. "Hydroxycarbonylalkyl" or "carboxyalkyl" means a group of the formula -R-(CO)-OH where R is alkylene as defined herein.

"Hydroxycarbonylalkoxy" means a group of the formula -0-R-C(O)-OH wherein R is alkylene as defined herein.

"Hydroxyalkyloxycarbonylalkyl" or "hydro xyalkoxycarbonylalkyl" means a group of the formula -R-C(O)-O-R-OH wherein each R is alkylene and may be the same or different. "Hydroxyalkyl" means an alkyl moiety as defined herein, substituted with one or more, preferably one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are not limited to, hydroxymethyl, 2 -hydroxy ethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy- 1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3 -hydroxypropyl

"Hydroxycyc Io alkyl" means a cycloalkyl moiety as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been replaced with a hydroxy substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.

"Quinoline" as used herein, unless indicated otherwise, encompasses all 8 membered bicyclic heteroaryls forming two fused six-membered rings, and having a single aza substitution therein, including partially saturated derivatives thereof. "Quinoline" thus encompasses isoquinoline, dihydroquino lines, tetrahydroquinolines and the like. Quinolines may be optionally substituted as defined herein with various groups including, inter alia, "oxo". "Quinoline" thus encompasses dihydroquinolinones, tetrahydroquinolinones and the like. "Optionally substituted", when used in association with "aryl", phenyl", "heteroaryl" "cycloalkyl" or "heterocyclyl", means an aryl, phenyl, heteroaryl, cycloalkyl or heterocyclyl which is optionally substituted independently with one to four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyl, haloalkoxy, heteroalkyl, -COR, -SO2R (where R is hydrogen, alkyl, phenyl or phenylalkyl), -(CR'R")n-COOR (where n is an integer from O to 5, R' and R" are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or -(CR'R")n-CONRaRb (where n is an integer from O to 5, R' and

R" are independently hydrogen or alkyl, and Ra and Rb are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). Certain preferred optional substituents for "aryl", phenyl", "heteroaryl" "cycloalkyl" or "heterocyclyl" include alkyl, halo, haloalkyl, alkoxy, cyano, amino and alkylsulfonyl. More preferred substituents are methyl, fluoro, chloro, trifiuoromethyl, methoxy, amino and methanesulfonyl. In certain embodiments optional substituents include oxo, alkyl, halo, haloalkyl, hydroxyalkyl and alkoxyalkyl, and in specific embodiments may be oxo alkyl, halo and hydroxyalkyl. "Leaving group" means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions. Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.

"Modulator" means a molecule that interacts with a target. The interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

"Disease" and "Disease state" means any disease, condition, symptom, disorder or indication. "Inert organic solvent" or "inert solvent" means the solvent is inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-bntanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.

"Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

"Pharmaceutically acceptable salts" of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include: 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, benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphtoic acid, 2 -hydroxy ethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylgluc amine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. The preferred pharmaceutically acceptable salts are the salts formed from acetic acid, hydrochloric acid, sulphuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt. "Protective group" or "protecting group" means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive nitrogen and/or oxygen atoms present in the reactants. For example, the terms "amino-protecting group" and "nitrogen protecting group" are used interchangeably herein and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures. Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. The artisan in the art will know how to chose a group for the ease of removal and for the ability to withstand the following reactions. "Solvates" means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate.

"Subject" means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term "subject" does not denote a particular age or sex.

"Arthritis" means diseases or conditions damage to joints of the body and pain associated with such joint damage. Arithritis includes rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis and gouty arthritis.

"Pain" includes, without limitation, inflammatory pain; surgical pain; visceral pain; dental pain; premenstrual pain; central pain; pain due to burns; migraine or cluster headaches; nerve injury; neuritis; neuralgias; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infection; post-traumatic injury; or pain associated with irritable bowel syndrome.

"Therapeutically effective amount" means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.

The terms "those defined above" and "those defined herein" when referring to a variable incorporates by reference the broad definition of the variable as well as preferred, more preferred and most preferred definitions, if any. "Treating" or "treatment" of a disease state includes:

(i) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.

(ii) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or

(iii) relieving the disease state , i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

The terms "treating", "contacting" and "reacting" when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product. Nomenclature and Structures

In general, the nomenclature used in this Application is based on AUTONOM™ v.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. Chemical structures shown herein were prepared using ISIS® version 2.2. Any open valency appearing on a carbon, oxygen sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen atom unless indicated otherwise. Where a nitrogen-containing heteroaryl ring is shown with an open valency on a nitrogen atom, and variables such as Ra, Rb or Rc are shown on the heteroaryl ring, such variables may be bound or joined to the open valency nitrogen. Where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral center are encompassed by the structure. Where a structure shown herein may exist in multiple tautomeric forms, all such tautomers are encompassed by the structure.

All patents and publications identified herein are incorporated herein by reference in their entirety.

Compounds of the Invention

The invention provides compounds of the formula I:


or pharmaceutically acceptable salts thereof, wherein: m is O or l; n is 0 or 1 ;

R1 is optionally substituted heteroaryl R2 is: optionally substituted aryl; optionally substituted heteroaryl;

C3_6cycloalkyl; or Ci_6alkyl; R3 is: hydrogen; Ci_6alkyl; alkylcarbonylalkyl; or alkoxyc arbonylalkyl ; R4 and R5 each independently is: hydrogen; or Ci-βalkyl; and

Ra is: hydrogen; Ci-ealkyl;

hydroxy-Ci_6alkyl;

Ci-ealkoxy-Ci-βalkyl.

In certain embodiments of formula I, R3, R4 and R5 are hydrogen.

In certain embodiments of formula I, R3, R4, R5 and Ra are hydrogen. In certain embodiments of formula I, m is 0.

In certain embodiments of formula I, n is 0.

In certain embodiments of formula I, R is hydrogen.

In certain embodiments of formula I, R4 is hydrogen.

In certain embodiments of formula I, R5 is hydrogen. In certain embodiments of formula I, Ra is hydrogen.

In certain embodiments of formula I, R1 is heteroaryl selected from: indolyl; quinolinyl; benzofuranyl; isobenzofuranyl; benzotriazol-yl; indazol-yl; 2-oxo-2,3-dihydro-indolyl; pyridinyl; 1 ,2,3,4-tetrahydro-quinolinyl; isoquinolinyl; 2-oxo-l,2,3,4-tetrahydro-quinolin-yl; pyrrolo[2,3-£]pyrazin-yl; 3,4-dihydrobenzo[l ,4]oxazin-yl; quinazolinyl; cinnolinyl; and 1-oxo- 1 ,2-dihydro-isoquinolinyl; each optionally substituted one, two or three times with a group or groups independently selected from: oxo; halo, Ci-βalkyl; halo-Ci-βalkyl; hydroxy- Ci-βalkyl; hydroxy Ci-βalkoxy- Ci-βalkyl; Ci_6alkoxy-Ci_6alkyl; or aminocarbonyl- Ci-βalkyl.

In certain embodiments of formula I, R1 is heteroaryl selected from: indolyl; quinolinyl; benzofuranyl; isobenzofuranyl; benzotriazol-yl; indazol-yl; 2-oxo-2,3-dihydro-indolyl; pyridinyl; 1 ,2,3,4-tetrahydro-quinolinyl; isoquinolinyl; 2-oxo-l,2,3,4-tetrahydro-quinolin-yl; pyrrolo[2,3-δ]pyrazin-yl; or 3,4-dihydrobenzo[l,4]oxazin-yl; each optionally substituted one, two or three times with a group or groups independently selected from: oxo; halo, Ci-βalkyl; halo-Ci-βalkyl; hydroxy-Ci-βalkyl; hydroxy Ci-βalkoxy- Ci-βalkyl; or Ci_6alkoxy-Ci_6alkyl.

In certain embodiments of formula I, R1 is heteroaryl selected from: indolyl; quinolinyl; benzofuranyl; isobenzofuranyl; benzotriazol-yl; 2-oxo-2,3-dihydro-indolyl; pyridinyl;

1,2,3,4-tetrahydro-quinolinyl; isoquinolinyl; 2-oxo-l,2,3,4-tetrahydro-quinolin-yl; pyrrolo[2,3-δ]pyrazin-yl; 3,4-dihydrobenzo[l ,4]oxazin-yl; cinnolinyl; and l-oxo-1,2-dihydro-isoquinolinyl; each optionally substituted one, two or three times with a group or groups independently selected from: oxo; halo, Ci-6alkyl; halo-Ci-βalkyl; hydroxy-Ci-βalkyl; hydroxy Ci-βalkoxy- Ci-6alkyl; or Ci_6alkoxy-Ci_6alkyl.

In certain embodiments of formula I, R1 is heteroaryl selected from: indolyl; quinolinyl; indazol-yl; 1,2,3,4-tetrahydro-quinolinyl; isoquinolinyl; 2-oxo-l ,2,3,4-tetrahydro-quinolin-yl;

3,4-dihydrobenzo[l,4]oxazin-yl; cinnolinyl; and l-oxo-l ,2-dihydro-isoquinolinyl; each optionally substituted one, two or three times with a group or groups independently selected from: oxo; halo, Ci-βalkyl; halo-Ci-βalkyl; hydroxy-Ci-βalkyl; or Ci-6alkoxy-Ci-6alkyl. In certain embodiments of formula I, R1 is heteroaryl selected from: indolyl; quinolinyl; 1,2,3,4-tetrahydro-quinolinyl; isoquinolinyl; 2-oxo-l,2,3,4-tetrahydro-quinolin-yl; 3,4-dihydrobenzo[l,4]oxazin-yl; cinnolinyl; and 1 -oxo- 1, 2 -dihydro-isoquinolinyl; each optionally substituted one, two or three times with a group or groups independently selected from: oxo; halo, Ci-6alkyl; halo-Ci-βalkyl; hydroxy-Ci-βalkyl; or Ci_6alkoxy-Ci_6alkyl. In certain embodiments of formula I, R1 is heteroaryl selected from: indolyl; quinolinyl; indazol-yl; 1,2,3,4-tetrahydro-quinolinyl; isoquinolinyl; 2-oxo-l,2,3,4-tetrahydro-quinolin-yl; and 3,4-dihydrobenzo[l,4]oxazin-yl; each optionally substituted one, two or three times with a group or groups independently selected from: oxo; halo, Ci-6alkyl; and hydroxy-Ci_6alkyl. In certain embodiments of formula I, R1 is heteroaryl selected from: indol-4-yl; quinolin-5-yl; indazol-6-yl; indazol-5-yl; 3 -oxo- 1, 3 -dihydro-isobenzofuranyl; benzotriazol-5-yl; indol-6-yl; indazol-5-yl; 2-oxo-2,3-dihydro-indol-5-yl; pyridin-3-yl; pyridin-4-yl; pyridin-2-yl; pyridin-3-yl; quinolin-6-yl; quinolin-7-yl; quinolin-8-yl; l,2,3,4-tefrahydro-quinolin-7-yl; isoquinolin-5-yl; 2-oxo-l,2,3,4-tetrahydro-quinolin-7-yl; pyrrolo[2,3-δ]pyrazin-2-yl; 3,4-dihydro-benzo[l ,4]oxazin-6-yl; 3-oxo-3,4-dihydro-benzo[l ,4]oxazin-6-yl; 3,4-dihydro-benzo[l,4]oxazin-6-yl 3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 1,2,3,4-tetrahydro-quinolin-6-yl; 2-oxo-l,2,3,4-tefrahydro-quinolin-6-yl; cinnolinyl; and 1 -oxo- 1,2-dihydro-isoquinolinyl; each optionally substituted once or twice with a group or groups independently selected from: halo, Ci-βalkyl; halo-Ci-βalkyl; hydroxy-Ci-βalkyl; or Ci_6alkoxy-Ci_6alkyl. In certain embodiments of formula I, R1 is heteroaryl selected from: indol-4-yl; quinolin-5-yl; indazol-6-yl; indazol-5-yl; indol-6-yl; quinolin-6-yl; quinolin-7-yl; quinolin-8-yl; 1,2,3,4-tetrahydro-quinolin-7-yl; isoquinolin-5-yl; 2-oxo-l,2,3,4-tetrahydro-quinolin-7-yl; 3,4-dihydro-benzo[l,4]oxazin-6-yl; 3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 3,4-dihydro-benzo[l,4]oxazin-6-yl 3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 1,2,3,4-tetrahydro-quinolin-6-yl; and 2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl; each optionally substituted once or twice with a group or groups independently selected from: halo, Ci-6alkyl; halo-Ci-βalkyl; hydroxy-Ci-βalkyl; or Ci_6alkoxy-Ci_6alkyl. In certain embodiments of formula I, R1 is heteroaryl selected from: indol-4-yl; quinolin-5-yl; indazol-6-yl; indazol-5-yl; indol-6-yl; quinolin-6-yl; quinolin-7-yl; quinolin-8-yl; 1,2,3,4-tetrahydro-quinolin-7-yl; isoquinolin-5-yl; 2-oxo-l,2,3,4-tetrahydro-quinolin-7-yl; 3,4-dihydro-benzo[l ,4]oxazin-6-yl; 3-oxo-3,4-dihydro-benzo[l ,4]oxazin-6-yl; 3,4-dihydro- benzo[l,4]oxazin-6-yl 3-0X0-3 ,4-dihydro-benzo[l,4]oxazin-6-yl; 1,2,3,4-tetrahydro-quinolin- 6-yl; and 2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl; each optionally substituted once or twice with a group or groups independently selected from: chloro; bromo; methyl; ethyl; or 2-hydroxy-ethyl. In certain embodiments of formula I, R1 is heteroaryl selected from: indol-4-yl; quinolin-5-yl; 3-oxo-l,3-dihydro-isobenzofuranyl; benzotriazol-5-yl; indol-6-yl; indazol-5-yl; 2-oxo-2,3-dihydro-indol-5-yl; 6-chloro-pyridin-3-yl; pyridin-4-yl; 2-chloro-pyridin-4-yl; pyridin-2-yl; 4-methyl-pyridin-3-yl; 5-bromo-quinolin-6-yl; 7-ethyl-quinolin-6-yl; 5-ethyl-quinolin-6-yl; 2-0X0-2 ,3 -dihydro-indol-6-yl; 5 -methyl- lH-indol-6-yl; 5-methyl-quinolin-6-yl; 6-bromo-2-oxo-l,2,3,4-tetrahydro-quinolin-7-yl; quinolin-8-yl; 6-methyl-quinolin-5-yl; 6-bromo-l-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-7-yl; isoquinolin-5-yl; 2-methyl-quinolin-5-yl; 5-ethyl- 1 -(2-hydroxy-ethyl)-indol-6-yl; 1 ,6-dimethyl-2 -oxo- 1 ,2,3,4-tetrahydro-quinolin-7-yl; 1 -2-hydroxy-ethyl)-2-oxo-l ,2,3,4-tetrahydro-quinolin-7-yl; 7-methyl-quinolin-6-yl; 5-methyl-5H-pyrrolo[2,3-δ]pyrazin-2-yl; 7-bromo-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-6-yl; 7-bromo-4-methyl-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 4,7-dimethyl-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 7-ethyl-4-methyl-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 6-methyl-quinolin-5-yl; 2-hydroxy-ethyl)-5-methyl-indazol-6-yl; l-(2-hydroxy-ethyl)-3,5-dimethyl-indol-6-yl; (6-ethyl-l-methyl-2-oxo-l ,2,3,4-tetrahydro-quinolin-7-yl; indazol-5-yl; l-(2-hydroxy-ethyl)-6-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-7-yl; 7-bromo-l-(2-hydroxy-ethyl)-2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl; 5-ethyl-2-methyl-quinolin-6-yl; 7-methyl-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 7-ethyl-3-oxo-3,4-dihydro-benzo[l ,4]oxazin-6-yl; 7-bromo-4-(2-hydroxy-ethyl)-3-oxo-3,4-dihydro-benzo[l ,4]oxazin-6-yl; 7-ethyl-4-(2-hydroxy-ethyl)-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 5-ethyl-l-methyl-indazol-6-yl; l,7-dimethyl-2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl; and 5-ethyl-l-(2-hydroxy-ethyl)-indazol-6-yl.

In certain embodiments of formula I, R1 is heteroaryl selected from: indol-4-yl; quinolin-5-yl; indol-6-yl; 5-bromo-quinolin-6-yl; 7-ethyl-quinolin-6-yl; 5-ethyl-quinolin-6-yl; 5-methyl-lH-indol-6-yl; 5-methyl-quinolin-6-yl; 6-bromo-2-oxo-l ,2,3,4-tetrahydro-quinolin-7-yl; quinolin-8-yl; 6-methyl-quinolin-5-yl; 6-bromo-l-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-7-yl; isoquinolin-5-yl; 2-methyl-quinolin-5-yl; 5-ethyl-l-(2-hydroxy-ethyl)-indol-6-yl; 1,6-dimethyl-2-oxo-l ,2,3,4-tetrahydro-quinolin-7-yl; 1-2 -hydroxy-ethyl)-2-oxo-l ,2,3,4-tetrahydro-quinolin-7-yl; 7-methyl-quinolin-6-yl; 7-bromo-3-oxo-3 ,4-dihydro-2H-benzo[l ,4]oxazin-6-yl; 7-bromo-4-methyl-3-oxo-3,4-dihydro-benzo[l ,4]oxazin-6-yl; 4,7- dimethyl-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 7-ethyl-4-methyl-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 6-methyl-quinolin-5-yl; 2-hydroxy-ethyl)-5-methyl-indazol-6-yl; 1-(2-hydroxy-ethyl)-3,5-dimethyl-indol-6-yl; 6-ethyl-l-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-7-yl; indazol-5-yl; l-(2-hydroxy-ethyl)-6-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-7-yl; 7-bromo-l-(2-hydroxy-ethyl)-2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl; 5-ethyl-2-methyl-quinolin-6-yl; 7-methyl-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 7-ethyl-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 7-bromo-4-(2-hydroxy-ethyl)-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 7-ethyl-4-(2-hydroxy-ethyl)-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 5-ethyl-l-methyl-indazol-6-yl; l,7-dimethyl-2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl; and 5-ethyl- 1 -(2-hydroxy-ethyl)-indazol-6-yl.

In certain embodiments of formula I, R1 is heteroaryl selected from: indol-4-yl; quinolin-5-yl; indol-6-yl; 5-bromo-quinolin-6-yl; 7-ethyl-quinolin-6-yl; 5-ethyl-quinolin-6-yl; 5-methyl-lH-indol-6-yl; 5-methyl-quinolin-6-yl; 6-bromo-2-oxo-l ,2,3,4-tetrahydro-quinolin-7-yl; quinolin-8-yl; 6-methyl-quinolin-5-yl; 6-bromo-l-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-7-yl; isoquinolin-5-yl; 2-methyl-quinolin-5-yl; 5-ethyl-l-(2-hydroxy-ethyl)-indol-6-yl; 1,6-dimethyl-2-oxo-l ,2,3,4-tetrahydro-quinolin-7-yl; 1-2 -hydroxy-ethyl)-2-oxo-l ,2,3,4-tetrahydro-quinolin-7-yl; 7-methyl-quinolin-6-yl; 7-bromo-3-oxo-3 ,4-dihydro-2H-benzo[l ,4]oxazin-6-yl; 7-bromo-4-methyl-3-oxo-3,4-dihydro-benzo[l ,4]oxazin-6-yl; 4,7-dimethyl-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 7-ethyl-4-methyl-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 6-methyl-quinolin-5-yl; 2-hydroxy-ethyl)-5-methyl-indazol-6-yl; 1-(2-hydroxy-ethyl)-3,5-dimethyl-indol-6-yl; 6-ethyl-l-methyl-2 -oxo- 1,2,3 ,4-tetrahydro-quinolin-7-yl; indazol-5-yl; l-(2-hydroxy-ethyl)-6-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-7-yl; 7-bromo-l-(2-hydroxy-ethyl)-2-oxo-l ,2,3,4-tetrahydro-quinolin-6-yl; 5-ethyl-2-methyl-quinolin-6-yl; 7-methyl-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 7-ethyl-3-oxo-3,4-dihydro-benzo[l ,4]oxazin-6-yl; 7-bromo-4-(2-hydroxy-ethyl)-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 7-ethyl-4-(2-hydroxy-ethyl)-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl; 5-ethyl-l-methyl-indazol-6-yl; 1 ,7-dimethyl-2-oxo-l ,2,3,4-tetrahydro-quinolin-6-yl; 5-ethyl-l-(2-hydroxy-ethyl)-indazol-6-yl; 3-methyl-cinnolin-5-yl; 2,6-dimethyl-quinolin-5-yl; 2-(2-hydroxy-ethyl)-l-oxo-l,2-dihydro-isoquinolin-5-yl; 2,6-dimethyl-l-oxo-l,2-dihydro-isoquinolin-5-yl; 1 ,6-dimethyl-isoquinolin-5 -yl; 1 -dimethylcarbamoylmethyl-5 -methyl- IH- indazol-6-yl; 5 -methyl- 1 -methylcarbamoylmethyl- lH-indazol-6-yl and 2-methyl- 1 -oxo-1 ,2-dihydro-isoquinolin-5 -yl.

In certain embodiments of formula I, R1 is indolyl optionally substituted once or twice with a group or groups independently selected from: oxo; halo, Ci-βalkyl; halo-Ci-βalkyl; hydroxy-Ci-βalkyl; or Ci_6alkoxy-Ci_6alkyl.

In certain embodiments of formula I, R1 is indazolyl optionally substituted once or twice with a group or groups independently selected from: oxo; halo, Ci-6alkyl; halo-Ci-βalkyl; hydroxy-Ci-βalkyl; or Ci_6alkoxy-Ci_6alkyl.

In certain embodiments of formula I, R1 is: quinolinyl; isoquinolinyl; dihydroquinolinyl; or tetrahydroquinolinyl; each optionally substituted one, two or three times with a group or groups independently selected from: oxo; halo, Ci-6alkyl; halo-Ci-βalkyl; hydroxy-Ci-βalkyl; or Ci-6alkoxy-Ci_6alkyl.

In certain embodiments of formula I, R1 is: benzo[l,4]oxazinyl; dihydrobenzo[l,4]xazinyl; or tetrahydrobenzo[l,4]xazinyl; each optionally substituted one, two or three times with a group or groups independently selected from: oxo; halo, Ci-βalkyl; halo-Ci-βalkyl; hydroxy-Ci-βalkyl; or Ci_6alkoxy-Ci_6alkyl. In certain embodiments of formula I, R1 is optionally substituted heteroaryl selected from: pyridinyl; indazolyl; indolyl; quinolinyl; quinoxalinylthiophenyl; benzimidazolyl; benzofuranyl; dihydroindolyl; tetrahydroquinolinyl; pyrazolyl; 2,3-dihydrobenzimidazolyl; benzothiazolyl; 2 -oxo- 1,2, 3, 4-tetrahydroquinolinyl; 2-oxo-2,3-dihydro-indolyl; 4-oxo-3,4-dihydro-quinazolinyl; 3,4-dihydrobenzo[l,4]oxazinyl; 2,3-dihydrobenzofuranyl; each of which may be optionally substituted once or twice with a substituent or substituents independently selected from: fluoro; chloro; bromo; methyl; methoxy; ethoxy; trifiuoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy. In certain embodiments of formula I, R1 is optionally substituted heteroaryl selected from: pyridinyl; indazolyl; indolyl; quinolinyl; quinoxalinyl; thiophenyl; benzimidazolyl; benzofuranyl; dihydroindolyl; tetrahydroquinolinyl; pyrazolyl; 2-oxo-2,3-dihydro-benzimidazolyl; 2,3-dihydrobenzimidazolyl; benzothiazolyl; 2 -oxo- 1,2, 3,4-tetrahydroquinolinyl; 2-oxo-3,4-dihydro-indolyl; 4-oxo-3,4-dihydro-quinazolinyl; 3,4-dihydroquinolinyl; 3,4-dihydrobenzo[l,4]oxazinyl; 2,3-dihydrobenzofuranyl; each of which may be optionally substituted once or twice with a substituent or substituents independently selected from: fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy; trifiuoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; or hydroxyethyl.

In certain embodiments of formula I, R1 is is heteroaryl selected from: pyridinyl; indazolyl; indolyl; quinolinyl; quinoxalinyl; thiophenyl; benzimidazolyl; benzofuranyl; dihydroindolyl; tetrahydroquinolinyl; pyrazolyl; 2,3-dihydrobenzimidazolyl; benzothiazolyl; 2-oxo-l, 2 ,3 ,4-tetrahydroquinolinyl; 2-oxo-2,3-dihydro-indolyl; 4-oxo-3,4-dihydro-quinazolinyl; 3,4-dihydrobenzo[l ,4]oxazinyl; 2,3-dihydrobenzofuranyl; each of which may be optionally substituted once or twice with halo, Ci-βalkyl. hydroxy-Ci-βalkyl or Ci-βalkoxy. In certain embodiments of formula I, R1 is heteroaryl selected from: pyridinyl; indazolyl; indolyl; quinolinyl; quinoxalinyl; thiophenyl; benzimidazolyl; benzofuranyl; dihydroindolyl; tetrahydroquinolinyl; pyrazolyl; 2,3-dihydrobenzimidazolyl; benzothiazolyl; 2-oxo-l, 2,3,4-tetrahydroquinolinyl; 2-oxo-2,3-dihydro-indolyl; 4-oxo-3,4-dihydro-quinazolinyl; 3,4-dihydrobenzo[l,4]oxazinyl; 2,3-dihydrobenzofuranyl; each of which may be optionally substituted once or twice with halo or Ci-βalkyl.

In certain embodiments of formula I, R1 is heteroaryl selected from: pyridin-2-yl; pyridin-4-yl; indazol-6-yl; indazol-5-yl; 3,4-dihydroquinolin-l-yl; indolyl-6-yl; indolyl-5-yl; quinolin-6-yl; quinolin-7-yl; quinolin-5-yl; quinolin-6-yl; quinoxalin-6-yl; thiophen-3-yl; benzimidazol-5-yl; benzofuran-5-yl; 2-oxo-2,3-dihydro-benzimidazol-5-yl; dihydroindolyl; tetrahydroquinolinyl; pyrazol-3-yl; 2,3-dihydrobenzimidazolyl; benzothiazol-5-yl; benzothiazol-6-yl; 2-oxo-l, 2,3 ,4-tetrahydroquinolin-7-yl; 2-oxo-3,4-dihydro-indol-6-yl; A-oxo-3,4-dihydro-quinazolin-6-yl; 3,4-dihydrobenzo[l ,4]oxazin-7-yl; 2,3-dihydrobenzofuran-4-yl; each of which may be optionally substituted once or twice with halo or Ci_6alkyl.

In certain embodiments of formula I, R1 is heteroaryl selected from: pyridin-2-yl; pyridin-4-yl; indazol-6-yl; indazol-5-yl; 3,4-dihydroquinolin-l-yl; indolyl-6-yl; indolyl-5-yl; quinolin-6-yl; quinolin-7-yl; quinolin-5-yl; quinolin-6-yl; quinoxalin-6-yl; thiophen-3-yl; benzimidazol-5-yl; benzofuran-5-yl; 2-oxo-2,3-dihydro-benzimidazol-5-yl; dihydroindolyl; tetrahydroquinolinyl; pyrazol-3-yl; 2,3-dihydrobenzimidazolyl; benzothiazol-5-yl; benzothiazol-6-yl; 2-oxo-l, 2,3 ,4-tetrahydroquinolin-7-yl; 2-oxo-3,4-dihydro-indol-6-yl; A-oxo-3,4-dihydro-quinazolin-6-yl; 3,4-dihydrobenzo[l ,4]oxazin-7-yl; 2,3-dihydrobenzofuran-4-yl; each of which may be optionally substituted once or twice with halo or Ci_6alkyl. In certain embodiments of formula I, R1 is heteroaryl selected from: 3-bromo-6-methoxy-pyridin-2-yl; 5-bromo-3-methyl-l-(toluene-4-sulfonyl)-indazol-6-yl; 5-bromo-3-methyl-indazol-6-yl; 5-bromo-3-methyl-indazol-6-yl; l-methyl-indol-6-yl; 7-methyl-quinolin-6-yl; 2-bromo-thiophen-3-yl; indol-6-yl; 2-methyl-benzofuran-5-yl; 1 -methyl- lH-indo 1-6 -yl; 6-methyl-quinolin-7-yl; 5-bromo-quinolin-6-yl; 7-methyl-quinoxalin-6-yl; 2,5-dimethyl- pyrazol-3-yl; 2-methyl-benzothiazol-5-yl; 6-bromo-2-oxo-2,3-dihydro-benzoimidazol-5-yl;

1 -methyl- IH- indol-5-yl; benzothiazol-6-yl; 5-methyl-quinolin-6-yl; 6-bromo-l-methyl-2-oxo-1, 2,3,4-tetrahydro-quinolin-7-yl; 2-oxo-2,3-dihydro-lH-indol-6-yl; 1-oxo-l, 2,3,4-tetrahydro-isoquinolin-7-yl; 1 ,5-dimethyl-indol-6-yl; 4,6-dimethyl-3 ,4-dihydro-benzo[l ,4]oxazin-7-yl; 1 ,3-dimethyl-indazol-6-yl; 2,3-dimethyl-indazol-6-yl; 2-methyl-indazol-6-yl; 2-methyl-indazol-5-yl; 5-ethyl-quinolin-6-yl; 7-bromo-2,3-dimethyl-indazol-6-yl; 2,3-dihydro-benzofuran-4-yl; 7-ethyl-quinolin-6-yl; quinolin-5-yl; l-(2-hydroxy-ethyl)-5-methyl-lH-indol-6-yl; l-methyl-indazol-6-yl; 7-bromo-l-methyl-indazol-6-yl; and 7-bromo- 2-methyl-indazol-6-yl. In certain embodiments of formula I, R1 is indazolyl optionally substituted once or twice with halo or Ci_6alkyl.

In certain embodiments of formula I, R1 is quinolinyl optionally substituted once or twice with halo or Ci_6alkyl.

In certain embodiments of formula I, R1 is optionally substituted heteroaryl which may comprise: pyridinyl; indazolyl; indolyl; quinolinyl; or benzofuranyl; each of which may be optionally substituted one, two or three times with a substituent or substituents independently selected from: fluoro; chloro; bromo; methyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxy ethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy. In certain embodiments of formula I, R1 is indol-4-yl; quinolin-5-yl.

In certain embodiments of formula I, R1 is indol-6-yl.

In certain embodiments of formula I, R1 is 5-bromo-quinolin-6-yl.

In certain embodiments of formula I, R1 is 7-ethyl-quinolin-6-yl.

In certain embodiments of formula I, R1 is 5-ethyl-quinolin-6-yl. In certain embodiments of formula I, R1 is 5-methyl-lH-indol-6-yl. In certain embodiments of formula I, R1 is 5-methyl-quinolin-6-yl.

In certain embodiments of formula I, R1 is 6-bromo-2-oxo-l,2,3,4-tetrahydro-quinolin-7-yl.

In certain embodiments of formula I, R1 is quinolin-8-yl.

In certain embodiments of formula I, R1 is 6-methyl-quinolin-5-yl. In certain embodiments of formula I, R1 is 6-bromo-l-methyl-2-oxo-l ,2,3,4-tetrahydro-quinolin-7-yl.

In certain embodiments of formula I, R1 is isoquinolin-5-yl.

In certain embodiments of formula I, R1 is 2-methyl-quinolin-5-yl.

In certain embodiments of formula I, R1 is 5-ethyl-l-(2-hydroxy-ethyl)-indol-6-yl. In certain embodiments of formula I, R1 is l,6-dimethyl-2-oxo-l,2,3,4-tetrahydro-quinolin-7-yi- In certain embodiments of formula I, R1 is l-2-hydroxy-ethyl)-2-oxo-l,2,3,4-tetrahydro-quinolin-7-yl.

In certain embodiments of formula I, R1 is 7-methyl-quinolin-6-yl.

In certain embodiments of formula I, R1 is 7-bromo-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin- 6-yl.

In certain embodiments of formula I, R1 is 7-bromo-4-methyl-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl.

In certain embodiments of formula I, R1 is 4,7-dimethyl-3-oxo-3,4-dihydro-benzo[l ,4]oxazin-6-yl.

In certain embodiments of formula I, R1 is 7-ethyl-4-rnethyl-3-oxo-3,4-dihydro-benzo[l ,4]oxazin-6-yl. In certain embodiments of formula I, R1 is 6-methyl-quinolin-5-yl.

In certain embodiments of formula I, R1 is 2-hydroxy-ethyl)-5-methyl-indazol-6-yl.

In certain embodiments of formula I, R1 is l-(2-hydroxy-ethyl)-3,5-dimethyl-indol-6-yl.

In certain embodiments of formula I, R1 is 6-ethyl-l-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-7-yl. In certain embodiments of formula I, R1 is indazol-5-yl.

In certain embodiments of formula I, R1 is l-(2-hydroxy-ethyl)-6-methyl-2-oxo-l,2,3,4-tetrahydro-quinolin-7-yl.

In certain embodiments of formula I, R1 is 7-bromo-l-(2-hydroxy-ethyl)-2-oxo-l, 2,3,4-tetrahydro-quinolin-6-yl. In certain embodiments of formula I, R1 is 5-ethyl-2-methyl-quinolin-6-yl.

In certain embodiments of formula I, R1 is 7-methyl-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yi- In certain embodiments of formula I, R1 is 7-ethyl-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl. In certain embodiments of formula I, R1 is 7-bromo-4-(2-hydroxy-ethyl)-3-oxo-3,4-dihydro-benzo[l,4]oxazin-6-yl.

In certain embodiments of formula I, R1 is 7-ethyl-4-(2-hydroxy-ethyl)-3-oxo-3,4-dihydro-benzo[l ,4]oxazin-6-yl.

In certain embodiments of formula I, R1 is 5-ethyl-l-methyl-indazol-6-yl.

In certain embodiments of formula I, R1 is l,7-dimethyl-2-oxo-l ,2,3,4-tetrahydro-quinolin-6-yi- In certain embodiments of formula I, R1 is 5-ethyl-l-(2-hydroxy-ethyl)-indazol-6-yl. In certain embodiments of formula I, R1 is 3-methyl-cinnolin-5-yl;. In certain embodiments of formula I, R1 is 2,6-dimethyl-quinolin-5-yl.

In certain embodiments of formula I, R1 is 2-(2-hydroxy-ethyl)-l-oxo-l,2-dihydro-isoquinolin-5-yi.

In certain embodiments of formula I, R1 is 2,6-dimethyl-l-oxo-l,2-dihydro-isoquinolin-5-yl. In certain embodiments of formula I, R1 is l,6-dimethyl-isoquinolin-5-yl. In certain embodiments of formula I, R1 is l-dimethylcarbamoylmethyl-S-methyl-lH-indazol-ό-yl. In certain embodiments of formula I, R1 is S-methyl-l-methylcarbamoylmethyl-lH-indazol-ό-yl. In certain embodiments of formula I, R1 is 2-methyl-l-oxo-l,2-dihydro-isoquinolin-5-yl. In certain embodiments of formula I, R2 is optionally substituted aryl. In certain embodiments of formula I, R2 is optionally substituted phenyl. In certain embodiments of formula I, R2 is phenyl optionally substituted one, two, three or four times with a substituent or substituents each independently selected from: halo; Ci-βalkyl; Ci-βalkoxy; halo-Ci-βalkyl; halo-Ci-βalkoxy; Ci-βalkylsulfonyl; Ci-6alkylsulfanyl; Ci_ δalkylsulfinyl; phenylsulfonyl wherein the phenyl portion is optionally substituted with Ci_ βalkyl; nitrile; hydroxy; Ci-βalkylcarbonyl; aminocarbonyl; Ci-βalkoxycarbonyl; Ci-6alkoxycarbonyl-Ci_6alkoxy; hydroxycarbonyl; hydroxycarbonyl-Ci-βalkoxy; Ci_ 6alkylaminocarbonyl-Ci_6alkoxy; Ci_6alkoxy-Ci_6alkoxy; hydroxy-Ci-βalkoxy; Ci_ 6alkylamino-Ci_6alkoxy; Ci_6alkylsulfony-Ci_6lalkoxy; hydroxy-Ci-βalkyl; C3-6cycloalkyl-Ci_ 6alkoxy; amino; amino-Ci_6alkyl; Ci-6alkenyl; Ci-6alkynyl; moφholinyl; morpholinyl-Ci-βalkyl; piperazinyl; piperidinyloxy; aminocarbonyl-Ci-βalkoxy; Ci_6alkoxyamino-Ci_6alkyl; hydroxy-Ci-6alkylamino-Ci_6alkyl; Ci-ealkoxycarbonylamino-Ci-ealkyl; Ci_

6alkylcarbonylamino-Ci-6alkyl; Ci-6alkylaminocarbonyl; Ci-ealkoxycarbonylCi-βalkyl; Ci-6alkylaminocarbonyl-Ci-6alkyl; Ci_6alkylamino-Ci_6alkyl; hydroxycarbonyl-Ci_6alkyl; or nitro; or two adjacent substituents may form a Ci-2alkylenedioxy or halo-Ci-2alkylenedioxy. In certain embodiments of formula I, R2 is phenyl optionally substituted once or twicewith a substituent or substituents each independently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difiuoromethoxy; methanesulfonyl; methanesulfanyl; methanesulfmyl; toluenesulfonyl; nitrile; acetyl; aminocarbonyl; methoxycarbonyl; methoxycarbonylmethoxy; carboxy; hydroxycarbonylmethoxy;

methylaminocarbonylmethoxy; methoxyethoxy; hydroxyethoxy; methylaminoethoxy; methanesulfonylpropyloxy; hydroxymethyl; hydroxyethyl; cyclopropylmethoxy; amino; or nitro; or two adjacent substituents may form methylenedioxy, ethylenedioxy or difluoromethylenedioxy. In certain embodiments of formula I, R2 is phenyl optionally substituted onece or twice with a substituent or substituents each independently selected from: halo; Ci-βalkyl; Ci-βalkoxy; halo-Ci-βalkyl; halo-Ci-βalkoxy; Ci-βalkylsulfonyl; nitrile; alkoxyalkoxy; hydroxyalkoxy; alkylsulfonylalkoxy; hydro xyalkyl; or C3_6Cycloalkyl-Ci_6alkoxy.

In certain embodiments of formula I, R2 is phenyl optionally substituted once or twice with a substituent or substituents each independently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.

In certain embodiments of formula I, R2 is phenyl optionally substituted once or twice with a substituent or substituents each independently selected from: fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.

In certain embodiments of formula I, R2 is phenyl substituted once or twice with a substituent or substituents each independently selected from: halo; methyl; methoxy; trifluoromethyl; difluoromethoxy; nitrile; or methanesulfonyl. In certain embodiments of formula I, R2 is phenyl substituted once or twice with a substituent or substituents each independently selected from: fluoro; chloro; methyl; methoxy; or nitrile.

In certain embodiments of formula I, R2 is phenyl substituted once or twice with fluoro.

In certain embodiments of formula I, R2 is: phenyl; 4-fluoro-phenyl; 3-fluoro-phenyl; 2-fluoro-phenyl; 2-chloro-phenyl; 3,4-difluoro-phenyl; 3,5-difluoro-phenyl; 3-methyl-phenyl; 4-methyl-phenyl; or 3-cyano-phenyl.

In certain embodiments of formula I, R2 is: phenyl; 4-fluoro-phenyl; 3-fluoro-phenyl; 2-fluoro-phenyl; 2-chloro-phenyl; 3,4-difluoro-phenyl; or 3,5-difluoro-phenyl.

In certain embodiments of formula I, R2 is 4-fluoro-phenyl.

In certain embodiments of formula I, R2 is 3-fluoro-phenyl. In certain embodiments of formula I, R2 is 3,4-difluoro-phenyl.

In certain embodiments of formula I, Ra is hydrogen.

In certain embodiments of formula I, Ra is Ci-βalkyl.

In certain embodiments of formula I, Ra is methyl.

In certain embodiments of formula I, Ra is hydroxy-Ci_6alkyl.

In certain embodiments of formula I, Ra is Ci-6alkoxy-Ci-6alkyl.

In certain embodiments, the compounds of formula I may be more specifically of formula II:


wherein: p is from 0 to 3; each R6 independently is: halo; Ci-βalkyl; Ci-βalkoxy; halo-Ci-βalkyl; halo-Ci-βalkoxy; Ci-6alkylsulfonyl; ornitrile; and

R1 and Ra are as defined herein. In certain embodiments of formula II, the subject compounds may be more specifically of formula Ha or formula lib;


wherein p, R , R and Ra are as defined herein.

In certain embodiments the subject compounds are of formula Ha. In certain embodiments the subject compounds are of formula lib.

In certain embodiments of any of formulas II, Ha and lib, p is 0, 1 or 2.

In certain embodiments of any of formulas II, Ha and lib, p is 1 or 2.

In certain embodiments of any of formulas II, Ha and lib, p is 1.

In certain embodiments of any of formulas II, Ha and lib, each R6 independently is: halo; C1- 6alkyl; or Ci-βalkoxy.

In certain embodiments of any of formulas II, Ha and lib, each R6 independently is fluoro or methyl.

In certain embodiments of any of formulas II, Ha and lib, R6 is halo.

In certain embodiments of any of formulas II, Ha and lib, R11 is fluoro. In certain embodiments of any of formulas II, Ha and lib p is 1 and R6 is halo.

In certain embodiments of any of formulas II, Ha and lib p is 1 and R6 is 3 -halo or 4-halo.

In certain embodiments of any of formulas II, Ha and lib p is 1 and R6 is fluoro.

In certain embodiments of any of formulas II, Ha and lib p is 1 and R6 is 3-fiuoro or 4-fiuoro.

In certain embodiments of any of formulas II, Ha and lib p is 1 and R6 is 4-fiuoro. In certain embodiments of any of formula II, Ha and lib, Ra is hydrogen.

Where any of R1, R2, R3, R4, R5, R6 and Ra is alkyl or contains an alkyl moiety, such alkyl is preferably lower alkyl, i.e. Ci-Cβalkyl, and in many embodiments is Ci-C4alkyl.

The invention also provides methods for treating a disease or condition mediated by or otherwise associated with a P2X7 receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention.

The invention also provides methods for treating an inflammatory, respiratory or diabetes condition, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention together with an effective amount of a P2X3 inhibitor.

The disease may be an inflammatory disease such as arthritis, and more particularly rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, glomerulonephritis, irritable bowel disease, and Crohn's disease.

The disease may be a pain condition, such as inflammatory pain; surgical pain; visceral pain; dental pain; premenstrual pain; central pain; pain due to burns; migraine or cluster headaches; nerve injury; neuritis; neuralgias; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infection; post-traumatic injury; or pain associated with irritable bowel syndrome.

The disease may be a respiratory disorder, such as chronic obstructive pulmonary disorder

(COPD), asthma, or bronchospasm, or a gastrointestinal (GI) disorder such as Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with GI distension.

The disease may be diabetes.

Representative compounds in accordance with the methods of the invention are shown in

Table 1.

TABLE 1













Synthesis

Compounds of the present invention can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below. The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser 's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplemental; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application. The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data. Unless specified to the contrary, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78 0C to about 150 0C, more preferably from about 0 0C to about 125 0C, and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20 0C. Scheme A below illustrates one synthetic procedure usable to prepare specific compounds of formula I, wherein X is halo and may be the same or different upon each occurence, Y is a leaving group, and p, R1 and R6 are as defined herein.


SCHEME A

In step 1 of Scheme A, a Grignard reaction is carried out wherein nicotinic acid compound a is reacted with phenyl magnesium halide compound b to afford a phenyl dihydropyridone carboxylic acid compound c. In many embodiments, for example, commercially available 6-chloro-nicotinic acid may be used for compound a. Numerous phenyl magnesium bromide compounds are readily prepared by well known techniques and may be used for compound b. In step 2, dihydropyridone compound c is optionally modified to introduce a leaving group Y to the acyl moiety of compound d. Carboxylic acid derivative compound d may comprise, for example, a carboxylic acid halide, a carboxylate ester or a carboxylic acid anhydride, depending upon the nature of leaving group Y. In many embodiments Y is halo such as chloro, such that compound d may be prepared by treatment of carboxylic acid compound c with oxalyl chloride, thionyl chloride, or like halogenating agent. In step 3, an amide coupling reaction is carried out wherein a heteroaryl amine compound e is reacted with compound d, to afford dihydropyridoneamide compound II, which is a compound of formula I in accordance with the invention. Heteroaryl amine compound e may comprise, for example, an amino-quinoline, an amino-indole, an amino-indazole, an amino-benzoxazine, or the like. Numerous heteroaryl amine compounds e are commercially available or are readily prepared using synthetic procedures well known in the art. Such heteroaryl amine compounds may in many embodiments be made by reduction of the corresponding aryl nitro compounds, as illustrated in the experimental examples below. Many variations on the procedure of Scheme A are possible and will suggest themselves to those skilled in the art. For example, in certain embodiments step 2 may be omitted, and other amide coupling reaction procedures using EDCI, HU, BOP, PyBOP or the like, may be used in step 3. Specific details for producing compounds of the invention are described in the Examples section below.

Utility The compounds of the invention are usable for the treatment of a wide range of inflammatory diseases and conditions such as arthritis, including but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic conditions. The subject compounds would be useful for the treatment of pulmonary disorders or lung inflammation, including adult respiratory distress syndrome, pulmonary sarcoidosis, asthma, silicosis, and chronic pulmonary inflammatory disease.

The compounds of the invention are also expected to find utility as analgesics in the treatment of diseases and conditions associated with pain from a wide variety of causes, including, but not limited to, inflammatory pain such as pain associated with arthritis (including rheumatoid arthritis and osteoarthritis), surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injuries (including fractures and sports injuries), and pain associated with functional bowel disorders such as irritable bowel syndrome. Further, compounds of the invention are useful for treating respiratory disorders, including chronic obstructive pulmonary disorder (COPD), asthma, bronchospasm, and the like. Additionally, compounds of the invention are useful for treating gastrointestinal disorders, including Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with GI distension, and the like.

The compounds of the invention are also useful for the treatment of muscular sclerosis and diabetes.

Administration and Pharmaceutical Composition The invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.

In general, the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.

Compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. A compound or compounds of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.

The compounds of the invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration. Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.

Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The compounds of the invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water. The compounds of the invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. The compounds of the invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify. The compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

The subject compounds may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump. The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofiuorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofiuoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatine or blister packs from which the powder may be administered by means of an inhaler.

When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylazacycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Representative pharmaceutical formulations containing a compound of the present invention are described below.

EXAMPLES

The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof. Unless otherwise stated, all temperatures including melting points (i.e., MP) are in degrees Celsius (0C). It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product. The following abbreviations may be used in the Preparations and Examples.

ABBREVIATIONS

BETBDMS 2-bromoethoxy tertbutyldimethylsilane DBU l,8-diazabicyclo[5.4.0]undec-7-ene

DCM dichloromethane/methylene chloride

DIPEA diisopropyl ethylamine (Hunig's base)

DME 1,2-dimethoxyethane (glyme)

DMF N,N-dimethylformamide DMFDMA N,N-dimethylformamide dimethyl acetal

DMSO dimethyl sulfoxide

DMAP 4-dimethylaminopyridine dppf 1,1 '-Bis(diphenylphosphino)ferrocene ECDI 1 -ethyl-3-(3 '-dimethylaminopropyl)carbodiimide

EtOAc ethyl acetate

EtOH ethanol gc gas chromatography

HATU O-(7- Azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

HMPA hexamethylphosphoramide

HOBt N-Hydroxybenzotriazole hplc high performance liquid chromatography

IPA isopropanol

IPBAPE isopropenylboronic acid pinacol ester

KHMDS potassium hexamethyl disilazane mCPBA m-chloroperbenzoic acid

MeCN acetonitrile

NMM N-methyl morpholine

NMP N-methyl pyrrolidinone

Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)

TBAF tetra-n-butyl ammonium fluoride tBDMSICl tert-butyl-dimethylsilyl chloride

TEA triethylamine

THF tetrahydrofuran

LDA lithium diisopropylamine

TBDMS tert-butyl dimethylsilyl chloride

TLC thin layer chromatography

Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene

Preparation 1

4-(4-Fluoro-phenvD-6-oxo-l,4,5,6-tetrahvdro-pvridine-3-carboxvlic acid

The synthetic procedure used in this preparation is outlined in Scheme B.


SCHEME B

4-Fluorophenylmagnesium bromide (2M in THF; 130 ml) was added dropwise at O0C to a stirring solution of 6-chloronicotinic acid (12.92 g) in 150 mL of THF . After the addition was complete the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was cooled to -6O0C and acetic acid (105 ml) was added dropwise, resulting in formation of a solid. After the addition was complete the reaction mixture was warmed to ambient temperature. The reaction mixture was then cooled to O0C and quenched by addition of saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate, and the organic layer was separated, washed with water and brine, dried OVCrNa2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in hot ethyl acetate . Upon standing a solid precipitate formed,, which was collected and dried to give 10.04 g of 4-(4-fluoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylic acid as a white solid. Preparation 2

Chiral Separation of (R) and (S) 4-(4-Fluoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3- carboxylic acid

The (R) and (S) isomers of 4-(4-fiuoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylic acid were separated using an R,R Whelk-Ol (Regis Technologies) chiral column, 30 mm LD. x 250 mm length, designed for use with supercritical CO2 fluid chromatography. Racemic 4-(4-Fluoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylic acid was dissloved in a 5% THF/95% methanol solution to 100 mg/ml concentration. The solution was filtered and warmed to 40° C. The solution was injected onto the column in 1.7 mL increments and eluted with 35% methanol (HPLC grade), 65% supercritical CO2 at 40 0C. The (S) isomer was recovered from the first fraction ([alpha]=+197.3° (CHCI3 c=0.629), mp. 210-2120C) and the (R) isomer was recovered from the second fraction ([alpha]=- 197.4° (CHCI3 c=0.618), mp. 213-2150C). Stacked injections were jused with a single run time of seven minutes.

Preparation 3 6-Amino-5-ethylquinoline

The synthetic procedure used in this preparation is outlined in Scheme C.

triethyl borane



SCHEME C To a mixture of 183 mg (0.22 mmol) of Pd(dppf)Cl2.CH2Cl2 and 4.38 g (13.44 mmol) of Cs2CO3 in 13 mL of DMF under Argon atmosphere was added a solution of 500 mg (2.24 mmol) of 6-amino-5-bromoquinoline (commercially available from ACES Pharma Product List). Triethylborane in hexanes (2.91 mL of 1.0 M solution) was added, and the reaction was heated to 50 0C for 22 hours, then poured into 50 mL of water, and extracted with diethyl ether. The combined ether layers were washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to an oil. The oil was purified via silica gel chromatography, eluting with 0 to 50% EtOAc/hexanes to give 386 mg (65.8%) of 6-amino-5-ethylquinolinas e a colorless oil. MS (ESI): m/z 173.2 (M+H)+.

Preparation 4 7-Amino-l,6-dimethyl-3,4-dihvdro-lH-quinolin-2-one

The synthetic procedure used in this preparation is outlined in Scheme D.



SCHEME D

Step 1 7-Amino-6-bromo-3,4-dihydro-lH-quinolin-2-one To a mixture of 2.27 g (14 mmol) 7-amino-3,4-dihydro-lH-quinolin-2-one suspended in 125 ml of 4:1 DCMMeOH was added 4.45 g (9.1 mmol) of tetra-n-butylammonium bromide.

The reaction mixture was stirred at room temperature for two hours and then was partitioned between dichloromethane and 10% aqueous sodium thiosulfate. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography, eluting with 75% ethyl acetate/hexanes, provided 1.09 g of 7-amino-6-bromo-3,4-dihydro-lH-quinolin-2-one.

Step 2 7-Amino-6-bromo-l-methyl-3,4-dihydro-lH-quinolin-2-one 7-Amino-6-bromo-3,4-dihydro-lH-quinolin-2-one 280 mg (1.16 mmol) was dissolved in 8 ml THF and cooled to O0C. KHMDS (2.56 ml, 1.27 mmol, 0.5 M in toluene) was then added dropwise, followed by dropwise addition of 80ml (1.27 mmol) CH3I. The mixture was stirred for 12 hours, then partitioned between ethyl acetate and brine. The organic layer was dried over MgSO4 filtered and concentrated under reduced pressure. Purification by column chromatography, eluting with 75% ethyl acetate/hexanes, provided 265 mg of 7-amino-6-bromo- 1 -methyl-3 ,4-dihydro- 1 H-quinolin-2-one. Step 3 7-Aamino-l,6-dimethyl-3,4-dihydro-lH-quinolin-2-one To 7-amino-6-bromo-l-methyl-3,4-dihydro-lH-quinolin-2-one 1(57 mg, 0.615 mmol) dissolved in 4 ml degassed dioxane was added 50 mg (0.0615 mmol) PdCl2dppf.CH2Cl2, K2CO3 (255 mg 1.845 mmol), 400 ul H2O, and 86 ul (0.615 mmol) trimethylboroxine. The mixture was heated to HO0C and stirred for 12 hours, then cooled and partitioned between ethyl acetate and brine. The organic layer was dried over MgSO4 filtered and concentrated under reduced pressure. Purification by column chromatography, eluting with 75% ethyl acetate/hexanes, provided 75 mg of 7-amino-l,6-dimethyl-3,4-dihydro-l H-quinolin-2-one.

Preparation 5 5-Bromo-quinolin-6-ylamine

The synthetic procedure used in this preparation is outlined in Scheme E.


SCHEME E

To a solution of quinolin-6-ylamine (503 mg, 3.49 mmol) in dichloromethane (17 mL) and methanol (8.6 mL) was added tetra-«-butylammonium tribromide (1.68 g, 3.49 mmol). The mixture was stirred at 25 0C for 90 minutes, and then 10 5 mL of aqueous sodium thiosulfate was added. The mixture was extracted with dichloromethane, and the combined extracts were washed with water, dried (Na2SO4), filtered and concentrated to dryness under reduced pressure. Purification by flash column (hexanes/ethylacetate gradient) gave 5-bromo-quinolin-6-ylamine (246 mg, 32 %).

Preparation 6 l-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-lH-indazol-6-ylamine The synthetic procedure used in this preparation is outlined in Scheme F.



BS

SCHEME F

Step 1 5-Methyl-6-nitro-lH-indazole 2,4-Dimethyl-5-nitroaniline (1.662 g, 10.00 mmol) was dissolved in glacial acetic acid (100 ml) and the mixture was cooled to 0°C. A solution of sodium nitrite (1 eq, 690 mg) in water (2 ml) was added while maintaining a temperature below 25 °C. Stirring was continued for three hours and the mixture was filtered. The filtrate was allowed to stand for three days at room temperature, then was concentrate under reduced pressure. The residue was diluted with water and the resulting mixture was stirred vigorously. The solid product was collected by filtration, washed thoroughly with cold water, and dried. The product was purified by flash chromatography (99:1 dichloromethane/methanol) to give 1.030 g (58.1%) of 5-methyl-6-nitro-lH-indazole as a solid. Step 2 l-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-lH-indazole 5-Methyl-6-nitro-lH-indazole (354 mg, 2.0 mmol) was dissolved in DMF (10 ml) and the mixture was cooled to 0°C with stirring. Lithium hexamethyldisilazane (2.2ml of 1.0 M toluene solution) was added dropwise. The mixture was allowed to stir for five minutes, and then (2-bromoethoxy)-tert-butyldimethylsilane (0.52ml, 2.4mmol) was added. The mixture was stirred for 30 minutes at 0°C, then allowed to warm to room temperature with stirring for four hours. The reaction was quenched with pH2 buffer solution, and the mixture was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 4:1 hexanes/ethyl acetate) to give 340 mg (50.7%) of l-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-lH-indazole as a white powder. Step 3 l-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-lH-indazol-6-ylamine l-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-lH-indazole (335mg, 1.OOmmol) was dissolved in 30 ml ofa 1 :1 mixture of ethanol and water. To this mixture was added ammonium chloride (108 mg) and iron powder (108 mg). The mixture was then stirred at reflux for two hours, then was cooled and filtered. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (95:5 dichloromethane/methanol) to give 240 mg (78.7%) of 1 -[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5 -methyl- lH-indazol-6-ylamine as a tan solid.

Preparation 7 l-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-lH-indol-6-ylamine The synthetic procedure used in this preparation is outlined in Scheme G.



SCHEME G Step 1 5-Methyl-6-nitroindoline

To a solution of 2.5 g 5-methylindoline in 20 ml. of concentrated. Sulfuric acid at 00C was added in portions 1.7 g of potassium nitrate, keeping the temperature below 5°C. After the addition was complete, the mixture was stirred at 5 0C for ten minutes and then poured onto ice. The aqueous solution was made alkykline with 10% sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine and then dried over sodium sulfate, filtered and concentrated in vacuo. The residue crystallized on standing to give 2.75 g of 5-methyl-6-nitroindoline as a yellow solid. Step 2 5-Methyl-6-nitroindole

5-Methyl-6-nitroindoline (0.75 gr) was dissolved in 20 mL dioxane and treated with 1.5 g of dichloro dicyano quinone. The solution was heated at 80 0C for two hours, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography to give 0.5 g of 5-methyl-6-nitroindole (e/z (M+H) 177).

Step 3 l-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-lH-indole To an ice cold solution of 352 mg of 5-methyl-6-nitroindole in 10 mL DMF was added drop wise 2.2 ml of IM toluene solution of lithium hexamethyldisilazide. The solution was stirred for five minutes and 0.5 ml (1.1 equivalents) bromoethoxy dimethyl-^-butyl silane was added. The mixture was stirred at 00C for 30 minutes and then stirred for 4 hours at room temperature. Sulfate buffer (pH2) was added and the mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to yield 300 mg of l-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-lH-indole. Step 4 l-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-lH-indol-6-ylamine l-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-lH-indole (300 mg) was dissolved in 10 ml ethanol and 25 mg wet Rainey nickel was added. The mixture was hydrogenated at atmospheric pressure until the solution decolorized. The solution was filtered through glass fiber paper under nitrogen and the filtrate was concentrated in vacuo to give 250 mg of l-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-lH-indol-6-ylamine.

Preparation 8

6-Amino-7-ethyl-4-methyl-4H-benzo[1.4]oxazin-3-one The synthetic procedure used in this preparation is outlined in Scheme H.


SCHEME H

Step 1 6-Nitro-4H-benzo[l,4]oxazin-3-one

A solution of 2-Amino-4-nitro phenol (6.0 g, 38.93 mmol) in methylene chloride ( 200 ml ) was cooled to O0C. Triethyl amine (16.3 ml, 116.9 mmol) was added followed by chloroacetyl chloride (3.42 ml, 42.8 mmol) portionwise. The mixture was stirred at room temperature for 18 hours, then diluted with methylene chloride. The organic phase was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to give 7.5 g of 6-nitro-4H-benzo[l,4]oxazin-3-one as a solid, 100%. Step 2 4-Methyl-6-nitro-4H-benzo[l,4]oxazin-3-one

NaH (0.57 g, 23.75 mmol) was added to a solution of 6-nitro-4H-benzo[l,4]oxazin-3-one (2.3 g, 11.85 mmol) in DMF (50 ml ) at 0 0C. The mixture was stirred at 0 0C for 10 minutes and then CH3I (1.5 ml, 24.04 mmol) was added. The mixture was stirred at 0 0C for one hour, then at room temperature for one hour. The mixture was partitioned between EtOAc and water. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure to give 2.5 g of 4-methyl-6-nitro-4H-benzo[l,4]oxazin-3-one as a solid, 100%.

Step 3 6-Amino-4-methyl-4H-benzo[l,4]oxazin-3-one Fe powder (4.1 g, 73.20 mmol) was added to a solution of 4-methyl-6-nitro-4H-benzo[l,4]oxazin-3-one (3.0 g, 14.42 mmol) in EtOH (100 ml) and water (50 ml). The mixture was stirred at 60 0C vigorously with a mechanic stirrer for 18 hours, then filtered through a celite cake. The filtrate was concentrated under reduced pressure to give 2.5Og of

6-amino-4-methyl-4H-benzo[l,4]oxazin-3-one as a solid, 98%. Step 4 6-Amino-7-bromo-4-methyl-4H-benzo[l,4]oxazin-3-one Tetra-tert-butyl ammonium bromide (6.77 g, 14.04 mmol) was added to a solution of 6-amino-4-methyl-4H-benzo[l,4]oxazin-3-one (2.5 g, 14.04 mmol) in methylene chloride (100 ml) and MeOH (50ml ). The mixture was stirred at room temperature for 20 minutes, then quenched with aquous sodium bisulfite solution. The mixture was extracted with methylene chloride, and the combined organic extracts were dried over MgSO4, filtered, concentrated under reduced pressure and purified via column chromatography to give 1.30 g of 6-amino-7-bromo-4-methyl-4H-benzo[l,4]oxazin-3-one as a light yellow solid, 40 %. Step 5 6-Amino-7-ethyl-4-methyl-4H-benzo[l,4]oxazin-3-one

A mixture of 6-amino-7-bromo-4-methyl-4H-benzo[l,4]oxazin-3-one (0.21 g, 0.82 mmol), triethylborane (2.47 ml of 1.0 M solution in hexane, 5.56 mmol), PdCl2dppf.CH2Cl2 (0.067 g, 0.082 mmol) and Cs2CO3 0.81 g, 2.46 mmol) in DMF (6 ml) was was heated at 50 0C under argon for 18 hours. The mixture was partitioned between EtOAc and water. The EtOAc layed was dried (MgSO4), filtered, concentrated under reduced pressure and purified with prep-plate TLC (hexanes: EtOAc 1 : 1) to give 0.095 g of 6-amino-7-ethyl-4-methyl-4H-benzo[l,4]oxazin-3-one as a tan solid, 63%.

Example 1 (S)-4-(4-Fluoro-phenyl)-6-oxo-l ,4,5,6-tetrahvdro-pyridine-3-carboxylic acid (5-ethyl- quinolin-6-yl)-amide The synthetic procedure used in this preparation is outlined in Scheme I.


EME I To a cooled (ice-bath) suspension of 150 mg (0.63 mmol) of (S)-4-(4-fiuoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylic acid in 15 mL of CH2Cl2 were added 0.081 mL (0.956 mmol) of oxalyl chloride, followed by a drop of DMF. The mixture was allowed to reach room temperature with stirring over two hours. Solvents were evaporated in in vacuo, and methylene chloride was added and solvent was removed in vacuo. Methynele chloride (10 mL) was again added and removed in vacuo, and theresidue dried in high vacuum for 20 minutes to give (S)-4-(4-fiuoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylic acid chloride, which was dissolved in 8 mL of dry CH3CN and transfered to a sealable tube under Argon atmosphere. DIPEA 0.22 mL (1.26 mmol), DMAP (few crystals) were added, followed by 6-amino-5-ethylquinoline (60 mg 0.348 mmol). The tube was sealed and heated with stirring to 120 0C for 24 hours. The tube contents were cooled to room temperature, saturated aqueous NaHCO3 solution (10 mL) was added and product extracted with EtOAc. The combined organic layers were washed with brine, dried overMgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2/MeOH/NH4OH (100/10/1) to give 30 mg (22.2%) of (S)-4-(4-Fluoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylic acid (5-ethyl-quinolin-6-yl)-amide as a pale yellow foam. MS (ESI): m/z 389 (M+H)+.

Additional compounds prepared using the above procedure are shown in Table 1.

EXAMPLE 2

(S)-4-(4-Fluoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylic acid [l-(2-hydroxy- ethyl)-5 -methyl- 1 H-indazol-6 -yl] -amide The synthetic procedure used in this preparation is outlined in Scheme J.

SCHEME J

Step 1 (S)-4-(4-Fluoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5 -methyl- 1 H-indazol-6-yl} -amide l-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-lH-indazol-6-ylamine (89 mg, 0.29 mmol) and (S)-4-(4-fluoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylic acid chloride (74 mg, 0.29 mmol, prepared as described in Example 1) were dissolved in pyridine (2 ml) together with a crystal of DMAP and sealed in a tube. The mixture was heated to 90 °C with stirring for 18 hours. Upon cooling the mixture was diluted with dilute aqueous HCl solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (95:5 dichloromethane/methanol) to give 46 mg (30.3%) of (S)-4-(4-fluoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylic acid {l-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-lH-indazol-6-yl}-amide as a yellow oil.

Step 2 (S)-4-(4-Fluoro-phenyl)-6-oxo-1.4.5.6-tetrahydro-pyridine-3-carboxylic acid [1-(2-hydroxy-ethyl)-5-methyl-lH-indazol-6-yl]-amide

(S)-4-(4-Fluoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylic acid {l-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-lH-indazol-6-yl}-amide (46 mg, 0.09 mmol) was dissolved in 3 ml of a 3:1 :1 mixture of acetic acid, water and THF. The mixture was allowed to stir overnight at room temperature. The solution was concentrated in vacuo, and the residue was purified by flash chromatography (95:5 dichloromethane/methanol) to give 24 mg (70.6%) of (S)-4-(4-Fluoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylic acid [l-(2-hydroxy-ethyl)-5 -methyl- lH-indazol-6-yl]-amide white crystalline solid; MS (ES+) mlz 409 (M + H). Additional compounds prepared using the above procedure are shown in Table 1.

EXAMPLE 3 (S)-4-(4-Fluoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylicacid {l-(2- hydroxyethyl)-5 -methyl- 1 H-indol-6-yl} -amide The synthetic procedure used in this preparation is outlined in Scheme K.


HEME K

Step 1 (S)-4-(4-Fluoro-phenyl)-6-oxo-l .4.5.6-tetrahydro-pyridine-3-carboxyh'c acid { l-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-lH-indol-6-yl} -amide l-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-lH-indol-6-ylamine was dissolved in 10 ml dichloromethane and 0.25 ml triethylamine. The solution was cooled to 00C and 150 mg of (S)-4-(4-fluoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylic acid chloride in 1.5 ml dichloromethane was added. The resulting mixture was stirred at 00C for one hour, then at room temperature for two hours. DMAP (100 mg) was added and the mixture stirred for another hour. The reaction mixture was then partitioned between pH 7 phosphate buffer and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography to give 70 mg of (S)-4-(4-fluoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylic acid {l-[2-(tert- butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-lH-indol-6-yl}-amide e/z 522 (M+H). Step 2 (S)-4-(4-Fluoro-phenyl)-6-oxo-l ,4,5,6-tetrahydro-pyridine-3-carboxylic acid { l-(2-hydroxyethyl)-5-methyl-lH-indol-6-yl}-amide

(S)-4-(4-Fluoro-phenyl)-6-oxo-l,4,5,6-tetrahydro-pyridine-3-carboxylic acid {l-[2-(tert- butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-lH-indol-6-yl}-amide (70 mg) was dissoved in a mixture of 1 ml THF, 1 ml. water and 3 ml. acetic acid. The solution was stirred under argon at room temperature for six hours. Saturated aqueous sodium bicarbonate solution was added until the pH was neutral. The mixture was extracted with ethyl acetate, and the combined organic fractions were dried over sodium sulfate and solvent removed in vacuo. The product was purified by flash chromatography, to give 55 mg of (S)-4-(4-fluoro-phenyl)-6-oxo- l,4,5,6-tetrahydro-pyridine-3-carboxylic acid {l-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5- methyl- lH-indol-6-yl} -amide; (M+H) 407.

Additional compounds prepared using the above procedure are shown in Table 1.

Example 4

Formulations

Pharmaceutical preparations for delivery by various routes are formulated as shown in the following Tables. "Active ingredient" or "Active compound" as used in the Tables means one or more of the Compounds of Formula I.

Composition for Oral Administration

The ingredients are mixed and dispensed into capsules containing about 100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration

The ingredients are combined and granulated using a solvent such as methanol. The formulation is then dried and formed into tablets (containing about 20 mg of active compound) with an appropriate tablet machine.

Composition for Oral Administration

The ingredients are mixed to form a suspension for oral administration.

Parenteral Formulation

The active ingredient is dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride is then added with stirring to make the solution isotonic. The solution is made up to weight with the remainder of the water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.

Suppository Formulation

The ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.

Topical Formulation

All of the ingredients, except water, are combined and heated to about 600C with stirring. A sufficient quantity of water at about 600C is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. about 100 g.

Nasal Spray Formulations Several aqueous suspensions containing from about 0.025-0.5 percent active compound are prepared as nasal spray formulations. The formulations optionally contain inactive ingredients such as, for example, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, and the like. Hydrochloric acid may be added to adjust pH. The nasal spray formulations may be delivered via a nasal spray metered pump typically delivering about 50-100 microliters of formulation per actuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 5 Intracellular Calcium Flux (FLIPR) Assay Compound and Reagent Preparation

Stock solutions of compounds were prepared from powders as a 10 mM DMSO stock solution. These solutions were stored at RT during the two week period of these experiments to prevent freeze-thaw of the DMSO stocks. The DMSO stocks were added to the appropriate assay buffer at a concentration of 10 μM, and then diluted serially to the final concentrations that were tested. No observable precipitate was formed at any time during this process. The aqueous solutions of compounds as well as ATP (Sigma A7699) and BzATP (Sigma B6396) were prepared fresh for each day of experiment. Cell culture: 1321Nl-hP2X2 and HEK293-rP2X2 132 INl cells stably expressing the full length human P2X7 gene (1321Nl-hP2X7) and HEK293 cells stably expressing the full length rat P2X7 gene (HEK293-rP2X7) were obtained from the Roche Cell Culture Facility. 132 INl -hP2X7 cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) high glucose supplemented with 10% FBS and 250 μg/mL G418. HEK293-rP2X7 cells were grown in DMEM/F-12 supplemented with 10% FBS, 1 mM CaCl2, 2 mM MgCl2, 2 mM L-Glutamine and 500 μg/ml G418. Cells were split such that they never became >70% confluent. Intracellular Calcium Flux (FLIPR)

On the day prior to the experiment, 1321Nl-hP2X7 or HEK293-rP2X7 cells were released into suspension with calcium-free PBS + Versene and washed by centrifugation with calcium-free PBS to remove the Versene. Cells were resuspended in growth medium at a density of 2.5 x 105 cells/mL and seeded into black walled, clear bottom 96 well plates (50,000 cells/well) approximately 18 hr prior to intracellular calcium flux experiments. On the day of the experiment, plates were washed with FLIPR buffer (calcium- and magnesium- free Hank's Balanced Salt Solution (HBSS) supplemented with 10 mM Hepes, 2.5 niM probenecid and 2 mM calcium chloride) using a BIO-TEK 96 channel plate washer and incubated with 2 mM fluo-3 dye at 37°C for one hr. The dye was then removed by plate washing and the cells were allowed to equilibrate for 20 min at room temperature with antagonist or vehicle (FLIPR buffer). Agonist (100 μM BzATP final concentration for hP2X7; 5 μM BzATP final concentration or rP2X7) was added online with the FLIPR and fluorescence measurements made at 1 sec intervals for 60 sec followed by 3 sec intervals for a further 4 min (5 min total). A final addition of 5 μM ionomycin was made and the maximal BzATP-evoked fluorescence normalized to the maximal ionomycin-evoked fluorescence.

Example 6 Human Whole Blood IL- lβ Release Assay

Compound & Reagent Preparation

10 mM stock solutions of compounds in DMSO (Sigma D2650) were prepared and used either fresh or after storage at -2O0C. Appropriate (20Ox) serial dilutions of the compounds were made in DMSO, then freshly diluted 1 to 20 (1Ox) with Dulbecco's phosphate buffered saline (DPBS; Mediatech Inc., 21-030), such that final DMSO concentration in the blood always equaled 0.5%.

30 mM ATP (Sigma A7699) was prepared immediately before use in 50 mM HEPES (Gibco 15630) and the pH adjusted to 7.2 with IM sodium hydroxide. Blood Donors Human blood donors were medication free and restricted from utilizing alcohol or caffeine for at least the 24 hr preceding collection. The blood was collected into sodium heparin vacutainer tubes and used the same day. Assay Method The OptEIA Human IL- lβ ELISA Set, OptEIA Coating Buffer, Assay Diluent and TMB Substrate Reagent Set used in the assay were commercially obtained from BD Pharmingen. Blood was diluted 1:1 with Dulbecco's PBS, LPS {Escherichia CoIi 0127:B8, Sigma L3129) added to a final concentration of 25 ng/mL and incubated for 2 hr at 370C. 48 μL of this LPS primed blood was added to 6 μL of the 10x compound in 5% DMSO/PBS in the appropriate well of a 96-well polypropylene plate. The blood and compound were mixed and allowed to incubate for 30 min at 370C. 6 μl of 30 mM ATP was added to the LPS-primed blood + compound, mixed thoroughly and incubated for a further 30 min at 370C. 96 μL of ELISA assay buffer was added to each well and the plate centrifuged at 40C 1 ,200 rpm for 10 min.

Supernatant was removed and assayed for IL- lβ using the OptiEIA kit according to the manufacturer's protocol (Serum may be frozen at -2O0C prior to assay). IC50S were calculated using XLfit.

Example 7 In vivo Assay for Asthma and Lung Function

BALb/cJ mice are immunized with a standard immunization protocol. Briefly, mice (N=8/group) are immunized i.p. with ovalbumin (OVA; 10 μg) in alum on days 0 and 14. Mice are then challenged with aerosolized OVA (5%) on day 21 and 22. Animals receive vehicle (p.o.) or a compound of the invention (100 mg/kg p.o.) all starting on day 20. Lung function is evaluated on day 23 using the Buxco system to measure PenH in response to an aerosol methacholine challenge. Mice are then euthanized and plasma samples collected at the end of the study.

While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.