US 20080039478A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0039478 A1 Kelly et al. (43) Pub. Date: Feb. 14, 2008

(54) BICYCLOHETEROARYL COMPOUNDS AS Publication Classification P2X7 MODULATORS AND USES THEREOF (51) Int. Cl. (75) Inventors: Michael G Kelly, Thousand Oaks, CA A 6LX 3/59 (2006.01) (US); John Kincaid, San Mateo, CA A6IP II/00 (2006.01) A6IP 9/00 (2006.01) (US) A6IP 25/00 (2006.01) Correspondence Address: A6IP 29/00 (2006.01) KLAUBER & JACKSON A6IP 3/00 (2006.01) 411. HACKENSACK AVENUE A6IP 35/00 (2006.01) A6IP 37/00 (2006.01) HACKENSACK, NJ 07601 A6IP 7/00 (2006.01) Assignee: Renovis, Inc. A6IP 9/00 (2006.01) (73) (52) U.S. Cl...... 514/264.11: 514/264.1 (21) Appl. No.: 11/773,106 (57) ABSTRACT (22) Filed: Jul. 3, 2007 Bicycloheteroaryl compounds are disclosed that have a formula represented by the following: Related U.S. Application Data n (62) Division of application No. 1 1/384,045, filed on Mar. L a 1'sB 17, 2006, now Pat. No. 7,297,700. Y i R. R." A N (60) Provisional application No. 60/664.903, filed on Mar. 21 *s R1 24, 2005. Provisional application No. 60/709,186, filed on Aug. 18, 2005. Provisional application No. Ws, -W O 60/710,077, filed on Aug. 22, 2005. Provisional appli The compounds may be prepared as pharmaceutical com cation No. 60/712,778, filed on Aug. 31, 2005. Pro positions, and may be used for the prevention and treatment visional application No. 60/721,390, filed on Sep. 28, of a variety of conditions in mammals including humans, 2005. Provisional application No. 60/753,194, filed including by way of non-limiting example, pain, inflamma on Dec. 22, 2005. tion, traumatic injury, and others. US 2008/0039478 A1 Feb. 14, 2008

BICYCLOHETEROARYL COMPOUNDS AS P2X7 amino acids long in the rP2X, receptor compared with 27-20 MODULATORS AND USES THEREOF amino acids in the others). The rP2X, receptor functions both as a channel permeable to Small cations and as a CROSS REFERENCE TO RELATED cytolytic pore. Brief applications of ATP (1-2s) transiently APPLICATIONS open the channel, as is the case of other P2X receptors. Repeated or prolonged applications of agonist cause cell 0001. The present application claims the priority of co permeabilization reducing the extracellular magnesium con pending provisional applications U.S. Ser. No. 60/664,903, centration potentiates this effect. The unique C-terminal filed on Mar. 24, 2005: U.S. Ser. No. 60/709,186 filed on domain of rP2X, is required for cell permeabilization and Aug. 18, 2005: U.S. Ser. No. 60/710,077 filed on Aug. 22, the lytic actions of ATP (Suprenant et al. Science 272:735 2005; U.S. Ser. No. 60/712,778 filed on Aug. 31, 2005; U.S. (1996)). Ser. No. 60/721,390 filed on Sep. 28, 2005; and U.S. Ser. No. 60/753,194 filed on Dec. 22, 2005. The disclosures of all of 0005. The P2Z/rP2X, receptor has been implicated in the aforementioned applications are incorporated by refer lysis of antigen-presenting cells by cytotoxic T lymphocytes, ence herein in their entireties. Applicants claim the benefits in the mitogenic stimulation of human T lymphocytes, as of these applications under 35 U.S.C. S 119(e). well as in the formation of multinucleated giant cells (Blan chard et al, Blood 85:3173 (1995); Falzoni et al., J. Clin. FIELD OF THE INVENTION Invest. 95:1207 (1995); Baricolrdi et al. Blood 87:682 (1996)). Certain functional differences exist between rodent 0002 This invention relates to novel compounds of the and man (Hickman et al. Blood 84:2452 (1994)). The human class bicycloheteroaryls that are capable of modulating macrophage P2X, receptor (P2X) has now been cloned and P2X, receptor activity, and to pharmaceutical compositions its functional properties determined (Rassendren et al., J. containing Such compounds. This invention also relates to Biol. Chem. 272:5482 (1997). When compared with the rat methods for preventing and/or treating conditions that are P2X, receptor, elicited cation-selective currents in the causally related to aberrant P2X, activity, such as inflam human P2X, receptor required higher concentrations of mation-related conditions in mammals, comprising (but not agonists, were more potentiated by removal of extracellular limited to) rheumatoid arthritis, osteoarthritis, Parkinson's magnesium ions, and revised more rapidly on agonist disease, uveitis, asthma, cardiovascular conditions including removal. Expression of chimeric molecules indicated that myocardial infarction, the treatment and prophylaxis of pain some of the differences between rat and human P2X, syndromes (acute and chronic or neuropathic), traumatic receptors could be revised by exchanging the respective brain injury, acute spinal cord injury, neurodegenerative C-terminal domains of the receptor proteins. disorders, inflammatory bowel disease and autoimmune disorders, using the compounds and pharmaceutical com 0006. It has been reported that certain compounds act as P2X, antagonists. For example, WO99/29660 and WO99/ positions of the invention. 29661 disclose that certain adamantane derivatives exhibit P2X, antagonistic activity having therapeutic efficacy in the BACKGROUND OF THE INVENTION treatment of rheumatoid arthritis and psoriasis. Similarly, 0003) Cell surface receptors for ATP can be divided into WO99/29686 discloses that certain heterocyclic derivatives metabotropic (P2Y/P2U) and ionotropic (P2X) classes. The are P2X, receptor antagonists and are useful as immuno metabotropic class belongs to the Superfamily of G protein Suppressive agents and treating rheumatoid arthritis, asthma, coupled receptors, with seven transmembrane segments. septic shock and atherosclerosis. Finally, WO00/71529 dis The ionotropic class members (P2X-P2X) are ligand closes certain Substituted phenyl compounds exhibiting gated ion channels, currently thought to be multisubunit immunosuppressing activity. All of the references described proteins with two transmembrane domains per subunit herein are incorporated herein by reference in their entirety. (Buell et al., Europ. J. Neurosci. 8:2221 (1996)). P2Z recep 0007. A need therefore exists for therapeutic agents, and tors have been distinguished from other P2 receptors in three corresponding pharmaceutical compositions and related primary ways (Buisman et al. Proc. Natl. Acad. Sci. USA methods of treatment, that address the conditions causally 85:7988 (1988); Cockcroft et al, Nature 279:541 (1979); related to aberrant P2X, activity, and it is toward the Steinberg et al., J. Biol. Chem. 262:3118 (1987)). First, fulfillment and satisfaction of that need, that the present activation of P2Z receptors leads not only to an inward ionic invention is directed. current, but also to cell permeabilization. Second, 3'-O-(4- benzoyl)benzoyl ATP (BZATP) is the most effective agonist, SUMMARY OF THE INVENTION and ATP itself is of rather low potency. Third, responses are 0008 Bicycloaryl derivatives of formulas I-VIa, and their strongly inhibited by extracellular magnesium ions, which pharmaceutical compositions are disclosed as therapeutic has been interpreted to indicate that ATP- is the active agents useful for the treatment of conditions in mammals agonist (DiVirgilio, Immunol. Today 16:524 (1995)). associated with abnormal or aberrant activity of the P2X, 0004. A seventh member of the P2X receptor family has receptor, including inflammatory-mediated conditions such been isolated from a rat cDNA library and, when expressed as (but not limited to) arthritis, myocardial infarction, the in human embryonic kidney (HEK293) cells, exhibits the treatment and prophylaxis of pain syndromes (acute and above three properties (Surprenant et al. Science 272:735 chronic neuropathic), traumatic brain injury, acute spinal (1996)). This receptor (rP2X) thus corresponds to the P2Z cord injury, neurodegenerative disorders, inflammatory receptor. rP2X, is structurally related to other members of bowel disease and immune dysfunctions such as autoim the P2X family but it has a longer cytoplasmic C-terminus mune disorders. domain (there is 35-40% amino acid identity in the corre 0009. It has now been found that the present bicyclohet sponding region of homology, but the C-terminus is 239 eroaryl compounds are capable of mediating the activity of US 2008/0039478 A1 Feb. 14, 2008 the P2X, receptor. This finding leads to novel compounds cloalkyl, alkylheterocycloalkyl, cycloalkylalkyl, or het having therapeutic value. It also leads to pharmaceutical erocycloalkylalkyl group, which can be optionally Sub compositions having the compounds of the present inven stituted by a substituent selected from hydroxyl, tion as active ingredients and to their use to treat, prevent or halogen and C-C alkoxy; ameliorate a range of conditions in mammals such as but not limited to inflammation of various genesis or etiology, for 0.019 n is 1, 2 or 3: example rheumatoid arthritis, cardiovascular disease, 0020) R' is selected from a 3-13 membered cycloalkyl, inflammatory bowel disease, acute, chronic, inflammatory heterocycloalkyl, aryl and heteroaryl ring system, and neuropathic pain, dental pain and headache (such as which can be optionally substituted with one or more migraine, cluster headache and tension headache) and other substituents independently selected from halo, conditions causally related to inflammation or immune dys hydroxyl, amino, cyano, Sulfo, Sulfanyl, Sulfinyl, function. amido, carboxy, ester, alkyl, Substituted alkyl, alkenyl, 0010. The compounds of the present invention are also Substituted alkenyl, alkynyl, Substituted alkynyl, and useful for the treatment of inflammatory pain and associated Sulfonamido; hyperalgesia and allodynia. They are also useful for the treatment of neuropathic pain and associated hyperalgesis 0021 each of R, R and R" is independently selected and allodynia (e.g. trigeminal or herpetic neuralgia, diabetic from hydrogen, Substituted or unsubstituted C-C, neuropathy, causalgia, sympathetically maintained pain and alkyl; or any of R and R can join together to form a deafferentation syndromes such as brachial plexus avulsion). cycloalkyl or cycloheteroalkyl ring of 3-7 atoms: The compounds of the present invention are also useful as 0022 R is hydrogen or a functional group selected anti-inflammatory agents for the treatment of arthritis, and from acyl, substituted acyl, substituted or unsubstituted as agents to treat Parkinson's Disease, uveitis, asthma, acylamino, Substituted or unsubstituted alkylamino, myocardial infarction, traumatic brain injury, spinal cord substituted or unsubstituted alkylthio, substituted or injury, neurodegenerative disorders, inflammatory bowel unsubstituted alkoxy, alkoxycarbonyl, Substituted disease and autoimmune disorders, renal disorders, obesity, alkoxycarbonyl, substituted or unsubstituted alkylary eating disorders, cancer, Schizophrenia, epilepsy, sleeping lamino, arylalkyloxy, Substituted arylalkyloxy, amino, disorders, cognition, depression, anxiety, blood pressure, aryl, substituted aryl, arylalkyl, substituted or unsub lipid disorders, and atherosclerosis. stituted sulfoxide, substituted or unsubstituted sulfone, 0011. In one aspect, this invention provides bicyclohet substituted or unsubstituted sulfanyl, substituted or eroaryl compounds which are capable of modulating the unsubstituted aminosulfonyl, substituted or unsubsti activity of the P2X, receptor, in vivo. In a further aspect, the tuted arylsulfonyl, sulfuric acid, sulfuric acid ester, compounds of the invention are capable of antagonizing substituted or unsubstituted dihydroxyphosphoryl, sub (Suppressing or inhibiting) the activity of the P2X, receptor, stituted or unsubstituted aminodihydroxyphosphoryl, and thereby treating those conditions, representative ones of azido, carboxy, Substituted or unsubstituted carbamoyl, which are causally related to aberrant P2X, activity. cyano, Substituted or unsubstituted cycloalkyl, Substi tuted or unsubstituted cycloheteroalkyl, substituted or 0012. Accordingly, in a first aspect of the invention, unsubstituted dialkylamino, halo, heteroaryloxy, Sub bicycloheteroaryl compounds are disclosed that are capable stituted or unsubstituted heteroaryl, substituted or of modulating the activity of the P2X, receptor in vivo, unsubstituted heteroalkyl, hydroxy, nitro, and thio; or having a formula (I): R is a 4-9 membered carbocyclic or heterocyclic ring which can be optionally substituted with at least one Substituent selected from a R' group; or the group n “R-L is H; L n1'sB Y i R. R." 0023 R is selected from H, alkyl, substituted alkyl, acyl, Substituted acyl, Substituted or unsubstituted acy A 21 N lamino, Substituted or unsubstituted alkylamino, Sub R1 stituted or unsubstituted alkylthio, substituted or unsub stituted alkoxy, alkoxycarbonyl, Substituted Wn-W O alkoxycarbonyl, substituted or unsubstituted alkylary lamino, arylalkyloxy, Substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsub 0013 wherein stituted sulfoxide, substituted or unsubstituted sulfone, 0014) A is selected from CRR, CO, and CS: substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubsti 0.015 B is selected from CR, CRR", CO, and CS: tuted arylsulfonyl, sulfuric acid, sulfuric acid ester, 0016 Y is independently selected from CR and substituted or unsubstituted dihydroxyphosphoryl, sub CR2R2"; stituted or unsubstituted aminodihydroxyphosphoryl, azido, carboxy, Substituted or unsubstituted carbamoyl, (0017 W. W. and Z are independently selected from cyano, Substituted or unsubstituted cycloalkyl, Substi CR and N, provided that all three of W. W. and Z can tuted or unsubstituted cycloheteroalkyl, substituted or not be N at the same time; unsubstituted dialkylamino, halo, heteroaryloxy, Sub 0018 L is a C-C alkylene group, heteroalkyl, 3 to 8 stituted or unsubstituted heteroaryl, substituted or membered cycloalkyl or heterocycloalkyl, alkylcy unsubstituted heteroalkyl, hydroxy, nitro, and thio; US 2008/0039478 A1 Feb. 14, 2008

0024 and the dotted bond is a single or a double bond; substituted or unsubstituted dihydroxyphosphoryl, sub stituted or unsubstituted aminodihydroxyphosphoryl, 0025 or a pharmaceuticallyp acceptablep salt, solvate or azido, carboxy, Substituted or unsubstituted carbamoyl, prodrug thereof, cyano, Substituted or unsubstituted cycloalkyl, Substi 0026 and stereoisomers and tautomers thereof. tuted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, Sub 0027. In a second aspect of the invention, bicyclohet stituted or unsubstituted heteroaryl, substituted or eroaryl compounds are disclosed that are capable of modu unsubstituted heteroalkyl, hydroxy, nitro, and thio; or lating the activity of the P2X, receptor in vivo, having a R is a 4-9 membered carbocyclic or heterocyclic ring formula (Ia): which can be optionally substituted with at least one Substituent selected from a R group; or the group Ia “R-L is H; R3 SL -B- 0037 R is selected from H, alkyl, substituted alkyl, Y R. R." acyl, Substituted acyl, Substituted or unsubstituted acy lamino, Substituted or unsubstituted alkylamino, Sub A stituted or unsubstituted alkylthio, substituted or unsub 21 P4 R1 stituted alkoxy, alkoxycarbonyl, Substituted alkoxycarbonyl, substituted or unsubstituted alkylary Ws, -W R2 lamino, arylalkyloxy, Substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsub stituted sulfoxide, substituted or unsubstituted sulfone, 0028 wherein substituted or unsubstituted sulfanyl, substituted or 0029) A is selected from CRR, CO, and CS: B is unsubstituted aminosulfonyl, substituted or unsubsti selected from CR, CRR, CO, and CS: tuted arylsulfonyl, sulfuric acid, sulfuric acid ester, substituted or unsubstituted dihydroxyphosphoryl, sub 0030 Y is independently selected from CR and stituted or unsubstituted aminodihydroxyphosphoryl, CR2R2"; azido, carboxy, Substituted or unsubstituted carbamoyl, (0031 W, W and Z are independently selected from cyano, Substituted or unsubstituted cycloalkyl, Substi CR and N, provided that all three of W. W. and Z can tuted or unsubstituted cycloheteroalkyl, substituted or not be N at the same time; unsubstituted dialkylamino, halo, heteroaryloxy, Sub stituted or unsubstituted heteroaryl, substituted or 0032 L is a C-C alkylene group, heteroalkyl, 3 to 8 unsubstituted heteroalkyl, hydroxy, nitro, and thio; membered cycloalkyl or heterocycloalkyl, alkylcy cloalkyl, alkylheterocycloalkyl, cycloalkylalkyl, or het 0038 and the dotted bond is a single or a double bond; erocycloalkylalkyl which can be optionally substituted by a Substituent selected from hydroxyl, halogen and 0039 or a pharmaceutically acceptable salt, solvate or C-C alkoxy: prodrug thereof, 0033 n is 1, 2 or 3: 0040 and stereoisomers and tautomers thereof. 0034) R' is selected from a 3-13 membered cycloalkyl, 0041. In a further embodiment, with respect to com heterocycloalkyl, aryl and heteroaryl ring system, pounds of formula I and Ia, n is 0. which can be optionally substituted with one or more 0042. In a further embodiment, with respect to com substituents independently selected from halo, pounds of formula I and Ia, L may be a bond and R is hydroxyl, amino, cyano, Sulfo, Sulfanyl, Sulfinyl, selected from H, acyl, substituted acyl, substituted or unsub amido, carboxy, ester, alkyl, Substituted alkyl, alkenyl, stituted aminocarbonyl, alkoxycarbonyl, Substituted alkoxy Substituted alkenyl, alkynyl, Substituted alkynyl, and carbonyl, substituted or unsubstituted sulfoxide, substituted Sulfonamido; or unsubstituted sulfone, substituted or unsubstituted ami 0035) each of R, R and R" is independently selected nosulfonyl, substituted or unsubstituted arylsulfonyl, ary from hydrogen, Substituted or unsubstituted C-C, loxycarbonyl, Substituted aryloxycarbonyl, heteroaryloxy alkyl; or any of R and Rican join together to form a carbonyl, and substituted heteroaryloxycarbonyl. cycloalkyl or cycloheteroalkyl ring of 3-7 atoms: 0043. In a further embodiment, with respect to com pounds of formula I and Ia, L is L'; and wherein L' is a bond, 0036), R is hydrogen or a functional group selected —CO— —SO - or a C-C alkylene group which can be from acyl, substituted acyl, substituted or unsubstituted optionally substituted by a substituent selected from alkyl, acylamino, Substituted or unsubstituted alkylamino, hydroxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl, Substituted dialkylaminoalkyl, halogen, carbamoyl, and C-C alkoxy. alkoxycarbonyl, substituted or unsubstituted alkylary In one particular embodiment, when A is CO or CS, L' is a lamino, arylalkyloxy, Substituted arylalkyloxy, amino, bond or C-C alkylene group. aryl, substituted aryl, arylalkyl, substituted or unsub 0044) In a further embodiment, with respect to com stituted sulfoxide, substituted or unsubstituted sulfone, pounds of formula I and Ia, L is L'; and wherein L' is a bond, substituted or unsubstituted sulfanyl, substituted or —CO-, -SO - or a C1-C5 alkylene group; and R is unsubstituted aminosulfonyl, substituted or unsubsti selected from hydrogen, substituted or unsubstituted alkyl, tuted arylsulfonyl, sulfuric acid, sulfuric acid ester, substituted or unsubstituted cycloalkyl, substituted or unsub US 2008/0039478 A1 Feb. 14, 2008 stituted heterocycloalkyl, substituted or unsubstituted aryl, Such as, for example traumatic brain injury and encephalitis; substituted or unsubstituted heteroaryl, substituted or unsub centrally-mediated neuropsychiatric diseases and disorders stituted bicycloaryl, and substituted or unsubstituted bicy Such as, for example depression mania, bipolar disease, cloheteroaryl. In one particular embodiment, when R is anxiety, Schizophrenia, eating disorders, sleep disorders and hydrogen L' is a bond or a C-Cs alkylene group. cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunction Such as, for example urinary 0045. In a further embodiment, with respect to com incontinence, urinary hesitancy, rectal hypersensitivity, fecal pounds of formula I and Ia, A, B and Y may all represent incontinence, benign prostatic hypertrophy and inflamma CR'R''. In another embodiment, A is CRR: and B and tory bowel disease; respiratory and airway disease and Y are independently selected from CR* and CRR. disorders such as, for example, allergic rhinitis, asthma and 0046. In a further embodiment, with respect to com reactive airway disease and chronic obstructive pulmonary pounds of formula I and Ia, A, B and Y may all represent disease; diseases and disorders which are mediated by or CH, and R represents hydrogen. result in inflammation Such as, for example rheumatoid arthritis and osteoarthritis, myocardial infarction, various 0047. In a further aspect, the present invention provides autoimmune diseases and disorders, uveitis and atheroscle pharmaceutical compositions comprising a bicyclohet rosis; itch/pruritus such as, for example psoriasis; obesity; eroaryl compound of the invention, and a pharmaceutical lipid disorders; cancer, blood pressure; spinal cord injury; carrier, excipient or diluent. In this aspect of the invention, and cardiovascular and renal disorders method comprises the pharmaceutical composition can comprise one or more administering an effective condition-treating or condition of the compounds described herein. Moreover, the com preventing amount of one or more of the pharmaceutical pounds of the present invention useful in the pharmaceutical compositions just described. compositions and treatment methods disclosed herein, are all pharmaceutically acceptable as prepared and used. 0051. In additional aspects, this invention provides meth ods for synthesizing the compounds of the invention, with 0.048. In a further aspect of the invention, this invention representative synthetic protocols and pathways disclosed provides a method of treating a mammal Susceptible to or later on herein. afflicted with a condition from among those listed herein, and particularly, such condition as may be associated with 0052 Accordingly, it is a principal object of this inven e.g. inflammation, such as rheumatoid arthritis, osteoarthri tion to provide a novel series of compounds, which can tis, uveitis, asthma, myocardial infarction, traumatic brain modify the activity of the P2X, receptor and thus avert or injury; Septic shock, atherosclerosis, chronic pulmonary treat any maladies that may be causally related thereto. obstructive disease (COPD), acute spinal cord injury, 0053. It is further an object of this invention to provide a inflammatory bowel disease and immune dysfunction, series of compounds that can treat or alleviate maladies or including autoimmune disorders, which method comprises symptoms of same. Such as pain and inflammation, that may administering an effective amount of one or more of the be causally related to the activation of the P2X, receptor. pharmaceutical compositions just described. 0054) A still further object of this invention is to provide 0049. In yet another method of treatment aspect, this pharmaceutical compositions that are effective in the treat invention provides a method of treating a mammal Suscep ment or prevention of a variety of disease states, including tible to or afflicted with a condition that is causally related the diseases associated with the central nervous system, to aberrant P2X, receptor activity, and that for example, cardiovascular conditions, chronic pulmonary obstructive gives rise to pain responses or that relates to imbalances in disease COPD), inflammatory bowel disease, rheumatoid the maintenance of basal activity of sensory nerves. The arthritis, osteoarthritis, and other diseases where an inflam amine compounds of the invention have use as analgesics matory component is present. for the treatment of pain of various geneses or etiology, for example acute, inflammatory pain (such as pain associated 0055) Other objects and advantages will become apparent with osteoarthritis and rheumatoid arthritis); various neuro to those skilled in the art from a consideration of the ensuing pathic pain syndromes (such as post-herpetic neuralgia, detailed description. trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillian Barre Syndrome, fibromyalgia, phan DETAILED DESCRIPTION OF THE tom limb pain, post-masectomy pain, peripheral neuropathy, INVENTION HIV neuropathy, and chemotherapy-induced and other iatro Definitions genic neuropathies); visceral pain, (Such as that associated with gastroesophageal reflex disease, irritable bowel syn 0056. When describing the compounds, pharmaceutical drome, inflammatory bowel disease, pancreatitis, and vari compositions containing Such compounds and methods of ous gynecological and urological disorders), dental pain and using Such compounds and compositions, the following terms have the following meanings unless otherwise indi headache (Such as migraine, cluster headache and tension cated. It should also be understood that, consistent with the headache). Scope of the present invention, any of the moieties defined 0050. In additional method of treatment aspects, this herein and/or set forth below may be substituted with a invention provides methods of treating a mammal Suscep variety of substituents, and that the respective definitions are tible to or afflicted with conditions that are causally related intended to include such substituted moieties within their to abnormal activity of the P2X, receptor, such as neurode Scope. By way of non-limiting example, Such substituents generative diseases and disorders including, for example, may include e.g. halo (Such as fluoro, chloro, bromo), —CN. Parkinson's disease, multiple Sclerosis; diseases and disor —CF, -OH, - OCF, C-C alkenyl, C-C alkynyl, ders which are mediated by or result in neuroinflammation C-C alkoxy, aryl and di-C-C alkylamino. US 2008/0039478 A1 Feb. 14, 2008

0057 “Acyl' refers to a radical C(O)R, where R is carbonatoms. The hydrocarbon chain may be either straight hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, aryla chained or branched. This term is exemplified by groups lkyl, heteroalkyl, heteroaryl, heteroarylalkyl as defined Such as methyl, ethyl, n-propyl, isopropyl. n-butyl, iso herein. Representative examples include, but are not limited butyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and the like. The to, formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl term “lower alkyl refers to alkyl groups having 1 to 6 carbonyl, benzoyl, benzylcarbonyl and the like. carbon atoms. The term “alkyl also includes “cycloalkyl 0.058 “Acylamino” refers to a radical NRC(O)R, as defined below. where R' is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, 0066 “Substituted alkyl includes those groups recited in aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl and the definition of “substituted herein, and particularly refers R is hydrogen, alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, to an alkyl group having 1 or more Substituents, for instance aryl, arylalkyl, heteroalkyl, heteroaryl or heteroarylalkyl, as from 1 to 5 substituents, and particularly from 1 to 3 defined herein. Representative examples include, but are not Substituents, selected from the group consisting of acyl, limited to, formylamino, acetylamino, cyclohexylcarbony acylamino, acyloxy, alkoxy, Substituted alkoxy, alkoxycar lamino, cyclohexylmethyl-carbonylamino, benzoylamino, bonyl, alkoxycarbonylamino, amino, Substituted amino, benzylcarbonylamino and the like. aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, Substituted 0059) “Acyloxy” refers to the group - OC(O)R where R cycloalkyl, halogen, hydroxyl, heteroaryl, keto, nitro, thio is hydrogen, alkyl, aryl or cycloalkyl. alkoxy, Substituted thioalkoxy, thioaryloxy, thioketo, thiol, 0060 “Substituted alkenyl' includes those groups recited alkyl-S(O)—, aryl-S(O)—, alkyl-S(O) , and aryl in the definition of “substituted herein, and particularly S(O) -. refers to an alkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 0067 “Alkylene' refers to divalent saturated aliphatic 3 Substituents, selected from the group consisting of acyl, hydrocarbyl groups particularly having up to about 11 acylamino, acyloxy, alkoxy, Substituted alkoxy, alkoxycar carbon atoms and more particularly 1 to 6 carbon atoms bonyl, alkoxycarbonylamino, amino, Substituted amino, which can be straight-chained or branched. This term is aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, exemplified by groups such as methylene (-CH ), eth aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, Substituted ylene (—CH2CH2—), the propylene isomers (e.g., cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, Sub —CHCHCH and —CH(CH)CH ) and the like. stituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl 0068 “Substituted alkylene' includes those groups S(O)—, aryl-S(O)—, alkyl-S(O) and aryl-S(O) recited in the definition of “substituted herein, and particu 0061 “Alkoxy” refers to the group -OR where R is larly refers to an alkylene group having 1 or more substitu alkyl. Particular alkoxy groups include, by way of example, ents, for instance from 1 to 5 substituents, and particularly methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert from 1 to 3 Substituents, selected from the group consisting butoxy, Sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbu of acyl, acylamino, acyloxy, alkoxy, Substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, Substituted toxy, and the like. amino, aminocarbonyl, aminocarbonylamino, aminocarbo 0062 “Substituted alkoxy' includes those groups recited nyloxy, aryl, aryloxy, azido, carboxyl, cyano, halogen, in the definition of “substituted herein, and particularly hydroxyl, keto, nitro, thioalkoxy, Substituted thioalkoxy, refers to an alkoxy group having 1 or more Substituents, for thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, instance from 1 to 5 substituents, and particularly from 1 to alkyl-S(O) - and aryl-S(O) - 3 Substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, Substituted alkoxy, alkoxycar 0069. “Alkenyl refers to monovalent olefinically unsat bonyl, alkoxycarbonylamino, amino, Substituted amino, urated hydrocarbyl groups preferably having up to about 11 aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, carbon atoms, particularly, from 2 to 8 carbon atoms, and aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, Substituted more particularly, from 2 to 6 carbon atoms, which can be cycloalkyl, halogen, heteroaryl, hydroxyl, keto, nitro, thio straight-chained or branched and having at least 1 and alkoxy, Substituted thioalkoxy, thioaryloxy, thioketo, thiol, particularly from 1 to 2 sites of olefinic unsaturation. Par alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)—and aryl-S(O)—. ticular alkenyl groups include ethenyl (-CH=CH-), n-pro penyl ( CH-CH=CH-), isopropenyl ( C(CH)=CH), 0063 “Alkoxycarbonylamino” refers to the group —NR vinyl and substituted vinyl, and the like. C(O)OR' where R is hydrogen, alkyl, aryl or cycloalkyl, and 0070) “Alkenylene' refers to divalent olefinically unsat R" is alkyl or cycloalkyl. urated hydrocarbyl groups particularly having up to about 11 0064 “Aliphatic' refers to hydrocarbyl organic com carbon atoms and more particularly 2 to 6 carbon atoms pounds or groups characterized by a straight, branched or which can be straight-chained or branched and having at cyclic arrangement of the constituent carbon atoms and an least 1 and particularly from 1 to 2 sites of olefinic unsat absence of aromatic unsaturation. Aliphatics include, with uration. This term is exemplified by groups such as ethe out limitation, alkyl, alkylene, alkenyl, alkenylene, alkynyl nylene (-CH=CH-), the propenylene isomers (e.g., and alkynylene. Aliphatic groups typically have from 1 or 2 -CH=CHCH and C(CH)=CH- and to about 12 carbon atoms. —CH=C(CH)—) and the like. 0065 “Alkyl refers to monovalent saturated aliphatic 0071 “Alkynyl refers to acetylenically unsaturated hydrocarbyl groups particularly having up to about 11 hydrocarbyl groups particularly having up to about 11 carbon atoms, more particularly as a lower alkyl, from 1 to carbon atoms and more particularly 2 to 6 carbon atoms 8 carbon atoms and still more particularly, from 1 to 6 which can be straight-chained or branched and having at US 2008/0039478 A1 Feb. 14, 2008 least 1 and particularly from 1 to 2 sites of alkynyl unsat 0082) “Alkoxyamino” refers to a radical N(H)OR uration. Particular non-limiting examples of alkynyl groups where R represents an alkyl or cycloalkyl group as defined include acetylenic, ethynyl ( C=CH), propargyl herein. (—CHC=CH), and the like. 0083) “Alkoxycarbonyl refers to a radical –C(O)- 0072 "Substituted alkynyl includes those groups recited alkoxy where alkoxy is as defined herein. in the definition of “substituted herein, and particularly 0084) “Alkylarylamino” refers to a radical-NRR' where refers to an alkynyl group having 1 or more substituents, for R represents an alkyl or cycloalkyl group and R' is an aryl instance from 1 to 5 substituents, and particularly from 1 to 3 Substituents, selected from the group consisting of acyl, as defined herein. acylamino, acyloxy, alkoxy, Substituted alkoxy, alkoxycar 0085 “Alkylsulfonyl refers to a radical-S(O)R where bonyl, alkoxycarbonylamino, amino, Substituted amino, R is an alkyl or cycloalkyl group as defined herein. Repre aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, sentative examples include, but are not limited to, methyl aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, Substituted sulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, Sub the like. stituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl 0086) “Alkylsulfinyl refers to a radical - S(O)R where S(O)—, aryl-S(O)—, alkyl-S(O) and aryl-S(O)— R is an alkyl or cycloalkyl group as defined herein. Repre 0.073 “Alkanoyl as used herein, which can include sentative examples include, but are not limited to, methyl “acyl, refers to the group R—C(O)—, where R is hydrogen sulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl and the or alkyl as defined above. like. 0074 "Aryl refers to a monovalent aromatic hydrocar 0087) “Alkylthio” refers to a radical –SR where R is an bon group derived by the removal of one hydrogen atom alkyl or cycloalkyl group as defined herein that may be from a single carbon atom of a parent aromatic ring system. optionally substituted as defined herein. Representative Typical aryl groups include, but are not limited to, groups examples include, but are not limited to, methylthio, eth derived from aceanthrylene, acenaphthylene, acephenan ylthio, propylthio, butylthio, and the like. thrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene, as 0088 “Amino” refers to the radical -NH. indacene, S-indacene, indane, indene, naphthalene, octacene, 0089 "Substituted amino” includes those groups recited octaphene, octalene, ovalene, penta-2,4-diene, pentacene, in the definition of "substituted’ herein, and particularly pentalene, pentaphene, perylene, phenalene, phenanthrene, refers to the group - N(R), where each R is independently picene, pleiadene, pyrene, pyranthrene, rubicene, triph selected from the group consisting of hydrogen, alkyl, enylene, trinaphthalene and the like. Particularly, an aryl substituted alkyl, alkenyl, substituted alkenyl, alkynyl, sub group comprises from 6 to 14 carbon atoms. stituted alkynyl, aryl, cycloalkyl, Substituted cycloalkyl, and 0075 "Substituted Aryl” includes those groups recited in where both R groups are joined to form an alkylene group. the definition of “substituted herein, and particularly refers When both R groups are hydrogen, —N(R) is an amino to an aryl group that may optionally be substituted with 1 or group. more substituents, for instance from 1 to 5 substituents, 0090 “Aminocarbonyl' or "amido” refers to the group particularly 1 to 3 substituents, selected from the group —C(O)NRR where each R is independently hydrogen, consisting of acyl, acylamino, acyloxy, alkenyl, Substituted alkyl, aryl and cycloalkyl, or where the R groups are joined alkenyl, alkoxy, Substituted alkoxy, alkoxycarbonyl, alkyl, to form an alkylene group. Substituted alkyl, alkynyl, Substituted alkynyl, amino, Sub stituted amino, aminocarbonyl, aminocarbonylamino, ami 0091 “Aminocarbonylamino” refers to the group —NR nocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, C(O)NRR where each R is independently hydrogen, alkyl, cycloalkyl, Substituted cycloalkyl, halogen, hydroxyl. nitro, aryl or cycloalkyl, or where two R groups are joined to form thioalkoxy, substituted thioalkoxy, thioaryloxy, thiol, alkyl an alkylene group. S(O)—, aryl-S(O)—, alkyl-S(O) and aryl-S(O), . 0092 “Aminocarbonyloxy' refers to the group 0.076 “Fused Aryl refers to an aryl having two of its ring —OC(O)NRR where each R is independently hydrogen, carbon in common with a second aryl ring or with an alkyl, aryl or cycloalkyl, or where the R groups are joined to aliphatic ring. form an alkylene group. 0.077 “Alkaryl” refers to an aryl group, as defined above, 0093 “Arylalkyloxy” refers to an O-arylalkyl radical Substituted with one or more alkyl groups, as defined above. where arylalkyl is as defined herein. 0078 “Aralkyl or “arylalkyl refers to an alkyl group, as 0094) “Arylamino” means a radical NHR where R defined above, Substituted with one or more aryl groups, as represents an aryl group as defined herein. defined above. 0.095 “Aryloxycarbonyl refers to a radical - C(O) O 0079) “Aryloxy” refers to O-aryl groups wherein aryl where aryl is as defined herein. “aryl' is as defined above. 0096) “Arylsulfonyl refers to a radical-S(O)R where 0080) “Alkylamino” refers to the group alkyl-NR' , R is an aryl or heteroaryl group as defined herein. wherein R is selected from hydrogen and alkyl. 0097 “AZido” refers to the radical —N 0081 “Arylamino” refers to the group aryl-NR' . 0098 “Bicycloaryl” refers to a monovalent aromatic wherein R is selected from hydrogen, aryl and heteroaryl. hydrocarbon group derived by the removal of one hydrogen US 2008/0039478 A1 Feb. 14, 2008

atom from a single carbon atom of a parent bicycloaromatic from 1 to 2 sites of olefinic unsaturation. Such cycloalkenyl ring system. Typical bicycloaryl groups include, but are not groups include, by way of example, single ring structures limited to, groups derived from indane, indene, naphthalene, Such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the tetrahydronaphthalene, and the like. Particularly, an aryl like. group comprises from 8 to 11 carbon atoms. 0.107 “Substituted cycloalkenyl' includes those groups 0099 “Bicycloheteroaryl” refers to a monovalent bicy recited in the definition of “substituted herein, and particu cloheteroaromatic group derived by the removal of one larly refers to a cycloalkenyl group having 1 or more hydrogen atom from a single atom of a parent bicyclohet substituents, for instance from 1 to 5 substituents, and eroaromatic ring system. Typical bicycloheteroaryl groups particularly from 1 to 3 substituents, selected from the group include, but are not limited to, groups derived from benzo consisting of acyl, acylamino, acyloxy, alkoxy, Substituted furan, benzimidazole, benzindazole, benzdioxane, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, Sub chromene, chromane, cinnoline, phthalazine, indole, indo stituted amino, aminocarbonyl, aminocarbonylamino, ami line, indolizine, isobenzofuran, isochromene, isoindole, nocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, isoindoline, isoquinoline, benzothiazole, benzoxazole, cycloalkyl, Substituted cycloalkyl, halogen, hydroxyl, keto, naphthyridine, benzoxadiazole, pteridine, purine, benzopy nitro, thioalkoxy, Substituted thioalkoxy, thioaryloxy, ran, benzpyrazine, pyridopyrimidine, quinazoline, quino thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)— line, quinolizine, quinoxaline, benzomorphan, tetrahy and aryl-S(O) - droisoquinoline, tetrahydroquinoline, and the like. Preferably, the bicycloheteroaryl group is between 9-11 0.108 “Fused Cycloalkenyl refers to a cycloalkenyl hav membered bicycloheteroaryl, with 5-10 membered het ing two of its ring carbon atoms in common with a second eroaryl being particularly preferred. Particular bicyclohet aliphatic or aromatic ring and having its olefinic unsatura eroaryl groups are those derived from benzothiophene, ben tion located to impart aromaticity to the cycloalkenyl ring. Zofuran, benzothiazole, indole, quinoline, isoquinoline, 01.09) “Cyanato” refers to the radical OCN. benzimidazole, benzoxazole and benzdioxane. 0110 “Cyano” refers to the radical —CN. 0100 “Carbamoyl refers to the radical - C(O)N(R) where each R group is independently hydrogen, alkyl, 0111 “Dialkylamino” means a radical NRR' where R cycloalkyl or aryl, as defined herein, which may be option and R' independently represent an alkyl, substituted alkyl, aryl, Substituted aryl, cycloalkyl, Substituted cycloalkyl, ally substituted as defined herein. cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, 0101) “Carboxy” refers to the radical –C(O)OH. or substituted heteroaryl group as defined herein. 0102) “Carboxyamino” refers to the radical N(H- 0112 “Ethenyl refers to substituted or unsubstituted )C(O)OH. —(C=C)—. 0103 “Cycloalkyl refers to cyclic hydrocarbyl groups 0113. “Ethylene' refers to substituted or unsubstituted having from 3 to about 10 carbon atoms and having a single —(C-C)—. cyclic ring or multiple condensed rings, including fused and bridged ring systems, which optionally can be substituted 0114 "Ethynyl refers to —(C=C)-. with from 1 to 3 alkyl groups. Such cycloalkyl groups 0115) “Halo' or “halogen” refers to fluoro, chloro, bromo include, by way of example, single ring structures Such as and iodo. Preferred halo groups are either fluoro or chloro. cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methyl cyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and 0.116) “Hydroxy” refers to the radical –OH. the like, and multiple ring structures such as adamantanyl. 0117) “Nitro” refers to the radical - NO, and the like. 0118 “Substituted” refers to a group in which one or 0104 “Substituted cycloalkyl includes those groups more hydrogen atoms are each independently replaced with recited in the definition of “substituted herein, and particu the same or different substituent(s). Typical substituents larly refers to a cycloalkyl group having 1 or more substitu include, but are not limited to, X, R', —O , =O, ents, for instance from 1 to 5 substituents, and particularly OR', SR' S, =S, NR'R'', =NR'', CX, from 1 to 3 Substituents, selected from the group consisting CF, CN, OCN, SCN, NO, NO=N, N. of acyl, acylamino, acyloxy, alkoxy, Substituted alkoxy, —S(O).O-, -S(O),OH, -S(O).R'', OS(O)O , alkoxycarbonyl, alkoxycarbonylamino, amino, Substituted OS(O),R'', -P(O)(O ), -P(O)(OR)(O), amino, aminocarbonyl, aminocarbonylamino, aminocarbo OP(O)(OR')(OR), C(O)R'', C(S)R'', nyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, C(O)OR, C(O)NR'R'', C(O)O, C(S)OR'', Substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thio NR-C(O)NR'R'' s NRC(S)NR'R'', alkoxy, Substituted thioalkoxy, thioaryloxy, thioketo, thiol, NRC(NR')NR'R'' and C(NR')NR'R'', where alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)—and aryl-S(O)— each X is independently a halogen; each R', R. R'' and R'' are independently hydrogen, alkyl, substituted alkyl, 0105 “Cycloalkoxy” refers to the group -OR where R aryl, substituted alkyl, arylalkyl, substituted alkyl, is cycloalkyl. Such cycloalkoxy groups include, by way of cycloalkyl, substituted alkyl, cycloheteroalkyl, substituted example, cyclopentoxy, cyclohexoxy and the like. cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, het 0106 “Cycloalkenyl refers to cyclic hydrocarbyl groups eroaryl, substituted heteroaryl, heteroarylalkyl, substituted having from 3 to 10 carbon atoms and having a single cyclic heteroarylalkyl, - NR'R'', C(O)R' or S(O) R' or ring or multiple condensed rings, including fused and optionally R' and R' together with the atom to which they bridged ring systems and having at least one and particularly are both attached form a cycloheteroalkyl or substituted US 2008/0039478 A1 Feb. 14, 2008

cycloheteroalkyl ring; and R' and R' are independently between 5-20 membered heteroaryl, with 5-10 membered hydrogen, alkyl, Substituted alkyl, aryl, Substituted alkyl, heteroaryl being particularly preferred. Particular heteroaryl arylalkyl, substituted alkyl, cycloalkyl, substituted alkyl, groups are those derived from thiophene, pyrrole, ben cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, Zothiophene, benzofuran, indole, pyridine, pyrimidine, substituted heteroalkyl, heteroaryl, substituted heteroaryl, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroiso heteroarylalkyl or substituted heteroarylalkyl. quinoline, imidazole, oxazole and pyrazine. 0119) Examples of representative substituted aryls include the following 0123 Examples of representative heteroaryls include the following:

-R6. R6 and Cy Cy Cy C. a.R 2 x R 7.

0120 In these formulae one of R and R7 may be hydrogen and at least one of R and R7 is each indepen C O CO dently selected from alkyl, alkenyl, alkynyl, cyclohet eroalkyl, alkanoyl, alkoxy, aryloxy, heteroaryloxy, alky lamino, arylamino, heteroarylamino, NR'COR', NR'SOR'', NRSOR, COOalkyl, COOaryl, CO OC CONR'R'', CONR'R'', NR'R'', SONR'R'', S-alkyl, S-alkyl, SOalkyl, SOalkyl, Saryl, SOaryl, SO.aryl; or R' and R may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or CS Cry more heteroatoms selected from the group N, O or S. R', R', and R'' are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, cycloalkyl, cycloheteroalkyl, aryl, wherein each Y is selected from carbonyl. N, NR', O and S. substituted aryl, heteroaryl, substituted or hetero alkyl or the and where R is defined herein. like. 0.124 Examples of representative cycloheteroalkyls 0121 “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon include the following atoms in the compound or group have been replaced by a nitrogen, oxygen, or Sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above Such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. cyclohet eroalkyl, aryl, e.g. heteroaryl, cycloalkenyl, cycloheteroalk sy is enyl, and the like having from 1 to 5, and especially from 1 to 3 heteroatoms. 0122) “Heteroaryl refers to a monovalent heteroaro S \, , , matic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, %Y -CN groups derived from acridine, arsindole, carbazole, B-car boline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isoch romene, isoindole, isoindoline, isoquinoline, tetrahydroiso quinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, O C. oxazole, perimidine, phenanthridine, phenanthroline, phena Zine, phthalazine, pteridine, purine, pyran, pyrazine, pyra Y XY Zole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, tetrahydroquinoline, quinolizine, -) quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, tria Zole, xanthene, and the like. Particularly, heteroaryl can include other saturated ring systems, and can therefore be derived from indoline, indolizine, tetrahydroquinoline, and tetrahydroisoquinoline. Preferably, the heteroaryl group is US 2008/0039478 A1 Feb. 14, 2008

0.133 - O R, -continued 0134) – CONCR), CONROR, X r 0135) - SOH, -S. R, -SON(R), C D X NN 0.136 –S(O)R, and -S(O),R, 0.137 wherein each R is independently an aryl or ali phatic, optionally with Substitution. Among hetero Substitu ents containing R groups, preference is given to those materials having aryl and alkyl R groups as defined herein. Where feasible, each R may include hydrogen. Also, where feasible, two R groups when on same atom may join to form a heterocyclic ring of 3-8 atoms. For example, two R groups wherein each X is selected from CR NR', O and S; and of NR, SONR, and CONR may join, together with the N each Y is selected from NR', O and S, and where R is R. atom, to form a N-morpholino, N-pyrrolo, N-piperidino, and R° and R' being as defined herein. N-pyrazolylo ring. Preferred hetero substituents are those listed above. 0125 Examples of representative cycloheteroalkenyls include the following: 0.138. As used herein, the term “cycloheteroalkyl refers to a stable heterocyclic non-aromatic ring and fused rings containing one or more heteroatoms independently selected from N, O and S. A fused heterocyclic ring system may include carbocyclic rings and need only include one hetero cyclic ring. Examples of heterocyclic rings include, but are O O O not limited to, piperazinyl, homopiperazinyl, piperidinyl and morpholinyl, and are shown in the following illustrative Cy C. C. examples: wherein each X is selected from CR, NR', O and S; and each Y is selected from carbonyl, N, NR', O and S, where sy is R" is as defined herein. 0126 Examples of representative aryl having hetero atoms containing Substitution include the following: S \, , ) -CIO –CIO. O -O wherein each X is selected from C R. CR, NR', O and S; and each Y is selected from carbonyl, NR', O and S. where R is as defined herein. 0127) “Hetero substituent” refers to a halo, O, S or N atom-containing functionality that may be present as an R' in a CR group present as substituents directly on W or Z of the compounds of this invention or may be present as a substituent in the “substituted aryl, heteroaryland aliphatic groups present in the compounds. 0128. Examples of hetero substituents include: 0129 -halo, 0130 - NO, NH, -NHR'. - N(R), 0131 - NRCOR, NRSOR, NRSOR, OH, CN, COR, optionally substituted with one or more groups selected from 0132) - COH, the group consisting of acyl, acylamino, acyloxy, alkoxy, US 2008/0039478 A1 Feb. 14, 2008

Substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, 0.148 “Sulfone' refers to the group —SOR. In particular amino, Substituted amino, aminocarbonyl, aminocarbony embodiments, R is selected from H. lower alkyl, alkyl, aryl lamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, and heteroaryl. cyano, cycloalkyl, Substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, Substituted thioalkoxy, 0149) “Thioaryloxy” refers to the group - SR where R is thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, aryl. alkyl-S(O) - and aryl-S(O). Substituting groups include 0150 “Thioketo” refers to the group =S. carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives. In the examples, M is CR 7, NR. O. or 0151. “Thiol” refers to the group - SH. S; Q is O, NR or S, where R is as defined herein. R7 and 0152 One having ordinary skill in the art of organic Rare independently selected from the group consisting of synthesis will recognize that the maximum number of het acyl, acylamino, acyloxy, alkoxy, Substituted alkoxy, eroatoms in a stable, chemically feasible heterocyclic ring, alkoxycarbonyl, alkoxycarbonylamino, amino, Substituted whether it is aromatic or non aromatic, is determined by the amino, aminocarbonyl, aminocarbonylamino, aminocarbo size of the ring, the degree of unsaturation and the Valence nyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, of the heteroatoms. In general, a heterocyclic ring may have Substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thio one to four heteroatoms So long as the heteroaromatic ring alkoxy, Substituted thioalkoxy, thioaryloxy, thioketo, thiol, is chemically feasible and stable. alkyl-S(O)—, aryl-S(O)—, alkyl-S(O) and aryl-S(O) 0153. “Pharmaceutically acceptable” means approved by 0139) “Dihydroxyphosphoryl” refers to the radical a regulatory agency of the Federal or a state government or PO(OH). listed in the U.S. Pharmacopoeia or other generally recog 0140 “Substituted dihydroxyphosphoryl' includes those nized pharmacopoeia for use in animals, and more particu groups recited in the definition of “substituted herein, and larly in humans. particularly refers to a dihydroxyphosphoryl radical wherein 0154 "Pharmaceutically acceptable salt” refers to a salt one or both of the hydroxyl groups are substituted. Suitable of a compound of the invention that is pharmaceutically substituents are described in detail below. acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid 0141 “Aminohydroxyphosphoryl” refers to the radical addition salts, formed with inorganic acids such as hydro PO(OH)NH, chloric acid, hydrobromic acid, Sulfuric acid, nitric acid, 0142 "Substituted aminohydroxyphosphoryl” includes phosphoric acid, and the like; or formed with organic acids those groups recited in the definition of “substituted herein, Such as acetic acid, propionic acid, hexanoic acid, cyclo and particularly refers to an aminohydroxyphosphoryl pentanepropionic acid, glycolic acid, pyruvic acid, lactic wherein the amino group is substituted with one or two acid, malonic acid. Succinic acid, malic acid, maleic acid, substituents. Suitable substituents are described in detail fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- below. In certain embodiments, the hydroxyl group can also hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic be substituted. acid, methanesulfonic acid, ethanesulfonic acid, 1.2-ethane 0143 “Thioalkoxy” refers to the group –SR where R is disulfonic acid, 2-hydroxyethanesulfonic acid, benzene alkyl. Sulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalene Sulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 0144) “Substituted thioalkoxy' includes those groups 4-methylbicyclo2.2.2-oct-2-ene-1-carboxylic acid, gluco recited in the definition of “substituted herein, and particu heptonic acid, 3-phenylpropionic acid, trimethylacetic acid, larly refers to a thioalkoxy group having 1 or more substitu tertiary butylacetic acid, lauryl Sulfuric acid, gluconic acid, ents, for instance from 1 to 5 substituents, and particularly glutamic acid, hydroxynaphthoic acid, Salicylic acid, Stearic from 1 to 3 Substituents, selected from the group consisting acid, muconic acid, and the like; or (2) salts formed when an of acyl, acylamino, acyloxy, alkoxy, Substituted alkoxy, acidic proton present in the parent compound either is alkoxycarbonyl, alkoxycarbonylamino, amino, Substituted replaced by a metal ion, e.g., an alkali metalion, an alkaline amino, aminocarbonyl, aminocarbonylamino, aminocarbo earth ion, or an aluminum ion; or coordinates with an nyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, organic base such as ethanolamine, diethanolamine, trietha Substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thio nolamine, N-methylglucamine and the like. Salts further alkoxy, Substituted thioalkoxy, thioaryloxy, thioketo, thiol, include, by way of example only, Sodium, potassium, cal alkyl-S(O)—, aryl-S(O)—, alkyl-S(O) and aryl-S(O) cium, magnesium, ammonium, tetraalkylammonium, and 0145 "Sulfanyl refers to the radical HS-. “Substituted the like; and when the compound contains a basic function sulfanyl refers to a radical such as RS-wherein R is any ality, salts of non toxic organic or inorganic acids, Such as substituent described herein. hydrochloride, hydrobromide, tartrate, mesylate, acetate, 0146 “Sulfonyl refers to the divalent radical —S(O)— maleate, oxalate and the like. The term “pharmaceutically “Substituted sulfonyl refers to a radical such as S(O)—R acceptable cation” refers to a non toxic, acceptable cationic wherein R is any substituent described herein. “Aminosul counter-ion of an acidic functional group. Such cations are fonyl' or "Sulfonamide' refers to the radical HNCO)S exemplified by Sodium, potassium, calcium, magnesium, and “substituted aminosulfonyl'substituted sulfonamide' ammonium, tetraalkylammonium cations, and the like. refers to a radical such as RN(O)S wherein each R is O155 “Pharmaceutically acceptable vehicle' refers to a independently any substituent described herein. diluent, adjuvant, excipient or carrier with which a com 0147 “Sulfoxide” refers to the divalent radical pound of the invention is administered. —S(O)—. “Substituted sulfoxide refers to a radical such as 0156 “Preventing” or “prevention” refers to a reduction S(O)—R, wherein R is any substituent described herein. in risk of acquiring a disease or disorder (i.e., causing at least US 2008/0039478 A1 Feb. 14, 2008 one of the clinical symptoms of the disease not to develop 0.164 "Tautomers' refer to compounds that are inter in a Subject that may be exposed to or predisposed to the changeable forms of a particular compound structure, and disease but does not yet experience or display symptoms of that vary in the displacement of hydrogen atoms and elec the disease). trons. Thus, two structures may be in equilibrium through 0157 “Prodrugs’ refers to compounds, including deriva the movement of 71 electrons and an atom (usually H). For tives of the compounds of the invention, which have cleav example, enols and ketones are tautomers because they are able groups and become by Solvolysis or under physiologi rapidly interconverted by treatment with either acid or base. cal conditions the compounds of the invention which are Another example of tautomerism is the aci- and nitro-forms pharmaceutically active in vivo. Such examples include, but of phenylnitromethane, that are likewise formed by treat are not limited to, choline ester derivatives and the like, ment with acid or base. Representative enol-keto structures N-alkylmorpholine esters and the like. and equilibrium are illustrated below: 0158 “Solvate” refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be | prepared e.g. in crystalline form and may be solvated or hydrated. Suitable Solvates include pharmaceutically accept able solvates, such as hydrates, and further include both 1. H r Stoichiometric Solvates and non-stoichiometric Solvates. 0159) “Subject” includes humans. The terms “human, | "patient” and “subject are used interchangeably herein. 1"| s= 29 0160 “Therapeutically effective amount’ means the N H1 amount of a compound that, when administered to a subject H H for treating a disease, is Sufficient to effect such treatment for N O N O the disease. The “therapeutically effective amount can vary N O depending on the compound, the disease and its severity, and N s the age, weight, etc., of the Subject to be treated. N H1 N 0161 "Treating or “treatment of any disease or disor der refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the 0.165 Tautomeric forms may be relevant to the attain disease or at least one of the clinical symptoms thereof). In ment of the optimal chemical reactivity and biological another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not activity of a compound of interest. be discernible by the subject. In yet another embodiment, 0166 The compounds of this invention may possess one “treating or “treatment” refers to modulating the disease or or more asymmetric centers; Such compounds can therefore disorder, either physically, (e.g., Stabilization of a discern ible symptom), physiologically, (e.g., stabilization of a be produced as individual (R)- or (S)-stereoisomers or as physical parameter), or both. In yet another embodiment, mixtures thereof. Unless indicated otherwise, the description “treating or “treatment” refers to delaying the onset of the or naming of a particular compound in the specification and disease or disorder, or even preventing the same. claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods 0162. It is also to be understood that compounds that have the same molecular formula but differ in the nature or for the determination of stereochemistry and the separation sequence of bonding of their atoms or the arrangement of of stereoisomers are well-known in the art. their atoms in space are termed "isomers'. Isomers that differ in the arrangement of their atoms in space are termed The Compounds “stereoisomers'. 0.167 The present invention provides bicycloheteroaryl 0163 Stereoisomers that are not mirror images of one compounds useful for preventing and/or treating a broad another are termed "diastereomers' and those that are non range of conditions, associated with abnormalities in the Superimposable mirror images of each other are termed activity of the P2X, receptor, among them, rheumatoid “enantiomers’. When a compound has an asymmetric cen ter, for example, it is bonded to four different groups, a pair arthritis, Parkinson's disease, uveitis, asthma, cardiovascu of enantiomers is possible. An enantiomer can be charac lar conditions such as myocardial infarction, the treatment terized by the absolute configuration of its asymmetric and prophylaxis of pain syndromes (acute and chronic or center and is described by the R- and S-sequencing rules of neuropathic), traumatic brain injury, acute spinal cord injury, Cahn and Prelog, or by the manner in which the molecule neurodegenerative disorders, inflammatory bowel disease rotates the plane of polarized light and designated as dex and immune dysfunctions such as autoimmune disorders or trorotatory or levorotatory (i.e., as (+) or (-)-isomers respec conditions, in mammals. tively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing 0.168. In a first aspect of the invention, bicycloheteroaryl equal proportions of the enantiomers is called a “racemic compounds are disclosed that are capable of modulating the mixture'. activity of the P2X, receptor in vivo, having a formula (I): US 2008/0039478 A1 Feb. 14, 2008

which can be optionally substituted with at least one Substituent selected from a R group; or the group “R-L is H; n L B n s 0179 R is selected from H, alkyl, substituted alkyl, Y i R. R." acyl, Substituted acyl, Substituted or unsubstituted acy A N lamino, Substituted or unsubstituted alkylamino, Sub stituted or unsubstituted alkylthio, substituted or unsub 21 * R1 stituted alkoxy, alkoxycarbonyl, Substituted Ws, -W O alkoxycarbonyl, substituted or unsubstituted alkylary lamino, arylalkyloxy, Substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsub 0169 wherein stituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or 0170 A is selected from CRR, CO, and CS: unsubstituted aminosulfonyl, substituted or unsubsti 0171 B is selected from CR, CRR", CO, and CS: tuted arylsulfonyl, sulfuric acid, sulfuric acid ester, substituted or unsubstituted dihydroxyphosphoryl, sub 0172 Y is independently selected from CR and CR, stituted or unsubstituted aminodihydroxyphosphoryl, R2"; azido, carboxy, Substituted or unsubstituted carbamoyl, (0173 W. W. and Z are independently selected from cyano, Substituted or unsubstituted cycloalkyl, Substi CR and N, provided that all three of W. W. and Z can tuted or unsubstituted cycloheteroalkyl, substituted or not be N at the same time; unsubstituted dialkylamino, halo, heteroaryloxy, Sub stituted or unsubstituted heteroaryl, substituted or 017.4 L is a C-C alkylene group, heteroalkyl, 3 to 8 unsubstituted heteroalkyl, hydroxy, nitro, and thio; and membered cycloalkyl or heterocycloalkyl, alkylcy cloalkyl, alkylheterocycloalkyl, cycloalkylalkyl, or het the dotted bond is a single or a double bond; erocycloalkylalkyl group, which can be optionally Sub 0180 or a pharmaceutically acceptable salt, solvate or stituted by a substituent selected from hydroxyl, prodrug thereof, halogen and C-C alkoxy; 0181 and stereoisomers and tautomers thereof. 0.175 n is 1, 2 or 3: 0182. In another aspect the present invention provides 0176) R' is selected from a 3-13 membered cycloalkyl, bicycloheteroaryl compounds bicycloheteroaryl compounds heterocycloalkyl, aryl and heteroaryl ring system, are disclosed that are capable of modulating the activity of which can be optionally substituted with one or more the P2X, receptor in vivo, having a formula (Ia): substituents independently selected from halo, hydroxyl, amino, cyano, Sulfo, Sulfanyl, Sulfinyl, amido, carboxy, ester, alkyl, Substituted alkyl, alkenyl, Ia Substituted alkenyl, alkynyl, Substituted alkynyl, and n L n1 Bis Sulfonamido; Y R. R." 0177) each of R, R and R" is independently selected from hydrogen, Substituted or unsubstituted C-C, A 21 P4 alkyl; or any of R and Rican join together to form a R1 cycloalkyl or cycloheteroalkyl ring of 3-7 atoms: Ws-w R2 0.178 R is hydrogen or a functional group selected from acyl, substituted acyl, substituted or unsubstituted acylamino, Substituted or unsubstituted alkylamino, 0183 wherein substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl, Substituted 0184) A is selected from CRR, CO, and CS: alkoxycarbonyl, substituted or unsubstituted alkylary lamino, arylalkyloxy, Substituted arylalkyloxy, amino, 0185 B is selected from CR, CRR", CO, and CS: aryl, substituted aryl, arylalkyl, substituted or unsub 0186 Y is independently selected from CR and CR, stituted sulfoxide, substituted or unsubstituted sulfone, R2"; substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubsti O187 W.s W' andal Z are 1ndependentVindependently selectedSelected ffrom tuted arylsulfonyl, sulfuric acid, sulfuric acid ester, CR and N, provided that all three of W. W. and Z can substituted or unsubstituted dihydroxyphosphoryl, sub not be N at the same time; stituted or unsubstituted aminodihydroxyphosphoryl, 0188 L is a C-C alkylene group, heteroalkyl, 3 to 8 azido, carboxy, Substituted or unsubstituted carbamoyl, membered cycloalkyl or heterocycloalkyl, alkylcy cyano, Substituted or unsubstituted cycloalkyl, Substi cloalkyl, alkylheterocycloalkyl, cycloalkylalkyl, or het tuted or unsubstituted cycloheteroalkyl, substituted or erocycloalkylalkyl group, which can be optionally Sub unsubstituted dialkylamino, halo, heteroaryloxy, Sub stituted by a substituent selected from hydroxyl, stituted or unsubstituted heteroaryl, substituted or halogen and C-C alkoxy; unsubstituted heteroalkyl, hydroxy, nitro, and thio; or R is a 4-9 membered carbocyclic or heterocyclic ring 0189 n is 1, 2 or 3: US 2008/0039478 A1 Feb. 14, 2008 13

0.190) R' is selected from a 3-13 membered cycloalkyl, selected from H, acyl, substituted acyl, substituted or unsub heterocycloalkyl, aryl and heteroaryl ring system, stituted aminocarbonyl, alkoxycarbonyl, Substituted alkoxy which can be optionally substituted with one or more carbonyl, substituted or unsubstituted sulfoxide, substituted substituents independently selected from halo, or unsubstituted sulfone, substituted or unsubstituted ami hydroxyl, amino, cyano, Sulfo, Sulfanyl, Sulfinyl, nosulfonyl, substituted or unsubstituted arylsulfonyl, ary amido, carboxy, ester, alkyl, Substituted alkyl, alkenyl, loxycarbonyl, Substituted aryloxycarbonyl, heteroaryloxy Substituted alkenyl, alkynyl, Substituted alkynyl, and carbonyl, and substituted heteroaryloxycarbonyl. Sulfonamido; 0196. In a further embodiment, with respect to com 0191) each of R, R and R" is independently selected pounds of formula I and Ia, L is L'; and wherein L' is a bond, from hydrogen, Substituted or unsubstituted C-C, —CO— —SO - or a C-C alkylene group which can be alkyl; or any of R and R can join together to form a optionally substituted by a substituent selected from alkyl, cycloalkyl or cycloheteroalkyl ring of 3-7 atoms: hydroxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, 0.192 R is hydrogen or a functional group selected dialkylaminoalkyl, halogen, carbamoyl, and C-C alkoxy. from acyl, substituted acyl, substituted or unsubstituted In one particular embodiment, when A is CO or CS, L' is a acylamino, Substituted or unsubstituted alkylamino, bond or C-C alkylene group. substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl, Substituted 0197). In a further embodiment, with respect to compound alkoxycarbonyl, substituted or unsubstituted alkylary of formula I and Ia, L is L'; and wherein L' is a bond, lamino, arylalkyloxy, Substituted arylalkyloxy, amino, —CO-, -SO - or a C-C alkylene group; and R is aryl, substituted aryl, arylalkyl, substituted or unsub selected from hydrogen, substituted or unsubstituted alkyl, stituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted cycloalkyl, substituted or unsub substituted or unsubstituted sulfanyl, substituted or stituted heterocycloalkyl, substituted or unsubstituted aryl, unsubstituted aminosulfonyl, substituted or unsubsti substituted or unsubstituted heteroaryl, substituted or unsub tuted arylsulfonyl, sulfuric acid, sulfuric acid ester, stituted bicycloaryl, and substituted or unsubstituted bicy substituted or unsubstituted dihydroxyphosphoryl, sub cloheteroaryl. In one particular embodiment, when R is stituted or unsubstituted aminodihydroxyphosphoryl, hydrogen, L' is a bond or a C-C alkylene group. azido, carboxy, Substituted or unsubstituted carbamoyl, 0.198. In a further embodiment, with respect to compound cyano, Substituted or unsubstituted cycloalkyl, Substi of formula I and Ia, A, B and Y may all represent CRR. tuted or unsubstituted cycloheteroalkyl, substituted or In another embodiment, A is CRR: and B and Y are unsubstituted dialkylamino, halo, heteroaryloxy, Sub independently selected from CR and CRR. stituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thio; or 0199. In another aspect the present invention provides R is a 4-9 membered carbocyclic or heterocyclic ring bicycloheteroaryl compounds bicycloheteroaryl compounds which can be optionally substituted with at least one are disclosed that are capable of modulating the activity of Substituent selected from a R' group; or the group the P2X, receptor in vivo, having a formula (II or IIa): “R-L is H; 0193 R' is selected from H, alkyl, substituted alkyl, acyl, Substituted acyl, Substituted or unsubstituted acy II lamino, Substituted or unsubstituted alkylamino, Sub n L1-B- stituted or unsubstituted alkylthio, substituted or unsub Y R. R." stituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylary A 21 N lamino, arylalkyloxy, Substituted arylalkyloxy, amino, R1 O aryl, substituted aryl, arylalkyl, substituted or unsub Ws-w O stituted sulfoxide, substituted or unsubstituted sulfone, IIa substituted or unsubstituted sulfanyl, substituted or R3a. unsubstituted aminosulfonyl, substituted or unsubsti L1-B- tuted arylsulfonyl, sulfuric acid, sulfuric acid ester, Y O R. R." substituted or unsubstituted dihydroxyphosphoryl, sub stituted or unsubstituted aminodihydroxyphosphoryl, A azido, carboxy, Substituted or unsubstituted carbamoyl, ----04 R1 cyano, Substituted or unsubstituted cycloalkyl, Substi tuted or unsubstituted cycloheteroalkyl, substituted or Ws-w H unsubstituted dialkylamino, halo, heteroaryloxy, Sub stituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thio; and 0200 wherein the dotted bond is a single or a double bond; or a pharmaceutically acceptable salt, Solvate or prodrug 0201 A is selected from CRR: thereof, and stereoisomers and tautomers thereof. 0202 B and Y are independently selected from CR 0194 In a further embodiment as to compounds of for and CPR; mula I and Ia, n may be 0. (0203 W. W. and Z are independently selected from 0.195. In a further embodiment, with respect to com CR and N, provided that all three of W. W. and Z can pounds of formula I and Ia, L may be a bond and R is not be N at the same time; US 2008/0039478 A1 Feb. 14, 2008 14

0204 L' is a bond, —CO-, -SO, or a C-Cs 0215. In a further embodiment, with respect to com alkylene group which can be optionally Substituted by pounds of formula II and IIa, A, B and Y may all represent a substituent selected from alkyl, hydroxy, hydroxy CH and the dotted bond is a single bond. alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, halogen, carbamoyl, and C-C alkoxy; 0216) In a further embodiment, with respect to com pounds of formula II and IIa, A is CH; and B and Y each 0205 n is 0, 1, 2 or 3: represent CH and the dotted bond is a double bond. 0206) R' is selected from a 3-13 membered cycloalkyl, 0217. In one embodiment, with respect to compounds of heterocycloalkyl, aryl and heteroaryl ring system, formula II and IIa, W' is N. which can be optionally substituted with one or more substituents independently selected from halo, 0218. In another embodiment, with respect to compounds hydroxyl, amino, cyano, Sulfo, Sulfanyl, Sulfinyl, of formula II and IIa, W is CR. amido, carboxy, ester, alkyl, Substituted alkyl, alkenyl, 0219. In another embodiment, with respect to compounds Substituted alkenyl, alkynyl, Substituted alkynyl, and of formula II and IIa, W' is CR" and R' is selected from Sulfonamido; hydrogen, halo, alkoxy, alkyl, and dialkylamino. 0207) each of R, R2, R, R and R" is indepen dently selected from hydrogen, substituted or unsub 0220. In another embodiment, with respect to compounds stituted C-C alkyl; or any of R and R can join of formula II and IIa, each of R and R' of the together to form a cycloalkyl or cycloheteroalkyl ring of 3-7 atoms; R. R." 0208 R is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocy u% cloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted bicycloaryl, and substituted or unsubstituted bicyclo group is H. heteroaryl; 0221) In another embodiment, with respect to compound 0209) R' is selected from H, alkyl, substituted alkyl, of formula II and IIa, wherein one of R and R of the acyl, Substituted acyl, Substituted or unsubstituted acy lamino, Substituted or unsubstituted alkylamino, Sub stituted or unsubstituted alkylthio, substituted or unsub R. R." stituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylary u% lamino, arylalkyloxy, Substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsub stituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or group is Me and the other is H. unsubstituted aminosulfonyl, substituted or unsubsti 0222. In another embodiment, with respect to compounds tuted arylsulfonyl, sulfuric acid, sulfuric acid ester, of formula II and IIa, each of R and R” of the substituted or unsubstituted dihydroxyphosphoryl, sub stituted or unsubstituted aminodihydroxyphosphoryl, azido, carboxy, Substituted or unsubstituted carbamoyl, R. R." cyano, Substituted or unsubstituted cycloalkyl, Substi tuted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, Sub u% stituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thio; and the dotted bond is a single or a double bond; group is Me. 0210 or a pharmaceuticallyp acceptablep salt, solvate or 0223) In another embodiment, with respect to compounds prodrug thereof, of formula II and IIa, n is 0 or 1. In one particular embodiment, n is 0. In yet another particular embodiment, in 0211 and stereoisomers and tautomers thereof. is 1. 0212. In one particular embodiment, with respect to com pounds of formula II and IIa, when R is hydrogen, L' is a 0224. In another embodiment, with respect to compounds bond or a C-C alkylene group. of formula II and IIa, wherein the 0213. In a further embodiment, with respect to com pounds of formula II and IIa, A, B and Y may all represent R. R." CRR and the dotted bond is a single bond. 0214. In a further embodiment, with respect to com u% pounds of formula II and IIa, A is CRR: and B and Y each represent CR and the dotted bond is a double bond. US 2008/0039478 A1 Feb. 14, 2008

group is selected from substituted or unsubstituted group is

RC Rb O RC Rb,

and wherein R, R and R are independently selected from H, halo, hydroxyl, substituted hydroxyl, alkyl, substituted alkyl, amino, Substituted amino, aryl and Substituted aryl. 0226. In another embodiment, with respect to compounds of formula II and IIa, the u%R. R."

group is as described in the preceding paragraph, and R. R. and R are independently selected from H, Br, C1, OH, Me, NHAc, Ph and F. In one particular embodiment, each of R, R and R is H. 0227. In another aspect the present invention provides bicycloheteroaryl compounds and bicycloheteroaryl com pounds are disclosed that are capable of modulating the activity of the P2X, receptor in vivo, and that have a formula (III, IIIa, IV or IVa): III R3a. Ra l N

21 N Rb, Ws, -W' O RC IIIa R3a. Ra l N O

21 N \ . Rb Ws, -W H RC IV 0225. In another embodiment, with respect to compound Ris Ra of formula II and IIa, wherein the YN N | N R. R." 21 Rb or u's Ws, -W O R1 RC US 2008/0039478 A1 Feb. 14, 2008 16

-continued -continued IVa. VI

R3a. R3 n L Ra Ll Ra nN.1 N O N N

N 21 N Rb 21 Rb or Nan-N O Ws, -W H Z RC RC WIa wherein L', R. W. Z. Wand n are as described for formula II or Ila; and wherein R, R and R are independently Ris Ra selected from H. halo, hydroxyl, substituted hydroxyl, alkyl, nN.1 N O Substituted alkyl, amino, Substituted amino, aryl and Substi tuted aryl. 21 N Rb, 0228. In one embodiment, with respect to compounds of formulae II-IVa, each of W. W. and Z is independently CR". Ns, -N H RC 0229. In one embodiment, with respect to compounds of formulae II-IVa, each of W. W. and Z is independently CH. and wherein L', R. Z, and n are as described for formula II 0230. In one embodiment, with respect to compounds of or Ila; and wherein R, RandR are independently selected formulae II-IVa, W is C-Me and W and Z both are CHs. from H. halo, hydroxyl, substituted hydroxyl, alkyl, substi 0231. In one embodiment, with respect to compounds of tuted alkyl, amino, Substituted amino, aryl and Substituted formulae II-IVa, W is N and W and Z both are CR's. aryl. 0232. In one embodiment, with respect to compounds of 0237. In one embodiment, with respect to compounds of formulae II-IVa, W is N and W and Z both are CHs. formulae II-VIa, n is 0. 0233. In one embodiment, with respect to compounds of 0238. In another embodiment, with respect to compounds formulae II-IVa, Z is CR" and W and W" both are Ns. of formulae II-VIa, n is 1. 0234. In one embodiment, with respect to compounds of 0239). In one embodiment, with respect to compounds of formulae II-IVa, Z is CH and W and W" both are Ns. formulae II-VIa, each of R, R and R is H. 0235. In one embodiment, with respect to compounds of 0240. In one embodiment, with respect to compounds of formulae II-IVa, Z is N and W and W" both are CR's. formulae II-VIa, each of R, R and R is Me. 0241. In another embodiment, with respect to compounds 0236. In another aspect the present invention provides bicycloheteroaryl compounds and bicycloheteroaryl com of formulae II-VIa, two of R, R and R is Me. pounds are disclosed, that are capable of modulating the 0242. In another embodiment, with respect to compounds activity of the P2X, receptor in vivo, having a formula (V. of formulae II-VIa, one of R, R and R is OH. Va., VI or Vla): 0243 In another embodiment, with respect to compounds V of formulae II-VIa, Z is CR" and R' is selected from Ris Ra hydrogen, halo, alkoxy, alkyl, and dialkylamino, 0244. In one embodiment, with respect to compounds of formulae II-VIa, Ln is a bond and R is H. 21 N Rb, 0245. In another embodiment, with respect to compounds Nin -N O of formulae II-VIa, Ln is a C-C alkylene group which can Z be optionally substituted by a substituent selected from RC alkyl, hydroxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, Wa dialkylaminoalkyl, halogen, carbamoyl, and C-C alkoxy; Ris Ra and R is H. NN O 0246. In another embodiment, with respect to compounds of formulae II-VIa, L' is —CO , or - SO . 21 N Rb 0247. In another embodiment, with respect to compounds NS-N H of formulae II-VIa, L' is C-C alkylene group which can be Z optionally substituted by a substituent selected from alkyl, RC hydroxy, hydroxyalkyl, amino alkyl, alkylaminoalkyl, dialkylaminoalkyl, halogen, carbamoyl, and C alkoxy. US 2008/0039478 A1 Feb. 14, 2008

0248. Further in accordance with compounds of formulae OPh, COPh, CF, CHF, OCF, t-Bu, SMe, CH=CH II-VIa, L' may be a substituted or unsubstituted C-C, COH, SOMe, SOMe, SOH, SOMe, and pyridyl. alkylene group, and particularly, may be CH, -(CH2) , 0256 In one particular embodiment, with respect to com —(CH) , or —(CH) . pound of formulae II-VIa, L' is a —CO , SO or a 0249. In one embodiment, with respect to compounds of C-Cs alkylene group and R is substituted or unsubstituted formulae II-VIa, R is substituted or unsubstituted alkyl. cycloalkyl, heterocycloalkyl, heteroaryl, bicycloaryl or 0250). In one particular embodiment, with respect to com bicycloheteroaryl. In another particular embodiment, the pounds of formulae II-VIa, R is substituted alkyl; and the substitution is selected from Me, Et, Ph, Cl, F, Br, CN, OH, substitution on alkyl is selected from aryl, heteroaryl, OMe, OPh, COPh, CF, CHF, OCF, t-Bu, S.Me, cycloalkyl, heterocycloalkyl, halo, alkoxy, hydroxy, cyano, CH=CH-COH, SOMe, SOMe, SOH, and SOMe. and aryloxy. In another particular embodiment, the Substi 0257. In one particular embodiment, with respect to com tution on alkyl is selected from Ph, Cl, F, Br, CN, OH, OMe, pound of formulae II-VIa, L' is a -CO , -SO, or a OPh, CF, CHF, OCF, t-Bu, SMe, SOMe, SOMe, SOH, C-C alkylene group and R is substituted or unsubstituted SOMe, pyridyl, cyclopropyl, cyclopenty1 and cyclohexyl. naphthalene, furanyl, thiophenyl, pyrrolyl pyrazolyl, imi 0251 Still further in accordance with the invention, and dazolyl, triazolyl pyridyl, pyrimidinyl, quinoline, isoquino with respect to the compounds of formulae II-VIa, where linyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, present, -L-R may be selected from H, Me, Et, benzyl, benzopyranyl, benzofuranyl, benzoxazinyl, or benzodioxa —(CH), OH, -(CH) NHMe, —(CH), OH, nyl. In another particular embodiment, the Substitution is -(CH-)-CH(OH) CH-OH, —(CH) COH, selected from Me, Et, Ph, Cl, F, Br, CN, OH, OMe, OPh, —(CH), NHEt, —(CH), NHEt, —(CH). NH COPh, CF, CHF, OCF, t-Bu, SMe, CH=CH-COH, (CH),OH, —(CH). NH-(CH),OH, —(CH), NH, SOMe, SOMe, SOH, and SOMe. —(CH) NHCONHSOMe, -(CH), NH-(CH)– 0258. In certain aspects, the present invention provides Me, or —(CH2)CO.H. prodrugs and derivatives of the compounds according to the 0252) In one embodiment, with respect to compounds of formulae above. Prodrugs are derivatives of the compounds formulae II-VIa, L' is a CO . —SO - or a C-C, of the invention, which have metabolically cleavable groups alkylene group and R is substituted or unsubstituted aryl. and become by Solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically 0253. In one particular embodiment, with respect to com active, in vivo. Such examples include, but are not limited pounds of formulae II-VIa, L' is a -CO-, -SO, or a to, choline ester derivatives and the like, N-alkylmorpholine C-C alkylene group and R is esters and the like. 0259) Other derivatives of the compounds of this inven N tion have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the 2 mammalian organism (see, Bundgard, H., Design of Pro drugs, pp. 7-9, 21-24. Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well know to practitioners of the art, and wherein n' is selected from 1-5 and each of R' is Such as, for example, esters prepared by reaction of the independently selected from hydrogen, alkyl, Substituted parent acid with a suitable alcohol, or amides prepared by alkyl, acyl, substituted acyl, substituted or unsubstituted reaction of the parent acid compound with a substituted or acylamino, Substituted or unsubstituted alkylamino, Substi unsubstituted amine, or acid anhydrides, or mixed anhy tuted or unsubstituted alkylthio, substituted or unsubstituted drides. Simple aliphatic or aromatic esters, amides and alkoxy, aryloxy, alkoxycarbonyl, Substituted alkoxycarbo anhydrides derived from acidic groups pendant on the nyl, Substituted or unsubstituted alkylarylamino, arylalky compounds of this invention are preferred prodrugs. In some loxy, Substituted arylalkyloxy, amino, aryl. Substituted aryl, cases it is desirable to prepare double ester type prodrugs arylalkyl, substituted or unsubstituted sulfoxide, substituted Such as (acyloxy)alkyl esters or (alkoxycarbonyl)oxy)alky or unsubstituted sulfone, substituted or unsubstituted sulfa nyl, substituted or unsubstituted aminosulfonyl, substituted lesters. Preferred are the C to C alkyl, C-C alkenyl, aryl, or unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid C7-C. Substituted aryl, and C7-Carylalkyl esters of the ester, substituted or unsubstituted dihydroxyphosphoryl, compounds of the invention. substituted or unsubstituted aminodihydroxyphosphoryl, azido, carboxy, Substituted or unsubstituted carbamoyl, Pharmaceutical Compositions cyano, Substituted or unsubstituted cycloalkyl, Substituted or 0260. When employed as pharmaceuticals, the com unsubstituted cycloheteroalkyl, substituted or unsubstituted pounds of this invention are typically administered in the dialkylamino, halo, heteroaryloxy, Substituted or unsubsti form of a pharmaceutical composition. Such compositions tuted heteroaryl, substituted or unsubstituted heteroalkyl, can be prepared in a manner well known in the pharmaceu hydroxy, nitro, and thio. tical art and comprise at least one active compound. 0254. In one particular embodiment, n' is 1, 2 or 3. In 0261 Generally, the compounds of this invention are another particular embodiment, n' is 1, or 2. In yet another administered in a pharmaceutically effective amount. The particular embodiment, n' is 1. amount of the compound actually administered will typi 0255) In one particular embodiment, each R" is indepen cally be determined by a physician, in the light of the dently selected from Me, Et, Ph, Cl, F, Br, CN, OH, OMe, relevant circumstances, including the condition to be treated, US 2008/0039478 A1 Feb. 14, 2008

the chosen route of administration, the actual compound 0267 The compounds of this invention can also be administered, the age, weight, and response of the individual administered by a transdermal device. Accordingly, trans patient, the severity of the patient’s symptoms, and the like. dermal administration can be accomplished using a patch 0262 The pharmaceutical compositions of this invention either of the reservoir or porous membrane type, or of a solid can be administered by a variety of routes including oral, matrix variety. rectal, transdermal, Subcutaneous, intravenous, intramuscu 0268. The above-described components for orally admin lar, and intranasal. Depending on the intended route of istrable, injectable or topically administrable compositions delivery, the compounds of this invention are preferably are merely representative. Other materials as well as pro formulated as either injectable or oral compositions or as cessing techniques and the like are set forth in Part 8 of salves, as lotions or as patches all for transdermal adminis Remington's Pharmaceutical Sciences, 17th edition, 1985, tration. Mack Publishing Company, Easton, Pa., which is incorpo 0263. The compositions for oral administration can take rated herein by reference. the form of bulk liquid solutions or suspensions, or bulk 0269. The compounds of this invention can also be powders. More commonly, however, the compositions are administered in Sustained release forms or from Sustained presented in unit dosage forms to facilitate accurate dosing. release drug delivery systems. A description of representa The term “unit dosage forms’ refers to physically discrete tive Sustained release materials can be found in Remington's units Suitable as unitary dosages for human Subjects and Pharmaceutical Sciences. other mammals, each unit containing a predetermined quan tity of active material calculated to produce the desired 0270. The following formulation examples illustrate rep therapeutic effect, in association with a Suitable pharmaceu resentative pharmaceutical compositions of this invention. tical excipient. Typical unit dosage forms include prefilled, The present invention, however, is not limited to the fol premeasured ampules or Syringes of the liquid compositions lowing pharmaceutical compositions. or pills, tablets, capsules or the like in the case of solid compositions. In Such compositions, the furanSulfonic acid Formulation 1 compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about Tablets 40% by weight) with the remainder being various vehicles 0271. A compound of the invention is admixed as a dry or carriers and processing aids helpful for forming the powder with a dry gelatin binder in an approximate 1:2 desired dosing form. weight ratio. A minor amount of magnesium Stearate is 0264. Liquid forms suitable for oral administration may added as a lubricant. The mixture is formed into 240-270 mg include a suitable aqueous or nonaqueous vehicle with tablets (80-90 mg of active amide compound per tablet) in buffers, Suspending and dispensing agents, colorants, flavors a tablet press. and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: Formulation 2 a binder Such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disinte Capsules grating agent such as alginic acid, Primogel, or corn starch; 0272. A compound of the invention is admixed as a dry a lubricant Such as magnesium Stearate; a glidant Such as powder with a starch diluent in an approximate 1:1 weight colloidal silicon dioxide; a Sweetening agent Such as Sucrose or saccharin; or a flavoring agent such as peppermint, methyl ratio. The mixture is filled into 250 mg capsules (125 mg of salicylate, or orange flavoring. active amide compound per capsule). 0265 Injectable compositions are typically based upon Formulation 3 injectable sterile saline orphosphate-buffered saline or other injectable carriers known in the art. As before, the active Liquid compound in Such compositions is typically a minor com ponent, often being from about 0.05 to 10% by weight with 0273 A compound of the invention (125 mg), sucrose the remainder being the injectable carrier and the like. (1.75 g) and Xanthan gum (4 mg) are blended, passed 0266 Transdermal compositions are typically formulated through a No. 10 mesh U.S. sieve, and then mixed with a as a topical ointment or cream containing the active ingre previously made Solution of microcrystalline cellulose and dient(s), generally in an amount ranging from about 0.01 to sodium carboxymethyl cellulose (11:89, 50 mg) in water. about 20% by weight, preferably from about 0.1 to about Sodium benzoate (10 mg), flavor, and color are diluted with 20% by weight, preferably from about 0.1 to about 10% by water and added with stirring. Sufficient water is then added weight, and more preferably from about 0.5 to about 15% by to produce a total volume of 5 mL. weight. When formulated as a ointment, the active ingredi Formulation 4 ents will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example Tablets an oil-in-water cream base. Such transdermal formulations 0274. A compound of the invention is admixed as a dry are well-known in the art and generally include additional powder with a dry gelatin binder in an approximate 1:2 ingredients to enhance the dermal penetration of Stability of weight ratio. A minor amount of magnesium Stearate is the active ingredients or the formulation. All such known added as a lubricant. The mixture is formed into 450-900 mg transdermal formulations and ingredients are included tablets (150-300 mg of active amide compound) in a tablet within the scope of this invention. press. US 2008/0039478 A1 Feb. 14, 2008

Formulation 5 disorders, sleep disorders and cognition disorders; epilepsy and seizure disorders; prostate, bladder and bowel dysfunc Injection tion Such as, for example urinary incontinence, urinary 0275 A compound of the invention is dissolved or sus hesitancy, rectal hypersensitivity, fecal incontinence, benign pended in a buffered sterile saline injectable aqueous prostatic hypertrophy and inflammatory bowel disease; res piratory and airway disease and disorders such as, for medium to a concentration of approximately 5 mg/ml. example, allergic rhinitis, asthma and reactive airway dis Formulation 6 ease and chronic obstructive pulmonary disease; diseases and disorders which are mediated by or result in inflamma Topical tion Such as, for example rheumatoid arthritis and osteoar thritis, myocardial infarction, various autoimmune diseases 0276 Stearyl alcohol (250 g) and a white petrolatum (250 and disorders, uveitis and atherosclerosis; itch/pruritus Such g) are melted at about 75° C. and then a mixture of a as, for example psoriasis; obesity; lipid disorders; cancer, compound of the invention (50 g) methylparaben (0.25 g), blood pressure; spinal cord injury; and renal disorders propylparaben (0.15 g), sodium lauryl Sulfate (10 g), and method comprises administering an effective condition propylene glycol (120 g) dissolved in water (about 370 g) is treating or condition-preventing amount of one or more of added and the resulting mixture is stirred until it congeals. the pharmaceutical compositions just described. Methods of Treatment 0281. As a further aspect of the invention there is pro 0277. The present compounds are used as therapeutic vided the present amine compounds for use as a pharma agents for the treatment of conditions in mammals that are ceutical especially in the treatment or prevention of the causally related or attributable to aberrant activity of the aforementioned conditions and diseases. We also provide P2X, receptor. Accordingly, the compounds and pharmaceu use of a present amine compound in the manufacture of a tical compositions of this invention find use as therapeutics medicament for the treatment or prevention of one of the for preventing and/or treating autoimmune, inflammatory aforementioned conditions and diseases. and cardiovascular conditions in mammals including 0282. Injection dose levels range from about 0.1 mg/kg/ humans. hour to at least 10 mg/kg/hour, all for from about 1 to about 0278 In a method of treatment aspect, this invention 120 hours and especially 24 to 96 hours. A preloading bolus provides a method of treating a mammal susceptible to or of from about 0.1 mg/kg to about 10 mg/kg or more may also afflicted with a condition associated with arthritis, uveitis, be administered to achieve adequate steady state levels. The asthma, myocardial infarction, traumatic brain injury, acute maximum total dose is not expected to exceed about 2 g/day spinal cord injury, inflammatory bowel disease and autoim for a 40 to 80 kg human patient. mune disorders, which method comprises administering an 0283 For the prevention and/or treatment of long-term effective amount of one or more of the pharmaceutical conditions, such as neurodegenerative and autoimmune con compositions just described. ditions, the regimen for treatment usually stretches over 0279. In yet another method of treatment aspect, this many months or years so oral dosing is preferred for patient invention provides a method of treating a mammal Suscep convenience and tolerance. With oral dosing, one to five and tible to or afflicted with a condition that gives rise to pain especially two to four and typically three oral doses per day responses or that relates to imbalances in the maintenance of are representative regimens. Using these dosing patterns, basal activity of sensory nerves. The present amines have each dose provides from about 0.01 to about 20 mg/kg of the use as analgesics for the treatment of pain of various geneses compound of the invention, with preferred doses each pro or etiology, for example acute, inflammatory pain (such as viding from about 0.1 to about 10 mg/kg and especially pain associated with osteoarthritis and rheumatoid arthritis); about 1 to about 5 mg/kg. various neuropathic pain syndromes (such as post-herpetic 0284 Transdermal doses are generally selected to pro neuralgia, trigeminal neuralgia, reflex sympathetic dystro vide similar or lower blood levels than are achieved using phy, diabetic neuropathy, Guillian Barre syndrome, fibro injection doses. myalgia, phantom limb pain, post-masectomy pain, periph eral neuropathy, HIV neuropathy, and chemotherapy 0285) When used to prevent the onset of a neurodegen induced and other iatrogenic neuropathies); Visceral pain, erative, autoimmune or inflammatory condition, the com (such as that associated with gastroesophageal reflex dis pounds of this invention will be administered to a patient at ease, irritable bowel syndrome, inflammatory bowel disease, risk for developing the condition, typically on the advice and pancreatitis, and various gynecological and urological dis under the Supervision of a physician, at the dosage levels orders), dental pain and headache (such as migraine, cluster described above. Patients at risk for developing a particular headache and tension headache). condition generally include those that have a family history of the condition, or those who have been identified by 0280. In additional method of treatment aspects, this genetic testing or screening to be particularly Susceptible to invention provides methods of treating a mammal Suscep developing the condition. tible to or afflicted with neurodegenerative diseases and disorders such as, for example Parkinson's disease, multiple 0286 The compounds of this invention can be adminis Sclerosis; diseases and disorders which are mediated by or tered as the sole active agent or they can be administered in result in neuroinflammation Such as, for example traumatic combination with other agents, including other compounds brain injury, and encephalitis; centrally-mediated neuropsy that demonstrate the same or a similar therapeutic activity, chiatric diseases and disorders such as, for example depres and that are determined to safe and efficacious for such sion mania, bipolar disease, anxiety, Schizophrenia, eating combined administration. US 2008/0039478 A1 Feb. 14, 2008 20

General Synthetic Procedures (21% in EtOH) (112.6 mL, 299 mmol). The reaction was 0287. The bicycloheteroaryl compounds of this invention heated at 60° C. overnight and monitored for completion via can be prepared from readily available starting materials lcms and TLC (DCM:MeOH: 95:5). Additional ethyl using the following general methods and procedures. It will 1-benzyl-3-oxopiperidine-4-carboxylate (2 g. 6.6 mmol) be appreciated that where typical or preferred process con was added after 12 h with continued heating at 60° C. The ditions (i.e., reaction temperatures, times, mole ratios of reaction was complete after 4 has indicated by LCMS. The reactants, solvents, pressures, etc.) are given, other process cooled reaction was reduced in vacuo and the residue was conditions can also be used unless otherwise Stated. Opti treated concentrated HCl (300 mL) and stirred overnight at mum reaction conditions may vary with the particular reac room temperature. The solvents were removed under tants or solvent used, but Such conditions can be determined vacuum and the resulting solids treated with EtOH (300 by one skilled in the art by routine optimization procedures. mL), stirred for 15 minutes, and then filtered. The mother 0288 Additionally, as will be apparent to those skilled in liquor was discarded and the precipitate dried in a vacuum the art, conventional protecting groups may be necessary to oven affording 7-benzyl-5,6,7,8-tetrahydropyrido3,4-dpy prevent certain functional groups from undergoing undes rimidin-4-ol (44 g) as the tri-HCl salt which was used ired reactions. The choice of a suitable protecting group for directly in the next step. a particular functional group as well as Suitable conditions for protection and deprotection are well known in the art. 0293 LCMS (ESI) m/z 242.2 M+H" For example, numerous protecting groups, and their intro duction and removal, are described in T. W. Greene and P. 0294 H NMR (300 MHz CDOD) & 7.98 (s, 1H), G. M. Wuts, Protecting Groups in Organic Synthesis, Sec 7.35-7.32 (m, 5H), 3.72 (s. 2H), 3.41-3.40 (m, 2H), 2.75 (t ond Edition, Wiley, New York, 1991, and references cited 2H), 2.57 (m, 2H). therein. 0289. The following schemes are presented with details b) 7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido 3,4- as to the preparation of representative bicycloheteroaryls dpyrimidine that have been listed hereinabove. The compounds of the invention may be prepared from known or commercially 0295) available starting materials and reagents by one skilled in the art of organic synthesis. O 0290 The intermediate heteroaryl amines, heteroaryl acids, acid chlorides (Intermediate 1-16) can be obtained NH POCl3, reflux using synthetic methods given below. He N 2 4h Intermediate 1 N oHCI Preparation of 7-benzyl-5,6,7,8-tetrahydropyrido3. C 4-dipyrimidin-4-amine a) 7-Benzyl-5,6,7,8-tetrahy dropyrido3.4dpyrimidin-4(3H)-one hydrochloride 0291) N r2 N

O 0296 7-Benzyl-5,6,7,8-tetrahydropyrido 3,4-dipyrimi O din-4-ol.HCl (35.5 g., 0.101 mol) was added in a 250 ml round bottom flask, equipped with a reflux condenser, fol lowed by the addition of POCl (100.5 g., 0.655 mol). The CuorO resulting mixture was refluxed for 4 h under argon, cooled HN1SNH NaOEt, EtOH, --- to room temperature, and diluted with DCM (200 mL). The •CH3OH 0° C.-RT, 28 h crude reaction was then poured into ice-cold water (200 mL) O and stirred overnight at 0°C. The layers were separated and the pH of aqueous layer was carefully adjusted to 7 via the NH addition of satd. NaHCO. The aqueous layer was extracted with DCM (3x100 mL) and the combined organics washed N 2 with satd. NaHCO (50 mL), dried over anhyd. NaSO, and N reduced in vacuo to yield 7-benzyl-4-chloro-5,6,7,8-tetrahy o3HCI dropyrido 3,4-dipyrimidine as a viscous dark brown oil (21 g, 80%). 0292 Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (30 0297 LCMS (ESI) m/z 260.1 M+H" g, 101 mmol) was combined with formamidine aceate (10.5 g, 101 mmol) and EtOH (450 mL) in a 2-liter flask. The 0298 H NMR (300 MHz CDOD) & 8.68 (s, 1H), resulting mixture was stirred at 0°C. and treated with NaOEt 7.36-7.29 (m, 5H), 3.75 (s. 2H), 3.65 (s. 2H), 2.86 (s, 4H). US 2008/0039478 A1 Feb. 14, 2008

c) 7-Benzyl-5,6,7,8-tetrahydropyrido 3,4-dpyrimi din-4-amine -continued OMe 0299) n C N NaH, THF N e rt N SN NH, MeOH, Ho N 2 100° C., 15 h N O NH2 C

O NH

N r 2 N 0300 7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido 3,4-d 0305) To a solution of 7-benzyl-4-methoxy-5,6,7,8-tet pyrimidine (9.83 g, 38 mmol) was dissolved in solution of rahydropyrido 3,4-dpyrimidine and 7-benzyl-5,6,7,8-tet NH in MeOH (7N, 60 mL) in a re-sealable tube. The sealed rahydropyrido3,4-dpyrimidin-4-amine (1.2 g., 5 mmol tube was heated at 100° C. for 21 h. The reaction was cooled (based on 5)) in THF (15 mL) was added NaH (60% in to room temperature and kept standing at room temperature mineral oil) (0.04 g, 1.67 mmol) and the resulting mixture for 48 h which led to the precipitation of the desired product was stirred for 1 h. 1-adamant-1-yl-acetyl chloride (1.11 g, 7-benzyl-5,6,7,8-tetrahydropyrido3,4-dipyrimidin-4- 0.86 mmol) was then added to the reaction mixture and the amine.(5.1 g, 56%). The mother liquor was evaporated and reaction stirred at room temperature for 18 h. The reaction dried under vacuum to yield a mixture of 4.12 g of desired was monitored by LCMS and treated with an additional product together with the side product 7-benzyl-4-methoxy amount each of NaH (0.3 g) and 1-adamant-1-yl-acetyl 5,6,7,8-tetrahydropyrido 3,4-dpyrimidine. chloride (0.3 g). Upon completion the reaction mixture was treated with saturated. NaHCO (50 mL) and extracted with 0301 LCMS (ESI) m/z 241.3 M+H" EtOAc (2x50 ml). The combined organics were dried over anhydrous NaSO, filtered and concentrated to yield 0302) H-NMR (300 MHz, CDC1) & 8.33 (s, 1H), 7.28 2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8-tetrahydro-pyrido (m, 5H), 4.86 (br's, 2H), 3.69 (s. 2H), 3.55 (s. 2H), 2.79 (t, 3,4-dpyrimidin-4-yl)-acetamide (2.06 g) 2H), 2.48 (t, 2H). 0306 LCMS (ESI) m/z. 417.5 M+H" 0303 °C NMR (75 MHz, CDC1,) & 1612, 161.1, 155.8, 137.6, 129.3, 128.6, 127.5, 110.2, 62.6, 57.6, 49.5, 23.2. 0307 'H-NMR (300 MHz, CDC1) & 8.68 (s, 1H), 7.50 (s, 1H), 7.30 (m, 5H), 3.70 (s, 4H), 2.74 (s, 4H), 2.30 (s. 2H), Intermediate 2 1.98 (br's, 3H), 1.65 (m, 12H). b) Representative Synthesis of Compound 6 Preparation of 2-adamantan-1-yl-N-(5,6,7,8-tetrahy dro-pyrido 3,4-dpyrimidin-4-yl)-acetamide Method 2-Adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido3,4- A dpyrimidin-4-yl)-acetamide Representative Synthesis of Compound 5 0308) a) 2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8-tetrahy dro-pyrido3,4-dipyrimidin-4-yl)-acetamide

0304 O NH NN He N 2 -- AcOH, rt, 15 h US 2008/0039478 A1 Feb. 14, 2008 22

dropwise in 30 minutes via a syringe. The reaction mixture -continued was stirred at 10-15° C. for 2 more hours with additional BF, etherate was added until complete consumption of the starting bromide before pouring onto ice. The water was adjusted to pH=9 followed by extraction with ether. The O aqueous layer was acidified with HCl to pH=3 followed by extraction with ether, dried, removal of organic solvent to NH give Solid product, which was taken on directly to the next step. r 0314 HNMR (300 MHz, CDC1), 2.13 (s. 2H), 1.74 (s, insul 1H), 1.02-1.38 (m, 12H), 8 0.82(s, 6H),

0309 To a solution of 2-adamantan-1-yl-N-(7-benzyl-5, 6,7,8-tetrahydro-pyrido3,4-dipyrimidin-4-yl)-acetamide in SOCl. glacial acetic acid (15 mL) in a 250 ml round bottom flask He was added 10% Pd/C (0.45 g). The resulting mixture was Toluene, DMF stirred for 15 h under an atmosphere of hydrogen (via a HO balloon), which was introduced after evacuation of air from the reaction vessel. The reaction was then filtered over celite, washed with EtOAc (20 mL) and the filtrate concentrated under reduced pressure. The residue was re-dissolved on EtOAc (50 mL) and stirred with aq. 10% NaOH solution (50 mL) for 1 h. The layers were separated and the aqueous layer C washed with EtOAc (5x50 mL). The combined organics were dried over anhyd. NaSO filtered and concentrated to yield 2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido 3,4-d pyrimidin-4-yl)-acetamide (0.68 g, 2.1 mmol, 87%) as a tan (3,5-Dimethyl-adamantan-1-yl)-acetyl chloride colored solid. 0315 Into a flask containing 3,5-dimethyl-adamantan-1- 0310 LCMS (ESI) m/z 327.3 M+H" yl)-acetic acid in toluene (50 ml) was added SOCl and 1 0311 H-NMR (300 MHz, CDC1) & 8.70 (s, 1H), 7.73 drop of DMF. Reaction was then heated to 60° C. for 1 hour. (s, 1H), 4.06 (s. 2H), 3.13 (t, J=5.7 Hz, 2H), 2.66 (t, 2H), After removal of solvent and co-evaporation with toluene (2 2.29 (s. 2H), 1.99 (brs, 3H), 1.71 (m. 12H). ml), the crude product was used without further purification. Intermediate 3 Intermediate 4 Preparation of Preparation of (3,5-Dimethyl-adamantan-1-yl)-acetyl chloride (3,5,7-Trimethyl-adamantan-1-yl)-acetyl chloride 0312 0316)

C H2SO4 -- Her C BFEt2O Br

O 0317 3.5,7-trimethyl adamantane-1-carboxylic acid was converted to it’s acid chloride per the procedure described HO for 3,5-dimethyl-adamantan-1-yl)-acetic acid. It was then homologated to the corresponding benzyl ester via the procedure described in Tetrahedron Letters, 1980, 21, 4461 4462. The benzyl ester was converted to the acid by standard (3.5-Dimethyl-adamantan-1-yl)-acetic acid hydrogenation conditions of 10% Pd/C in MeOH/ EtOAc::1:1. The acid was then converted to the acid chlo 0313 The bromide (24.32 g, 100 mmol) in dichloroet ride via standard treatment with thionyl chloride at reflux for hane was added into 90% HSO solution at 10° C. (cold 1 to 2 hours. Excess reagent was azeotropically removed water bath). The reaction mixture was stirred at 10° C. for with hexanes and the resulting acid chloride was used 1 hr. Then BF, etherate (2.84 g. 20 mmol) was added without further purification. US 2008/0039478 A1 Feb. 14, 2008 23

Intermediate 5 -continued Preparation of Intermediate 7 2-Adamantan-1-yl-2-methyl-propionyl chloride 0318)

C

0323 Prepared in an analogous manner to that for 2-Ada mantan-1-yl-2-methyl-propionyl chloride. Intermediate 5.

2-Adamantan-1-yl-2-methyl-propionic acid methyl Method B ester Representative synthesis of Compound 341 0319. The methyl ester was prepared via the route described in Tetrahedron Letters, 1978, 17, 1455-1458. Thus N-(7-Benzyl-5,6,7,8-tetrahydro-pyrido 3,4-dpyrimi 1-bromoadamantane (6.17 g. 28.7 mmol), (1-methoxy-2- din-4-yl)-2-(3,5-dimethyl-adamantan-1-yl)-aceta methylprop-1-enyloxy)-trimethylsilane (5.5 g. 31.6 mmol), mide and ZnCl (300 mg) in DCM (40 ml) was stirred at rt for 3 days. The reaction was monitored for the disappearance of 0324) the bromide by LCMS and worked up according to the literature reference. NH2 2-Adamantan-1-yl-2-methyl-propionic acid 0320) The methyl ester was dissolved in DMSO (15 ml) -- and treated with NaSMe (6.654g, 9.3 mmol. 2 equiv.) and N heated at 80° C. for 3 h. The reaction was cooled to room temperature and treated with 100 ml of water, extracted with Et2O and the layers were then separated. The aqueous layer was acidified to ph 3 to give 1.07 g of 2-Adamantan-1-yl O 2-methyl-propionic acid as a white Solid. NaH, DMF C rt, 1 h 2-Adamantan-1-yl-2-methyl-propionyl chloride 0321 2-Adamantan-1-yl-2-methyl-propionyl chloride was prepared via treatment with SOCl at reflux for 1 to 2 h. Excess reagent was removed under reduced pressure and the mixture azeotroped with hexanes and the resulting acid O chloride was used without further purification in the next step.

Intermediate 6 and 7 Preparation of 2-Methyl-2-(3,5,7-trimethyl-adaman tan-1-yl)-propionyl chloride and 2-(3,5-dimethyl CuCo adamantan-1-yl)-2-methyl-propionyl chloride 0325 The reaction was performed in DMF under an inert 0322 atmosphere as follows: 7-benzyl-5,6,7,8-tetrahydropyrido 3,4-dpyrimidin-4-amine (30 mg, 0.012 mmol) in 1 ml of Intermediate 6 DMF was treated with 15 mg of NaH and the result stirred at rt for 10 minutes. 40 uL intermediate 3 was added and stirring continued for 1 h at rt. After quenching with water (8 ml) and Satd. NaHCO (10 ml) the resulting mixture was extracted with EtO. The combined organics were concen C trated under reduced pressure to give the crude product, which was purified by HPLC to give the pure product (19 mg, 0.042 mmol) in a 35% yield. US 2008/0039478 A1 Feb. 14, 2008 24

Representative Synthesis of Compound 334 Compound 339 Adamantane-1-carboxylic acid (7-benzyl-5,6,7,8- 0333 Prepared by reacting 7-benzyl-5,6,7,8-tetrahydro tetrahydro-pyrido3,4-dipyrimidin-4-yl)-amide pyrido 3,4-dpyrimidin-4-amine with Intermediate 5. 0326 Compound 341 N 0334 Prepared by reacting 7-benzyl-5,6,7,8-tetrahydro pyrido 3,4-dpyrimidin-4-amine with Intermediate 3. n N -- N 2 Compound 343 N 0335) Prepared by reacting 7-benzyl-5,6,7,8-tetrahydro O CHCI, DIPEA pyrido 3,4-dpyrimidin-4-amine with Intermediate 7. u-wave 160° C. 600s C Her Compound 344

O 0336 Prepared by reacting 7-benzyl-5,6,7,8-tetrahydro pyrido3,4-dpyrimidin-4-amine with Intermediate 4. HN Compound 345 0337 Prepared by reacting 7-benzyl-5,6,7,8-tetrahydro CuOC pyrido 3,4-dpyrimidin-4-amine with Intermediate 6. Compound 346 0327 In a 20 ml microwave vessel was added 7-benzyl 0338 Prepared by reacting 7-benzyl-5,6,7,8-tetrahydro 5,6,7,8-tetrahydro-pyrido3,4-dipyrimidin-4-ylamine (1.5 g. pyrido 3,4-dpyrimidin-4-amine with 3,5,7-trimethyl-ada 6.3 mmole) in 7.0 ml of chloroform, diisopropylethylamine mantane-1-carbonyl chloride. (2.2 ml, 12.6 mmole) and 1-adamantane carbonylchloride (2.51 g, 12.6 mmole). The reaction was heated at 160°C. for 0339. The following examples were prepared by debezy 7.0 minutes in a microwave. After completion the solvent lation of the corresponding N-benzyl derivatives and in a was evaporated and the residue was dissolved in EtOAc and manner analogous to that given for the preparation of washed with sat. NaHCO, washed with brine and dried over 2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido 3,4-dipyri sodium sulphate. The solvents were removed under reduced midin-4-yl)-acetamide (Compound 6). pressure and the residue was chromatographed using chlo roform (100%) to give the desired product as a white solid Compound 11 (1.06 g). 0340 Prepared by debenzylation of Compound 9. 0328 ESI-MS m/z 403 M+H". 0329. The following examples were prepared in a manner Compound 12 analogous to that given for Method A or Method B using 7-benzyl-5,6,7,8-tetrahydropyrido3,4-dipyrimidin-4-amine 0341 Prepared by debenzylation of Compound 10. and the appropriate intermediate acid or acid chloride as listed in the table below. Compound 25 Compound 9 0342 Prepared by debenzylation of Compound 24. 0330 Prepared by reacting 7-benzyl-5,6,7,8-tetrahydro pyrido3,4-dpyrimidin-4-amine with cyclohexylacetyl Intermediate 8 chloride. 2-Adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido3,4- Compound 10 dpyrimidin-4-yl)-isobutyramide 0331 Prepared by reacting 7-benzyl-5,6,7,8-tetrahydro 0343 Prepared by debenzylation of Compound 339. pyrido3,4-dpyrimidin-4-amine with cycloheptylacetyl chloride. Intermediate 9 Compound 24 2-(3,5-Dimethyl-adamantan-1-yl)-N-(5,6,7,8-tet 0332 Prepared by reacting 7-benzyl-5,6,7,8-tetrahydro rahydro-pyrido3,4-dipyrimidin-4-yl)-acetamide pyrido 3,4-dpyrimidin-4-amine with 3-(3-methoxyphenyl )propanoyl chloride. 0344 Prepared by debenzylation of Compound 341 US 2008/0039478 A1 Feb. 14, 2008 25

Intermediate 10 -continued Preparation of Adamantane-1-carboxylic acid (5,6, 7,8-tetrahydro-pyrido 3,4-dpyrimidin-4-yl)-amide

0345) O O r NH HN Pd(OH)-C, O n N H2(g) NN sul N N O 0349 2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido3, 4-dipyrimidin-4-yl)-acetamide (0.05 g, 0.153 mmol) and HN 2,3-dihydrobenzob.14dioxine-6-carbaldehyde (0.0504g, 0.306 mmol) in DCE (1 mL) was treated with NaBH(OAc), (0.065 g, 0.306 mmol) and the resulting mixture agitated r overnight at room temperature. The crude reaction was H1 - N2 purified by HPLC affording the desired compound. 0350 LCMS (ESI) m/z 474.9 M+H" 0346 Adamantane-1-carboxylic acid (7-benzyl-5,6,7,8- tetrahydro-pyrido3,4-dpyrimidin-4-yl)-amide (1.1 g, 2.64 0351 NMR (300 MHz, CDOD): 8 8.65 (s, 1H), 6.86 mmole) was suspended in 30 ml of methanol. To the mixture 6.79 (m, 3H), 4.21 (s, 4H), 3.62 (m, 4H), 2.76 (s, 4H), 2.22 was added palladium hydroxide on carbon (20% wit, 0.41 g) (s. 2H), 1.97 (brs, 3H), 1.74-1.64 (m, 12H). and the reaction was shaken under 60 PSI of hydrogen gas 0352. The reductive alkylation products with other alde for 16 hrs. The mixture was filtered through celite and the hydes and ketones to obtain specified examples in Table filtrate was concentrated to give the desired product as an off 1 A-1E were obtained in an analogous manner by using white solid (0.8 g). 2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido 3,4-dipyri midin-4-yl)-acetamide, or the appropriate corresponding 0347 ESI-MS m/z. 313 M+H". amine (0.05 g, 0.153 mmol) and 2 mmol of the correspond General methods for the preparation of substituted ing aldehyde or ketone and reducing agent. 5,6,7,8-tetrahydropyrido3,4-dipyrimidin-4-yl aceta Method D mides Method C Representative Example 0348 Representative Synthesis of Compound 46 Compound 361 0353)

O

NH --

HN O -- HN r2 N HN r e r N O F NaBH(OAc)3 -- DIPEA, DCE, rt, 5h DCE, rt --- O C

F O US 2008/0039478 A1 Feb. 14, 2008 26

-continued -continued C

O Hess

HN O F n- N N O F O HN 0354) To a solution of 1,1-dimethyl-2-adamantyl-N-(5,6, NN 7,8-tetrahydropyrido 3,4-dpyrimidin-4-yl)acetamide (29 mg, 0.082 mmol) in anhydrous dichloroethane (2 mL) was O N 2 added diisopropylethylamine (0.04 mL, 0.24 mmol) and N 2,6-difluorobenzoyl chloride (21.7 mg, 0.12 mmol) at room temperature. After stirring at room temperature for 5 h, the reaction was quenched with water (0.5 mL) and evaporated to dryness. The dry residue was purified by prep-HPLC directly and afforded desired product. 0359. In one well of a 96-well polypropylene reaction 0355 LCMS (ESI) m/z. 495.3 M+H" plate was added 2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8-tet rahydropyrido 3,4-dpyrimidin-4-yl)acetamide (3.27 mg, 10 0356) NMR (300 MHz, CDC1): 8 8.80 (s, 0.5H), 8.72 (s, umol) in 100 ul of anhydrous chloroform. To the reaction 0.5H), 7.64 (m, 1H), 7.37 (m, 1H), 6.97 (m, 2H), 5.01 (s, was added benzoyl chloride (2.1 mg, 15umol), followed by 1H), 4.56 (s, 1H), 4.04 (t, 1H), 3.57 (t, 1H), 2.85 (t, 1H), 2.75 diisopropylethylamine (5.2 mg, 40 Limol). The reaction plate (t, 1H), 2.03 (brm, 3H), 1.57-1.73 (m, 12H), 1.27 (s, 3H), was heated at 50° C. for 15 minutes and the solvent was 1.24 (s, 3H). evaporated. The residue was dissolved in DMSO and puri 0357 Specific representative examples of N-benzoyland fied using LC-MS based purification. N-sulfonyl derivatives of 1,1-dimethyl-2-adamantyl-N-(5,6, 0360 ESI-MS m/z 431 M+H". 7,8-tetrahydropyrido 3,4-dpyrimidin-4-yl)acetamide given 0361 Specified examples of Table 1A-1E compounds in Table 1 A-1E can be or were prepared in an analogous manner by using either 1,1-dimethyl-2-adamantyl-N-(5,6,7, were prepared in an analogous manner using the appropriate 8-tetrahydropyrido 3,4-dpyrimidin-4-yl)acetamide (29 mg, acyl chloride 0.082 mmol) or 2-(3,5-dimethyl)adamantyl-N-(5,6,7,8-tet rahydropyrido3,4-dipyrimidin-4-yl)acetamide (26 mg. Method F 0.073 mmol), and 0.12 mmol of the corresponding acyl A parallel synthetic method for N-Sulphonylation chlorides and sulfonyl chlorides. of 2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8tetrahydro pyrido3,4-dpyrimidin-4-yl)acetamide Method E A parallel synthetic method for N-benzoylation of Representative Example 2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8-tetrahydro pyrido3,4-dpyrimidin-4-yl)acetamide Compound 143 0358 Representative synthesis of Compound 220 0362

O -- N

N r2 N US 2008/0039478 A1 Feb. 14, 2008 27

-continued -continued O O EtOH, AcOH Si-BHCN \-Cl -wave 130° C., 300s Y. —- He

O N

O N r 2 S1 N

O

0363. In one well of a 96-well polypropylene reaction plate was added 2-2-Adamantan-1-yl-N-(7-benzenesulfo nyl-5,6,7,8-tetrahydropyrido3,4-dipyrimidin-4-yl)aceta mide (3.27 mg, 10umol) in 100 ul of anhydrous chloroform. 0367. In a 2.0 ml-wave vessel was added 2-Adamantan To the reaction was added benzenesulphonyl chloride (2.64 1-yl-N-(7-benzenesulfonyl-5,6,7,8-tetrahydropyrido3,4-d mg, 15 umol), followed by diisopropylethylamine (5.2 mg, pyrimidin-4-yl)acetamide (3.27 mg, 10 mol) in 600 ul of 40 umol). The reaction plate was heated at 50° C. for 15 absolute ethanol. To the reaction was added benzaldehyde minutes and the solvent was evaporated. The residue was (2.1 mg, 15 mol), followed by acetic acid (601) and silica dissolved in DMSO and purified using LC-MS based puri bound sodium cyanoborohydride (15 mg, 15 mol). The fication reaction was heated at 120° C. for 5 minutes and the solvent 03.64 ESI-MS m/z 467 M+H". was evaporated. The residue was dissolved in DMSO and purified using LC-MS based purification. 0365 Specified examples of Table 1A-1E compounds were prepared in an analogous manner using the appropriate 0368 ESI-MS m/z. 417 M+H". sulphonyl chloride. 0369 Specified examples of Table 1A-1E compounds Method G were prepared in an analogous manner using the appropriate aldehyde A parallel synthetic method for N-benzylation of 2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8-tetrahydro Method H pyrido3,4-dpyrimidin-4-yl)acetamide A parallel synthetic method for N-benzoylation of Representative Example Adamantane-1-carboxylic acid (5,6,7,8-tetrahydro pyrido3,4-dpyrimidin-4-yl)-amide Compound 5 Representatitive Example 0366) Compound 394 0370

O

N ulNN -- US 2008/0039478 A1 Feb. 14, 2008 28

-continued -continued C O

O He HN

O OM-N-- r N \ N O O O N r2 N 0375. In one well of a 96-well polypropylene reaction plate was added 2-adamantane-1-carboxylic acid (5.6.7.8- tetrahydro-pyrido3,4-dpyrimidin-4-yl)-amide (3.12 mg. 10 umol) in 100 ul of anhydrous chloroform. To the reaction was added benzenesulphonyl chloride (2.64 mg, 15 umol), followed by diisopropylethylamine (5.2 mg, 40 umol). The 0371. In one well of a 96-well polypropylene reaction reaction plate was heated at 50° C. for 15 minutes and the plate was added adamantane-1-carboxylic acid (5.6.7.8- solvent was evaporated. The residue was dissolved in tetrahydro-pyrido3,4-dpyrimidin-4-yl)-amide (3.12 mg. DMSO and purified using LC-MS based purification. 10 umol) in 100 ul of anhydrous chloroform. To the reaction was added benzoyl chloride (2.1 mg, 15umol), followed by 0376 ESI-MS m/z 453 M+H". diisopropylethylamine (5.2 mg, 40 umol). The reaction plate was heated at 50° C. for 15 minutes and the solvent was 0377 Specified examples of Table 1A-1E compounds evaporated. The residue was dissolved in DMSO and puri were prepared in an analogous manner using the appropriate fied using LC-MS based purification. sulphonyl chloride.

0372 ESI-MS m/z. 417 M+H". Method J 0373 Specified examples of Table 1A-1E compounds were prepared in an analogous manner using the appropriate A parallel synthetic method for N-benzylation of acyl chloride Adamantane-1-carboxylic acid (5,6,7,8-tetrahydro pyrido3,4-dpyrimidin-4-yl)-amide Method I Representative Example A parallel synthetic method for N-Sulphonylation of Adamantane-1-carboxylic acid (5,6,7,8-tetrahy dro-pyrido3,4-dipyrimidin-4-yl)-amide Compound 334 0378) Representative Example Compound 481 0374) O

O HN --

HN N r2 r -- N N e O EtOH, AcOH Si-BHCN \ -Cl -wave 130° C., 300s Y - He US 2008/0039478 A1 Feb. 14, 2008 29

desired product. The crude reaction mixtures were poured -continued into water (200 mL), resulting in the precipitation of a brown solid, which was filtered and dried. The aqueous filtrate was O extracted with DCM (2x100 mL). The organic layer was filtered through a Horizon Technology Dry Disk and con centrated. The crude solids and oil were purified via column HN chromatography first with DCM/MeOH (20:1) of 7-benzyl 5,6,7,8-tetrahydropyrido 3,4-dpyrimidine-4-carbonitrile. NN (2.1 g, 55%) - - 0384 ESI-MS m/z 251.3 M+H". N 0385 H NMR (300 MHz, CDOD) & 8.99 (s, 1H), 0379. In a 2.0 ml microwave vessel was added adaman 7.4-7.3 (m, 5H), 3.79 (s. 2H), 3.73 (s. 2H), 3.05 (t, 2H), 2.91 tane-1-carboxylic acid (5,6,7,8-tetrahydro-pyrido 3,4-dpy (t, 2H). rimidin-4-yl)-amide (3.12 mg, 10 umol) in 600 ul of abso lute ethanol. To the reaction was added benzaldehyde (2.1 b) Methyl 7-benzyl-5,6,7,8-tetrahydropyrido 3,4-d mg, 15 umol), followed by acetic acid (60 ul) and silica pyrimidine-4-carboxylate bound sodium cyanoborohydride (15 mg, 15 umol). The reaction was heated at 120° C. for 5 minutes and the solvent 0386 was evaporated. The residue was dissolved in DMSO and purified using LC-MS based purification 0380 ESI-MS m/z 403 M+H". 0381 Specified examples of Table 1A-1E compounds n N sat. HCI/MeoH, uW were prepared in an analogous manner using the appropriate 70° C. 1 h aldehyde. N e N Intermediate 11 Preparation of 7-benzyl-5,6,7,8-tetrahydropyrido3. O On 4-dpyrimidine-4-carboxylic acid n N a) 7-Benzyl-5,6,7,8-tetrahydropyrido 3,4-dpyrimi dine-4-carbonitrile 1 - N 0382) 0387 7-benzyl-5,6,7,8-tetrahydropyrido3,4-dipyrimi dine-4-carbonitrile (2.1 g, 8.38 mmol) was dissolved in satd. C solution of HCl MeOH (15 mL) in a microwave tube. The vial was heated in a microwave reactor at 70° C. for 1 h. The s Zn(CN)2, Pd(PPh3)4 reaction was cooled and depressurized and concentrated DMF, W 160° C., N 2 50 min under reduced pressure. The crude oil was dissolved in N MeOH followed by removal of MeOH under reduced pres sure to assist with the remove of excess HC1. The red-brown CN oil was dissolved in minimal amount of water (10 mL) and added to an ice cold sat. NaHCO solution (200 mL). The aqueous layer was extracted with DCM (3x100 mL). The SN combined organic layers were then filtered through a Hori Zon Technologies Dry Disk and concentrated. The resulting Out Ne red-brown oil was purified by flash chromatographed using DCM/MeOH (20:1) as elutant. The pure fractions were combined, treated with norite, filtered through a pad of celite 0383 Four 10-20 mL microwave vials were each charged and the filtrate concentrated to afford methyl 7-benzyl-5.6, with 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido 3,4-dpy 7,8-tetrahydropyrido 3,4-dpyrimidine-4-carboxylate (1.01 rimidine (1 g, 4 mmol), Pd(PPh.) (500 mg, 0.4 mmol) and Zn(CN) (300 mg, 2 mmol) were suspended in dry DMF (7 g, 42.3%.) mL). These sealed suspensions were then heated at 160° C. 0388 ESI-MS m/z 284.3 M+H". for 50 min in a microwave reactor. After cooling the reaction mixture an aliquot was taken and the sample tested by 0389) H NMR (300 MHz, CDOD) & 8.94 (s, 1H), LCMS. The reaction showed 100% conversion of 7-benzyl 7.4-7.3 (m, 5H), 3.96 (s.3H), 3.76 (s. 2H), 3.73 (s. 2H), 3.15 4-chloro-5,6,7,8-tetrahydropyrido3,4-dipyrimidine tO (t, 2H), 2.82 (t, 2H), US 2008/0039478 A1 Feb. 14, 2008 30

c) 7-Benzyl-5,6,7,8-tetrahydropyrido 3,4-dpyrimi dine-4-carboxylic acid -continued 0390)

NN 10% NaOHA MeOH 859 C., 1 h N 2 N

0395. In a 2-dram vial, intermediate 11 (0.5 g, 1.85 mmol) was dissolved in DMF (1 mL) with 1-adamanty1 methylamine (0.37 g, 2.24 mmol) and HATU (1.2 g, 2.8 mmol) followed by DIEA (300 uL., 2.79 mmol) was added to the mixture. The vial was sealed and placed on an orbital shaker for 16 h. The reaction mixture was diluted with DCM (50 mL). The organic layer was washed with sat. NaHCO 0391) Methyl 7-benzyl-5,6,7,8-tetrahydropyrido 3,4-d solution (1x25 mL) and water (1x25 mL). The organic layer was filtered through a Horizon Technologies Dry Disk and pyrimidine-4-carboxylate (0.2g, 0.705 mmol) was dissolved concentrated. The crude product was purified by column in MeOH (10 mL). 10% NaOH solution (1.5 mL) was chromatography to afford 7-benzyl-N-adamantylmethyl-5, added. The solution was heated at 85° C. for 1 h. Solvent 6,7,8-tetrahydropyrido 3,4-dpyrimidine-4-carboxamide was removed under reduced pressure. The aqueous. layer (0.048 g 6.2%) which was taken on to the next step without was acidified to ca. pH 4. The aqueous layer was then further purification. extracted with DCM (2x50 mL) to remove organic impuri ties. The acidic aqueous layer was dried on the lyophilizer. 0396 ESI-MS m/z 417.1 M+H". The resulting solids were washed with MeOH (10 mL) and 0397) 'H NMR (300 MHz, CDOD) & 8.91 (s, 1H), filtrate concentrated to give 7-benzyl-5,6,7,8-tetrahydropy 7.4-7.3 (m, 5H), 3.75 (s. 2H), 3.7 (s. 2H), 3.25 (t, 2H), 3.08 rido3,4-dipyrimidine-4-carboxylic acid (0.173 g, 0.642 (s. 2H), 2.81 (t, 2H), 1.98 (s, 3H), 1.78-1.6 (m, 12H). mmol, 91%) as a brown oil. The resulting product was used Intermediate 12 without further purification. Preparation of 1-(aminomethyl)-3,3-dimethylcyclohexanol 0392) ESI-MS m/z 270.3 M+H". hydrochloride 0393) 'H NMR (300 MHz, CD,OD) & 8.75 (s, 1H), 0398 7.4-7.3 (m, 5H), 3.74 (s. 2H), 3.65 (s. 2H), 3.00 (t, 2H), 2.82 (t, 2H). HO NH2 Preparation of Compound 17 7-Benzyl-N-adamantylmethyl-5,6,7,8-tetrahydropy rido3,4-dipyrimidine-4-carboxamide 0394) H-Cl

O OH 0399 Prepared by standard LAH reduction in THF at 0° C. using 1.49 g (9.74 mmol) of 1-hydroxy-3,3-dimethylcy clohexanecarbonitrile and 740 mg (19.48 mmol) of LAH. NN -- The mixture was stirred at room temperature overnight. The mixture was quenched with 740 ul of water and 740 ul of sulN 15% methanol in water, stirred for 2 hours and then filter NH2 ered. The filtrate was washed with EtOAc, concentrated under reduced pressure and dried under high vacuum. The dark viscous oil was taken up in 50 ml of EtOAc and was HATU, DIEA treated with 20 ml of 4M HCl solution in 1,4-dioxane DMF, rt followed by 10% MeOH and then heated to ensure disso lution. Upon cooling to room temperature followed by further cooling to -78° C. 1 g (73%) of the recrystallized HCl salt of 1-(aminomethyl)-3,3-dimethylcyclohexanol was obtained. US 2008/0039478 A1 Feb. 14, 2008

Intermediates 13, 14 and 15 -continued Preparation of 1-(aminomethyl)cycloheptanol, (1-p-tolylcyclohexyl)methanamine and cycloheptylmethanamine H O N 04.00 NN Intermediate 13 is 1 - N

0404 In a round bottom flask, 7-Benzyl-5,6,7,8-tetrahy dro-pyrido3,4-dpyrimidine-4-carboxylic acid(adamantan HN 1-ylmethyl)-amide (1.15 g, 2.74 mmol) was dissolved in glacial acetic acid (10 mL) with stirring and 10% Pd/C (417 mg) was added. The Suspension was stirred under an atmo Intermediate 14 sphere of H for 16 h. By LCMS and TLC (DCM NH2 :MeOH:20:1), no starting material appeared to be present. The desired m/z was observed at 327.3 (M--H). The reaction mixture was then filtered through a pad of celite. The filtrate was concentrated. The resulting oil was re-dissolved in EtOAc (50 mL) with stirring. A 10% NaOH solution (50 mL) was added. The mixture was stirred at RT for 1 h. The layers were separated and the aqueous layer was extracted Intermediate 15 with EtOAc (3x50 mL). The combined organic layers were HO NH2 filtered through a Horizon Technologies Dry Disk and con centrated. The crude oil was chromatographed using DCM/ MeOH (0-30% gradient) as elutant affording 0.133 g of the title compound. 04.05 ESI-MS m/z 327.3 M+H". 0406) "H NMR (300 MHz, CDOD) & 8.96 (s, 1H), 4.13 04.01 The title intermediates were prepared in an analo (s. 2H), 3.3-3.2 (m, 4H), 3.07 (s. 2H), 1.98 (s.3H), 1.79-1.6 gous manner to that for 1-(aminomethyl)-3,3-dimethylcy (m. 12H). clohexanol using the appropriate nitrile. Preparation of Compounds 2 and 3 Preparation of Compounds 1, 4, 58, 59 and 60 and 1: 0407. The title compounds were prepared in a manner analogous to that given for intermediate 16 using Com 0402. The title compounds were prepared in a manner pounds 4 and 1 as starting materials, respectively. analogous to that given for Compound 17 using the Inter mediate 11 and the appropriate amine. Method K 0408 General procedure for the N-benzylation of 5,6,7, Intermediate 16 8-Tetrahydro-pyrido 3,4-dpyrimidine-4-carboxylic acid (adamantan-1-ylmethyl)-amide Preparation of 5,6,7,8-tetrahydro-pyrido3,4-dipyri midine-4-carboxylic acid (adamantan-1-ylmethyl)- Preparation of a representative example Compound amide 137 0403) 04.09

H O N se AcOH, 16h

N r2 N US 2008/0039478 A1 Feb. 14, 2008 32

-continued -continued

O F

H NaBH(OAc)3 He DCE,rt NH

F -N--OH NNe H O N 0414. A solution of 2-adamantan-1-yl-N-(5,6,7,8-tet F F rahydro-pyrido3,4-dipyrimidin-4-yl)-acetamide (0.1 g, 0.306 mmol) and 2-Methoxymethyl-oxirane (0.035 g, 0.398 N r 2 mmol) in i-ProH (5 mL) was stirred at 60° C. for 20 h. The N reaction vessel was allowed to cool to room temperature, opened, and the volatiles were removed under reduced vacuum. The crude product was purified by HPLC to afford 0410. In a 2-dram vial, a solution of 5,6,7,8-Tetrahydro 2-adamantan-1-yl-N-7-(2-hydroxy-3-methoxy-propyl)-5,6, pyrido3,4-dpyrimidine-4-carboxylic acid (adamantan-1- 7,8-tetrahydro-pyrido3,4-dipyrimidin-4-yl)-acetamide ylmethyl)-amide (0.44 g., 0.134 mmol) in DCE was added followed by 2,4-difluorbenzaldehyde (0.26 g., 0.18 mmol). (Compound 13) (0.0134 g., 0.032 mmol, 100%) in 100% The solution was placed on an orbital shaker at room purity as determined by LCMS. ESI-MS m/z 415.5M+H". temperature for 1 h. Sodium triacetoxyborohydride (0.43 g, 0415 H-NMR (300 MHz, CDC1): 8 8.71 (s, 1H), 7.88 0.2 mmol) was added. The mixture was agitated for an (s, 1H), 3.99 (m, 1H), 3.86 (d. 1H), 3.71 (d. 1H), 3.46 (m, additional 16 h at room temperature. LCMS and TLC 2H), 3.40 (s.3H), 2.94 (m. 1H), 2.76 (m, 3H), 2.70-2.55 (m, (DCM:MeOH::20:1), indicated that no starting material 2H), 2.28 (s. 2H), 1.99 (brs, 3H), 1.74-1.65 (m, 12H). remained. The reaction was quenched by the addition of MeOH (0.5 mL). The mixture was then filtered through a Preparation of a Representative Example Compound 23 pad of celite. The pad was subsequently washed with MeOH (2 mL). The filtrate was concentrated and the crude solid was purified via HPLC to yield the title compound (0.0166 g) as a yellow oil. 0411 ESI-MS m/z 453.3 M+H". 0412) H NMR (300 MHz, CDOD) & 8.92 (s, 1H), 7.51 (q, 2H), 6.97, (t, 1H), 3.81 (s. 2H), 3.38 (s. 2H), 3.25 (t, 2H), 3.23 (s. 2H), 2.84 (t, 2H), 1.98 (s, 3H), 1.79-1.6 (m, 12H). 0413 Specified examples of Table 1A-1E compounds were prepared from 5,6,7,8-tetrahydro-pyrido3,4-dipyrimi dine-4-carboxylic acid (adamantan-1-ylmethyl)-amide, and Compound 2 in an analogous manner using the appropriate aldehyde. i-PrCH, 60° C., 20 h. Her Preparation of a Representative Example Compound 13

NH

OH NN NH --

resul- N2 NN is 1 - 0416) 2-Adamantan-1-yl-N-7-(2,3-dihydroxy-propyl)-5, N O 6,7,8-tetrahydro-pyrido3,4-dipyrimidin-4-yl)-acetamide was synthesized from 2-adamantan-1-yl-N-(5,6,7,8-tetrahy Auos i-ProH, 60° C., 20 h. dro-pyrido 3,4-dpyrimidin-4-yl)-acetamide (0.05 g, 0.153 mmol) and glycidol (0.015 g, 0.2 mmol) in i-PrCH (3 mL) US 2008/0039478 A1 Feb. 14, 2008 in a manner analogous to the preparation of Compound 13. Preparation of a Representative Example Compound 18 Preparative TLC purification using DCM/MeOH/TEA (10:1:1)) afforded the desired product (0.0074 mg, 12%). 0417. ESI-MS m/z 401.3 M+H". Preparation of a Representative Example Compound 19 O

NH --

HN r2 N O

NH -- EtOH, DIPEA 1N1B 750 C. 17 h NN HO . HN 2 N

EtOH, DIPEA HO Br -- O N-1N1 759 C., 17 h NH NN

O o1N1 N e NH 0422 2-Adamantan-1-yl-N-7-(2-hydroxy-ethyl)-5,6,7, NN 8-tetrahydro-pyrido3,4-dpyrimidin-4-yl)-acetamide was synthesized from 2-adamantan-1-yl-N-(5,6,7,8-tetrahydro HOS-1-N-N N2 pyrido 3,4-dpyrimidin-4-yl)-acetamide (0.05 g, 0.153 mmol), 2-bromoethanol (0.019 g, 0.15 mmol) and DIPEA (0.052 g, 0.4 mmol) in EtOH (4 mL) in a manner analogous to compound 21 The crude reaction was purified by HPLC 0418. A solution of 2-adamantan-1-yl-N-(5,6,7,8-tet affording the desired product (0.0064.g., 0.017 mmol. 12%). rahydro-pyrido 3,4-dipyrimidin-4-yl)-acetamide (0.05 g, 0.153 mmol), 3-bromo-1-propanol (0.021 g, 0.15 mmol) and 0423 ESI-MS m/z. 371.3 M+H". DIPEA (0.045 g, 0.35 mmol) in EtOH (4 mL) was stirred at Preparation of a Representative Example Compound 22 75° C. for 17 h. The reaction vessel was allowed to cool to room temperature, opened, and the volatiles were removed 0424 The title compound was prepared in a manner on a rotary evaporator. The residue was redissolved in THF analogous to that given for Compound 21 using the appro (3 mL). PL-NCO resin (300 mg) was added, and the priate starting materials. resulting Suspension was stirred at room temperature for 16 h. The resin was filtered and the volatiles were removed Preparation of 7-Benzyl-3-methyl-5,6,7,8-tetrahy under vacuum. The crude product was purified by HPLC to dro-2.7naphthyridine-4-carboxylic acid (adaman afford 2-adamantan-1-yl-N-7-(3-hydroxy-propyl)-5,6,7,8- tan-1-ylmethyl)-amide (Compound 368) tetrahydro-pyrido 3,4-dpyrimidin-4-yl)-acetamide (0.0098 g, 17%). 0425)

0419 ESI-MS m/z 385.5 M+H". O

0420 H-NMR (300 MHz, CDC1): 8 8.71 (s, 1H), 7.65 NC (s, 1H), 3.82 (t, 2H), 3.75 (s. 2H), 2.86-2.75 (m, 6H), 2.30 TiCl4, Etn -- o -e- (s. 2H), 1.99 (br's, 3H), 1.83 (m, 2H), 1.74-1.60 (m, 12H). CHCl2, 0421. The title compound was prepared in a manner N NH2 25° C., 24h analogous to that given for Compound 21 using the appro Bn priate starting material. US 2008/0039478 A1 Feb. 14, 2008 34

Preparation of 7-benzyl-3-methyl-5,6,7,8-tetrahy -continued dro-2.7naphthyridine-4-carboxylic acid amide 0429

CN

N NaOH, EtOH He 100° C. Phn-N 2N CH2Cl2. O NH2 25° C., 24h He N 2N NaOH, 259 C. N N h Phn-N 2N CN 0430 NaOH (9.1 mg, 2.24 mmol) was added to 0.5 ml of EtOH, which contained 30 mg (0.114 mmol) of the nitrile N Me and the resulting mixture was heated at 100° C. overnight. The mixture was acidified by concentrated HCl to pH>2 and -N 2N extracted with dichloromethane. The pH of the aqueous Bn layer was then adjusted to 7 and extracted with dichlo rmethane. The combined DCM layers were washed with brine, dried, and concentrated under reduced pressure to afford the crude product, which was purified by column 0426. A solution of O-aminocrotononitrile (12 g, 147 chromatography using MeOH:DCM (3-25%) to afford the mmol) and NEt (37 mL, 266 mmol) in CHCl (150 mL) pure product (22 mg, 0.078 mmol) in a 69% yield. was cooled with an ice bath to 0°. TiCl (7.9 mL, 72 mmol) Preparation of 7-benzyl-3-methyl-5,6,7,8-tetrahy in CHCl (100 mL) was added slowly with stirring fol dro-2.7naphthyridine-4-carboxylic acid (adaman lowed by N-benzyl-4-piperidone (21.4 mL, 120 mmol) in tan-1-ylmethyl)-amide one portion. The mixture was stirred for 24 h at ambient temperature and the volatiles were removed under reduced 0431 pressure. Ethyl ether (400 mL) was added, and the resulting mixture was stirred vigorously until the residue was ground O NH2 to a fine powder. The powder was filtered off and washed with ethyl ether (400 mL) and evaporation of the solvent afforded (E)-3-amino-2-(1-benzyl-1,2,3,6-tetrahydro-pyri N -- din-4-yl)-but-2-enenitrile as an oil (20 g, 70%), which was Phn-N 2 N used without further purification. Excess NaH, DMF, 0427 To a solution of (E)-3-amino-2-(1-benzyl-1,2,3,6- He tetrahydro-pyridin-4-yl)-but-2-enenitrile (15g, 0.056 mole) rt to 60-70° C. in dichloromethane (200 mL), freshly prepared benzotria Zol-1-ylmethylene-dimethyl-ammonium chloride (12 g, Br 0.068 mole) was added in one portion. The mixture was stirred for 24h at ambient temperature. NaOH (2N, 200 mL) was added, and the resulting mixture was stirred vigorously for 5 min. The phases were separated and the aqueous phase was extracted with dichloromethane (100 mL). The com O NH bined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The crude product was purified by column chromatography to give 7-benzyl N 3-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboni trile as a colorless oil (8.9 g, 53% yield). Phn-N 2N 0428 H NMR (CDC1) & 8.28 (s, 1H), 7.36-7.31 (m, 5H), 3.72 (s. 2H), 3.59 (s. 2H), 3.01 (t, 2H), 2.80 (t, 2H), 0432 7-benzyl-5,6,7,8-tetrahydro-3-methyl-2,7-naph 2.71 (s, 3H) thyridine-4-carboxamide (40 mg, 0.142 mmol) was taken up US 2008/0039478 A1 Feb. 14, 2008 in anhydrous DMF (0.5 ml) under an inert atmosphere. NaH (60% in mineral oil) (6.8 mg, 0.17 mmol) was added to the -continued reaction vessel and the mixture stirred for 30 minutes until O the evolution of hydrogen gas ceased. To this mixture was added 1-adamantylmethylbromide in DMF (0.5 ml) and O1. NaOtBu reaction was stirred at room temperature for 4 hr. The THF, rt reaction was monitored by TLC and LCMS. Excess NaH and I-adamantylmethylbromide and heated from 40 to 75° MeO OMe C. for 3 days. The mixture was cooled to room temperature, and added to ice water. The aqueous layer was extracted with EtOAc, washed with water, brine, dried over sodium sulfate, OH O and reduced in vacuo. The crude was purified by flash chromatography followed by prep. TLC using MeOH:DCM N1 No (5-10%) to afford the title compound. (5 mg, 8%). l l Preparation of 2-Adamantan-1-yl-N-(7-benzyl-5,6,7, N 8-tetrahydro-17 naphthyridin-4-yl)-acetamide (Compound 342) 0436 To a suspension of NaOtBu (4.23g, 34.57 mM) in 0433 THF (50 mL) was added a mixture of ethyl 3-amino-1- benzyl-1,2,5,6-tetrahydropyridine-4-carboxylate (3.0 g, 11.52 mM) and methyl 3,3-dimethoxypropanoate (5.12 g, O 34.57 mM) in THF (20 mL) in one portion and the mixture 1N was agitated at ambient temperature overnight. The mixture -- was concentrated to half the volume before being quenched N with ice-cold water. The homogeneous Solution was O extracted ethyl ether and the aqueous layer was carefully NH4OAC - > MeOH, rt acidified with HCl until acidic. The precipitate was filtered, washed with water, and dried under vacuum to obtain the title compound as an off-white solid (1.6 g. 47%). Preparation of 7-benzyl-4-hydroxy-5,6,7,8-tetrahy dro-17 naphthyridine-3-carboxylic acid 0437

Preparation of 5-amino-1-benzyl-1,2,3,6-tetrahydro pyridine-4-carboxylic acid ethyl ester OH O 0434 Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (25 N O 10% NaOH g, 83.96 mM) and ammonium acetate (32.36 g. 419.79 mM) reflux in MeOH (250 mL) were agitated overnight. The mixture N 2 was concentrated, the crude product was dissolved in meth N ylene chloride and washed sequentially with aqueous Satu rated potassium carbonate Solution and water. The organic OH O was dried and reduced in vacuo to yield the title compound (24.0 g, 110%, higher yield possibly due to accluded sol N OH vents) as an oil which solidified on standing. N 2 Preparation of 7-benzyl-4-hydroxy-5,6,7,8-tetrahy N dro-1,7naphthyridine-3-carboxylic acid methyl ester 0435) 0438. In a round bottom flask, 7-Benzyl-4-hydroxy-5.6, 7,8-tetrahydro-1.7naphthyridine-3-carboxylic acid methyl ester (56 mg) was dissolved in methanol (15 mL) and a 10% NaOH solution in water (5 mL) was added with stirring. The mixture was heated at reflux for 2 hours, reduced in vacuo, and the aqueous remainder was acidified with 1N HC1. The aqueous layer was extracted with dichloromethane. The aqueous layer was concentrated to give 0.06 grams of the product as its hydrochloride Salt after drying. US 2008/0039478 A1 Feb. 14, 2008 36

d) 7-Benzyl-5,6,7,8-tetrahydro-1.7 naphthyridin-4-ol -continued N 0439 OH CO2H Ph N r N Cu, 270° C., N1 4. -- 1000 psi, iPrOH Ph N1 N 4. OH 0446 7-Benzyl-4-chloro-5,6,7,8-tetrahydro-1,7naph thyridine (0.417 mmol) was treated with 5 equiv. of NaNs (135 mg) in DMF (0.5 ml) and heated to 70° C. for 4 h. The residue was dissolved on 50 ml of DCM and washed with Ph N r brine. The organic layer was concentrated to afford a black N1 4. oil, which was purified by column chromatography to afford the desired azide (61 mg), which was used directly in the 0440 7-Benzyl-4-hydroxy-5,6,7,8-tetrahydro-1.7naph next step. thyridine-3-carboxylic acid (0.025 g, 0.089 mmol) in 2 ml of 0447 ESI-MS m/z 266.5 M+H) 1-PrOH and column packed with Cu(O) was heated to 270° C. under 1000 psi in a continuous flow reactor. The flow rate 7-Benzyl-5,6,7,8-tetrahydro-1.7 was adjusted to 1.5 ul/min. After cooling, filtering, and naphthyridin-4-ylamine washing with methanol the filtrate was concentrated to afford 50 mg (0.208 mmol) of the desired product. 0448 0441. ESI-MS m/z. 241.1 M+H". N Preparation of 7-benzyl-4-chloro-5,6,7,8-tetrahydro 1.7naphthyridine N PS-PPh3 Ph N 2 H2O/THF 0442 N1 N OH NH2

N POCl, N Ph N 2 reflux Ph N 2 N1 N N1 N C 0449 4-azido-7-benzyl-5,6,7,8-tetrahydro-1,7-naphthy ridine (0.06 g., 0.226 mmol) was treated with 0.5 g of Phn-N 4. PS–PPh, resin in a 8ml mixture THF:HO (18:1) at 32° C. O) ON. *The reaction was monitored by LCMS and TLC. The reaction mixture was filtered and washed with THF and 0443) 7-Benzyl-5,6,7,8-tetrahydro-1.7naphthyridin-4- methanol. The combined filtrate was concentrated and used ol (0.1 g, 0.417 mmol) in 3 ml of POC1 was refluxed for 40 directly in the next step. ESI-MS m/z 240.3 M+H". minutes. LCMS indicated complete coversion to the desired product. The excess POCl was removed under reduced Preparation of 2-Adamantan-1-yl-N-(7-benzyl-5.6.7. pressure and taken on to the next step without further 8-tetrahydro-17 naphthyridin-4-yl)-acetamide purification. (Compound 342) 0444 ESI-MS m/z 259.5 M+H". 0450 Preparation of 4-Azido-7-benzyl-5,6,7,8-tetrahydro 1.7 naphthyridine N 0445) -- Ph N 2 N1 N

O N NaN, NMM, 1,4-dioxane Ph N DMF, 70° C. C t US 2008/0039478 A1 Feb. 14, 2008 37

under argon. The reaction was monitored by TLC and -continued LCMS. Excess acid chloride was added and the reaction was stirred. The contents were concentrated and purified by HPLC to afford the desired product (3.3 mg, 4%). 04.52 ESI-MS m/z 416.7 M+H".

HN O Exemplary Compounds of the Invention 0453. In addition to the compounds exemplified above, the following compounds recited below in Tables 1A-1E, which comprise various Substituted amides of this invention, Ph N r N1 4. are prepared or can be prepared using the procedure and synthetic schemes described above, or some modification thereof, and the corresponding starting materials, appropri 0451 7-Benzyl-5,6,7,8-tetrahydro-1.7naphthyridin-4- ate reagents, and purification methods known to those ylamine (48 mg, 0.202 mmol) in 6 ml of dioxane was treated skilled in the art. Modifications of the methods described with NMM (22 ul, 0.202 mmol) followed by adamantan-1- herein are within the scope of the invention and will be yl-acetyl chloride (0.043 g, 0.202 mmol) and stirred at rt obvious to one of skill in the art.

TABLE 1A Adamantane Substituted Amide Compounds R3b R3c R3a.

R3d L NN R3e 21 N1

5 CH, H H H 15 CH, H H MeOS 27 CH, C H H 28 CH, F H H 29 CH2 MeO H H 30 CH2 MeO H MeO 31 CH, Me H H 32 CH, Me H H Me 33 CH, F H 34 CH, C H 35 CH, MeO H 36 CH2 MeO MeO 37 CH2 MeO H MeO 38 CH, Me H 39 CH, Me MeO 40 CH, MeO 41 CH2 C 42 CH, CN 44 CH, Me 45 CH, C2H5 47 CH, F 62 CH, AcNH 65 CH, H 2-Pyridyl H 68 CH, PO H 70 CH, CF H 71 CH, t-Bu 72 CH, CF 74 CH, CFO 75 CH, PO 76 CH, CFO H 77 CH, OCHF, H 78 CH, OCHF,

US 2008/0039478 A1 Feb. 14, 2008 39

TABLE 1 A-continued Adamantane Substituted Amide Compounds R3b R3c R3a.

R3d L NN R3e 21 N- N

ID Ll R3a R3b R3e R3d R3e l R2 R2" RR Rb Re 176 SO, O-(3,4-diCIPh) 177 SO, O-(4-CFPh) 178 SO, (3,4-di CIPh)O 179 SO, 4-MeOPh 181 SO, C CF 190 SO, OCHF, 191 SO, PO 192 SO, C 193 SO, C 194 SO, C6Hs 195 SO, CF 196 SO, 1-pyrazolyl 197 SO, MeO MeO 199 SO, Me 201 SO, CF 202 SO, C 203 SO, 204 SO, C C 205 SO, C 206 SO, 207 SO, Me C 208 SO, C C 209 SO, 210 SO, C C 211 SO, C 212 SO, Me 214 SO, Me MeO 215 SO, 216 SO, MeO MeO 217 SO, Me Me 218 CO C C 220 CO 221 CO C6Hs 226 CO C 227 CO 228 CO CFO 229 CO C2H5 230 CO Me 232 CO 233 CO CF 234 CO MeO 242 CO CN 243 CO CF 245 CO C C 246 CO MeO MeO 247 CO 2SO CO MeO 2S1 CO 253 CO C 257 CO CN 258 CO C C 266 CO CF 267 CO CF 268 CO CFO 269 CO CFO US 2008/0039478 A1 Feb. 14, 2008 40

TABLE 1 A-continued Adamantane Substituted Amide Compounds

ID Re

270 CO 271 CO 272 CO 275 CO 277 CO 278 CO 279 CO 28O CO 282 CO 291 CO 292 CO 294 CO 301 CO 310 CO 312 CO 314 CO 315 CO 319 32O 322 323 324 325 326 327 328 329 330 331 334 339 341 343 344 345 346 347 348 349 s 352 3S4 355 358 359 360 361 362 363 364 C 369 370 371 372 374 376 380 US 2008/0039478 A1 Feb. 14, 2008 41

TABLE 1 A-continued Adamantane Substituted Amide Compounds R3b R3c R3a.

R3d L NN R3e 21 N- N

ID Ll R3a R3b R3e R3d R3e l R2 R2" RR Rb Re 381 SO, H 1 H H H Me Me 382 CO H Me 1 H H Me Me 383 CO H CF 1 H H Me Me 385 CO H C C 1 H H Me Me 387 CO 1 H H Me Me 389 CO C 1 H H Me Me 390 CO 1 H H Me Me 391 CO C C 1 H H Me Me 392 CO C C O 394 CO O 399 CO C O 400 CO O 401 CO CFO O 402 CO C2H5 O 403 CO Me O 40S CO O 406 CO CF O 407 CO MeO O 414 CO CN O 415 CO CF O 417 CO C C O 418 CO MeO MeO O 419 CO O 422 CO MeO O 423 CO O 42S CO C O 429 CO CN O 430 CO C C O 438 CO CF O 439 CO CF O 440 CO CFO O 441 CO CFO O 442 CO CF O 443 CO C CF O 444 CO C O 447 CO MeO MeO O 449 CO O 4SO CO Me O 451 CO O 452 CO O 454 CO C C O 461 CO Me O 462 CO MeO O 464 CO C O 469 CO t-Bu O 475 CO MeO O 476 CO MeO MeO O 478 CO C O 479 CO C C O 481 SO O 482 SO Me O 487 SO MeO O 488 SO C O 489 SO, MeO MeO O 490 SO, F O 492 SO CF H O US 2008/0039478 A1 Feb. 14, 2008 42

TABLE 1 A-continued Adamantane Substituted Amide Compounds

ID Ll R3a R3b R3e R3d R3e l R2 R2 RR Rb Re 493 SO CFO O 497 SO CFO H O 498 SO, MeO H O 500 SO, C CN O 501 SO, H O 502 SO, CN O 506 SO, O-2-pyridyl O 507 SO, O-3-pyridyl O 508 SO, O-4-pyridyl O 509 SO, O-(4-MeOPh) O 510 SO, O-(4-CFPh) O 511 SO, O-(3,4-di O CIPh) 512 SO, 4-MeOPh O 514 SO, CF C O 523 SO, CHFO O 524 SO, CH5O O 525 SO, C O 526 SO, C O 527 SO, C6Hs O 528 SO, CF O 529 SO, 1-pyrazolyl O 530 SO, MeO MeO O 532 SO, CFO O 533 SO, Me O 535 SO, CF O 536 SO, C O 537 SO, O 538 SO, C C O 539 SO, C O 540 SO, O 541 SO, C Me O 542 SO, C C O 543 SO, O 544 SO, C C O 545 SO, C O 546 SO, Me O 548 SO, MeO Me O 549 SO, MeO MeO O 550 SO, Me Me O 551 SO, CN O 562 CH, MeO O 566 CH MeO MeO O 568 CH, CHO O 569 CH, Br MeO O 570 CH, C C O 571 CH, CN O 572 CH, t-Bu O 574 CH, CF O 575 CH, N.Me, O 576 CH, CH5O O 577 CH, C O 584 CH MeO O 585 CH, Me Me O 586 CH, MeO MeO C O 588 CH, OCHPh MeO O US 2008/0039478 A1 Feb. 14, 2008 43

TABLE 1 A-continued

Adamantane Substituted Amide Compounds

R3b R3c R3a.

R3d L1 NN R3e 21 Nsu-N

ID Ll R3a R3b R3e R3d R3e l R2 R2" RR Rb Re

590 CH, C C O 591 CH, H MeO MeO O 592 CH, MeO OCHPh O 593 CH, MeO HO O 594 CH MeO MeO Br O 595 CH, F CN O 597 CH, Br O 598 CH, H C O 601 CH, C O 602 CH, Me O 603 CH, CN O 604 CH, CF O 605 CH, H O 606 CH, H Me O 607 CH, O 608 CH, MeO MeO O 609 CH, O 611 CH, C O 612 CH, CF O 614 CH, H Br O 615 CH, H MeO O 616 CH, NHAc O 617 CH, H Br O 618 CH, Br H O 620 CH, CFO O 621 CH, CHFO O 622 CH, OCH-(4-F-Ph) O 623 CH, MeO MeO O 624 CH, MeO O 625 CH, H C2H5O O 626 CH, H (3-CFPh)O) O 628 CH, MeO H O 629 CH, F MeO O 630 CH, C2H5O O 631 CH, MeO H MeO O 632 CH, H CFO O 633 CH, MeO H MeO O 635 CH, C O

US 2008/0039478 A1 Feb. 14, 2008

TABLE 1D-continued

Substituted Amide Compounds R3N N

N. R. la

NS-N O

ID L-R R1a

137 (2,4-difluorophenyl)methyl (1-adamantylmethyl) 138 (7,10-dioxabicyclo-A.4.0deca-1,3,5- (1-adamantylmethyl) trien-4-ylmethyl) 139 (2-fluorophenyl)methyl (1-adamantylmethyl) 316 (3-fluorophenyl)methyl (1-adamantylmethyl) 335 (3-methoxyphenyl)methyl (1-adamantylmethyl) 336 (o-tolylmethyl) (1-adamantylmethyl) 337 (2-chlorophenyl)methyl (1-adamantylmethyl) 338 (4-fluorophenyl)methyl (1-adamantylmethyl) 340 benzo1.3dioxol-5-ylmethyl (1-adamantylmethyl)

0457) TABLE 1 E-continued TABLE 1E Misc. Amide Compounds Misc. Amide Compounds

368 636

O N N O

F N CH3 N N 2N

342

O CuCo

US 2008/0039478 A1 Feb. 14, 2008

0459. The following biological examples, Examples 1-9, cells are washed away. Adherent cells are cultured for 7-14d are offered to illustrate the present invention and are not to in this medium plus interferon-Y (human for human cells) be construed in any way as limiting its scope. In the (1000 units/ml). Macrophages are recovered from the cul examples below, all temperatures are in degrees Celsius ture flask by pipetting with cold phosphate-buffered saline (unless otherwise indicated). and plated onto glass coverslips for electrophysiological or other experiments carried out 12-24 h later. EXAMPLE 1. 0460 The P2X, receptor is strongly expressed in mac EXAMPLE 2 rophage-derived cell lines, including, but not limited to, Electrophysiological Experiments J774 (mouse macrophage line, American Type Culture Col lection (ATCC), Rockville, Md., ATCC TIB-67), P388 0464 Whole cell recordings are made using the EPC9 (mouse cell line, ATCC CCL-46), P815 (mouse mast cell patch-clamp amplifier and Pulse acquisition programs mastocytoma-derived line, ATCC TIB-64), THP-1 (Human (HEKA, Lambrecht, Germany). Whole-cell recordings are monocyte-derived cell line, ATCC TIB202) and U937 obtained from cells, e.g. J774A.1 cells (American Type (human cell line derived from histiocytic lymphoma, Culture Collection, Rockville, Md., ATCC TIB-67)); ago induceable to monocyte differentiation, ATCC CRL-1593.2) nists are applied for periods of 1 to 3 s by a fast-flow U-tube and in isolated macrophage cultures. Human or non-human delivery system E. M. Fenwick, A. Marty, E. Neher, J. animal macrophages are isolated using the procedure noted Physiol, (London) 331, 577 (1982). The internal pipette below. Solution is 140 mM cesium-aspartate or potassium-aspartate, 20 mM. NaCl, 10 mM EGTA, and 5 mM Hepes; normal 0461) The P2Z/P2X, receptor can be characterized by external solution is 145 mM NaCl, 2 mM KC1, 2 mM CaCl, measuring channel opening, for instance ion flux, and/or by 1 mM MgCl, 10 mM Hepes, and 12 mM glucose. Low assessing pore formation, including by monitoring dye divalent external Solution is nominally magnesium-free with uptake or cell lysis in cells naturally expressing this receptor. 0.3 mM CaCl-Concentration-response curves are con Compounds such as ATP, 2" and 3'-(O)-(4-benzoyl benzoyl) structed in low divalent Solution by recording currents in ATP (BZATP) effect the formation of pores in the plasma response to 1 s applications of agonist at 8 min intervals with membrane of these cells, particularly at low extracellular normal external solution present for 6 min before each divalention concentrations (Buisman et al. Proc. Natl. Acad. application. This protocol is necessary to prevent the devel Sci. USA 85:7988 (1988); Zambon et al. Cell. Immunol opment of sustained inward currents. 156:458 (1994); Hickman et al Blood 84:2452 (1994)). Large molecular size dyes, including propidium dye YO 0465 Reversal potentials (E.) are obtained by applica PRO-1, can be seen entering macrophage-derived cell lines tion of ATP (300 uM) or BZATP (30 uM)(controls), or the during cell recordings (Hickman et al. Blood 84:24.52 compound being tested, while the membrane is held at (1994); Wiley et al, Br J Pharmacol 112:946 (1994); Stein various potentials or by application of Voltage ramps from berg etal, J Biol Chem 262:8884 (1987)). Ethidium bromide -120 to 30 or 50 mV. Permeability ratios are calculated from (a fluorescent DNA probe) can also be monitored, where an E by first computing C(=PN/P where P is permeability) increase in the fluorescence of intracellular DNA-bound for internal (i) and external (O) concentrations Na=20 ethidium bromide is observed. Expression of recombinant mM, Na-145 mM, K=0 mM, and K=140 mM from rat or human rP2X, in cells, including HEK293 cells, and in C=(145/exp(EFIRT)-20)/140 (where F is the Faraday, R Xenopus oocytes demonstrates influx and pore formation by is the gas constant, and T is the absolute temperature). Other whole cell recordings and YO-PRO-1 fluorescence P/PN values, when X=145 mM, Na=20 mM, K= (Suprenant et al. Science 272:735 (1996); Rassendren et al. 140 mM, and Na-K =X)=0 mM, are computed from J Biol Chem 272:5482 (1997)). P/P=(exp)EF/RT) (20+140C))/145. In order of size, X is cesium, methylamine, tris(hydroxymethyl)-ami 0462. The compounds of the invention may be tested for nomethane, tetraethylammonium, and N-methyl-D-glucam antagonist activity at the P2X, receptor. Tests that may be performed include and are selected from: (i) electrophysi ine. The internal solution also contains 10 mM EGTA and 5 ological experiments; (ii) YO-PRO1 fluorescence; (iii) mM Hepes. External solutions also contain 10 mM glucose ethidium bromide fluorescence; and (iv) IL-10 release from and normal or low concentrations of divalent cations; pH is stimulated macrophages, including as described below. maintained at 7.3 with HCl, histidine, or Hepes as required, Compounds can be tested in vivo in animal models includ and the osmolarity of all solutions is 295 to 315. ing for inflammation models (e.g. paw edema model, col EXAMPLE 3 lagen-induced arthritis, EAE model of MS). Isolation of Human Macrophages YO-PRO1 Fluorescence 0463 Monocyte-derived human or non-human animal 0466. The Photonics Imaging (IDEA) system for micro macrophage cultures are prepared as described by Blanchard scopic fluorescence measurements (Photonics, Planegg, et al (Blanchard et al., J. Cell Biochem 57:452 (1995); Germany) is used. Coverslips are placed at the stage of a Blanchard et al., J. Immunol 147:2579 (1991)). Briefly, Zeiss Axiovert 100 or equivalent inverted microscope and monocytes are isolated from leukocyte concentrates viewed under oil immersion with a 40x Fluor objective. obtained from a healthy Volunteer. Leukocytes are sus YO-PRO-1 (10 uM: Molecular Probes, Eugene, Oreg.) is pended in RPMI 1460 medium (Life Techologies, Inc.) with added to the Superfusion fluid during electrophysiological 20% serum (human for human cells), 2 mM glutamine, 5 recordings 3 to 6 min before switching to low divalent mM HEPES, and 100 g/ml streptomycin. Cells are allowed Solution and washed out upon Switching back to normal to adhere to culture flasks for 1-2 h, after which nonadherent divalent solution, after which the fluorescent lamp is turned US 2008/0039478 A1 Feb. 14, 2008 52 on and cells are examined with a fluorescein isothiocyanate per well in 100 ul serum-free RPMI 1640 in 96-well plates filter. YO-PRO1 fluorescence is measured using 491/509 nm and incubated for 1 hour at 37° C. in a 5% CO/95% excitation/emission wavelengths. Images are obtained at humidified tissue culture incubator. After 1 hour, the 5-20s intervals during continuous Superfusion (2 ml/min) medium is replaced with 100 uL complete culture medium with YO-PRO1 and varying concentrations of control ATP, (RPMI 1640, 10% human serum-type AB (heat inactivated), BZATP or compound to be tested. For each experiment, the 25 mM HEPES, 2 mM glutamine, 50U/ml each of penicillin time course of YO-PRO1 fluorescence is obtained for 10-20 and streptomycin) and incubated overnight (16 hours). individual cells and then averaged to obtain the mean fluorescence signal. Results are expressed as mean signal at Dosing Regimen 3 min for rP2X-7, and the signal at 10 min is used for P2X, 0471. The next day, the culture medium is replaced with and human macrophage cells. All experiments are carried 100 uL fresh complete culture medium in the absence or out at room temperature. presence of human beta amyloid 1-42 peptide (5 uM) and incubated at 37° C. in a 5% CO/95% humidified tissue EXAMPLE 4 culture incubator for 5 hours. Medium is then removed and discarded. Each well is washed once with Hanks buffered Ethidium Bromide saline (HBSS) containing 1 mM CaCl, followed by the 0467 Compounds of the invention are tested for antago addition of 80 uL of HBSS/CaCl-inhibiting compound of nist activity at the P2X, receptor by monitoring Ethidium the present invention (10x stock in HBSS/CaCl for a final Bromide entering P2X, receptor-expressing cells on pore concentration of 23 nM and 206 nM) and incubated 15 formation. The test is performed in 96-well flat bottomed minutes in the tissue culture incubator followed by the microtitre plates, the wells being filled with 250 ul of test addition of either 10 uL of HBSS/CaCl, or 10 uL of benzoyl solution comprising 200 ul of a suspension of P2X,-express ATP (BZATP; 3 mM stock in HBSS/CaCl for a 300 uM final ing cells (e.g. THP-1 cells, J774 cells, etc.)(2.5x10 cells/ml) concentration) and incubated for a further 30 minutes in the containing 10"Methidium bromide, 25uL of a high potas tissue culture incubator. Medium is then removed to new sium buffer solution containing 10MBZATP and 25uL of 96-well plates for storage at -70° C. until the IL-1B content a high potassium buffer Solution containing test compound. is quantitated by ELISA (from R&D Systems). The cells are The plate is covered with a plastic sheet and incubated at 37° washed once with HBSS/CaCl followed by lysing the cells C. for one hour. The plate is then read in a Perkin-Elmer with 100 ul ice cold lysis buffer (100 mM Tris, pH 7.6, 1% fluorescent plate reader, excitation 520 nm, emission 595 Triton X-100, and 1 tablet per 30 ml Complete TM protease nm, slit widths: Ex 15 nm, EM 20 nm. For the purposes of inhibitor from Roche Biochemicals, Inc). Cell lysates are comparison, BZATP (a P2X, receptor agonist) and pyridoxal stored at -70° C. until the IL-1B is quantitated by ELISA. 5-phosphate (a P2X, receptor agonist) are used separately in the test as controls. From the readings obtained, a plCso EXAMPLE 6 figure is calculated for each test compound. This figure is the negative logarithm of the concentration of test compound In Vivo Animal Models necessary to reduce the BZATP agonist activity by 50%. 0472 A. This example illustrates the efficacy of the compounds of this invention in the treatment of multiple EXAMPLE 5 Sclerosis. As described herein, an experimental autoimmune encephalomyelitis (EAE) model is used to show such effi 0468. IL-1 B Release cacy. The following procedures are employed in this model. 0469. This Example demonstrates the testing of the com pounds of this invention for efficacy as inhibitors of P2X7 Animals mediated release of IL-1 B from human macrophages acti 0473 SJL/J female mice, 8 wks. old, are obtained from vated by the Alzheimer's beta amyloid peptide 1-42. Jackson Laboratories. Cell Isolation Antigens 0470 Monocytes are isolated from peripheral blood 0474) Myelin Proteolipid Protein (PLP 139-151) mononuclear cells (PBMCs) as follows. Whole blood is (HSLGKWLGHPDKF) (Cat it H-2478) is obtained from layered directly onto Histopak 1077-1 columns (Sigma BACHEM, Bioscience, Inc., King of Prussia, Pa. Biochemicals) and centrifuged at 800xg for 15 minutes. The PBMC band of cells is removed to a fresh 50 ml culture tube 0475 Complete Freund's Adjuvant H37 Ra 1 mg/ml and diluted 1:1 with wash buffer (Phosphate buffered saline, Mycobacterium Tuberculosis H37 R is obtained from pH 7.4 containing 2 mM EDTA and 5 mg/ml BSA) followed Difco (Cat # 31 14-60-5, 6X10 ml). by centrifugation at 800xg for 5 minutes. Cells are then 0476 Mycobacterium Tuberculosis is also obtained from washed by sequential resuspension of the cell pellet in wash Difco, (Cat it 31 14-33-8, 6.times. 100 mg). buffer and centrifugation at 600xg for 5 minutes. The wash process is repeated until the Supernatent is clear of contami Pertussis Toxin nating platelets (generally, 5 to 6 washes). Monocytes are 0477 Bordetella Pertussis, (Lyophilized powder contain then purified from the PBMCs by negative selection using a ing PBS and lactose) is obtained from List Biological monocyte isolation kit (Miltenyi Biotec, Inc.) that contains Laboratories, (Product #180, 50 ug). antibodies to non-monocytic cells, running the cells over a magnetic column to remove antibody-bound cells, and col Induction of EAE in Mice lecting the flow through Volume of monocytes. Monocytes 0478 PLP139-151 peptide is dissolved in HO:PBS (1:1) are washed once with wash buffer and seeded at 10E5 cells solution to a concentration 7.5 mg/10 ml (for 75 lug PLP per US 2008/0039478 A1 Feb. 14, 2008

group) and emulsified with an equal Volume of CFA Supple expose the right common, internal and external carotid mented with 40 mg/10 ml heated-killed mycobacterium arteries. The right common carotid artery is isolated with a tuberculosis H37R. Mice are injected s.c. with 0.2 ml of 5-0 silk suture. During surgery the suture is released allow peptide emulsion in the abdominal flank (0.1 ml on each ing reperfusion every 2-4 minutes. The right external carotid side). On the same day and 72 hours later, mice are injected and Superior thyroid arteries are also isolated and the Supe i.v. with 100% of 35 ng and 50 ng of Bordetella Pertussis rior thyroid is cauterized, while the external carotid is ligated toxin in Saline respectively. distally with a 5-0 silk suture. Another 5-0 silk suture is loosely tied around the external carotid artery. The occipital Clinical Assessment artery is isolated, ligated and incised. The internal carotid is STAGE O: Normal isolated. STAGE 0.5: Partial limp tail 0485 With the common and external carotid arteries STAGE 1: Complete Limp Tail immobilized, an aneurysm clip is placed onto the internal carotid artery. A small incision is made at the distal end of STAGE 2: Impaired righting reflex the external carotid. A 3-0 nylon suture coated with poly L-lysine is then inserted into the external carotid and up into STAGE 2.5: Righting reflex is delayed (ot weak enough to the common carotid artery. The loosely tied 5-0 silk suture be stage 3). around the external carotid is now gently tightened around STAGE 3: Partial hind limb paralysis the filament. The external carotid artery is then incised and STAGE 3.5: One leg is completely paralyzed, and one leg is the remaining piece of the external carotid artery with the partially paralyzed, filament is rotated so that the filament may be inserted into the internal carotid artery the length of insertion depending STAGE 4: Complete hind limb paralysis on the weight and rat Strain. In Sprague Dawley rats the monofilament is inserted 18-19 mm (18 mm for rats weigh STAGE 4.5: Legs are completely paralyzed and Moribund ing <300 gm, 19 mm for rats weighing 2300 gm) effectively STAGE 5: Death due to EAE blocking blood flow to the middle cerebral artery. 0479 Clinical Courses of EAE 0486 The external jugular vein will be cannulated with PE 50 tubing for I.V. administration of compounds. The Acute phase: First clinical episode (Day 10-18) cannula will be exteriorized at the previously shaven, scruff Remission: Phase of clinical improvement following a clini of the neck and sutured in place. The wound will be closed cal episode; characterized by a reduction (>=one grade) in by means of suture. The right femoral artery is catheterized clinical score for at least two days after the peak score of for blood gas and glucose determination during Surgery. acute phase or a disease relapse. 0487. Two hours after the insertion of the monofilament 0480 Relapse: Increase of at least one grade in clinical suture the rats are re-anesthetized with the same anesthetic score for at least two days after remission has been attained. combination used initially and placed back into the nose cone with the reduction of isoflurane concentration to 2%. 0481. The animals treated with the compounds of this The neck incision is reopened to expose the external carotid invention generally would be expected to show improve artery. The restoration of blood flow is accomplished by ments in clinical scores. completely withdrawing the intraluminal suture from the 0482 B. This Example illustrates a protocol for deter carotid arteries. The incision is then closed with 3-0 silk in mining the efficacy of the compounds of the present inven an interrupted Stitch. tion for the treatment of stroke using an animal model. Compound Administration 0483 Male Sprague Dawley rats (Charles River) weigh 0488 Five groups of 15 animals are subjected to the ing 280-320 g are given free access to food and water and above methodology. Compounds are infused (I.V.) at various acclimatized for a minimum of 4 days before use in experi doses (dose response) over different time periods post ments. All rats for use in studies are to be fasted beginning MCAo. A pre-determined concentration is infused over a at 3:00 pm the day prior to surgery but given free access to pre-selected time period beginning at various intervals post water. Prior to surgery each rat is weighed. The rat is initially MCAo. Vehicle-treated controls receive an infusion of nor induced with 5% isoflurane (Aerrane, Fort Dodge), com mally 0.9 ml/hr. A positive control compound is run at the bined with 30% O., 70% NO for 2-5 minutes. The rat is same time. then placed on a circulating water-heating pad and into a nose cone for spontaneous respiration of anesthetic gases. Neurological Tests The isoflurane is reduced to 2%. A rectal probe is inserted 0489 Prior to surgery, 2 hours following the onset of and body temperature maintained at 36.5-37.5°C. The hair ischaemia and 24 hours after ischaemia, a battery of neuro is clipped at all Surgical sites and these regions will then be logical tests are performed. The postural reflex test, which is scrubbed with Betadine. designed to examine upper body posture, when the rat is Surgical Procedure suspended by the tail above a flat surface. A normal rat will extend the entire body and both forelimbs towards the 0484. A temporalis muscle probe is placed into the right surface. Rats with an infarction will consistently flex the temporalis muscle and “brain' temperature' is monitored. A contralateral limb and show signs of body rotation. midline neck incision is made in the upper thorax of the rat. Careful dissection, isolation and retraction of the sternomas 0490 The rats response to a gentle lateral push with a toideus, digastricus, and sternohyoideus muscles is made to finger behind the shoulders is observed and noted. A normal US 2008/0039478 A1 Feb. 14, 2008 54 rat would resist Such a push, whereas a rat with an infarction colonic instillation of DNBS (2,4-dinitrobenzene sulfonic will not. The elicited forelimb placing in response to visual acid, 30 mg in 0.5 ml ethanol 3.0%) after which, 2 ml of air and tactile stimuli. The animal is held by the body so that the is gently injected through the cannula to ensure that the lateral or dorsal forepaw Surface is placed against a bench. Solution remains in the colon. Test Substance is administered This test is repeated but on this occasion obstructing the orally (PO) at a dose of 50 mg/kg or intraperitoneally (IP) at view of the rat. 30 mg/kg once daily for 7 consecutive days. DNBS is instillated into the distal colon of each animal 2 hours after 0491. Upon completion of each experiment, all animals dosing on the second day. The control group is similarly are deeply anaesthetized with isoflurane (5%), euthanized by treated with vehicle alone and sulfasalazine (300 mg/kg, decapitation, and the brains removed, the extent and location PO) is used as reference agent. Animals are fasted 24 hours of the ischaemic damage is verified histologically by means before DNBS challenge and 24 hours after the final treat of tetrazolium chloride. ment when they are sacrificed and each colon is removed 0492 C. This Example illustrates the anti-inflammatory and weighed. During the experiments, presence of diarrhea activity of the compounds of this invention using a model of is recorded daily. When the abdominal cavity is opened 2,4-dinitrobenzenesulfonic acid (DNBS) induced distal coli before removal of the colon, adhesions between the colon tis (a model of inflammatory bowel disease). and other organs are noted. After weighing the colon, the extent of colonic ulceration is observed and noted as well. Test Substance and Dosing Pattern Colon-to-body weight ratio is then calculated for each 0493 A compound of this invention is dissolved in animal according to the formula: Colon (g)/BWx100%. The vehicle of 2% Tween 80 in distilled water for oral admin “Net' increase in ratio of Vehicle-control+DNBS group istration at a dose of 50 mg/kg or dissolved in vehicle of 2% relative to Vehicle-control group is used as a base value for Tween 80 and 0.9% NaCl for intraperitoneal injection at 30 comparison with test Substance treated groups and expressed mg/kg. The dose is given once daily for 7 consecutive days. as % decrease in inflammation. A 30 percent or more (30%) Dosing volume was 10 ml kg. DNBS is challenged 2 hours decrease in “Net colon-to-body weight ratio for each test after dosing on the second day. substance treated group relative to the “Net' vehicle+DNBS treated group is considered significant. Animals 0498 D. This Example illustrates the anti-inflammatory 0494. In these studies, male Wistar, Long Evans rats activity of the present compounds using a model of carra provided by the animal breeding center of MDS Panlabs geenan induced paw edema (a model of inflammation, Taiwan, Ltd. and Balb/cByJ derived male mice (weighing carrageenan). 20+2 gms), provided by National Laboratory Animals Breeding Research center (ALBRC, Taiwan), may be used. Test Substance and Dosing Pattern Space allocation of 6 animals may be 45x23x15 cm. Ani 0499. A compound of this invention is dissolved in mals are housed in APECR cages (Allentown Caging, vehicle of 2% Tween 8070.9% NaCl and administered intra Allentown, N.J. 08501, USA) in a positive pressure isolator peritoneally at a dose of 30 mg/kg 30 minutes before (NuAire(R), Mode: Nu-605, airflow velocity 50+5 ft/min, carrageenan (1% 0.1 ml/paw) challenge. Dosing Volume is HEPA Filter) and maintained in a controlled temperature 10 ml/kg. (22°C.-24°C.) and humidity (60%-80%) environment with 12 hours light dark cycles for at least one week in MDS Animals Panlabs Taiwan laboratory prior to being used. Free access 0500 Animals are conditioned in accordance with the to standard lab chow for rats (Fwusow Industry Co., Lim procedures set forth in the previous Example. ited, Taiwan) and tap water is granted. All aspects of this work including housing, experimentation and disposal of Chemicals animals would be performed in general accordance with the 0501 Carrageenan is obtained from TCI, Japan; Pyrogen International Guiding Principles for Biomedical Research free saline is from Astar, Taiwan; and Aspirin is purchased Involving Animals (CIOMS Publication No. ISBN 92 from ICN BioMedicals, USA. 90360194, 1985). Equipment Chemicals 0502 Glass syringe (1 ml and 2 ml Mitsuba, Japan), 0495) DNBS is obtained from TCI, Tokyo, Japan, ethanol Hypodermic needle 24Gx 1" (Top Corporation, Japan), is from Merck, Germany and Sulfasalazine is purchased Plethysmometer #7150 (Ugo Basile, Italy), and Water cell from Sigma, USA. 25 mm Diameter, #7157 (UGO Basile, Italy). Equipment Method 0496 Electriconic scale (Tanita, Model 1140, Japan), 0503 Test substance (Example) is administered IP (30 Electriconic scale (Sartorius, R160P, Germany), Glass mg/kg) to groups of 3 Long Evans derived male overnight Syringe (2 ml, Mitsuba, Japan), Rat oral needle, Hypodermic fasted rats weighing 150+20 gms 30 minutes before right needle (25GXI" TOP Corporation, Japan), Stainless Scissors hind paw injection of carrageenan (0.1 ml of 1% Suspension (Klappenclear, Germany), Stainless Forceps (Klappenclear, intraplantar). Hind paw edema, as a measure of inflamma Germany). tion, is recorded 3 hours after carrageenan administration Method using a plethysmometer (Ugo Basile Cat. #7150) with water cell (25 mm diameter, Cat. #7157). Reduction of hind paw 0497 Groups of 3 Wistar derived male rats weighing edema by 30 percent or more (e.30%) indicated significant 180+20 gms are used. Distal colitis is induced by intra acute anti-inflammatory activity. US 2008/0039478 A1 Feb. 14, 2008

0504 E. This Example illustrates the anti-inflammatory are used. The animal room is lighted artificially at a 12-hr activity of the present compounds using a model of Balb/c light-dark cycle (e.g. from 7:00 A.M. to 7:00 P.M.) with mice subjected to monoclonal antibody (mAb) type II col water and food Supply ad libitum. Animals are allocated lagen induced arthritis. randomly into groups. Test Substance and Dosing Pattern Model Induction 0505) A compound of this invention is dissolved in 0512 Sciatic nerve ligation (SNL, Seltzer's model): vehicle of 2% Tween 80/0.9% NaCl, at doses of 50 or 30 and Under anesthesia with pentobarbital (50 mg/kg, i.p.) and administered orally (50 mg/kg) or intraperitoneally at 30 aseptic techniques, the selective nerve injury is created by mg/kg once daily for 3 consecutive days after monoclonal tightly ligating the selective portion of the common Sciatic antibody of collagen is injected. Dosing volume is 20 ml kg. nerve according to the method of Seltzer (1990). Briefly, the high-thigh level of the left sciatic nerve is exposed after skin Animals incision and blunt separation of muscles at a site near the 0506 Animals are conditioned in accordance with the trochanter just distal to the point at which the posterior procedures set forth in the previous Example. biceps semitendious nerve nerve branches from the common sciatic nerve. The nerve is then fixed in this position with Chemicals fine forceps by pinching the epineurium on its dorsal aspect, 0507 Lipopolysaccharide is obtained from Sigma, USA; taking care not to press the nerve against underlying struc Indomethacin is from Sigma, USA; Arthrogen-CIATM tures. An 8-0 silicon-treated silk suture is inserted into the Monoclonal Antibodies D8, F10, DI-2G and A2 are obtained nerve with a 3/8 curved, reversed-cutting mini-needle, and from IBL, Japan; Phosphated-Buffer Saline is purchased tightly ligated so that the dorsal /3-/2 of the nerve is trapped from Sigma, USA; and Tween 80 is from Wako, Japan. in the ligature. The muscles are sutured in layers, and the skin closed with wound clips. Animals are then returned to Equipment their home cages. Rats exhibiting postoperative neurological 0508 Plethysmometer (Ugo Basile, Italy) and Water Cell deficits or poor grooming are excluded from the experi (Ugo Basile, Italy). mentS. Method Equipment 0509 Groups of 5 Balb/cByJ mice strain, 6-8 weeks of 0513. The following equipment is used in the current age, are used for the induction of arthritis by monoclonal studies: von Frey filament set (Touch-test Sensory Evalua antibodies (mAbs) responding to type II collagen, plus tor, North Coast Medical Inc., Morgan Hill, Calif.). lipopolysaccharide (LPS). The animals are administered intravenously with a combination of 4 different mAbs in a Statistical Methods: total of 4 mg/mouse at day 0, and followed by intravenous 0514 Within each experiment mean, standard error of the 25 ug of LPS 72 hours later (day 3). From day 3, one hour mean (SEM) and Statistical significance are calculated using after LPS administration, ML-659 at 50 mg/kg (PO) or 30 the average, standard error of the mean and unpaired, mg/kg (IP) and vehicle (2% Tween 80/0.9% NaCl, PO) as two-tailed t-Test functions, respectively, using Microsoft well as the positive control indomethacin, 3 mg/kg (PO) are Excel(R). Statistical significance of effects observed between administrated once daily for 3 consecutive days. A plethys individual experiments is determined, using Prism (Graph mometer (Ugo Basile Cat #7150) with water cell (12 mm Pad Software Inc., San Diego, Calif.). for the one-way or diameter) is used for the measurement of increase in Volume two-way analysis of variance (ANOVA) function. Statistical of the two hind paws at day 0, 5, 7, 10, 14, and 17. The analyses are performed with a confidence limit of 0.95 and percent inhibition of increase in volume is calculated by the a significance level of 0.05. following formula: Inhibition (%): 1-(Tn-To)/(Cn-Co)x100 EXAMPLE 8 Where: Pore Formation Co (Cn): Volume of day 0 (day n) in vehicle control 0515) THP-1 cells (ATCC Cat #285-IF-100) are plated in To (Tn): volume of day 0 (day n) in test compound-treated 96 well plates at a concentration of 200,000 cells per well group and allowed to differentiate in RPMI-1640 media (ATCC Cat # 30-2001) containing 10% FBS, 100 IU/mL penicillin, The reduction of both of two hind paws edema by more than 100 ug/mL streptomycin, 100 ng/mL LPS and 100 ng/mL 30% is considered significant. IFN-Y for 16 hours. Following differentiation, the cells are EXAMPLE 7 pretreated with the compound of interest at the appropriate concentration for 30 minutes in RPMI-1640 media contain ing 100 IU/mL penicillin, 100 ug/mL streptomycin. The Neuropathic Pain Model pretreatment media is then replaced with assay buffer (20 0510) This example illustrates the analgesic activity of mM HEPES, 10 mM D-glucose, 118 mM NMDG, 5 mM the compounds of this invention using a Sciatic Nerve KC1, 0.4 mM CaCl) containing 5 uMYo-Pro 1 (Molecular ligation model of mononeuropathic pain. Probes Cat if Y3603) and the compound of interest at the appropriate concentration and the cells are incubated for an Test System additional 10 minutes. 2',3'-O-(4-benzoylbenzoyl)-adenos 0511 Adult male Sprague Dawley (SD) rats weighing ine 5'-triphosphate (Sigma Aldrich Cati B6396) is then 250-300gm (Charles River Laboratories, San Diego, Calif.) added to a final concentration of 40 uM and fluoroscence US 2008/0039478 A1 Feb. 14, 2008 56 readings measured at 491/509 excitation/emission every minute for 50 minutes using a Tecan Safire plate reader. TABLE 3 During this time temperature is maintained at of 37° C. Background adjusted fluorescence levels between drug AmideOle CompoundOOOLS treated and non-treated cells are used to calculate the percent Method of MW MS IL-1B inhibition ID Synthesis (calcd) (obs) % inhibition 1 A 4O6.91 -- 2 A 27437 -- EXAMPLE 9 3 A 282.35 -- 4 A 36449 -- IL-1B Release Assay (Alternate Method) 5 A 416.57 417.78 ---- 6 A 326.44 327.58 -- 0516 THP-1 cells (ATCC Cat #285-IF-100) are plated in is: 3. : 96 well plates at a concentration of 200,000 cells per well 9 A. 364.49 365.72 -- and allowed to differentiate in RPMI-1640 media (ATCC 10 A. 378.52 379.69 -- Cat # 30-2001) containing 10% FBS, 100 IU/mL penicillin, R A is is : 100 ug/mL streptomycin, 100 ng/mL LPS and 100 ng/mL 13 414.55 415.66 -- IFN-Y for 16 hours. Following differentiation, the cells are 3. is: -- treated for an additional 2 hours in RPMI-1640 media 16 C 41755 418.71 : containing 100 IU/mL penicillin, 100 ug/mL streptomycin 17 A 416.57 417.82 ------and fresh LPS at 100 ng/mL. The cells are then pretreated for k . 30 minutes with the compound of interest at the appropriate 2O C 302.42 303.73 -- concentration in RPMI media containing 100 IU/mL peni- 21 A 332.45 333.72 -- cillin,- - - - 100 ug/mL Streptomycin. Following the pretreatment 2322 A 400.523.18.42 4O164319.53 -- 2',3'-O-(4-benzoylbenzoyl)-adenosine 5'-triphosphate 24 A. 402.SO 403.75 --

(Sigma Aldrich Cati B6396) is added to a final concentra- 3. A 3. 289.50 ------tion of 250 uM and the cells incubated for an additional 45 27 C 451.01 452.29 ------minutes. 30 uIl of cell supernatant is then collected and 28 C 434.56 435.77 ------IL-1B levels determined via ELISA (R&D systems Cat. ii 3. is: : HSLB50) according to manufacturer's recommendations 31 C 430.59 431.90 ------using the Tecan Safire plate reader. Background adjusted 32 C 444.62 445.63 -- IL-1B levels of drug treated and non-treated cells are used to 3334 C 434.56451.01 435.25451.31 -- calculate the percent inhibition. 35 C 446.59 447.69 ------36 C 476.62 477.44 -- 0517. The synthetic and biological examples described in 37 C 476.62 477.43 -- this application are offered tO illustrate this invention and are 3839 C 43460.62 O.S9 431.82461.77 -- not to be construed in any way as limiting the scope of this 40 C 446.59 447.73 -- invention. In the examples, all temperatures are in degrees 2. 2. S. -- Celsius (unless otherwise indicated). The compounds that 43 C 41755 418.67 : have been prepared in accordance with the invention along 44 C 43 O.S9 431.69 -- with their biological activity data are presented in the 2. t i. following Table (Table 3). The syntheses of compounds of 47 C 452-55 453.26 ------this invention are carried out in accordance with the methods 48 K 365.48 366.60 -- set forth above 49 K 365.48 366.63 -- 50 K 398.94 399.32 -- 51 K 398.94 399.32 -- Activity of Compounds of the Invention 52 K 365.48 366.66 -- 53 K 398.94 399.34 -- 0518). The O% Inhibition- data for the representative com- 55S4 K 378.52394.52 395.60379.73 -- pounds of the inventions are given in Table 3 below. For 56 K 442.58 443.64 -- purpose of Table 3, activity of each compound is expressed 57 K 421.54 422.67 -- follows: 58 A 394.52 395.10 -- aS TOTOWS 59 A 408.54 40941 --

- 0 ------60 A 454.61 455.49 -- “+” compound exhibited 0-25% inhibition at 0.3 uM 61 C 417.SS 418.74 -- 62 C 473.62 474.72 ------“++’ compound exhibited 25-50% inhibition at 0.3 uM 63 C 444.62 445.88 -- 64 C 455.6O 456.71 -- “+++’ compound exhibited 50-75% inhibition at 0.3 uM 65 C 493.6S 494.87 -- 66 C 436.62 437.43 -- & G ++++’99 compound exhibited- 0 75%O or greater inhibition------at 6768 C 42O.S6SO8.66 421.70SO9.74 ------0.3 M 69 C 467.61 468.86 ------70 C 484.56 485.78 -- 0519 Compounds with a percent inhibition represented 71 C 472.67 473.75 -- by “++++’ are of particular interest. US 2008/0039478 A1 Feb. 14, 2008 57

TABLE 3-continued TABLE 3-continued Amide Compounds Amide Compounds Method of MW MS IL-1B Method of MW MS IL-1B ID Synthesis (calcd) (obs) % inhibition ID Synthesis (calcd) (obs) % inhibition

72 484.56 485.77 480.63 481.24 ------73 467.61 468.86 47 432.59 433.30 ------74 SOO.S6 SO1.76 48 418.56 419.26 -- 75 SO8.66 509.76 49 496.63 497.39 ------76 SOO.S6 SO1.82 50 SO1.05 SO1.20 77 482.57 483.69 51 526.65 527.26 78 482.57 483.70 52 484.59 485.33 79 498.69 499.85 53 480.63 481.24 8O 462.64 463.81 -- -- S4 S34.60 535.18 81 420.56 421.67 ------55 S35.49 535.03 82 4O6.53 4O7.71 ------57 537.68 S38.42 83 457.04 457.37 ------58 519.07 S1930 84 459.57 460.72 59 538.59 539.32 85 448.58 449.68 60 546.69 S47.31 86 448.58 44967 ---- 61 SSO.60 SS1.34 87 483.03 483.37 ---- 62 496.63 497.40 88 483.03 483.38 ------64 484.62 485.35 89 489.66 490.73 65 526.06 526.20 90 496.56 497.98 66 484.59 485.33 91 489.62 490.72 67 491.61 492.23 92 489.62 490.78 ------68 SO1.05 SO1.20 ------93 379.51 380.67 69 485.61 486.30 ---- 94 379.51 380.74 72 S59.69 S60.15 ------95 464.58 465.80 ------73 S59.69 S60.16 96 502.55 SO3.68 74 S59.69 S60.15 ------97 502.55 503.67 ---- 75 588.73 589.31 ------98 482.63 483.72 ---- 77 626.70 627.38 ---- 99 476.62 477.63 81 569. OS 569.20 ---- OO 476.62 477.65 ---- 82 616.62 617.35 ------O1 476.62 477.63 ---- 83 S48.63 549.32 ---- O2 464.58 465.83 84 498.62 499.25 ------O3 464.58 465.79 85 549.52 549.26 ---- O4 464.58 46581 ------86 549.52 549.27 ------05 458.60 459.75 87 S48.63 549.33 ------O6 502.55 503.70 89 515.07 515.29 ------O7 502.55 SO3.68 90 S32.61 S33.16 ------O8 502.55 SO3.68 91 558.70 559.21 09 502.55 503.75 92 SO1.05 SO1.21 ------10 502.55 503.70 93 S19.04 S1929 11 502.55 503.76 94 S42.70 543.28 ------12 480.65 481.61 95 S34.60 535.20 13 474.65 475.72 97 526.65 527.28 ------14 SOO.S6 SO1.8O 98 498.65 499.31 15 486.61 487.73 99 480.63 481.26 ------16 462.66 463.75 200 524.64 S25.34 17 462.59 463.68 2O2 S19.04 S19.28 ---- 18 431.58 432.87 2O3 SO2.58 503.25 19 464.58 465.80 -- -- 204 S35.49 535.07 2O 484.56 485.78 205 S19.04 519.27 21 408.59 40980 2O6 SO2.58 SO3.26 22 422.61 423.72 2O7 515.07 515.29 ------23 434.56 435.69 208 S35.49 535.08 ------24 4O6.57 4O7.78 209 SO2.58 SO3.26 ------25 398.57 399.68 210 S35.49 535.08 26 368.48 369.61 211 S19.04 519.27 27 384.56 385.67 212 498.62 499.28 ------28 370.54 371.71 214 S10.66 511.41 29 392.54 393.76 215 484.59 48534 ------30 396.51 397.70 216 526.65 527.28 ------31 502.55 503.73 217 494.66 495.35 33 403.48 404.68 218 499.44 499.16 ------34 403.48 404.68 219 368.48 369.24 35 392.46 393.40 220 43 O.S.S 431. SO ------36 408.54 4O9.70 222 465.98 466.32 ------37 452.55 451.46 ------223 382.51 383.30 38 474.60 475.66 ------224 474.60 475.26 39 434.56 435.90 ---- 225 444.58 445.36 40 490.60 491.78 227 448.54 449.15 41 490.60 491.82 228 514.55 515.31 42 404.53 40S.38 ------229 458.60 459.39 ------43 466.60 467.26 230 444.58 445.36 ------US 2008/0039478 A1 Feb. 14, 2008 58

TABLE 3-continued TABLE 3-continued Amide Compounds Amide Compounds Method of MW MS IL-1B Method of MW MS IL-1B ID Synthesis (calcd) (obs) % inhibition ID Synthesis (calcd) (obs) % inhibition

231 450.62 451.27 ---- 307 412.53 413.33 ---- 232 466.53 467.27 ------3O8 432.53 433.33 233 498. SS 499.29 ------309 472.59 473.26 ------234 460.57 461.28 ---- 310 478.56 479.13 ------235 466.67 467.33 ------311 482.59 483.31 236 520.67 S21.33 ------312 490.60 49129 237 43154 432.39 313 486.61 487.33 238 422.57 42326 ------316 434.56 435.41 239 SO4.63 505.27 ---- 317 488.63 489.69 240 398. SO 399.25 3.18 SO4.67 505.72 241 462.57 463.29 ------319 485.46 485.45 242 455.56 456.28 ------320 444.62 445.88 243 498. SS 499.29 ------321 460.57 461.74 244 436.60 437.27 ---- 322 452.55 453.60 245 499.44 499.17 ------323 469.00 469.60 246 490.60 49129 ---- 324 481.04 481.39 247 466.53 467.27 ------325 S19.01 51944 248 458.60 459.38 326 469.00 469.61 249 460.57 461.29 327 552.56 553.75 250 460.57 461.29 ------328 469.00 469.60 ------251 448.54 449.15 329 469.00 469.61 ------252 410.56 411.30 ---- 330 552.72 553.96 ------253 464.99 465.22 ------331 S48.68 549.84 254 SO4.63 505.27 332 455.60 456.75 ------255 410.56 411.30 ---- 333 488.63 489.78 ------256 474.60 475.26 ------334 402.54 403.72 ------257 455.56 456.31 335 446.59 447.72 ---- 258 499.44 499.18 ------336 43 O.S9 431.84 ------260 394.52 395.18 ------337 451.01 451.37 ---- 261 474.60 475.27 338 B 434.56 435.75 ------262 424.59 425.28 339 444.62 445.89 263 436.60 437.28 ------340 460.57 461.72 ------264 495.02 495.34 ------341 444.62 445.92 26S 479.02 479.13 ---- 342 415.58 416.81 266 516.54 517.29 343 472.67 473.86 267 516.54 517.28 ---- 344 458.65 459.60 269 514.55 515.31 ---- 345 486.70 487.64 270 498. SS 499.30 346 444.62 445.68 271 532.99 533.17 ------347 480.60 481.32 272 482.98 483.30 ------348 479.06 479.41 273 511.63 51246 ------349 458.65 459.61 274 S23.63 524.50 350 SO2.66 SO3.48 275 490.60 49129 ------351 483.66 484.42 276 488.58 489.33 ------352 462.61 463.48 277 466.53 467.27 ------353 SO8.68 509.78 278 444.58 445.37 ------3S4 529.10 529.37 279 466.53 467.27 ------355 S30.64 531.58 28O 448.54 449.19 ------356 57.7.57 577.60 281 465.98 466.32 357 543.13 543.54 282 499.44 499.19 ------358 472.63 473.79 283 435.53 436.32 ------359 526.60 527.74 284 448.57 44922 ---- 360 S27.49 527.55 285 448.57 44922 361 494-58 495.77 286 564.61 565.37 ------362 511.04 511.57 288 510.64 S1145 363 494-58 495.82 290 480.61 481.29 ------364 S27.49 527.50 291 444.58 445.37 ------365 464.65 465.74 292 460.57 461.28 ------366 464.65 46581 293 448.56 449.20 ------367 452.64 453.70 294 464.99 465.23 ------368 429.60 430.78 295 479.62 480.21 369 462.61 463.49 296 421.50 422.09 ------370 479.06 479.01 -- -- 297 449.SS 450.19 371 462.61 463.49 ------298 465.98 466.32 ------372 458.65 459. SO ------299 435.53 436.32 373 SO2.66 SO3.34 ------300 490.65 491.32 374 480.60 481.34 ---- 301 486.66 487.36 ------375 483.66 484.34 ---- 3O2 S23.47 523.35 ------376 462.61 463-47 ---- 303 481.60 482.22 ------377 SO8.68 SO9.31 ------304 43154 432.38 378 57.7.57 577.18 ------306 519.56 S2O.28 379 543.13 543.50 ------US 2008/0039478 A1 Feb. 14, 2008 59

TABLE 3-continued TABLE 3-continued Amide Compounds Amide Compounds Method of MW MS IL-1B Method of MW MS IL-1B ID Syn hesis (calcd) (obs) % inhibition ID Syn hesis (calcd) (obs) % inhibition

380 529.10 529.26 -- 488 487.02 487.25 -- 381 S30.64 531.21 -- 489 S1 2.63 S13.33 ------382 472.63 473.40 ---- 490 470.57 471.35 ------383 526.60 S2741 -- 491 466.60 467.2S 384 464.65 46SSO ---- 492 520.57 S21.23 ------385 527.49 S27.34 -- 493 536.57 537.30 ---- 386 464.65 46SSO ---- 494 523.65 524.45 ------387 494.58 495.26 -- 495 SOS.04 505.09 ---- 388 452.64 453.34 -- 497 536.57 537.30 389 511.04 511.25 ---- 498 482.60 483.30 : 390 494.58 495.26 -- 499 470.60 471.38 391 527.49 527.33 -- 500 S1 2.03 S12.29 ------394 416.52 417.34 ---- 5O1 470.57 471.35 ---- 398 43 O.S.S 431.33 ------503 471.58 472.28 399 450.97 451.08 -- 505 520.61 S21.23 400 434.51 435.30 -- SO6 S45.66 S46.17 ------401 500.52 SO1.23 -- 509 574.70 575.32 ------402 444.58 445.32 -- 510 612.67 613.09 ------403 43 O.S.S 431.33 ---- 512 558.70 559.19 ---- 40S 452.50 453.02 ---- S14 555.02 555.07 406 484.52 485.32 ---- 515 6O2.60 603.35 ------407 446. SS 447.19 -- S16 S34.60 S35.14 ---- 409 SO6.65 507.30 -- 517 484.59 485.32 ---- 413 448.54 449.02 ---- S18 S35.49 53504 ------414 441.53 442.31 ---- 519 S35.49 535.03 ------415 484.52 485.32 -- 52O S34.60 S35.14 ---- 417 485.41 485.29 -- 522 SO1.05 SO1.20 ------418 476.57 477.23 ---- 523 S18.58 S1929 419 452.50 453.03 -- 524 S44.67 545.25 ------421 446. SS 447.19 -- 525 487.02 487.24 422 446. SS 447.19 ---- 526 SOS.O1 505.07 ---- 423 435.30 ---- 527 S28.67 529.17 ------424 397.24 -- 528 520.57 S21.23 ---- 425 451.09 -- 531 484.62 48534 ---- 428 461.28 -- 532 536.57 537.30 430 485.28 ---- 533 466.60 467.2S ------433 461.27 ---- 534 S10.61 511.35 ------436 481.16 ---- 535 520.57 S21.23 ---- 437 465.13 -- 536 SOS.O1 SOS.06 ---- 438 SO3.26 ---- 537 488.56 489:26 ---- 439 503.27 ---- 538 S21.47 S21.11 ---- 442 485.32 ---- 539 SOS.O1 505.05 ---- 443 S19.28 ---- S4O 488.56 489.25 444 469.29 -- 541 SO1.05 SO1.19 ------446 S10.36 ---- S42 S21.47 S21.10 449 453.03 ---- 543 488.56 489:26 ---- 450 431.33 -- 545 SOS.O1 505.03 ---- 451 453.02 -- S46 484.59 485.32 452 435.31 ---- S48 496.63 497.36 : 453 452.10 -- 549 S1 2.63 S13.33 ---- 454 485.29 ---- 550 480.63 481.21 455 422O2 552 438.66 439.43 ------459 531.09 553 492.66 493.37 ---- 460 467.26 554 43 O.S9 431.35 ------461 431.33 : 555 3S4SO 355.27 463 435.32 ---- 556 408.59 4O936 464 451.09 ---- 557 366.51 367.23 466 408.19 558 382.55 383.31 ---- 470 SO921 : 559 43 O.S9 431.35 ---- 471 468.20 ---- S60 403.53 404:45 ---- 475 465.18 ---- S62 432.56 433.30 476 477.23 ---- S64 446.SS 44720 ------477 473.25 ---- 565 452.60 453.09 ------479 485.29 -- 566 462.59 463.29 480 391.30 567 484.60 48534 ---- 481 453.02 ---- 568 494.64 495.34 482 467.24 ---- 570 471.43 471.34 ---- 483 SO3.26 ------571 427.55 428.17 ------485 419.24 572 458.65 459.3S ------486 40S.33 576 494.64 495.35 ------487 483.29 ---- 583 382.55 383.31 US 2008/0039478 A1 Feb. 14, 2008 60

0522 All publications, including but not limited to pat TABLE 3-continued ents and patent applications, cited in this specification are herein incorporated by reference as if each individual pub Amide Compounds lication were specifically and individually indicated to be Method of MW MS IL-1B incorporated by reference herein as though fully set forth. ID Synthesis (calcd) (obs) % inhibition

S84 432.56 433.30 -- ... (canceled) 585 43 O.S9 431.35 ---- ... (canceled) S86 497.04 497.38 -- ... (canceled) S88 S38.69 539.37 ---- 589 460.57 461.27 ------... (canceled) 590 471.43 471.33 -- ... (canceled) 591 462.59 463.29 -- ... (canceled) 592 S38.69 539.37 ------593 448.56 449.09 -- 7. (canceled) 594 541.49 541.24 -- 8. (canceled) 595 445.54 446.17 -- 9. (canceled) 596 446. SS 44720 ------597 481.44 481.OS ------10. (canceled) 598 436.98 437.12 -- 11. (canceled) 599 480.99 481.17 -- 12. (canceled) 6O1 436.98 437.12 ------13. (canceled) 6O2 416.57 417.37 ---- 603 427.55 428.16 -- 14. (canceled) 604 470.54 471.38 ------15. (canceled) 60S 420.53 421.21 -- 16. (canceled) 606 416.57 417.37 -- 607 420.53 421.21 ------17. (canceled) 608 462.59 463.30 -- 18. (canceled) 610 403.53 404.46 -- 19. (canceled) 611 454.97 455.21 ------612 488.53 489.30 ------20. (canceled) 613 482.42 482.13 -- 21. (canceled) 614 481.44 481.04 -- 22. (canceled) 615 432.56 433.30 ------618 499.43 499.13 -- 23. (canceled) 619 394.56 395.19 -- 24. (canceled) 62O 486.54 487.29 ---- 25. (canceled) 621 JJ 468. SS 469.31 ------622 526.65 527.31 ---- 26. (canceled) 623 480.58 481.25 -- 27. (canceled) 624 468. SS 469.32 -- 28. (canceled) 625 446.59 447.23 -- 29. (canceled) 626 562.63 S63.31 ---- 627 482.53 483.31 ------30. (canceled) 628 450.55 451.2O -- 31. (canceled) 629 450.55 451.2O -- 32. (canceled) 630 446.59 447.22 ------631 462.59 463.29 -- 33. (canceled) 632 486.54 487.29 ---- 34. (canceled) 633 462.59 463.29 -- 35. (canceled) 634 437.97 438.15 -- 635 454.97 455.22 -- 36. (canceled) 636 43 O.S6 -- 37. (canceled) 38. (canceled) A - Method of synthesis described in “Synthetic Methods' section 39. (canceled) 40. (canceled) 0520. At least some of the chemical names of compounds 41. (canceled) of the invention as given and set forth in this application, 42. (canceled) may have been generated on an automated basis by use of a 43. (canceled) commercially available chemical naming software program, and have not been independently verified. Representative 44. (canceled) programs performing this function include the Lexichem 45. (canceled) naming tool sold by Open Eye Software, Inc. and the 46. (canceled) Autonom Software tool sold by MDL, Inc. Also, the various 47. (canceled) groups as recited in Tables 1A-1D may be attached to the 48. (canceled) core structure in a conventional manner which should occur 49. A method for preventing, treating or ameliorating in a to those skilled in the art. mammal a disease or condition that is causally related to the aberrant activity of the P2X, receptor in vivo, which com 0521. From the foregoing description, various modifica prises administering to the mammal an effective disease tions and changes in the compositions and methods of this treating or condition-treating amount of a pharmaceutical invention will occur to those skilled in the art. All such composition, said pharmaceutical composition comprising a modifications coming within the scope of the appended pharmaceutically acceptable carrier and a pharmaceutically claims are intended to be included therein. effective amount of a compound having a formula: US 2008/0039478 A1 Feb. 14, 2008 61

Sulfuric acid, sulfuric acid ester, substituted or unsub stituted dihydroxyphosphoryl substituted or unsubsti II tuted aminodihydroxyphosphoryl azido, carboxy, Sub R3a. L1-B- stituted or unsubstituted carbamoyl cyano, Substituted Y R. R." or unsubstituted cycloalkyl substituted or unsubstituted cycloheteroalkyl substituted or unsubstituted dialky A N lamino, halo, heteroaryloxy, Substituted or unsubsti Y *. O tuted heteroaryl substituted or unsubstituted het Nan -N O eroalkyl, hydroxy, nitro, and thio; Z IIa R3a. and the dotted bond is a single or a double bond, L1-B- Y R. R." or a pharmaceutically acceptable salt thereof, A X and stereoisomers and tautomers thereof. 's R1 50. The method of claim 49, wherein the disease or Nan -N H condition is a pain condition. Z 51. The method of claim 49, wherein the disease or condition is an autoimmune disease. wherein 52. The method of claim 49, wherein the disease or condition is an inflammatory disease or condition. A is selected from CRR: 53. The method of claim 49, wherein the disease or B and Y are independently selected from CR* and condition is a neurological or neurodegenerative disease or CR2aR2b: condition. Z is CR: 54. A method for preventing, treating or ameliorating in a mammala disease or condition selected from: pain including L' is a bond, —CO—SO - or a C1-C5 alkylene group acute, inflammatory and neuropathic pain, chronic pain, which can be optionally substituted by a substituent dental pain and headache including migraine, cluster head selected from alkyl hydroxy hydroxyalkylaminoalkyl ache and tension headache, Parkinson's disease, multiple alkylaminoalkyl dialkylaminoalkyl halogen, carbam Sclerosis; diseases and disorders which are mediated by or oyl and C-C alkoxy: result in neuroinflammation, traumatic brain injury and encephalitis; centrally-mediated neuropsychiatric diseases n is 0, 1, 2 or 3, and disorders, depression mania, bipolar disease, anxiety, R" is selected from a 3-13 membered cycloalkyl which Schizophrenia, eating disorders, sleep disorders and cogni can be optionally substituted with one or more sub tion disorders; epilepsy and seizure disorders; prostate, stituents independently selected from halo hydroxy bladder and bowel dysfunction, urinary incontinence, uri lamino cyano Sulfo Sulfanyl, Sulfinyl amido, carboxy, nary hesitancy, rectal hypersensitivity, fecal incontinence, ester, alkyl substituted alkyl alkenyl substituted alkenyl benign prostatic hypertrophy and inflammatory bowel dis alkynyl Substituted alkynyl and Sulfonamido: ease; respiratory and airway disease and disorders, allergic rhinitis, asthma and reactive airway disease and chronic each of R*, RR and R" is independently selected obstructive pulmonary disease; diseases and disorders which from hydrogen, Substituted or unsubstituted C-C, are mediated by or result in inflammation, arthritis, rheu alkyl; or any of R and R can join together to form a matoid arthritis and osteoarthritis, myocardial infarction, cycloalkyl or cycloheteroalkyl ring of 3-7 atoms: various autoimmune diseases and disorders, uveitis and R is selected from hydrogen substituted or unsubstituted atherosclerosis; itch/pruritus, psoriasis; obesity; lipid disor alkyl substituted or unsubstituted cycloalkyl substituted ders; cancer, blood pressure; spinal cord injury; and renal or unsubstituted heterocycloalkyl substituted or unsub disorders which comprises administering to the mammal an stituted aryl substituted or unsubstituted heteroaryl, effective disease-treating or condition-treating amount of a substituted or unsubstituted bicycloaryl, and substi pharmaceutical composition, tuted or unsubstituted bicycloheteroaryl; provided said pharmaceutical composition comprising a pharma when R is hydrogen L' is a bond or a C-C alkylene ceutically acceptable carrier and a pharmaceutically grOup, effective amount of a compound having a formula: R" is selected from H, alkyl substituted alkyl acyl substi tuted acyl substituted or unsubstituted acylamino sub stituted or unsubstituted alkylamino substituted or II unsubstituted alkylthio, substituted or unsubstituted R3 alkoxy, alkoxycarbonyl Substituted alkoxycarbonyl SL - B substituted or unsubstituted alkylarylamino arylalky Y | R. R." loxy substituted arylalkyloxy amino aryl, substituted A N aryl, arylalkyl substituted or unsubstituted sulfoxide, 21 R1 O Substituted or unsubstituted sulfone substituted or unsubstituted sulfanyl substituted or unsubstituted ami Ns-N O nosulfonyl substituted or unsubstituted arylsulfonyl US 2008/0039478 A1 Feb. 14, 2008 62

and the dotted bond is a single or a double bond, -continued IIa or a pharmaceutically acceptable salt thereof, R3a. L1-B- and stereoisomers and tautomers thereof. Y R. R." 55. The method of claim 54, wherein the disease or condition is Parkinson's disease. A X 56. The method of claim 54, wherein the disease or Yss condition is rheumatoid arthritis. Nan -N H 57. The method of claim 54, wherein the disease or Z condition is traumatic brain injury. 58. The method of claim 54, wherein the disease or wherein condition is osteoarthritis. 59. The method of claim 54, wherein the disease or A is selected from CRR: condition is pain. B and Y are independently selected from CR* and 60. The method of claim 54, wherein the disease or CR2aR2b: condition is neuropathic pain. Z is CR: 61. A method of treating a mammal Suffering from at least one symptom selected from the group consisting of symp L' is a bond, —CO—SO - or a C-C alkylene group toms of exposure to capsaicin, symptoms of burns or irri which can be optionally substituted by a substituent tation due to exposure to heat, symptoms of burns or Selected from alkyl, hydroxy, hydroxyalkyl, ami irritation due to exposure to light, symptoms of burns, noalkyl, alkylaminoalkyl, dialkylaminoalkyl halogen, bronchoconstriction or irritation due to exposure to tear gas, carbamoyl and C-C alkoxy; and symptoms of burns or irritation due to exposure to acid, n is 0, 1, 2 or 3, which comprises administering to the mammal an effective R" is selected from a 3-13 membered cycloalkyl which disease-treating or condition-treating amount of a pharma can be optionally substituted with one or more sub ceutical composition, stituents independently selected from halo, hydroxyl, said pharmaceutical composition comprising a pharma amino, cyano, Sulfo, Sulfanyl. Sulfinyl amido, carboxy, ceutically acceptable carrier and a pharmaceutically ester, alkyl substituted alkyl alkenyl substituted alkenyl effective amount of a compound having a formula: alkynyl Substituted alkynyl and Sulfonamido:

each of R. R. R. and R" is independently selected II from hydrogen, Substituted or unsubstituted C-C, R3a. alkyl: or any of R and R' can join together to form a L1-B- cycloalkyl or cycloheteroalkyl ring of 3-7 atoms: Y R. R." R is selected from hydrogen, substituted or unsubstituted A N alkyl, substituted or unsubstituted cycloalkyl substi tuted or unsubstituted heterocycloalkyl substituted or Y. *. O Nan -N O unsubstituted aryl substituted or unsubstituted het Z eroaryl substituted or unsubstituted bicycloaryl and IIa substituted or unsubstituted bicycloheteroaryl; pro R3a. vided when R is hydrogen L' is a bond or a C-Cs la-B- alkylene group, Y R. R." R is selected from H. alkyl substituted alkyl acyl substi A X tuted acyl Substituted or unsubstituted acylamino, Sub 's R1 stituted or unsubstituted alkylamino, substituted or Nan -N H unsubstituted alkylthio, substituted or unsubstituted Z alkoxy, alkoxycarbonyl Substituted alkoxycarbonyl substituted or unsubstituted alkylarylamino arylalky loxy, Substituted arylalkyloxy, amino, aryl, Substituted wherein aryl, arylalkyl substituted or unsubstituted sulfoxide, A is selected from CRR: Substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl substituted or unsubstituted ami B and Y are independently selected from CR and nosulfonyl substituted or unsubstituted arylsulfonyl CR2aR2b: Sulfuric acid sulfuric acid ester substituted or unsub stituted dihydroxyphosphoryl substituted or unsubsti Z is CR: tuted aminodihydroxyphosphoryl azido carboxy Sub L' is a bond, —CO—SO - or a C1-C5 alkylene group stituted or unsubstituted carbamoyl cyano, Substituted which can be optionally substituted by a substituent or unsubstituted cycloalkyl substituted or unsubstituted selected from alkyl hydroxy hydroxyalkylaminoalkyl cycloheteroalkyl, substituted or unsubstituted dialky alkylaminoalkyl dialkylaminoalkyl halogen, carbam lamino halo heteroaryloxy substituted or unsubstituted oyl and C-C alkoxy: heteroaryl substituted or unsubstituted heteroalkyl hydroxy, nitro, and thio; n is 0, 1, 2 or 3, US 2008/0039478 A1 Feb. 14, 2008 63

R" is selected from a 3-13 membered cycloalkyl which or unsubstituted cycloalkyl substituted or unsubstituted can be optionally substituted with one or more sub cycloheteroalkyl substituted or unsubstituted dialky stituents independently selected from halo hydroxy lamino, halo, heteroaryloxy, Substituted or unsubsti lamino cyano Sulfo Sulfanyl, Sulfinyl amido, carboxy, tuted heteroaryl, substituted or unsubstituted het ester, alkyl substituted alkyl alkenyl substituted alkenyl eroalkyl, hydroxy, nitro, and thio; alkynyl Substituted alkynyl and Sulfonamido: and the dotted bond is a single or a double bond; each of R, RR and R" is independently selected from hydrogen, Substituted or unsubstituted C-C, or a pharmaceutically acceptable salt thereof. alkyl: or any of R and R can join together to form a and stereoisomers and tautomers thereof. cycloalkyl or cycloheteroalkyl ring of 3-7 atoms: 62. The method of claim 61, wherein the pain is associ ated with a condition selected from the group consisting of R is selected from hydrogen substituted or unsubstituted postmastectomy pain syndrome, stump pain, phantom limb alkyl substituted or unsubstituted cycloalkyl substituted pain, oral neuropathic pain, Charcot's pain, toothache, Ven or unsubstituted heterocycloalkyl substituted or unsub omous Snake bite, spider bite, insect sting, postherpetic stituted aryl substituted or unsubstituted heteroaryl, neuralgia, diabetic neuropathy, reflex sympathetic dystro substituted or unsubstituted bicycloaryl, and substi phy, trigeminal neuralgia, osteoarthritis, rheumatoid arthri tuted or unsubstituted bicycloheteroaryl; provided tis, fibromyalgis, Guillain-Barre Syndrome, meralgia pares when R is hydrogen L' is a bond or a C-C alkylene thetica, burning-mouth Syndrome, bilateral peripheral grOup, neuropathy, causalgia, Sciatic neuritis, peripheral neuritis, R is selected from H. alkyl substituted alkyl acyl substi polyneuritis, segmental neuritis, Gombault's neuritis, neu tuted acyl substituted or unsubstituted acylamino sub ronitis, cervicobrachial neuralgia, cranial neuralgia, egnicu stituted or unsubstituted alkylamino substituted or late neuralgia, glossopharyngial neuralgia, migranous neu unsubstituted alkylthio, substituted or unsubstituted ralgia, idiopathic neuralgia, intercostals neuralgia, alkoxy, alkoxycarbonyl Substituted alkoxycarbonyl mammary neuralgia, mandibular joint neuralgia, Morton’s substituted or unsubstituted alkylarylamino arylalky neuralgia, nasociliary neuralgia, occipital neuralgia, red loxy substituted arylalkyloxy amino aryl, substituted neuralgia, Sluder's neuralgia splenopalatine neuralgia, aryl, arylalkyl substituted or unsubstituted sulfoxide, Supraorbital neuralgia, Vidian neuralgia, sinus headache, Substituted or unsubstituted sulfone substituted or tension headache, labor, childbirth, intestinal gas, menstrua unsubstituted sulfanyl substituted or unsubstituted ami tion, cancer, and trauma. nosulfonyl substituted or unsubstituted arylsulfonyl 63. (canceled) Sulfuric acid, sulfuric acid ester, substituted or unsub 64. (canceled) stituted dihydroxyphosphoryl substituted or unsubsti 65. (canceled) tuted aminodihydroxyphosphoryl azido, carboxy, Sub 66. A method according to any of claims 49, 54 or 61, stituted or unsubstituted carbamoyl cyano, Substituted wherein said compound is selected from

Name STRUCTURE

5,6,7,8-Tetrahydro-pyrido 3,4- dpyrimidine-4-carboxylic acid cyclohexylmethyl-amide:

7-Benzyl-5,6,7,8-tetrahydro-pyrido 3,4- dpyrimidine-4-carboxylic acid cyclohexylmethyl-amide: