Krause, James E. (Madison, CT, US)

10/401113

01/22/2004

03/27/2003

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514/397

(IPC1-7): A61K031/426; A61K031/16; A61K031/4178; A61K031/427; A61K031/4709

Neurogen Corporation, Leslie-anne Horvath (Patent Department, Branford, CT, 06405, US)

What is claimed is:

1. A composition comprising a therapeutically effective amount of at least one C5a antagonist and a therapeutically effective amount of at least one C5a receptor-inactive therapeutic agent, wherein the C5a antagonist is a compound of the formula: 26 or a pharmaceutically acceptable salts thereof, wherein 27 is: i) a 5-membered heteroaryl ring system, in which x is 0; A is carbon, nitrogen, oxygen, or sulfur; and E and G are independently carbon or nitrogen, provided that the 5-membered heteroaryl ring system does not contain more than 3 heteroatoms or more than 1 oxygen or sulfur atom; or ii) a 6-membered heteroaryl ring system, in which x is 1; A, B, E, and G are independently chosen from carbon and nitrogen, provided that the 6-membered heteroaryl ring system does not contain more than 3 nitrogen atoms. R and R1 independently represent: i) hydrogen, hydroxy, halogen, amino, cyano, nitro, —CHO, —CONH2, C1-C6haloalkyl, or C1-C6 haloalkoxy; ii) C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6 alkoxy, C3-C7cycloalkyl, (C3-C7cycloalkyl)C1-C4alkyl, mono- or di-C1-C6alkylamino, mono- or di-C1-C6alkyl aminoC1-C6alkyl, mono- or di-C1-C6alkylcarboxamide, C1-C6alkoxycarbonyl, —NHSOnC1-C6alkyl, —SOnN(C1-C6alkyl) (C1-C6alkyl), or phenyl-SOn—, each of which is optionally substituted, wherein n is 0, 1 or 2; or iii) naphthyl, phenyl, phenylC1-C4carbhydryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heteroarylC1-C4carbhydryl, each of which is optionally substituted; If E is nitrogen, R2 is chosen from C1-C7alkyl, C2-C7alkenyl, C2-C7 alkynyl, C3-C7cycloalkyl(C1-C4alkyl), benzyl and C1-C6haloalkyl; If E is carbon, R2 is chosen from halogen, hydroxy, C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7alkoxy, C1-C7alkylamino, C3-C7cycloalkyl(C1-C4alkyl), benzyl, C1-C6haloalkyl, and C1-C6haloalkoxy; R3 is hydrogen, C1-C6alkyl, C2-C6alkenyl, hydroxyC[-C6alkyl, C1-C6haloalkyl, C3-C7cycloalkyl, (C3-C7cycloalkyl)C1-C4alkyl, or phenyl(C1-C4alkyl); or when x is 0, R1 and R3 may be joined to form an optionally substituted (C3-C7)cycloalkyl; R4 is i) hydrogen; ii) C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7cycloalkenyl, (C3-C7cycloalkyl)C1-C4alkyl, (C3-C7cycloalkenyl)C1-C4alkyl, or hexahydro-1,3-benzodioxolylmethyl, each of which is optionally substituted; iii) optionally substituted arylC1-C4alkyl having 1 or 2 fused or pendant rings; iv) optionally substituted arylC1-C4alkyl, wherein the aryl portion is fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; v) optionally substituted heterocycloalkyl(C0C4alkyl); vi) optionally substituted heteroarylC1-C2alkyl having from 1 to 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; or vii) optionally substituted saturated or partially unsaturated heterocyclic(C0C4alkyl) having from 4 to 7 ring members, 1 or 2 of which ring members are N, S or O, with remaining ring members being carbon; R5 and R6 are independently chosen from hydrogen and C1-C6alkyl; z is 1, 2, or 3; Ar1 is i) optionally substituted aryl having 1 or 2 fused or pendant rings; ii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iii) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; Ar2 is i) optionally substituted C3-C7cycloalkyl, C3-C7cycloalkyl(C1-C4alkyl), C3-C7cycloalkenyl, C3-C7cycloalkenyl(C1-C4alkyl), or hexahydro-1,3-benzodioxolyl; ii) optionally substituted aryl having 1 or 2 fused or pendant rings; iii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iv) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; and y is 1 or 2.

2. A composition according to claim 1, wherein x is 0, A and G are carbon, and E is nitrogen.

3. A composition according to claim 2, wherein: Ar1 is phenyl, substituted with from 0 to 3 substituents independently chosen from hydroxy, cyano, halogen, methyl, ethyl, methoxy, and ethoxy; and R1 is phenyl substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, —CONH2, —OC(═O)CH3, —COOH, methylthio, ethylthio, and —SO2CH3.

4. A composition according to claim 3, wherein z is 1, R2 is C3-C5alkyl and R3 is hydrogen or methyl.

5. A composition according to claim 4, wherein R4 is: i) 1,3-benzodioxol-5-ylmethyl or 2,3-dihydro-1,4-benzodioxin-6-ylmethyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, methyl and methoxy; or ii) benzyl substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, pentafluoroethyl, —CF2CHF2, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, —OCF2CHF2, —CONH2, —C(═O)OCH3, —OC(═O)CH3, —COOH, methylthio, ethylthio, —SO2NH2, and —SO2CH3.

6. A composition according to claim 5, wherein R5 is hydrogen or methyl; R6 is hydrogen; and Ar2 is: i) benzo[1,3]dioxole or 2,3-dihydro-benzo[1,4]dioxine, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, methyl and methoxy; or ii) phenyl substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, pentafluoroethyl, —CF2CHF2, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, —OCF2CHF2, —CONH2, —C(═O)OCH3, —OC(═O)CH3, —COOH, methylthio, ethylthio, —SO2NH2, and —SO2CH3

7. A composition according to claim 1, wherein the C5a antagonist exhibits C5a antagonist activity with an IC50 of less than 100 nM in a standard assay for C5a antagonist activity.

8. A composition according to claim 1, wherein C5a receptor-inactive therapeutic agent is an NSAID.

9. A composition according to claim 1, wherein the C5a receptor-inactive therapeutic agent is a cyclo-oxygenase enzyme inhibitor.

10. A composition according to claim 1, wherein the C5a receptor-inactive therapeutic agent is an inhibitor of the cyclo-oxygenase 2 enzyme.

11. A composition according to claim 1, wherein the C5a receptor-inactive therapeutic agent is a gold compound or a salicylate.

12. A composition according to claim 1, wherein C5a receptor-inactive therapeutic agent is a steroid.

13. A composition according to claim 12, wherein C5a receptor-inactive therapeutic agent is a corticosteroid.

14. A composition according to claim 1, wherein C5a receptor-inactive therapeutic agent is methotrexate or leflunomide.

15. A composition according to claim 1, wherein C5a receptor-inactive therapeutic agent is a TNF antagonist.

16. A composition according to claim 1, wherein the C5a receptor-inactive therapeutic agent is a cholesterol lowering agent.

17. A composition according to claim 16, wherein the cholesterol lowering agent is an HMG-CoA reductase inhibitor.

18. A composition according to claim 1, wherein the C5a receptor-inactive therapeutic agent is a platelet aggregation inhibitor.

19. A composition according to claim 1, wherein the C5a receptor-inactive therapeutic agent is an anti-hypertensive agent.

20. A composition according to claim 19, wherein the antihypertensive agent is an adrenergic receptor stimulator.

21. A composition according to claim 19, wherein the antihypertensive agent is an alpha/beta adrenergic receptor antagonist, beta adrenergic receptor antagonist, ACE inhibitor, angiotensin II receptor antagonist, calcium channel blocker, diuretic, or periphereal vasodilator.

22. A composition comprising a therapeutically effective amount of at least one C5a antagonist and a therapeutically effective amount of at least one C5a receptor-inactive therapeutic agent, wherein the C5a antagonist is selected from: 1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl]) aminomethylimidazole; 1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N-[4-dimethylaminophenylmethyl]-N-phenylmethyl) aminomethylimidazole; 1-(1-Butyl)-2-(2-methylphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl) aminomethylimidazole; 1-(1-Butyl)-2-(4-fluorophenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])amino-methylimidazole; 1-(1-Butyl)-2-(2-methylphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])amino-methylimidazole; 1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[naphth-2-ylmethyl]-N-phenylmethyl)amino methylimidazole; 1-(1-Butyl)-2-(3-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl) aminomethylimidazole; 1-(1-Butyl)-2-(3-fluorophenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])amino-methylimidazole; 1-(1-Butyl)-2-(3-methoxyphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)-aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-{1-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)amino}ethylimidazole; 1-(1-Pentyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl) aminomethylimidazole; Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)amine; Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imdiazol-4-ylmethyl]-amine; 4-({Benzyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl)-amino}-methyl)benzamide; 4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}3-chloro-phenol; 4-({[1-(3-Butyl-2-phenyl-3H-imidazol-4-yl)-pentyl]-cyclohexymethyl-amino}-methyl)-phenol; 4-{[Benzyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amino]-methyl}benzamide; 1-(1-Propyl)-2-phenyl-5-(N-[indol-5-ylmethyl]-N-phenylmethyl) aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[1-(S)-phenylethyl]-N-phenylmethyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[1-(R)-phenylethyl]-N-phenylmethyl)aminomethylimidazole 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-dichlorophenyl]methyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenylmethyl]) aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-methoxyphenylmethyl])-aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{1-propyl}phenylmethyl])aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-dichlorophenylethyl])aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[4-nitrophenylmethyl])aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{1-propyloxy}phenylmethyl])aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[quinol-6-ylmethyl])-aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2,3-dichlorophenylmethyl])-aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-dimethylphenylmethyl])-aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[indan-2-yl])-aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2-phenylethyl])aminomethylimidazole; 1-(1-Propyl)-2-phenyl-5-(N-[1,4-benzodioxan-6-ylmethyl]-N-phenylmethyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-ethyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-propyl])aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-butyl])aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cycloheptylmethyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-isobutyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2-cyclopentylethyl])aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3-cyclopentylpropyl])amino-methylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-n-octyl])aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclopropylmethyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclopentylmethyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclohexylmethyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[t-amyl])aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-{3-methyl}butyl)]aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-{2,2-dimethyl}butyl]) aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-methyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2-thiophenylmethyl])aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[indol-5-ylmethyl])aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[{1-methylindol-5-yl}methyl])aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[4-hydroxy-2-chlorophenyl]-methyl)aminomethylimidazole; 1-(1-Butyl)-2-(3-fluorophenyl)-5-(1-[N-{2-chloro-4-hydroxyphenyl}methyl-N-phenylmethyl]) aminoethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[2,3-dihydrobenzo[b]furan-5-yl]methyl)aminomethylimidazole; 1-Butyl-2-(4-fluorophenyl)-5-(1-[N-{3,4-methylenedioxyphenyl}methyl-N-phenylmethyl]-amino)ethylimidazole; 1-(1-Butyl)-2-(2-thienyl)-5-(N-[3,4-methylenedioxyphenyl]methyl-N-phenylmethyl]aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4,5-trimethoxyphenylmethyl]-N-phenylmethyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-phenylmethyl-N-[3,4-dimethoxyphenylmethyl])aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[4-dimethylaminophenylmethyl]-N-phenylmethyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[4-methylaminophenylmethyl]-N-phenylmethyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3-methyl-4-aminophenylmethyl]-N-phenylmethyl)aminomethylimidazole); 1-(1-Butyl)-2-phenyl-5-(N-[2,3-dichlorophenylmethyl]-N-phenylmethyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-dichlorophenylmethyl]-N-phenylmethyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-[3,4-difluorophenylmethyl]-N-phenylmethyl)aminomethylimidazole; 1-(1-Butyl)-2-phenyl-5-(N-(benzo[b]thiophen-5-ylmethyl)-N-phenylmethyl)aminomethylimidazole; and 1-(1-Butyl)-2-phenyl-5-(N-[4-ethoxyphenylmethyl]-N-phenylmethyl)aminomethylimidazole.

23. A composition comprising a therapeutically effective amount of at least one C5a antagonist and a therapeutically effective amount of at least one C5a receptor-inactive therapeutic agent, wherein the C5a antagonist is selected from: N-benzyl-N-(2,3-dihydro-1H-indan-2-yl)-2-[1-(3-methylphenyl)-3,4-dihydroisoquinolin-2(1H)-yl]acetamide; N-benzyl-N-(2,3-dihydro-1H-indan-2-yl)-2-[1-(4-methylphenyl)-3,4-dihydroisoquinolin-2(1H)-yl]acetamide; N-benzyl-N-(2,3-dihydro-1H-indan-2-yl)-2-[1-(4-methoxyphenyl)-3,4-dihydroisoquinolin-2(1H)-yl]acetamide; N-[(5-bromo-2-phenyl-1,3-thiazol-4-yl)methyl]-N-isopentyl-2-(1H-pyrrol-1-yl)benzamide; N-butyl-N-[(5-chloro-2-phenyl-1,3-thiazol-4-yl)methyl]-2-(1H-pyrrol-1-yl)benzamide; N-[(5-chloro-2-phenyl-1,3-thiazol-4-yl)methyl]-N-isobutyl-2-(1H-pyrrol-1-yl)benzamide; N-[(5-chloro-2-phenyl-1,3-thiazol-4-yl)methyl]-N-isopentyl-2-(1H-pyrrol-1-yl)benzamide; N-[(5-chloro-2-phenyl-1,3-thiazol-4-yl)methyl]-N-cyclopentyl-2-(1H-pyrrol-1-yl)benzamide; 8-bromo-N-[(2-phenylquinolin-4-yl)methyl]-N-propyl-1-naphthamide; N-(2-chlorobenzyl)-N-(2-phenylethyl)-9H-fluorene-4-carboxamide; 2-(2-iodophenyl)-N-[(2-phenylquinolin-4-yl)methyl]-N-propylacetamide; 2-(2-phenoxyphenyl)-N-[(2-phenylquinolin-4-yl)methyl]-N-propylacetamide; 2-(2-methoxyphenyl)-N-[(2-phenylquinolin-4-yl)methyl]-N-propylacetamide; 2-(2-bromophenyl)-N-[(2-phenylquinolin-4-yl)methyl]-N-propylacetamide; N-benzyl-N-[2-(2-chlorophenyl)ethyl]-9H-fluorene-4-carboxamide; N-benzyl-N-(3-phenylbutyl)-9H-fluorene-4-carboxamide; N-benzyl-N-[2-(4-chlorophenyl)ethyl]-9H-fluorene-4-carboxamide; N-benzyl-N-(2,3-dihydro-1H-indan-2-yl)-1,1′-biphenyl-2-carboxamide; N-benzyl-N-(2,3-dihydro-1H-indan-2-yl)-9H-fluorene-4-carboxamide; N-benzyl-N-[2-(4-fluorophenyl)ethyl]-9H-fluorene-4-carboxamide; N-benzyl-N-[2-(4-methoxyphenyl)ethyl]-9H-fluorene-4-carboxamide; N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]-9H-fluorene-4-carboxamide; 2-chloro-N-{[1-(2,3-dihydro-1H-indan-2-yl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-(4-methoxybenzyl)benzamide; N-{[1-(2,3-dihydro-1H-indan-2-yl)-2-phenyl-1H-imidazol-5-yl]methyl}-2,5-difluoro-N-(4-methoxybenzyl)benzamide; N-(cyclohexylmethyl)-N-{[1-(2,3-dihydro-1H-indan-2-yl)-2-phenyl-1H-imidazol-5-yl]methyl}-2,5-difluorobenzamide; 5-chloro-N{[1-(2,3-dihydro-1H-indan-2-yl)-2-phenyl-1H-imidazol-5-yl]methyl}-2-methoxy-N-(4-methoxybenzyl)benzamide; 5-chloro-N-(cyclohexylmethyl)-N-{[1-(2,3-dihydro-1H-indan-2-yl)-2-phenyl-1H-imidazol-5-yl]methyl}-2-methoxybenzamide; N-{[1-(2,3-dihydro-1H-indan-2-yl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-(4-methoxybenzyl)-2-(trifluoromethyl)benzamide; N-benzyl-2,5-dichloro-N-{[1-(2,3-dihydro-1H-indan-2-yl)-2-phenyl-1H-imidazol-5-yl]methyl}benzamide; 2,5-dichloro-N-{[1-(2,3-dihydro-1H-indan-2-yl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-(4-methoxybenzyl)benzamide; 2,5-dichloro-N-(cyclohexylmethyl)-N-{[1-(2,3-dihydro-1H-indan-2-yl)-2-phenyl-1H-imidazol-5-yl]methyl}benzamide; 2-bromo-N-{[1-(2,3-dihydro-1H-indan-2-yl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-(4-methoxybenzyl)benzamide; N-{[1-(2,3-dihydro-1H-indan-2-yl)-2-phenyl-1H-imidazol-5-yl]methyl)}-N-(4-methoxybenzyl)-2-(2-phenylethyl)benzamide; N-{[1-(2,3-dihydro-1H-indan-2-yl)-2-phenyl-1H-imidazol-5-yl]methyl}-2-iodo-N-(4-methoxybenzyl)benzamide; 3-chloro-N-{[1-(2,3-dihydro-1H-indan-2-yl)-2-phenyl-1H-imidazol-5-yl]methyl}-2,6-dimethoxy-N-(4-methoxybenzyl)benzamide; and 2-bromo-N-{[1-(2,3-dihydro-1H-indan-2-yl)-2-phenyl-1H-imidazol-5-yl]methyl}-5-methoxy-N-(4-methoxybenzyl)benzamide.

24. A composition comprising a therapeutically effective amount of at least one C5a antagonist and a therapeutically effective amount of at least one C5a receptor-inactive therapeutic agent, wherein the C5a antagonist is selected from: Ethyl 4-(3-{butyl [(4-chloro-2-phenyl-1-propyl-1H-imidazol-5-yl)methyl]amino}propyl)benzoate; Ethyl 4-[3-(butyl {[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}amino)propyl]benzoate; 4-{3-[[(1-Butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]propyl}benzoic acid; 4-[3-(Butyl {[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}amino)propyl]benzoic acid; methyl (4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}phenyl)acetate; methyl 2-(4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}phenyl)propanoate; methyl 2-(4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}phenyl)-2-methylpropanoate; methyl (3-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}phenyl)acetate; (4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}phenyl)acetic acid; 2-(4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}phenyl)propanoic acid; 2-(4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}phenyl)-2-methylpropanoic acid; (3-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}phenyl)acetic acid; N-{[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)butan-1-amine; 4-[(butyl {[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}amino)methyl]benzenesulfonamide; 4-{[{[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}(isopentyl)amino]methyl}benzenesulfonamide; 4-{[[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}benzenesulfonamide; N-{[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}-N-[(3-chloro-1H-indol-5-yl)methyl]-3-methylbutan-1-amine; 5-{[{[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}(isopentyl)amino]methyl}-1H-indole-3-carbonitrile; 4-{[{[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}benzenesulfonamide; N-{[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}-N-(quinoxalin-6-ylmethyl)butan-1-amine; 5-(5-{butyl[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]amino}pentyl)isoxazol-3-ol; methyl [[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino](phenyl)acetate; N-[(1-butyl-2-phenyl-4-vinyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)amine; methyl 4-{[[(1-butyl-2-phenyl-4-vinyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoate; N-[(1-butyl-4-phenyl-2-vinyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)amine; N-[(1-butyl-4-ethyl-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)amine; methyl 4-{[[(1-butyl-4-ethyl-2-phenyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoate; (1S)-N-(1,3-benzodioxol-5-ylmethyl)-1-(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)-N-methylpentan-1-amine; N-[(1-butyl-4-chloro-2-phenyl-1H-imidazol-5-yl)methyl]-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(quinoxalin-6-ylmethyl)amine; 4-{[[(1-butyl-2-phenyl-4-vinyl-1H-imidazol-5-yl)methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoic acid; N-{1-[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]ethyl}-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)butan-1-amine; N-{1-[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]ethyl}-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-3-methylbutan-1-amine; N-{1-[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]ethyl}-N-(1H-indol-5-ylmethyl)butan-1-amine; N-{[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}-3-methyl-N-[(2-methyl-1H-indol-5-yl)methyl]butan-1-amine; 1-(1-butyl-2-phenyl-1H-imidazol-5-yl)-N-(cyclohexylmethyl)-N-methylpentan-1-amine; 4-{[[(1-butyl-4-ethyl-2-phenyl-1H-imidazol-5-y])methyl](2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoic acid; N-{[4-chloro-1-(ethoxymethyl)-2-phenyl-1H-imidazol-5-yl]methyl}-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)amine; 1-(4-chloro-2-phenyl-1H-imidazol-5-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-N-(3-ethoxybenzyl)methanamine; N-{[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine; 1-(1-butyl-2,4-diphenyl-1H-imidazol-5-yl)-N-(cyclohexylmethyl)-N-(1,2,3,4-tetrahydroquinolin-6-ylmethyl)methanamine; 1-[1-butyl-2-phenyl-4-(trifluoromethyl)-1H-imidazol-5-yl]-N-(cyclohexylmethyl)-N-(1,2,3,4-tetrahydroquinolin-6-ylmethyl)methanamine; N-{[4-bromo-1-butyl-2-(2,6-diethylphenyl)-1H-imidazol-5-yl]methyl}-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine; methyl 4-{[{[1-butyl-4-(4-methylphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoate; methyl 4-{[{[1-butyl-4-(3-fluorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl benzoate; 4-{[[[1-butyl-4-(4-methylphenyl)-2-phenyl-1H-imidazol-5-yl]methyl}(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoic acid; 4-{[{[1-butyl-4-(3-fluorophenyl)-2-phenyl-1H-imidazol-5-yl]methyl}(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]methyl}benzoic acid; N-{[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}-N-(3-methoxybenzyl)butan-1-amine; N-{[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}-N-(3-ethoxybenzyl)butan-1-amine; N-{[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}-N-(1H-indol-5-ylmethyl)-3,3-dimethylbutan-1-amine; 6-[(butyl {[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}amino)methyl]-3,4-dihydroquinolin-2(1H)-one; and N-{[1-butyl-4-chloro-2-(2-methylphenyl)-1H-imidazol-5-yl]methyl}-N-(1,2,3,4-tetrahydroquinolin-6-ylmethyl)butan-1-amine.

25. A pharmaceutical composition comprising a therapeutically effective amount of a C5a antagonist, a therapeutically effective amount of a C5a receptor-inactive therapeutic agent and a physiologically acceptable carrier, wherein the C5a antagonist is a compound of the formula: 28 or a pharmaceutically acceptable salts thereof, wherein 29 is: i) a 5-membered heteroaryl ring system, in which x is 0; A is carbon, nitrogen, oxygen, or sulfur; and E and G are independently carbon or nitrogen, provided that the 5-membered heteroaryl ring system does not contain more than 3 heteroatoms or more than 1 oxygen or sulfur atom; or ii) a 6-membered heteroaryl ring system, in which x is 1; A, B, E, and G are independently chosen from carbon and nitrogen, provided that the 6-membered heteroaryl ring system does not contain more than 3 nitrogen atoms. R and R1 independently represent: i) hydrogen, hydroxy, halogen, amino, cyano, nitro, —CHO, —CONH2, C1-C6haloalkyl, or C1-C6 haloalkoxy; ii) C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6 alkoxy, C3-C7cycloalkyl, (C3-C7cycloalkyl)C1-C4alkyl, mono- or di-C1-C6alkylamino, mono- or di-C1-C6alkylaminoC1-C6alkyl, mono- or di-C1-C6alkylcarboxamide, C1-C6alkoxycarbonyl, —NHSOnC1-C6alkyl, —SOnN(C1-C6alkyl) (C1-C6alkyl), or phenyl-SOn—, each of which is optionally substituted, wherein n is 0, 1, or 2; or iii) naphthyl, phenyl, phenylC1-C4carbhydryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heteroarylC1-C4carbhydryl, each of which is optionally substituted; If E is nitrogen, R2 is chosen from C1-C7alkyl, C2-C7alkenyl, C2-C7 alkynyl, C3-C7cycloalkyl(C1-C4alkyl), benzyl and C1-C6haloalkyl; If E is carbon, R2 is chosen from halogen, hydroxy, C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7alkoxy, C1-C7alkylamino, C3-C7cycloalkyl(C1-C4alkyl), benzyl, C1-C6haloalkyl, and C1-C6haloalkoxy; R3 is hydrogen, C1-C6alkyl, C2-C6alkenyl, hydroxyC1-C6alkyl, C1-C6haloalkyl, C3-C7cycloalkyl, (C3-C7cycloalkyl)C1-C4alkyl, or phenyl(C1-C4alkyl); or when x is 0, R1 and R3 may be joined to form an optionally substituted (C3-C7)cycloalkyl; R4 is i) hydrogen; ii) C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7cycloalkenyl, (C3-C7cycloalkyl)C1-C4alkyl, (C3-C7cycloalkenyl)C1-C4alkyl, or hexahydro-1,3-benzodioxolylmethyl, each of which is optionally substituted; iii) optionally substituted arylC1-C4alkyl having 1 or 2 fused or pendant rings; iv) optionally substituted arylC1-C4alkyl, wherein the aryl portion is fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; v) optionally substituted heterocycloalkyl(C0-C4alkyl); vi) optionally substituted heteroarylC1-C2alkyl having from 1 to 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; or vii) optionally substituted saturated or partially unsaturated heterocyclic(C0-C4alkyl) having from 4 to 7 ring members, 1 or 2 of which ring members are N, S or O, with remaining ring members being carbon; R5 and R6 are independently chosen from hydrogen and C1-C6alkyl; z is 1,2, or 3; Ar1 is i) optionally substituted aryl having 1 or 2 fused or pendant rings; ii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iii) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; Ar2 is i) optionally substituted C3-C7cycloalkyl, C3-C7cycloalkyl(C1-C4alkyl), C3-C7cycloalkenyl, C3-C7cycloalkenyl(C1-C4alkyl), or hexahydro-1,3-benzodioxolyl; ii) optionally substituted aryl having 1 or 2 fused or pendant rings; iii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iv) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; and y is 1 or 2.

26. A pharmaceutical composition according to claim 25, wherein the pharmaceutical composition is an injectible solution, a tablet, a capsule, or a pill.

27. A pharmaceutical composition according to claim 25, wherein the pharmaceutical composition is an inhalable preparation.

28. A pharmaceutical composition according to claim 25, wherein the pharmaceutical composition is a topical preparation.

29. A package comprising a pharmaceutical composition according to claim 25 and instructions for using the pharmaceutical composition to treat a patient suffering from a condition with a pathogenic inflammatory component.

30. A package according to claim 29, wherein the condition is an autoimmune disorder, asthma, cardio- or cerebrovascular disease, psoriasis, reperfusion injury, burn, traumatic CNS or spinal cord injury, rheumatoid arthritis, psoriasis, asthma, or cardio or cerebrovascular disease.

31. A package comprising a pharmaceutical composition according to claim 25 and instructions for using the pharmaceutical composition to reduce the risk of myocardial infarction or stroke in a patient at risk for myocardial infarction or stroke.

32. A method for treating a condition with a pathogenic inflammatory component in a patient, comprising administering to a patient a therapeutically effective amount of a C5a receptor antagonist and a therapeutically effective amount of a C5a receptor-inactive therapeutic agent, wherein the C5a antagonist is a compound of the formula: 30 or a pharmaceutically acceptable salts thereof, wherein 31 is: i) a 5-membered heteroaryl ring system, in which x is 0; A is carbon, nitrogen, oxygen, or sulfur; and E and G are independently carbon or nitrogen, provided that the 5-membered heteroaryl ring system does not contain more than 3 heteroatoms or more than 1 oxygen or sulfur atom; or ii) a 6-membered heteroaryl ring system, in which x is 1; A, B, E, and G are independently chosen from carbon and nitrogen, provided that the 6-membered heteroaryl ring system does not contain more than 3 nitrogen atoms. R and R1 independently represent: i) hydrogen, hydroxy, halogen, amino, cyano, nitro, —CHO, —CONH2, C1-C6haloalkyl, or C1-C6 haloalkoxy; ii) C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6 alkoxy, C3-C7cycloalkyl, (C3-C7cycloalkyl)C1-C4alkyl, mono- or di-C1-C6alkylamino, mono- or di-C1-C6alkylaminoC1-C6alkyl, mono- or di-C1-C6alkylcarboxamide, C1-C6alkoxycarbonyl, —NHSOnC1-C6alkyl, —SOnN(C1-C6alkyl) (C1-C6alkyl), or phenyl-SOn—, each of which is optionally substituted, wherein n is 0, 1 or 2; or iii) naphthyl, phenyl, phenylC1-C4carbhydryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heteroarylC1-C4carbhydryl, each of which is optionally substituted; If E is nitrogen, R2 is chosen from C1-C7alkyl, C2-C7alkenyl, C2-C7 alkynyl, C3-C7Cycloalkyl(C1-C4alkyl), benzyl and C1-C6haloalkyl; If E is carbon, R2 is chosen from halogen, hydroxy, C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7alkoxy, C1-C7alkylamino, C3-C7cycloalkyl(C1-C4alkyl), benzyl, C1-C6haloalkyl, and C1-C6haloalkoxy; R3 is hydrogen, C1-C6alkyl, C2-C6alkenyl, hydroxyC1-C6alkyl, C1-C6haloalkyl, C3-C7cycloalkyl, (C3-C7cycloalkyl)C1-C4alkyl, or phenyl(C1-C4alkyl); or when x is 0, R1 and R3 may be joined to form an optionally substituted (C3-C7)cycloalkyl; R4 is i) hydrogen; ii) C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7cycloalkenyl, (C3-C7Cycloalkyl)C1-C4alkyl, (C3-C7cycloalkenyl)C1-C4alkyl, or hexahydro-1,3-benzodioxolylmethyl, each of which is optionally substituted; iii) optionally substituted arylC1-C4alkyl having 1 or 2 fused or pendant rings; iv) optionally substituted arylC1-C4alkyl, wherein the aryl portion is fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; v) optionally substituted heterocycloalkyl(C0C4alkyl); vi) optionally substituted heteroarylC1-C2alkyl having from 1 to 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; or vii) optionally substituted saturated or partially unsaturated heterocyclic(Co-C4alkyl) having from 4 to 7 ring members, 1 or 2 of which ring members are N, S or O, with remaining ring members being carbon; R5 and R6 are independently chosen from hydrogen and C1-C6alkyl; z is 1, 2, or 3; Ar1 is i) optionally substituted aryl having 1 or 2 fused or pendant rings; ii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iii) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; Ar2 is i) optionally substituted C3-C7cycloalkyl, C3-C7cycloalkyl(C1-C4alkyl), C3-C7cycloalkenyl, C3-C7cycloalkenyl(C1-C4alkyl), or hexahydro-1,3-benzodioxolyl; ii) optionally substituted aryl having 1 or 2 fused or pendant rings; iii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iv) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; and y is 1 or 2.

33. A method according to claim 32, wherein the disorder is an autoimmune disorder, asthma, cardio- or cerebrovascular disease, psoriasis, reperfusion injury, burn, traumatic CNS or spinal cord injury, rheumatoid arthritis, asthma, psoriasis, or cardio- or cerebrovascular disease.

34. A method according to claim 32, wherein the patient is a human.

35. A process for preparing a pharmaceutical composition, which comprises combining a therapeutically effective amount of a C5a antagonist, a therapeutically effective amount of a therapeutic agent that is not a C5a antagonist, and a pharmaceutically acceptable carrier, wherein the C5a antagonist is a compound of the formula: 32 or a pharmaceutically acceptable salts thereof, wherein 33 is: i) a 5-membered heteroaryl ring system, in which x is 0; A is carbon, nitrogen, oxygen, or sulfur; and E and G are independently carbon or nitrogen, provided that the 5-membered heteroaryl ring system does not contain more than 3 heteroatoms or more than 1 oxygen or sulfur atom; or ii) a 6-membered heteroaryl ring system, in which x is 1; A, B, E, and G are independently chosen from carbon and nitrogen, provided that the 6-membered heteroaryl ring system does not contain more than 3 nitrogen atoms. R and R1 independently represent: i) hydrogen, hydroxy, halogen, amino, cyano, nitro, —CHO, —CONH2, C1-C6haloalkyl, or C1-C6 haloalkoxy; ii) C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C1-C6 alkoxy, C3-C7cycloalkyl, (C3-C7cycloalkyl)C1-C4alkyl, mono- or di-C1-C6alkylamino, mono- or di-C1-C6alkylaminoC1-C6alkyl, mono- or di-C1-C6alkylcarboxamide, C1-C6alkoxycarbonyl, —NHSOnC1-C6alkyl, —SOnN(C1-C6alkyl) (C1-C6alkyl), or phenyl-SOn—, each of which is optionally substituted, wherein n is 0, 1 or 2; or iii) naphthyl, phenyl, phenylC1-C4carbhydryl, 5- or 6-membered heteroaryl, or 5- or 6-membered heteroary]C1-C4carbhydryl, each of which is optionally substituted; If E is nitrogen, R2 is chosen from C1-C7alkyl, C2-C7alkenyl, C2-C7 alkynyl, C3-C7cycloalkyl(C1-C4alkyl), benzyl and C1-C6haloalkyl; If E is carbon, R2 is chosen from halogen, hydroxy, C1-C7alkyl, C2-C7alkenyl, C2-C7alkynyl, C1-C7alkoxy, C1-C7alkylamino, C3-C7cycloalkyl(C1-C4alkyl), benzyl, C1-C6haloalkyl, and C1-C6haloalkoxy; R3 is hydrogen, C1-C6alkyl, C2-C6alkenyl, hydroxyC1-C6alkyl, C1-C6haloalkyl, C3-C7cycloalkyl, (C3-C7cycloalkyl)C1-C4alkyl, or phenyl(C1-C4alkyl); or when x is 0, R1 and R3 may be joined to form an optionally substituted (C3-C7)cycloalkyl; R4 is i) hydrogen; ii) C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, C3-C7Cycloalkenyl, (C3-C7cycloalkyl)C1-C4alkyl, (C3-C7cycloalkenyl)C1-C4alkyl, or hexahydro-1,3-benzodioxolylmethyl, each of which is optionally substituted; iii) optionally substituted arylC1-C4alkyl having 1 or 2 fused or pendant rings; iv) optionally substituted arylC1-C4alkyl, wherein the aryl portion is fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; v) optionally substituted heterocycloalkyl(C0C4alkyl); vi) optionally substituted heteroarylC1-C2alkyl having from 1 to 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; or vii) optionally substituted saturated or partially unsaturated heterocyclic(C0C4alkyl) having from 4 to 7 ring members, 1 or 2 of which ring members are N, S or O, with remaining ring members being carbon; R5 and R6 are independently chosen from hydrogen and C1-C6alkyl; z is 1, 2, or 3; Ar1 is i) optionally substituted aryl having 1 or 2 fused or pendant rings; ii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iii) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; Ar2 is i) optionally substituted C3-C7cycloalkyl, C3-C7cycloalkyl(C1-C4alkyl), C3-C7cycloalkenyl, C3-C7cycloalkenyl(C1-C4alkyl), or hexahydro-1,3-benzodioxolyl; ii) optionally substituted aryl having 1 or 2 fused or pendant rings; iii) optionally substituted phenyl fused to a 5- to 7-membered saturated or partially unsaturated ring having 0, 1, or 2 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon; or iv) optionally substituted heteroaryl having 1 or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring from 1 to 3 heteroatoms independently selected from N, O, and S; and y is 1 or 2.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Application No. 60/368,925, filed Mar. 28, 2002.

FIELD OF THE INVENTION

[0002] This invention relates generally to compositions and methods for treating diseases that are associated with inflammation. The invention relates more specifically to compositions comprising a C5a antagonist and a C5a receptor-inactive therapeutic agent, and to therapeutic methods in which a C5a antagonist and a C5a receptor-inactive therapeutic agent are administered to a patient.

BACKGROUND

[0003] Inflammation is a localized defense mechanism that is elicited by tissue damage or injury, and serves to destroy, dilute or wall off both injurious agents and injured tissues. Individuals suffering from inflammation typically experience redness, heat, swelling, pain and loss of function in the afflicted area. In addition, inflammatory responses cause or exacerbate the harmful effects of many diseases. Inhibition of inflammatory responses in patients afflicted with such diseases can decrease symptom severity and improve treatment outcome.

[0004] Harmful inflammation typically involves the pathogenic activation of the complement system, and in particular the C5a anaphylatoxin. C5a, a 74 amino acid peptide, is a complement component generated early in the terminal phase of the complement cascade by the proteolytic cleavage (by C5 convertase) of the complement component plasma protein C5, and is itself a plasma protein and a key mediator of inflammation. C5a promotes both vascular and cellular inflammatory responses; it has both anaphylatoxic (e.g., bronchoconstricting and vascular spasmogenic) and chemotactic effects. C5a is a potent chemoattractant for polymorphonuclear leukocytes, bringing neutrophils, basophils, eosinophils and monocytes to sites of inflammation and/or cellular injury and is one of the most potent chemotactic agents known for a wide variety of inflammatory cell types. C5a also primes neutrophils for various antibacterial functions (e.g., phagocytosis). Additionally, C5a stimulates the release of various inflammatory mediators (e.g., activated oxygen radicals, histamines, TNF-alpha, IL-1, IL-6, IL-8, prostaglandins, and leukotrienes) from various cell types and the release of lysosomal enzymes and other cytotoxic components from granulocytes. The anaphylatoxic actions of C5a result from its stimulation of smooth muscle contraction. Both the anaphylatoxic and chemotactic effects of C5a are believed to be mediated through its interaction with the C5a receptor (CD88 antigen), a 52 kD membrane-bound cell surface G-protein coupled receptor (GPCR).

[0005] A wide variety of diseases and medical procedures can result in harmful inflammation, and inhibition of C5a-mediated inflammatory responses in patients afflicted with diseases or undergoing procedures that are associated with such inflammation can be beneficial. Diseases associated with harmful inflammation include, for example, diseases of the joints, lungs, kidneys, heart, skin, liver, and digestive system, and as well as more generally, trauma and auto-immune and infectious diseases. For example, in mice, inhibition of C5a receptor activity was found to improve survival rates for sepsis (Riedemann et al. (2002) J. Clin. Invest. 110:101-108). Medical procedures associated with harmful inflammation include, for example, organ transplantation, tissue grafts, cardiopulmonary bypass and hemodialysis.

[0006] Asthma

[0007] Asthma is a lung disease characterized by a usually reversible airway obstruction, airway inflammation and increased airway responsiveness to stimuli. The airway obstruction in an asthma attack is thought to be due to the combination of bronchospasm of the smooth muscles of the bronchial tree, increased mucous section, edema of airway mucosa due to increased vascular permeability, cellular infiltration of the airway walls, and injury to airway epithelium. Studies in animal models have implicated both IgE and the complement system (and C5a in particular) in airway hyperresponsiveness and asthma pathogenesis.

[0008] Asthma may be triggered by a variety of causes such as allergic reactions, a secondary response to infections, industrial or occupational exposures, ingestion of certain chemicals or drugs, exercise, and vasculitis. Regardless of the trigger, many of the pathological features of asthma can be attributed to mast cell degranulation. Such responses are, at least in part, mediated by IgE antibodies, which trigger mast cell degranulation in the lung interstitium. The mast cell degranulation releases, among other factors, histamine, bradykinin, and slow-reacting substance of anaphylaxis (SRS-A) which includes the leukotrienes C, D and E, prostaglandins including PGF 2 , PGF 2α and PGD 2 , and thromboxane A 2 . The histamine then attaches to receptor sites in the larger bronchi, causing irritation, inflammation and edema. The SRS-A attaches to receptor sites in the smaller bronchi, causing edema and attracting prostaglandins, which enhance the effects of histamine in the lungs. With the help of the prostaglandins, histamine also stimulates excessive mucous secretion, further narrowing the bronchial lumen. When the asthmatic inhales, the narrowed bronchial lumen still expands slightly, allowing air to reach the alveoli. However, upon exertion to exhale, the increased thoracic pressure closes the bronchial lumen completely. Thus, in an asthma attack, air can enter, but not exit the lungs. Mucous then fills the lung bases, inhibiting alveolar ventilation. In an effort to compensate for lowered alveolar ventilation, blood is shunted to other alveoli. Without adequate compensation, hypoxia, and in extreme cases, respiratory acidosis may result.

[0009] In many cases, there are two phases to an allergic asthma attack, an early phase and a late phase which follows 4-6 hours after bronchial stimulation. The early phase includes the immediate inflammatory response including the reactions caused by the release of cellular mediators from mast cells. Late phase reactions develop over a period of hours and are characterized histologically by an early influx of polymorphonuclear leukocytes and fibrin deposition followed later by infiltration of eosinophils. Late phase reactions increase airway reactivity and lead to prolonged asthmatic exacerbations that may last from hours to days to months in some subjects.

[0010] Asthma is most commonly treated with oral and inhaled bronchodilators. Such agents alleviate the symptoms of asthma, but have no effect on the underlying inflammation. Corticosteroids are also used to treat the inflammation, but these drugs can have serious side effects and many patients continue to suffer from incompletely controlled asthma.

[0011] Skin Disorders Associated with Inflammation

[0012] The complement system is an important skin defense mechanism, and complement activation (particularly C5a) is involved in the pathogenesis of a variety of skin conditions such as bullous pemphigoid, lichen planas, herpes gestationis and psoriasis.

[0013] Psoriasis is one of the most common dermatologic diseases, affecting about 2 percent of the population. This condition presents as elevated lesions that vary in size from one to several centimeters, and results from an overproduction of epidermal cells. The increased production of epidermal cells is due to a shortened cell cycle time, an increase in the absolute number of cells capable of proliferating and an increased rate of division. The thickened epidermis, overgrowth of blood vessels, and infiltration of neutrophils and lymphocytes account for the psoriatic lesions being raised and easily palpable. T cell mediated immune responses appear to be responsible for the inflammation and hyperproliferation of epidermal cells. Neutrophils are found in psoriatic lesions, associated with increased levels of plasminogen activator. Psoriatic fibroblasts have increased levels of enzymes involved in collagen synthesis, secondary to expansion of the papillary dermis. Psoriatic plaques comprise HLA-DR positive keratinocytes and Langerhans cells, as well as activated T cells expressing elevated levels of IL-2 receptors and secreting cytokines including TNF and interleukin-6, which stimulate skin cell growth.

[0014] It is not known what causes psoriasis, although there is evidence of a genetic predisposition and an autoimmune etiology. Onset may be triggered by systemic infections such as strep throat infection, skin injury, vaccinations, and certain oral medications such as steroids, which induce inflammation and excessive skin cell reproduction. Psoriasis can be exacerbated by additional factors such as stress and diet. Regardless of the trigger, C5a activation appears to play a direct role in the pathogenesis of the disease.

[0015] Rheumatoid Arthritis

[0016] Rheumatoid arthritis (RA) is a chronic disease characterized by persistent joint inflammation (inflammatory synovitis). Early clinical manifestations of the disease include pain, swelling and tenderness of the joints that is initially poorly localized. Many patients exhibit general fatigue, weakness, loss of appetite, low-grade fever and musculoskeletal symptoms before joint pain becomes localized. As the disease progresses, joint pain, swelling and stiffness become more evident. Movement, particularly after periods of inactivity, becomes painful and difficult. The persistent inflammation caused by rheumatoid arthritis often leads to destruction or weakening of ligaments and tendons, and destruction of cartilage and bone. Deformities of the hands and feet, due to fibrous or bony ankylosis or soft tissue contracture, are often present in advanced disease. Current treatments of RA can be divided into two types—therapies which act to alleviate the symptoms of the disease, such as pain medications, and disease-modifying therapies which act on some underlying cause of the disease and slow its progression, such as steroids. Inhibitors of cyclooxygenase (COX) enzymes, which inhibit prostaglandin production and thereby reduce inflammation are commonly used to treat rheumatoid arthritis. Such compounds may inhibit COX enzymes non-specifically (e.g., the salicylates), or may specifically inhibit COX-2. Injections of gold sodium thiomalate and oral administration of gold compounds have also been shown to suppress the synovitis of active rheumatoid arthritis. In some case, surgery may be performed.

[0017] Considerable experimental evidence has demonstrated the presence of increased levels of C5a in rheumatoid arthritis. Antibodies that bind to C5 and inhibit the conversion of C5 to C5a (and C5b) by C5 convertase have been shown to be effective in reducing symptoms of rheumatoid arthritis in animal models of arthritis. A C5a receptor antagonist also showed activity as an anti-arthritic agent in a rat RA model (Woodruff et al. (2002) Arthritis Rheum 46:2476-85).

[0018] Other Autoimmune Disorders

[0019] A number of other autoimmune disorders and pathologic autoimmune responses are known to have an inflammatory component, such as multiple sclerosis, myasthenia gravis, Alzheimer's disease, glomerulonephritis, Crohn's disease, lupus erythematosus and irritable bowel syndrome. Considerable experimental evidence has demonstrated the presence of increased levels of C5a in a number of autoimmune diseases and inflammatory disorders. In addition, anti-C5 antibodies also been used to treat glomerulonephritis, a disease characterized by inflammation of the kidney (see U.S. Pat. No. 6,355,245).

[0020] Medical Procedures

[0021] A variety of medical procedures involve the introduction of foreign matter into the patient's body. Such procedures generally trigger, and are complicated by, inflammation. For example, inflammation may result from cardiopulmonary bypass surgery or hemodialysis. Rejection of transplanted organs and tissue grafts also has an inflammatory component. In some cases, for example, the blood supply to the transplant becomes blocked due to inflammation of the blood vessels leading to the transplanted organ. Current therapy for transplant rejection involves a regimen of immunosuppressants, including cyclosporin A, tacrolimus, and rapamycin (sirolimus). However, patients continue to have a 20 to 50 percent risk of rejecting a donated organ during the first three years following transplantation, and less than 50 percent of patients have functioning transplants after 10 years. Additionally, chronic use of immunosuppressants can lead to impairment of the recipients' immune system.

[0022] Cardio- and Cerebrovascular Disease

[0023] Low-level inflammation has been correlated to the incidence of heart attack and stroke. C-reactive protein, a marker for inflammation, has been shown to be associated with increased risk for cardiovascular events (Ridker et al. (2002) N. Engl. J. Med. 347:1557-1565). In a study of men with levels of C-reactive protein considered to be within the normal range, the benefits of aspirin in the prevention of heart attack and stroke were more pronounced in individuals with higher levels of C-reactive protein, suggesting that aspirin's anti-inflammatory effects are responsible for the reduction in heart attacks and strokes (Ridker et al (1997) N. Eng. J. Med. 336:973079).

[0024] Ischemia-Reperfusion Injury

[0025] Ischemia is a condition in which blood flow (and thus oxygen) is restricted to a part of the body and may occur, for example, due to thrombosis or surgery. Reperfusion injury occurs when a blood flow is restored to a blood vessel that has been previously occluded. Reperfusion injury has also been found to occur during surgeries in which blood vessels are not occluded but in which a heart bypass pump is employed. The hypoxic conditions in occluded blood vessels induces the production of a number of pro-inflammatory cytokines. While prompt restoration of blood flow is necessary to restore normal function, reperfusion also causes the destruction of additional cells and an intense inflammatory reaction that involves C5a activation. The pro-inflammatory cytokines produced while the vessel was occluded causes leads leukocyte recruitment and subsequent destruction of the endothelium. Additional damage may occur due to obstruction of microcapillaries by leukocytes. In mice, inhibition of C5a receptor activity has been found to improve survival rates for ischemia-reperfusion injury (De Vries et al. (2003) Transplantation 75:375-82). A small molecule C5a receptor antagonist also was shown to protect kidneys from ischemia-reperfusion injury in rats (Arumugam et al. (2003) Kidney Int. 63:134-42).

[0026] While some treatments are presently available for both inflammatory and non-inflammatory disease components, there remains a need in the art for improved anti-inflammatory medications and methods for using such improved medications in combination with currently available therapies. The present invention fulfills this need and provides further related advantages.

SUMMARY OF THE INVENTION

[0027] In a first aspect, the invention provides compositions useful for the treatment of diseases with inflammatory components, such as arthritis (particularly rheumatoid arthritis) and other autoimmune disorders, asthma, cardio- and cerebrovascular disease, psoriasis, reperfusion injury, and traumatic CNS and spinal cord injury. Such compositions comprise at least one C5a receptor antagonist (hereinafter a “C5a antagonist”) and at least one C5a receptor-inactive therapeutic agent (i.e., a therapeutic agent that is not a C5a antagonist).

[0028] Preferred properties for C5a antagonists for use in the practice of the invention are one or preferably 2 or most preferably all 3 of: 1) having a molecular mass less than 700 a.m.u. 2) being nonpeptidic (i.e., do not contain amino acids joined by a peptide bond; preferably do not contain any amino acid moiety) and 3) having minimal agonist activity (i.e., induce an increase in the basal activity of the C5a receptor in the absence of C5a that is less than 5% of the increase that would be induced by C5a, preferably inducing no statistically significant increase). Preferred C5a antagonists for used in the practice of the invention include neutral antagonists and inverse agonists of the C5a receptor.

[0029] Within certain embodiments, the C5a receptor-inactive therapeutic agent is an NSAID, a cyclo-oxygenase enzyme inhibitor, a gold compound, a salicylate, a steroid such as a corticosteroid, methotrexate, lefunomide, a TNF antagonist, a cholesterol lowering agent, an HMG-CoA reductase inhibitor, a platelet aggregation inhibitor, or an anti-hypertensive agent.

[0030] Within further aspects, the present invention provides pharmaceutical compositions, comprising a C5a antagonist in combination with a C5a receptor-inactive therapeutic agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutical formulations, such as tablets, pills and capsules, containing a C5a antagonist and a C5a receptor-inactive therapeutic agent are included in the invention. Pharmaceutical formulations of the invention may include additional active or inert ingredients. Processes for preparing such pharmaceutical compositions and pharmaceutical formulations are included in the invention.

[0031] Also provided are packages comprising such a pharmaceutical composition and instructions for use to treat a patient suffering from arthritis or another autoimmune disorder, asthma, cardio- and cerebrovascular disease, psoriasis, reperfusion injury, or traumatic CNS or spinal cord injury. The C5a antagonist and a C5a receptor-inactive therapeutic agent may be provided each in a separate container within the package or—where both are to be given by the same route of administration—preferably combined in a single formulation.

[0032] Methods are further provided, within other aspects for treating a patient suffering from arthritis or another autoimmune disorder, asthma, cardio- or cerebrovascular disease, psoriasis, reperfusion injury, burns, or traumatic CNS or spinal cord injury, comprising administering to the patient a therapeutically effective amount of a C5a receptor antagonist in combination with a therapeutically effective amount of a C5a receptor-inactive therapeutic agent. The combination therapy provided herein encompasses either or both of 1) the administration of a C5a antagonist and a C5a receptor-inactive therapeutic agent together, preferably in a single pharmaceutical formulation, and 2) the administration of a C5a antagonist in a first formulation and the separate administration of a C5a receptor-inactive therapeutic agent in a second pharmaceutical formulation.

[0033] These and other aspects of the present invention will become apparent upon reference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

[0034] Terminology

[0035] A “C5a antagonist” or “C5a receptor antagonist” is any compound that exhibits C5a antagonist activity within the a C5a receptor-mediated chemotaxis, radioligand binding assay, or calcium mobilization assay as provided herein. In other words, in a calcium mobilization assay, a compound is a C5a antagonist if incubation of cells with 1 uM of C5a antagonist results in at least a 2-fold increase in the fluorescence response relative to that measured in the presence of C5a alone. In a chemotaxis assay, a compound is a C5a antagonist if it displays an affinity constant or IC 50 of 1 uM or less. Preferably, a C5a antagonist displays an IC 50 of less than 500 nM, 200 nM, 100 nM, 50 nM, 25 nM, 10 nM or 5 nM (in a chemotaxis and/or calcium mobilization assay) in a standard C5a receptor-mediated chemotaxis assay, radioligand binding assay, or calcium mobilization assay. In certain embodiments, C5a antagonists provided herein inhibit activation and/or activity of a primate C5a receptor, such as human C5a receptor, which may be a cloned, recombinantly expressed receptor or a naturally expressed receptor. For treating non-human animals of any particular species, a compound exhibiting high affinity for the C5a receptor of that particular species is preferred.

[0036] As used herein, “therapeutic agent” refers to a compound which has been shown to exhibit clinical efficacy in reducing the symptoms of one or more of arthritis (preferably rheumatoid arthritis) or another autoimmune disorder, asthma, cardio- or cerebrovascular disease, psoriasis, reperfusion injury, burns, or traumatic CNS or spinal cord injury. A “C5a receptor-inactive therapeutic agent” is such an agent that does not satisfy the criteria (above) for a C5a antagonist.

[0037] As used herein, “active agent” refers to either or both of the C5a antagonist and the C5a receptor-inactive therapeutic agent. This term is intended to encompass all salt, ester and prodrug forms of C5a antagonists and C5a receptor-inactive therapeutic agents, even where the prodrug is not active itself but is converted to the active form after administration to the patient.

[0038] An active agent is said to be “administered” if it is caused to be contacted with a patient so as to provide a detectable therapeutic effect. Administration may be oral, intranasal, topical, rectal or parenteral. The term parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal and intraperitoneal injection, as well as any similar injection or infusion technique.

[0039] A “condition with a pathogenic inflammatory component” is any disease, disorder or injury that is caused, prolonged or exacerbated by C5a-mediated inflammation. Such conditions include, but are not limited to, arthritis (such as rheumatoid arthritis) and other autoimmune disorders (e.g., multiple sclerosis, myasthenia gravis, Alzheimer's disease, glomerulonephritis, Crohn's disease, Guillain-Barre Syndrome, lupus erythematosus and irritable bowel syndrome); asthma and other lung disorders, including respiratory distress syndrome; skin conditions and injuries such as psoriasis, bullous pemphigoid, lichen planas, burns and wounds; cardio- and cerebrovascular disease, including restenosis; ischemia-reperfusion injury; trauma (e.g., CNS); sepsis and other infections; hemorrhagic shock; and multiple organ system failure. Such conditions also include medical procedures such as organ transplantation (e.g., lung), tissue grafts, hemodialysis, and cardiopulmonary bypass surgery, where recovery may be inhibited or delayed as a result of inflammation.

[0040] C5a antagonists used in the compositions and methods provided herein are generally described using standard nomenclature. Certain compounds described herein contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like (e.g., asymmetric carbon atoms) so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. Unless otherwise specified all optical isomers and mixtures thereof are encompassed for compounds having asymmetric centers. In addition, compounds with carbon-carbon double bonds may occur in Z- and E-forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers, but rather encompasses all tautomeric forms.

[0041] The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11 C, 13 C, and 14 C.

[0042] Certain compounds are described herein using a general formula, such as Formula I, that includes variables, such as various R groups, Ar 1 , Ar 2 , and x. Unless otherwise specified, each variable within such a formula is defined independently of other variables. Thus, for example, if a group is shown to be substituted with 0-2 R*, then said group may optionally be substituted with up to two R* groups and R* at each occurrence is selected independently from the definition of R*. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0043] A “substituent,” as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a “ring substituent” may be a moiety such as a halogen, alkyl group, haloalkyl group or other substituent discussed herein that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member. The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound (i.e., a compound that can be isolated, characterized and tested for biological activity). When a substituent is oxo (i.e., =0), then 2 hydrogens on the atom are replaced. When aromatic moieties are substituted by an oxo group, the aromatic ring is replaced by the corresponding partially unsaturated ring. For example a pyridyl group substituted by oxo is a tetrahydropyridone.

[0044] The phrase “optionally substituted” indicates that a group may either be unsubstituted or substituted at one or more of any of the available positions, typically 1, 2, 3, 4, or 5 positions, by one or more suitable substituents such as those disclosed herein. Various groups within the compounds and formulae set forth herein are “optionally substituted” including, for example, R 1 , R 2 , and Ar 1 . Optional substitution may also be indicated by the phrase “substituted with from 0 to X substituents,” in which X is the maximum number of substituents.

[0045] Suitable substituents include, for example, halogen, cyano, amino, hydroxy, nitro, azido, carboxamido, —COOH, SO 2 NH 2 , alkyl (e.g., C 1 -C 8 alkyl), alkenyl (e.g., C 2 -C 8 alkenyl), alkynyl (e.g., C 2 -C 8 alkynyl), alkoxy (e.g., C 1 -C 8 alkoxy), alkyl ether (e.g., C 2 -C 8 alkyl ether), alkylthio (e.g., C 1 -C 8 alkylthio), mono- or di-(C 1 -C 8 alkyl)amino, haloalkyl (e.g., C 1 -C 6 haloalkyl), hydroxyalkyl (e.g., C 1 -C 6 hydroxyalkyl), aminoalkyl (e.g., C 1 -C 6 aminoalkyl), haloalkoxy (e.g., C 1 -C 6 haloalkoxy), alkanoyl (e.g., C 1 -C 8 alkanoyl), alkanone (e.g., C 1 -C 8 alkanone), alkanoyloxy (e.g., C 1 -C 8 alkanoyloxy), alkoxycarbonyl (e.g., C 1 -C 8 alkoxycarbonyl), mono- and di-(C 1 -C 8 alkyl)amino, mono- and di-(C 1 -C 8 alkyl)aminoC 1 -C 8 alkyl, mono- and di-(C 1 -C 8 alkyl)carboxamido, mono- and di-(C 1 -C 8 alkyl)sulfonamido, alkylsulfinyl (e.g., C 1 -C 8 alkylsulfinyl), alkylsulfonyl (e.g., C 1 -C 8 alkylsulfonyl), aryl (e.g., phenyl), arylalkyl (e.g., (C 6 -C 18 aryl)C 1 -C 8 alkyl, such as benzyl and phenethyl), aryloxy (e.g., C 6 -C 18 aryloxy such as phenoxy), arylalkoxy (e.g., (C 6 -C 18 aryl)C 1 -C 8 alkoxy) and/or 3- to 8-membered heterocyclic groups. Certain groups within the formulas provided herein are optionally substituted with from 1 to 3, 1 to 4 or 1 to 5 independently selected substituents.

[0046] A dash (“—”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —CONH 2 is attached through the carbon atom.

[0047] As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, and where specified, having the specified number of carbon atoms. Thus, the term C 1 -C 6 alkyl, as used herein, indicates an alkyl group having from 1 to 6 carbon atoms. “C 0 -C 4 alkyl” refers to a bond or a C 1 -C 4 alkyl group. Alkyl groups include groups having from 1 to 8 carbon atoms (C 1 -C 8 alkyl), from 1 to 6 carbon atoms (C 1 -C 6 alkyl) and from 1 to 4 carbon atoms (C 1 -C 4 alkyl), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. “Aminoalkyl” is an alkyl group as defined herein substituted with one or more —NH 2 groups. “Hydroxyalkyl” is a hydroxy group as defined herein substituted with one or more —OH groups.

[0048] “Alkenyl” refers to a straight or branched hydrocarbon chain comprising one or more unsaturated carbon-carbon bonds, such as ethenyl and propenyl. Alkenyl groups include C 2 -C 8 alkenyl, C 2 -C 6 alkenyl and C 2 -C 4 alkenyl groups (which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively), such as ethenyl, allyl or isopropenyl.

[0049] “Alkynyl” refers to straight or branched hydrocarbon chains comprising one or more triple carbon-carbon bonds. Alkynyl groups include C 2 -C 8 alkynyl, C 2 -C 6 alkynyl and C 2 -C 4 alkynyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively. Alkynyl groups include for example groups such as ethynyl and propynyl.

[0050] “Alkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

[0051] The term “alkanoyl” refers to an acyl group in a linear or branched arrangement (e.g., —(C═O)-alkyl). Alkanoyl groups include C 2 -C 8 alkanoyl, C 2 -C 6 alkanoyl and C 2 -C 4 alkanoyl groups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. “Cialkanoyl” refers to —(C═O)—H, which (along with C 2 -C 8 alkanoyl) is encompassed by the term “C 1 -C 8 alkanoyl.”

[0052] The term, “alkyl ether” refers to a linear or branched ether substituent linked via a carbon-carbon bond. Alkyl ether groups include C 2 -C 8 alkyl ether, C 2 -C 6 alkyl ether and C 2 -C 6 alkyl ether groups, which have 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. By way of example, a C 2 alkyl ether group has the structure —CH 2 —O—CH 3 .

[0053] The term “alkoxycarbonyl” refers to an alkoxy group linked via a carbonyl (i.e., a group having the general structure —C(═O)—O-alkyl). Alkoxycarbonyl groups include C 2 -C 8 , C 2 -C 6 , and C 2 -C 4 alkoxycarbonyl groups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. “C 1 alkoxycarbonyl” refers to —C(═O)OH, and is encompassed by “C 1 -C 8 alkoxycarbonyl.”

[0054] “Alkanoyloxy,” as used herein, refers to an alkanoyl group linked via an oxygen bridge (i.e., a group having the general structure —O—C(═O)-alkyl). Alkanoyloxy groups include C 2 -C 8 , C 2 -C 6 , and C 2 -C 4 alkanoyloxy groups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively.

[0055] As used herein, the term “alkylthio” refers to an alkyl group attached via a thioether linkage. Alkylthio groups include C 1 -C 8 alkylthio, C 1 -C 6 alkylthio and C 1 -C 4 alkylthio, which have from 1 to 8, 1 to 6 or 1 to 4 carbon atoms, respectively.

[0056] “Alkylsulfinyl,” as used herein, refers to an alkyl group attached via a sulfinyl linkage. Alkylsulfinyl groups include C 1 -C 8 alkylsulfinyl, C 1 -C 6 alkylsulfinyl, and C 1 -C 4 alkylsulfinyl, which have from 1 to 8, 1 to 6, and 1 to 4 carbon atoms, respectively.

[0057] By “alkylsulfonyl,” as used herein, is meant an alkyl group attached via a sulfonyl linkage. Alkylsulfonyl groups include C 1 -C 8 alkylsulfonyl, C 1 -C 6 alkylsulfonyl, and C 1 -C 4 alkylsulfonyl, which have from 1 to 8, 1 to 6, and 1 to 4 carbon atoms, respectively.

[0058] “Alkylamino” refers to a secondary or tertiary amine having the general structure —NH-alkyl or —N(alkyl)(alkyl), wherein each alkyl may be the same or different. Such groups include, for example, mono- and di-(C 1 -C 8 alkyl)amino groups, in which each alkyl may be the same or different and may contain from 1 to 8 carbon atoms, as well as mono- and di-(C 1 -C 6 alkyl)amino groups and mono- and di-(C 1 -C 4 alkyl)amino groups. Alkylaminoalkyl refers to an alkylamino group linked via an alkyl group (i.e., a group having the general structure -alkyl-NH-alkyl or -alkyl-N(alkyl)(alkyl)). Such groups include, for example, mono- and di-(C 1 -C 8 alkyl)aminoC 1 -C 8 alkyl, mono- and di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, and mono- and di-(C 1 -C 4 alkyl)aminoC 1 -C 4 alkyl, in which each alkyl may be the same or different.

[0059] The term “carboxamido” or “amido” refers to an amide group (i.e., —(C═O)NH 2 ). “Alkylcarboxamido” refers to —NHC(═O)alkyl, preferably —NHC(═O)C 1 -C 2 alkyl.

[0060] The term “cycloalkyl” refers to hydrocarbon ring groups, having the specified number of carbon atoms, usually from 3 to about 8 ring carbon atoms, or from. Cycloalkyl groups include C 3 -C 8 , and C 3 -C 7 cycloalkyl groups, which have from 3 to 8 and 3 to 7 carbon atoms, respectively. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups, as well as bridged and caged saturated ring groups such as norbornane or adamantane and the like.

[0061] In the term “(cycloalkyl)alkyl,” “cycloalkyl” and “alkyl” are as defined above, and the point of attachment is on the alkyl group. This term encompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethyl, and cyclohexylethyl.

[0062] The term “halogen” indicates fluorine, chlorine, bromine, or iodine.

[0063] “Haloalkyl” refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified numbe