Aryl imidazoles and related compounds as C5a receptor modulators

• US 7,186,734 B2
• Filed: 03/28/2003
• Issued: 03/06/2007
• Est. Priority Date: 03/29/2002
• Status: Expired due to Fees

• Current Assignee: Novartis International Pharmaceutical Limited (Novartis Ag)
• Original Assignee: Neurogen Corporation (Ligand Pharmaceuticals, Inc.)
• Inventors: Maynard, George D., Gao, Yang, Chenard, Bertrand L., Thurkauf, Andrew, Zhao, He
• Primary Examiner(s): Saeed; Kamal A.
• Assistant Examiner(s): ANDERSON, REBECCA L
• Application Number:
  US10/405,989
• Publication Number:
  US 20040116424A1
• Time in Patent Office: 1,439 Days
• Field of Search: 548/340.1, 548/311.7, 514/400, 514/397, 514/341, 546/274.1
• US Class Current: 514/341
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 7/08 Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 233/68 : Halogen atoms
• CPC Class Codes: C07D 235/02 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 235/30 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 237/12 : Halogen atoms or nitro radicals
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

The invention provides Aryl substituted imidazoles, pyrazoles, pyridizines and related compounds of the Formula

where the variables are defined herein.

Such compounds are ligands of C5a receptors. Preferred compounds of the invention act bind to C5a receptors with high affinity and exhibit neutral antagonist or inverse agonist activity at C5a receptos. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating a variety of inflammatory and immune system disorders.

Claims

1. A compound of Formula I:

2. A compound or salt according to claim 1 wherein

R₁ is chosen from:

i) hydrogen, hydroxy, halogen, amino, cyano, nitro, —

CHO, —

CONH₂, C₁–

C₆haloalkyl, C₁–

C₆haloalkoxy,

ii) C₁–

C₆alkyl, C₁–

C₆alkenyl, C₁–

C₆alkynyl, C₁–

C₆alkanoyl, C₁–

C₆alkoxy, C₃–

C₇cycloalkyl, (C₃–

C₇cycloalkyl)C₁–

C₄alkyl, mono- and di-C₁–

C₆alkylamino, mono- and di-C₁–

C₆alkylaminoC₁–

C₆alkyl, mono- and di-C₁–

C₆alkylcarboxamide, C₁–

C₆alkoxycarbonyl, —

NHSO_nC₁–

C₆alkyl, —

SO_n(C₁–

C₆alkyl), —

(C₁–

C₆alkyl)SO_n(C₁–

C₆alkyl), —

SO_nN(C₁–

C₆alkyl) (C₁–

C₆alkyl), and phenyl-SO_n—

, each of which is substituted with from 0 to 3 substituents independently chosen from hydrogen, hydroxy, halogen, amino, cyano, oxo, C₁–

C₄alkyl, C₁–

C₄alkoxy, and C₁–

C₂alkoxycarbonyl, and

iii) naphthyl, phenyl, phenylC₁–

C₄carbhydryl, pyridyl, thiazolyl, pyrimidinyl, thienyl, pyridylC₁–

C₄carbhydryl, thiazolylC₁–

C₄carbhydryl, pyrimidinylC₁–

C₄carbhydryl, and thienylC₁–

C₄carbhydryl, each of which is substituted with from 0 to 3 substitutuents independently chosen from hydroxy, halogen, amino, cyano, nitro, —

COOH, —

CONH₂, —

SO₂NH₂, C₁–

C₆haloalkyl, C₁–

C₆haloalkoxy, C₁–

C₆alkyl, C₁–

C₆alkoxy, 1,3-dioxol-5-yl, C₁–

C₆alkanoyl, C₁–

C₆alkylsulfonyl, C₁–

C₆alkylsulfinyl, C₁–

C₆alkylthio, C₂–

C₆alkanone;

C₁–

C₆alkanoyl;

C₂–

C₆alkyl ether;

C₁–

C₆ alkanoyloxy;

C₁–

C₆alkoxycarbonyl, and C₁–

C₆alkylcarboxamide;

R₂, when E is Nitrogen, is chosen from C₁–

C₇alkyl, substituted with from 0 to 3 substitutents independently chosen from hydroxy, halogen, amino, cyano, oxo, C₁–

C₄alkyl, C₁–

C₄alkoxy, C₂–

C₇ alkenyl, C₂–

C₇ alkynyl, C₃–

C₇cycloalkyl(C₁–

C₄alkyl), benzyl, C₁–

C₆haloalkyl, and C₁–

C₆haloalkoxy;

R₂, when E is Carbon, is chosen from (i) hydrogen;

halogen, and hydroxy; and

(ii) C₁–

C₇alkyl substituted with from 0 to 3 substitutents independently chosen from hydroxy, halogen, amino, cyano, oxo, C₁–

C₄alkyl, C₁–

C₄alkoxy, C₂–

C₇alkenyl, C₂–

C₇alkynyl, C₁–

C₇alkoxy;

C₁–

C₇alkylamino;

C₃–

C₇cycloalkyl(C₁–

C₄alkyl), benzyl, C₁–

C₆haloalkyl, and C₁–

C₆haloalkoxy;

R₄ represents C₁–

C₆alkyl, C₂–

C₆ alkenyl, C₂–

C₆ alkynyl, C₃–

C₇ cycloalkyl, C₃–

C₇ cycloalkenyl, (C₃–

C₇cycloalkyl)C₁–

C₄alkyl, (C₃–

C₇cycloalkenyl)C₁–

C₄alkyl, or hexahydro-1,3-benzodioxolylmethyl, each of which is substituted with from 0 to 3 substitutents independently chosen from hydrogen, hydroxy, halogen, amino, cyano, C₁–

C₂alkyl, C₁–

C₂alkoxy, and C₁–

C₂alkoxycarbonyl;

or

R₄ represents;

(i) arylC₀–

C₄alkyl having 1 ring or 2 fused or pendant rings,

(ii) benzyl fused to a 5 to 7 membered saturated or partially unsaturated ring that (a) has 0, 1 or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 3 substituents independently chosen from halogen, C₁–

C₄alkyl, C₁–

C₄alkoxy, C₁–

C₂haloalkyl, and C₁–

C₂haloalkoxy,

(iii) heterocycloalkyl(C₀–

C₄alkyl), or

(iv) heteroarylC₀–

C₂alkyl, having 1 ring to 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S,

wherein each of (i), (ii) (iii) and (iv) are substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —

COOH, —

CONH₂, —

SO₂NH₂, oxo, C₁–

C₆haloalkyl, C₁–

C₆haloalkoxy, C₁–

C₆alkyl, C₁–

C₆alkoxy, mono- and di-(C₁–

C₆)alkylamino, C₁–

C₆alkanoyl, C₁–

C₆sulfonate, C₁–

C₆alkylsulfonyl, C₁–

C₆alkylsulfinyl, C₁–

C₆alkylthio, C₂–

C₆alkanone, C₂–

C₆alkyl ether;

C₁–

C₆alkanoyloxy;

C₁–

C₆alkoxycarbonyl, and C₁–

C₆alkylcarboxamide; and

Ar₁ represents phenyl, quinolinyl, isoquinolinyl, phthalizinayl, benzimidazolyl, indanyl, tetralinyl, chromanyl, naphthyl, pyridyl, pyrimidinyl, pyridizinyl, pyrazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, oxazolyl, furanyl, or thienyl, each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, C₁–

C₆alkylamino, C₁–

C₆alkylaminoC₁–

C₆alkyl, cyano, nitro, C₁–

C₆haloalkyl, C₁–

C₆ haloalkoxy, C₁–

C₆alkyl, and C₁–

C₆ alkoxy.

3. A compound or salt according to claim 2 wherein A is carbon;

and E is nitrogen.

4. A compound or salt according to claim 2 wherein E is carbon;

and A is nitrogen.

5. A compound or salt according to claim 2 wherein and A and E are nitrogen.

6. A compound or salt according to claim 2 wherein R₅ is hydrogen;

and R₆ is hydrogen, methyl, or ethyl.

7. A compound or salt according to claim 2 wherein

R₅ is hydrogen, R₆ is hydrogen, methyl, or ethyl;

and

Ar₁ is phenyl, pyrazolyl, or thienyl, each of which is substituted with 0 to 2 substituents independently chosen from halogen, hydroxy, C₁–

C₂alkyl, C₁–

C₂alkoxy, C₁–

C₂haloalkyl, and C₁–

C₂haloalkoxy.

8. A compound or salt according to claim 2 wherein R₅ and R₆ are hydrogen, and Ar₁ is unsubstituted phenyl or unsubstituted thienyl.

9. A compound or salt according to claim 2 wherein R₁ is phenyl substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —

COOH, —

CONH₂, —

SO₂NH₂, C₁–

C₆ haloalkyl, C₁–

C₆haloalkoxy, C₁–

C₆alkyl, C₁–

C₆alkoxy, 1,3-dioxol-5-yl, C₁–

C₆alkanoyl, C₁–

C₆alkylsulfonyl, C₁–

C₆alkylsulfinyl, C₁–

C₆alkylthio, C₂–

C₆alkanone;

C₁–

C₆alkanoyl;

C₂–

C₆alkyl ether;

C₁–

C₆alkanoyloxy, C₁–

C₆alkoxycarbonyl, and C₁–

C₆alkylcarboxamide.

10. A compound or salt according to claim 2 wherein R₁ is phenyl substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —

COOH, —

CONH₂, —

SO₂NH₂, C₁–

C₂ haloalkyl, C₁–

C₂ haloalkoxy, C₁–

C₂alkyl, and C₁–

C₂alkoxy.

11. A compound or salt according to claim 2 wherein R₁ is unsubstituted phenyl.

12. A compound or salt according to claim 2 wherein R₁ is thienyl or pyridyl, each of which is substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —

COOH, —

CONH₂, —

SO₂NH₂, C₁–

C₂ haloalkyl, C₁–

C₂ haloalkoxy, C₁–

C₂alkyl, and C₁–

C₂alkoxy.

13. A compound or salt according to claim 2 wherein R₁ is hydrogen.

14. A compound or salt according to claim 2 wherein R₁ is halogen, C₁–

C₄alkyl, C₁–

C₄alkoxy, cyano, trifluoromethyl, pentafluoroethyl, C₁–

C₂alkylaminoC₁–

C₂alkyl, hydroxymethyl, or hydroxyethyl.

15. A compound or salt according to claim 2 wherein R₂ is propyl, butyl, pentyl, 3-methylbutyl, or methoxyethyl.

16. A compound or salt according to claim 2 wherein R₃ is hydrogen.

17. A compound or salt according to claim 2 wherein R₃ is C₁–

C₅ alkyl.

18. A compound or salt according to claim 2 wherein R₄ represents C₁–

C₆alkyl, C₂–

C₆ alkenyl, C₂–

C₆ alkynyl, C₃–

C₇ cycloalkyl, C₃–

C₇ cycloalkenyl, (C₃–

C₇cycloalkyl)C₁–

C₄alkyl, (C₃–

C₇cycloalkenyl)C₁–

C₄alkyl, or hexahydro-1,3-benzodioxolylmethyl, each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, C₁–

C₂alkyl, C₁–

C₂alkoxy, and C₁–

C₂alkoxycarbonyl.

19. A compound or salt according to claim 2 wherein R₄ represents cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexylmethyl, cyclohexenylmethyl, cyclhexenyl, or hexahydro-1,3-benzodioxolylmethyl.

20. A compound or salt according to claim 2 wherein R₄ represents cyclohexylmethyl.

21. A compound or salt according to claim 2 wherein

R₄ represents

(i) aryl or aryl(C₁–

C₂)alkyl having 1 ring or 2 fused or pendant rings,

(ii) benzyl fused to a 5- to 7-membered saturated or partially unsaturated ring that (a) has 0, 1, or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 3 substituents independently chosen from halogen, C₁–

C₄alkyl, C₁–

C₄alkoxy, C₁–

C₂haloalkyl, and C₁–

C₂haloalkoxy;

(iii) saturated or partially unsaturated heterocyclic(C₀–

C₄alkyl) having 1 ring or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S;

or

(iv) heteroaryl or heteroaryl(C₀–

C₂alkyl), having 1 ring or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S, wherein each of (i), (ii), (iii), and (iv) are substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —

COOH, —

CONH₂, —

SO₂NH₂, oxo, C₁–

C₆ haloalkyl, C₁–

C₆haloalkoxy, C₁–

C₆alkyl, C₁–

C₆alkoxy, C₁–

C₆alkanoyl, C₁–

C₆sulfonate, C₁–

C₆alkylsulfonyl, C₁–

C₆alkylsulfinyl, C₁–

C₆alkylthio, C₁–

C₆alkanone, C₂–

C₆alkyl ether, C₁–

C₆ alkanoyloxy, C₁–

C₆alkoxycarbonyl, and C₁–

C₆alkylcarboxamide.

22. A compound or salt according to claim 2 wherein R₄ represents benzyl substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —

COOH, —

CONH₂, —

SO₂NH₂, C₁–

C₆ haloalkyl, C₁–

C₆ haloalkoxy, mono- and di-(C₁–

C₆)alkylamino, C₁–

C₆ alkyl, C₁–

C₆alkoxy, C₁–

C₆alkanoyl, C₁–

C₆alkylsulfonate, C₁–

C₆alkylsulfonyl, C₁–

C₆alkylsulfinyl, C₁–

C₆alkylthio, C₂–

C₆alkanone, C₂–

C₆alkyl ether, C₁–

C₆ alkanoyloxy, C₁–

C₆alkoxycarbonyl, and C₁–

C₆alkylcarboxamide.

23. A compound or salt according to claim 2 wherein R₄ represents benzyl substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —

COOH, —

CONH₂, —

SO₂NH₂, —

SH, C₁–

C₂haloalkyl, C₁–

C₂ haloalkoxy, mono- and di-(C₁–

C₂)alkylamino, C₁–

C₄alkoxy, C₁–

C₂alkanoyl, C₁–

C₂alkylsulfonate, C₁–

C₂alkylsulfonyl, C₁–

C₂alkylsulfinyl, C₁–

C₂alkylthio, C₂–

C₃alkanone, C₂–

C₆alkylether, C₁–

C₄ alkanoyloxy, C₁–

C₄alkoxycarbonyl, and C₁–

C₂alkylcarboxamide.

24. A compound or salt according to claim 2 wherein R₄ represents benzyl substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —

COOH, —

CONH₂, —

SO₂NH₂, pentafluoroethyl, tetrafluoromethyl, trifluoromethyl, difluoromethyl, pentafluoroethoxy, tetrafluoroethoxy, trifluoromethoxy, difluoromethoxy, C₁–

C₂ alkyl, C₁–

C₄alkoxy, C₁–

C₂alkanoyl, C₁–

C₂alkylsulfonate, C₁–

C₂alkylsulfonyl, C₁–

C₂alkylsulfinyl, C₁–

C₂alkylthio, C₂–

C₃alkanone;

C₁–

C₄ alkanoyloxy, ethoxycarbonyl, methoxycarbonyl, and —

NH₂(C═

O)CH₃.

25. A compound or salt according to claim 2 wherein R₄ represents pyridylmethyl, pyrimidylmethyl, thienylmethyl, napthylmethyl, indolylmethyl, benzoxadialolylmethyl, benzoxazolylmethyl, quinazolinylmethyl, benzothiazolylmethyl, or benzimidazolylmethyl, each of which is optionally substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, amino, cyano, C₁–

C₂ alkyl, C₁–

C₂alkoxy, C₁–

C₂haloalkyl, C₁–

C₂haloalkoxy, and mono- and di-(C₁–

C₂)alkylamino.

26. A compound or salt according to claim 2 wherein R₄ represents benzyl fused to a 5- to 7-membered saturated or partially unsaturated ring that (a) has 0, 1, or 2 ring atoms independently chosen from N, O and S, with remaining ring atoms being carbon, and (b) is substituted with from 0 to 3 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —

COOH, —

CONH₂, —

SO₂NH₂, oxo, C₁–

C₆ haloalkyl, C₁–

C₆ haloalkoxy, C₁–

C₆alkyl, C₁–

C₆alkoxy, mono- and di-(C₁–

C₆)alkylamino, C₁–

C₆alkanoyl, C₁–

C₆sulfonate, C₁–

C₆alkylsulfonyl, C₁–

C₆alkylsulfinyl, C₁–

C₆alkylthio, C₂–

C₆alkanone, C₂–

C₆alkyl ether;

C₁–

C₆ alkanoyloxy;

C₁–

C₆alkoxycarbonyl, and C₁–

C₆alkylcarboxamide.

27. A compound or salt according to claim 2 wherein R₄ represents 1,3-benzodioxol-5-ylmethyl, 2,3-dihydro-1-benzofuran-6-ylmethyl, 2,3-dihydro-1-benzofuran-5-ylmethyl, 2,3-dihydro-1,4-benzodioxin-6-ylmethyl, chroman-6-ylmethyl, chroman-7-ylmethyl, 1,3-benzothiazolylmethyl, 2,3-dihydroindol-5-ylmethyl, each of which is substituted from 0 to 2 substituents independently selected from hydroxy, halogen, amino, cyano, oxo, C₁–

C₂haloalkyl, C₁–

C₂haloalkoxy, C₁–

C₂alkyl, C₁–

C₂alkoxy, mono- and di-(C₁–

C₂)alkylamino.

28. A compound or salt according to claim 2 wherein R₄ is a saturated or partially unsaturated heterocyclic(C₀–

C₄alkyl) group 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, substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —

COOH, —

CONH₂, —

SO₂NH₂, oxo, C₁–

C₆ haloalkyl, C₁–

C₆haloalkoxy, C₁–

C₆alkyl, C₁–

C₆alkoxy, mono- and di-(C₁–

C₆)alkylamino, C₁–

C₆alkanoyl, C₁–

C₆sulfonate, C₁–

C₆alkylsulfonyl, C₁–

C₆alkylsulfinyl, C₁–

C₆alkylthio, C₂–

C₆alkanone, C₂–

C₆alkylether, C₁–

C₆alkanoyloxy, C₁–

C₆alkoxycarbonyl, and C₁–

C₆alkylcarboxamide.

29. A compound or salt according to claim 2 wherein R₄ is morpholinyl(C₀–

C₄alkyl), azetidinyl(C₀–

C₄alkyl), piperazinyl(C₀–

C₄alkyl), piperidinyl(C₀–

C₄alkyl), pyrrolidinyl(C₀–

C₄alkyl), tetrahydropyranyl(C₀–

C₄alkyl), or tetrahydropyridinyl(C₀–

C₄alkyl), each of which is substituted by from 0 to 2 substituents independently selected from hydroxy, halogen, amino, cyano, oxo, C₁–

C₂ alkyl, C₁–

C₂alkoxy, C₁–

C₂haloalkyl, C₁–

C₂haloalkoxy, mono- and di-(C₁–

C₂)alkylamino.

30. A compound according to claim 2 wherein R₄ is a heteroaryl or heteroaryl(C₁–

C₂alkyl) group, having 1 ring or 2 fused or pendant rings, from 5 to 7 members in each ring, and in at least one ring 1 to 3 heteroatoms selected from N, O, and S, substituted with from 0 to 4 substituents independently chosen from hydroxy, halogen, amino, cyano, nitro, —

COOH, —

CONH₂, —

SO₂NH₂, oxo, C₁–

C₆ alkyl, C₁–

C₆alkoxy, C₁–

C₆haloalkyl, C₁–

C₆haloalkoxy, C₁–

C₆alkanoyl, C₁–

C₆sulfonate, C₁–

C₆alkylsulfonyl, C₁–

C₆alkylsulfinyl, C₁–

C₆alkylthio, C₁–

C₆alkanone, C₂–

C₆alkyl ether, C₁–

C₆ alkanoyloxy, C₁–

C₆alkoxycarbonyl, and C₁–

C₆alkylcarboxamide.

31. A compound according to claim 2 wherein R₄ is pyridylmethyl, pyrimidinylmethyl, thienylmethyl, naphthylmethyl, indolylmethyl, benzoxadiazolylmethyl, benzoxazolylmethyl, quinazolinylmethyl, or benzimidazolylmethyl, each of which is substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, amino, cyano, C₁–

C₂haloalkyl, C₁–

C₂haloalkoxy, C₁–

C₂ alkyl, and C₁–

C₂alkoxy.

32. A pharmaceutical composition comprising at least one compound or salt according to claim 1, or a prodrug or hydrate thereof, in combination with a physiologically acceptable carrier or excipient.

33. A compound or salt according to claim 1, wherein the compound exhibits an IC₅₀ of 500 nM or less in a standard in vitro C5a receptor-mediated chemotaxis or calcium mobilization assay.

34. A method for treating a patient suffering from rheumatoid arthritis, psoriasis, reperfusion injury, or bronchial asthma comprising administering to the patient a C5a receptor modulatory amount of a compound according to claim 1.

35. A method for treating a patient suffering from myocardial infarction, atherosclerosis, ischemic heart disease, or ischemia-reperfusion injury comprising administering to the patient a C5a receptor modulatory amount of a compound according to claim 1.

36. A pharmaceutical composition according to claim 32, wherein the pharmaceutical composition is formulated as an injectible fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup, or a transdermal patch.