1-aryl-4-substituted isoquinolines

• US 20070249665A1
• Filed: 05/06/2005
• Published: 10/25/2007
• Est. Priority Date: 05/08/2004
• Status: Active Grant

• Current Assignee: Novartis International Pharmaceutical Limited (Novartis Ag)
• Original Assignee: Neurogen Corporation (Ligand Pharmaceuticals, Inc.)
• Inventors: Lee, Kyungae
• Granted Patent: US 7,915,288 B2
• Time in Patent Office: Days
• US Class Current: 514/307
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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 217/14 other than aralkyl radicals
• CPC Class Codes: C07D 217/16 substituted by oxygen atoms
• CPC Class Codes: C07D 217/22 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

1-aryl-4-substituted isoquinoline or 1-aryl-3,4-disubstituted isoquinoline analogues of Formula I and Formula II, as follows:
wherein R₁, R₂, R₃, R₈, R₉, A and Ar are defined herein. Such compounds are ligands of C5a receptors. Preferred compounds of Formula I and II bind to C5a receptors with high affinity and exhibit neutral antagonist or inverse agonist activity at C5a receptors. The present invention also relates to pharmaceutical compositions comprising such compounds, and to the use of such compounds in treating a variety of inflammatory, cardiovascular, and immune system disorders. In addition, the present invention provides labeled 1-aryl-4-substituted isoquinolines or 1-aryl-3,4-disubstituted isoquinolines, which are useful as probes for the localization of C5a receptors.

Claims

2. A compound according to Formula II:

or a pharmaceutically acceptable salt thereof, wherein;

Ar is substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl;

A is OR₄, NR₄R₅, or CR₄(XR_y)₂;

R₁ is chosen from;

(i) hydrogen, halogen, amino, and cyano; and

(ii) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₄haloalkyl, C₁-C₄haloalkoxy, mono- and di-(C₁-C₆alkyl)amino, (C₃-C₇cycloalkyl)C₀-C₄alkyl, (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl and —

S(O_n)C₁-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R_x;

R₃ represents between 0 and 4 substituents, each of which is independently selected from hydrogen, halogen, hydroxy, amino, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionally substituted mono- and di-alkylamino, optionally substituted aminoalkyl, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted heterocycle, optionally substituted heterocycle-oxy, -E-(CR_CR_D)_m-Z, -E-(CR_CR_D)_m—

XR_A;

R₄ is;

(i) C₂-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, mono- or di-(C₁-C₄alkylamino)C₂-C₄alkyl, (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl, arylC₀-C₄alkyl, or heteroarylC_0-4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R_x, C₂-C₄alkanoyl, mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and di-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl and XR_y;

or

(ii) joined to R₅ to form, with the nitrogen to which R₄ and R₅ are bound, a heterocycle having from 1 to 3 rings, 5 to 7 ring members in each ring, wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from R_x, oxo and W-Z;

R₅ is;

(i) hydrogen;

(ii) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, (C₃-C₇carbocycle)C₀-C₄alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy;

or

(iii) joined to R₄ to form an optionally substituted heterocycle;

R₈ and R₉ are independently selected from;

(i) hydrogen, halogen, hydroxy, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₆alkylamino or C₃-C₇cycloalkyl C₀-C₄alkyl;

E is a single covalent bond, oxygen, or NR_A;

X is a single covalent bond, —

CR_AR_B—

, —

O—

, —

C(═

O)—

, —

C(═

O)O—

, —

S(O)_n—

or —

NR_B—

; and

R_y is;

(i) hydrogen;

or

(ii) C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, C₃-C₁₀carbocycleC₀-C₄alkyl or (3- to 10-membered heterocycle)C₀-C₄alkyl, each of which is substituted with from 0 to 6 substituents independently selected from R_x, oxo, —

NH(C₁-C₆alkanoyl), —

N(C₁-C₆alkyl)C₁-C₆alkanoyl, —

NHS(O_n)C₁-C₆alkyl, —

N(S(O_n)C₁-C₆alkyl)₂, —

S(O_n)NHC₁-C₆alkyl and —

S(O_n)N(C₁-C₆alkyl)₂;

W is a single covalent bond, —

CR_AR_B—

, —

NR_B—

or —

O—

;

Z is independently selected at each occurrence from 3- to 7-membered carbocycles and heterocycles, each of which is substituted with from 0 to 4 substituents independently selected from halogen, oxo, —

COOH, hydroxy, amino, cyano, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, mono- and di-(C₁-C₆alkyl)amino and —

S(O_n) C₁-C₆alkyl; and

R_A and R_B are independently selected at each occurrence from;

(i) hydrogen; and

(ii) C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, saturated or partially saturated (C₃-C₁₀carbocycle)C₀-C₄alkyl and saturated or partially saturated (3- to 10-membered heterocycle)C₀-C₄alkyl, each of which is substituted with from 0 to 6 substituents independently selected from oxo, hydroxy, halogen, cyano, amino, C₁-C₆alkoxy, mono- and di-(C₁-C₄alkyl)amino, —

COOH, —

C(═

O)NH₂, —

NHC(═

O)(C₁-C₆alkyl), —

N(C₁-C₆alkyl)C(═

O)(C₁-C₆alkyl), —

NHS(O_n)C₁-C₆alkyl, SO₃H, —

S(O_n)C₁-C₆alkyl, —

S(O_n)NHC₁-C₆alkyl, —

S(O_n)N(C₁-C₆alkyl)C₁-C₆alkyl and Z;

R_C and R_D are independently selected from R_A, hydroxy, C_1-6alkoxy, and oxo;

R_x is independently chosen at each occurrence from halogen, hydroxy, amino, cyano, nitro, —

COOH, —

C(═

O)NH₂, C₁-C₆alkoxycarbonyl, mono- and di-(C_1-6alkyl)aminocarbonyl, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, mono- and di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy, C₁-C₂hydroxyalkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, and —

S(O_n)C₁-C₆alkyl;

m is an integer independently selected at each occurrence from 0-8; and

n is an integer independently selected at each occurrence from 0, 1 and 2.

1. A compound according to Formula I

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is selected from hydrogen, halogen, cyano, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted (cycloalkyl)alkoxy, or optionally substituted heterocycloalkyl;

R₂ is selected from the group consisting of —

NR₄R₅, —

(CR_AR_B)OR₄, —

CR_AR_BNR₄R₅, —

C(R_A′

)═

CR_AR_B, and —

CR_AR_BQ;

R₃ represents between 0 and 4 substituents, each of which is independently selected from halogen, hydroxy, amino, cyano, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted haloalkoxy, optionally substituted hydroxyalkyl, optionally substituted alkoxyalkyl, optionally substituted mono- and di-alkylamino, optionally substituted aminoalkyl, -E-(CR_CR_D)_m-Z, and -E-(CR_CR_D)_m—

XR_A;

R₄ is;

(i) C₂-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, mono- or di-(C₁-C₄alkylamino)C₂-C₄alkyl, (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl, arylC₀-C₄alkyl, or (heteroaryl)C_0-4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R_x, C₂-C₄alkanoyl, mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and di-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl and XR_y;

or

(ii) joined to R₅ to form, with the nitrogen to which R₄ and R₅ are bound, a heterocycle having from 1 to 3 rings, 5 to 7 ring members in each ring, wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from R_x, oxo and W-Z;

R₅ is;

(i) hydrogen;

(ii) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, (C₃-C₇carbocycle)C₀-C₄alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy;

or

(iii) joined to R₄ to form an optionally substituted heterocycle;

Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl, wherein Ar is optionally substituted heteroaryl when R₂ is —

NR₄R₅;

R_A, R_A′

, and R_B, which may be the same or different, are independently selected at each occurrence from;

(i) hydrogen and hydroxy, and (ii) alkyl groups, cycloalkyl groups, and (cycloalkyl)alkyl groups, each of which is optionally substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, cyano, amino, C_1-6alkoxy, —

NH(C_1-6alkyl), —

N(C_1-6alkyl)(C_1-6alkyl), —

NHC(═

O)(C_1-6alkyl), —

N(C_1-6alkyl)C(═

O)(C_1-6alkyl), —

NHS(O)_n(C_1-6alkyl), —

S(O)_n(C_1-6 alkyl), —

S(O)_nNH(C_1-6alkyl), —

S(O)_nN(C_1-6 alkyl)(C_1-6alkyl), and Z;

E is a single covalent bond, oxygen, or NR_A;

X is independently selected at each occurrence from the group consisting of —

CH₂—

, —

CHR_B—

, —

O—

, —

C(═

O)—

, —

C(═

O)O—

, —

S(O)_n—

, —

NH—

, —

NR_B—

, —

C(═

O)NH—

, —

C(═

O)NR_B—

, —

S(O)_nNH—

, —

S(O)_nNR_B—

, —

NHC(═

O)—

, —

NR_BC(═

O)—

, —

NHS(O)_n—

, and —

NR_BS(O)_n—

;

Y and Z are independently selected at each occurrence from 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which are optionally substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C_1-4alkyl, —

O(C_1-4alkyl), —

NH(C_1-4alkyl), —

N(C_1-4alkyl)(C_1-4alkyl), and —

S(O)_n(alkyl);

Q is an optionally substituted carbocyclic or optionally substituted heterocyclic group which are saturated, unsaturated or aromatic and comprises between 3 and 18 ring atoms arranged in 1, 2, or 3 rings which are fused, spiro or coupled by a bond;

m is independently selected at each occurrence from integers ranging from 0 to 8; and

n is an integer independently selected at each occurrence from 0, 1, and 2.

3. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R₃ is absent.

4. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R₁ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, (C₃-C₇cycloalkyl)-C₀-C₄alkyl.

5. A compound or pharmaceutically acceptable salt thereof according to claim 4, wherein R₁ is hydrogen, C₁-C₄alkyl or C₁-C₄alkoxy.

6. A compound or pharmaceutically acceptable salt thereof according to claim 5, wherein R₁ is hydrogen, methyl, ethyl, or methoxy.

7. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R₃ represents between 0 and 2 substituents, each of which is independently selected from C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, mono- and di-(C_1-6alkyl)amino, (amino)C_0-6alkyl.

8. A compound or pharmaceutically acceptable salt thereof according to claim 7, wherein R₃ represents between 0 and 2 substituents, each of which is independently selected from C_1-6alkyl, and C_1-6alkoxy.

9. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.

10. A compound or pharmaceutically acceptable salt thereof according to claim 9, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.

11. A compound or pharmaceutically acceptable salt thereof according to claim 10, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C_1-6alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6alkynyl, optionally substituted C_1-6alkoxy, optionally substituted (C_1-6alkoxy)C_1-6alkyl, optionally substituted (amino)C_1-6alkyl, optionally substituted mono- and di-(C_1-6alkyl)amino.

12. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein

R₄ is:

(i) C₂-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, mono- or di-(C₁-C₄alkylamino)C₂-C₄alkyl, (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl, pyridylC₀-C₄alkyl, pyrimidinylC₀-C₄alkyl, thienylC₀-C₄alkyl, imidazolylC₀-C₄alkyl, pyrrolylC₀-C₄alkyl, pyrazolylC₀-C₄alkyl, benzoisothiazolyl or tetrahydronapthyl, each of which is substituted with from 0 to 4 substituents independently chosen from R_x, C₂-C₄alkanoyl, mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and di-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl and XR_y;

or

(ii) joined to R₅ to form, with the nitrogen to which R₄ and R₅ are bound, a heterocycle having from 1 to 3 rings, 5 to 7 ring members in each ring, wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from R_x, oxo and W-Z; and

R₅ is;

(i) hydrogen;

(ii) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, (C₃-C₇carbocycle)C₀-C₄alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy;

or

(iii) joined to R₄ to form an optionally substituted heterocycle.

13. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein A is NR₄R₅.

14. A compound or pharmaceutically acceptable salt thereof according to claim 13, wherein:

R₄ is chosen from (C₃-C₇cycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl, pyridylC₀-C₄alkyl, pyrimidinylC₀-C₄alkyl, thienylC₀-C₄alkyl, imidazolylC₀-C₄alkyl, pyrrolylC₀-C₄alkyl, pyrazolylC₀-C₄alkyl, indolylC₀-C₄alkyl, indazolylC₀-C₄alkyl, benzocycloalkenylC₀-C₄alkyl, decahydronaphthylC₀-C₄alkyl, benzoisothiazolylC₀-C₄alkyl, tetrahydroquinolinylC₀-C₄alkyl and tetrahydronaphthylC₀-C₄alkyl, each of which is substituted with from 0 to 4 groups independently chosen from R_x, mono- and di-C₁-C₄alkylamino(C₁-C₄alkyl), mono- and di-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl, C₂-C₄alkanoyl and C₂-C₄alkanoyloxy; and

R₅ is C₁-C₆alkyl, C₂-C₆alkenyl or (C₃-C₇carbocycle)C₀-C₄alkyl.

15. A compound or pharmaceutically acceptable salt thereof according to claim 13, wherein R₄ and R₅ are joined to form a saturated or partially saturated heterocycle containing 1 or 2 fused or spiro rings;

wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, —

COOH, —

CH₂COOH, C_1-6alkoxycarbonyl, —

CH₂CO₂—

C_1-6alkyl, —

C(═

O)NH₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, mono- and di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, —

S(O_n)C₁-C₆alkyl, SO₃H, and phenyl.

16. A compound or pharmaceutically acceptable salt thereof according to claim 15, wherein R₄ and R₅ are joined to form a saturated 4- to 7-membered heterocyclic ring that is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy difluoromethoxy, —

COOH, —

CH₂COOH, C_1-2alkoxycarbonyl, and —

CH₂CO₂—

C_1-2alkyl.

17. A compound or pharmaceutically acceptable salt thereof according to claim 16, wherein the heterocyclic ring is azepanyl, morpholinyl, homomorpholinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, piperidinyl, or homopiperidinyl.

18. A compound or pharmaceutically acceptable salt thereof according to claim 15, wherein R₄ and R₅ are joined to form a heterocycle containing 2 rings;

wherein each of the rings is substituted with from 0 to 3 substituents independently selected from the group consisting of halogen, hydroxy, amino, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, and difluoromethoxy.

19. A compound or pharmaceutically acceptable salt thereof according to claim 18, wherein the heterocycle is tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, indazolyl, indolinyl, phenylimidazolyl, pyridooxazinyl, or benzoxazinyl.

20. A compound or pharmaceutically acceptable salt thereof according to claim 13, wherein the compound is according to Formula III:

wherein;

R₃ and R_3a are independently selected from hydrogen, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, COOH, CONH₂, SO₂NH₂, hydroxy, halogen, or amino;

R₁₃ represents from 0 to 3 substituents independently chosen from;

(i) R_x; and

(ii) phenyl and pyridyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and mono- and di-(C₁-C₄alkyl)amino; and

G is CH₂, sulfur, oxygen or NR_E;

wherein R_E is;

(i) hydrogen;

or

(ii) C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, phenyl or a 5- or 6-membered heteroaryl ring, each of which is substituted with from 0 to 3 substituents independently chosen from R_x.

21. A compound or pharmaceutically acceptable salt thereof according to claim 20, wherein G is oxygen.

22. A compound or pharmaceutically acceptable salt thereof according to claim 20, wherein R₁₃ represents from 0 to 2 substituents independently chosen from halogen, methyl, methoxy, ethyl, phenyl, and phenoxy, wherein each phenyl or phenoxy group is substituted with between 0 and 3 substituents chosen from R_x.

23. A compound or pharmaceutically acceptable salt thereof according to claim 20, wherein:

R₁ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, (C₃-C₇cycloalkyl)-C₀-C₄alkyl

R₈ and R₉ are independently chosen from hydrogen, halogen, hydroxy, C₁-C₆alkyl, C₁-C₆alkenyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl and C₁-C₆alkoxy; and

Ar is phenyl, 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.

24. A compound or pharmaceutically acceptable salt thereof according to claim 23, wherein R₃ represents between 0 and 2 substituents, each of which is independently selected from hydroxy, methyl, ethyl, or methoxy.

25. A compound or pharmaceutically acceptable salt thereof according to claim 23, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.

26. A compound or pharmaceutically acceptable salt thereof according to claim 25, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.

27. A compound or pharmaceutically acceptable salt thereof according to claim 25, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C_1-6alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6alkynyl, optionally substituted C_1-6alkoxy, optionally substituted (C_1-6alkoxy)C_1-6alkyl, optionally substituted (amino)C_1-6alkyl, optionally substituted mono- and di-(C_1-6alkyl)amino.

28. A compound or pharmaceutically acceptable salt thereof according to claim 13, wherein the compound has the formula:

wherein;

R₃ and R_3a are independently selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, COOH, CONH₂, SO₂NH₂, hydroxy, halogen, and amino;

R₁₀ and R₁₁ are independently chosen from hydrogen, C₁-C₆alkyl, C₁-C₂haloalkyl and C₃-C₇cycloalkyl(C₀-C₂alkyl); and

R₁₂ represents from 0 to 3 substituents independently chosen from R_x, mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkoxy) and YZ;

or two adjacent R₁₂ groups are joined to form a fused 5- to 7-membered carbocyclic or heterocyclic ring.

29. A compound or pharmaceutically acceptable salt thereof according to claim 28, wherein R₁₂ represents from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, mono- and di-(C₁-C₂alkyl)amino, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy and (C₃-C₇cycloalkyl)C₀-C₂alkyl.

30. A compound or pharmaceutically acceptable salt thereof according to claim 28, wherein:

R₁ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, (C₃-C₇cycloalkyl)-C₀-C₄alkyl;

R₈ and R₉ are independently chosen from hydrogen, halogen, hydroxy, C₁-C₆alkyl, C₁-C₆alkenyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl and C₁-C₆alkoxy; and

Ar is phenyl, 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, and triazolyl, each of which is optionally mono-, di-, or tri-substituted.

31. A compound or pharmaceutically acceptable salt thereof according to claim 28, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.

32. A compound or pharmaceutically acceptable salt thereof according to claim 31, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.

33. A compound or pharmaceutically acceptable salt thereof according to claim 31, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C_1-6alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6alkynyl, optionally substituted C_1-6alkoxy, optionally substituted (C_1-6alkoxy)C_1-6alkyl, optionally substituted (amino)C_1-6alkyl, optionally substituted mono- and di-(C_1-6alkyl)amino.

34. A compound or pharmaceutically acceptable salt thereof according to claim 13, wherein the compound has the formula:

wherein;

R₃ and R_3a are independently selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, COOH, CONH₂, SO₂NH₂, hydroxy, halogen, and amino;

R₁₂ and R₁₃ independently represent from 0 to 3 substituents independently chosen from R_x;

R₁₄ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₂haloalkyl or (C₃-C₇cycloalkyl)C₀-C₂alkyl, COOH, CONH₂, CH₂COOH, CH₂CONH₂, C_1-6alkoxycarbonyl, CH₂CO₂—

C_1-6alkyl, or SO₃H; and

x is 0, 1 or2.

35. A compound or pharmaceutically acceptable salt thereof according to claim 34, wherein x is 1.

36. A compound or pharmaceutically acceptable salt thereof according to claim 34, wherein:

R₁₂ and R₁₃ independently represent from 0 to 2 substituents independently chosen from halogen, methyl, methoxy and ethyl; and

R₁₄ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl or C₃-C₇cycloalkyl(C₀-C₂alkyl).

37. A compound or pharmaceutically acceptable salt thereof according to claim 34, wherein:

R₁ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, (C₃-C₇cycloalkyl)-C₀-C₄alkyl;

R8 and R₉ are independently chosen from hydrogen, halogen, hydroxy, C₁-C₆alkyl, C₁-C₆alkenyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl and C₁-C₆alkoxy; and

Ar is phenyl which is mono-, di-, or tri-substituted, or 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indolyl, indazolyl, pyrrolyl, furanyl, indolyl, indazolyl and triazolyl, each of which is optionally mono-, di-, or tri-substituted.

38. A compound or pharmaceutically acceptable salt thereof according to claim 34, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.

39. A compound or pharmaceutically acceptable salt thereof according to claim 38, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.

40. A compound or pharmaceutically acceptable salt thereof according to claim 38, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C_1-6alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6alkynyl, optionally substituted C_1-6alkoxy, optionally substituted (C_1-6alkoxy)C_1-6alkyl, optionally substituted (amino)C_1-6alkyl, optionally substituted mono- and di-(C_1-6alkyl)amino.

41. A compound or pharmaceutically acceptable salt thereof according to claim 13, wherein the compound has the formula:

wherein;

R₃ and R_3a are independently selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, COOH, CONH₂, SO₂NH₂, hydroxy, halogen, and amino;

R₁₂ and R₁₃ represent from 0 to 3 substituents independently chosen from R_x;

G is CH₂, NH, sulfur or oxygen;

G₃ is N, CH, or CR_x and

x is 0, 1 or 2.

42. A compound or pharmaceutically acceptable salt thereof according to claim 41, wherein x is 1.

43. A compound or pharmaceutically acceptable salt thereof according to claim 41, wherein R₁₂ and R₁₃ independently represent from 0 to 2 substituents independently chosen from halogen, methyl, methoxy and ethyl.

44. A compound or pharmaceutically acceptable salt thereof according to claim 41, wherein:

R₁ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, (C₃-C₇cycloalkyl)-C₀-C₄alkyl;

R₈ and R₉ are independently chosen from hydrogen, halogen, hydroxy, C₁-C₆alkyl, C₁-C₆alkenyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl and C₁-C₆alkoxy; and

Ar is phenyl which is mono-, di-, or tri-substituted, or 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indolyl, indazolyl, pyrrolyl, furanyl, indolyl, indazolyl and triazolyl, each of which is optionally mono-;

di-, or tri-substituted.

45. A compound or pharmaceutically acceptable salt thereof according to claim 41, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.

46. A compound or pharmaceutically acceptable salt thereof according to claim 45, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.

47. A compound or pharmaceutically acceptable salt thereof according to claim 45, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C_1-6alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6alkynyl, optionally substituted C_1-6alkoxy, optionally substituted (C_1-6alkoxy)C_1-6alkyl, optionally substituted (amino)C_1-6-alkyl, optionally substituted mono- and di-(C_1-6alkyl)amino.

48. A compound or pharmaceutically acceptable salt thereof according to claim 13, wherein the compound has the formula:

wherein

R₃ and R_3a are independently selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, COOH, CONH₂, SO₂NH₂, hydroxy, halogen, and amino;

R₁₂ and R₁₃ independently represent from 0 to 3 substituents independently chosen from R_x;

G is CH₂, NH or oxygen; and

x is 0, 1 or 2.

49. A compound or pharmaceutically acceptable salt thereof according to claim 48, wherein x is 1.

50. A compound or pharmaceutically acceptable salt thereof according to claim 48, wherein G is CH₂.

51. A compound or pharmaceutically acceptable salt thereof according to claim 48, wherein R₁₂ and R₁₃ independently represent from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, mono- and di-(C₁-C₂alkyl)amino, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and (C₃-C₇cycloalkyl)C₀-C₂alkyl.

52. A compound or pharmaceutically acceptable salt thereof according to claim 51, wherein R₁₂ and R₁₃ independently represent from 0 to 2 substituents independently chosen from halogen, C₁-C₂alkyl and C₁-C₂alkoxy.

53. A compound or pharmaceutically acceptable salt thereof according to claim 51, wherein:

R₅ is C₁-C₆alkyl; and

R₁₂ and R₁₃ each represent from 0 to 2 substituents independently chosen from halogen, methyl, methoxy and ethyl.

54. A compound or pharmaceutically acceptable salt thereof according to claim 51, wherein:

R₁ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, (C₃-C₇cycloalkyl)-C₀-C₄alkyl;

R₈ and R₉ are independently chosen from hydrogen, halogen, hydroxy, C₁-C₆alkyl, C₁-C₆alkenyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl and C₁-C₆alkoxy; and

Ar is phenyl which is mono-, di-, or tri-substituted, or 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl, indolyl, indazolyl, and triazolyl, each of which is optionally mono-, di-, or tri-substituted.

55. A compound or pharmaceutically acceptable salt thereof according to claim 48, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.

56. A compound or pharmaceutically acceptable salt thereof according to claim 55, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.

57. A compound or pharmaceutically acceptable salt thereof according to claim 55, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C_1-6alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6alkynyl, optionally substituted C_1-6alkoxy, optionally substituted (C_1-6alkoxy)C_1-6alkyl, optionally substituted (amino)C_1-6alkyl, optionally substituted mono- and di-(C_1-6alkyl)amino.

58. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein:

A is OR₄; and

R₄ is C₂-C₆alkyl, C₂-C₆alkenyl, phenylC₀-C₄alkyl, naphthylC₀-C₄alkyl, pyridylC₀-C₄alkyl, pyrimidinylC₀-C₄alkyl, thienylC₀-C₄alkyl, imidazolylC₀-C₄alkyl or pyrrolylC₀-C₄alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R_x, mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and di-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl and C₂-C₄alkanoyl.

59. A compound or pharmaceutically acceptable salt thereof according to claim 58, wherein R₄ is phenyl, benzyl, pyridyl or pyridylmethyl, each of which is substituted with from 0 to 4 substituents independently chosen from R_x, mono- and di-C₁-C₄alkylamino(C₀-C₄alkyl), mono- and di-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl and C₂-C₄alkanoyl.

60. A compound or pharmaceutically acceptable salt thereof according to claim 58, wherein:

R₁ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, (C₃-C₇cycloalkyl)-C₀-C₄alkyl

R₃ represents between 0 and 2 substituents, each of which is independently selected from C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, mono- and di-(C_1-6alkyl)amino, (amino)C_0-6alkyl;

R₈ and R₉ are independently chosen from hydrogen, halogen, hydroxy, C₁-C₆alkyl, C₁-C₆alkenyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl and C₁-C₆alkoxy; and

Ar is phenyl which is mono-, di-, or tri-substituted, or 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl, indolyl, indazolyl, and triazolyl, each of which is optionally mono-, di-, or tri-substituted.

61. A compound or pharmaceutically acceptable salt thereof according to claim 58, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.

62. A compound or pharmaceutically acceptable salt thereof according to claim 61, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.

63. A compound or pharmaceutically acceptable salt thereof according to claim 61, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C_1-6alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6alkynyl, optionally substituted C_1-6alkoxy, optionally substituted (C_1-6alkoxy)C_1-6alkyl, optionally substituted (amino)C_1-6alkyl, optionally substituted mono- and di-(C_1-6alkyl)amino.

64. A compound or pharmaceutically acceptable salt thereof according to claim 58, wherein the compound has the formula:

wherein;

D is CH or N;

R₃ and R_3a are independently selected from the group consisting of hydrogen, C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, COOH, CONH₂, SO₂NH₂, hydroxy, halogen, and amino;

R₂₁ represents from 0 to 3 substituents independently chosen from R_x and LR_d;

or two adjacent R₂₁ groups are joined to form a fused 5- to 7-membered carbocyclic or heterocyclic ring that is substituted with from 0 to 3 substituents independently chosen from R_x;

L is a single covalent bond or —

CH₂—

; and

R_d is piperazinyl, morpholinyl, piperidinyl or pyrrolidinyl.

65. A compound or pharmaceutically acceptable salt thereof according to claim 64, wherein:

R₂₁ represents from 0 to 3 substituents independently chosen from R_x and LR_d;

R₁ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, (C₃-C₇cycloalkyl)-C₀-C₄alkyl;

R₈ and R₉ are independently chosen from hydrogen, halogen, hydroxy, C₁-C₆alkyl, C₁-C₆alkenyl, (C₃-C₆cycloalkyl)C₀-C₄alkyl and C₁-C₆alkoxy; and

Ar is phenyl which is mono-, di-, or tri-substituted, or 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl, indolyl, indazolyl, and triazolyl, each of which is optionally mono-, di-, or tri-substituted.

66. A compound or pharmaceutically acceptable salt thereof according to claim 64, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.

67. A compound or pharmaceutically acceptable salt thereof according to claim 66, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.

68. A compound or pharmaceutically acceptable salt thereof according to claim 66, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C_1-6alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6alkynyl, optionally substituted C_1-6alkoxy, optionally substituted (C_1-6alkoxy)C_1-6alkyl, optionally substituted (amino)C_1-6alkyl, optionally substituted mono- and di-(C_1-6alkyl)amino.

69. A compound or pharmaceutically acceptable salt thereof according to claim 64, wherein the group designated:

is chosen from naphthyl, tetrahydronaphthyl, benzofuranyl, benzodioxolyl, indanyl, indolyl, indazolyl, benzodioxolyl, benzo[1,4]dioxanyl and benzoxazolyl, each of which is substituted with from 0 to 3 substituents independently chosen from R_x.

70. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R₂ is —

NR₄R₅; and

Ar is heteroaryl.

71. A compound or pharmaceutically acceptable salt thereof according to claim 70, wherein R₃ is absent.

72. A compound or pharmaceutically acceptable salt thereof according to claim 70, wherein R₁ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, (C₃-C₇cycloalkyl)-C₀-C₄alkyl.

73. A compound or pharmaceutically acceptable salt thereof according to claim 72, wherein R₁ is hydrogen, C₁-C₄alkyl or C₁-C₄alkoxy.

74. A compound or pharmaceutically acceptable salt thereof according to claim 73, wherein R₁ is hydrogen, methyl, ethyl, or methoxy.

75. A compound or pharmaceutically acceptable salt thereof according to claim 70, wherein R₃ represents between 0 and 2 substituents, each of which is independently selected from C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, mono- and di-(C_1-6alkyl)amino, (amino)C_0-6alkyl.

76. A compound or pharmaceutically acceptable salt thereof according to claim 75, wherein R₃ represents between 0 and 2 substituents, each of which is independently selected from C_1-6alkyl, and C_1-6alkoxy.

77. A compound or pharmaceutically acceptable salt thereof according to claim 70, wherein Ar is pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.

78. A compound or pharmaceutically acceptable salt thereof according to claim 77, wherein Ar is substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C_1-6alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6alkynyl, optionally substituted C_1-6alkoxy, optionally substituted (C_1-6alkoxy)C_1-6alkyl, optionally substituted (amino)C_1-6alkyl, optionally substituted mono- and di-(C_1-6alkyl)amino.

79. A compound or pharmaceutically acceptable salt thereof according to claim 70, wherein

R₄ is:

(i) C₂-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, mono- or di-(C₁-C₄alkylamino)C₂-C₄alkyl, (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl, pyridylC₀-C₄alkyl, pyrimidinylC₀-C₄alkyl, thienylC₀-C₄alkyl, imidazolylC₀-C₄alkyl, pyrrolylC₀-C₄alkyl, pyrazolylC₀-C₄alkyl, benzoisothiazolyl or tetrahydronapthyl, each of which is substituted with from 0 to 4 substituents independently chosen from R_x, C₂-C₄alkanoyl, mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and di-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl and XR_y;

or

(ii) joined to R₅ to form, with the nitrogen to which R₄ and R₅ are bound, a heterocycle having from 1 to 3 rings, 5 to 7 ring members in each ring, wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from R_x, oxo and W-Z; and

R₅ is;

(i) hydrogen;

(ii) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, (C₃-C₇carbocycle)C₀-C₄alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy;

or

(iii) joined to R₄ to form an optionally substituted heterocycle.

80. A compound or pharmaceutically acceptable salt thereof according to claim 70, wherein:

R₄ is chosen from (C₃-C₇cycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl, pyridylC₀-C₄alkyl, pyrimidinylC₀-C₄alkyl, thienylC₀-C₄alkyl, imidazolylC₀-C₄alkyl, pyrrolylC₀-C₄alkyl, pyrazolylC₀-C₄alkyl, indolylC₀-C₄alkyl, indazolylC₀-C₄alkyl, benzocycloalkenylC₀-C₄alkyl, decahydronaphthylC₀-C₄alkyl, benzoisothiazolylC₀-C₄alkyl, tetrahydroquinolinylC₀-C₄alkyl and tetrahydronaphthylC₀-C₄alkyl, each of which is substituted with from 0 to 4 groups independently chosen from R_x, mono- and di-C₁-C₄alkylamino(C₁-C₄alkyl), mono- and di-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl, C₂-C₄alkanoyl and C₂-C₄alkanoyloxy; and

R₅ is C₁-C₆alkyl, C₂-C₆alkenyl or (C₃-C₇carbocycle)C₀-C₄alkyl.

81. A compound or pharmaceutically acceptable salt thereof according to claim 70, wherein R₄ and R₅ are joined to form a saturated or partially saturated heterocycle containing 1 or 2 fused or spiro rings;

wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, —

COOH, —

CH₂COOH, C_1-6alkoxycarbonyl, —

CH₂CO₂—

C_1-6alkyl, —

C(═

O)NH₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, mono- and di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, —

S(O_n)C₁-C₆alkyl, SO₃H, and phenyl.

82. A compound or pharmaceutically acceptable salt thereof according to claim 81, wherein R₄ and R₅ are joined to form a saturated 4- to 7-membered heterocyclic ring that is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy difluoromethoxy, —

COOH, —

CH₂COOH, C_1-2alkoxycarbonyl, and —

CH₂CO₂—

C_1-2alkyl.

83. A compound or pharmaceutically acceptable salt thereof according to claim 82, wherein the heterocyclic ring is azepanyl, morpholinyl, homomorpholinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, piperidinyl, or homopiperidinyl.

92. A compound or pharmaceutically acceptable salt thereof according to claim 91, wherein the heterocyclic ring is azepanyl, morpholinyl, homomorpholinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, piperidinyl, or homopiperidinyl.

93. A compound or salt thereof according to any one of claims 1, 2, or 84, wherein the compound exhibits an IC₅₀ of 25 nM or less in a standard in vitro C5a receptor-mediated chemotaxis or calcium mobilization assay.

94. A compound or salt thereof according to any one of claims 1, 2, or 84, wherein the compound exhibits less than 5% agonist activity in a GTP binding assay.

95. A pharmaceutical composition comprising at least one compound or salt thereof according to any one of claims 1, 2, or 84, in combination with a physiologically acceptable carrier or excipient.

96. A pharmaceutical composition according to claim 95, wherein the pharmaceutical composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup, or a transdermal patch.

97. A method for inhibiting signal-transducing activity of a cellular C5a receptor, comprising contacting a cell expressing C5a receptor with at least one compound or salt thereof according to any one of claims 1, 2, or 84, and thereby reducing signal transduction by C5a receptor.

98. A method according to claim 97, wherein the cell is contacted in vivo in an animal.

99. A method according to claim 97, wherein the animal is a human.

100. A method of inhibiting binding of C5a to C5a receptor in vitro, the method comprising contacting C5a receptor with at least one compound or salt thereof according to any one of claims 1, 2, or 84, under conditions and in an amount sufficient to detectably inhibit C5a binding to C5a receptor.

101. A method of inhibiting binding of C5a to C5a receptor in a human patient, comprising contacting cells expressing C5a receptor with at least one compound or salt thereof according to any one of claims 1, 2, or 84, in an amount sufficient to detectably inhibit C5a binding to cells expressing a cloned C5a receptor in vitro, and thereby inhibiting binding of C5a to C5a receptor in the patient.

102. A method for treating a patient suffering from rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusion injury, or bronchial asthma comprising administering to the patient a therapeutically effective amount of a compound or salt thereof according to any one of claims 1, 2, or 84.

103. A method for treating a patient suffering from stroke, myocardial infarction, atherosclerosis, ischemic heart disease, fibrosis, cardiac fibrosis, or ischemia-reperfusion injury comprising administering to the patient a therapeutically effective amount of a compound or salt thereof according to any one of claims 1, 2, or 84.

104. A method for treating a patient suffering from cystic fibrosis, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt thereof according to any one of claims 1, 2, or 84.

105. A method for treating a patient suffering from inflammation, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt thereof according to any one of claims 1, 2, or 84.

106. A method for inhibiting C5a receptor-mediated cellular chemotaxis, comprising contacting mammalian white blood cells with a therapeutically effective amount of a compound or salt thereof according to any one of claims 1, 2, or 84.

107. A method for localizing C5a receptor in a tissue sample, comprising:

(a) contacting the tissue sample containing C5a receptor with a detectably labeled compound according to any one of claims 1, 2, or 84 under conditions that permit binding of the compound to C5a receptors; and

(b) detecting the bound compound.

108. A method according to claim 107, wherein the compound is radiolabeled.

109. A packaged pharmaceutical preparation, comprising:

(a) a pharmaceutical composition according to claim 96 in a container; and

(b) instructions for using the composition to treat a patient suffering from inflammation.

110. A packaged pharmaceutical preparation, comprising:

(a) a pharmaceutical composition according to claim 96 in a container; and

(b) instructions for using the composition to treat a patient suffering from rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusion injury, or bronchial asthma.

111. A packaged pharmaceutical preparation, comprising:

(a) a pharmaceutical composition according to claim 96 in a container; and

(b) instructions for using the composition to treat stroke, myocardial infarction, atherosclerosis, ischemic heart disease, or ischemia-reperfusion injury.

84. A compound according to Formula IX:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is selected from the group consisting of hydrogen, halogen, cyano, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted (cycloalkyl)alkoxy, and optionally substituted heterocycloalkyl;

R₃ represents between 0 and 4 substituents, each of which is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted aminoalkyl, optionally substituted mono- and di-alkylamino, —

O—

(CR_AR_B)_m—

XR_A, —

O—

(CR_AR_B)_m—

Y, —

N(R_B)—

(CR_AR_B)_m—

XR_A, —

N(R_B)—

(CR_AR_B)_m—

Y;

R₄ is;

(i) C₂-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, mono- or di-(C₁-C₄alkylamino)C₂-C₄alkyl, (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl, arylC₀-C₄alkyl, or (heterocycle)C_0-4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from R_x, C₂-C₄alkanoyl, mono- and di-(C₁-C₄alkyl)amino(C₁-C₄alkyl), mono- and di-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl and XR_y;

or

(ii) joined to R₅ to form, with the nitrogen to which R₄ and R₅ are bound, a heterocycle having from 1 to 3 rings, 5 to 7 ring members in each ring, wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from R_x, oxo and W-Z;

R₅ is;

(i) hydrogen;

(ii) C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, (C₃-C₇carbocycle)C₀-C₄alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy;

or

(iii) joined to R₄ to form an optionally substituted heterocycle;

Ar is optionally substituted naphthyl or optionally substituted heteroaryl;

R_A and R_B, which may be the same or different, are independently selected at each occurrence from;

hydrogen, hydroxy, and straight or branched alkyl groups, cycloalkyl groups, (cycloalkyl)alkyl groups and are optionally further substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, cyano, amino, C_1-6alkoxy, —

NH(C_1-6alkyl), —

N(C_1-6alkyl)(C_1-6alkyl), —

NHC(═

O)(C_1-6alkyl), —

N(C_1-6alkyl)C(═

O)(C_1-6alkyl), —

NHS(O)_n(C_1-6alkyl), —

S(O)_n(C_1-6 alkyl), —

S(O)_nNH(C_1-6alkyl), —

S(O)_nN(C_1-6 alkyl)(C_1-6alkyl), and Z;

X is independently selected at each occurrence from the group consisting of —

CH₂—

, —

CHR_B—

, —

O—

, —

C(═

O)—

, —

C(═

O)O—

, —

S(O)_n—

, —

NH—

, —

NR_B—

, —

C(═

O)NH—

, —

C(═

O)NR_B—

, —

S(O)_nNH—

, —

S(O)_nNR_B—

, —

NHC(═

O)—

, —

NR_BC(═

O)—

, —

NHS(O)_n—

, and —

NR_BS(O)_n—

;

Y and Z are independently selected at each occurrence from 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which are optionally substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C_1-4alkyl, —

O(C_1-4alkyl), —

NH(C_1-4alkyl), —

N(C_1-4alkyl)(C_1-4alkyl), and —

S(O)_n(alkyl),

m is an integer independently selected at each occurrence from integers in range of 0-8; and

n is an integer independently selected at each occurrence from 0, 1, and 2.

85. A compound or pharmaceutically acceptable salt thereof according to claim 84, wherein Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, benzoimidazolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.

86. A compound or pharmaceutically acceptable salt thereof according to claim 85, wherein Ar is substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C_1-6alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6alkynyl, optionally substituted C_1-6alkoxy, optionally substituted (C_1-6alkoxy)C_1-6alkyl, optionally substituted (amino)C_1-6alkyl, optionally substituted mono- and di-(C_1-6alkyl)amino.

87. A compound or pharmaceutically acceptable salt thereof according to claim 84, wherein Ar is indazolyl, indolyl, or benzoimidazolyl, each of which is optionally substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C_1-6alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6alkynyl, optionally substituted C_1-6alkoxy, optionally substituted (C_1-6alkoxy)C_1-6alkyl, optionally substituted (amino)C_1-6alkyl, optionally substituted mono- and di-(C_1-6alkyl)amino.

88. A compound or pharmaceutically acceptable salt thereof of claim 84, wherein

R₁ is hydrogen, C_1-6alkyl, C_1-6alkoxy, halogen, C_1-6haloalkyl, C_1-6haloalkoxy, C_3-8cycloalkyl, C_3-8cycloalkyl-C_1-6alkyl;

and

R₃ represents between 0 and 2 substituents, each of which is independently selected from C_1-6alkyl, C_1-6alkoxy, C_1-6haloalkyl, C_1-6haloalkoxy, mono- and di-(C_1-6alkyl)amino, (amino)C_0-6alkyl.

89. A compound or pharmaceutically acceptable salt thereof according to claim 84, wherein:

R₄ is chosen from (C₃-C₇cycloalkyl)C₀-C₄alkyl, phenylC₀-C₄alkyl, pyridylC₀-C₄alkyl, pyrimidinylC₀-C₄alkyl, thienylC₀-C₄alkyl, imidazolylC₀-C₄alkyl, pyrrolylC₀-C₄alkyl, pyrazolylC₀-C₄alkyl, indolylC₀-C₄alkyl, indazolylC₀-C₄alkyl, benzocycloalkenylC₀-C₄alkyl, decahydronaphthylC₀-C₄alkyl, benzoisothiazolylC₀-C₄alkyl, tetrahydroquinolinylC₀-C₄alkyl and tetrahydronaphthylC₀-C₄alkyl, each of which is substituted with from 0 to 4 groups independently chosen from R_x, mono- and di-C₁-C₄alkylamino(C₁-C₄alkyl), mono- and di-C₁-C₄alkylamino(C₁-C₄alkoxy), (3- to 7-membered heterocycloalkyl)C₀-C₄alkyl, C₂-C₄alkanoyl and C₂-C₄alkanoyloxy; and

R₅ is C₁-C₆alkyl, C₂-C₆alkenyl or (C₃-C₇carbocycle)C₀-C₄alkyl.

90. A compound or pharmaceutically acceptable salt thereof according to claim 84, wherein R₄ and R₅ are joined to form a saturated or partially saturated heterocycle containing 1 or 2 fused or spiro rings;

wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, —

COOH, —

CH₂COOH, C_1-6alkoxycarbonyl, —

CH₂CO₂—

C_1-6alkyl, —

C(═

O)NH₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, mono- and di-(C₁-C₆alkyl)amino, C₁-C₆alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, —

S(O_n)C₁-C₆alkyl, SO₃H, and phenyl.

91. A compound or pharmaceutically acceptable salt thereof according to claim 90, wherein R₄ and R₅ are joined to form a saturated 4- to 7-membered heterocyclic ring that is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy difluoromethoxy, —

COOH, —

CH₂COOH, C_1-2alkoxycarbonyl, and —

CH₂CO₂—

C_1-2alkyl.

92-1. A compound or salt thereof according to any one of claims 1, 2, or 84, wherein the compound exhibits an IC₅₀ of 500 nM or less in a standard in vitro C5a receptor-mediated chemotaxis or calcium mobilization assay.