Matriptase inhibitors and methods of use

• US 7,019,019 B2
• Filed: 12/18/2003
• Issued: 03/28/2006
• Est. Priority Date: 12/23/2002
• Status: Expired due to Fees

• Current Assignee: Dendreon Pharmaceuticals, Inc. (Ya Fei Yuan,)
• Original Assignee: Dendreon Corporation (Bausch Health Cos., Inc.)
• Inventors: Levy, Odile Esther, Komandla, Mallareddy, Duncan, David F., Semple, Joseph E., Tamiz, Amir P., Alfaro-Lopez, L. Josue, Moreno, Ofir
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US10/740,946
• Publication Number:
  US 20040186060A1
• Time in Patent Office: 831 Days
• Field of Search: 514/352, 514/369, 514/438, 546/312, 548/205, 549/77
• US Class Current: 514/352
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 333/38 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The present invention provides matriptase inhibitors and compositions thereof useful for treating cancer. Martripase is a trypsin-like serine protease active in the development of cancerous conditions, such as tumors and metastasis of cancer.

Claims

1. A compound of the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkyl, an optionally substituted C₁-C₈ alkoxy, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted carboxy, an optionally substituted carboxyalkyl, an optionally substituted carboxyalkenyl, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted carbamoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylalkyl, an optionally substituted C₁-C₈ alkylthio, an optionally substituted C₁-C₈ alkylsulfinyl, an optionally substituted C₁-C₈ alkylsulfonyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aryl, an optionally substituted arylsulfinyl, an optionally substituted arylsulfonyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted aralkylsulfonyl, an optionally substituted amino, and an acid isostere;

n is a value of 0 to about 6;

R² is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylalkyl, an optionally substituted amino, an optionally substituted carbamoyl, an optionally substituted carboxyalkyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted heteroararyl, an optionally substituted cycloalkyl, an optionally substituted ureido, an optionally substituted sulfamoyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, an optionally substituted aralkylsulfonylcarbamoyl and hydroxy;

or

R¹, R² and the atoms to which they are attached, join to form an optionally substituted 5- or 6-membered heterocyclic or carbocylic ring;

R³ is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted carboxyalkyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted heteroaralkenyl, an optionally substituted heteroararyl, and an optionally substituted cycloalkyl group;

or

R¹ and R³, or R² and R³, together with the atoms to which they are attached, join to form an optionally substituted 5- or 6-membered heterocyclic or carbocylic ring;

R⁴ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl;

or

R³, R⁴, or R², R⁴ and the atoms to which they are attached, join to form an optionally substituted 5- or 6-membered heterocyclic or carbocylic ring;

R⁵ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl, an optionally substituted aralkyl, or, alternatively, R⁴, R⁵ and the atoms to which they are attached, join to form a 5- or 6-membered heterocyclic or heteroaryl ring;

R⁶ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl;

or

R⁵, R⁶ and the atoms to which they are attached, join to form an optionally substituted 5- or 6-membered heterocyclic or carbocylic ring;

‘

A’

is a member selected from the group consisting of an optionally substituted C₁-C₈ alkylene, a five- or a six-membered optionally substituted cycloalkyl group, a 5 to 10-membered optionally substituted aryl group and a 5 to 10-membered optionally substituted heteroaryl group, wherein said 5 to 10-membered optionally substituted heteroaryl group has from 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O, and S, wherein ‘

A’

can optionally have a heteroatom for attachment;

X is a heteroatom selected from the group consisting of S, O and N;

R⁷, if present, is a member selected from the group consisting of hydrogen, hydroxy, an optionally substituted C₁-C₈ alkyl, an optionally substituted C₁-C₈ alkoxy, an optionally substituted aryl, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted C₁-C₈ alkanoyloxy, an optionally substituted alkylcarbamoyl, an optionally substituted alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonyloxy;

alternatively, A, R⁷, and the atoms to which they are attached, join to form a 5- to 10-membered optionally substituted heteroaryl group, wherein said 5- to 10-membered optionally substituted heteroaryl group has at least 1 optionally substituted nitrogen and the dotted line is either a bond or is absent; and

R⁸ and R⁹ are members independently selected from the group consisting of hydrogen, hydroxy, an optionally substituted C₁-C₈ alkyl, an optionally substituted alkoxy, an optionally substituted aryl, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted alkanoyloxy, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted alkoxycarbonyl, and an optionally substituted C₁-C₈ alkoxycarbonyloxy, in an alternative embodiment, R⁷ and R⁹ and the atoms to which they are attached, join to form a 5- to 7-membered heterocyclic or heteroaryl ring.

2. The compound of claim 1, wherein

is a member selected from the group consisting of:

wherein R¹¹ is a member selected from the group consisting of hydrogen, hydroxyl, and an optionally substituted C₁-C₈ alkyl; and

Q, Y and Z are each independently selected from the group consisting of an optionally substituted carbon, an optionally substituted nitrogen, an oxygen and a sulfur, provided however at least one of Q, Y and Z is carbon and wherein the dotted line is an optional double bond.

3. The compound of claim 2, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkoxy, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted amino, an optionally substituted carbamoyl, an optionally substituted C₁-C₈ alkylsulfonyl, an optionally substituted aryl, optionally substituted arylsulfonyl, and a carboxylic acid isostere;

n is a value of about 1 to 4;

R² is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted amino, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted ureido, an optionally substituted sulfamoyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl and hydroxy;

R³ is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted heteroaralkyl, and an optionally substituted carboxy; and

R⁵ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl.

4. The compound of claim 3, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkoxy, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted amino, and an optionally substituted carboxy an optionally substituted carbamoyl, an optionally substituted C₁-C₈ alkylsulfonyl, an optionally substituted aralkylsulfonyl, optionally substituted arylsulfonyl, and an acid isostere;

n is a value of about 1 to 2;

R² is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted amino, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted carbamoyl, an optionally substituted ureido, an optionally substituted sulfamoyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, an optionally substituted arylsulfonylcarbamoyl and hydroxy; and

R⁶ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl.

5. The compound of claim 3, wherein R² is selected from an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl, an optionally substituted carbamoyl, an optionally substituted ureido, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, and hydroxy.

6. The compound of claim 3, wherein R² is an optionally substituted C₁-C₈ alkoxycarbonyl.

7. The compound of claim 2, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an C₁-C₆ alkyl, carboxyl group, C₁-C₆ alkyl-OC(O)NH—

, C₁-C₆ alkylOC(O)—

, C₁-C₆ alkylC(O)—

, C₁-C₆ alkylSO₂—

, C₁-C₆ alkylOC(O)NR¹² wherein R¹² is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl and NR¹³R¹⁴C(O)—

, wherein R¹³R¹⁴ are each independently selected from the group of hydrogen, and an optionally substituted C₁-C₈ alkyl.

8. The compound of claim 7, wherein said compound has the formula

wherein:

R² is selected from an optionally substituted alkylcarbamoyl group, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl, an optionally substituted carbamoyl, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, and an optionally substituted ureido.

9. The compound of claim 7, wherein said compound has the formula

wherein:

R² is selected from an optionally substituted C₁-C₆ alkylcarbamoyl group, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl, an optionally substituted carbamoyl, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, and an optionally substituted ureido.

10. The compound of claim 2, wherein said compound has the formula

wherein:

R³ is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted carboxyalkyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted heteroaralkenyl, an optionally substituted heteroararyl, and an optionally substituted cycloalkyl group.

11. The compound of claim 2, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkyl, an optionally substituted C₁-C₈ alkoxy, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted carboxy, an optionally substituted carboxyalkyl, an optionally substituted carboxyalkenyl, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted carbamoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylalkyl, an optionally substituted C₁-C₈ alkylthio, an optionally substituted C₁-C₈ alkylsulfinyl, an optionally substituted C₁-C₈ alkylsulfonyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aryl, an optionally substituted arylsulfinyl, an optionally substituted arylsulfonyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted aralkylsulfonyl, an optionally substituted amino, and an acid isostere;

R³ is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted carboxyalkyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted heteroaralkenyl, an optionally substituted heteroararyl, and an optionally substituted cycloalkyl group;

or

R² and R³, together with the atoms to which they are attached, join to form an optionally substituted 5- or 6-membered heterocyclic or carbocylic ring.

12. The compound of claim 2, wherein said compound has the formula

wherein:

R² is selected from an optionally substituted C₁-C₆ alkylcarbamoyl group, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl, an optionally substituted carbamoyl, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, and an optionally substituted ureido.

13. The compound of claim 1, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkoxy, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted carbamoyl, an optionally substituted amino, and an optionally substituted carboxy;

n is a value of about 1 to 2;

R² is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted amino, an optionally substituted carboxy, an optionally substituted ureido, an optionally substituted sulfamoyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl and hydroxy;

R³ is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkoxycarbonyl, and an optionally substituted carboxy; and

R⁶ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl; and

Q, Y and Z are each independently selected from the group consisting of a carbon, an optionally substituted nitrogen, an oxygen and a sulfur, provided however at least one of Q, Y and Z is carbon.

14. The compound of claim 13, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkoxy, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted carbamoyl, an optionally substituted amino, and an optionally substituted carboxy;

n is a value of about 1 to 2; and

R² is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted amino, and an optionally substituted carboxy, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted ureido, an optionally substituted sulfamoyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl and hydroxy.

15. A pharmaceutical composition, said pharmaceutical composition comprising:

wherein;

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkyl, an optionally substituted C₁-C₈ alkoxy, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted carboxy, an optionally substituted carboxyalkyl, an optionally substituted carboxyalkenyl, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted carbamoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylalkyl, an optionally substituted C₁-C₈ alkylthio, an optionally substituted C₁-C₈ alkylsulfinyl, an optionally substituted C₁-C₈ alkylsulfonyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aryl, an optionally substituted arylsulfinyl, an optionally substituted arylsulfonyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted aralkylsulfonyl, an optionally substituted amino, and an acid isostere;

n is a value of 0 to about 6;

R² is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylalkyl, an optionally substituted amino, an optionally substituted carbamoyl, an optionally substituted carboxyalkyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted heteroararyl, an optionally substituted cycloalkyl, an optionally substituted ureido, an optionally substituted sulfamoyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, an optionally substituted aralkylsulfonylcarbamoyl and hydroxy;

or

R¹, R² and the atoms to which they are attached, join to form an optionally substituted 5- or 6-membered heterocyclic or carbocylic ring;

R³ is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted carboxyalkyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted heteroaralkenyl, an optionally substituted heteroararyl, and an optionally substituted cycloalkyl group;

or

R¹ and R³, or R² and R³, together with the atoms to which they are attached, join to form an optionally substituted 5- or 6-membered heterocyclic or carbocylic ring;

R⁴ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl;

or

R³, R⁴, or R², R⁴ and the atoms to which they are attached, join to form an optionally substituted 5- or 6-membered heterocyclic or carbocylic ring;

R⁵ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl, an optionally substituted aralkyl, or, alternatively, R⁴, R⁵ and the atoms to which they are attached, join to form a 5- or 6-membered heterocyclic or heteroaryl ring;

R⁶ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl;

or

R⁵, R⁶ and the atoms to which they are attached, join to form an optionally substituted 5- or 6-membered heterocyclic or carbocylic ring;

‘

A’

is a member selected from the group consisting of an optionally substituted C₁-C₈ alkylene, a five- or a six-membered optionally substituted cycloalkyl group, a 5 to 10-membered optionally substituted aryl group and a 5 to 10-membered optionally substituted heteroaryl group, wherein said 5 to 10-membered optionally substituted heteroaryl group has from 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O, and S, wherein ‘

A’

can optionally have a heteroatom for attachment;

X is a heteroatom selected from the group consisting of S, O and N;

R⁷, if present, is a member selected from the group consisting of hydrogen, hydroxy, an optionally substituted C₁-C₈ alkyl, an optionally substituted C₁-C₈ alkoxy, an optionally substituted aryl, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted C₁-C₈ alkanoyloxy, an optionally substituted alkylcarbamoyl, an optionally substituted alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonyloxy;

alternatively, A, R⁷, and the atoms to which they are attached, join to form a 5- to 10-membered optionally substituted heteroaryl group, wherein said 5- to 10-membered optionally substituted heteroaryl group has at least 1 optionally substituted nitrogen and the dotted line is either a bond or is absent; and

R⁸ and R⁹ are members independently selected from the group consisting of hydrogen, hydroxy, an optionally substituted C₁-C₈ alkyl, an optionally substituted alkoxy, an optionally substituted aryl, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted alkanoyloxy, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted alkoxycarbonyl, and an optionally substituted C₁-C₈ alkoxycarbonyloxy, in an alternative embodiment, R⁷ and R⁹ and the atoms to which they are attached, join to form a 5- to 7-membered heterocyclic or heteroaryl ring.

16. The composition of claim 15, wherein

is a member selected from the group consisting of:

wherein R¹¹ is a member selected from the group consisting of hydrogen, hydroxyl, and an optionally substituted C₁-C₈ alkyl; and

Q, Y and Z are each independently selected from the group consisting of an optionally substituted carbon, an optionally substituted nitrogen, an oxygen and a sulfur, provided however at least one of Q, Y and Z is carbon and wherein the dotted line is an optional double bond.

17. The composition of claim 16, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkoxy, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted amino, an optionally substituted carbamoyl, an optionally substituted C₁-C₈ alkylsulfonyl, an optionally substituted aryl, optionally substituted arylsulfonyl, and a carboxylic acid isostere;

n is a value of about 1 to 4;

R² is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted amino, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted ureido, an optionally substituted sulfamoyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl and hydroxy;

R³ is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted heteroaralkyl, and an optionally substituted carboxy; and

R⁵ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl.

18. The composition of claim 17, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkoxy, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted amino, and an optionally substituted carboxy an optionally substituted carbamoyl, an optionally substituted C₁-C₈ alkylsulfonyl, an optionally substituted aralkylsulfonyl, optionally substituted arylsulfonyl, and an acid isostere;

n is a value of about 1 to 2;

R² is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted amino, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted carbamoyl, an optionally substituted ureido, an optionally substituted sulfamoyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, an optionally substituted arylsulfonylcarbamoyl and hydroxy; and

R⁶ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl.

19. The composition of claim 17, wherein R² is selected from an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl, an optionally substituted carbamoyl, an optionally substituted ureido, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, and hydroxy.

20. The composition of claim 17, wherein R² is an optionally substituted C₁-C₈ alkoxycarbonyl.

21. The composition of claim 16, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an C₁-C₆ alkyl, carboxyl group, C₁-C₆ alkyl-OC(O)NH—

, C₁-C₆ alkylOC(O)—

, C₁-C₆ alkylC(O)—

, C₁-C₆ alkylSO₂—

, C₁-C₆ alkylOC(O)NR¹² wherein R¹² is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl and NR¹³R¹⁴C(O)—

, wherein R¹³R¹⁴ are each independently selected from the group of hydrogen, and an optionally substituted C₁-C₈ alkyl.

22. The composition of claim 21, wherein said compound has the formula

wherein:

R² is selected from an optionally substituted alkylcarbamoyl group, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl, an optionally substituted carbamoyl, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, and an optionally substituted ureido.

23. The composition of claim 21, wherein said compound has the formula

wherein:

R² is selected from an optionally substituted C₁-C₆ alkylcarbamoyl group, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl, an optionally substituted carbamoyl, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, and an optionally substituted ureido.

24. The composition of claim 16, wherein said compound has the formula

wherein:

R³ is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted carboxyalkyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted heteroaralkenyl, an optionally substituted heteroararyl, and an optionally substituted cycloalkyl group.

25. The composition of claim 16, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkyl, an optionally substituted C₁-C₈ alkoxy, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted carboxy, an optionally substituted carboxyalkyl, an optionally substituted carboxyalkenyl, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted carbamoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylalkyl, an optionally substituted C₁-C₈ alkylthio, an optionally substituted C₁-C₈ alkylsulfinyl, an optionally substituted C₁-C₈ alkylsulfonyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aryl, an optionally substituted arylsulfinyl, an optionally substituted arylsulfonyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted aralkylsulfonyl, an optionally substituted amino, and an acid isostere;

R³ is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted carboxyalkyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted heteroaralkenyl, an optionally substituted heteroararyl, and an optionally substituted cycloalkyl group;

or

R² and R³, together with the atoms to which they are attached, join to form an optionally substituted 5- or 6-membered heterocyclic or carbocylic ring.

26. The composition of claim 16, wherein said compound has the formula

wherein:

R² is selected from an optionally substituted C₁-C₆ alkylcarbamoyl group, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl, an optionally substituted carbamoyl, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, and an optionally substituted ureido.

27. The composition of claim 15, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkoxy, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted carbamoyl, an optionally substituted amino, and an optionally substituted carboxy;

n is a value of about 1 to 2;

R² is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted amino, an optionally substituted carboxy, an optionally substituted ureido, an optionally substituted sulfamoyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl and hydroxy;

R³ is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkoxycarbonyl, and an optionally substituted carboxy; and

R⁶ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl; and

Q, Y and Z are each independently selected from the group consisting of a carbon, an optionally substituted nitrogen, an oxygen and a sulfur, provided however at least one of Q, Y and Z is carbon.

28. The composition of claim 27, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkoxy, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted carbamoyl, an optionally substituted amino, and an optionally substituted carboxy;

n is a value of about 1 to 2; and

R² is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted amino, and an optionally substituted carboxy, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted ureido, an optionally substituted sulfamoyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl and hydroxy.

29. A method for treating a condition in a mammal by decreasing or inhibiting the serine protease activity of matriptase or MTSP1, wherein the condition is selected from the group consisting of leukemia, lymphomas, breast cancer, gastrointestinal cancer, esophageal cancer, stomach cancer, colon cancer, bowel cancer, colorectal cancer, prostate cancer, bladder cancer, testicular cancer, ovarian cancer, uterine cancer, cervical cancer, brain cancer, lung cancer, bronchial cancer, pancreatic cancer, thyroid cancer, bone cancer and skin cancer, said method comprising:

administering an effective amount of a compound of the formula;

wherein;

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkyl, an optionally substituted C₁-C₈ alkoxy, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted carboxy, an optionally substituted carboxyalkyl, an optionally substituted carboxyalkenyl, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted carbamoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylalkyl, an optionally substituted C₁-C₈ alkylthio, an optionally substituted C₁-C₈ alkylsulfinyl, an optionally substituted C₁-C₈ alkylsulfonyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aryl, an optionally substituted arylsulfinyl, an optionally substituted arylsulfonyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted aralkylsulfonyl, an optionally substituted amino, and an acid isostere;

n is a value of 0 to about 6;

R² is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylalkyl, an optionally substituted amino, an optionally substituted carbamoyl, an optionally substituted carboxyalkyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted heteroararyl, an optionally substituted cycloalkyl, an optionally substituted ureido, an optionally substituted sulfamoyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, an optionally substituted aralkylsulfonylcarbamoyl and hydroxy;

or

R¹, R² and the atoms to which they are attached, join to form an optionally substituted 5- or 6-membered heterocyclic or carbocylic ring;

R³ is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted carboxyalkyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted heteroaralkenyl, an optionally substituted heteroararyl, and an optionally substituted cycloalkyl group;

or

R¹ and R³, or R² and R³, together with the atoms to which they are attached, join to form an optionally substituted 5- or 6-membered heterocyclic or carbocylic ring;

R⁴ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl;

or

R³, R⁴, or R², R⁴ and the atoms to which they are attached, join to form an optionally substituted 5- or 6-membered heterocyclic or carbocylic ring;

R⁵ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl, an optionally substituted aralkyl, or, alternatively, R⁴, R⁵ and the atoms to which they are attached, join to form a 5- or 6-membered heterocyclic or heteroaryl ring;

R⁶ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl;

or

R⁵, R⁶ and the atoms to which they are attached, join to form an optionally substituted 5- or 6-membered heterocyclic or carbocylic ring;

‘

A’

is a member selected from the group consisting of an optionally substituted C₁-C₈ alkylene, a five- or a six-membered optionally substituted cycloalkyl group, a 5 to 10-membered optionally substituted aryl group and a 5 to 10-membered optionally substituted heteroaryl group, wherein said 5 to 10-membered optionally substituted heteroaryl group has from 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O, and S, wherein ‘

A’

can optionally have a heteroatom for attachment;

X is a heteroatom selected from the group consisting of S, O and N;

R⁷, if present, is a member selected from the group consisting of hydrogen, hydroxy, an optionally substituted C₁-C₈ alkyl, an optionally substituted C₁-C₈ alkoxy, an optionally substituted aryl, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted C₁-C₈ alkanoyloxy, an optionally substituted alkylcarbamoyl, an optionally substituted alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonyloxy;

alternatively, A, R⁷, and the atoms to which they are attached, join to form a 5- to 10-membered optionally substituted heteroaryl group, wherein said 5- to 10-membered optionally substituted heteroaryl group has at least 1 optionally substituted nitrogen and the dotted line is either a bond or is absent; and

R⁸ and R⁹ are members independently selected from the group consisting of hydrogen, hydroxy, an optionally substituted C₁-C₈ alkyl, an optionally substituted alkoxy, an optionally substituted aryl, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted alkanoyloxy, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted alkoxycarbonyl, and an optionally substituted C₁-C₈ alkoxycarbonyloxy, in an alternative embodiment, R⁷ and R⁹ and the atoms to which they are attached, join to form a 5- to 7-membered heterocyclic or heteroaryl ring, to decrease or inhibit the serine protease activity of matriptase or MTSP1.

30. The method of claim 29, wherein

is a member selected from the group consisting of:

wherein R¹¹ is a member selected from the group consisting of hydrogen, hydroxyl, and an optionally substituted C₁-C₈ alkyl; and

Q, Y and Z are each independently selected from the group consisting of an optionally substituted carbon, an optionally substituted nitrogen, an oxygen and a sulfur, provided however at least one of Q, Y and Z is carbon and wherein the dotted line is an optional double bond.

31. The method of claim 30, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkoxy, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted amino, an optionally substituted carbamoyl, an optionally substituted C₁-C₈ alkylsulfonyl, an optionally substituted aryl, optionally substituted arylsulfonyl, and a carboxylic acid isostere;

n is a value of about 1 to 4;

R² is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted amino, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted ureido, an optionally substituted sulfamoyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl and hydroxy;

R³ is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted heteroaralkyl, and an optionally substituted carboxy; and

R⁵ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl.

32. The method of claim 31, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkoxy, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted amino, and an optionally substituted carboxy an optionally substituted carbamoyl, an optionally substituted C₁-C₈ alkylsulfonyl, an optionally substituted aralkylsulfonyl, optionally substituted arylsulfonyl, and an acid isostere;

n is a value of about 1 to 2;

R² is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted amino, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted carbamoyl, an optionally substituted ureido, an optionally substituted sulfamoyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted heteroarylalkylsulfonamide, an optionally substituted arylsulfonylcarbamoyl and hydroxy; and

R⁶ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl.

33. The method of claim 31, wherein R² is selected from an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl, an optionally substituted carbamoyl, an optionally substituted ureido, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, and hydroxy.

34. The method of claim 31, wherein R² is an optionally substituted C₁-C₈ alkoxycarbonyl.

35. The method of claim 30, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an C₁-C₆ alkyl, carboxyl group, C₁-C₆ alkyl-OC(O)NH—

, C₁-C₆ alkylOC(O)—

, C₁-C₆ alkylC(O)—

, C₁-C₆ alkylSO₂—

, C₁-C₆ alkylOC(O)NR¹² wherein R¹² is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl and NR¹³R¹⁴C(O)—

, wherein R¹³R¹⁴ are each independently selected from the group of hydrogen, and an optionally substituted C₁-C₈ alkyl.

36. The method of claim 35, wherein said compound has the formula

wherein:

R² is selected from an optionally substituted alkylcarbamoyl group, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl, an optionally substituted carbamoyl, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, and an optionally substituted ureido.

37. The method of claim 35, wherein said compound has the formula

wherein:

R² is selected from an optionally substituted C₁-C₆ alkylcarbamoyl group, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl, an optionally substituted carbamoyl, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, and an optionally substituted ureido.

38. The method of claim 30, wherein said compound has the formula

wherein:

R³ is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted carboxyalkyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted heteroaralkenyl, an optionally substituted heteroararyl, and an optionally substituted cycloalkyl group.

39. The method of claim 30, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkyl, an optionally substituted C₁-C₈ alkoxy, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted carboxy, an optionally substituted carboxyalkyl, an optionally substituted carboxyalkenyl, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted carbamoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylalkyl, an optionally substituted C₁-C₈ alkylthio, an optionally substituted C₁-C₈ alkylsulfinyl, an optionally substituted C₁-C₈ alkylsulfonyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aryl, an optionally substituted arylsulfinyl, an optionally substituted arylsulfonyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted aralkylsulfonyl, an optionally substituted amino, and an acid isostere;

R³ is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted carboxyalkyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted heteroaralkenyl, an optionally substituted heteroararyl, and an optionally substituted cycloalkyl group;

or

R² and R³, together with the atoms to which they are attached, join to form an optionally substituted 5- or 6-membered heterocyclic or carbocylic ring.

40. The method of claim 30, wherein said compound has the formula

wherein:

R² is selected from an optionally substituted C₁-C₆ alkylcarbamoyl group, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl, an optionally substituted carbamoyl, an optionally substituted heteroarylalkylsulfonamide, and an optionally substituted ureido.

41. The method of claim 29, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkoxy, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted carbamoyl, an optionally substituted amino, and an optionally substituted carboxy;

n is a value of about 1 to 2;

R² is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted amino, an optionally substituted carboxy, an optionally substituted ureido, an optionally substituted sulfamoyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl and hydroxy;

R³ is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkoxycarbonyl, and an optionally substituted carboxy; and

R⁶ is a member selected from the group consisting of hydrogen, an optionally substituted C₁-C₈ alkyl, and an optionally substituted aryl; and

Q, Y and Z are each independently selected from the group consisting of a carbon, an optionally substituted nitrogen, an oxygen and a sulfur, provided however at least one of Q, Y and Z is carbon.

42. The method of claim 41, wherein said compound has the formula

wherein:

R¹ is a member selected from the group consisting of an optionally substituted C₁-C₈ alkoxy, an optionally substituted carboxy, an optionally substituted C₁-C₈ alkanoyl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted carbamoyl, an optionally substituted amino, and an optionally substituted carboxy;

n is a value of about 1 to 2; and

R² is a member selected from the group consisting of an optionally substituted aryl, an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonyl, an optionally substituted amino, and an optionally substituted carboxy, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted ureido, an optionally substituted sulfamoyl, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted arylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl and hydroxy.