Matriptase inhibitors and methods of use

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.

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.