Thiol sulfonamide metalloprotease inhibitors

A compound or a salt thereof wherein:

• the compound or salt is characterizeable in that the compound or salt selectively inhibits in vitro activity of human MMP-13 over in vitro activity of human MMP-1;
• the compound corresponds in structure to a formula selected from the group consisting of:
• PhR11 is phenyl substituted with R11 at the 4-position;
• R11 is selected from the group consisting of C3-C8-alkoxy, C3-C8-alkyl, phenoxy, phenylthio, benzamido, phenylazo, and phenyl;
• R2 is selected from the group consisting of:
• hydrogen,
• C1-C6-alkyl,
• 5- to 6-member heterocyclo-C2-C3-alkyl, wherein:
• one ring atom of the heterocyclo is nitrogen,
• one ring atom of the heterocyclo is selected from the group consisting of nitrogen, carbon, and oxygen, and
• the remaining ring atoms of the heterocyclo are carbon, and single-ring heteroaryl-C1-C4-alkyl, wherein:
• one ring atom of the heteroaryl is nitrogen,
• one ring atom of the heteroaryl is selected from the group consisting of nitrogen and carbon, and
• the remaining ring atoms of the heteroaryl are carbon;
• R4 is C1-C6-alkyl;
• R9 is selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, phenyl, and single-ring heteroaryl;
• R2 may be hydrogen only when R11 is phenylazo;
• and
• the compound comprises at least one heterocyclic ring.

A compound or a salt thereof, wherein:

• the compound or salt is characterizeable in that the compound or salt selectively inhibits in vitro activity of human MMP-13 over in vitro activity of human MMP-1;
• the compound corresponds in structure to a formula selected from the group consisting of:
• PhR11 is phenyl substituted with R11 at the 4-position;
• R11 is selected from the group consisting of phenoxy, phenylthio, benzamido, phenylazo, and phenyl, wherein:
• the phenoxy, phenylthio, benzamido, phenylazo, or phenyl is substituted at the 3-position, 4-position, or both with a single atom or a substituent composing a longest chain of up to five atoms, not counting any hydrogen in the substituent;
• R2 is selected from the group consisting of:
• hydrogen,
• C1-C6-alkyl,
• 5- to 6-member heterocyclo-C2-C3-alkyl, wherein:
• one of the ring atoms of the heterocyclo is nitrogen,
• one of the ring atoms of the heterocyclo is selected from the group consisting of nitrogen, carbon, and oxygen, and
• the remaining ring atoms of the heterocyclo are carbon, and single-ring heteroaryl-C1-C4-alkyl, wherein:
• one ring atom of the heteroaryl is nitrogen,
• one ring atom of the heteroaryl is selected from the group consisting of nitrogen and carbon, and
• the remaining ring atoms of the heteroaryl are carbon;
• R4 C1-C6-alkyl;
• R9 is selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, phenyl and single-ring heteroaryl;
• R2 may be hydrogen only when R11 is phenylazo;
• and
• the compound comprises at least one heterocyclic ring.

A compound or a salt thereof, wherein:

• the compound or salt is characterizeable in that the compound or salt selectively inhibits in vitro activity of human MMP-13 over in vitro activity of human MMP-1;
• the compound corresponds in structure to a formula selected from the group consisting of:
• W is selected from the group consisting of oxygen and sulfur;
• R9 is selected from the group consisting of alkyl, aryl, alkoxy, cycloalkyl, aryloxy, arylalkoxy, arylalkyl, heteroaryl, and aminoalkyl, wherein the aminoalkyl nitrogen optionally is substituted with:
• up to two substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl, and alkylcarbonyl, or
• two substituents such that the two substituents, together with the aminoalkyl nitrogen, form a 5- to 8-member heterocyclo or heteroaryl ring;
• R1 is selected from the group consisting of alkyl, cycloalkyl, heterocyclo, arylalkyl, heteroarylalkyl, arylalkoxyalkyl, aryloxyalkyl, hydroxyalkyl, alkylcarbonylalkyl, arylalkylcarbonylalkyl, arylcarbonyalkyl, haloalkyl, arylalkylaryl, aryloxyalkylaryl, arylalkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioalkyl, alkythioaryl, arylthioalkyl, alkylthioarylalkyl, arylalkylthioalkyl, arylalylthioaryl, a sulfoxide of any of said thio substituents, a sulfone of any of said thio substituents, aryl;
• heteroaryl, and a fused ring structure comprising at least two 5- to 6-member rings selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclo, wherein:
• any aryl or heteroaryl in R1 optionally is substituted with one or more substituents independently selected from the group consisting of halo, C1-C10-alkyl, C1-C10-alkoxy, nitro, cyano, perfluoroalkyl, trifluoromethylalkyl, hydroxy, thiol, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylalkyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylalkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, cycloalkylamino, heteroarylalkoxy, heteroarylalkylthio, heteroarylalkylamino, arylalkoxy, arylalkylthio, arylalkylamino, heterocyclic, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylcarbonyloxy, arylalkylcarbonyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylakylthio, amino, alkylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkylcarbonylamino, N-monosubstituted aminoalkyl, and N,N-disubstituted aminoalkyl, wherein:
• the substituent(s) on the monosubstituted or disubstituted aminoalkyl nitrogen is/are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, arylalkoxycarbonyl, alkoxycarbonyl, and alkylcarbonyl, or
• the disubstituted aminoalkyl nitrogen and its two substituents form a 5 to 8 member heterocyclo or heteroaryl ring;
• as to R2:
• R2 is selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkynylalkyl, alkenylalkyl, thioalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, alkoxyalkyl, arylalkoxyalkyl, alkoxyalkoxyalkyl, aryloxyalkyl, hydroxyalkyl, hydroxycarbonyl, hydroxycarbonylalkyl, hydroxycarbonylarylalkyl, and aminoalkyl, wherein the aminoalkyl nitrogen optionally is substituted with:
• up to two substituents independently selected from the group consisting of alkyl, arylalkyl, cycloalkyl, and alkylcarbonyl, or
• two substituents such that the two substituents, together with the aminoalkyl nitrogen, form a 5- to 8-member heterocyclo or heteroaryl ring, or
• R2 and R4, together with the atoms to which they are bonded, form a 4- to 8-member ring;
• as to R4:
• R4 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aryloxyalkyl, arylalkoxyalkyl, arylalkyl, aryl, heteroaryl, heteroarylalkyl, hydroxycarbonylalkyl alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, alkoxycarbonyl, perfluoroalkyl, trifluoromethylalkyl, thioalkyl, alkylthioalkyl, arylthioalkyl, arylalkylthioalkyl, heteroarylalkyl thioalkyl, a sulfoxide of any of said thio substituents, a sulfone of any of said thio substituents, and aminocarbonylalkyl, wherein the nitrogen of the aminocarbonylalkyl optionally is substituted with:
• up to two substituents independently selected from the group consisting of alkyl arylalkyl, cycloalkyl, and alkylcarbonyl, or
• two substituents such that the two substituents, together with the amino nitrogen, form a 5- to 8-member heterocyclo or heteroaryl ring, or
• R2 and R4, together with the atoms to which they are bonded, form a 4- to 8-member ring;
• R2 may be hydrogen only when R1 is 4-(phenylazo)phenyl;
• and
• the compound comprises at least one heterocyclic ring.