Heterocyclic side chain containing metalloprotease inhibitors

A compound having a structure according to Formula (I):

• 32
• wherein:
• (A) R1 is selected from —OH and —NHOH;
• (B) R2 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl and heteroarylalkyl;
• (C) A is a substituted or unsubstituted, monocyclic heterocycloalkyl having from 3 to 8 ring atoms of which 1 to 3 are heteroatoms;
• or A can be connected to R2 where, together, they form a substituted or unsubstituted, monocyclic heterocycloalkyl having from 3 to 8 ring atoms of which 1 to 3 are heteroatoms;
• (D) n is from 0 to about 4;
• (E) E is selected from a covalent bond, C1-C4 alkyl, —C(═O)—, —C(═O)O—, C(═O)N(R3)—, —SO2— and —C(═S)N(R3)—, where R3 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
• (F) X is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, C(═O)R4, —C(═O)OR4, —C(═O)NR4R4′ and —SO2R4, where R4 and R4′ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
• or X and R3 join to form a substituted or unsubstituted, monocyclic heterocycloalkyl having from 3 to 8 ring atoms of which 1 to 3 are heteroatoms;
• (G) G is selected from —S—, —O—, —N(R5)—, —C(R5)═C(R5′)—, —N═C(R5)— and —N═N—, where R5 and R5′ each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;
• and
• (H) Z is selected from:
• (1) cycloalkyl and heterocycloalkyl;
• (2) —L—(CR6R6′)aR7 where:
• (a) a is from 0 to about 4;
• (b) L is selected from —C≡C—, —CH═CH—, —N═N—, —O—, —S— and —SO2—;
• (c) each R6 and R6′ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy and alkoxy;
• and
• (d) R7 is selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl;
• and, if L is —C≡C— or —CH═CH—, then R7 may also be selected from —C(═O)NR8R8′ where (i) R8 and R8′ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, or (ii) R8 and R8′, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
• (3) —NR9R9′ where:
• (a) R9 and R9′ each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl and —C(═O)—Q—(CR10R10′)bR11 where:
• (i) b is from 0 to about 4;
• (ii) Q is selected from a covalent bond and —N(R12)—;
• and
• (iii) each R10 and R10′ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy and alkoxy;
• R11 and R12 (i) each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, or (ii) together with the atoms to which they are bonded, they join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
• or R9 and R12, together with the nitrogen atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 2 to 3 are heteroatoms;
• or
• (b) R9 and R9′, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
• and
• (4)
• 33
• (CR13R13′)c—A′—G′, where:
• (a) E′ and M are independently selected from —CH— and —N—;
• (b) L′ is selected from —S—, —O—, —N(R14)—, —C(R14)═C(R14′)—, N═C(R14)— and —N═N—, where R14 and R14′ each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;
• (c) c is from 0 to about 4;
• (d) each R13 and R13′ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, —heterocycloalkyl, halogen, haloalkyl, hydroxy and alkoxy;
• (e) A′ is selected from a covalent bond, —O—, —SOd—, —C(═O)—, C(═O)N(R15)—, —N(R15)— and —N(R15)C(═O)—;
• where d is from 0 to 2 and R15 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkyl;
• and
• (f) G′ is —(CR16R16′)e—R17 where e is from 0 to about 4;
• each R16 and R16′ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy;
• and R17 is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;
• or R16 and R17, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms;
• or R13 and R17, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms;
• or an optical isomer, diastereomer or enantiomer for Formula (I), or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof.