Benzimidazole anti-inflammatory compounds Number:7,056,918 from the United States Patent and Trademark Office (PTO) owispatent The present invention relates to novel triazolo-pyridines of the formula I ##STR00001## wherein Het is an optionally substituted 5-membered heterocycle containing one to two heteroatoms selected from nitrogen, sulfur and oxygen wherein at least one of said heteroatoms atoms must be nitrogen; R.sup.2 is selected from the group consisting of hydrogen, (C.sub.1 C.sub.6)alkyl or other suitable substituents; R.sup.3 is selected from the group consisting of hydrogen, (C.sub.1 C.sub.6)alkyl or other suitable substituents; s is an integer from 0 5; to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention are potent inhibitors of MAP kinases, preferably p38 kinase. They are useful in the treatment of inflammation, osteoarthritis, rheumatoid arthritis, cancer, repurfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.<H Benzimidazole, inflammatory, Benzimidazole, a, 7056918.html, Patent, pto, 7056918

Title: Benzimidazole anti-inflammatory compounds

Abstract: The present invention relates to novel triazolo-pyridines of the formula I ##STR00001## wherein Het is an optionally substituted 5-membered heterocycle containing one to two heteroatoms selected from nitrogen, sulfur and oxygen wherein at least one of said heteroatoms atoms must be nitrogen; R.sup.2 is selected from the group consisting of hydrogen, (C.sub.1 C.sub.6)alkyl or other suitable substituents; R.sup.3 is selected from the group consisting of hydrogen, (C.sub.1 C.sub.6)alkyl or other suitable substituents; s is an integer from 0 5; to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention are potent inhibitors of MAP kinases, preferably p38 kinase. They are useful in the treatment of inflammation, osteoarthritis, rheumatoid arthritis, cancer, repurfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.

Patent Number: 7,056,918 Issued on 06/06/2006 to Dombroski, et al.

Inventors: Dombroski; Mark A. (Waterford, CT); Letavic; Michael A. (Mystic, CT); McClure; Kim F. (Mystic, CT)
Assignee: Pfizer, Inc. (New York, NY)

Appl. No.: 094717

Filed: March 11, 2002

Current U.S. Class: 514/234.5 ; 514/254.06; 514/256; 514/314; 514/322; 514/338; 514/387; 544/139; 544/333; 544/370; 544/405; 546/167; 546/199; 546/273.7; 548/305.1; 548/306.1

Current International Class: A61K 31/4184 (20060101); C07D 403/04 (20060101); C07D 403/14 (20060101)

Field of Search: 548/306.1,305.1 546/273.7,167,199 544/370,405,333,139 514/387,234.5,254.06,255.05,256,322,338,314,255

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5717100	February 1998	Selnick et al.
5756499	May 1998	Adams et al.
5777097	July 1998	Lee et al.

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Primary Examiner: Stockton; Laura L.
Attorney, Agent or Firm: Lappin; Julie M. Ashbrook; Charles

Parent Case Text

This application claims the benefit U.S. Provisional Application 60/274,791, filed Mar. 9, 2001.

Claims

What is claimed is:

1. A compound of the formula ##STR00648## wherein R.sup.1 and R.sup.2 are each independently selected from the group consisting of hydrogen, (C.sub.1 C.sub.6)alkyl, (C.sub.3 C.sub.10)cycloalkyl, phenyl, (C.sub.1 C.sub.10)heteroaryl and (C.sub.1 C.sub.10)heterocyclic; each of the aforesaid (C.sub.1 C.sub.6)alkyl, (C.sub.3 C.sub.10)cycloalkyl, phenyl, (C.sub.1 C.sub.10)heteroaryl and (C.sub.1 C.sub.10)heterocyclic substituents may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, perhalo(C.sub.1 C.sub.6)alkyl, phenyl, (C.sub.3 C.sub.10)cycloalkyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic, formyl, --CN, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, phenyl-(C.dbd.O)--, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, phenyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, --NO.sub.2, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-(C.dbd.O)--NH--, phenyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, H.sub.2N--(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-HN--(C.dbd.O)--NH--, [(C.sub.1 C.sub.6)alkyl-].sub.2N--(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-HN--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, [(C.sub.1 C.sub.6)alkyl-].sub.2N--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-HN--(C.dbd.O)--NH--, (phenyl-).sub.2N--(C.dbd.O)--NH--, phenyl-HN--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, (phenyl-).sub.2N--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-O--(C.dbd.O)--NH--, phenyl-O--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, (C.sub.1 C.sub.6)alkyl-SO.sub.2NH--, phenyl-SO.sub.2NH--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, phenyl-SO.sub.2--, hydroxy, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, phenoxy, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--, phenyl-(C.dbd.O)--O--, H.sub.2N--(C.dbd.O)--O--, (C.sub.1 C.sub.6)alkyl-HN--(C.dbd.O)--O--, [(C.sub.1 C.sub.6)alkyl-].sub.2N--(C.dbd.O)--O--, phenyl-HN--(C.dbd.O)--O--, and (phenyl-).sub.2N--(C.dbd.O)--O--; wherein two adjacent substituents on said R.sup.1 or R.sup.2 (C.sub.3 C.sub.10)cycloalkyl, phenyl, (C.sub.1 C.sub.10)heteroaryl, or (C.sub.1 C.sub.10)heterocyclic may be taken together with the carbon or heteroatom to which they are attached to form a five to six membered carbocyclic or heterocyclic ring; wherein each of said moieties containing a phenyl alternative may optionally be substituted by one or two radicals independently selected from the group consisting of (C.sub.1 C.sub.6)alkyl, halo, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkyl and perhalo(C.sub.1 C.sub.6)alkoxy; each R.sup.3 is independently selected from the group consisting of halo, (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, perhalo(C.sub.1 C.sub.6)alkyl, phenyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.3 C.sub.10)cycloalkyl, hydroxy, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, phenoxy, (C.sub.1 C.sub.10)heteroaryl-O--, (C.sub.1 C.sub.10)heterocyclic-O--, (C.sub.3 C.sub.10)cycloalkyl-O--, (C.sub.1 C.sub.6)alkyl-S--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, (C.sub.1 C.sub.6)alkyl-NH--SO.sub.2--, --NO.sub.2, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, (C.sub.1 C.sub.6)alkyl-SO.sub.2--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-(C.dbd.O)--NH--, phenyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, --CN, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, phenyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, phenyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-NH--(C.dbd.O)-- and (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--; wherein said phenyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic and (C.sub.3 C.sub.10)cycloalkyl moieties of said phenyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.3 C.sub.10)cycloalkyl, phenoxy, (C.sub.1 C.sub.10)heteroaryl-O--, (C.sub.1 C.sub.10)heterocyclic-O--, (C.sub.3 C.sub.10)cycloalkyl-O--, phenyl-(C.dbd.O)--NH--, phenyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, phenyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--, and (C.sub.3 C.sub.10)cycloalkyl-NH--(C.dbd.O)-- may optionally be substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, chloro, trifluoromethyl, (C.sub.1 C.sub.6)alkcoxy, (C.sub.6 C.sub.10)aryloxy, trifluoromethoxy, difluoromethoxy and (C.sub.1 C.sub.6)alkyl; wherein two adjacent R.sup.3 groups may be taken together with the carbon atoms to which they are attached to form a three to six membered carbocyclic or heterocyclic ring; s is an integer from zero to five; R.sup.6 is selected from the group consisting of hydrogen, halo and R.sup.9--B--(CH.sub.2).sub.n--; n is an integer from zero to six; each B is independently a bond, --(CHR.sup.10)--, --O--, --S--, --(SO.sub.2)--, --(C.dbd.O)--, --O--(C.dbd.O)--, --(C.dbd.O)--O--, --(C.dbd.O)--NR.sup.10--, --(R.sup.10--N)--, --(R.sup.10--N)--SO.sub.2--, ----(R.sup.10--N)--(C.dbd.O)--, --SO.sub.2--(NR.sup.10)--, --(R.sup.10--N)--(C.dbd.O)--(NR.sup.11)--, --(O)--(C.dbd.O)--(NR.sup.10)-- or --(R.sup.10--N)--(C.dbd.O)--O--; R.sup.5 is selected from the group consisting of hydrogen, R.sup.14--(CR.sup.15H).sub.p--, phenyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.3 C.sub.10)cycloalkyl, (C.sub.1 C.sub.6)alkyl-(SO.sub.2)--, phenyl-(SO.sub.2)--, H.sub.2N--(SO.sub.2)--, (C.sub.1 C.sub.6)alkyl-NH--(SO.sub.2)--, [(C.sub.1 C.sub.6)alkyl-].sub.2N--(SO.sub.2)--, phenyl-NH--(SO.sub.2)--, (phenyl-).sub.2N--(SO.sub.2)--, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, phenyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-O--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-O--(C.dbd.O)--, H.sub.2N--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl-].sub.2N--(C.dbd.O)--, (phenyl-).sub.2N--(C.dbd.O)--, phenyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, and (C.sub.3 C.sub.10)cycloalkyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, wherein each of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R.sup.5 alternatives may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, R.sup.16 (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, perhalo(C.sub.1 C.sub.6)alkyl, (C.sub.3 C.sub.10)cycloalkyl, phenyl, benzyl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, formyl, --CN, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--, phenyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-O--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-O--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-NH--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, phenyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, hydroxy, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, (C.sub.3 C.sub.10)cycloalkyl-O--, phenoxy, (C.sub.1 C.sub.10)heterocyclic-O--, (C.sub.1 C.sub.10)heteroaryl-O--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--O--, phenyl-(C.dbd.O)--O--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--O--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--O--, --NO.sub.2, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, formamidyl, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--NH--, phenyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--NH--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-(C.dbd.O)-[(C.sub.1 C.sub.6)alkyl-N]--, (C.sub.1 C.sub.6)alkyl-SO.sub.2NH--, (C.sub.3 C.sub.10)cycloalkyl-SO.sub.2NH--, phenyl-SO.sub.2NH--, (C.sub.1 C.sub.10)heterocyclic-SO.sub.2NH-- and (C.sub.1 C.sub.10)heteroaryl-SO.sub.2NH--; wherein each of said phenyl and heteroaryl moiety alternatives may optionally be substituted by one or two radicals independently selected from halo, (C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkoxy, perfluoro(C.sub.1 C.sub.6)alkyl and perfluoro(C.sub.1 C.sub.6)alkoxy; p is an integer from one to six; R.sup.9 is selected from the group consisting of hydrogen, --CF.sub.3, --C.ident.N, R.sup.13--(R.sup.12CH).sub.m--, phenyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic and (C.sub.3 C.sub.10)cycloalkyl; wherein each of the aforesaid R.sup.9 phenyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic and (C.sub.3 C.sub.10) cycloalkyl substituents may optionally be substituted by one to four moieties independently selected from the group consisting of (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, perhalo(C.sub.1 C.sub.6)alkyl, phenyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.3 C.sub.10)cycloalkyl, hydroxy, perhalo(C.sub.1 C.sub.6)alkoxy, phenoxy, (C.sub.1 C.sub.10)heteroaryl-O--, (C.sub.1 C.sub.10)heterocyclic-O--, (C.sub.3 C.sub.10)cycloalkyl-O--, (C.sub.1 C.sub.6)alkyl-S--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, (C.sub.1 C.sub.6)alkyl-NH--SO.sub.2--, amino, (C.sub.1 C.sub.6)alkylamino, (C.sub.1 C.sub.6)alkyl-SO.sub.2--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)-[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-(C.dbd.O)--NH--, phenyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, --CN, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, phenyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, phenyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-NH--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O-- and phenyl-(C.dbd.O)--O--; wherein two adjacent substituents on said R.sup.9 (C.sub.1 C.sub.10)heterocyclic or (C.sub.3 C.sub.10)cycloalkyl may be taken together with the carbon or heteroatoms to which they are attached to form a five to six membered heterocyclic or carbocyclic ring; m is an integer from one to six; R.sup.10 is hydrogen, (C.sub.1 C.sub.6)alkyl-SO.sub.2-- or (C.sub.1 C.sub.6)alkyl; R.sup.11 is hydrogen or (C.sub.1 C.sub.6)alkyl; each R.sup.12 is independently selected from the group consisting of hydrogen, amino, (C.sub.1 C.sub.6)alkoxy and (C.sub.1 C.sub.6)alkyl; R.sup.13 is selected from the group consisting of hydrogen, (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, phenyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.3 C.sub.10)cycloalkyl, hydroxy, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, phenoxy, (C.sub.1 C.sub.10)heteroaryl-O--, (C.sub.1 C.sub.10)heterocyclic-O--, (C.sub.3 C.sub.10)cycloalkyl-O--, (C.sub.1 C.sub.6)alkyl-S--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, (C.sub.1 C.sub.6)alkyl-NH--SO.sub.2--, --NO.sub.2, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, (C.sub.1 C.sub.6)alkyl-SO.sub.2--NH--, phenyl-SO.sub.2--NH--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-SO.sub.2--[((C.sub.1 C.sub.6)alkyl)-N]--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-(C.dbd.O)--NH--, phenyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, --CN, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, phenyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, phenyl-[((C.sub.1-C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.1-C.sub.10)heteroaryl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--, (C.sub.3-C.sub.10)cycloalkyl-NH--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O-- and phenyl-(C.dbd.O)--O--; R.sup.14 is selected from the group consisting of hydrogen, halo, (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, perhalo(C.sub.1 C.sub.6)alkyl, (C.sub.3 C.sub.10)cycloalkyl, phenyl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.6)alkyl-(S.dbd.O)--, phenyl-(S.dbd.O)--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, phenyl-SO.sub.2--, H.sub.2N--SO.sub.2--, (C.sub.1 C.sub.6)alkyl-NH--SO.sub.2--, phenyl-NH--SO.sub.2--, [(C.sub.1 C.sub.6)alkyl-].sub.2N--SO.sub.2--, (phenyl-).sub.2N--SO.sub.2--, formyl, --CN, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, phenyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--, HO--(C.dbd.O)--, R.sup.16--(C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-O--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-O--(C.dbd.O)--, H.sub.2N--(C.dbd.O)--, R.sup.16--(C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-NH--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, phenyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, hydroxy, R.sup.16--(C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, (C.sub.3 C.sub.10)cycloalkyl-O--, phenoxy, (C.sub.1 C.sub.10)heterocyclic-O--,

(C.sub.1 C.sub.10)heteroaryl-O--, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--O--, phenyl-(C.dbd.O)--O--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--O--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--O--, --NO.sub.2, amino, R.sup.16--(C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, formamidyl, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--NH--, phenyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--NH--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--NH--, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, R.sup.16--(C.sub.1 C.sub.6)alkyl-SO.sub.2NH--, (C.sub.3 C.sub.10)cycloalkyl-SO.sub.2NH--, phenyl-SO.sub.2NH--, (C.sub.1 C.sub.10)heterocyclic-SO.sub.2NH-- and (C.sub.1 C.sub.10)heteroaryl-SO.sub.2NH--; wherein each of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R.sup.14 alternatives may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, R.sup.16--(C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, perhalo(C.sub.1 C.sub.6)alkyl, (C.sub.3 C.sub.10)cycloalkyl, phenyl, benzyl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.6)alkyl-(S.dbd.O)--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, formyl, --CN, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--, phenyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-O--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-O--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-O--(C.dbd.O)--, H.sub.2N--(C.dbd.O)--, R.sup.16--(C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-NH--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, phenyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, hydroxy, R.sup.16--(C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, (C.sub.3 C.sub.10)cycloalkyl-O--, phenoxy, (C.sub.1 C.sub.10)heterocyclic-O--, (C.sub.1 C.sub.10)heteroaryl-O--, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--O--, phenyl-(C.dbd.O)--O--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--O--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--O--, --NO.sub.2, amino, R.sup.16--(C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, formamidyl, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--NH--, phenyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--NH--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--NH--, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, R.sup.16--(C.sub.1 C.sub.6)alkyl-SO.sub.2NH--, (C.sub.3 C.sub.10)cycloalkyl-SO.sub.2NH--, phenyl-SO.sub.2NH--, (C.sub.1 C.sub.10)heterocyclic-SO.sub.2NH-- and (C.sub.1 C.sub.10)heteroaryl-SO.sub.2NH--; wherein each of said phenyl and heteroaryl moiety alternatives may optionally be substituted by one or two radicals independently selected from the group consisting of halo, (C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkoxy, perfluoro(C.sub.1 C.sub.6)alkyl and perfluoro(C.sub.1 C.sub.6)alkoxy; each R.sup.15 is independently selected from the group consisting of hydrogen, halo, (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, perhalo(C.sub.1 C.sub.6)alkyl, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, hydroxy, (C.sub.1 C.sub.6)alkoxy, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, formamidyl and (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--; each R.sup.16 is independently selected from the group consisting of hydrogen, halo, (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, perhalo(C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.10)heterocyclic, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, hydroxy, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--, --NO.sub.2, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, formamidyl and (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--; wherein said (C.sub.1 C.sub.10)heterocyclic may optionally be substituted by one to three substitutents independently selected from the group consisting of halo, (C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkoxy, benzyl, amino, (C.sub.1 C.sub.6)alkylamino and [(C.sub.1 C.sub.6)alkyl].sub.2-amino; or R.sup.5 and R.sup.6 or may be taken together with the atoms to which they are attached to form an optionally substituted five to ten membered saturated, unsaturated or aromatic ring optionally containing two to three heteroatoms independently selected from NH, N, O, S, SO or SO.sub.2; wherein said ring may be optionally substituted by one to three substituents independently selected from the group consisting of oxo, halo, (C.sub.1 C.sub.6)alkyl, phenyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.3 C.sub.10)cycloalkyl, hydroxy, (C.sub.1 C.sub.6)alkoxy, phenoxy, (C.sub.1 C.sub.10)heteroaryl-O--, (C.sub.1 C.sub.10)heterocyclic-O--, (C.sub.3 C.sub.10)cycloalkyl-O--, (C.sub.1 C.sub.6)alkyl-S--, (C.sub.1 C.sub.6)alkyl-(S.dbd.O)--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, phenyl-S--, phenyl-(S.dbd.O)--, phenyl-SO.sub.2--, (C.sub.1 C.sub.6)alkyl-NH--SO.sub.2--[(C.sub.1 C.sub.6)alkyl].sub.2- N--SO.sub.2--, phenyl-NH--SO.sub.2--, (phenyl).sub.2-N--SO.sub.2--, phenyl-[N(C.sub.1 C.sub.6)alkyl]-SO.sub.2--, formyl, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, phenyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-O--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-O--(C.dbd.O)--, H.sub.2N--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, phenyl-[(C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-[(C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-NH--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2amino, (C.sub.1 C.sub.6)alkyl-SO.sub.2--NH--, phenyl-SO.sub.2--NH--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-SO.sub.2--[((C.sub.1 C.sub.6)alkyl)-N]--, formamidyl, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-(C.dbd.O)--NH--, phenyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--NH--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--NH--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--NH--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, H.sub.2N(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-HN--(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-HN--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--NH--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-HN--(C.dbd.O)--NH--, phenyl-HN--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, (phenyl).sub.2-N--(C.dbd.O)--NH--, (phenyl).sub.2-N--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, (C.sub.1 C.sub.10)heteroaryl-HN--(C.dbd.O)--NH--, (C.sub.1 C.sub.10)heteroaryl-HN--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, [(C.sub.1 C.sub.10)heteroaryl].sub.2-N--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, [(C.sub.1 C.sub.10)heteroaryl].sub.2-N--(C.dbd.O)--NH--, (C.sub.1 C.sub.10)heterocyclic-HN--(C.dbd.O)--NH--, (C.sub.1 C.sub.10)heterocyclic-HN--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, [(C.sub.1 C.sub.10)heterocyclic].sub.2-N--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, [(C.sub.1 C.sub.10)heterocyclic].sub.2-N--(C.dbd.O)--NH--, (C.sub.3 C.sub.10)cycloalkyl-HN--(C.dbd.O)--NH--, (C.sub.3 C.sub.10)cycloalkyl-HN--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, [(C.sub.3 C.sub.10)cycloalkyl].sub.2- N--(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, [(C.sub.3 C.sub.10)cycloalkyl].sub.2-N--(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--, phenyl-(C.dbd.O)--O--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--O--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--O--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--O--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--O--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--O--, phenyl-NH--(C.dbd.O)--O--, (C.sub.1 C.sub.10)heteroaryl-NH--(C.dbd.O)--O--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--O-- and (C.sub.3 C.sub.10)cycloalkyl-NH--(C.dbd.O)--O--; with the proviso that when R.sup.6 is R.sup.9--B--(CH.sub.2).sub.n--; n is zero and B is a bond; then R.sup.9 must be other than phenyl; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein R.sup.1 or R.sup.2 are independently optionally substituted (C.sub.1 C.sub.6)alkyl, phenyl, (C.sub.3 C.sub.10)cycloalkyl, (C.sub.1 C.sub.10)heteroaryl or (C.sub.1 C.sub.10)heterocyclic.

3. A compound according to claim 1, wherein R.sup.1 or R.sup.2 are each independently (C.sub.1 C.sub.6)alkyl, optionally substituted with one to four groups independently selected from halo, (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkyl, perhalo(C.sub.1 C.sub.6)alkoxy, --CN, --NO.sub.2, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-CO.sub.2--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, (C.sub.1 C.sub.6)alkyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-SO.sub.2NH--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, optionally substituted phenyl-(C.dbd.O)--, optionally substituted phenyl-(C.dbd.O)--O--, optionally substituted phenoxy, optionally substituted phenyl-NH--(C.dbd.O)--, optionally substituted phenyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, optionally substituted phenyl-(C.dbd.O)--NH-- and optionally substituted phenyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--.

4. A compound according to claim 1, wherein R.sup.2 is (C.sub.1 C.sub.4)alkyl.

5. A compound according to claim 4, wherein R.sup.1 is (C.sub.1 C.sub.5)alkyl or (C.sub.3 C.sub.6)cycloalkyl.

6. A compound according to claim 1, wherein R.sup.1 is optionally substituted (C.sub.3 C.sub.6)cycloalkyl and R.sup.2 is (C.sub.1 C.sub.6)alkyl.

7. A compound according to claim 1, wherein R.sup.1 and R.sup.2 are each independently (C.sub.1 C.sub.6)alkyl.

8. A compound according to claim 1, wherein R.sup.1 is optionally substituted phenyl and R.sup.2 is (C.sub.1 C.sub.6)alkyl.

9. A compound according to claim 1, wherein R.sup.1 is optionally substituted (C.sub.1 C.sub.10)heterocyclic and R.sup.2 is (C.sub.1 C.sub.6)alkyl.

10. A compound according to claim 1, wherein R.sup.1 is optionally substituted (C.sub.1 C.sub.10)heteroaryl and R.sup.2 is (C.sub.1 C.sub.6)alkyl.

11. A compound according to claim 1, wherein R.sup.1 or R.sup.2 is hydrogen.

12. A compound according to claim 1, wherein R.sup.5 is hydrogen.

13. A compound according to claim 1, wherein R.sup.5 is (C.sub.1 C.sub.10)heterocyclic or (C.sub.1 C.sub.10)heteroaryl; wherein each of the aforesaid heterocyclic and heteroaryl substituents may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, (C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkoxy, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)-- and [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--.

14. A compound according to claim 1, wherein R.sup.5 is R.sup.14--(CHR.sup.15).sub.p--, p is 1 6; and R.sup.14 is selected from the group consisting of hydrogen, (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, perhalo(C.sub.1 C.sub.6)alkyl, (C.sub.3 C.sub.10)cycloalkyl, phenyl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.1 C.sub.10)heteroaryl, phenyl-(S.dbd.O)--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, phenyl-SO.sub.2--, H.sub.2N--SO.sub.2--, (C.sub.1 C.sub.6)alkyl-NH--SO.sub.2--, phenyl-NH--SO.sub.2--, [(C.sub.1 C.sub.6)alkyl-].sub.2N--SO.sub.2--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, phenyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--, HO--(C.dbd.O)--, R.sup.16--(C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-O--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-O--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-O--(C.dbd.O)--, H.sub.2N--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-NH--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, phenyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-[N--(C.sub.1 C.sub.6)alkyl]-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, hydroxy, R.sup.16--(C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, (C.sub.3 C.sub.10)cycloalkyl-O--, phenoxy, (C.sub.1 C.sub.10)heterocyclic-O--, (C.sub.1 C.sub.10)heteroaryl-O--, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--O--, phenyl-(C.dbd.O)--O--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--O--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--O--, --NO.sub.2, amino, R.sup.16--(C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, formamidyl, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--NH--, phenyl-(C.dbd.O)--NH--, R.sup.16--(C.sub.1 C.sub.6)alkyl-SO.sub.2NH--, (C.sub.3 C.sub.10)cycloalkyl-SO.sub.2NH--, phenyl-SO.sub.2NH--, (C.sub.1 C.sub.10)heterocyclic-SO.sub.2NH-- and (C.sub.1 C.sub.10)heteroaryl-SO.sub.2NH--; wherein each of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R.sup.14 alternatives may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, R.sup.16--(C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, perhalo(C.sub.1 C.sub.6)alkyl, (C.sub.3 C.sub.10)cycloalkyl, phenyl, benzyl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.6)alkyl-(S.dbd.O)--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, formyl, --CN, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--, phenyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-O--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-O--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-O--(C.dbd.O)--, H.sub.2N--(C.dbd.O)--, R.sup.16--(C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-NH--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, phenyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, hydroxy, R.sup.16--(C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, (C.sub.3 C.sub.10)cycloalkyl-O--, phenoxy, (C.sub.1 C.sub.10)heterocyclic-O--, (C.sub.1 C.sub.10)heteroaryl-O--, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--O--, phenyl-(C.dbd.O)--O--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--O--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--O--, --NO.sub.2, amino, R.sup.16--(C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, formamidyl, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--NH--, phenyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--NH--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--NH--, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-(C.dbd.O)--[(C.sub.1 C.sub.6)alkyl-N]--, R.sup.16--(C.sub.1 C.sub.6)alkyl-SO.sub.2NH--, (C.sub.3 C.sub.10)cycloalkyl-SO.sub.2NH--, phenyl-SO.sub.2NH--, (C.sub.1 C.sub.10)heterocyclic-SO.sub.2NH-- and (C.sub.1 C.sub.10)heteroaryl-SO.sub.2NH--; and wherein each of said phenyl and heteroaryl moiety alternatives may optionally be substituted by one or two radicals independently selected from halo, (C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkoxy, amino, (C.sub.1 C.sub.6)alkylamino and [(C.sub.1 C.sub.6)alkyl].sub.2-amino.

15. A compound according to claim 1, wherein R.sup.5 is R.sup.14--(CHR.sup.15).sub.p--, p is 1 6; and R.sup.14 is selected from the group consisting of hydrogen, (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.3 C.sub.10)cycloalkyl, phenyl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.1 C.sub.10)heteroaryl, HO--(C.dbd.O)--, R.sup.16--(C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N--(C.dbd.O)--, R.sup.16--(C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O), [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, phenyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, hydroxy, R.sup.16--(C.sub.1 C.sub.6)alkoxy, phenoxy, amino, R.sup.16--(C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, and R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--; wherein each of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R.sup.14 alternatives may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, R.sup.16--(C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, perhalo(C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, formyl, --CN, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N--(C.dbd.O)--, R.sup.16--(C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2N--(C.dbd.O)--, hydroxy, R.sup.16--(C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--, amino, R.sup.16--(C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, formamidyl, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, R.sup.16--(C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]-- and R.sup.16--(C.sub.1 C.sub.6)alkyl-SO.sub.2NH--; each R.sup.15 is independently selected from the group consisting of hydrogen, halo, (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, perhalo(C.sub.1 C.sub.6)alkyl, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, hydroxy, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, formamidyl and (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--; wherein no more than two of said R.sup.15 groups may be other than hydrogen; and each R.sup.16 is independently selected from the group consisting of hydrogen, halo, (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, perhalo(C.sub.1 C.sub.6)alkyl, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, hydroxy, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--, --NO.sub.2, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, formamidyl and (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--.

16. A compound according to claim 1, wherein R.sup.6 is hydrogen.

17. A compound according to claim 1, wherein R.sup.6 is R.sup.9--B--(CH.sub.2).sub.n-- and n is zero.

18. A compound according to claim 1, wherein R.sup.6 is R.sup.9--B--(CH.sub.2).sub.n-- and n is an integer from one to five.

19. A compound according to claim 1, wherein R.sup.6 is R.sup.9--B--(CH.sub.2).sub.n--; n is zero; B is a bond and R.sup.9 is selected from the group consisting of hydrogen, --CF.sub.3, --C.ident.N, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic or (C.sub.3 C.sub.10)cycloalkyl; wherein each of the aforesaid (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic and (C.sub.3 C.sub.10)cycloalkyl may optionally be substituted by one to three moieties independently selected from the group consisting of halo, (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.1 C.sub.6)alkynyl, perhalo(C.sub.1 C.sub.6)alkyl, hydroxy, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, (C.sub.1 C.sub.6)alkyl-S--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, (C.sub.1 C.sub.6)alkyl-NH--SO.sub.2--, --NO.sub.2, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, (C.sub.1 C.sub.6)alkyl-SO.sub.2--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, --CN, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2N--(C.dbd.O)-- and (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--.

20. A compound according to claim 1, wherein R.sup.6 is R.sup.9--B--(CH.sub.2).sub.n--; n is zero; B is --(C.dbd.O)--NR.sup.10--, --(R.sup.10--N)--, --(R.sup.10--N)--SO.sub.2--, --(R.sup.10--N)--(C.dbd.O)--, >C.dbd.O, --O--(C.dbd.O)--, --SO.sub.2--(NR.sup.10)--, or --(R.sup.10--N)--(C.dbd.O)--(NR.sup.11)--; and R.sup.9 is selected from the group consisting of hydrogen, (C.sub.3 C.sub.10)cycloalkyl or phenyl; wherein the aforesaid phenyl and (C.sub.3 C.sub.10)cycloalkyl may optionally be substituted by one to three moieties independently selected from the group consisting of halo, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, perhalo(C.sub.1 C.sub.6)alkyl, hydroxy, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, (C.sub.1 C.sub.6)alkyl-S--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, (C.sub.1 C.sub.6)alkyl-NH--SO.sub.2--, --NO.sub.2, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, (C.sub.1 C.sub.6)alkyl-SO.sub.2--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[N(C.sub.1 C.sub.6)alkyl]-, --CN, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)-- and (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--.

21. A compound according to claim 1, wherein R.sup.6 is R.sup.9--B--(CH.sub.2).sub.n--; n is zero; B is --(C.dbd.O)--NR.sup.10--, --(R.sup.10--N)--, >C.dbd.O, --O--(C.dbd.O)--, --(R.sup.10--N)--(C.dbd.O)-- or --(R.sup.10--N)--(C.dbd.O)--(NR.sup.11)--; R.sup.9 is R.sup.13--(R.sup.12CH).sub.m--; m is 1 6; R.sup.10 is hydrogen or methyl; R.sup.12 is hydrogen or methyl; and R.sup.13 is selected from the group consisting of hydrogen, (C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkoxy, phenyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.3 C.sub.10)cycloalkyl, amino, (.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2amino, (C.sub.1 C.sub.6)alkyl-SO.sub.2--NH--, phenyl-SO.sub.2--NH--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--[N--(C.sub.1 C.sub.6)alkyl]-, phenyl-SO.sub.2--[N--(C.sub.1 C.sub.6)alkyl]-, hydroxy, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, phenoxy, (C.sub.1 C.sub.10)heteroaryl-O--, (C.sub.1 C.sub.10o)heterocyclic-O--, (C.sub.3 C.sub.10)cycloalkyl-O--, (C.sub.1 C.sub.6)alkyl-S--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, (C.sub.1 C.sub.6)alkyl-NH--SO.sub.2--, --NO.sub.2, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, (C.sub.1 C.sub.6)alkyl-SO.sub.2--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[N(C.sub.1 C.sub.6)alkyl]-, phenyl-(C.dbd.O)--NH--, phenyl-(C.dbd.O)--[N--(C.sub.1 C.sub.6)alkyl]-, --CN, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, phenyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-NH--(C.dbd.O)--, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, phenyl-[N--((C.sub.1 C.sub.6)alkyl)]-(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O-- and phenyl-(C.dbd.O)--O--.

22. A compound according to claim 1, wherein R.sup.6 is R.sup.9--B--(CH.sub.2).sub.n--; n is zero; B is --(R.sup.10--N)--; R.sup.9 is hydrogen or R.sup.13--(R.sup.12CH).sub.m--; m is 1 6; R.sup.10 is hydrogen or methyl; R.sup.12 is hydrogen or methyl; and R.sup.13 is selected from the group consisting of hydrogen, (C.sub.1 C.sub.6)alkyl, hydroxy, (C.sub.1 C.sub.6)alkoxy, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2amino, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, phenyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic and (C.sub.3 C.sub.10)cycloalkyl.

23. A compound according to claim 1, wherein R.sup.6 is R.sup.9--B--(CH.sub.2).sub.n--; n is one to four; B is --(C.dbd.O)--NR.sup.10--, --(R.sup.10--N)--, --(R.sup.10--N)--(C.dbd.O)-- or --(R.sup.10--N)--(C.dbd.O)--(NR.sup.11)--; R.sup.9 is R.sup.13--(R.sup.12CH).sub.m--; m is 1 6; R.sup.10 is hydrogen or methyl; R.sup.12 is hydrogen or methyl; and R.sup.13 is selected from the group consisting of hydrogen, (C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkoxy, phenyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.3 C.sub.10)cycloalkyl, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2amino, (C.sub.1 C.sub.6)alkyl-SO.sub.2--NH--, phenyl-SO.sub.2--NH--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--[N--(C.sub.1 C.sub.6)alkyl]-, phenyl-SO.sub.2--[N--(C.sub.1 C.sub.6)alkyl]-, hydroxy, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, phenoxy, (C.sub.1 C.sub.10)heteroaryl-O--, (C.sub.1 C.sub.10)heterocyclic-O--, (C.sub.3 C.sub.10)cycloalkyl-O--, (C.sub.1 C.sub.6)alkyl-S--, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, (C.sub.1 C.sub.6)alkyl-NH--SO.sub.2--, --NO.sub.2, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, (C.sub.1 C.sub.6)alkyl-SO.sub.2--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-(C.dbd.O)--NH--, phenyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, --CN, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, phenyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-NH--(C.dbd.O)--, HO--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N(C.dbd.O)-- (C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, phenyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O-- and phenyl-(C.dbd.O)--O--.

24. A compound according to claim 1, wherein s is an integer from zero to four and each R.sup.3 is independently selected from the group consisting of halo, (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, perhalo(C.sub.1 C.sub.6)alkyl, phenyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.3 C.sub.10)cycloalkyl, hydroxy, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, phenoxy, (C.sub.1 C.sub.10)heteroaryl-O--, (C.sub.1 C.sub.10)heterocyclic-O--, (C.sub.3 C.sub.10)cycloalkyl-O--, (C.sub.1 C.sub.6)alkyl-S, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, (C.sub.1 C.sub.6)alkyl-NH--SO.sub.2--, --NO.sub.2, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, (C.sub.1 C.sub.6)alkyl-SO.sub.2--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-(C.dbd.O)--NH--, phenyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, --CN, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, phenyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--, HO--(C.dbd.O), (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N(C.dbd.O)--(C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, phenyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-NH--(C.dbd.O)-- and (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--.

25. A compound according to claim 1, wherein s is an integer from zero to four and each R.sup.3 is independently selected from the group consisting of halo, (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl, perhalo(C.sub.1 C.sub.6)alkyl, phenyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic, (C.sub.3 C.sub.10)cycloalkyl, hydroxy, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, phenoxy, (C.sub.1 C.sub.10)heteroaryl-O--, (C.sub.1 C.sub.10)heterocyclic-O--, (C.sub.3 C.sub.10)cycloalkyl-O--, (C.sub.1 C.sub.6)alkyl-S, (C.sub.1 C.sub.6)alkyl-SO.sub.2--, (C.sub.1 C.sub.6)alkyl-NH--SO.sub.2--, --NO.sub.2, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, (C.sub.1 C.sub.6)alkyl-SO.sub.2--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--NH--, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, phenyl-(C.dbd.O)--NH--, phenyl-(C.dbd.O)--[((C.sub.1 C.sub.6)alkyl)-N]--, --CN, (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--, phenyl-(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-(C.dbd.O)--, HO--(C.dbd.O), (C.sub.1 C.sub.6)alkyl-O--(C.dbd.O)--, H.sub.2N(C.dbd.O)--(C.sub.1 C.sub.6)alkyl-NH--(C.dbd.O)--, [(C.sub.1 C.sub.6)alkyl].sub.2-N--(C.dbd.O)--, phenyl-NH--(C.dbd.O)--, phenyl-[((C.sub.1 C.sub.6)alkyl)-N]--(C.dbd.O)--, (C.sub.1 C.sub.10)heteroaryl-NH--(C.dbd.O)--, (C.sub.1 C.sub.10)heterocyclic-NH--(C.dbd.O)--, (C.sub.3 C.sub.10)cycloalkyl-NH--(C.dbd.O)-- and (C.sub.1 C.sub.6)alkyl-(C.dbd.O)--O--.

26. A compound according to claim 1, wherein s is an integer from zero to four and each R.sup.3 is independently selected from the group consisting of halo, --CN, (C.sub.1 C.sub.6)alkyl, (C.sub.2 C.sub.6)alkenyl, (C.sub.2 C.sub.6)alkynyl and perhalo(C.sub.1 C.sub.6)alkyl.

27. A compound according to claim 1, wherein s is an integer from zero to four and zero, one or two of R.sup.3 are independently selected from the group consisting of halo, (C.sub.1 C.sub.6)alkyl, perhalo(C.sub.1 C.sub.6)alkyl, hydroxy, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, --CN, and H.sub.2N(C.dbd.O)--.

28. A compound according to claim 1, wherein s is an integer from zero to four and one of R.sup.3is selected from the group consisting of optionally substituted phenyl, (C.sub.1 C.sub.10)heteroaryl, (C.sub.1 C.sub.10)heterocyclic and (C.sub.3 C.sub.10)cycloalkyl.

29. A compound according to claim 1, wherein s is an integer from zero to three and each R.sup.3 is independently selected from the group consisting of halo, (C.sub.1 C.sub.6)alkyl, perhalo(C.sub.1 C.sub.6)alkyl, hydroxy, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy, --NO.sub.2, amino, (C.sub.1 C.sub.6)alkylamino, [(C.sub.1 C.sub.6)alkyl].sub.2-amino, --CN, and H.sub.2N(C.dbd.O)--.

30. A compound according to claim 1, wherein s is an integer from zero to two and each R.sup.3 is independently selected from the group consisting of halo, (C.sub.1 C.sub.6)alkyl, perhalo(C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkoxy, perhalo(C.sub.1 C.sub.6)alkoxy and --CN.

31. A compound according to claim 1, wherein s is an integer from zero to three and each R.sup.3 is independently selected from the group consisting of fluoro, chloro and methyl.

32. A compound according to claim 1, wherein s is an integer from zero to three and each R.sup.3 is independently selected from the group consisting of fluoro, chloro and methyl.

Description

The present invention relates to novel benzimidazoles, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention are potent inhibitors of MAP kinases, preferably p38 kinase. They are useful in the treatment of inflammation, osteoarthritis, rhematoid arthritis, cancer, reperfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.

Intracellular signal transduction is the means by which cells respond to extracellular stimuli. Regardless of the nature of the cell surface receptor (e.g. protein tyrosine kinase or seven-transmembrane G-protein coupled), protein kinases and phosphatases along with phopholipases are the essential machinery by which the signal is further transmitted within the cell [Marshall, J. C. Cell, 80, 179 278 (1995)]. Protein kinases can be categorized into five classes with the two major classes being, tyrosine kinases and serine/threonine kinases depending upon whether the enzyme phosphorylates its substrate(s) on specific tyrosine(s) or serine/threonine(s) residues [Hunter, T. Methods in Enzymology (Protein Kinase Classification) p. 3, Hunter, T.; Sefton, B. M.; eds. vol. 200, Academic Press; San Diego, 1991].

For most biological responses, multiple intracellular kinases are involved and an individual kinase can be involved in more than one signaling pathway. These kinases are often cytosolic and can translocate to the nucleus or the ribosomes where they can affect transcriptional and translational events, respectively. The involvement of kinases in transcriptional control is presently much better understood than their effect on translation as illustrated by the studies on growth factor induced signal transduction involving MAP/ERK kinase [Marshall, C. J. Cell, 80, 179 (1995); Herskowitz, I. Cell, 80, 187 (1995); Hunter, T. Cell, 80, 225 (1995); Seger, R., and Krebs, E. G. FASEB J., 726735 (1995)].

While many signaling pathways are part of normal cell homeostasis, numerous cytokines (e.g., IL-1 and TNF) and certain other mediators of inflammation (e.g., COX-2, and iNOS) are produced only as a response to stress signals such as bacterial lippopolysaccharide (LPS). Early evidence suggesting that the signal transduction pathway leading to LPS-induced cytokine biosynthesis involved protein kinases came from studies of Weinstein [Weinstein, et al., J. Immunol 151, 3829(1993)] but the specific protein kinases involved were not identified. Working from a similar perspective, Han [Han, et al., Science 265, 808(1994)] identified murine p38 as a kinase which is tyrosine phosphorylated in response to LPS. Additional evidence of the involvement of the p38 kinase in LPS-stimulated signal transduction pathway leading to the initiation of proinflammatory cytokine biosynthesis was provided by the discovery of p38 kinase (CSBP 1 and 2) by Lee [Lee; et al,. Nature, 372, 739(1994)] as the molecular target for a novel class of anti-inflammatory agents. Thus, compounds which inhibit p38 will inhibit IL-1 and TNF synthesis in human monocytes. Such results have been reported by [Lee, et al., Int. J. Immunopharmac. 10(7), 835(1988)] and [Lee; et al., Annals N.Y. Acad. Sci., 696, 149(1993)].

##STR00002##

It is now accepted that CSBP/p38 is a one of several kinases involved in a stress-response signal transduction pathway which is parallel to and largely independent of the analogous mitogen-activated protein kinase (MAP) kinase cascade (FIG. 1). Stress signals, including LPS, pro-inflammatory cytokines, oxidants, UV light and osmotic stress, activate kinases upstream from CSBP/p38 which in turn phosphorylate CSBP/p38 at threonine 180 and tyrosine 182 resulting in CSBP/p38 activation. MAPKAP kinase-2 and MAPKAP kinase-3 have been identified as downstream substrates of CSBP/p38 which in turn phosphorylate heat shock protein Hsp 27. It is now known that MAPKAP-2 is essential for LPS induced TNF.alpha. biosynthesis [Kotlyarov et al. Nature Cell Biol., 1, 94 (1999), see also Cohen, P. Trends Cell Biol., 353 361(1997)].

In addition to inhibiting IL-1 and TNF, CSBP/p38 kinase inhibitors also decrease the synthesis of a wide variety of pro-inflammatory proteins including, IL-6, IL-8, GM-CSF and COX-2. Inhibitors of CSBP/p38 kinase have also been shown to suppress the TNF-induced expression of VCAM-1 on endothelial cells, the TNF-induced phosphorylation and activation of cytosolic PLA2 and the IL-1 stimulated synthesis of collagenase and stromelysin. These and additional data demonstrate that CSBP/p38 is involved not only cytokine synthesis, but also in cytokine signaling [CSBP/p38 kinase reviewed in Cohen, P. Trends Cell Biol., 353 361 (1997)].

Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages. IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation [See, e.g,. Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)]. The myriad of known biological activities of IL-1 include the activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.

There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease. These include rheumatoid arthritis, osteoarthritis, endotoxemia and/or toxic shock syndrome, other acute or chonic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, and acute synovitis. Recent evidence also links IL-1 activity to diabetes and pancreatic .beta. cells, Dinarello, J. Clinical Immunology, 5 (5), 287 297 (1985).

Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid information, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis.

Interleukin-8 (IL-8) is a chemotactic factor produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. Its production from endothelial cells is induced by IL-1, TNF, or lipopolysachharide (LPS). IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T-lymphocytes, and basophils. In addition it induces histamine release from basophils from both normal and atopic individuals as well lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis, this may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration. Conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophils into the inflammatory site) would benefit by compounds which are suppressive of IL-8 production.

IL-1 and TNF affect a wide variety of cells and tissues and these cytokines as well as other leukocyte derived cytokines are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.

Inhibition of signal transduction via CSBP/p38, which in addition to IL-1, TNF and IL-8 described above is also required for the synthesis and/or action of several additional pro-inflammatory proteins (i.e., IL-6, GM-CSF, COX-2, collagenase and stromelysin), is expected to be a highly effective mechanism for regulating the excessive and destructive activation of the immune system. This expectation is supported