Substituted pyrazolyl compounds for the treatment of inflammation

A compound of formula I

• 124
• wherein
• A is (CH2)m-Q-(CH2)n, wherein each CH2 may be independently substituted with one or more substitution selected from the group consisting of:
• hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl;
• Q is selected from the group consisting of:
• S(O)p, O, CR15═N,N═CR15, —CO—O—, —CO—NH—, —CO—N(alkyl)-, and NR5;
• m is 0 to 3, inclusive;
• n is 0 to 3, inclusive;
• p is 0 to 2, inclusive;
• B is a 5 or 6 membered heteroaryl, or aryl, optionally saturated, or optionally substituted with R1, R2, or R12;
• X is selected from the group consisting of:
• N and C;
• Y and Z are independently selected from the group consisting of:
• N, C, CH, CR3, S, and O;
• R1 is selected from the group consisting of:
• hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from the group consisting of:
• S, SO, SO2, O, and NR6;
• wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optional substituted with, hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, NO2, OR5, OCOOR5, CO2R17 CON(R6)R7, COR6 SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from the group consisting of:
• S, SO, SO2, O, and NR6;
• R2 is selected from the group consisting of:
• halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON(R6)R7, NHCONHR6, CO2H, and haloalkyl;
• R1 and R2 may be taken together to form a 5 to 7 membered saturated or unsaturated carbocyclic ring optionally containing 0 to 3 heteroatoms selected from the group consisting of:
• N, O, or S, and wherein said ring is optionally substituted with R1;
• R3 is selected from the group consisting of:
• substituted or unsubstituted amidine, alkylamino, aminoalkyl, CONHR16, NH2, NHCOR6, and CH2NHCOR6;
• R4 is selected from the group consisting of:
• halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N(R8)R8′, NHR9, NHCOR9, NR9COR9, NHCO(OR9), NR9CO(OR9), NR8SO2R10, NHSO2N(R10)R10′, NR6CON(R10)R10′, COR9, CO2R8, CON(R8)R8′, wherein R8 and R8′ may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6, and wherein R10 and R10′ may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6 wherein said aryl, heterocyclic, heteroaryl, or alkenyl are optionally substituted with R9;
• R5 is selected from the group consisting of:
• hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclicalkyl, and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclicalkyl, or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of:
• OR14, N(R14)R14′ and glycols;
• R6 is independently selected from the group consisting of:
• hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
• R7 is independently selected from the group consisting of:
• hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
• R8 is independently selected from the group consisting of:
• hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
• R8′ is independently selected from the group consisting of:
• hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
• R9 is independently selected from the group consisting of:
• hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic, cycloalkyl, heterocyclicalkyl, haloalkyl, arylalkylamino, amino, aminoalkyl, aminoacyl, nitro, azido, and heteroarylalkyl, wherein alkyl, aryl, heteroaryl, aminoalkyl, or arylalkyl are optionally substituted with one or more radical selected from the group consisting of:
• alkylsulfonamide, sulfamyl, alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, isothiocyanate, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy, and heterocyclic optionally substituted with alkyl, alkylamino, aminoalkyl, hydroxyalkyl, and alkylaminoalkyl;
• R10 is independently selected from the group consisting of:
• hydrido, lower alkyl, heteroaryl, heterocyclic, haloalkyl, arylalkylamino, heteroarylalkyl, aryl, and arylalkyl, wherein aryl, heteroaryl, heterocyclic, or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, and heterocyclic,
• R10′ is independently selected from the group consisting of:
• hydrido, lower alkyl, heteroaryl, heterocyclic, haloalkyl, arylalkylamino, heteroarylalkyl, aryl, and arylalkyl, wherein aryl, heteroaryl, heterocyclic, or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, and heterocyclic,
• R11 is selected from the group consisting of:
• hydrido, halogen, haloalkyl, CN, CO2R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, and CONH2;
• R12 is selected from the group consisting of:
• hydrido, halogen, alkyl, and alkoxy;
• R13 is selected from the group consisting of:
• hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclicalkyl, and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclicalkyl, or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of:
• OR14, N(R14)R14′, and glycols;
• R14 is independently selected from the group consisting of:
• hydrido, and lower alkyl;
• R14′ is independently selected from the group consisting of:
• hydrido, and lower alkyl;
• R15 is selected from the group consisting of:
• hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl,;
• wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic;
• and
• R16 is independently selected from the group consisting of:
• hydrido, aryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, and alkoxyalkyl;
• with the proviso that when R1 is sulfamyl, then R4 is not halogen, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkylamido, N-monoarylamido, alkyl, N,N-dialkylamido, N-alkyl-N-arylamido, haloalkyl, hydrido, hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl, amino, alkylamino, heterocyclic, nitro, and acylamino, and/or when R4 is sulfamyl, then R1 is not sulfamyl, halogen, alkyl, alkoxy, hydroxyl and haloalkyl;
• or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof.