Oxazoles for treating cytokine mediated diseases

A compound of the formula:

• 9
• wherein:
• R1 and R2 are independently selected from an optionally substituted aryl or heteroaryl group, provided that at least one of R1 and R2 is an optionally substituted heteroaryl, and further provided that both R1 and R2 are not the same heteroaryl group;
• wherein when one of R1 and R2 is an optionally substituted aryl ring, the ring is substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl substituent, is halo, cyano, —C(Z)NR7R17, —C(Z)OR23, —(CR10R20)m COR36, —SR5, —SOR5, —OR36, halo-substituted-C1-4 alkyl, C1-4 alkyl, -ZC(Z)R36, —NR10C(Z)R23, or —(CR10R20)mNR10R20;
• and which, for other positions of substitution, is halo, —(CR OR20)m″-cyano, —C(Z)NR16R26, —C(Z)OR8, —(CR10R20)m″COR8, —(CR10R20)m′S(O)mR8, —(CR10R20)m′OR8, halo-substituted-C1-14 alkyl, —C1-4 alkyl, —(CR10R20)m″NR10C(Z)R8, —(CR10R20)m′NR10S(O)m, R11, —(CR10R20)m″NR10S(O)m′NR7R17, —(CR10R20)m″ZC(Z)R8 or —(CR10R20)m″NR16R26;
• and when one of R1 and R2 is an optionally substituted heteroaryl group, the substituent groups include one or two substituents each of which is independently selected from C1-4 alkyl, halo, C1-4 alkoxy, C1-4 alkylthio, NR10R20, or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR22;
• R3 is —XaP(Z)(XbR13)2, Xc or —(CR10R20)n R4;
• R4 is Q-(Y1)t;
• Q is an aryl or heteroaryl group;
• Xc is hydrogen, —(CR10R20)n (Y2)p, —(CR10R20)n—C≡C— (CR10R20)n(y2)p, —(CR10R20)n—C_C— (CR10R20)n (Y2)p, or halosubstituted C1-10 alkyl;
• t is an integer having a value of 1 to 3;
• p is 0 or an integer having a value of 1, provided that when p is 0 then Y2 is hydrogen;
• Xa is —NR8—, —O—, —S— or a C1-10 alkylene chain optionally substituted by C1-4 alkyl and optionally interrupted by —NR8—, —O— or —S—;
• Xb is independently selected from —(CR10R20)n, —NR8—, —O— or —S—;
• Z is oxygen or sulfur;
• n is 0 or an integer having a value of 1 to 10;
• n′ is an integer having a value of 1 to 10;
• m is 0, or the integer 1 or 2;
• m′ is 1 or 2;
• m″ is 0 or an integer having a value of 1 to 5;
• Y1 is independently selected from hydrogen, C1-5 alkyl, halo-substituted C1-5 alkyl, halogen, —Xa—P(Z)-(XbR13)2 or —(CR10R20)nY2;
• Y2 is halogen, —OR8, —NO2, —S(O)m′R11, —SR8, —S(O)m′NR8R9, —NR8R9, —O(CR10R20)n′NR8R9, —C(O)R8, —CO2R8, —CO2(CR10R20)n′CONR8R9, -ZC(O)R8, —CN, —C(Z)NR8R9, —NR10C(Z)R8, —C(Z)NR8OR9, —NR10C(Z)NR8R9, —NR10S(O)m′R11, —N(OR21)C(Z)NR8R9, —N(OR21)C(Z)R8, —C(═NOR21)R8—NR10C(═NR15)SR11, —NR OC(═NR15)NR8R9, —NR10C(═CR14R24)SR11, —NR10C(═CR14R24)NR8R9, —NR10C(O)C(O)NR8R9, —NR10C(O)C(O)OR10, —C(═NR13)NR8R9, —C(═NOR13)NR8R9, —C(═NR13)ZR11, —OC(Z)NR8R9;
• —NR10S(O)2CF3, —NR10C(Z)OR10, 5-(R18)-1,2,4-oxadizaol-3-yl or 4-(R12)-5-(R18R19)-4,5-dihydro-1,2,4-oxadiazol-3-yl;
• R5 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties —SR5 being —SNR7R17 and —SOR5 being —SOH;
• R6 is C1-4 alkyl, halo-substituted-C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or C3-cycloalkyl;
• R7 and R17 is each independently selected from hydrogen or C1-4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR22;
• R8 is hydrogen, heterocyclyl, heterocyclylalkyl or R11;
• R9 is hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or R8 and R9 may together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR12;
• R10 and R20 is each independently selected from hydrogen or C1-4 alkyl;
• R11 is C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
• R12 is hydrogen, —C(Z)R13 or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl;
• R13 is hydrogen, C1-10 alkyl, cycloalkyl, heterocyclyl, aryl” arylalkyl, heteroaryl or heteroarylalkyl;
• R14 and R24 is each independently selected from hydrogen, alkyl, nitro or cyano;
• R15 is hydrogen, cyano, C1-4 alkyl, C3-7 cycloalkyl or aryl;
• R16 and R26 is each independently selected from hydrogen or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR12;
• R18 and R19 is each independently selected from hydrogen, C1-4alkyl, substituted alky, optionally substituted aryl, optionally substituted arylalkyl or together R18 and R19 denote a oxygen or sulfur,
• R21 is hydrogen, a pharmaceutically acceptable cation, C1-10 alkyl, C3-7 cycloalkyl, aryl, aryl C1-4 alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or C1-10 alkanoyl;
• R22 is R10 or C(Z)-C1-4 alkyl;
• R23 is C1-4 alkyl, halo-substituted-C1-4 alkyl, or C3-5 cycloalkyl;
• R36 is hydrogen or R23;
• or a pharmaceutically acceptable salt thereof.