IL-8 receptor antagonists

A method of treating a chemokine mediated disease state, wherein the chemokine binds to an IL-8 α or β receptor in a mammal, which comprises administering to said mammal an effective amount of a compound of the formula:

• wherein
• Z is cyano, OR11, C(O)NR15R16, R18, C(O)R11, C(O)OR11, or S(O)2R17;
• R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
• R1 is independently selected from hydrogen;
• halogen;
• nitro;
• cyano;
• halosubstituted C1-10 alkyl;
• C1-10 alkyl;
• C2-10 alkenyl;
• C1-10 alkoxy;
• halosubstitutedC1-10alkoxy;
• azide;
• (CR8R8)q S(O)tR4;
• hydroxy;
• hydroxyC1-4alkyl;
• aryl;
• arylC1-4alkyl;
• aryloxy;
• aryl C1-4 alkyloxy;
• heteroaryl;
• heteroarylalkyl;
• heterocyclic, heterocyclic C1-4alkyl;
• heteroaryl C1-4 alkyloxy;
• aryl C2-10 alkenyl;
• heteroaryl C2-10 alkenyl;
• heterocyclic C2-10 alkenyl;
• (CR8R8)qNR4R5;
• C2-10alkenylC(O)NR4R5;
• (CR8R8)q C(O)NR4R5;
• (CR8R8)qC(O)NR4R10;
• S(O)3R8;
• (CR8R8)q C(O)R11;
• C2-10alkenyl C(O)R11;
• C2-10alkenylC(O)OR11;
• (CR8R8)q C(O)OR12;
• (CR8R8)q OC(O) R11;
• (CR8R8)qNR4C(O)R11;
• (CR8R8)qNHS(O)2R19;
• (CR8R8)q S(O)2NR4R5;
• or two R1 moieties together may form O—(CH2)sO— or a 5 to 6 membered saturated or unsaturated ring, and wherein the aryl, heteroaryl and heterocyclic moieities may be optionally substituted;
• q is 0, or an integer having a value of 1 to 10;
• t is 0, or an integer having a value of 1 or 2;
• s is an integer having a value of 1 to 3;
• v is 0, or an integer having a value of 1 to 4;
• R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, heterocyclic C1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from oxygen, nitrogen or sulfur;
• Y is independently selected from hydrogen;
• halogen;
• nitro;
• cyano;
• halosubstituted C1-10 alkyl;
• C1-10 alkyl;
• C2-10 alkenyl;
• C1-10 alkoxy;
• halosubstitutedC1-10alkoxy;
• azide;
• (CR8R8)q S(O)tR4;
• hydroxy;
• hydroxyC1-4alkyl;
• aryl;
• arylC1-4alkyl;
• aryloxy;
• arylC1-4 alkyloxy;
• heteroaryl;
• heteroarylalkyl;
• heteroarylC1-4alkyloxy;
• heterocyclic, heterocyclic C1-4alkyl;
• arylC2-10 alkenyl;
• heteroarylC2-10 alkenyl;
• heterocyclic C2-10 alkenyl;
• (CR8R8)qNR4R5;
• C2-10 alkenyl C(O)NR4R5;
• (CR8R8)q C(O)NR4R5;
• (CR8R8)qC(O)NR4R10;
• S(O)3R8;
• (CR8R8)q C(O)R11;
• C2-10alkenylC(O)R11;
• C2-10 alkenyl C(O)OR11;
• C(O)R11;
• (CR8R8)qC(O)OR12;
• (CR8R8)qOC(O) R11;
• (CR8R8)q NR4C(O)R11;
• (CR8R8)qNHS(O)2Rd;
• (CR8R8)q S(O)2NR4R5;
• or two Y moieties together may form O—(CH2)sO— or a 5 to 6 membered saturated or unsaturated ring, and wherein the aryl, heteroaryl and heterocyclic moieities may be optionally substituted;
• n is an integer having a value of 1 to 3;
• m is an integer having a value of 1 to 3;
• R6 and R7 are independently hydrogen or a C1-4 alkyl group;
• or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom selected from oxygen, nitrogen or sulfur;
• R8 is independently selected from hydrogen or C1-4 alkyl;
• R10 is C1-10 alkyl C(O)2R8;
• R11 is hydrogen, C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC1-4alkyl;
• R12 is hydrogen, C1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;
• R13 and R14 are independently hydrogen, optionally substituted C1-4 alkyl or one of R13 and R14 may be optionally substituted aryl;
• R15 and R16 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, optionally substituted heterocyclicC1-4alkyl, or R15 and R16 may together with the nitrogen to which they are attached form a 5 to 7 member ring optionally containing an additional heteroatom selected from oxygen, nitrogen, or sulfur;
• R17 is C1-4 alkyl, NR15R16, OR11, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC1-4alkyl;
• R18 is optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC1-4alkyl;
• R19 is C1-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl, wherein the all of these moieties may be optionally substituted;
• Rd is NR6R7, alkyl, arylC1-4 alkyl, arylC2-4 alkenyl, heteroaryl, hetroaryl—C1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclicC1-4 alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, and heterocyclic alkyl rings may be optionally substituted;
• the E′ containing ring may be absent or present, and when present, is selected from
• the E containing ring may be absent or present, and when present, is selected from
• or a pharmaceutically acceptable salt thereof.