Benzoisothiazole-substituted compounds useful as IL-8 receptor antagonists

A compound of the formula:

• wherein
• R is —NH—C(X)—NH—(CR13R14)v—Z;
• Z is W, optionally substituted heteroaryl, optionally substituted C5-8 cycloalkyl, optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl;
• X is ═O, or ═S;
• A is CR20R21;
• R1 is independently selected from hydrogen;
• halogen;
• nitro;
• cyano;
• halosubstituted C1-10 alkyl;
• C1-10 alkyl;
• C2-10 alkenyl;
• C1-10 alkoxy;
• halosubstituted C1-10 alkoxy;
• azide;
• (CR8R8)qS(O)tR4, hydroxy;
• hydroxy C1-4alkyl;
• aryl;
• aryl C1-4 alkyl;
• aryloxy;
• arylC1-4 alkyloxy;
• heteroaryl;
• heteroarylalkyl;
• heterocyclic;
• heterocyclicC1-4alkyl;
• heteroarylC1-4 alkyloxy;
• arylC2-10 alkenyl;
• heteroarylC2-10 alkenyl;
• heterocyclicC2-10 alkenyl;
• (CR8R8)qNR4R5;
• C2-10alkenylC(O)NR4R5;
• (CR8R8)qC(O)NR4R5;
• (CR8R8)qC(O)NR4R10;
• S(O)3H;
• S(O)3R8;
• (CR8R8)qC(O)R11;
• C2-10 alkenylC(O)R 11;
• C2-10alkenylC(O)OR11;
• (CR8R8)qC(O)OR11;
• (CR8R8)qC(O)OR12;
• (CR8R8)qOC(O)R11;
• (CR8R8)qNR4C(O)R11;
• (CR8R8)qC(NR4) NR4R5;
• (CR8R8)qNR4C(NR5)R11;
• (CR8R8)qNHS(O)2R17;
• and (CR8R8)qS(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 containing rings may be optionally substituted;
• n is an integer having a value of 1 to 3;
• m is an integer having a value of 1 or 3;
• 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, or 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 and sulfur;
• Y is independently selected from hydrogen;
• halogen;
• nitro;
• cyano;
• halosubstituted C1-10 alkyl;
• C1-10 alkyl;
• C2-10 alkenyl;
• C1-10 alkoxy;
• halosubstituted C1-10 alkoxy;
• azide;
• (CR8R8)qS(O)tR4;
• hydroxy;
• hydroxyC1-4alkyl;
• aryl;
• aryl C1-4 alkyl;
• aryloxy;
• arylC1-4 alkyloxy;
• heteroaryl;
• heteroarylalkyl;
• heteroaryl C1-4 alkyloxy;
• heterocyclic, heterocyclicC1-4alkyl;
• aryl C2-10 alkenyl;
• heteroarylC2-10 alkenyl;
• heterocyclicC2-10alkenyl;
• (CR8R8)qNR4R5;
• C2-10alkenylC(O)NR4R5;
• (CR8R8)qC(O)NR4R5;
• (CR8R8)qC(O)NR4R10;
• S(O)3H;
• S(O)3R8;
• (CR8R8)qC(O)R11;
• C2-10 alkenylC(O)R11;
• C2-10alkenylC(O)OR11;
• (CR8R8)qC(O)OR11;
• (CR8R8)qC(O)OR12;
• (CR8R8)qOC(O)R11;
• (CR8R8)qNR4C(O)R11;
• (CR8R8)qC(NR4) NR4R5;
• (CR8R8)qNR4C(NR5)R11;
• (CR8R8)qNHS(O)2R18;
• and (CR8R8)qS(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 containing rings, may be optionally substituted;
• 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 which heteroatom is selected from oxygen, nitrogen and sulfur;
• R8 is independently 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 an optionally substituted aryl;
• R15 and R16 are independently hydrogen, or an optionally substituted C1-4 alkyl;
• R17 is C1-4alkyl, arylalkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;
• R18 is NR6R7, alkyl, arylC1-4 alkyl, arylC2-4alkenyl, heteroaryl, heteroaryl-C1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC1-4 alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;
• R20 and R21 are independently halogen, cyano, halosubstituted C1-10alkyl, C3-10alkyl, aryl, aryl C1-4 alkyl, heteroaryl;
• heteroarylalkyl, heterocyclic, heterocyclic C1-4alkyl, (CR8R8)qOR4, (CR8R8)qC(O)R11, (CR8R8)qC(O)OR11, (CR8 R8)qC(O)OR12;
• (CR8R8)qOC(O)R11, (CR8R8)qNR4R5, (CR8R8)qNR4C(O)R11, or (CR8R8)qC(O)NR4R5, or together R20 and R21 may form ═R22;
• and wherein the aryl, heteroaryl, and heterocyclic containing rings may be optionally substituted;
• R22 is a C1-4 alkyl, aryl C1-4 alkyl, heteroarylalkyl, or heterocyclic C1-4alkyl, such that attachment is through the alkyl moiety, where present, and wherein all of these moieties may be optionally substituted;
• W is
• or
• the E containing ring is selected from
• and
• the asterix * denoting point of attachment of the ring;
• or a pharmaceutically acceptable salt thereof.