Substituted bicyclic heteroaryl compounds and their use as integrin antagonists

A compound of general formula (I):

• R1—Z1—Het—L1—Ar1—L2—Y (I)
• wherein:
• Het represents a saturated, partially saturated or fully unsaturated 8 to 10 membered bicyclic ring system containing at least one heteroatom selected from O, S or N, optionally substituted by one or more aryl group substituents;
• R1 represents aryl, heteroaryl, optionally substituted alkyl, alkenyl or alkynyl where each is optionally substituted by R2, —Z2R3, —Z3H, —C(═O)—R3, —NR4—C(═Z3)—R3, —NR4—C(═O)—OR3, —NR4SO2—R3, —SO2—NY1Y2, —NY1Y2 or —C(═Z3)—NY1Y2, or optionally substituted cycloalkyl or heterocycloalkyl where each is optionally substituted by R3, —Z2R3, —Z3H, —C(═O)—R3, —NR4—C(═Z3)—R3, —NR4—C(═O)—OR3, —NR4—SO2—R3, —SO2—NY1Y2, —NY1Y2 or —C(═Z3)—NY1Y2;
• R2 represents aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocycloalkyl;
• R3 represents alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl;
• R4 represents hydrogen or lower alkyl;
• R5 is a direct bond or an alkylene chain, an alkenylene chain or an alkynylene chain;
• R6 is a direct bond, cycloalkylene, heterocycloalkylene, arylene, heteroaryldiyl, —C(═Z3)—NR4—, —NR4—C(═Z3)—, —Z3—, —C(═O)—, —C(═NOR4)—, —NR4—, —NR4—C(═Z3)—NR4—, —SO2—NR4—, —NR4—SO2—, —O—C(═O)—, —C(═O)—O—, —NR4—C(═O)—O— or —O—C(═O)—NR4—;
• R7 is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
• R8 is alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, or alkyl substituted by aryl, an acidic functional group (or corresponding protected derivative), cycloalkyl, heteroaryl, heterocycloalkyl, —Z3H, —Z2R3, —C(═O)—NY3Y4 or —NY3Y4;
• R9 is hydrogen, R3 or alkyl substituted with alkoxy, cycloalkyl, hydroxy, mercapto, alkylthio or —NY3Y4;
• R10 is hydrogen or a group consisting amino acid side chains and corresponding protected derivatives, an acidic functional group or corresponding protected derivative, R3, —Z2R3, —C(═O)—R3, or —C(═O)—NY3Y4, or alkyl substituted by an acidic functional group or corresponding protected derivative or by R3, —Z2R3, —NY3Y4, —NH—C(═O)—R3, —C(═O)—R5—NH2, —C(═O)—Ar2—NH2, —C(═O)—R5—CO2H, or —C(═O)—NY3Y4;
• or R9 and R10 together with the atoms to which they attached form a 3- to 6-membered heterocycloalkyl ring;
• R11 is C1-6alkylene, optionally substituted by R3;
• R12 is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
• R13 is hydrogen, or alkyl optionally substituted by aryl, an acidic functional group or corresponding protected derivative, cycloalkyl, heteroaryl, heterocycloalkyl, —Z3H, —Z2R3, —C(═O)—NY3Y4 or —NY3Y4;
• Ar1 is heteroaryldiyl;
• Ar2 is arylene or heteroaryldiyl;
• L1 represents a —R5—R6— linkage;
• L2 represents:
• (i) a direct bond;
• (ii) an alkylene, alkenylene, alkynylene, cycloalkenylene, cycloalkylene, heteroaryldiyl, heterocycloalkylene or arylene linkage each optionally substituted by (a) an acidic functional group (or corresponding protected derivative), R3, —Z3H, —Z2R8, —C(═O)—R3, —N(R7)—C(═O)—R8, —N(R7)—C(═O)—OR8, —N(R7)—C(═O)—NR4R8, —N(R7)—SO2—R8, —NY3Y4, or —[C(═O)—N(R9)—C(R4)(R10)]p—C(═O)—NY3Y4, or by (b) alkyl substituted by an acidic functional group (or corresponding protected derivative), or by —Z3H, —Z2R3, —C(═O)—NY3Y4 or —NY3Y4;
• (iii) a —[C(═O)—N(R9)—C(R4)(R10)]p— linkage;
• (iv) a —Z4—R11— linkage;
• (v) a —C(═O)—CH2—C(═O)— linkage;
• (vi) a —R11—Z4—R11— linkage;
• or
• (vii) a —L3—L4—L5— linkage;
• L3 represents a direct bond and L5 represents an alkylene chain, or
• L3 represents an alkylene chain and L5 represents a direct bond or an alkylene chain;
• L4 represents a cycloalkylene or heterocycloalkylene linkage;
• Y is carboxy or an acid bioisostere;
• Y1 and Y2 are independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl;
• or the group —NY1Y2 may form a cyclic amine;
• Y3 and Y4 are independently hydrogen, alkenyl, alkyl, alkynyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, or alkyl substituted by alkoxy, aryl, cyano, cycloalkyl, heteroaryl, heterocycloalkyl, hydroxy, oxo, —NY1Y2, or one or more —CO2R7 or —C(═O)—NY1Y2 groups;
• or the group —NY3Y4 may form a 5- to 7-membered cyclic amine which (i) may be optionally substituted with one or more substituents selected from alkoxy, carboxamido, carboxy, hydroxy, oxo (or a 5-, 6- or 7-membered cyclic acetal derivative thereof), R8;
• (ii) may also contain a further heteroatom selected from O, S, SO2, or NY5;
• and (iii) may also be fused to additional aryl, heteroaryl, heterocycloalkyl or cycloalkyl rings to form a bicyclic or tricyclic ring system;
• Y5 is hydrogen, alkyl, aryl, arylalkyl, —C(═O)—R12, —C(═O)—OR12 or —SO2R12;
• Z1 represents a direct bond, an alkylene chain or NR4, O or S(O)n;
• Z2 is O or S(O)n;
• Z3is O or S;
• Z4 is O, S(O)n, NR13, SO2NR13, NR13C(═O), C(═O)NR13 or C(═O);
• and
• n is zero or an integer 1 or 2;
• p is zero or an integer 1 to 4;
• and the corresponding N-oxides, and their prodrugs;
• and pharmaceutically acceptable salts and solvates of such compounds and their N-oxides and prodrugs;
• but excluding compounds where an oxygen, nitrogen or sulphur atom is attached directly to a carbon carbon multiple bond of an alkenyl or alkynyl residue.