Tetrahydroisoquinoline analogs as modulators of chemokine receptor activity

A method of treating chemokinereceptor-mediated disorders comprising administering to a patient in need thereof a therepeutically effective amount of at least one compound of formula I

• including enantiomers, diastereomers, and salts thereof, wherein
• R1 is alkyl, aryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, arylcycloalkyl cycloalkylalkyl, cycloalkyl-alkoxy, alkoxyalkyl, alkylthioalkyl, aryloxyalkyl, arylalkoxyalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, or heteroarylalkyl, and where these groups may be optionally substituted with 1 to 3 J1 groups which may be the same or different and the R1 aryls may be further optionally substituted with 1 to 5 halogens, aryl, —CF3, —OCF3, 1-3 hydroxyls, 2 of which substituents where possible, may be joined by a methylene bridge;
• R2 is H, alkyl, aryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, aryloxyalkyl, arylalkoxyalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkylalkoxy, heteroaryl, or heteroarylalkyl, and where these groups may be optionally substituted with a J1a group and the aryls may be further optionally substituted with 1 to 5 halogens, —CF3, —OCF3, or 1-3 hydroxyls;
• X is a bond, —O—, or —NR4—;
• R3 and R3a are the same or different and are independently selected from H, alkoxy, halogen, —CF3, alkyl, or aryl;
• R4, R4a, R4b, R4c, R4d, R4e, R4f, R4g, R4h, R4i, R4j, R4k, and R4l are the same or different and are independently selected from H, C1-C6alkyl, or aryl;
• m, n and p are the same or different and are independently 0 or 1;
• Y is a bond,
• where x and y are the same or different and are independently 0 to 3 and z is 1 to 3;
• R5 and R5a are the same or different and are independently H, alkyl, alkoxy, hydroxyl, halogen, —CF3, aryl, alkaryl, and cycloalkyl;
• or R5 and R5a can be independently joined to one or both of R6 and R7 groups (see X2) to form an alkylene bridge of 1 to 5 carbon atoms;
• or R5 and R5a can be joined together to form a ring of from 4-7 carbon atoms;
• X2 is aryl optionally substituted with 1 to 3 J1 groups which may be the same or different, cycloheteroalkyl optionally substituted with 1 to 3 J1 groups which may be the same or different, pyridinyl optionally substituted with 1 to 3 J1 groups which may be the same or different,
• R6 and R7 are the same or different and are independently H or alkyl where the alkyl may be optionally substituted with halogen, 1 to 3 hydroxys, 1 to 3 C1-C10alkanoyloxy, 1 to 3 C1-C6 alkoxy, phenyl, phenoxy, or C1-C6alkoxycarbonyl;
• or R6 and R7 can together form —(CH2)tX5(CH2)u— where X5 is —C(R4c)(R4d)—, —C(R4c)(NT1T1a)—, —O— or —N(R4e)—, t and u are the same or different and are independently 0 to 4;
• R8 is H, C1-C6alkyl, —CF3, alkaryl, or aryl, and wit h the alkyl and aryl groups being optionally substituted with 1 to 3 hydroxys, 1 to 3 C1-C10alkanoyloxy, 1 to 3 C1-C6 alkoxy, phenyl, phenoxy or C1-C6alkoxycarbonyl;
• R9 and R10 are the same or different and are independently H, C1-C6alkyl, —CF3, alkaryl, aryl, or halogen, and with the alkyl and aryl groups being optionally substituted with 1 to 3 hydroxys, 1 to 3 C1-C10 alkanoyloxy, 1 to 3 C1-6 alkoxy, phenyl, phenoxy or C1-C6 alkoxycarbonyl;
• X3 is a bond, —C(O)—, —C(O)O—, —C(O)N(R4f)—, —S(O)2—, or —S(O)2N(R4f)—;
• X4 is a bond, —O—, —OC(O)—, —N(R4g)—, —N(R4g)C(O)—, —N (R4g)C(O)N(R4h)—, —N(R4g)S(O)2—, —N(R4g)S(O)2N(R4h), —OC(O)N(R4g)—, —C(O)—, —C(O)N(R4g)—, —S—, —S(O)2—, or —S(O)2N(R4g)—;
• J1 and J1a are the same or different and are independently nitro, halogen, hydroxyl, —OCF3, —CF3, alkyl, aryl, —(CH2)v CN, —(CH2)vN(T1a)C(O)T1, —(CH2)vN(T1a)C(O)OT1, —(CH2)vN(T1a)C(O)N(T1a)T1, —(CH2)vNT1(T1a), —(CH2)vN(T1a)SO2T1, —(CH2)vC(O)N(T1)T1, —(CH2)vC(O)OT1, —(CH2)vOC(O)OT1, —(CH2)vOC(O)T1, —(CH2)vOC(O)OT1, —(CH2)vOC(O)T1, —(CH2)vOC(O)N(T1a)T1, —(CH2)vN(T1a)SO2N(T1b)T1, —(CH2)vOT1, —(CH2)vSO2T1, —(CH2)vSO2N(T1a)T1, —(CH2)vC(O)T1, —(CH2)vCH(OH)T1, or heteroaryl as defined below, with v being 0-3;
• T1, T1a and T1b are the same or different and are independently H, alkyl, alkenyl, alkynyl, lower alkythioalkyl, alkoxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, or cycloalkyl, each of which may be optionally substituted with halogen, hydroxyl, —C(O)NR4iR4j, —NR4iC(O)R4j, —CN, —N(R4i)SO2R11, —OC(O)R4i, —SO2 NR4iR4j, —SOR11, —SO2R11, alkoxy, —COOH, cycloheteroalkyl, or —C(O)OR11;
• with the proviso that T1 cannot be hydrogen when it is connected to sulfur, as in SO2T1;
• or T1 and T1a or T1 and T1b can together form —(CH2)rX5a(CH2)s— where X5a is —C(R4k)(R4l)—, —C(R4k)(NT1T1a)—, —O— or —N(R4k)—, r and s are the same or different and are independently 0 to 4;
• R11 is C1-C6alkyl or aryl;
• with the proviso that
• (1) where m is O and n is 1, the moiety —X4—R2 is other than alkyl or alkoxy;
• and
• (2) where X is a bond and X2 is amino, then m is 1.