Piperidinyl piperidine derivatives useful as inhibitors of chemokine receptors

A compound in isolated and pure form, said compound represented by the structural formula IB

• or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
• Y is selected from the group consisting of R—X— and —N(R20)(R21);
• X is selected from the group consisting of —C(R13)2—, —C(R13)(R19)—, —C(O)—, —O—,
• R is selected from the group consisting of R6-phenyl, R6-pyridyl, R6-thiophenyl, R6-naphthyl, and
• n is 0, 1, 2, 3 or 4;
• s is 0, 1, 2, 3 or 4;
• t is 1, 2, 3 or 4
• L and M are independently selected from the group consisting of CH and N;
• R1 is selected from the group consisting of hydrogen, alkyl, and allkenyl;
• R2 is selected from the group consisting of
• R3 is selected from the group consisting of R6-phenyl, R6-heteroaryl and R6-naphthyl;
• R4 is selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cyclopropylmethyl, —CH2CH2OH, —CH2CH2Oalkyl, —CH2C(O)—O-alkyl, —CH2C(O)NH2, —CH2C(O)—NHalkyl, and —CH2C(O)—N(alkyl)2;
• R5 is selected from the group consisting of hydrogen and alkyl;
• R6 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF3, CF3O—, CH3C(O)—, —CN, CH3SO2—, CF3SO2—, R14-phenyl, R14-benzyl, CH3C(═NOCH3)—, CH3C(═NOCH2CH3)—,
• —NH2, —NHCOCF3, NHCONHalkyl, —NHC(O)alkyl, —NHS(O2)alkyl, 5-membered heteroaryl and
• wherein W is —O—, —NH— or —N(CH3)—;
• each R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, —NR11R12, —OH, —CF3, —O-alkyl, —O-acyl, and —O-haloalkyl;
• R9 is selected from the group of consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, acyl, heteroaryl, arylalkyl-, and heterocyclyl;
• R11, R12, each R13, each R14, R15, R16, and R32 are independently selected from the group consisting of hydrogen and alkyl;
• R19 is selected from the group consisting of R6-phenyl, R6-heteroaryl, R6-naphthyl, cycloalkyl, cycloalkylalkyl, and alkoxyalkyl;
• R20 is selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, alkyl-C(O)—, aryl-C(O)—, haloalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, alkylsulfonyl, arylsulfonyl, alkoxysulfonyl, alkoxyalkyl, and —N(R13)C(O)alkyl;
• R21 is selected from the group consisting of:
• p is a number from 0-4;
• q is a number from 0-4;
• T is selected from the group consisting of aryl and heteroaryl, each of said aryl and heteroaryl being optionally independently substituted with R24 and R25;
• R22 is selected from the group consisting of hydrogen, arylalkyl, alkyl, R26-arylalkyl-, R26-heteroarylalkyl-, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, R26-arylsulfonyl-, —C(O)-alkyl, —C(O)-cycloalkyl, R26-aryl-C(O)—, —C(O)NR27R28, and —SO2NR27R28;
• R23 is selected from the group consisting of hydrogen, alkyl, and haloalkyl;
• R24 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, arylalkyl, heteroarylalkyl, alkyl-C(O)—, aryl-C(O)—, alkylsulfonyl, arylsulfonyl, alkoxyalkyl, —N(R13)C(O)alkyl, and —C(O)N(R13)2;
• R25 is selected from the group consisting of alkyl-C(O)-heterocyclyl, -alkyl-CN, -alkyl-N(R13)C(O)-alkyl-NR29R30, -alkyl-N(R13)C(O)-alkyl(aryl)-NR29R30, -alkyl-N(R13)C(O)-heterocyclyl, -alkyl-N(R13)C(O)-heteroalkyl, -alkyl-N(R13)C(O)— arylhydroxyalkyl, -alkyl-N(R13)C(O)—C(O)(aryl), -alkyl-N(R13)C(O)—C(O)alkyl, -alkyl-N(R13)C(O)—C(O)-heteroaryl, heterocyclyl, -alkyl-O—C(O)Z, -alkyl-S(O2)-alkyl-NR29R30, -haloalkyl-C(O)OR30, -haloalkyl-C(O)N(R30R31), -alkyl-S(O2)R30, —S(O2)— (hydroxyalkyl), -alkyl-C(O)R30, -alkyl-C(R30)(═N—OR31), —N(R13)C(O)-alkyl-N(CHR29R30), and —S(O2)heterocyclyl;
• Z is selected from the group consisting of heterocyclyl, NR30R31, —O(alkyl), —O(cycloalkyl) and —OH;
• R26 is 1, 2, or 3 substituents independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, —CF3, —OCF3, CH3C(O)—, —CN, CH3SO2—, CF3SO2—, and —NH2;
• R27 is selected from the group consisting of H, alkyl and cycloalkyl;
• R28 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl and arylalkyl;
• or R27 and R28 together are (C2-C6) alkyl and form a ring with the nitrogen atom to which they are shown attached;
• R29 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, hydroxyalkyl, aryl, heteroaryl, alkyloxy, alkylsulfonyl, cycloalkylsulfonyl, alkylarylsulfonyl, arylsulfonyl, C(O)alkyl, C(O)aryl, C(O)arylalkyl, C(O)cyclalkyl and —C(O)NR30R31;
• each R30 and R31 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, and heteroaryl;
• and
• R33 is selected from the group consisting of hydrogen, -alkyl, fluoroalkyl-, R9-arylalkyl-, R9-heteroaryl-, alkylsulfonyl-, cycloalkylsulfonyl, fluoroalkylsulfonyl, R9-arylsulfonyl-, R9-heteroarylsulfonyl-, N(R22)(R23)—SO2—, alkyl-C(O)—, cycloalkylC(O)—, fluoroalkyl-C(O)—, R9-aryl-C(O)—, alkyl-NH—C(O)— or R9-aryl-NH—C(O)—.

A process for preparing a compound represented by the structural formula IC:

• or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
• Y is selected from the group consisting of R—X— and —N(R20)(R21);
• X is selected from the group consisting of —C(R13)2—, —C(R13)(R19)—, —C(O)—, —O—,
• R is selected from the group consisting of R6-phenyl, R6-pyridyl, R6-thiophenyl, R6-naphthyl, and
• n is 0, 1, 2, 3 or 4;
• s is 0, 1, 2, 3 or 4;
• t is 1, 2, 3 or 4
• L and M are independently selected from the group consisting of CH and N;
• R1 is selected from the group consisting of hydrogen, alkyl, and allkenyl;
• R2 is selected from the group consisting of
• R3 is selected from the group consisting of R6-phenyl, R6-heteroaryl and R6-naphthyl;
• R4 is selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cyclopropylmethyl, —CH2CH2OH, —CH2CH2Oalkyl, —CH2C(O)—O-alkyl, —CH2C(O)NH2, —CH2C(O)—NHalkyl, and —CH2C(O)—N(alkyl)2;
• R5 is selected from the group consisting of hydrogen and alkyl;
• R6 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF3, CF3O—, CH3C(O)—, —CN, CH3SO2—, CF3SO2—, R14-phenyl, R14-benzyl, CH3C(═NOCH3)—, CH3C(═NOCH2CH3)—,
• —NH2, —NHCOCF3, NHCONHalkyl, —NHC(O)alkyl, —NHS(O2)alkyl, 5-membered heteroaryl and
• wherein W is —O—, —NH— or —N(CH3)—;
• each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, halogen, —NR11R12, —OH, —CF3, —O-alkyl, —O-acyl, and —O-haloalkyl;
• R9 is selected from the group of consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, acyl, heteroaryl, arylalkyl-, and heterocyclyl;
• R11, R12, each R13, each R14, R15, R16, and R32 are independently selected from the group consisting of hydrogen and alkyl;
• R19 is selected from the group consisting of R6-phenyl, R6-heteroaryl, R6-naphthyl, cycloalkyl, cycloalkylalkyl, and alkoxyalkyl;
• R20 is selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl, alkyl-C(O)—, aryl-C(O)—, haloalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, alkylsulfonyl, arylsulfonyl, alkoxysulfonyl, alkoxyalkyl, and
• —N(R13)C(O)alkyl;
• R21 is selected from the group consisting of:
• p is a number from 0-4;
• q is a number from 0-4;
• T is selected from the group consisting of aryl and heteroaryl, each of said aryl and heteroaryl being optionally independently substituted with R24 and R25;
• R22 is selected from the group consisting of hydrogen, arylalkyl, alkyl, R26-arylalkyl-, R26-heteroarylalkyl-, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, R26-arylsulfonyl-, —C(O)-alkyl, —C(O)-cycloalkyl, R26-aryl-C(O)—, —C(O)NR27R28, and —SO2NR27R28;
• R23 is selected from the group consisting of hydrogen, alkyl, and haloalkyl;
• R24 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, arylalkyl, heteroarylalkyl, alkyl-C(O)—, aryl-C(O)—, alkylsulfonyl, arylsulfonyl, alkoxyalkyl, —N(R13)C(O)alkyl, and —C(O)N(R13)2;
• R25 is selected from the group consisting of alkyl-C(O)-heterocyclyl, -alkyl-CN, -alkyl-N(R13)C(O)-alkyl-NR29R30, -alkyl-N(R13)C(O)-alkyl(aryl)-NR29R30, -alkyl-N(R13)C(O)-heterocyclyl, -alkyl-N(R13)C(O)-heteroalkyl, -alkyl-N(R13)C(O)— arylhydroxyalkyl, -alkyl-N(R13)C(O)—C(O)(aryl), -alkyl-N(R13)C(O)—C(O)alkyl, -alkyl-N(R13)C(O)—C(O)-heteroaryl, heterocyclyl, -alkyl-O—C(O)Z, -alkyl-S(O2)-alkyl-NR29R30, -haloalkyl-C(O)OR30, -haloalkyl-C(O)N(R30R31), -alkyl-S(O2)R30, —S(O2)— (hydroxyalkyl), -alkyl-C(O)R30, alkyl-C(R30)(═N—OR31), —N(R13)C(O)-alkyl-N(CHR29R30), and —S(O2)heterocyclyl;
• Z is selected from the group consisting of heterocyclyl, NR30R31, —O(alkyl), —O(cycloalkyl) and —OH;
• R26 is 1, 2, or 3 substituents independently selected from the group consisting of hydrogen, halo, alkyl, alkoxy, —CF3, —OCF3, CH3C(O)—, —CN, CH3SO2—, CF3SO2—, and —NH2;
• R27 is selected from the group consisting of H, alkyl and cycloalkyl;
• R28 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl and arylalkyl;
• or R27 and R28 together are (C2-C6) alkyl and form a ring with the nitrogen atom to which they are shown attached;
• R29 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, hydroxyalkyl, aryl, heteroaryl, alkyloxy, alkylsulfonyl, cycloalkylsulfonyl, alkylarylsulfonyl, arylsulfonyl, C(O)alkyl, C(O)aryl, C(O)arylalkyl, C(O)cyclalkyl and —C(O)NR30R31;
• each R30 and R31 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, and heteroaryl;
• R33 and R36 are independently selected from the group consisting of hydrogen, -alkyl, fluoroalkyl-, R9-arylalkyl-, R9-heteroaryl-, alkylsulfonyl-, cycloalkylsulfonyl, fluoroalkylsulfonyl, R9-arylsulfonyl-, R9-heteroarylsulfonyl-, N(R22)(R23)—SO2—, alkyl-C(O)—, cycloalkylC(O)—, fluoroalkyl-C(O)—, R9-aryl-C(O)—, alkyl-NH—C(O)— or R9-aryl-NH—C(O)—;
• R34 is selected from the group consisting of R35O— and R35R36N—;
• each R35 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aralkyl, alkylaryl, aryl, and heteroaryl;
• comprising reacting a reacting an amine of the formula
• with a carboxylic acid of formula R2COOH or an acid chloride of formula R2C(O)Cl, wherein Y, R1, R2, R14, R15 and R16 are as set forth in formula IC.