New ccr2 receptor antagonists and uses thereof

A method for the treatment of a CCR2 mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I)

• wherein:
• R1 is selected from —H, -halogen, —CN, —O—C1-C4-alkyl, —C1-C4-alkyl, —CH═CH2, —C≡CH, —CF3, —OCF3, —OCF2H, and —OCFH2;
• R7 is a ring selected from —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C5-C10-aryl, and —C5-C10-hetero aryl,
• wherein the ring R7 is optionally substituted with one or more groups selected from —CF3, —O—CF3, —S—CF3, —CN, —C1-C6-alkyl, —C(CH3)2—CN, and -halogen,
• or wherein the ring R7 is optionally substituted with one or more groups selected from —C1-C6-alkyl, —O—C1-C6-alkyl, —C5-C10-aryl, —C5-C10-hetero aryl, —C3-C8-cyclo alkyl, —C3-C8-heterocyclyl, —C2-C6-alkenyl, and —C2-C6-alkynyl, optionally being substituted by one or more groups selected from —OH, —NH2, —C1-C3-alkyl, —O—C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, -methyl, and ═O;
• R2 is selected from —H, -halogen, —CN, —O—C2-C4-alkyl, —C1-C4-alkyl, —CH═CH2, —C≡CH, —CF3, —OCF3, —OCF2H, and —OCFH2;
• R3 is selected from —H, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, —OCH3, —CF3, and —CN;
• n is 2;
• G and E are independently selected from C—H or N, wherein at least one of E or G is N;
• Z is C,
• and R4 and R5 are independently selected from —H, —C1-C6-alkyl, —NH2, —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C5-C10-aryl, —C5-C10-heteroaryl, and —C(O)—N(R8,R8′), with R8 and R8′ independently being selected from —H, and —C1-C6-alkyl;
• and R4 and R5 if different from —H are optionally independently substituted with one or more groups selected from -halogen, —OH, —CF3, —CN, —C1-C6-alkyl, —O—C1-C6-alkyl, —O—C3-C8-cycloalkyl, —O—C3-C8-heterocyclyl, —O—C5-C10-aryl, —O—C5-C10-heteroaryl, —C0-C6-alkylene-CN, —C0-C4-alkylene-O—C1-C4-alkyl, —C0-C4-alkylene-O—C3-C8-cycloalkyl, —C0-C4-alkylene-O—C3-C8-heterocyclyl, —C0-C4-alkylene-O—C5-C10-aryl, —C0-C4-alkylene-O—C5-C10-heteroaryl, —C0-C4-alkylene-Q-C0-C4-alkyl-N(R9,R9′), —C0-C4-alkylene-N(R10)-Q-C1-C4-alkyl, —C0-C4-alkylene-N(R10)-Q-C3-C8-cycloalkyl, —C0-C4-alkylene-N(R10)-Q-C3-C8-heterocyclyl, —C0-C4-alkylene-N(R10)-Q-C5-C10-aryl, —C0-C4-alkylene-N(R10)-Q-C5-C10-heteroaryl, —C0-C4-alkylene-Q-N(R11,R11′), —C0-C4-alkylene-N(R12)-Q-N(R13,R13′), —C0-C4-alkylene-R14, —C0-C4-alkylene(R20,R20′), —C0-C4-alkylene-Q-C1-C6-alkyl, —C0-C4-alkylene-Q-C3-C8-cycloalkyl, —C0-C4-alkylene-Q-C3-C8-heterocyclyl, —C0-C4-alkylene-Q-C5-C10-aryl, —C0-C4-alkylene-Q-C5-C10-heteroaryl, —C0-C4-alkylene-O-Q-N(R15,R15′), and —C0-C4-alkylene-N(R16)-Q-O—(R17);
• wherein Q is selected from —C(O)—, and —SO2—;
• R10, R12, R16, are independently selected from —H, —C1-C6-alkyl, and —C3-C6-cycloalkyl, wherein R9, R9′, R11, R11′, R13, R13′, R15, R15′, are independently selected from —H, —C1-C6-alkyl, and —C3-C6-cycloalkyl, or
• R9 and R9′, R11 and R11′, R13 and R13′, R15 and R15′ together form a —C2-C6-alkylene group;
• R14 and R17 are independently selected from —H, —C1-C6-alkyl, —C5-C10-aryl, —C5-C10-heteroaryl, —C3-C8-cycloalkyl, and —C3-C8-heterocyclyl, wherein said —C3-C8-heterocyclyl optionally comprises nitrogen and/or —SO2— in the ring;
• wherein R14 and R17 are optionally substituted with one or more groups selected from —OH, —OCH3, —CF3, —COOH, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —SO2—C1-C4-alkyl;
• and
• R20 and R20′ together form a spiro-C3-C8-carbocycle or spiro-C3-C8-heterocycle comprising one or more group selected from O in the ring, and wherein said spirocycle is optionally further bi-valently substituted by an annellated ring forming group selected from —C1-C6-alkylene, —C2-C6-alkenylene, and —C4-C6-alkynylene and wherein said spirocycle is optionally further substituted with one or more groups selected from —OH, —OCH3, —CF3, —COOH, —OCF3, —CN, -halogen;
• or Z is C,
• and R4 denotes —H and R5 is a group of the structure -L1-R18,
• wherein L1 is selected from —NH—, —N(C1-C4-alkyl)-, and a bond,
• R18 is selected from —C5-C10-aryl, —C5-C10-heteroaryl, —C3-C8-cycloalkyl, and —C3-C8-heterocyclyl, wherein
• R18 is optionally substituted by one or more groups selected from halogen, —CF3, —OCF3, —CN, —OH, —O—C1-C4-alkyl, —C1-C6-alkyl, —NH—C(O)—C1-C6-alkyl, —N(C1-C4-alkyl)-C(O)—C1-C6-alkyl, —C(O)—C1-C6-alkyl, —S(O)2—C1-C6-alkyl, —NH—S(O)2—C1-C6-alkyl, —N(C1-C4-alkyl)-S(O)2—C1-C6-alkyl, and —C(O)—O—C1-C6-alkyl,
• and R4, R5 and R18 are optionally further substituted by spiro-C3-C8-cycloalkyl or spiro-C3-C8-heterocyclyl such that together with R4, R5 and/or R18 a spirocycle is formed, wherein said spiro-C3-C8-heterocyclyl optionally comprises one or more groups selected from nitrogen, —C(O)—, —SO2—, and —N(SO2—C1-C4-alkyl)- in the ring;
• and
• R6 is selected from —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
• or
• an acid addition salt with a pharmacologically acceptable acid.