Dpp-IV Inhibitors

A compound of the formula (I)

• or a pharmaceutically acceptable salt thereof, wherein a dotted line indicates an optionally present double bond and wherein
• Z is selected from the group consisting of phenyl;
• naphthyl;
• indenyl;
• C3-7 cycloalkyl;
• indanyl;
• tetralinyl;
• decalinyl;
• heterocycle;
• and heterobicycle, wherein Z is optionally substituted with one or more R10, wherein R10 is independently selected from the group consisting of halogen;
• CN;
• OH;
• NH2;
• oxo (═O), where the ring is at least partially saturated;
• R11;
• and R12;
• R11 is selected from the group consisting of C1-6 alkyl;
• O—C1-6 alkyl;
• and S—C1-6 alkyl, wherein R11 is optionally interrupted by oxygen and wherein R11 is optionally substituted with one or more halogen independently selected from the group consisting of F;
• and Cl;
• R12 is selected from the group consisting of phenyl;
• heterocycle;
• and C3-7 cycloalkyl, wherein R12 is optionally substituted with one or more R13, wherein R13 is independently selected from the group consisting of halogen;
• CN;
• OH;
• NH2;
• oxo (═O), where the ring is at least partially saturated;
• C1-6 alkyl;
• O—C1-6 alkyl;
• and S—C1-6 alkyl;
• R1, R4 are independently selected from the group consisting of H;
• F;
• and R14;
• R2, R5, R6, R7 are independently selected from the group consisting of H;
• F;
• and R15;
• R14 is independently selected from the group consisting of C1-6 alkyl;
• O—C1-6 alkyl;
• N(R14a)—C1-6 alkyl;
• S—C1-6 alkyl;
• C3-7 cycloalkyl;
• O—C3-7 cycloalkyl;
• N(R14a)—C3-7 cycloalkyl;
• S—C3-7 cycloalkyl;
• —C1-6 alkyl-C3-7 cycloalkyl;
• O—C1-6 alkyl-C3-7 cycloalkyl;
• N(R14a)—C1-6, alkyl-C3-7, cycloalkyl;
• S—C1-6 alkyl-C3-7 cycloalkyl;
• heterocycle;
• O-heterocycle;
• N(R14a)heterocycle;
• S-heterocycle;
• C1-6 alkyl-heterocycle;
• O—C1-6 alkyl-heterocycle;
• N(R14a)—C1-6 alkyl-heterocycle;
• S—C1-6 alkyl-heterocycle;
• wherein R14 is optionally substituted with one or more halogen independently selected from the group consisting of F;
• and Cl;
• R14a is selected from the group consisting of H;
• and C1-6 alkyl;
• optionally R6 is selected from the group consisting of —C(R6aR6b)—O—C1-6 alkyl;
• —C(R6aR6)—O—C7 cycloalkyl;
• —C(R6aR6b)—S—C1-6 alkyl;
• —C(R6aR6b)—S—C3-7 cycloalkyl;
• —C(R6aR6b)—N(R6c)—C1-6 alkyl;
• and —C(R6aR6b)—N(R6c)—C3-7 cycloalkyl, wherein each C1-6 alkyl and C3-7 cycloalkyl is optionally substituted with one or more R6d, wherein R6d is independently selected from the group consisting of halogen;
• C1-6 alkyl;
• and C3-7 cycloalkyl;
• R6a, R6b, R6c are independently selected from the group consisting of H;
• and C1-6 alkyl;
• R15 is independently selected from the group consisting of C1-6 alkyl;
• C3-7 cycloalkyl;
• and —C1-6 alkyl-C3-7 cycloalkyl, wherein R15 is optionally substituted with one or more R15a, wherein R15a is independently selected from the group consisting of F;
• Cl;
• and OH;
• R3 is selected from the group consisting of H;
• and C1-6 alkyl;
• optionally one or more pairs of R1, R2, R3, R4, R5, R6a, R6b, R7 independently selected from the group consisting of R1/R2;
• R2/R3;
• R3/R4;
• R4/R5;
• R5/R6;
• R6a/R6b and R6/R7 form a C3-7 cycloalkyl ring, which is optionally substituted with one or more of R15b, wherein R15b is independently selected from the group consisting of F;
• Cl;
• and OH;
• n is 0, 1, 2 or 3;
• X is selected from the group consisting of —C(R16Rc)—;
• —C(Ra)═CRc—;
• —C(R16Ra)—CRc═, —C(R16Ra)—O—;
• —C(R16Ra)—S—;
• —C(R16Ra)—S(O)—;
• —C(R16Ra)—S(O)2—;
• —C(R16Ra)—NRc—;
• and —C(R16Ra)—CR17Rc—;
• R8 is selected from the group consisting of H;
• F;
• OH;
• and C1-6 alkyl, optionally substituted with one or more halogen selected from the group consisting of F;
• and Cl;
• R9, R16, R17 are independently selected from the group consisting of H;
• F;
• and C1-6 alkyl, optionally substituted with one or more halogen selected from the group consisting of F;
• and Cl;
• Ra, Rb, Rc, are independently selected from the group consisting of H;
• F. Cl;
• CN;
• —Y—H;
• and —Y-T,
• A is selected from the group consisting of —Y—H and —Y-T,
• provided that at most two of Ra, Rb, Rc, A are independently —Y-T;
• optionally Rc is selected from the group consisting of —C1-6 alkyl;
• —O—C3-7 cycloalkyl;
• —C1-6 alkyl;
• —S—C3-7 cycloalkyl;
• —N(R18)—C1-6 alkyl;
• and —N(R18)—C3-7 cycloalkyl, wherein each C1-6 alkyl and C3-7 cycloalkyl is optionally substituted with one or more R18a, wherein R18a is independently selected from the group consisting of halogen;
• C1-6 alkyl;
• and C3-7 cycloalkyl, provided that n is 1;
• R18 is independently selected from the group consisting of H;
• C1-6 alkyl;
• optionally a pair of Ra, Rb, Rc selected from the group consisting of Ra/Rc;
• and Rb/Rc forms a ring Z1;
• Z1 is selected from the group consisting of Z2;
• and Z3;
• Z2 is selected from the group consisting of phenyl;
• naphthyl;
• and Indenyl;
• wherein Z2 is optionally substituted with one or more R19;
• wherein R19 is independently selected from the group consisting of halogen;
• CN;
• COOR20;
• OR20;
• C(O)N(R20R20a);
• S(O)2N(R20R20a);
• C1-6 alkyl;
• O—C1-6 alkyl;
• S—C1-6 alkyl;
• COO—C1-6 alkyl;
• OC(O)—C1-6 alkyl;
• C(O)N(R2)—C1-6 alkyl;
• S(O)2N(R20)—C1-6 alkyl;
• S(O)N(R20)—C1-6 alkyl;
• S(O)2—C1-6 alkyl;
• S(O)—C1-6 alkyl;
• N(R20)S(O)—C1-6 alkyl;
• and N(R20)S(O)—C1-6 alkyl;
• wherein each C1-6 alkyl is optionally substituted with one or more halogen selected from the group consisting of F;
• and Cl;
• Z3 is selected from the group consisting of C3-7 cycloalkyl;
• indanyl;
• tetralinyl;
• decalinyl;
• heterocycle;
• and heterobicycle;
• wherein Z3 is optionally substituted with one or more R21, wherein R21 is independently selected from the group consisting of halogen;
• CN;
• OR22;
• oxo (═O), where the ring is at least partially saturated;
• N(R22R22a);
• COOR22;
• C(O)N(R22R22a);
• S(O)2N(R22R22a);
• S(O)N(R22R22a);
• C1-6 alkyl;
• O—C1-6 alkyl;
• S—C1-6 alkyl;
• N(R22)—C1-6 alkyl;
• COO—C1-6 alkyl;
• OC(O)—C1-6 alkyl;
• C(O)N(R22)—C1-6 alkyl;
• N(R22)—C(O)—C1-6 alkyl;
• S(O)2N(R22)—C1-6 alkyl;
• S(O)N(R22)—C1-6 alkyl;
• S(O)2—C1-6 alkyl;
• S(O)—C1-6 alkyl;
• N(R22)S(O)2—C1-6 alkyl;
• and N(R22)S(O)—C1-6 alkyl;
• wherein each C1-6 alkyl is optionally substituted with one or more halogen selected from the group consisting of F;
• and Cl;
• Optionally R21 is C(O)R22, provided that C(O)R22 is bound to a nitrogen, which is a ring atom of a heterocycle or heterobicycle;
• R20, R20a, R22, R22a are independently selected from the group consisting of H;
• C1-6 alkyl;
• C3-7 cycloalkyl;
• and —C1-6 alkyl-C3-7 cycloalkyl;
• Y is selected from the group consisting of a covalent bond;
• —C1-6 alkyl-T0-;
• —C1-6 alkyl-O-T0-;
• —C1-6 alkyl-S-T0-;
• —C1-6 alkyl-S(O)-T0-;
• —C1-6 alkyl-S(O)2-T0-;
• —C1-6 alkylN(R23)-T0-;
• —C(O)—O—;
• —C(O)O—C1-6 alkyl-T0-;
• —C1-6 alkyl-C(O)O—;
• —C1-6 alkyl-C(O)O—C1-6 alkyl-T0-;
• C(O)N(R23)—;
• —C(O)N(R23)—C1-6 alkyl-T0-;
• —C1-6 alkyl-C(O)N(R23)—;
• and —C1-6 alkyl-C(O)N(R23)—C1-6, alkyl-T0-;
• wherein each C1-6 alkyl is optionally substituted with one or more F;
• T0 is selected from the group consisting of a covalent bond;
• —C1-6 alkyl;
• —C1-6 alkyl-O—;
• —C1-6 alkyl-N(R23)—;
• —C(O)—;
• —C(O)—C1-6 alkyl;
• —C(O)—C1-6 alkyl-O—;
• —C(O)—C1-6 alkyl-N(R23)—;
• —C(O)O—;
• —C(O)O—C1-6 alkyl-;
• —C(O)O—C1-6 alkyl-O—;
• —C(O)O—C1-6 alkyl-N(R23)—;
• —C(O)N(R23)—;
• —C(O)N(R23)—C1-6 alkyl-;
• —C(O)N(R23)—C1-6 alkyl-O—;
• —C(O)N(R23)—C1-6 alkyl-N(R24)—;
• —S(O)2—;
• —S(O)2—C1-6 alkyl-;
• —S(O)2—C1-6 alkyl-O—;
• and —S(O)2—C1-6 alkyl-N(R23)—;
• wherein each C1-6 alkyl is optionally substituted with one or more F;
• R23, R24 are independently selected from the group consisting of H;
• and C1-6 alkyl;
• T is selected from the group consisting of T1;
• and T2;
• T1 is selected from the group consisting of phenyl;
• naphthyl;
• and indenyl;
• wherein T1 is optionally substituted with one or more R25;
• wherein R25 is independently selected from the group consisting of halogen;
• CN;
• R26;
• COOH;
• OH;
• C(O)NH2;
• S(O)2NH2;
• S(O)NH2;
• COOT3;
• OT3;
• ST3;
• C(O)N(R27)T3;
• S(O)2N(R27)T3;
• S(O)N(R27)T3 and T3;
• T2 is selected from the group consisting of C3-7 cycloalkyl;
• indanyl;
• tetralinyl;
• decalinyl;
• heterocycle;
• and heterobicycle;
• wherein T2 is optionally substituted with one or more R28, wherein R28 is independently selected from the group consisting of halogen;
• CN;
• R29;
• OH;
• oxo (═O), where the ring is at least partially saturated;
• NH2;
• COOH;
• C(O)NH2;
• S(O)2NH2;
• S(O)NH2;
• COOT3;
• OT3;
• C(O)N(R30)T3;
• S(O)2N(R30)T3;
• S(O)N(R30);
• N(R30)T3;
• and T3;
• optionally R28 is C(O)R30, provided that C(O)R30 is bound to a nitrogen, which is a ring atom of a heterocycle or heterobicycle;
• R28 is selected from the group consisting of C1-8 alkyl;
• O—C1-6 alkyl;
• S—C1-6 alkyl;
• COO—C1-6 alkyl;
• OC(O)—C1-3 alkyl;
• C(O)N(R31)—C1-6 alkyl;
• S(O)2N(R31)C1-6 alkyl;
• S(O)N(R31)—C1-6 alkyl;
• S(O)—C1-6 alkyl;
• S(O)2—C1-6 alkyl;
• N(R31)S(O)2—C1-6 alkyl;
• and N(R31)S(O)—C1-6 alkyl;
• wherein each C1-6 alkyl is optionally substituted with one or more R32, wherein R32 is independently selected from the group consisting of F;
• COOR33;
• C(O)N(R33R34);
• S(O)2N(R33R34);
• OR33;
• N(R33R34);
• T3;
• O-T3;
• and N(R33)-T3;
• R29 is selected from the group consisting of C1-6 alkyl;
• O—C1-6 alkyl;
• S—C1-6 alkyl;
• N(R35)—C1-6 alkyl;
• COO—C1-6 alkyl;
• OC(O)—C1-6 alkyl;
• C(O)N(R35)—C1-6 alkyl;
• N(R35)—C(O)—C1-6 alkyl;
• S(O)2N(R35)—C1-6 alkyl;
• S(O)N(R35)—C1-6 alkyl;
• S(O)—C1-6 alkyl;
• S(O)2—C1-6 alkyl;
• —N(R35)S(O)2—C1-6 alkyl;
• and —N(R3)S(O)—C1-6 alkyl;
• wherein each C1-6 alkyl is optionally substituted with one or more R32a, wherein R32a is independently selected from the group consisting of F;
• COOR36;
• C(O)N(R36R37);
• S(O)2N(R36R37);
• S(O)N(R36R37);
• ORE;
• N(R36R37);
• T3;
• O-T3;
• and N(R36)-T3;
• R27, R30, R31, R33, R34, R35, R36, R37 are independently selected from the group consisting of H;
• and C1-6 alkyl;
• T3 is selected from the group consisting of T4;
• and T5;
• T4 is selected from the group consisting of phenyl;
• naphthyl;
• and indenyl;
• wherein T4 is optionally substituted with one or more R38, wherein R38 is independently selected from the group consisting of halogen;
• CN;
• COOR39;
• OR39;
• C(O)N(R39R40);
• S(O)2N(R39R40);
• C1-6 alkyl;
• O—C1-6 alkyl;
• S—C1-6 alkyl;
• COO—C1-6 alkyl;
• OC(O)—C1-6 alkyl;
• C(O)N(R39)—C1-6 alkyl;
• S(O)2N(R39)—C1-6 alkyl;
• S(O)N(R39)—C1-6 alkyl;
• S(O)2—C1-6 alkyl;
• S(O)C1-6 alkyl;
• N(R39)S(O)2—C1-6 alkyl;
• and N(R39)S(O)—C1-6 alkyl;
• wherein each C1-6 alkyl is optionally substituted with one or more halogen selected from the group consisting of F;
• and Cl;
• T5 is selected from the group consisting of heterocycle;
• heterobicycle;
• C3-7 cycloalkyl;
• indanyl;
• tetralinyl;
• and decalinyl;
• wherein T5 is optionally substituted with one or more R41, wherein R41 is independently selected from the group consisting of halogen;
• CN;
• OR42;
• oxo (═O), where the ring is at least partially saturated;
• N(R42R43);
• COOR42;
• C(O)N(R42R43);
• S(O)2N(R42R43);
• S(O)N(R42R43);
• C1-6 alkyl;
• O—C1-6 alkyl;
• S—C1-6 alkyl;
• N(R42)—C1-6 alkyl;
• COO—C1-6 alkyl;
• OC(O)—C1-6 alkyl;
• C(O)N(R42)—C1-6 alkyl;
• N(R42)—C(O)—C1-6 alkyl;
• S(O)2N(R42)—C1-6 alkyl;
• S(O)N(R42)—C1-6 alkyl;
• S(O)2—C1-6 alkyl;
• S(O)—C1-6 alkyl;
• N(R42)S(O)2—C1-6 alkyl;
• and N(R42)S(O)—C1-6 alkyl;
• wherein each C1-6 alkyl is optionally substituted with one or more halogen selected from the group consisting of F;
• and Cl;
• optionally R41 is C(O)R42, provided that C(O)R42 is bound to a nitrogen, which is a ring atom of a heterocycle or heterobicycle;
• R39, R40, R42, R43, are independently selected from the group consisting of H;
• and C1-6 alkyl;
• C3-7 cycloalkyl, and —C1-6 alkyl-C3-7 cycloalkyl,
• provided that if Z is phenyl, R1 to R9 are hydrogen, n is 1, X is CH2 and Rb is hydrogen, then A is not —C(O)—NH2 or —C(O)—NH(t-butyl).