Compounds inhibiting leucine-rich repeat kinase enzyme activity

A compound of the formula:

• I:
• wherein R1 is selected from the group consisting of:
• a) hydrogen,
• b) halo,
• c) cyano,
• d) hydroxyl,
• e) C2-6 alkenyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano and R5;
• f) OC2-6 alkenyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano and R5;
• g) R5,
• h) OR5,
• i) R7,
• j) S(O)mR5,
• k) S(O)mR7,
• l) (C═O)R7,
• m) (C═O)R5,
• n) (C═O)OR5,
• o) NRcRd, and
• p)
• X1, X2 and X3 are each independently selected from the group consisting of a bond or CReRf;
• Y is O, CRaRb or NRc;
• Z is O, CRaRb or NRc;
• Rz is selected from the group consisting of hydrogen and C1-3 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, NH(C1-3 alkyl), N(C1-3 alkyl)2, OC1-6 alkyl, and C3-8 cycloalkyl;
• A is CH or N;
• R2 is selected from the group consisting of hydrogen and C1-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of:
• a) halo,
• b) cyano,
• c) R5,
• d) R7,
• e) OR5, and
• f) NRcRd;
• R3 is selected from the group consisting of:
• a) hydrogen,
• b) C1-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR5 and NRcRd,
• c) C3-8 cycloalkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR5 and NRcRd,
• d) heterocyclyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, oxo, R5, OR5 and NRcRd,
• e) heteroaryl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, oxo, R5, OR5 and NRcRd;
• f) C4-8 cycloalkenyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OR5 and NRcRd,
• g) (C═O)R7,
• h) (C═O)R5,
• i) S(O)mR5, and
• j) S(O)mR7;
• or R2 and R3 can be taken together with the atoms to which they are attached to form a 3 to 8 membered heterocyclic or heteroaryl ring, wherein said ring may contain from one to three heteroatoms selected from N, O and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, and which ring is optionally substituted with one to four substituents each independently selected from the group consisting of:
• a) halo,
• b) oxo,
• c) cyano,
• d) OR5,
• e) NRcRd,
• f) SO3H,
• g) S(O)mR5,
• h) S(O)mR7
• i) R5,
• j) R6,
• k) R7,
• l) (C═O)R5,
• m) (C═O)OR5,
• n) (C═O)R7, and
• o) (C═O)NRcRd;
• R4 is selected from the group consisting of:
• hydrogen, halo, cyano, OR5, aryl, heteroaryl, C3-8 cycloalkyl, C4-8 cycloalkenyl, C4-8 heterocyclyl and C1-6 alkyl, which is optionally substituted with one to three substitutents independently selected from the group consisting of halo, cyano, OC1-3 alkyl, NRcRd and hydroxy;
• R5 is selected from the group consisting of hydrogen or C1-6 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of:
• a) halo,
• b) hydroxyl,
• c) OC1-6 alkyl,
• d) NRcRd,
• e) (C═O)NRcRd,
• f) S(O)mR8,
• g) S(O)mR7,
• h) R7, and
• i) OR7;
• R6 is C1-6 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo and hydroxyl;
• or R5 and R6 can be taken together with the atoms to which they are attached to form a 4 to 8 membered heterocyclic, 3 to 8 membered carbocyclic, aryl or heteroaryl ring, wherein said heterocyclic and heteroaryl rings may contain from one to three heteroatoms selected from N, O and S, wherein said heterocyclic, carbocyclic, aryl and heteroaryl rings are optionally substituted with one to three substituents independently selected from the group consisting of:
• a) halo,
• b) oxo,
• c) cyano,
• d) hydroxyl,
• e) C1-3 alkyl, which is optionally substituted with one to three halo,
• f) C3-8 cycloalkyl,
• g) OC1-3 alkyl, which is optionally substituted with one to three halo, and
• h) OC3-8 cycloalkyl;
• R7 is selected from the group consisting of C4-8 heterocyclyl, C3-8 cycloalkyl, C4-8 cycloalkenyl, aryl or heteroaryl, wherein said heterocyclyl, cycloalkyl, cycloalkenyl, aryl and heteroaryl groups are optionally substituted with one to three substituents independently selected from the group consisting of:
• a) halo,
• b) cyano,
• c) hydroxyl,
• d) oxo,
• e) C1-3 alkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, heterocyclyl, OC1-3 alkyl and NRcRd,
• f) OC1-3 alkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, heterocyclyl, OC1-3 alkyl, NRcRd, aryl and heteroaryl,
• g) C3-8 cycloalkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, heterocyclyl, OC1-3 alkyl and NRcRd,
• h) aryl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, heterocyclyl, OC1-3 alkyl, S(O)mNRcRd, C(O)NRcRd and NRcRd,
• i) heteroaryl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, heterocyclyl, OC1-3 alkyl, S(O)mNRcRd, C(O)NRcRd and NRcRd,
• j) heterocyclyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, OC1-3 alkyl and NRcRd,
• k) C4-8 cycloalkenyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo, cyano, heterocyclyl, OC1-3 alkyl and NRcRd;
• R8 is hydrogen or C1-6 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of:
• a) halo,
• b) cyano,
• c) hydroxyl,
• d) OC1-3 alkyl, which is optionally substituted with one to four substituents independently selected from the group consisting of hydroxyl, halo and NReRf, and
• e) C3-8 cycloalkyl;
• R9 is selected from the group consisting of:
• a) C1-3 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo,
• b) halo,
• c) cyano,
• d) hydroxyl, and
• e) OC1-3 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo;
• Ra is selected from the group consisting of hydrogen and C1-6 alkyl;
• Rb is selected from the group consisting of hydrogen and C1-6 alkyl;
• Rc is selected from the group consisting of:
• a) hydrogen,
• b) C1-3 alkyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, heteroaryl, aryl, NH(C1-3 alkyl), N(C1-3 alkyl)2, OC1-6 alkyl, and C3-8 cycloalkyl;
• Rd is selected from the group consisting of:
• a) hydrogen,
• b) C3-8 cycloalkyl,
• c) C3-6 heterocyclyl,
• d) C1-3 alkyl,
• e) (C═O)C1-3 alkyl,
• f) aryl, and
• g) heteroaryl;
• wherein said cycloalkyl, heterocyclyl, alkyl, aryl and heteroaryl groups are each optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxyl, cyano, R8, SO2R8, OC1-6 alkyl and C3-8 cycloalkyl;
• or Rc and Rd can be taken together with the atoms to which they are attached to form a 3 to 8 membered heterocyclic ring, wherein said ring may contain from one to three heteroatoms selected from N, O and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, and which ring is optionally substituted with one to four substituents each independently selected from the group consisting of halo, cyano, hydroxyl, C1-3 alkyl and OC1-3 alkyl;
• Re is selected from the group consisting of hydrogen and C1-3 alkyl;
• Rf is selected from the group consisting of hydrogen and C1-3 alkyl;
• m is an integer from zero to two;
• or a pharmaceutically acceptable salt thereof.