Heteroaryl derivatives

摘要

Compounds of formula (I) described herein are both phosphodiesterase 4 (PDE4) enzyme inhibitors and muscarinic M3 receptor antagonists and are useful for the prevention and/or treatment of diseases of the respiratory tract characterized by airway obstruction.

主权项

1. A compound of formula (I):wherein
each R1 is hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, hydroxy, —SO2NR6R7, —CN, —NR8SO2R9, —NR6R7, —CONR6R7, or —NR8COR9, wherein said (C1-C4) alkyl is optionally substituted by one or more groups selected from (C3-C7) cycloalkyl, hydroxyl, and —NR6R7 and wherein said (C1-C4) alkoxy is optionally substituted by one or more halogen atoms or (C3-C7) cycloalkyl groups, wherein
R6 is hydrogen or (C1-C6) alkyl;R7 is hydrogen or (C1-C6) alkyl;R8 is hydrogen or (C1-C6) alkyl;R9 is hydrogen or (C1-C6) alkyl; n is an integer ranging from 1 to 3; each R2 is hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4)haloalkyl, hydroxy, —SO2NR10R11, —CN, or —NR12SO2R13, wherein said (C1-C4) alkyl and said (C1-C4) alkoxy are optionally substituted by one or more (C3-C7) cycloalkyl groups, wherein
R10 is hydrogen or (C1-C6) alkyl;R11 is hydrogen or (C1-C6) alkyl;R12 is hydrogen or (C1-C6) alkyl;R13 is hydrogen or (C1-C6) alkyl; m is an integer ranging from 1 to 3; R3 and R4 are different or the same and are each independently:
H;(C3-C7) cycloalkylcarbonyl;(C1-C6) alkyl, optionally substituted by one or more substituents selected from (C3-C7) cycloalkyl or (C5-C7) cycloalkenyl;(C1-C6) haloalkyl;(C3-C7) cycloalkyl;(C5-C7) cycloalkenyl;(C2-C6) alkenyl; or(C2-C6) alkynyl; or R3 and R4, together with the interconnecting atoms, form a 2,2-difluoro-1,3-dioxolane ring of formula (r) fused to the phenyl moiety which bears groups —OR3 and —OR4, wherein asterisks indicate carbon atoms shared with such phenyl ring: each R5, whenever present, is independently CN, NO2, CF3, or a halogen atom; k is 0 or an integer ranging from 1 to 3; L1 is:
a bond,—(CH2)p—,[3]-(CH2)p—O-[4][3]-(CH2)p—NR10—(CH2)t-[4][3]-(CH2)p—OC(O)-[4][3]-(CH2)p—NR10C(O)-[4][3]-(CH2)p—NR10S(O2)-[4] or[3]-(CH2)p—S(O2)—N(R10)-[4] wherein [3] and [4] represent, respectively, the point of attachment of group L1 to the carbonyl group and to the ring W1 and wherein
R10 is as described above,p is an integer ranging from 1 to 4 andt is an integer ranging from 1 to 4; W1 is a divalent (C5-C6) heteroarylene group; W2 is aryl or heteroaryl; L2 is —(CH2)q— wherein q is 1 or 2; L3 is a bond or —(CH2)s— wherein s is 1 or 2; X is N or [1]-N(R19)—CH<[2] wherein [1] represents the point of attachment of group X to L2 and [2] represents the point of attachment of group X to the group W2 and to the group L3-C(O)OA and wherein R19 is hydrogen, (C1-C6) alkyl, or benzyl or, when W2 is a phenyl ring, R19 is optionally a (C1-C6) alkylene connected to W2 in ortho position with respect to X, so as to form with W2 and together with the interconnecting atoms a condensed ring as per formula (t) wherein “” indicate a point of attachment to the rest of the molecule: A is:
a group-(CH2)s—NR16R17 wherein s is an integer ranging from 1 to 4 and R16 and R17 are independently hydrogen or (C1-C4) alkyl; ora saturated monocyclic, bicyclic or tricyclic heterocyclic ring system containing one N heteroatom or NR18 group wherein R18 is (C1-C4) alkyl or benzyl; an N-oxides on the pyridine ring, or a pharmaceutically acceptable salt thereof.