INDOLIZINE DERIVATIVES

摘要

Disclosed herein are indolizine compounds of general formula I, wherein R1-R7, X and Y are as disclosed in the application, useful as inhibitors of lipoprotein associated phospholipase A2 (Lp-PLA2) and/or 15-lipoxygenase (15-LOX), as well as methods of preparation and use thereof, and compositions thereof Advantageously, certain compounds disclosed herein are capable of inhibiting both Lp-PLA2 and 15-LOX. Accordingly, provided herein are methods of inhibiting one or both of Lp-PLA2 and 15-LOX, and methods of treating diseases or conditions associated with Lp-PLA2 and/or 15-LOX.;

主权项

1. A method of treating a disease or condition associated with at least one of a lipoprotein associated phospholipase A2 (Lp-PLA2) and a 15-lipoxygenase (15-LOX) in a patient comprising administering to said patient a therapeutically effective amount of a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:
X and Y are independently C(O), C(S), NH, NRa, S, or O, where Y can be present or absent; R1 is a non-interfering substituent selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, ORa, SRa, OC(O)Rb, OC(O)NH2, OC(O)NHRa, OC(O)NRaRa, OC(O)ORa, C(O)Rb, C(O)NH2, C(O)NHRa, C(O)NRaRa, C(O)ORa, NH2, NRcH, NRcRc, NRbC(O)NH2, NRbC(O)Ra, NRbC(O)ORa and NRbC(O)NRbRb, wherein each of C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, ORa, SRa, OC(O)Rb, OC(O)NHRa, OC(O)NRaRa, OC(O)ORa, C(O)Rb, C(O)NHRa, C(O)NRaRa, C(O)ORa, NRcH, NRcRc, NRbC(O)NH2, NRbC(O)Ra, NRbC(O)ORa and NRbC(O)NRbRb, is optionally substituted by one or more substituents independently selected from halogen, OH, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, ORa, SRa, OC(O)RbOC(O)NH2, OC(O)NHRa, OC(O)NRaRa, OC(O)ORa, C(O)Rb, C(O)NH2, C(O)NHRa, C(O)NRaRa, C(O)ORa, NO2, NH2, NRcH, NRcRc, NRbC(O)NH2, NRbC(O)Ra, NRbC(O)ORa and NRbC(O)NRbRb, with the proviso that when Y is C(O), R1 is not C(O)NH2, C(O)NHRd or C(O)NRcRd; R2 is a non-interfering substituent selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, ORa, SRa, OC(O)Rb, OC(O)NH2, OC(O)NHRa, OC(O)NRaRa, OC(O)ORa, C(O)Rb, C(O)NH2, C(O)NHRa, C(O)NRaRa, C(O)ORa, NH2, NRcH, NRcRc, NRbC(O)NH2, NRbC(O)Ra, NRbC(O)ORa and NRbC(O)NRbRb, wherein each of C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, ORa, SRa, OC(O)Rb, OC(O)NHRa, OC(O)NRaRa, OC(O)ORa, C(O)Rb, C(O)NHRa, C(O)NRaRa, C(O)ORa, NRcH, NRcRc, NRbC(O)NH2, NRbC(O)Ra, NRbC(O)ORa and NRbC(O)NRbRb, is optionally substituted by one or more substituents independently selected from halogen, OH, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, ORa, SRa, OC(O)Rb, OC(O)NH2, OC(O)NHRa, OC(O)NRaRa, OC(O)ORa, C(O)Rb, C(O)NH2, C(O)NHRa, C(O)NRaRa, C(O)ORa, NO2, NH2, NRcH, NRcRc, NRbC(O)NH2, NRbC(O)Ra, NRbC(O)ORa and NRbC(O)NRbRb, R3 is a non-interfering substituent selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C4 cycloalkyl, ORd, SRd, OC(O)Re, OC(O)NH2, OC(O)NHRd, OC(O)NRdRd, OC(O)ORd, C(O)Re, C(O)NH2, C(O)NHRd, C(O)NRdRd, C(O)ORd, NH2, NRfH, NRfRf, NReC(O)NH2, NReC(O)Rd, NReC(O)ORd and NReC(O)NReRe, wherein each C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C4 cycloalkyl, ORd, SRd, OC(O)Re, OC(O)NHRd, OC(O)NRdRd, OC(O)ORd, C(O)Re, C(O)NHRd, C(O)NRdRd, C(O)ORd, NRfH, NRfRf, NReC(O)NH2, NReC(O)Rd, NReC(O)ORd and NReC(O)NReRe is optionally substituted by one or more substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and C3-C4 cycloalkyl; with the proviso that when X is C(O), R3 is not C(O)NH2, C(O)NHRd or C(O)NRdRd; R4, R5, R6 and R7 are each non-interfering substituents independently selected from H, OH, halogen, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, ORa, SRa, OC(O)Rb, OC(O)NH2, OC(O)NfIRa, OC(O)NRaRa, OC(O)ORa, C(O)Rb, C(O)NH2, C(O)NHRa, C(O)NRaRa, C(O)ORa, NH2, NRcH, NReRe, NRbC(O)NH2, NRbC(O)Ra, NRbC(O)ORa and NRbC(O)NRbRb, wherein each of C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, ORa, SRa, OC(O)Rb, OC(O)NHRa, OC(O)NRaRa, OC(O)ORa, C(O)Rb, C(O)NHRa, C(O)NRaRa, C(O)ORa, NRcH, NRcRc, NRbC(O)NH2, NRbC(O)Ra, NRbC(O)ORa and NRbC(O)NRbRb, is optionally substituted by one or more substituents independently selected from halogen, OH, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, ORa, SRa, OC(O)Rb, OC(O)NH2, OC(O)NHRa, OC(O)NRaRa, OC(O)ORa, C(O)Rb, C(O)NH2, C(O)NHRa, C(O)NRaRa, C(O)ORa, NH2, NRcH, NRcRc, NRbC(O)NH2, NRbC(O)Ra, NRbC(O)ORa and NRbC(O)NRbRb; Ra is C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-4 cycloalkyl, alkylchalcogen, arylchalcogen, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, or heteroarylalkyl; Rb is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-4 cycloalkyl, cyclopropyl, amino, alkylchalcogen, arylchalcogen, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, or heteroarylalkyl; Rc is C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-4 cycloalkyl, alkylchalcogen, arylchalcogen, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, or heteroarylalkyl; Rd is C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-4 cycloalkyl, or amino; Re is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-4 cycloalkyl, cyclopropyl, or amino; and Rf is C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-4 cycloalkyl.