NOVEL TRICYCLIC COMPOUNDS

摘要

The invention provides a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), or (Il) as defined herein, pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions.

主权项

1. A compound of formula (Ib)pharmaceutically acceptable salts, or stereoisomers thereof wherein
R1 is H, deuterium, halogen, CF3, CN, ORa, N(Ra)(Rb), OCF3, —C(O)—N(Ra)(Rb), —C(O)—ORa, —C(O)-optionally substituted (C1-C6)alkyl, —C(O)-optionally substituted (C3-C6)cycloalkyl, —C(O)-optionally substituted (C6-C10)aryl, —C(O)-optionally substituted (C1-C10)heteroaryl, —C(O)-optionally substituted (C1-C10)heterocyclyl, —S-optionally substituted (C1-C6)alkyl, —S(O)— optionally substituted (C1-C6)alkyl, —S(O)2-optionally substituted (C1-C6)alkyl, —S(O)2N(Ra)(Rb), optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, or optionally substituted (C6-C10)aryl; or R1 is —Z101-L1-Z102 wherein
Z101 is optionally substituted (C1-C6)alkylene, optionally substituted (C1-C10)heteroarylene, optionally substituted (C1-C10)heterocyclylene, or optionally substituted (C6-C10)arylene;L1 is a bond, optionally substituted (C1-C4)alkylene, —CH2C(O), —C(O)—, —C(O)CH2—, —N(Ra)—, —O—, -optionally substituted (C1-C4)alkylene-N(Ra)C(O)—, -optionally substituted (C1-C4)alkylene-C(O)N(Ra)—, —C(O)N(Ra)—, —N(Ra)C(O)—, —C(O)N(Ra)-optionally substituted (C1-C4)alkylene-, —N(Ra)C(O)-optionally substituted (C1-C4)alkylene-, —C(O)N(Ra)-optionally substituted (C1-C4)alkylene-C(O), —N(Ra)C(O)-optionally substituted (C1-C4)alkylene-C(O)—, —C(O)-optionally substituted (C1-C4)alkylene-N(Ra)C(O)—, —C(O)-optionally substituted (C1-C4)alkylene-C(O)N(Ra)—, -optionally substituted (C1-C4)alkylene-N(Ra)C(O)—, —N(Ra)C(O)-optionally substituted (C1-C4)alkylene, -optionally substituted (C1-C4)alkylene-N(Ra)C(O)-optionally substituted (C1-C4)alkylene-, -optionally substituted (C1-C4)alkylene-C(O)N(Ra)-optionally substituted (C1-C4)alkylene-, -optionally substituted (C1-C4)alkylene-N(Ra)S(O)2—, -optionally substituted (C1-C4)alkylene-S(O)2N(Ra)—, —N(Ra)S(O)2CH2—, —S(O)2N(Ra)-optionally substituted (C1-C4)alkylene-, —C(O)N(Ra)S(O)2—, —S(O)2N(Ra)C(O)—, —S(O)2—, —S(O)2N(Ra)—, —N(Ra)S(O)2—, —O—(C1-C4)alkylene-, (C1-C6)alkylene-O—, —C(O)N(Ra)—(C1-C6) alkylene-C(O)—, or —C(O)—(C1-C6)alkylene-N(Ra)C(O)—;Z102 is H, —CN, —N(Ra)(Rb), —ORa, optionally substituted (C1-C6)alkyl, optionally substituted (C1-C4)alkoxy, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted bridged (C5-C12)cycloalkyl, or optionally substituted bridged (C2-C10)heterocyclyl; R2 is H, deuterium, halogen, CF3, CN, ORa, N(Ra)(Rb), OCF3, —C(O)-optionally substituted (C1-C6)alkyl, —C(O)-optionally substituted (C3-C6)cycloalkyl, —S-optionally substituted (C1-C6)alkyl, —S(O)2-optionally substituted (C1-C6)alkyl, —S(O)2N(Ra)(Rb), optionally substituted (C1-C6)alkoxy, —C(O)N(Ra)(Rb), —S(O)2-optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, or optionally substituted (C1-C10)heterocyclyl; R3 is deuterium, CF3, CN, —C(O)ORa, ORa, OCF3, N(Ra)(Rb), substituted (C1-C6)alkyl, optionally substituted (C3-C7)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, or substituted (C6-C10)aryl; or R3 is -A-D-E-G, wherein: A is a bond, —C(O)—, substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkenylene, optionally substituted (C2-C6)alkynylene, optionally substituted (C3-C12)cycloalkylene, optionally substituted (C2-C6)heterocyclylene, -optionally substituted (C1-C6)alkylene-N(Ra)—, —Re—C(O)N(Ra)—Re—, —Re—N(Ra)C(O)—Re—, —Re—O—Re—, —N(Ra)—Re—, —S—Re—, —S(O)2—Re—, —S(O)Re—, —C(O—Ra)(Rb)—Re—, —S(O)2N(Ra)—Re—, —N(Ra)S(O)2—Re— or —N(Ra)C(O)N(Rb)—Re—; D is an optionally substituted (C2-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkylene, optionally substituted (C3-C10)cycloalkylene, optionally substituted bridged (C5-C10)cycloalkenylene, optionally substituted (C3-C10)cycloalkenylene, substituted (C6-C10)arylene, optionally substituted (C1-C10)heteroarylene, optionally substituted bridged (C2-C10)heterocyclylene or an optionally substituted (C2-C10)heterocyclylene; E is a bond, —Re—, —Re—C(O)—Re—, —Re—C(O)C(O)—Re—, —Re—C(O)O—Re—, —Re—C(O)C(O)N(Ra)—Re—, —Re—N(Ra)—C(O)C(O)—Re—, —Re—C(O)N(Ra)C(O)Re—, —Re—O—Re—, —Re—S(O)2—Re—, —Re—S(O)—Re—, —Re—S—Re—, —Re—N(Ra)—Re—, —Re—N(Ra)C(O)—Re—, —ReC(O)N(Ra)Re—, —Re— OC(O)N(Ra)—Re—, —Re—N(Ra)C(O)ORe—, —Re— OC(O)—Re—, —Re—N(Ra)C(O)N(Rb)—Re—, or —Re—S(O)2N(Ra)—Re—; or E is where in all cases, E is linked to either a carbon or a nitrogen atom in D; G is H, deuterium, —N(Ra)(Rb), halogen, —ORa, —SRa, —S(O)Ra, —NO2, —C(O)ORa, —CN, —C(O)N(Ra)(Rb), —N(Ra)C(O)Rb, —N(Ra)C(O)ORb, —OC(O)N(Ra), —N(Ra)C(O)N(Rb)2, —C(O—Ra)(Rb)2, —C(O)Ra, —CF3, —OCF3, —S(O)2N(Ra)(Rb), —S(O)2N(Ra)C(O)Rb, an optionally substituted (C1-C6)alkyl, an optionally substituted (C2-C6)alkenyl, an optionally substituted (C2-C6)alkynyl, an optionally substituted (C3-C10)cycloalkyl, an optionally substituted (C1-C10)heteroaryl, an optionally substituted (C1-C10)heterocyclyl, an optionally substituted (C6-C10)aryl, an optionally substituted —(C1-C6)alkyl-(C3-C10)cycloalkyl, an optionally substituted —(C1-C6)alkyl-(C6-C10)aryl, an optionally substituted —(C1-C6)alkyl-(C1-C10)heteroaryl, or an optionally substituted —(C1-C6)alkyl-(C1-C10)heterocyclyl;
wherein in a moiety containing —N(Ra)(Rb), the nitrogen, Ra and Rb may form a ring such that —N(Ra)(Rb) represents an optionally substituted (C2-C10)heterocyclyl or an optionally substituted (C1-C10)heteroaryl linked through a nitrogen; R5 is H, deuterium, N(Ra)(Rb), halogen, CN, CF3, ORa, optionally substituted (C1-C6)alkyl, OCF3, —C(O)-optionally substituted (C1-C6)alkyl, —C(O)-optionally substituted (C3-C6)cycloalkyl, —S-optionally substituted (C1-C6)alkyl, —S(O)-optionally substituted (C1-C6)alkyl, —S(O)2-optionally substituted (C1-C6)alkyl, —S(O)2N(Ra)(Rb), optionally substituted (C1-C6)alkyl, or optionally substituted (C1-C6)alkoxy; R6 is H, deuterium, halogen, CF3, CN, ORa, N(Ra)(Rb), OCF3, —C(O)—N(Ra)(Rb), —C(O)—ORa, —C(O)-optionally substituted (C1-C6)alkyl, —C(O)-optionally substituted (C3-C6)cycloalkyl, —C(O)-optionally substituted (C6-C10)aryl, —C(O)-optionally substituted (C1-C10)heteroaryl, —C(O)-optionally substituted (C1-C10)heterocyclyl, —S-optionally substituted (C1-C6)alkyl, —S(O)— optionally substituted (C1-C6)alkyl, —S(O)2-optionally substituted (C1-C6)alkyl, —S(O)2N(Ra)(Rb), optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, or optionally substituted (C6-C10)aryl; or R6 is —Z201-L2-Z202 wherein
Z201 is optionally substituted (C1-C6)alkylene, optionally substituted (C1-C10)heteroarylene, optionally substituted (C1-C10)heterocyclylene, or optionally substituted (C6-C10)arylene;L2 is a bond, optionally substituted (C1-C4)alkylene, —CH2C(O), —C(O)—, —C(O)CH2—, —N(Ra)—, —O—, -optionally substituted (C1-C4)alkylene-N(Ra)C(O)—, -optionally substituted (C1-C4)alkylene-C(O)N(Ra)—, —C(O)N(Ra)—, —N(Ra)C(O)—, —C(O)N(Ra)S(O)2—, —S(O)2N(Ra)C(O)—, —C(O)N(Ra)-optionally substituted (C1-C4)alkylene-, —N(Ra)C(O)-optionally substituted (C1-C4)alkylene-, -optionally substituted (C1-C4)alkylene-N(Ra)C(O)-optionally substituted (C1-C4)alkylene-, -optionally substituted (C1-C4)alkylene-C(O)N(Ra)-optionally substituted (C1-C4)alkylene-, -optionally substituted (C1-C4)alkylene-N(Ra)S(O)2—, -optionally substituted (C1-C4)alkylene-S(O)2N(Ra)—, —N(Ra)S(O)2 CH2—, —S(O)2N(Ra)-optionally substituted (C1-C4)alkylene-, —S(O)2—, —S(O)2N(Ra)—, —N(Ra)S(O)2—, —(C1-C4)alkylene-O—, or —O—(C1-C4)alkylene-;Z202 is H, —CN, —N(Ra)(Rb), —ORa, optionally substituted (C1-C6)alkyl, optionally substituted (C1-C4)alkoxy, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted bridged (C5-C12)cycloalkyl, or optionally substituted bridged (C2-C10)heterocyclyl; R7 is H, deuterium, optionally substituted-(CH2)n—P(═O)(ORa)(Ra), optionally substituted —(CH2)n—O—P(═O)(ORa)(ORa), optionally substituted-(CH2)n—P(═O)(ORa)(Ra), —CH═CH P(═O)(ORa)(ORa); Ra and Rb are each independently H, deuterium, an optionally substituted (C1-C10)alkyl, optionally substituted (C2-C10)alkenyl, optionally substituted (C2-C10)alkynyl, an optionally substituted (C1-C10)alkyl-O—(C1-C10)alkyl, optionally substituted (C3-C10)cycloalkyl, an optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted —(C1-C6)alkylene-(C3-C10)cycloalkyl, an optionally substituted —(C1-C6)alkylene-(C6-C10)aryl, optionally substituted —(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted —(C1-C6)alkylene-(C1-C10)heterocyclyl; Re for each occurrence is independently a bond, an optionally substituted (C1-C10)alkylene, an optionally substituted (C2-C10)alkenylene, an optionally substituted (C2-C10)alkynylene, an optionally substituted —(C1-C10)alkylene-O—(C1-C10)alkylene group, an optionally substituted (C3-C10)cycloalkylene, an optionally substituted (C6-C10)arylene, an optionally substituted (C1-C10)heteroarylene, or an optionally substituted (C1-C10)heterocyclylene; and n is 1, 2 or 3;provided that R1 and R6 are not both H,
wherein the optional substituents are independently selected from (C1-C8)alkyl groups, (C2-C8)alkenyl groups, (C2-C8)alkynyl groups, (C3-C10)cycloalkyl groups, halogen, halogenated (C1-C8)alkyl groups, —O—(C1-C8)alkyl groups, —OH, —S—(C1-C8)alkyl groups, —SH, —NH(C1-C8)alkyl groups, —N((C1-C8)alkyl)2 groups, —NH7, —C(O)NH7, —C(O)NH(C1-C8)alkyl groups, —C(O)N((C1-C8)alkyl)2, —NHC(O)H, —NHC(O)(C1-C8)alkyl groups, —NHC(O)(C3-C8)cycloalkyl groups, —N((C1-C8)alkyl)C(O)H, —N((C1-C8)alkyl)C(O)(C1-C8)alkyl groups, —NHC(O)NH2, —NHC(O)NH(C1-C8)alkyl groups, —N((C1-C8)alkyl)C(O)NH2 groups, —NHC(O)N((C1-C8)alkyl)2 groups, —N((C1-C8)alkyl)C(O)N((C1-C8)alkyl)2 groups, —N((C1-C8)alkyl)C(O)NH((C1-C8)alkyl), —C(O)H, —C(O)(C1-C8)alkyl groups, —CN, —NO2, —S(O)(C1-C8)alkyl groups, —S(O)2N((C1-C8)alkyl groups, —S(O)2N((C1-C8)alkyl)2 groups, —S(O)2NH(C1-C8)alkyl groups, —S(O)3NH(C3-C8)cycloalkyl groups, —S(O)2NH2 groups, —NHS(O)2(C1-C8)alkyl groups, —N((C1-C8)alkyl)S(O)2(C1-C8)alkyl groups, —(C1-C8)alkyl-O—(C1-C8)alkyl groups, —O—(C1-C8)alkyl-O—(C1-C8)alkyl groups, —C(O)OH, —C(O)O(C1-C8)alkyl groups, NHOH, NHO(C1-C8)alkyl groups, —O-halogenated (C1-C8)alkyl groups, —S(O)2-halogenated (C1-C8)alkyl groups, —S-halogenated (C1-C8)alkyl groups, —(C1-C6)heterocyclyl, —(C1-C6)heteroaryl, -phenyl, —NHC(O)O—(C1-C6)alkyl groups, —N((C1-C6)alkyl)C(O)O—(C1-C6)alkyl groups, —C(═NH)—(C1-C6)alkyl groups, —C(═NOH)— (C1-C6)alkyl groups, or —C(═N—O— (C1-C6)alkyl)-(C1-C6)alkyl groups.