Aryl and arylalkyl substituted pyrazolyl and pyrimidinyl tricyclic enones as antioxidant inflammation modulators

摘要

The present application relates to: (a) compounds of Formula (I):;
and salts thereof, wherein R1, R2, R3, R4, R5, R6, m, n, X and Y are as defined in the specification; (b) compositions comprising such compounds and salts; and (c) methods of use of such compounds, salts, and compositions, particularly use for the treatment and prevention of diseases such as those associated with oxidative stress and inflammation.

主权项

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein is a single or double bond; m is 0 or 1; n is 1 or 2; p is 1, 2, or 3; q is 1, 2, or 3; r is 1, 2, 3, or 4; X is NC—, F3C—, R1xC(O)—, or O2N—; Y is G1-, G1-(CRaRb)—, G2-, or G2-(CRaRb)—; R1 and R2 are each independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, amido, amino, halogen, hydroxy, GR1a-, GR1a-(CRaRb)p—, GR1b-, R1aC(O)—, (R1a)2N—, GR1aNH—, GR1a-(CRaRb)p—NH—, GR1aO—, and R1aCO2—; or R1 and R2 joined together with the carbon atom to which they are attached form a C3-C6-cycloalkyl, C3-C6-cycloalkenyl, or 4-6-membered heterocycle optionally substituted with C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, cyano, halogen, hydroxy, Or oxo; R3 is absent, hydrogen, C1-C6-alkyl, C2-C4-alkenyl, C1-C6-fluoroalkyl, G3a- or G3a-(CRaRb)q—; provided that R3 is absent when and only when the atom to which it is attached forms part of a double bond; R4 is hydrogen, C1-C6-alkyl, C2-C4-alkenyl, C1-C6-fluoroalkyl, amino, C1-C6-alkylamino, C1-C6-dialkylamino, C1-C6-alkoxy, cyano, halogen, hydroxy, G4a-, G4b-, G4a-(CRaRb)p—, G4b-(CRaRb)p—, G4aO— or G4aNH—; R5 is absent, hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, GR5a-, GR5a-(CRaRb)—, R5aC(O)—, GR5aC(O)—, hydroxy-C1-C6-alkyl-C(O)—, R5aO2C—, GR5aO2C—, GR5aHNC(O)—, R5aO2CNHCH2C(O)—, H2NHCH2C(O)—, R5aSO2—, or GR5aSO2—; provided that R5 is absent when and only when the atom to which it is attached forms part of a double bond; R6 is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, amino, C1-C6-alkylamino, C1-C6-dialkylamino, hydroxy, G6a-, G6aN(Ra)—, G6aO— or G6b-; Ra and Rb are, at each occurrence, independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; R1a is, at each occurrence, independently hydrogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl or C1-C4-haloalkyl; R1x is hydroxy, C1-C6-alkoxy, amino, C1-C6-alkylamino, C1-C6-dialkylamino, or C1-C6-alkylsulfonylamino; RG1a is, at each occurrence, independently hydrogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl or C1-C4-haloalkyl; RG1b is, at each occurrence, independently C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl or C1-C4-haloalkyl; RG2a is, at each occurrence, independently hydrogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl or C1-C4-haloalkyl; RG2b is, at each occurrence, independently C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl or C1-C4-haloalkyl; RG4a is, at each occurrence, independently C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl or C1-C4-haloalkyl; R5a is, at each occurrence, independently hydrogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl or C1-C4-haloalkyl; RG6a is, at each occurrence, independently C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl or C1-C4-haloalkyl; RG6b is, at each occurrence, independently hydrogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl or C1-C4-haloalkyl; RG6c is, at each occurrence, independently C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl or C1-C4-haloalkyl; RG6d is, at each occurrence, independently hydrogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl or C1-C4-haloalkyl; G1 is phenyl optionally substituted with 1, 2, 3, 4 or 5 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, carboxy, cyano, cyano-C1-C6-alkyl, halogen, halo-C1-C6-alkyl, hydroxy, hydroxy-C1-C6-alkyl, RG1bO2C—, RG1aHN(O)C—, (RG1a)2N(O)C—, G1aC(O)—, G1bHN(O)C—, G1b-, RG1aC(O)N(RG1a)—, RG1b(O)CN(RG1a)—, RG1bO2SN(RG1a)—, (RG1a)2N—, G1bO—, G1bCH2O—, RG1aCO2—, (RG1a)2NCO2—, HS—, RG1bS—, RG1bS(O)—, RG1bSO2— or (RG1a)2NSO2—; G2 is a 5-6-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, carboxy, cyano, cyano-C1-C6-alkyl, halogen, halo-C1-C6-alkyl, hydroxy, hydroxy-C1-C6-alkyl, RG2bCO2—, RG2aHNC(O)—, (RG2a)2NC(O)—, G2aC(O)—, G2bHNC(O)—, G2b-, RG2aC(O)N(RG2a)—, RG2bOC(O)N(RG2a)—, RG2bSO2N(RG2a)—, (RG2a)2N—, G2bO—, G2bCH2O—, RG2aCO2—, (RG2a)2NCO2—, HS—, RG2bS—, RG2bS(O)—, RG2bSO2—, or (RG2a)2NSO2—; G1a is a 4-6-membered heterocycle optionally substituted with 1, 2, 3 or 4 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, cyano, halogen, hydroxy, or oxo; G1b is phenyl or 5-6-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, cyano, halogen, hydroxy, or nitro; GR1a is phenyl or 5-6-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, cyano, halogen, hydroxy, or nitro; GR1b is a 4-6-membered heterocycle optionally substituted with 1, 2, 3 or 4 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, cyano, halogen, hydroxy, or oxo; G2a is a 4-6-membered heterocycle optionally substituted with 1, 2, 3 or 4 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, cyano, halogen, hydroxy, or oxo; G2b is phenyl or 5-6-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, cyano, halogen, hydroxy, or nitro; G3a is phenyl or 5-6-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, cyano, halogen, or hydroxy; G4a is phenyl or 5-6-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 C1-C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, amido, carboxy, cyano, halogen, hydroxy, RG4aO2C—, RG4aC(O)—, (RG4a)2NC(O)—, or G4a1-; G4a1 is phenyl or 5-6-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, cyano, halogen, hydroxy, or nitro; G4b is a 4-6-membered heterocycle optionally substituted with 1, 2, 3 or 4 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, cyano, halogen, hydroxy, or oxo; GR5a is phenyl or 5-6-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, cyano, halogen, hydroxy, or nitro; G6a is C6-C10-aryl or 5-10-membered heteroaryl optionally substituted with 1, 2, 3, or 4 C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, amino, C1-C6-alkylsulfonylamino, carboxy, halogen, hydroxy, hydroxyC1-C6-alkyl, RG6aC(O)—, RG6aO2C—, HO2C—(CRaRb)r—, RG6aO2C—(CRaRb)r—, (RG6b)2N(O)C—(CRaRb)r—, RG6aCO2—(CRaRb)r—, G6c-, or G6d-; G6b is 4-6-membered heterocycle optionally substituted with 1, 2, 3, or 4 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, cyano, halogen, hydroxy, or oxo; G6c is phenyl or 5-6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, amino, C1-C6-alkylsulfonylamino, di(C1-C6-alkylsulfonyl)amino, C1-C6-alkylsulfonylaminoC1-C6-alkyl, carboxy, cyano, halogen, hydroxy, hydroxyC1-C6-alkyl, RG6cC(O)—, RG6cO2C—, (RG6d)2NC(O)—, HO2C—(CRaRb)r—, RG6cO2C—(CRaRb)r—, (RG6d)2NC(O)—(CRaRb)r—, or RG6cCO2—(CRaRb)r—; and G6d is 4-6-membered heterocycle optionally substituted with 1, 2, 3, or 4 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, cyano, halogen, hydroxy, or oxo.