Tricyclic Compounds as Modulators of TNF-alpha Synthesis and as PDE4 Inhibitors

A method of treating rheumatoid arthritis comprising administering to a human a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

• wherein:
• A1 is O or S;
• A2 is O or S;
• U is N;
• V is C—(CH2)vRV;
• W is C—(CH2)wRW;
• X is C—(CH2)xRX;
• Y is C—(CH2)yRY;
• Z is C—(CH2)zRZ;
• R1 is —(CH2)qRQ;
• R2 is —(CH2)sRS;
• wherein
• each of q, s, w, x, y, and z individually is 0, 1, 2, 3, or 4;
• v is zero;
• RQ is selected from the group consisting of:
• alkyl,
• cycloalkyl,
• phenyl,
• benzyl,
• tetrahydrofuranyl,
• tetrahydropyranyl,
• pyrrolidinyl,
• piperidinyl, and
• —OR8, wherein
• the cycloalkyl is optionally substituted with one or more Rc;
• the phenyl and benzyl are each independently optionally substituted with one or more Ra;
• and
• the tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and piperidinyl are each independently optionally substituted with one or more Rhc;
• RV is chloro or —OCH3;
• each of RS, RW, RX, RY, and RZ is independently selected from the group consisting of
• alkyl;
• alkenyl;
• alkynyl;
• aryl;
• aryl substituted with one or more Ra;
• azido;
• cyano;
• cycloalkyl;
• cycloalkyl substituted with one or more Rc;
• fused cycloalkylaryl substituted with one or more Rf1;
• fused arylcycloalkyl substituted with one or more Rf2;
• fused heterocyclyaryl substituted with one or more Rf3;
• fused arylheterocyclyl substituted with one or more Rf4;
• fused cycloalkylheteroaryl substituted with one or more Rf5;
• fused heteroarylcycloalkyl substituted with one or more Rf6;
• fused heterocyclylheteroaryl substituted with one or more Rf7;
• halogen;
• haloalkyl;
• heterocyclyl;
• heterocyclyl substituted with one or more Rhc;
• heteroaryl;
• heteroaryl substituted with one or more Rha;
• hydrogen;
• —NR3R4;
• —C(O)NR3R4;
• —C(O)R5;
• —C(O)2R6;
• —S(O)nR7;
• —OR8;
• and
• nitro;
• wherein
• each of R3 and R4 is independently selected from the group consisting of H, acyl, alkyl, alkoxy, alkoxyalkyl, alkylsulfonyl, aryl, cycloalkyl, heterocyclyl and heteroaryl;
• j is 0, 1, or 2;
• each R5, R6, R7, and R8 is independently selected from the group consisting of
• hydrogen;
• alkyl;
• alkenyl;
• alkynyl;
• alkoxy;
• aryl;
• aryl substituted with one or more Ra;
• cycloalkyl;
• cycloalkyl substituted with one or more Rc;
• halogen;
• haloalkyl;
• heterocyclyl;
• heterocyclyl substituted with one or more Rhc;
• heteroaryl;
• and
• heteroaryl substituted with one or more Rha;
• wherein each of Ra, Rc, Rf1, Rf2, Rf3, Rf4, Rf5, Rf6, Rf7, Rhc and Rha is independently selected from the group consisting of acyl, alkyl, alkenyl, alkynyl, alkoxy, amide, amino, aryl, cyano, cycloalkyl, halogen, haloalkyl, haloalkoxy, heteroaryl, hydroxy, nitro, —C(O)OR9, —SO2R10, —SR11, —C(O)R12, —C(O)NR13, —NH—SO2—R14, —SO2—NR15R16, and —SO2—CH2—SO2—CH3;
• and wherein
• each of R9, R10, R11, R12, R13 R14, R15, and R16 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl.