Substituted bicyclic compounds

摘要

Disclosed are compounds of Formulas (I), (II), (III), (IV), and (V):;
and/or a salt thereof, wherein R1 is —OH or —OP(O)(OH)2, and X1, X2, X3, R2, R2a, Ra, Rb, and Rc are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

主权项

1. A compound of Formulas (I): or a salt thereof, wherein: R1 is —OH or —OP(O)(OH)2; R2 is R2a or R2b; represents either a single bond to R2a or a double bond to R2b; R2a is —(CH2)3-6CH3, —(CH2)1-4CH═CRxRx, —(CH2)1-4CH═CRx(CH2CH3), —CH═CH(CH2)1-3C(Rx)3, —CH═CH(CH2)1-3OCH3, —(CH2)1-3CH═CHCH═CRxRx, —CH═CH(CH2)1-3CH═CRxRx, —CH═CHRz, —(CH2)1-3Rz, —(CH2)1-3O(CH2)0-3Rz, —(CH2)1-3S(CH2)0-3Rz, —CH2S(O)Rz, —CH2S(O)2Rz, —O(CH2)1-2Rz, —O(CH2)1-2O(CH2)0-2Rz, —OC(O)Rz, —(CH2)1-4O(CH2)0-9C(Rx)3, —(CH2)1-4O(CH2)0-9CF3, —(CH2)1-4CRxRxO(CH2)0-4C(Rx)3, —(CH2)1-3O(CH2)1-4CH═CRx(CH2)0-3CH3, —(CH2)1-30(CH2)1-4CH═CRxRx, —(CH2)1-3O(CH2)1-4C(OH)RxRx, —(CH2)1-3O(CH2)1-4O(CH2)0-3CH3, —(CH2)1-3S(CH2)0-4C(Rx)3, —(CH2)0-3O(CH2)1-4S(CH2)0-3C(Rx)3, —(CH2)1-3S(CH2)1-4Si(CH3)3, —(CH2)1-3S(O)(CH2)0-4C(Rx)3, —(CH2)1-3S(O)2(CH2)0-4C(Rx)3, —(CH2)1-5NRxRx, —O(CH2)1-7C(Rx)3, —O(CH2)1-4O(CH2)0-4C(Rx)3, —O(CH2)1-4CH═CRx(CH2)0-3CH3, —O(CH2)1-4O(CH2)0-3C(Rx)3, —O(CH2)1-4O(CH2)1-3CH═CRxRx, —O(CH2)1-4O(CH2)1-3C≡CRx, —C(O)(CH2)0-4C(Rx)3, —OC(O)(CH2)0-4C(Rx)3, —OC(O)CRxRx(CH2)0-4C(Rx)3, —OC(O)NRx(CH2)0-5C(Rx)3, —NRxC(O)NRx(CH2)0-5C(Rx)3, —C(CH3)═N—O(CH2)0-5C(Rx)3, —C(CH3)═N—O(CH2)1-2(phenyl), —C(CH3)═N—O(CH2)1-2(fluorophenyl), —C(CH3)═N—O(CH2)1-2(methoxyphenyl), phenyl, or pyridinyl; R2b is
(i) a 6-membered spiro-ring having one oxygen atom and substituted with Rb, wherein Rb is H or —(CH2)3CH3; or(ii) ═N—O—(CH2)3CH3, ═N—O—CH2CH(CH3)2, ═N—OCH2CH2(phenyl), or ═N—O—CH2CH2CH2(phenyl); Ra is H each Rb is H each Rc is H, each Rx is independently H or —CH3; and Rz is phenyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, thiophenyl, thiazolyl, oxetanyl, C3-6 cycloalkyl, adamantanyl, or tetrahydropyranyl, each substituted with zero to 4 substituents independently selected from F, Cl, I, C1-4 alkyl, —O(C1-3 alkyl), —CF3, —OCF3, —(CH2)1-6OCH3, —CH2NRxRx, —C(O)NRxRx, —C(O)NRx(C1-4 alkyl), and —CH2C(O)NRxRx; with the proviso that R2 is not —(CH2)5CH3.