Not anilinicos Derivatives of 1,1 dioxides fenilisotiazol - 3 (2H) - ona, Methods for their preparation, Pharmaceutical compositions containing them and their use for the manufacture of medicaments for the treatment of diseases mediated by Liver x receptor Modulation.

摘要

Derivatives of 1,1 dioxides fenilisotiazol - 3 (2H) - ona, processes for preparing such Compounds, to their utility for the Modulation of nuclear Hormone Receptors, Liver x receptor (LXR)? (Nr1h3) and / or? (NR1 H2) and / or in the treatment and Prevention of clinical conditions including cardiovascular diseases such as atherosclerosis, inflammatory diseases,Alzheimer's disease, Lipid Disorders (dyslipidemia) or not associated with insulin resistance, Type 2 Diabetes and other manifestations of the metabolic syndrome, to methods for their Therapeutic use and to pharmaceutical compositions containing them.Claim 1: a compound of General formula (1) or its Salt acceptable for pharmaceutical use, wherein R1 represents; X is optionally substituted with one or more of the following: F substituents selected regardless of, Oh, CN, nrara, Orb, SRB, sirbrbrb, RB, S (o) C (so2rb, RB, OR) (o) C (o) NRAC nrara, RB, C (OR) ora, OC (or RB), so2nrara, nraso2rb, NRAC (ORB), OC (or nrara NRAC), (OR) nrara,Or c1-4 alkyl is optionally substituted with one or more of the following: F substituents selected regardless of, Oh, CN, nrara, Orb, SRB, sirbrbrb, RB, S (o) C (o) so2rb, RB, or nrara (NRAC); r1 is heterociclilo or cycloalkyl or each optionally substituted with one or more of The following Selected substituents regardless of: F, Oh, CN, nrara, Orb, SRBSirbrbrb, S (OR) so2rb, RB, RB, C (o) C (o) nrara, NRAC (o) C (o) or RB, RB, OC (OR), so2nrara, nraso2rb, NRAC (ORB), OC (or nrara (NRAC), or nrara or rent) C1 - 4 which is optionally substituted with one or more of the following: F substituents selected regardless of, Oh, CN, nrara, Orb, SRB, sirbrb Rb, RB, so2rb s (o) C (o) C (o) nrara RB, RB, NRAC (o) C (o), ora, OC (or RB), so2nrara, nraso2rb, Orb (NRAC)OC (or nrara NRAC), or (OR) nrara or R1 is phenyl or heteroaryl each optionally substituted with one or more of the following: Selected regardless of halogen substituents (CL, F, BR, i) Oh, CN, NO2, nrara, Orb, SRB, sirbrbrb, S (o) so2rb, RB, RB, C (o) C (o) nrara, NRAC (or RB), C (OR) ora, OC (OR) Rb, so2nrara, nraso2rb, NRAC (ORB), OC (OR) nrara oso2rb NRAC (,, OR) nrara, so2nhc (or RB)Or c1-4 alkyl, optionally substituted with one or more of the following: F substituents selected regardless of, Oh, CN, nrara, Orb, SRB, sirbrbrb, S (OR) so2rb, RB, RB, C (o) C (o) nrara, NRAC (or RB), C (OR) ora oC (OR), RB, so2nrara, nraso2rb, NRAC (ORB), OC (or nrara NRAC), or (OR) nrara R1 is cycle; or Alquily or heterociclily,Cycloalkyl or heterociclilo where each one is optionally substituted with one or more of the following: F substituents selected regardless of, Oh, CN, nrara, Orb, SRB, sirbrbrb, S (OR) so2rb, RB, RB, C (o) C (o) nrara, NRAC (or RB, C (o) ORA), OC (or RB), so2nrara, nraso2rb, NRAC (ORB), OC (or ID) Ara (NRAC) nrara,Or c1-4 alkyl is optionally substituted with one or more of the following: F substituents selected regardless of, Oh, CN, nrara, Orb, SRB, sirbrbrb, S (OR) so2rb, RB, RB, C (o) C (o) nrara, NRAC (or RB, C (o) ora), OC (or RB), so2nrara, nraso2rb, NRAC (ORB), OC (or nrara (NRAC), or nrara or R1); and S fenily or heteroarily,PHENYL or heteroaryl where each is optionally substituted with one or more of the following: Selected regardless of halogen substituents (CL, F, BR, i) Oh, CN, NO2, nrara, Orb, SRB, sirbrbrb, S (OR) so2rb, RB, RB, C (o) C (o) nrara, NRAC (o) C (o) or RB, RB, OC (OR), so2nrara, nraso2rb, Orb (NRAC), OC (OR) nrara oso2rb NRAC (,, OR) nrara, so2nhc (or RB)Or c1-4 alkyl, optionally substituted with one or more of the following: F substituents selected regardless of, Oh, CN, nrara, Orb, SRB, sirbrbrb, S (OR) so2rb, RB, RB, C (o) C (o) nrara, NRAC (or RB), C (OR) ora oC (OR), RB, so2nrara, nraso2rb NRAC Orb, (OR), (OR) nrara, OCNRAC (OR) is nrara; R2 represents phenyl optionally substituted with one or more of the following: Selected regardless of halogen substituents (CL, F, BR, i) Oh, CN, NO2, nrara, Orb, SRB, sirbrbrb, S (OR) so2rb, RB, RB, C (o) (o) C (o) NRAC nrara, RB, C (OR) ora, OC (or RB), so2nrara, nraso2r (b) NRAC Orb, OC (OR) nrara oso2rb NRAC (,, OR) nrara, so2nhc (or RB)Or c1-4 alkyl, optionally substituted with one or more of the following: F substituents selected regardless of, Oh, CN, nrara, Orb, SRB, sirbrbrb, S (OR) so2rb, RB, RB, C (o) C (o) nrara, NRAC (or RB), C (OR) ora oC (OR), RB, so2nrara, nraso2rb NRAC Orb, (OR), (OR) nrara, OCNrara (NRAC); R3 represents x that is optionally substituted with one or more of the following: F substituents selected regardless of, Oh, CN, nrara, Orb, SRB, sirbrbrb, S (OR) so2rb, RB, RB, C (o) C (o) nrara, NRAC (or RB) C (OR), ora, OC (or RB), so2nrara, nraso2rb, NRAC (ORB), OC (or nrara (NRAC), Nrara), orOr c1-4 alkyl, optionally substituted with one or more of the following: F substituents selected regardless of, Oh, CN, nrara, Orb, SRB, sirbrbrb, S (OR) so2rb RB, RB, C (o), or (OR) or nrara NRAC; R3 is MP or het3p, where M and each het3 is optionally substituted in the Aromatic Ring Tico with one or more of the following: F substituents selected regardless of, Oh, CN,Nrara, Orb, SRB, sirbrbrb, RB, S (o) C (o) so2rb, RB, RB, NRAC (o) C (o) C (o) nrara, ora, OC (or RB), so2nrara, nraso2rb, NRAC (ORB), OC (or nrara (NRAC), or nrara QT), Q, r, het1, het1t, RT, he2, het2t or c1-4 alkyl, optionally substituted with one or more of the following Selected substituents which Ntemente: F, Oh, CN, nrara, Orb, SRB, sirbrbrb, S (OR) so2rb, RB, RB, C (o) C (o) nrara, NRAC (or RB)C (OR) ora, OC (or RB), so2nrara, nraso2rb, NRAC (ORB), OC (or nrara (NRAC), or nrara), and where M or het3 each is optionally substituted in the Aromatic Ring with one or more of the following selected regardless of halogen substituents (CI: F, I, BR), Oh, CN, nrara, Orb, SRB, sirbrbrb S (OR) so2rb, RB, RB, C (o) C (o) nrara, NRAC (o) C (o) or RB, RB, OC (OR), so2nrara, nraso2rb, Orb (NRAC)OC (OR) nrara oso2rb NRAC (,, OR) nrara, so2nrac (or RB), Q, QT, het1, het1t, r, RT, het2, het2t or c1-4 alkyl, optionally substituted with one or more of the following: F substituents selected regardless of, Oh, CN, nrara, Orb sirbrbrb, SRB, RB, S (o) C (o), so2rb, RB, C (or nrara (NRAC), or C (RB), or ORA), OC (or RB), so2nrara, nraso2rb, NRAC (ORB), OC (or nrara NRAC), (OR) or nrara; R3 is AP or het5p,And for het5 where each is optionally substituted with one or more of the following: sustltuyentes selected regardless of halogen (F, CL, BR, i) Oh, CN, NO2, nrara, Orb, SRB, sirbrbrb, S (OR) so2rb, RB, RB, C (o) C (o) nrara, NRAC (o) C (o) or RB, RB, OC (OR), so2nrara, nraso2rb, Orb (NRAC) OC (OR) nrara oso2rb NRAC (,, OR) nrara, so2nrbc (or RB), Q, QT, het1, het1t, r, RT, het2, het2t,Or c1-4 alkyl, optionally substituted with one or more of the following: F substituents selected regardless of, Oh, CN, nrara, Orb, SRB, sirbrbrb, S (OR) so2rb, RB, RB, C (o) C (o) nrara, NRAC (or RB), C (OR) ora oC (OR), RB, so2nrara, nraso2rb NRAC Orb, (OR), (OR) nrara, OCOr nrara (NRAC); or is or het4 R3 and each is optionally substituted in the Aromatic Ring with one or more of the following: F substituents selected regardless of, Oh, CN, nrara, Orb, SRB, sirbrbrb, S (OR) so2rb, RB, RB, C (or c) (o) nrara, NRAC (o) C (o) or RB, RB, OC (OR), so2nrara, NRAS O2rb, NRAC (ORB), OC (or nrara NRAC), (OR) nrara, QZ, het1, Q, r, het1z, RZ, het2, het2z,Or c1-4 alkyl, optionally substituted with one or more of the following: F substituents selected regardless of, Oh, CN, nrara, Orb, SRB, sirbrbrb, S (OR) so2rb, RB, RB, C (o) C (o) nrara, NRAC (or RB), C (OR) ora oC (OR), RB, so2nrara, nraso2rb, NRAC (ORB), OC (or nrara NRAC), (OR) nrara,And each het4 is optionally substituted in the Aromatic Ring with one or more of the following: Selected regardless of halogen substituents (CL, F, BR, i) Oh, CN, nrara, Orb, SRB, sirbrbrb, S (o) C (so2rb, RB, RB, C (o) or nrara NRAC), (o) C (o) or RB, RB, OC (OR), so2nrara, nraso2r (b) NRAC Orb, OC (OR) nrara oso2rb NRAC (,, OR) nrara, so2nrac (or RB), Q, QZ, het1, het1z, RZ, het2 het2z,,,Or c1-4 alkyl is optionally substituted with one or more of the following: F substituents selected regardless of, Oh, CN, nrara, Orb, SRB, sirbrbrb, S (OR) so2rb, RB, RB, C (o) C (o) nrara, NRAC (or RB, C (o) ora), OC (or RB), so2nrara, nraso2rb (NRAC), Orb, OC (NRAC) nrara, nrara and (OR); L The above definitions x represents a linear or branched alkyl group,Saturated or unsaturated with 1 to 6 carbon ATOMS, where the alkyl group can be optionally interrupted by sirbrb, o, S, S (o) C (o), SO2, NRA, OC (o) C (o) or (NRAC), C (OR) NRA so2nra or nraso2; and joins the nitrogen at position 2 of the isotiazol - 3 (2H) - 1,1 dioxide Ona and represents A group alquileno linear or branched, saturated or unsaturated with 1 to 3 carbon ATOMS,Where the alkyl group can be optionally interrupted or terminated by one of the following: o, S, sirbrb, S (o) C (o), SO2, OC (o) C (o) or NRCC (o) C (o) and / or NRC NRC, and is optionally substituted with one or more of the following: Oh substituents selected regardless of F CN, nrara, c1-4 alkyl, Orb, SRB, sirbrbrb,S (or RB) or so2rb; Z and E or het4 binds to one of the following: Q, R het1, or het2, alquileno Group and represents a linear or branched, saturated or unsaturated with 1 to 6 carbon ATOMS, where the Group alquileno can be optionally interrupted or terminated by one of the or, as follows: S, sirbrb, S (o) C (o), SO2, OC (o) C (o) or (NRAC), C (OR) NRA, the NRA, so2nra,Nraso2 or one of the following: o, S, sirbrb, S (o) C (o), SO2, OC (o) C (o) or (NRAC), C (OR) NRA, the NRA, so2nra, nraso2 and / or z is optionally substituted with one or more the following Selected substituents Regardless of: Oh, nrcrc, NS, F, C (or RC), Orb, SRC, sirbrbrb, S (or RC), so2rc, Phenyl fenilalquilo c1-3,C1-4 alkyl or which is optionally substituted with one or more of the following: F, Oh, nrara, SRB, sirbrbrb, S (or RB), so2rb, Orb; M represents a ring monocarbocu00edclico