Compounds and compositions as selective estrogen receptor degraders

摘要

The present invention relates to compounds of formula I:;in which n, m, X, Y1, R1, R2, R3, R4 and R5 are defined in the Summary of the Invention; capable of being both potent antagonists and degraders of estrogen receptors. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with aberrant estrogen receptor activity.

主权项

1. A compound of formula I: in which: n is selected from 0, 1 and 2; m is selected from 0, 1 and 2; X is selected from O and NR6; wherein R6 is C1-4alkyl; Y1 is selected from N and CR7; wherein R7 is selected from hydrogen and C1-4alkyl; R1 is hydrogen; R2 is selected from hydrogen and halo; R3 is selected from —CH2CH2R8b and —CR8a═CR8aR8b; wherein each R8a is independently selected from hydrogen, fluoro and C1-4alkyl; and R8b is selected from —C(O)OR9a, —C(O)NR9aR9b, —C(O)NHOR9a, —C(O)X2R9a and a 5-6 member heteroaryl selected from: wherein the dotted line indicates the point of attachment with —CH2CH2 or —CR8a═CR8a of R3; wherein X2 is C1-4alkylene; R9a and R9b are independently selected from hydrogen, C1-4alkyl, hydroxy-substituted-C1-4alkyl and halo-substituted-C1-4alkyl; wherein said heteroaryl of R8b is unsubstituted or substituted with a group selected from C1-4alkyl and C3-8cycloalkyl; R4 is selected from hydrogen, C1-4alkyl, halo and C1-3alkoxy; R5 is selected from C6-10aryl and a 5-6 member heteroaryl selected from: wherein the dotted line indicates the point of attachment with the benzothiophene core; wherein said C6-10aryl or heteroaryl of R5 is substituted with 1 to 3 R5a groups independently selected from hydroxy, amino, C1-4alkyl, halo, nitro, cyano, halo-substituted-C1-4alkyl, cyano-substituted-C1-4alkyl, hydroxy-substituted-C1-4alkyl, halo-substituted-C1-4alkoxy, C1-4alkoxy, —SF5, —NR11aR11b, —C(O)R11a and a 4-7 member saturated ring containing one other heteroatom or group selected from O, NH, and S(O)0-2; wherein R11a and R11b are independently selected from hydrogen and C1-4alkyl; or R11a and R11b together with the nitrogen to which they are both attached form a 4 to 7 member saturated ring containing one other heteroatom or group selected from O, NH, and S(O)0-2; wherein said 4-7 member ring of R5a can be unsubstituted or substituted with C1-4alkyl; or a pharmaceutically acceptable salt thereof.