发明名称 SUBSTITUTED ALDEHYDE COMPOUNDS AND METHODS FOR THEIR USE IN INCREASING TISSUE OXYGENATION
摘要 Provided are cycloalkyl- and cycloalkenyl-substituted benzaldehydes and heteroaldehydes of formula (I) that act as allosteric modulators of hemoglobin, methods and intermediates for their preparation, pharmaceutical compositions containing the modulators, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from increased tissue oxygenation.;
申请公布号 US2016039801(A1) 申请公布日期 2016.02.11
申请号 US201414776723 申请日期 2014.03.14
申请人 GLOBAL BLOOD THERAPEUTICS, INC. ;CYTOKINETICS, INC. 发明人 METCALF Brian;CHUANG Chihyuan;LI Zhe
分类号 C07D405/14;C07C62/36;C07D231/12;C07D233/64;C07D401/12;C07D405/04;C07D213/61;C07C47/575;C07D213/65;C07C69/757;C07D213/64 主分类号 C07D405/14
代理机构 代理人
主权项 1. A compound of Formula (I): or a tautomer or pharmaceutically acceptable salt thereof, wherein: Q is cycloalkyl or cycloalkenyl optionally substituted with one to three Ra; Y is O, S(O)q or CR1aR1b, where R1a is H or halo, andR1b is selected from the group consisting of H, halo, and OH; X is selected from the group consisting of O, S(O)q, CH(CH2)nR8, and C(R9)2, where q is 0, 1 or 2,n is 0 or 1,R8 is OH, andR9 is independently H or halo; or Y—X taken together is —NHC(O)— or —C(O)NH—; T1, T2, T3, and T4 are independently C or N provided that at least one of T1, T2, T3, and T4 is C; R2, R3, R4, and R5 are independently absent or selected from the group consisting of hydrogen, halo, Rb, ORd, —O(CH2)zORd, —O(CH2)zNRdRd, OC(O)Re, SRd, CN, NO2, CO2Rd, CONRdRd, C(O)Rd, OC(O)NRdRd, NRdRd, NRdC(O)Re, NRdC(O)2Re, NRdC(O)NRdRd, S(O)Re, S(O)2Re, NRdS(O)2Re, S(O)2NRdRd, and N3, where z is 0, 1, 2, 3, 4, 5, or 6; or R5 is —(CH2)pR5a, where p is 0 or 1 and R5a is OH; R6 and R7 together form oxo or an aldehyde protecting group, or R6 together with R1b, R8, or R5 forms a cyclic ether, where one of R1b, R8, or R5a is O, R6 is a bond, andR7 is selected from the group consisting of OH, C1-8alkoxy, and haloC1-8alkoxy; each Ra is independently selected from the group consisting of of halo, CN, Rb, ORd, O(CH2)uORd, O(CH2)uNRdRd, O(CH2)uNRdC(O)Re, O(CH2)uNRdC(O)2Re, O(CH2)uNRdS(O)2Re, NH2, —(CH2)kOC(O)Re, —(CH2)kSRd, NO2, —(CH2)kCO2(C1-8alkyl)OH, —(CH2)kCO2(C1-8alkyl)(heteroaryl)C(O)(C1-8alkyl), —(CH2)kCO2Rd, —(CH2)kCONRdRd, —(CH2)kNRdC(O)Re, —(CH2)kNRdC(O)2Re, —(CH2)k C(O)Rd, —(CH2)kOC(O)NRdRd, —NRd(CH2)uORd, —NRd(CH2)uNRdRd, —NRd(CH2)uNRdC(O)Re, —NRd(CH2)uNRdC(O)2Re, —NRd(CH2)uNRdS(O)2Re, —(CH2)kNRdC(O)Re, —(CH2)kNRdC(O)2Rd, —(CH2)kNRdC(O)NRdRd, —(CH2)kS(O)Re, —(CH2)kS(O)2Re, —(CH2)kNRdS(O)2Re, —(CH2)kS(O)2NRdRd, N3, —(CH2)karyl optionally substituted with one to three Rc, —NRd(CH2)karyl optionally substituted with one to three Rc, —(CH2)kheteroaryl optionally substituted with one to three Rc, —NRd(CH2)kheteroaryl optionally substituted with one to three Rc, —(CH2)kheterocycloalkyl optionally substituted with one to three Rc,  and —NRd(CH2)kheterocycloalkyl optionally substituted with one to three Rc where k is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6; each Rb is independently selected from the group consisting of C1-8alkyl, C2-8alkenyl, and C2-8 alkynyl, each optionally independently substituted with one to three halo, ORd, or NRdRd; each Rc is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, C2-8alkenyl, haloC2-8alkenyl, C2-8alkynyl, haloC2-8alkynyl, (CH2)mORf, OC(O)Rg, SRf, CN, NO2, CO2Rf, CONRfRf, C(O)Rf, OC(O)NRfRf, (CH2)mNRfRf, NRfC(O)Rg, NRfC(O)2Rg, NRfC(O)NRfRf, S(O)Rg, S(O)2Rg, NRfS(O)2Rg, S(O)2NRfRf, N3, heteroaryl optionally substituted with one to three Rh, cycloalkyl optionally substituted with one to three Rh, and heterocycloalkyl optionally substituted with one to three Rh where m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; each Rh is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, ORj, OC(O)R, SRj, NO2, CO2Rj, CONRjRj, C(O)Rj, OC(O)NRjRj, NRjRj, NRjC(O)Rt, NRjC(O)2Rt, NRjC(O)NRjRj, S(O)Rt, S(O)2Rt, NRjS(O)2Rt, and S(O)2NRjRj; each Rd is independently selected from the group consisting of hydrogen, C1-8 alkyl, haloC1-8alkyl, C2-8 alkenyl, haloC2-8alkenyl, C2-8 alkynyl, haloC2-8alkynyl, —(CH2)kheterocycloalkyl, and —(CH2)uO—(CH2)uH where k is 0, 1, 2, 3, 4, 5, or 6 and each u is independently 1, 2, 3, 4, 5, or 6; Rf and Rj are each independently selected from the group consisting of hydrogen, C1-8 alkyl, haloC1-8alkyl, C2-8 alkenyl, haloC2-8alkenyl, C2-8 alkynyl, and haloC2-8alkynyl; and Re, Rg, and Rt are each independently selected from the group consisting of C1-8alkyl, haloC1-8alkyl, C2-8 alkenyl, haloC2-8alkenyl, C2-8 alkynyl, and haloC2-8alkynyl; provided that X and Y are not both O; provided that when X is O, R1b is not OH; and provided that when Y is O, and n is 0, R8 is not OH.
地址 South San Francisco CA US