发明名称 SUBSTITUTED BENZALDEHYDE COMPOUNDS AND METHODS FOR THEIR USE IN INCREASING TISSUE OXYGENATION
摘要 Provided are substituted benzaldehydes and derivatives thereof that act as allosteric modulators of hemoglobin, methods and intermediates for their preparation, pharmaceutical compositions comprising the modulators, and methods for their use in treating disorders mediate by hemoglobin and disorders that would benefit from increased tissue oxygenation.
申请公布号 US2015344472(A1) 申请公布日期 2015.12.03
申请号 US201514662156 申请日期 2015.03.18
申请人 Global Blood Therapeutics, Inc. ;Cytokinetics, Inc. ;The Regents of the University of California 发明人 Metcalf Brian;Chuang Chihyuan;Warrington Jeffrey;Paulvannan Kumar;Jacobson Matthew P.;Hua Lan;Morgan Bradley
分类号 C07D471/04;C07D215/14;C07D257/04;C07D213/80;C07D211/62;C07D231/56;C07D401/04 主分类号 C07D471/04
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 selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl, each optionally substituted with one to three Ra; Y is O or CR1aR1b, where R1a is H or halo and R1b is selected from the group consisting of H, halo, and OH; X is selected from the group consisting of O, >CH(CH2)nR8, and C(R9)2 where n is 0 or 1, R8 is OH, and R9 is independently H or halo; or Y—X taken together is —NHC(O)— or —C(O)NH—; R2, R3, R4, and R5 are independently 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, and R7 is selected from the group consisting of OH, C1-8alkoxy, and haloC1-8alkoxy; each Ra is independently selected from the group consisting of halo, oxo, 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, CN, 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)kC(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 Re, —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 Re, —(CH2)kheterocycloalkyl optionally substituted with one to three Re, 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 Re is independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, C2-8alkenyl, haloC2-8 alkenyl, 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, 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; Rd, 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; provided that when Y is O, and n is O, R8 is not OH; and provided that when R6 and R7 together are oxo, Y is CH2, X is O or CH2, and R5 is H, halo, OH, CHO, or OCH3, then Q is V or W; V is selected from the group consisting ofand naphthalene containing three to four ring nitrogen atoms; wherein V is optionally substituted with one to three Ra; and W is selected from the group consisting of pyridin-2-yl, pyridin-3-yl, and pyridine-4-yl,wherein W is optionally substituted with one to three Ra or is substituted with one to three Ra when W is pyridin-2-yl, pyridin-3-yl, or pyridine-4-yl, and wherein the wavy line signifies the point of attachment to Y, provided that when V isoptionally substituted with one Ra, then at least one of R2, R3, R4, and R5 is ORd; and provided that when V isthen V is substituted with one to three Ra.
地址 South San Francisco CA US