发明名称 THERAPEUTIC COMPOUNDS AND USES THEREOF
摘要 The present invention relates to compounds of formula (I) or formula (II):;;and to salts thereof, wherein R1-R4 of formula (I) and R1-R3 of formula (II) have any of the values defined herein, and compositions and uses thereof. The compounds are useful as inhibitors of CBP and/or EP300. Also included are pharmaceutical compositions comprising a compound of formula (I) of formula (II) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various CBP and/or EP300-mediated disorders.
申请公布号 US2016158207(A1) 申请公布日期 2016.06.09
申请号 US201514952821 申请日期 2015.11.25
申请人 Constellation Pharmaceuticals, Inc. ;Genentech, Inc. 发明人 Adler Marc;Albrecht Brian K.;Bronner Sarah;Chen Kevin X.;Côté Alexandre;Crawford Terry;Cyr Patrick;Egen Jackson;Kauder Steven;Lai Kwong Wah;Liao Jiangpeng;Magnuson Steven;Murray Jeremy;Pastor Richard;Romero F. Anthony;Taylor Alexander M.;Tsui Vickie Hsiao-Wei;Wang Fei;Zhu Bing-Yan
分类号 A61K31/437;A61K31/538;A61K31/5415;A61K31/4709;A61K31/498;A61K45/06;A61K31/55;C07D519/00;A61K31/4375;A61K31/4725;A61K31/496;A61K31/5377;C07D471/04;A61K31/506 主分类号 A61K31/437
代理机构 代理人
主权项 1. A compound of formula (1) or formula (II):or a salt thereof, wherein: R1 of Formula (I) is C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R1 is optionally substituted with one or more groups Rb; R2 of Formula (I) is selected from C6-C20 aryl, C1-C20 heteroaryl, —(C6-C20 aryl)-(C1-C20 heteroaryl), —(C1-C20 heteroaryl)-(C6-C20 aryl), and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, —(C6-C20 aryl)-(C1-C20 heteroaryl) and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl) is independently optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —I, —NO2, —N(Ra)2, —CN, —C(O)—N(Ra)2, —S(O)—N(Ra)2, —S(O)2—N(Ra)2, —O—Ra, —S—Ra, —O—C(O)—Ra, —O—C(O)—O—Ra, —C(O)—Ra, —C(O)—O—Ra, —S(O)—Ra, —S(O)2—Ra, —O—C(O)—N(Ra)2, —N(Ra)—C(O)—ORa, —N(Ra)—C(O)—N(Ra)2, —N(Ra)—C(O)—Ra, —N(Ra)—S(O)—Ra, —N(Ra)—S(O)—S(Ra), —N(Ra)—S(O)—N(a)2, and —N(Ra)—S(O)2—N(Ra)2; R3 of Formula (I) is C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R3 is optionally substituted with one or more groups Re; or R2 and R3 of Formula (I) taken together with the nitrogen to which they are attached form a 3-12 membered heterocycle that is optionally substituted with one or more groups Re; R4 of Formula (I) is C1-4alkyl, C2-4alkenyl, C2-6alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, —C(O)—N(Rh)2, —S(O)—N(Rh)2, —S(O)2—N(Rh)2, —C(O)—Rh, —C(O)—O—Rh, —S(O)—Rh, or—S(O)2—Rh, wherein any C1-4alkyl, C2-4alkenyl, C2-4alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(Rh)2, —S(O)—N(Rh)2, —S(O)2—N(Rh)2, —O—Rh, —S—Rh, —O—C(O)—Rh, —O—C(O)—O—Rh, —C(O)—Rh, —C(O)—O—Rh, —S(O)—Rh, —S(O)2—Rh, —O—C(O)—N(Rh)2, —N(Rh)—C(O)—ORh, —N(Rh)—C(O)—N(Rh)2, —N(Rh)—C(O)—Ra, —N(Rh)—S(O)—Rh, —N(Rh)—S(O)2—Rh, —N(Rh)—S(O)—N(Rh)2, and —N(Rh)—S(O)2—N(Rh)2; each Ra of Formula (I) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-6alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rb of Formula (I) is independently selected from oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —O—C(O)—O—Rc, —C(O)—Rc, —C(O)—O—Rc, —S(O)—Rc, —S(O)2—Rc, —O—C(O)—N(Rc)2, —N(Rc)—C(O)—ORc, —N(Rc)—C(O)—N(Rc)2, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—S(O)2—Rc, —N(Rc)—S(O)—N(Rc)2, and —N(Rc)—S(O)2—N(Rc)2, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —C(O)—Rc, —C(O)—O—Rc, —S(O)—Rc, —S(O)2—Rc, —C(O)—N(Rc)2, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—S(O)2—R and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rc of Formula (I) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO2, —N(Rd)2, —CN, —C(O)—N(Rd)2, —S(O)—N(Rd)2, —S(O)2—N(Rd)2, —O—Rd, —S—Rd, —O—C(O)—Rd, —C(O)—Rd, —C(O)—O—Rd, —S(O)—Rd, —S(O)2—Rd, —C(O)—N(Rd)2, —N(Rd)—C(O)—Rd, —N(Rd)—S(O)—Rd, N(Rd)—S(O)2—Rd, and C1-4alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-6alkyl, cyano, —N(Rd)2, —O—Rd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6alkyl; each Rd of Formula (I) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-6alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Re of Formula (I) is independently selected from oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO2, —N(Rf)2, —CN, —C(O)—N(Rf)2, —S(O)—N(Rf)2, —S(O)2—N(Rf)2, —O—Rf, —S—Rf, —O—C(O)—Rf, —O—C(O)—O—Rf, —C(O)—Rf, —C(O)—O—Rf, —S(O)—Rf, —S(O)2—Rf, —O—C(O)—N(Rf)2, —N(Rf)—C(O)—ORf, —N(Rf)—C(O)—N(Rf)2, —N(Rf)—C(O)—Rf, —N(Rf)—S(O)—Rf, —N(Rf)—S(O)2—Rf, —N(Rf)—S(O)—N(Rf)2, and —N(Rf)—S(O)2—N(Rf)2, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO2, —N(Rf)2, —CN, —C(O)—N(Rf)2, —S(O)—N(Rf)2, —S(O)2—N(Rf)2, —O—Rf, —S—Rf, —O—C(O)—Rf, —C(O)—Rf, —C(O)—O—Rf, —S(O)—Rf, —S(O)2—Rf, —C(O)—N(R1)2, —N(Rf)—C(O)—Rf, —N(Rf)—S(O)—Rf, —N(Rf)—S(O)2—Rf, carbocycle, and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rf of Formula (I) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO2, —N(Rg)2, —CN, —C(O)—N(Rg)2, —S(O)—N(Rg)2, —S(O)2—N(Rg)2, —O—Rg, —S—Rg, —O—C(O)—Rg, —C(O)—Rg, —C(O)—O—Rg, —S(O)—Rg, —S(O)2—Rg, —C(O)—N(Rg)2, —N(Rg)—C(O)—Rg, —N(Rg)—S(O)—Rg, N(Rg)—S(O)2—Rg, and C1-6alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-6alkyl, cyano, —N(Rg)2, —O—Rg, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6alkyl; each Rg of Formula (I) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1alkoxy, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-6alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rg are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rh of Formula (I) is independently selected from hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, and C2-5cycloalkyl, wherein each C1-4alkyl, C2-4alkenyl, C2-4alkynyl, and C2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-3alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; and R1 of Formula (II) is selected from C6-C20 aryl, C1-C20 heteroaryl, —(C6-C20 aryl)-(C1-C20 heteroaryl), and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl), wherein each C6-C20 aryl, C1-C20 heteroaryl, —(C6-C20 aryl)-(C1-C20 heteroaryl) and —(C1-C20 heteroaryl)-(C1-C20 heteroaryl) is independently optionally substituted with one or more substituent groups independently selected from Rc, oxo, —F, —Cl, —Br, —I, —NO2, —N(Ra)2, —CN, —C(O)—N(Ra)2, —S(O)—N(Ra)2, —S(O)2—N(Ra)2, —O—Ra, —S—Ra, —O—C(O)—Ra, —O—C(O)—O—Ra, —C(O)—Ra, —C(O)—O—Ra, —S(O)—Ra, —S(O)2—Ra, —O—C(O)—N(Ra)2, —N(Ra)—C(O)—ORa, —N(Ra)—C(O)—N(Ra)2, —N(Ra)—C(O)—Ra, —N(Ra)—S(O)—Ra, —N(Ra)—S(O)2—Ra, —N(Ra)—S(O)—N(Ra)2, and —N(Ra)—S(O)2—N(Ra)2; R2 of Formula (II) is C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle, wherein each C1-12alkyl, C2-12alkenyl, C2-12alkynyl, 3-12 membered carbocycle, and 3-12 membered heterocycle of R2 is optionally substituted with one or more groups Rb; R3 of Formula (II) is C1-4alkyl, C2-4alkenyl, C2-4alkynyl, 3-5 membered carbocycle, 3-5 membered heterocycle, —C(O)—N(Re)2, —S(O)—N(Re)2, —S(O)2—N(Re)2, —C(O)—Re, —C(O)—O—Re, —S(O)—Re, or —S(O)2—Re, wherein any C1-4alkyl, C2-4alkenyl, C2-4alkynyl, 3-5 membered carbocycle, and 3-5 membered heterocycle is optionally substituted with one or more substituent groups independently selected from —F, —Cl, —Br, —I, 3-5 membered carbocycle, —C(O)—N(Re)2, —S(O)—N(Re)2, —S(O)2—N(Re)2, —O—Re, —S—Re, —O—C(O)—Re, —O—C(O)—O—Re, —C(O)—Re, —C(O)—O—Re, —S(O)—Re, —S(O)2—Re, —O—C(O)—N(Re)2, —N(Re)—C(O)—ORe, —N(Re)—C(O)—N(Re)2, —N(Re)—C(O)—Re, —N(Re)—S(O)—Re, —N(Re)—S(O)2—Re, —N(Re)—S(O)—N(Re)2, and —N(Re)—S(O)2—N(Re)2; each Ra of Formula (II) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-6alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Ra are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rb of Formula (II) is independently selected from oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —F, —Cl, —Br, —I, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Rc, —S—Rc, —O—C(O)—Rc, —O—C(O)—O—Rc, —C(O)—Rc, —C(O)—O—Rc, —S(O)—Rc, —S(O)2—Rc, —O—C(O)—N(Rc)2, —N(Rc)—C(O)—ORc, —N(Rc)—C(O)—N(Rc)2, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—S(O)2—Rc, —N(Rc)—S(O)—N(Rc)2, and —N(Rc)—S(O)2—N(Rc)2, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more groups independently selected from oxo, halo, —NO2, —N(Rc)2, —CN, —C(O)—N(Rc)2, —S(O)—N(Rc)2, —S(O)2—N(Rc)2, —O—Re, —S—Rc, —O—C(O)—Rc, —C(O)—Rc, —C(O)—O—Rc, —S(O)—Rc, —S(O)2—Rc, —C(O)—N(Rc)2, —N(Rc)—C(O)—Rc, —N(Rc)—S(O)—Rc, —N(Rc)—S(O)2—Rc and C1-6alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; each Rc of Formula (II) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein any C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, carbocyclyl, heterocyclyl, halo, —NO2, —N(Rd)2, —CN, —C(O)—N(Rd)2, —S(O)—N(Rd)2, —S(O)2—N(Rd)2, —O—Rd, —S—Rd, —O—C(O)—Rd, —C(O)—Rd, —C(O)—O—Rd, —S(O)—Rd, —S(O)2—Rd, —C(O)—N(Rd)2, —N(Rd)—C(O)—Rd, —N(Rd)—S(O)—Rd, N(Rd)—S(O)2—Rd, and C1-6alkyl, which carbocyclyl and C1-6alkyl are optionally substituted with one or more groups independently selected from oxo, halo, C1-6alkyl, cyano, —N(Rd)2, —O—Rd, heterocyclyl, and carbocyclyl that is optionally substituted with one or more groups independently selected from halo, and C1-6alkyl; each Rd of Formula (II) is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl, wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, carbocyclyl, and heterocyclyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-6alkoxy, carbocyclyl, heterocyclyl, and C1-C6 alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; or two Rd are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from oxo, halo and C1-3alkyl that is optionally substituted with one or more groups independently selected from oxo and halo; and each Re of Formula (II) is independently selected from hydrogen, C4alkyl, C2-4alkenyl, C2-4alkynyl, and C2-5cycloalkyl, wherein each C1-4alkyl, C2-4alkenyl, C2-4alkynyl, and C2-5cycloalkyl is optionally substituted with one or more groups independently selected from oxo, halo, amino, hydroxyl, C1-3alkoxy, and C1-C3 alkyl that is optionally substituted with one or more groups independently selected from halo; provided that R1 is not unsubstituted phenyl, when R2 is carboxymethyl or 2-carboxyethyl.
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