发明名称 Bromodomain inhibitors and uses thereof
摘要 The present invention relates to compounds useful as inhibitors of bromodomain-containing proteins. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
申请公布号 US9422292(B2) 申请公布日期 2016.08.23
申请号 US201214114983 申请日期 2012.05.04
申请人 Constellation Pharmaceuticals, Inc. 发明人 Albrecht Brian K.;Gehling Victor S.;Hewitt Michael Charles;Taylor Alexander M.;Harmange Jean-Christophe
分类号 A61K31/551;C07D471/14;C07D487/04 主分类号 A61K31/551
代理机构 McCarter & English, LLP 代理人 McCarter & English, LLP ;Davis Steven G.;DeGrazia Michael J.
主权项 1. A compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein: R1 is alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or halo, each of which is optionally substituted; or CN, ORA, NRARB, N(RC)S(O)qRARB, N(RA)C(O)RB, N(RC)C(O)NRARB, N(RA)C(O)ORA, N(RC)C(S)NRARB, S(O)qRA, C(O)RA, C(O)ORA, OC(O)RA, or C(O)NRARB; each RA is independently optionally substituted alkyl; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted carbocyclic; or hydrogen;each RB is independently optionally substituted alkyl; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted carbocyclic; or hydrogen;each RC is independently optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted carbocyclic; or hydrogen; each of A1, A2, A3, and A4 is independently CR, N, NR, O, or S; B is phenyl optionally substituted with 1 to 5 independently selected R4 groups; R2 and R3 are each independently H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, —OR, —SR, —CN, —N(R′)(R″), —C(O)R, —C(S)R, —CO2R, C(O)N(R′)(R″), —C(O)SR, or —(CH2)pRx; or R2 and R3 together with the atoms to which each is attached, forms an optionally substituted 3-7 membered saturated or partially unsaturated spiro-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R6 is H, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl —OR, —SR, —N(R′)(R″), —C(O)R, —CO2R, —C(O)N(R′)(R″), or —(CH2)pRx; R7 is H, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, —OR, —SR, —N(R′)(R″), —C(O)R, —CO2R, —C(O)N(R′)(R″), or —(CH2)pRx; or R6 and R7 together with the atoms to which each is attached, forms an optionally substituted 3-7 membered saturated or unsaturated spiro-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or any one of R2 and R3, together with any one of R6 and R7, together with the atoms to which each is attached, may form an optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl; each Rx is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, —OR, —SR, —CN, —N(R′)(R″), —C(O)R, —C(S)R, —CO2R, —C(O)N(R′)(R″), —C(O)SR, —C(O)C(O)R, —C(O)CH2C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO2R, —SO2N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″), —N(R′)C(S)N(R′)(R″), —N(R′)SO2R, —N(R′)SO2N(R′)(R″), —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR, —C(═N(R′))N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″); each R is independently hydrogen, C1-6 aliphatic, a 5-6 membered aryl ring, a 3-7 membered saturated, partially unsaturated, or completely unsaturated carbocyclic ring, a 7-12 membered bicyclic saturated, partially unsaturated, or completely unsaturated carbocyclic ring, a 3-7 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated, partially unsaturated, or completely unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered bicyclic saturated, partially unsaturated, or completely unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted; each R′ is independently —R, —C(O)R, —C(S)R, —CO2R, —C(O)N(R)2, —C(S)N(R)2, —S(O)R, —SO2R, —SO2N(R)2, or two R on the same nitrogen are taken together with their intervening atoms to form a 3-7 membered monocyclic saturated, partially unsaturated, or completely unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered bicyclic saturated, partially unsaturated, or completely unsaturated fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heteroaryl ring; or a 7-12 membered bicyclic heteroaryl; each of which is optionally substituted; each R″ is independently —R, —C(O)R, —C(S)R, —CO2R, —C(O)N(R)2, —C(S)N(R)2, —S(O)R, —SO2R, —SO2N(R)2, or two R on the same nitrogen are taken together with their intervening atoms to form a 3-7 membered monocyclic saturated, partially unsaturated, or completely unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered bicyclic saturated, partially unsaturated, or completely unsaturated fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heteroaryl ring; or a 7-12 membered bicyclic heteroaryl; each of which is optionally substituted; or R′ and R″, together with the atoms to which each is attached, can form a 3-7 membered monocyclic saturated, partially unsaturated, or completely unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered bicyclic saturated, partially unsaturated, or completely unsaturated fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heteroaryl ring; or a 7-12 membered bicyclic heteroaryl; each of which is optionally substituted; each R4 is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, halogen, —OR, —SR, —N(R′)(R″), —CN, —NO2, —C(O)R, —C(S)R, —CO2R, —C(O)N(R′)(R″), —C(O)SR, —C(O)C(O)R, —C(O)CH2C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO2R, —SO2N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″), —N(R′)C(S)N(R′)(R″), —N(R′)SO2R, —N(R′)SO2N(R′)(R″), —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR, —C(═N(R′))N(R′)(R″), —OC(O)R, or —OC(O)N(R1)(R″); each R5 is independently —R, halogen, —OR, —SR, —N(R′)(R″), —CN, —NO2, —C(O)R, —C(S)R, —CO2R, —C(O)N(R′)(R″), —C(O)SR, —C(O)C(O)R, —C(O)CH2C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO2R, —SO2N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″), —N(R′)C(S)N(R′)(R″), —N(R′)SO2R, —N(R′)SO2N(R′)(R″), —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR, —C(═N(R′))N(R′)(R″), —OC(O)R, or —OC(O)N(R1)(R″); r is 0 or 1; n is 0-5; each q is independently 0, 1, or 2; and each p is independently an integer selected from 1-6.
地址 Cambridge MA US