发明名称 HETEROMAROMATIC COMPOUNDS USEFUL FOR THE TREATMENT OF PROLFERATIVE DISEASES
摘要 The present invention provides novel compounds of Formula (I) and Formula (II), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase, such as a cyclin-dependent kinase (CDK) (e.g., cyclin-dependent kinase 7 (CDK7)), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject. (I);
申请公布号 US2016264552(A1) 申请公布日期 2016.09.15
申请号 US201415030265 申请日期 2014.10.17
申请人 SYROS PHARMACEUTICALS, INC. 发明人 Ciblat Stephane;Deroy Patrick;Leblanc Melissa;Marineau Jason J.;Moore Joel;Roy Stephanie;Siddiqui M. Arshad;Sprott Kevin;Winter Dana K.;Kabro Anzhelika;Leger Serge;Miller Tom;Schmidt Darby;Bradley Michael
分类号 C07D401/14;A61K45/06;C07D417/14;C07D403/04;C07D413/14;A61K31/5377;C07D401/04;C07D417/04;C07D451/04;C07D403/14;A61K31/635;A61K31/506;C07D413/04 主分类号 C07D401/14
代理机构 代理人
主权项 1. A compound having the structural formula I:or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: ring A is an optionally substituted heteroaryl ring of any one of the Formulae (i-1)-(i-6):wherein: each instance of V1, V2, V3, V4, V5, V6, V7, V8, V9, V10, V11, V12, V13, V14 and V15 is independently O, S, N, N(RA1), C, or C(RA2); each instance of RA1 is independently selected from hydrogen, deuterium, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; each instance of RA2 is independently selected from hydrogen, deuterium, halogen, —CN, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORA2a, —N(RA2a)2, and —SRA2a, wherein each occurrence of RA2a is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or any two RA1, any two RA2, or one RA1 and one RA2 are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring; each X is independently selected from N and CH, wherein at least one X is N; W is selected from N and C(R1a); each of R1a, if present, and R1b is independently selected from hydrogen, deuterium, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —ORB1a, —N(RB1a)2 and —SRB1a, wherein each occurrence of RB1a is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R1a and R1b are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring; R2 is an optionally substituted C1-C4 alkylene or an optionally substituted C2-C4 alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene are optionally and independently replaced with —O—, —S—, or —N(R6)—; Q is selected from: R5,  and a 4-14 membered, divalent, fused or spirofused bicyclic ring system comprising a total of 0 to 4 ring heteroatoms independently selected from N, O and S, and optionally substituted with 1 to 6 independently selected R3, wherein: each ring in the bicyclic ring system is independently selected from heterocyclyl, carbocyclyl, aromatic or heteroaromatic,one atom in each ring of the bicyclic ring system is attached to the rest of the compound, andt is 0, 1, 2, 3, or 4;wherein each represents a portion of Q bound to the rest of the compound; and “*” represents a portion of Q bound to R2; each instance of R3, if present, is independently selected from deuterium, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORC1, —N(RC1)2, and —SRC1, wherein each occurrence of RC1 is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R3 groups bound to the same ring carbon atom are taken together to form ═O, or two R3 groups bound to the same or different ring carbon atoms are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring; R4 is selected from a bond, an optionally substituted C1-C4 alkylene, and an optionally substituted C2-C4 alkenylene or alkynylene, wherein: one or more methylene units of the alkylene, alkenylene or alkynylene other than a methylene unit bound to a nitrogen atom is optionally and independently replaced with —O—, —S—, —N(R6)—, or —S(═O)2—, andtwo substituents on either the same or adjacent carbon atoms in the alkylene, alkenylene or alkynylene are taken together to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; R5 is selected from a bond, an optionally substituted C1-C4 alkylene, and an optionally substituted C2-C4 alkenylene or alkynylene, wherein: one or more methylene units of the alkylene, alkenylene or alkynylene is optionally and independently replaced with —O—, —S—, —N(R6)—, or —S(═O)2—, andtwo substituents on either the same or adjacent carbon atoms in the alkylene, alkenylene or alkynylene are optionally taken together to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; each R6 is independently selected from hydrogen, and —C1-C6 alkyl; R7 is any one of the Formulae (ii-1)-(ii-20): wherein: R7 and Q are para or meta to each other;L3 is a bond, an optionally substituted C1-C7 alkylene, or an optionally substituted C2-C5 alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene are optionally and independently replaced with —O—, —S—, —S(O)—, —S(O)2, or —N(R6)—;L4 is a bond, an optionally substituted C1-C4 alkylene, or an optionally substituted C2-C4 alkenylene or alkynylene;each of RE1, RE2 and RE3 is independently selected from hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH2OR9, —CH2N(R9)2, —CH2SR9, —CN, —OR9, —N(R9)2, and —SR9, wherein each occurrence of R9 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, orRE1 and RE3, or RE2 and RE3, or RE1 and RE2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;RE4 is a leaving group;RE5 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH2ORE5a, —CH2N(RE5a)2, —CH2SRE5a, —ORE5a, —N(RE5a)2, and —SRE5a, wherein each occurrence of RE5a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two RE5a groups are joined to form an optionally substituted heterocyclic ring;Y is O, S, or N(RE6); wherein RE6 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;z is 0, 1, 2, 3, 4, 5, or 6; each instance of R8, if present, is independently selected from deuterium, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORD1, —N(RD1)2, and —SRD1, wherein each occurrence of RD1 is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, and optionally substituted aryl, optionally substituted heteroaryl, or two R8 groups are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14; and wherein the compound is other than:
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