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US 12,582,641 B2Granted
Sulfur-containing compound based on glutarimide skeleton and application thereof
AssigneeShanghaitech University
InventorsXiaobao Yang, Biao Jiang, Xing Qiu, Ning Sun, Renhong Sun, Linyi Liu, Chaowei Ren
Life of this patent
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Abstract
The present disclosure relates to a compound of Formula (I) or a salt, a solvate, an isotopically enriched analog, a tautomer, a polymorph, a stereoisomer thereof, or a mixture of stereoisomers thereof, and their use for treating a tumor. The present disclosure also relates to a compound of Formula (I′) or a pharmaceutically acceptable salt, a solvate, an isotopically enriched analog, a tautomer, a polymorph, a stereoisomer thereof, or a mixture of stereoisomers thereof, and their use for treating a tumor.
Claims53
A compound of Formula (Ia)
- or a salt, a solvate, an isotopically enriched analog, a tautomer, a stereoisomer thereof, or a mixture of stereoisomers thereof, wherein
- A represents CH2 or C(O);
- Y represents O;
- and
- R, L, and X1 are as defined in the following (1) or (2);
- (1) R represents S, S(O), or S(O)2,
- L represents a linear or branched C1-40 alkylene group optionally substituted one or more substituent(s) selected from halogen, cyano, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, a 3- to 12-membered heterocyclyl, or any combination thereof, wherein the linear or branched C1-40 alkylene group is optionally interrupted one or more times by one or more groups selected from:
- O, C(O), S, S(O), S(O)2, C(O)N(R1), N(R2)C(O), N(R3), N(R4)C(O)N(R5), wherein R1, R2, R3, R4, and R5 each independently represent H or C1-3 alkyl,
- cycloalkylene optionally substituted with substituent(s) selected from the group consisting of halogen, cyano, C1-5 alkyl, C1-3 alkoxy, halogenated C1-3 alkyl, amino, hydroxyl, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, oxo, and any combination thereof,
- arylene optionally substituted with substituent(s) selected from the group consisting of C1-5 alkyl, halogenated C1-3 alkoxy, cyano, C1-3 alkoxy, halogenated C1-3 alkyl, halogen, amino, hydroxyl, methanesulfonyloxy, trifluoromethanesulfonyloxy, and p-toluenesulfonyloxy,
- heterocyclylene optionally substituted with substituent(s) selected from the group consisting of C1-5 alkyl, C1-3 alkoxy, cyano, trifluoromethyl, halogen, amino, hydroxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, and oxo,
- heteroarylene optionally substituted with substituent(s) selected from the group consisting of C1-5 alkyl, C1-3 alkoxy, cyano, trifluoromethyl, halogen, amino, hydroxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, and p-toluenesulfonyloxy,
- or any combination thereof;
- and
- X1 represents any one of (a1)-(a8) below:
- (a1) NR6R7, C(O)NReRf, NHC(O)R8, NHC(O)NR9R10, ORh, or SH, wherein R6, R7, Re, Rf, Rh, R9, and R10 each independently represent:
- (i) H;
- (ii) linear or branched C1-10 alkyl optionally substituted with one or more substituent(s) selected from halogen, cyano, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, a 3- to 12-membered heterocyclyl, or any combination thereof;
- (iii) cycloalkyl optionally substituted with substituent(s) selected from halogen, cyano, C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkyl, amino, hydroxyl, or any combination thereof;
- (iv) aryl optionally substituted with substituent(s) selected from C1-5 alkyl, halogenated C1-3 alkoxy, cyano, C1-3 alkoxy, halogenated C1-3 alkyl, halogen, amino, and hydroxyl;
- (v) heterocyclyl optionally substituted with substituent(s) selected from C1-5 alkyl, C1-3 alkoxy, cyano, trifluoromethyl, halogen, amino, and hydroxy;
- or (vi) heteroaryl optionally substituted with substituent(s) selected from C1-3 alkyl, C1-3 alkoxy, cyano, trifluoromethyl, halogen, amino, and hydroxy;
- wherein R6 and R7 are not H at the same time;
- and wherein R8 represents a linear or branched C1-8 alkyl, C5-C14 aryl, a 5- to 10-membered heteroaryl, or a 3- to 12-membered heterocyclyl;
- or
- wherein Re and Rf together with the nitrogen atom to which they are attached form a 5- to 8-membered heterocyclyl;
- or
- wherein R6 represents H, and R7 represents ethyl which is substituted with 2,6-dichloro-3-fluorophenyl;
- or
- wherein R6 represents H, and R7 represents thiazolyl which is substituted with C(O)NHRd, wherein Rd represents C1-5 alkyl or 2-chloro-6-methylphenyl;
- or
- wherein R6 represents H or methyl;
- and R7 represents a group of optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl, with each group being optionally substituted with substituent(s) selected from:
- (i) halogen, (ii) C1-5 alkyl, (iii) di(C1-6 alkyl)phosphono, (iv) C1-6 alkylsulfonyl, (v) oxo, (vi) cyano, (vii)6-membered aryl optionally substituted with substituent(s) selected from C1-6 alkyl, halogen and halogenated C1-3 alkyl, (viii) 5- or 6-membered heterocyclyl optionally substituted with substituent(s) selected from C1-6 alkyl and halogen, or (ix) 5- or 6-membered heteroaryl optionally substituted with substituent(s) selected from C1-6 alkyl and halogen;
- (a2) quaternary ammonium salt group having the Formula N+RaRbRcX−, wherein Ra, Rb, and Rc each independently represent C1-20 alkyl group, and X− represents F−, Cl−, Br−, or I−;
- or wherein Ra and Rb together with the nitrogen atom to which they are attached form 5- to 8-membered heterocyclyl, and the ring atoms of the 5- to 8-membered heterocyclyl optionally comprise a heteroatom selected from oxygen, nitrogen, and sulfur, and Rc represents C1-20 alkyl;
- and X− represents F−, Cl−, Br−, or I−;
- (a3) linear or branched C1-10 alkyl optionally substituted with one or more fluorine;
- (a4) cycloalkyl optionally substituted with substituent(s) selected from halogen, oxo, cyano, trifluoromethyl, amino, hydroxy, C1-3 alkoxy, halogenated C1-3 alkoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, C1-6 alkyl, C1-3 alkoxycarbonyl, or any combination thereof;
- (a5) aryl substituted with substituent(s) selected from halogenated C1-3 alkyl, amino, hydroxy, C1-3 alkoxy, halogenated C1-3 alkoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, C1-6 alkyl, halogenated C2-4 alkenyl, or any combination thereof;
- (a6) 4-(bromomethyl)-2-fluorophenyl;
- (a7) heteroaryl optionally substituted with substituent(s) selected from the group consisting of halogen, cyano, amino, hydroxy, C1-3 alkoxy, halogenated C1-3 alkoxy, halogenated C1-3 alkyl, bis(C1-6 alkyl)phosphono, C1-6 alkylsulfonyl, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, C1-6 alkyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heterocyclyl, optionally substituted 5- or 6-membered heteroaryl, and any combination thereof, wherein said optionally substituted phenyl is optionally substituted with substituent(s) selected from the group consisting of C1-6 alkyl, cyano, halogenated C1-3 alkyl, amino, hydroxyl, halogen, and any combination thereof;
- and said optionally substituted 5- or 6-membered heterocyclyl is optionally substituted with substituent(s) selected from the group consisting of:
- C1-6 alkyl, cyano, halogenated C1-3 alkyl, amino, hydroxyl, halogen, and any combination thereof;
- and said optionally substituted 5- or 6-membered heteroaryl is optionally substituted with substituent(s) selected from the group consisting of:
- C1-6 alkyl, halogenated C1-3 alkyl, amino, hydroxyl, halogen, and any combination thereof;
- or
- (a8) a group represented by Formula (G2):
- wherein, A1 represents CH2 or C(O);
- Y1 represents O;
- and
- Z represents S, S(O), or S(O)2;
- or
- (2) R represents S,
- L represents a linear or branched C1-40 alkylene group optionally substituted with one or more substituent(s) selected from halogen, cyano, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, a 3- to 12-membered heterocyclyl, or any combination thereof, wherein the linear or branched C1-40 alkylene group is optionally interrupted one or more times by one or more groups selected from:
- O, C(O), S, S(O), S(O)2, C(O)N(R1), N(R2)C(O), N(R3), N(R4)C(O)N(R5), wherein R1, R2, R3, R4, and R5 each independently represent H or C1-3 alkyl,
- cycloalkylene optionally substituted with substituent(s) selected from halogen, cyano, C1-5 alkyl, C1-3 alkoxy, halogenated C1-3 alkyl, amino, hydroxyl, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, oxo, or any combination thereof,
- arylene optionally substituted with substituent(s) selected from C1-5 alkyl, halogenated C1-3 alkoxy, cyano, C1-3 alkoxy, halogenated C1-3 alkyl, halogen, amino, hydroxyl, methanesulfonyloxy, trifluoromethanesulfonyloxy, and p-toluenesulfonyloxy,
- heterocyclylene optionally substituted with substituent(s) selected from C1-5 alkyl, C1-3 alkoxy, cyano, trifluoromethyl, halogen, amino, hydroxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, and oxo,
- heteroarylene optionally substituted with substituent(s) selected from C1-5 alkyl, C1-3 alkoxy, cyano, trifluoromethyl, halogen, amino, hydroxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, and p-toluenesulfonyloxy, or
- any combination thereof;
- and
- X1 represents:
- heterocyclyl optionally substituted with substituent(s) selected from halogen, cyano, amino, hydroxy, C1-3 alkoxy, halogenated C1-3 alkoxy, halogenated C1-3 alkyl, C1-6 alkylsulfonyl, bis(C1-6 alkyl)phosphono, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, oxo, optionally substituted 5- or 6-membered heterocyclyl, optionally substituted 5- or 6-membered heteroaryl, C1-6 alkyl, or any combination thereof, wherein said optionally substituted 5- or 6-membered heterocyclyl is optionally substituted with substituent(s) selected from:
- C1-6 alkyl, cyano, halogenated C1-3 alkyl, amino, hydroxyl, halogen, or any combination thereof;
- and said optionally substituted 5- or 6-membered heteroaryl is optionally substituted with substituent(s) selected from:
- C1-6 alkyl, halogenated C1-3 alkyl, amino, hydroxyl, halogen, or any combination thereof.
64 more elements
A compound of Formula (I′)
- or a salt, a solvate, an isotopically enriched analog, a tautomer, a stereoisomer thereof, or a mixture of stereoisomers thereof, wherein
- A represents CH2 or C(O);
- B, U, V, and W represent CH;
- Y represents O;
- R represents S, S(O), or S(O)2;
- L represents a linear or branched C1-40 alkylene group optionally substituted with one or more substituent(s) selected from halogen, cyano, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, a 3- to 12-membered heterocyclyl, or any combination thereof, wherein the linear or branched C1-40 alkylene group is optionally interrupted one or more times by one or more groups selected from:
- O, C(O), S, S(O), S(O)2, S(O)2N(R1), N(R2) S(O)2, C(O)N(R1), N(R2)C(O), N(R3), or N(R4)C(O)N(R5), wherein R1, R2, R3, R4, and R5 each independently represent H or C1-3 alkyl,
- cycloalkylene optionally substituted with substituent(s) selected from the group consisting of halogen, C1-5 alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, and oxo,
- arylene optionally substituted with substituent(s) selected from the group consisting of halogen, C1-5 alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy, and p-toluenesulfonyloxy,
- heterocyclylene optionally substituted with substituent(s) selected from the group consisting of halogen, C1-5 alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, and oxo,
- heteroarylene optionally substituted with substituent(s) selected from the group consisting of halogen, C1-5 alkyl, methanesulfonyloxy, trifluoromethanesulfonyloxy, and p-toluenesulfonyloxy, or
- any combination thereof;
- and
- L1 represents H or C1-3 alkyl;
- and
- wherein when L1 represents H,
- X1 represents NHC(O)Ri or SRj, wherein Ri and Rj each independently represent cycloalkyl optionally substituted with substituent(s) selected from C1-6 alkyl, oxo, halogen, cyano, trifluoromethyl, amino, hydroxy, C1-3 alkoxy, halogenated C1-3 alkoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, or any combination thereof, or
- X1 represents cycloalkyl optionally substituted with substituent(s) selected from C1-6 alkyl, oxo, halogen, cyano, trifluoromethyl, amino, hydroxy, C1-3 alkoxy, halogenated C1-3 alkoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, or any combination thereof;
- or
- when L1 represents C1-3 alkyl, X1 represents:
- NR6R7, wherein R6 represents H or C1-6 alkyl, and R7 represents cycloalkyl optionally substituted with substituent(s) selected from C1-6 alkyl, oxo, halogen, cyano, trifluoromethyl, amino, hydroxy, C1-3 alkoxy, C1-3 halogenated alkoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, or any combination thereof;
- or
- heterocyclyl, optionally substituted with substituent(s) selected from C1-6 alkyl, oxo, halogen, cyano, trifluoromethyl, amino, hydroxy, C1-3 alkoxy, halogenated C1-3 alkoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, or any combination thereof.
20 more elements
Dependencies are inferred from the claim text.