Granted Patent B2

US 12,390,532 · App. 17/618,685 · Granted Aug 19, 2025

Inventors: Xiaobao Yang (Pudong Shanghai, CN); Biao Jiang (Pudong Shanghai, CN); Xiaoling Song (Pudong Shanghai, CN); Ning Sun (Pudong Shanghai, CN); Chaowei Ren (Pudong Shanghai, CN); Ying Kong (Pudong Shanghai, CN); Jianshui Zhang (Pudong Shanghai, CN); Jinju Chen (Pudong Shanghai, CN); Yan Li (Pudong Shanghai, CN); Yuedong Zhou (Pudong Shanghai, CN)

Assignee: SHANGHAITECH UNIVERSITY

A61K47/55A61K47/54A61K47/545A61K47/548A61P35/00

Abstract

Claims (70)

1. A compound represented by formula (I):

wherein ALK-TKIs are covalently connected to LIN through group A, and wherein ULM is covalently connected to LIN;

wherein group A represents C(O) or is absent;

ALK-TKIs represent the structure of the following formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie) or formula (If):

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 31 , R 32 , R 33 and R 34 each independently represents H or methyl, and R 13 and R 30 each independently represents H, methyl or ethyl;

the ULM represents the structure of the following formula (II):

wherein

B represents CH 2 or C(O); X, Y, Z, and W are the same or different and each independently represents CH or N; and R represents ethynylene; and

LIN is a linking group and represents —U-alkylene-, wherein

the alkylene is linear or branched alkylene optionally interrupted one or more times by one or more groups selected from the following groups: C(O)NH, NHC(O), O, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, heteroarylene, or any combination thereof, wherein the linear or branched alkylene is optionally substituted by one or more substituents, and

the group U represents C(O), or the group U is absent;

or a salt thereof, an enantiomer thereof, a stereoisomer thereof, a solvate thereof, a polymorph thereof.

2. The compound represented by formula (I) as defined in claim 1 , or the salt thereof, the enantiomer thereof, the stereoisomer thereof, the solvate thereof, the polymorph thereof, wherein the compound represented by formula (I) is also the compound represented by formula (Ia-1), formula (Ib-1), formula (Ic-1), formula (Id-1), formula (Ie-1) or formula (If-1):

3. The compound represented by formula (I) as defined in claim 1 , or the salt thereof, the enantiomer thereof, the stereoisomer thereof, the solvate thereof, the polymorph thereof, wherein the B represents CH2 or C(O); X, Y, Z, and W each independently represents CH; and R represents ethynylene.

4. The compound represented by formula (I) as defined in claim 1 , or the salt thereof, the enantiomer thereof, the stereoisomer thereof, the solvate thereof, the polymorph thereof, wherein the LIN represents:

—U—C 1-30 alkylene-, —U—(CH 2 ) n1 —(C(O)NH—(CH 2 ) n2 ) m1 —, —U—(CH 2 ) n1 —(NHC(O)—(CH 2 ) n2 ) m1 , —U—(CH 2 ) n1 —(O(CH 2 ) n2 ) m1 —, —U—(CH 2 ) n1 —(O(CH 2 ) n2 ) m1 —(O(CH 2 ) n3 ) m2 —, —U—(CR a1 R a2 ) n1 —(O(CR a3 R a4 ) n2 ) m1 —, —U—(CR a5 R a6 ) n1 —(O(CR a7 R a8 ) n2 ) m1 —(O(CR a9 R a10 ) n3 ) m2 —, —U—(CH 2 ) n1 —(C(O)NH—(CH 2 ) n2 ) m1 —(O(CH 2 ) n3 ) m2 —, —U—(CH 2 ) n1 —(O(CH 2 ) n2 ) m1 —O—(CH 2 ) n3 —C(O)NH—(CH 2 ) n4 —(O(CH 2 ) n5 ) m2 —O—(CH 2 ) n6 —, —U—(CR a11 R a12 ) n1 —(O(CR a13 R a14 ) n2 ) m1 —O—(CR a15 R a16 ) n3 —C(O)NH—(CR a17 R a18 ) n4 —(O(CR a19 R a20 ) n5 ) m2 —O—(CR a21 R a22 ) n6 —, —U—(CR a23 R a24 ) n1 —C(O)NH—(O(CR a25 R a26 ) n2 ) m1 —, —U—(CH 2 ) n1 —(NHC(O)—(CH 2 ) n2 ) m1 —(O(CH 2 ) n3 ) m2 —, linear or branched —U-alkylene chain-having the carbon chain interrupted one or more times by one or more groups selected from alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof, or —U—(CH 2 ) n1 —(O(CH 2 ) n2 ) m1 -having alkylene carbon chain interrupted one or more times by one or more groups selected from arylene, heterocyclylene, heteroarylene or any combination thereof;

wherein R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , R a10 , R a11 , R a12 , R a13 , R a14 , R a15 , R a16 , R a17 , R a18 , R a19 , R a20 , R a21 , R a22 , R a23 , R a24 , R a25 , R a26 each independently represents H, linear or branched C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl, wherein in the same LIN, R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , R a10 , R a11 , R a12 , R a13 , R a14 , R a15 , R a16 , R a17 , R a18 , R a19 , R a20 , R a21 , R a22 , or R a23 , R a24 , R a25 , R a26 are not H at the same time;

n1, n2, n3, n4, n5, n6, m1, m2 each independently represents an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and

the group U represents C(O), or the group U is absent; and

wherein, the alkylene in the LIN is optionally substituted by one or more substituents.

5. The compound represented by formula (I) as defined in claim 4 , or the salt thereof, the enantiomer thereof, the stereoisomer thereof, the solvate thereof, the polymorph thereof, wherein, the LIN represents —U—C 1-30 alkylene chain-, and the C 1-30 alkylene chain is optionally substituted by one or more substituents selected from hydroxyl, amino, mercapto, halogen or any combination thereof,

or the LIN represents —U—(CH 2 ) n1 —C(O)NH—(CH 2 ) n2 —, wherein n1 and n2 each independently represents an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20,

or the LIN represents —U—(CH 2 ) n1 —NHC(O)—(CH 2 ) n2 —, wherein n1 and n2 each independently represents an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

6. The compound represented by formula (I) as defined in claim 4 , or the salt thereof, the enantiomer thereof, the stereoisomer thereof, the solvate thereof, the polymorph thereof, wherein the LIN represents:

—U—CH 2 —; —U—(CH 2 ) 2 —; —U—(CH 2 ) 3 —; —U—(CH 2 ) 4 —; —U—(CH 2 ) 5 —; —U—(CH 2 ) 6 —; —U—(CH 2 ) 7 —; —U—(CH 2 ) 8 —; —U—(CH 2 ) 9 —; —U—(CH 2 ) 10 —; —U—(CH 2 ) 11 —; —U—(CH 2 ) 12 —; —U—(CH 2 ) 13 —; —U—(CH 2 ) 14 —; —U—(CH 2 ) 15 —; —U—(CH 2 ) 16 —; —U—(CH 2 ) 17 —; —U—(CH 2 ) 18 —; —U—(CH 2 ) 19 —; —U—(CH 2 ) 20 —; —U—(CH 2 ) 21 —; —U—(CH 2 ) 22 —; —U—(CH 2 ) 23 —; —U—(CH 2 ) 24 —; —U—(CH 2 ) 25 —; —U—(CH 2 ) 26 —; —U—(CH 2 ) 27 —; —U—(CH 2 ) 28 —; —U—(CH 2 ) 29 —; or —U—(CH 2 ) 30 —;

wherein the group U represents C(O), or the group U is absent,

or the LIN represents: —U—CH 2 C(O)NHCH 2 —, —U—CH 2 C(O)NH(CH 2 ) 2 —, —U—CH 2 C(O)NH(CH 2 ) 3 —, —U—CH 2 C(O)NH(CH 2 ) 4 —, —U—CH 2 C(O)NH(CH 2 ) 5 —, —U—CH 2 C(O)NH(CH 2 ) 6 , —U—CH 2 C(O)NH(CH 2 ) 7 —, —U—CH 2 C(O)NH(CH 2 ) 8 —, —U—CH 2 C(O)NH(CH 2 ) 9 —, —U—(CH 2 C(O)NH(CH 2 ) 10 —, —U—(CH 2 ) 2 C(O)NHCH 2 —, —U—(CH 2 ) 2 C(O)NH(CH 2 ) 2 —, —U—(CH 2 ) 2 C(O)NH(CH 2 ) 3 —, —U—(CH 2 ) 2 C(O)NH(CH 2 ) 4 —, —U—(CH 2 ) 2 C(O)NH(CH 2 ) 5 —, —U—(CH 2 ) 2 C(O)NH(CH 2 ) 6 —, —U—(CH 2 ) 2 C(O)NH(CH 2 ) 7 —, —U—(CH 2 ) 2 C(O)NH(CH 2 )—, —U—(CH 2 ) 3 C(O)NHCH 2 —, —U—(CH 2 ) 3 C(O)NH(CH 2 ) 2 —, —U—(CH 2 ) 3 C(O)NH(CH 2 ) 3 —, —U—(CH 2 ) 3 C(O)NH(CH 2 ) 4 —, —U—(CH 2 ) 3 C(O)NH(CH 2 ) 5 —, —U—(CH 2 ) 3 C(O)NH(CH 2 ) 6 —, —U—(CH 2 ) 3 C(O)NH(CH 2 ) 7 —, —U—(CH 2 ) 3 C(O)NH(CH 2 ) 3 —, —U—(CH 2 ) 4 C(O)NHCH 2 —, —U—(CH 2 ) 4 C(O)NH(CH 2 ) 2 —, —U—(CH 2 ) 4 C(O)NH(CH 2 ) 3 —, —U—(CH 2 ) 4 C(O)NH(CH 2 ) 4 —, —U—(CH 2 ) 4 C(O)NH(CH 2 ) 5 —, —U—(CH 2 ) 4 C(O)NH(CH 2 ) 6 —, —U—(CH 2 ) 5 C(O)NHCH 2 —, —U—(CH 2 ) 5 C(O)NH(CH 2 ) 2 —, —U—(CH 2 ) 5 C(O)NH(CH 2 ) 3 —, —U—(CH 2 ) 5 C(O)NH(CH 2 ) 4 —, —U—(CH 2 ) 5 C(O)NH(CH 2 ) 5 —, —U—(CH 2 ) 5 C(O)NH(CH 2 ) 6 —, —U—(CH 2 ) 6 C(O)NHCH 2 —, —U—(CH 2 ) 6 C(O)NH(CH 2 ) 2 —, —U—(CH 2 ) 6 C(O)NH(CH 2 ) 3 —, —U—(CH 2 ) 6 C(O)NH(CH 2 ) 4 —, —U—(CH 2 ) 6 C(O)NH(CH 2 ) 5 —, —U—(CH 2 ) 6 C(O)NH(CH 2 ) 6 —, —U—(CH 2 ) 6 C(O)NH(CH 2 ) 7 —, —U—(CH 2 ) 7 C(O)NHCH 2 —, —U—(CH 2 ) 7 C(O)NH(CH 2 ) 2 —, —U—(CH 2 ) 7 C(O)NH(CH 2 ) 3 —, —U—(CH 2 ) 7 C(O)NH(CH 2 ) 4 —, —U—(CH 2 ) 7 C(O)NH(CH 2 ) 5 —, —U—(CH 2 ) 7 C(O)NH(CH 2 ) 6 —, —U—(CH 2 ) 7 C(O)NH(CH 2 ) 7 —, —U—(CH 2 ) 8 C(O)NHCH 2 —, —U—(CH 2 ) 8 C(O)NH(CH 2 ) 2 —, —U—(CH 2 ) 8 C(O)NH(CH 2 ) 3 —, —U—(CH 2 ) 8 C(O)NH(CH 2 ) 4 —, —U—(CH 2 ) 8 C(O)NH(CH 2 ) 5 —, —U—(CH 2 ) 9 C(O)NH(CH 2 ) 6 —, —U—(CH 2 )C(O)NH(CH 2 ) 7 —, —U—(CH 2 )C(O)NH(CH 2 )—, —U—(CH 2 ) 9 C(O)NHCH 2 —, —U—(CH 2 ) 9 C(O)NH(CH 2 ) 2 —, —U—(CH 2 ) 9 C(O)NH(CH 2 ) 3 —, —U—(CH 2 ) 9 C(O)NH(CH 2 ) 4 —, —U—(CH 2 ) 9 C(O)NH(CH 2 ) 5 —, —U—(CH 2 ) 9 C(O)NH(CH 2 ) 6 —, —U—(CH 2 ) 9 C(O)NH(CH 2 ) 7 —, —U—(CH 2 ) 9 C(O)NH(CH 2 ) 8 —, —U—(CH 2 ) 9 C(O)NH(CH 2 ) 9 —, —U—(CH 2 ) 10 C(O)NHCH 2 —, —U—(CH 2 ) 10 C(O)NH(CH 2 ) 2 —, —U—(CH 2 ) 10 C(O)NH(CH 2 ) 3 —, —U—(CH 2 ) 10 C(O)NH(CH 2 ) 4 —, —U—(CH 2 ) 10 C(O)NH(CH 2 )N- or —U—(CH 2 ) 10 C(O)NH(CH 2 ) 10 —, or the LIN represents: —U—CH 2 NHC(O)CH—, —U—CH 2 NHC(O)(CH 2 ) 2 —, —U—CH 2 NHC(O)(CH 2 ) 3 —, —U—CH 2 NHC(O)(CH 2 ) 4 —, —U—CH 2 NHC(O)(CH 2 ) 5 —, —U—CH 2 NHC(O)(CH 2 ) 6 —, —U—CH 2 NHC(O)(CH 2 ) 7 —, —U—CH 2 NHC(O)(CH 2 ) 8 —, —U—CH 2 NHC(O)(CH 2 ) 9 —, —U—CH 2 NHC(O)(CH 2 ) 3 —, —U—(CH 2 ) 2 NHC(O)CH 2 —, —U—(CH 2 ) 2 NHC(O)(CH 2 ) 2 —, —U—(CH 2 ) 2 NHC(O)(CH 2 ) 3 —, —U—(CH 2 ) 2 NHC(O)(CH 2 ) 4 —, —U—(CH 2 ) 2 NHC(O)(CH 2 ) 5 —, —U—(CH 2 ) 3 NHC(O)CH 2 —, —U—(CH 2 ) 3 NHC(O)(CH 2 ) 2 —, —U—(CH 2 ) 3 NHC(O)(CH 2 ) 3 —, —U—(CH 2 ) 3 NHC(O)(CH 2 ) 4 —, —U—(CH 2 ) 3 NHC(O)(CH 2 ) 5 —, —U—(CH 2 ) 4 NHC(O)CH 2 —, —U—(CH 2 ) 4 NHC(O)(CH 2 ) 2 —, —U—(CH 2 ) 4 NHC(O)(CH 2 ) 3 —, —U—(CH 2 ) 4 NHC(O)(CH 2 ) 4 —, —U—(CH 2 ) 4 NHC(O)(CH 2 ) 5 —, —U—(CH 2 ) 4 NHC(O)(CH 2 ) 6 —, —U—(CH 2 ) 4 NHC(O)(CH 2 ) 7 —, —U—(CH 2 ) 5 NHC(O)CH 2 —, —U—(CH 2 ) 5 NHC(O)(CH 2 ) 2 —, —U—(CH 2 ) 5 NHC(O)(CH 2 ) 3 —, —U—(CH 2 ) 5 NHC(O)(CH 2 ) 4 —, —U—(CH 2 ) 5 NHC(O)(CH 2 ) 5 —, —U—(CH 2 ) 5 NHC(O)(CH 2 ) 6 —, —U—(CH 2 ) 6 NHC(O)CH 2 —, —U—(CH 2 ) 6 NHC(O)(CH 2 ) 2 —, —U—(CH 2 ) 6 NHC(O)(CH 2 ) 3 —, —U—(CH 2 ) 6 NHC(O)(CH 2 ) 4 —, —U—(CH 2 ) 6 NHC(O)(CH 2 ) 5 —, —U—(CH 2 ) 6 NHC(O)(CH 2 ) 6 —, —U—(CH 2 ) 6 NHC(O)(CH 2 ) 7 —, —U—(CH 2 ) 7 NHC(O)CH 2 —, —U—(CH 2 ) 7 NHC(O)(CH 2 ) 2 —, —U—(CH 2 ) 7 NHC(O)(CH 2 ) 3 —, —U—(CH 2 ) 7 NHC(O)(CH 2 ) 4 —, —U—(CH 2 ) 7 NHC(O)(CH 2 ) 5 —, —U—(CH 2 ) 7 NHC(O)(CH 2 ) 6 —, —U—(CH 2 ) 7 NHC(O)(CH 2 ) 7 —, —U—(CH 2 ) 8 NHC(O)CH 2 —, —U—(CH 2 ) 9 NHC(O)(CH 2 ) 2 —, —U—(CH 2 )NHC(O)(CH 2 ) 3 —, —U—(CH 2 )NHC(O)(CH 2 )—, —U—(CH 2 ) 9 NHC(O)CH 2 —, —U—(CH 2 ) 9 NHC(O)(CH 2 ) 2 —, —U—(CH 2 ) 9 NHC(O)(CH 2 ) 3 —, —U—(CH 2 ) 9 NHC(O)(CH 2 ) 9 —, or —U—(CH 2 ) 10 NHC(O)(CH 2 ) 10 —.

7. The compound represented by formula (I) as defined in claim 1 , or the salt thereof, the enantiomer thereof, the stereoisomer thereof, the solvate thereof, the polymorph thereof, wherein the compound is selected from:

8-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-yn-1-yl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hex-5-yn-1-yl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hept-6-yn-1-yl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-yn-1-yl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)non-8-yn-1-yl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

3-(4-(4-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)but-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-(5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-(6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)hex-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-(7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)hept-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-(8-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)oct-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-(9-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)non-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

8-(4-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)hex-5-ynoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)hept-6-ynoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

2-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl)piperidin-4-yl)piperazin-1-yl)-N-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)acetamide;

2-(4-(1-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl)piperidin-4-yl)piperazin-1-yl)-N-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hex-5-yn-1-yl)acetamide;

2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-N-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)acetamide;

2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-N-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hex-5-yn-1-yl)acetamide;

3-(4-(4-((1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)but-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-(5-((1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-(6-((1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)hex-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-(7-((1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)hept-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-(8-((1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-(methoxyphenyl)piperidin-4-yl)amino)oct-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-(9-((1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)non-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(5-(5-((1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(5-(6-((1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)amino)hex-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(5-(5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(5-(6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)hex-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

4-(5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)pent-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione;

3-(4-(5-((1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)(methyl)amino)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

8-(4-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-ynoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hex-5-ynoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hept-6-ynoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oct-7-ynoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

8-(4-(4-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)non-8-ynoyl)piperazin-1-yl)piperidin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;

3-(4-(5-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-5-oxopent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-(6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-6-oxohex-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-(7-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-7-oxohept-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;

3-(4-(8-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-8-oxooct-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; or

3-(4-(9-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)-9-oxonon-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

8. A pharmaceutical composition, comprising the compound represented by formula (I) as defined in claim 1 , the pharmaceutically acceptable salt thereof, the enantiomer thereof, the stereoisomer thereof, the solvate thereof or the polymorph thereof, and at least one pharmaceutically acceptable carrier.

9. A method for the treatment or prevention of anaplastic large cell lymphoma or triple negative breast cancer, comprising administering an effective amount of the compound represented by formula (I) as defined in claim 1 , the pharmaceutically acceptable salt thereof, the enantiomer thereof, the stereoisomer thereof, the solvate thereof or the polymorph thereof to a subject.

Assignments (1)

Priority Claims (1)

Continuity (1)

References Cited (24)