WO2023066350A1 - Crbn e3连接酶配体化合物、基于该配体化合物开发的蛋白降解剂及它们的应用 - Google Patents
Crbn e3连接酶配体化合物、基于该配体化合物开发的蛋白降解剂及它们的应用 Download PDFInfo
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- WO2023066350A1 WO2023066350A1 PCT/CN2022/126516 CN2022126516W WO2023066350A1 WO 2023066350 A1 WO2023066350 A1 WO 2023066350A1 CN 2022126516 W CN2022126516 W CN 2022126516W WO 2023066350 A1 WO2023066350 A1 WO 2023066350A1
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- Prior art keywords
- dioxopiperidin
- methyl
- dione
- alkyl
- diazabicyclo
- Prior art date
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Definitions
- the present disclosure relates to a cereblon (CRBN) E3 ubiquitin ligase ligand compound of formula (I) and formula (II), a protein degradation compound of formula (III) comprising the same, and applications thereof.
- the CRBN E3 ubiquitin ligase ligand compound can effectively treat or prevent diseases or diseases mediated by cereblon protein.
- the protein degrading compound of formula (III) is effective in treating or preventing diseases or conditions associated with the degraded protein.
- the bifunctional protein degradation targeting drug consists of three parts, one end is a ligand warhead that can bind to a specific target protein, the other end is a small molecule ligand of E3 ubiquitin ligase, and the middle is connected by link units of different lengths and types.
- Bifunctional protein-degrading small molecule compounds can use the binding effect of ligands at both ends to simultaneously bind specific target proteins and E3 ubiquitin ligases, thereby recruiting E3 ubiquitin ligases to the vicinity of specific target proteins, and enabling E3 ubiquitin ligases to The target protein is marked with ubiquitination. Target proteins marked by multiple ubiquitination are recognized and degraded by the proteasome in vivo.
- the biggest difference of protein degradation-targeted drugs is that the whole cell is mobilized as the drug effector unit.
- This drug mode of action only requires small molecule drugs to bind to the target protein briefly, and it is enough to label the target protein as "need to clean up". Therefore, a low concentration of drug dose can meet the requirements, greatly reducing the risk of off-target effects. And it may be able to fundamentally eliminate the tumor progression caused by the abnormal expression of the driver gene and the drug resistance caused by the acquired mutation of the driver gene.
- E3 ubiquitin ligases involved in the design of protein degradation-targeted drugs include more than 500 different proteins, each with different cellular expression profiles, and can be divided into multiple classes according to their structural elements of E3 functional activity. At present, only a few ligases have been successfully applied to the research of preclinical degraders, and Cereblon (CRBN) E3 ubiquitin ligase is one of the most widely used E3 ubiquitin ligases.
- CRBN-type E3 ubiquitin ligase ligands include thalidomide and its analogs pomalidomide and lenalidomide, all of which have a phthalimide skeleton.
- CRBN-type E3 ubiquitin ligase ligands themselves can also act as molecular glues to induce degradation of specific proteins. Cereblon (CRBN) forms a functional E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1) and Cullin 4 A. In the complex, CRBN functions as a substrate receptor, and molecules such as thalidomide After the glue degrading agent combines with CRBN, it will induce CRBN to recognize new substrate proteins to be ubiquitinated and further recognized and degraded by proteasome.
- DDB1 DNA-binding protein 1
- CRBN ligands have been widely used in protein degradation, and a series of CRBN ligand-based protein degradation small molecules that utilize the function of the CRBN E3 ubiquitin ligase complex have also been gradually developed. Since CRBN ligands can be used not only as molecular glue degraders to induce the degradation of different substrate proteins, but also as part of bifunctional protein degradation drugs to achieve effective degradation of specific disease-causing proteins, at the same time, a variety of amine compounds There are unavoidable side effects and drug resistance problems, so it is of great significance to design novel and optimized E3 ubiquitinated ligase ligands, and to study their ability to bind to CRBN and biological activity, and then apply them to biologics. Functional Protein Degradation Small Molecule Drugs.
- the purpose of the present disclosure is to provide novel CRBN ligands, protein degradation molecules designed based on the novel CRBN ligands and various target protein ligands, their uses, and their methods of use.
- An advantage of the compounds provided herein is that they can have a wide range of pharmacological activities through the degradation/inhibition of a variety of different pathogenic protein classes or families.
- the present disclosure provides a novel CRBN ligand, which itself can be used as a molecular glue to bind CRBN E3 ligase, and then induce CRBN substrate proteins (including but not limited to GSPT1, IKZF1, Degradation of IKZF2, IKZF3 (Aiolos) and IKZF4 proteins).
- CRBN substrate proteins including but not limited to GSPT1, IKZF1, Degradation of IKZF2, IKZF3 (Aiolos) and IKZF4 proteins.
- novel CRBN ligands of the present disclosure may be compounds of formula (I) or salts, stereoisomers (including enantiomers), solvates, isotopically enriched analogs, prodrugs or Polymorphs:
- A represents CO, CH2 or CD2 ;
- R 1 , R 2 , R 3 and R 4 are the same or different and independently represent, for example, hydrogen, deuterium, halogen, optionally deuterated C 1-6 alkyl, optionally deuterated C 1-6 alkane Oxygen, or halogenated C 1-6 alkyl;
- R 5 , R 6 , R 7 and R 8 are the same or different and each independently represents, for example, R 9 , hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, optionally deuterated C 1 -6 alkyl, optionally deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein R 5 , R 6 , R 1 to 3 of 7 and R 8 represent R 9 ;
- R 9 represents a group RU-, wherein,
- U represents a bond, or U represents N(R 10 ) or O, wherein R 10 represents, for example, H, or optionally deuterated C 1-6 alkyl;
- R represents an optionally substituted nitrogen-containing heterocyclic group, and the optionally substituted nitrogen-containing heterocyclic group is an optionally substituted nitrogen-containing monocyclic heterocyclic group or an optionally substituted nitrogen-containing bridging heterocyclic group;
- R 5 , R 6 , R 7 and R 8 represents R 9 and said compound of formula (I) is not deuterated:
- R represents the optionally substituted nitrogen-containing bridged heterocyclic group
- the compound of formula (I) does not include the following compounds:
- R 6 and R 7 represents R 9 , wherein the group R represents a substituted nitrogen-containing monocyclic heterocyclic group, and the other of R 6 and R 7 , R 5 and R 8 are each independently represents hydrogen, halogen, hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 2-6 alkenyl, or In the case of C2-6 alkynyl, the other of R6 and R7 , 1 to 3 of R5 and R8 represent halogen, and the nitrogen-containing monocyclic heterocyclic group is replaced by one or more Substituents selected from the following substituents: hydroxyl, amino, mercapto, nitro, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, NH 2 - C 1-6 alkylene, C 1-6 alkyl-NH-, C
- R 6 and R 7 When A represents CO and one of R 6 and R 7 represents R 9 , wherein the group R represents an unsubstituted nitrogen-containing monocyclic heterocyclic group, the other of R 6 and R 7 represents hydrogen, halogen, hydroxyl, Mercapto, nitro, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, and R 5 and R 8 each independently represent a halogen;
- R 5 and R 8 represents R 9 , wherein the group R represents a substituted nitrogen-containing monocyclic heterocyclic group, and the other of R 5 and R 8 , R 6 and R 7 are independently represents hydrogen, halogen, hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 2-6 alkenyl, or In the case of C2-6 alkynyl, the other of R5 and R8 , 1 to 3 of R6 and R7 represent halogen, and the nitrogen-containing monocyclic heterocyclic group is replaced by one or more Substituents selected from the following substituents: hydroxyl, amino, mercapto, nitro, halogen, cyano, CHO, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl-NH-,
- R represents an unsubstituted nitrogen-containing monocyclic heterocyclic group
- the other of R 5 and R 8 and/or R 7 is independently represents halogen
- R represents hydrogen, halogen, hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkyl, C 2 -6 alkenyl, or C 2-6 alkynyl;
- R 6 and R 7 represents R 9
- the group R represents a substituted nitrogen-containing monocyclic heterocyclic group
- the other of R 6 and R 7 , R 5 and R 8 are each independently represent hydrogen, halogen, hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl
- the other of R 6 and R 7 , 1 to 3 of R 5 and R 8 represent halogen
- the nitrogen-containing monocyclic heterocyclic group is replaced by one or A plurality of substituents selected from the following substitutions: hydroxyl, amino, mercapto, nitro, halogen, CHO, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkyl-NH-, NH 2
- R 6 and R 7 represents R 9 , wherein the group R represents an unsubstituted nitrogen-containing monocyclic heterocyclic group, R 5 represents halogen, the other of R 6 and R 7 and /or R 8 each independently represent halogen, hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 2-6 Alkenyl, or C 2-6 alkynyl;
- R 5 and R 8 represents R 9 , wherein the group R represents a substituted nitrogen-containing monocyclic heterocyclic group, and the other of R 5 and R 8 , R 6 and R 7 are each independently represent hydrogen, halogen, hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, the other of R 5 and R 8 , 1 to 3 of R 6 and R 7 represent halogen, and the nitrogen-containing monocyclic heterocyclic group is replaced by one or more Substituents selected from the following substituents: hydroxyl, amino, mercapto, nitro, halogen, CHO, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl, C 1 -6 alkoxy, C 1-6 alkyl-NH-, NH
- R 5 and R 8 represents R 9 , wherein the group R represents an unsubstituted nitrogen-containing monocyclic heterocyclic group
- R 5 and R 8 , R 6 and R 7 Each independently represents hydrogen, halogen, hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 2-6 alkenyl , or C 2-6 alkynyl
- the other of R 5 and R 8 , R 6 and R 7 are not hydrogen at the same time, and when R 6 is halogen, the R 5 and R 8 The other and R7 are not simultaneously hydrogen.
- the CRBN ligand of the present disclosure may be a compound of formula (II) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorphic form thereof thing:
- A represents CO, CH2 or CD2 ;
- R 1 , R 2 , R 3 and R 4 are the same or different and independently represent, for example, hydrogen, deuterium, halogen, optionally deuterated C 1-6 alkyl, optionally deuterated C 1-6 alkane Oxygen, or halogenated C 1-6 alkyl;
- R b represents that the benzene ring is substituted by n R b , and each R b is the same or different and independently represents, for example, hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano, or Select deuterated C 1-6 alkyl, optional deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
- R a (R a ) m means that the benzene ring is substituted by m R a , each R a is the same or different and each independently represents the following structure:
- U 1 and U 2 are the same or different and each independently represents, for example, a bond, N(R d ) or O, wherein R d represents, for example, H or optionally deuterated C 1-6 alkyl;
- R c represents an optionally substituted nitrogen-containing monocyclic heterocyclic group or an optionally substituted nitrogen-containing bridging heterocyclic group
- W represents hydrogen, an optionally substituted nitrogen-containing monocyclic heterocyclic group, an optionally substituted nitrogen-containing bridging heterocyclic group, an optionally substituted cycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted aryl group, C 2-6 alkenyl, C 2-6 alkynyl, leaving group, CHO, COOH, NH 2 , hydroxyl, or mercapto; and
- W represents an optionally substituted nitrogen-containing monocyclic heterocyclic group, an optionally substituted nitrogen-containing bridged heterocyclic group, an optionally substituted cycloalkyl group, an optionally substituted heteroaryl group or an optionally substituted aryl group
- LIN represents a bond, an optionally substituted methylene group, or an optionally substituted linear or branched C 2-30 alkylene group, wherein the main carbon of the linear or branched C 2-30 alkylene group is One or more groups R e and/or one or more groups R f or any combination of one or more groups R e and R f may optionally be inserted into the chain, said groups R e , R f Or the combination of the group R e and R f breaks the carbon-carbon bond between one or more pairs of adjacent carbon atoms of the main carbon chain; each group R e is selected from O, N(R g ), C(O), C(O)O, OC(O), S(O), S(O) 2 ,
- LIN represents optionally substituted methylene, or optionally substituted A linear or branched C 2-30 alkylene group, wherein the main carbon chain of the linear or branched C 2-30 alkylene group is optionally inserted with one or more groups R e and/ Or one or more groups R f or any combination of one or more groups R e and R f , the group R e , R f or the combination of groups R e and R f will make the main carbon chain
- each group R e is selected from O, N(R g ), C(O), C(O)O, OC(O), S(O), S(O) 2 , S(O) 2 NH, NHS(O) 2 , C(O)N(R g ), N(R
- LIN represents an optionally substituted methylene group
- W represents an optionally substituted nitrogen-containing monocyclic heterocyclic group or an optionally substituted nitrogen-containing bridged heterocyclic group
- n represents an integer 0, 1, 2, or 3
- the sum of m and n is an integer 1, 2, 3 or 4; provided that, when the compound of formula (II) When not being deuterated, the compound of formula (II) is not the following compound:
- the protein degrading molecules of the present disclosure are compounds of formula (III) or salts, stereoisomers (including enantiomers), solvates, isotopically enriched analogs, prodrugs or polymorphs thereof :
- PBM-R 1 -W 1 - represents the targeting moiety capable of binding protein
- ULM represents the ligand moiety capable of binding E3 ubiquitin ligase
- LIN is the linking moiety
- PBM-R 1 -W 1 - co-operates with the group LIN Valence connect ULM;
- ULM represents the structure of the following formula (ULM):
- A represents CO, CH2 or CD2 ;
- R 1 , R 2 , R 3 and R 4 are the same or different and independently represent, for example, hydrogen, deuterium, halogen, optionally deuterated C 1-6 alkyl, optionally deuterated C 1-6 alkane Oxygen, or halogenated C 1-6 alkyl;
- R b n means that the benzene ring is optionally substituted by n R b , and each R b is the same or different and each independently represents, for example, hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, amino, cyano Group, optional deuterated C 1-6 alkyl, optional deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl ;
- n represents the integer 0, 1, 2 or 3;
- U 1 and U 2 are the same or different and each independently represents, for example, a bond, N(R d ) or O, wherein R d represents, for example, H or optionally deuterated C 1-6 alkyl;
- R c represents an optionally substituted nitrogen-containing monocyclic heterocyclic group or an optionally substituted nitrogen-containing bridging heterocyclic group
- LIN represents a bond, an optionally substituted methylene group, or an optionally substituted linear or branched C 2-30 alkylene group, wherein the main carbon of the linear or branched C 2-30 alkylene group is One or more groups R e and/or one or more groups R f or any combination of one or more groups R e and R f may optionally be inserted into the chain, said groups R e , R f Or the combination of the group R e and R f breaks the carbon-carbon bond between one or more pairs of adjacent carbon atoms of the main carbon chain; each group R e is selected from O, N(R g ), C(O), C(O)O, OC(O), S(O), S(O) 2 , S(O) 2 NH, NHS(O) 2 , C(O)N(R g ), N(R g )C(O), or N(R g )C(O)N(R g ), wherein each R g independently represents H or C
- W 1 is t connected rings W 2 represented by the following structural formula:
- Each ring W is the same or different and each independently is an optionally substituted nitrogen-containing monocyclic heterocyclylene, an optionally substituted nitrogen-containing bridged heterocyclylene, or an optionally substituted cycloalkylene, and
- t represents the integer 1 or 2;
- R1 means:
- C 1-6 alkylene eg methylene
- R 1a is hydrogen or C 1-6 alkyl
- R 2a is optionally substituted C 1-6 alkylene or optionally substituted C 2- 6 alkenylene
- each R 3a is the same or different and each independently is, for example, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl , halogenated C 1-6 alkyl, C 1-6 alkoxy, or halogenated C 1-6 alkoxy;
- one or more hydrogens of the compound of formula (III) are optionally replaced by deuterium;
- the compound of formula (III) when the compound of formula (III) is not substituted by deuterium, the compound of formula (III) does not include the following compounds:
- R 1 represents a bond
- W 1 represents a piperidinylene group
- LIN represents a methylene group
- R c represents a piperazinylene group, 2,5-diazabicyclo[2.2.1]heptane Alkylidene, 8-azabicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3.1]nonaneylidene
- R b represents Fluorine
- n represents an integer 1, 2 or 3
- U1 and U2 are the same or different and each independently represents a bond, NH or O; or
- R 1 represents a bond
- W 1 represents a piperazinylene group
- LIN represents a methylene group
- R c represents a piperidinylene group, 2,5-diazabicyclo[2.2.1]heptane Alkylidene, 8-azabicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3.1]nonaneylidene
- R b represents Fluorine
- n represents an integer 1, 2 or 3
- U 1 and U 2 are the same or different and each independently represents a bond, NH or O;
- R 1 represents a bond
- W 1 represents piperidinylene
- LIN represents methylene
- R c represents piperazinylene, 2,5-diazabicyclo[2.2.1]heptane Alkylidene, 8-azabicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3.1]nonaneylidene
- R b represents Fluorine
- n represents an integer 1, 2 or 3
- U1 and U2 are the same or different and each independently represents a bond, NH or O; or
- R 1 represents a bond
- W 1 represents a piperazinylene group
- LIN represents a methylene group
- R c represents a piperidinylene group, 2,5-diazabicyclo[2.2.1]heptane Alkylidene, 8-azabicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3.1]nonaneylidene
- R b represents Fluorine
- n represents an integer 1, 2 or 3
- U 1 and U 2 are the same or different and each independently represents a bond, NH or O;
- R 1 represents a bond or -O-CH 2 -CH 2 -
- W 1 represents piperidinylene
- LIN represents methylene
- R c represents piperazinylene, 2,5- Diazabicyclo[2.2.1]heptaneylidene, 8-azabicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3. 1] nonane subgroup
- R represents hydrogen
- U and U are identical or different and each independently represents a bond, NH or O; or
- R 1 represents a bond or -O-CH 2 -CH 2 -
- W 1 represents piperazinylene
- LIN represents methylene
- R c represents piperidinylene, 2,5- Diazabicyclo[2.2.1]heptaneylidene, 8-azabicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3. 1] nonane subgroup
- R b represents hydrogen
- U 1 and U 2 are the same or different and each independently represents a bond, NH or O;
- R 1 represents a bond or represents -O-CH 2 -CH 2 -
- W 1 represents piperidinylene
- LIN represents methylene
- R c represents piperazinylene, 2,5 -Diazabicyclo[2.2.1]heptaneylidene, 8-azabicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3 .1]
- Nonaneylidene R b represents hydrogen
- U 1 and U 2 are the same or different and each independently represents a bond, NH or O; or
- R 1 represents a bond or represents -O-CH 2 -CH 2 -
- W 1 represents piperazinylene
- LIN represents methylene
- R c represents piperidinylene, 2,5 -Diazabicyclo[2.2.1]heptaneylidene, 8-azabicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3 .1]
- Nonaneylidene R b represents hydrogen
- U 1 and U 2 are the same or different and each independently represents a bond, NH or O.
- the present disclosure provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorphs, and at least one pharmaceutically acceptable carrier.
- the present disclosure provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (II) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorphs, and at least one pharmaceutically acceptable carrier.
- the present disclosure provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (III) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorphs, and at least one pharmaceutically acceptable carrier.
- kits or kit comprising:
- a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising it; or
- a compound of formula (II) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising it; or
- the present disclosure provides a compound of formula (I) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph thereof or comprising the same as A pharmaceutical composition of active ingredients for use as a medicament.
- the present disclosure further provides compounds of formula (I) or salts, stereoisomers (including enantiomers), solvates, isotopically enriched analogs, prodrugs or polymorphs thereof or comprising A pharmaceutical composition as an active ingredient for treating or preventing diseases or conditions mediated by cereblon protein.
- the diseases or conditions mediated by the cereblon protein include, but are not limited to, tumors, infectious diseases, autoinflammatory diseases, inflammatory diseases, autoimmune diseases, neurological diseases, respiratory diseases, anemia, Hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, congestive heart failure, myocardial infarction, Onwerichter's syndrome, Richter's syndrome (Richter syndrome, RS), acute liver failure or diabetes.
- tumors infectious diseases, autoinflammatory diseases, inflammatory diseases, autoimmune diseases, neurological diseases, respiratory diseases, anemia, Hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, congestive heart failure, myocardial infarction, Onwerichter's syndrome, Richter's syndrome (Richter syndrome, RS), acute liver failure or diabetes.
- MODS multiple organ dysfunction syndrome
- sarcoidosis sarcoidosis
- adult respiratory distress syndrome congestive heart failure
- the present disclosure provides a compound of formula (II) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph thereof or comprising the same as A pharmaceutical composition of active ingredients for use as a medicament.
- the present disclosure further provides compounds of formula (II) or salts, stereoisomers (including enantiomers), solvates, isotopically enriched analogs, prodrugs or polymorphs thereof or comprising A pharmaceutical composition as an active ingredient for treating or preventing diseases or conditions mediated by cereblon protein.
- the present disclosure provides a compound of formula (III) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph thereof or comprising the same as A pharmaceutical composition of active ingredients for use as a medicament.
- the present disclosure further provides compounds of formula (III) or salts, stereoisomers (including enantiomers), solvates, isotopically enriched analogs, prodrugs or polymorphs thereof or comprising Pharmaceutical composition as an active ingredient for the treatment and/or prophylaxis of a disease or condition selected from the group consisting of tumors, infectious diseases, autoinflammatory diseases, inflammatory diseases, autoimmune diseases, neurological diseases, respiratory diseases , anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, congestive heart failure, myocardial infarction, Wengwerricht syndrome, Richter Richter syndrome (RS), acute liver failure, diabetes, Kennedy disease, seborrheic alopecia, hirsutism, skin disease, cardiovascular disease, dysfunctional uterine bleeding, anemia, pediatric aplastic Anemia, endometriosis, transplant rejection, polycystic ovary syndrome, or thyroid disease.
- a disease or condition selected from the group consisting
- the present disclosure provides a compound of formula (I) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph thereof for use in the preparation of the present invention
- a compound of formula (I) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph thereof for use in the preparation of the present invention
- the present disclosure also provides the use of a compound of formula (I) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph for the preparation of the present invention.
- Disclosed methods are compounds of formula (III) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs or polymorphs thereof.
- the present disclosure provides a compound of formula (II) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph thereof for use in the preparation of the present invention
- a compound of formula (II) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph thereof for use in the preparation of the present invention
- the present disclosure also provides the use of a compound of formula (II) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug, or polymorph for the preparation of the present invention.
- Disclosed methods are compounds of formula (III) or salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs or polymorphs thereof.
- the present disclosure also provides compounds of formula (I) or salts, stereoisomers (including enantiomers), solvates, isotopically enriched analogs, prodrugs or polymorphs thereof for the preparation of Use of a medicament for treating or preventing a disease or condition mediated by a cereblon protein.
- the present disclosure also provides a compound of formula (II) or a salt thereof, a stereoisomer (including an enantiomer), a solvate, an isotopically enriched analog, a prodrug or a polymorph for preparing Use of a medicament for treating or preventing a disease or condition mediated by a cereblon protein.
- the present disclosure also provides a compound of formula (III) or its salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph for the preparation of Use of a medicament for the treatment and/or prevention of a disease or condition selected from the group consisting of tumors, infectious diseases, autoinflammatory diseases, inflammatory diseases, autoimmune diseases, neurological diseases, respiratory diseases, anemia, hemorrhagic shock, Transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoidosis, adult respiratory distress syndrome, congestive heart failure, myocardial infarction, Wengwericht syndrome, Richter syndrome (Richter syndrome, RS), acute liver failure, diabetes, Kennedy disease, seborrheic alopecia, hirsutism, skin disease, cardiovascular disease, dysfunctional uterine bleeding, anemia, pediatric aplastic anemia, endometriosis syndrome, transplant rejection, polycystic ovary syndrome, or thyroid disease.
- a disease or condition selected from the group consist
- the present disclosure also provides a method for treating or preventing a disease or condition mediated by a cereblon protein in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or Salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs or polymorphs thereof, or pharmaceutical compositions comprising them.
- the present disclosure also provides a method for treating or preventing a disease or condition mediated by a cereblon protein in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (II), or Salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs or polymorphs thereof, or pharmaceutical compositions comprising them.
- a method for treating or preventing a disease or condition mediated by a cereblon protein in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula (II), or Salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs or polymorphs thereof, or pharmaceutical compositions comprising them.
- the present disclosure also provides a method of treating or preventing a disease or condition in a subject, wherein the disease or condition comprises a tumor, an infectious disease, an autoinflammatory disease, an inflammatory disease, an autoimmune disease , neurological disease, respiratory disease, anemia, hemorrhagic shock, transplant rejection, multiple organ dysfunction syndrome (MODS), sarcoid disease, adult respiratory distress syndrome, congestive heart failure, myocardial infarction, Unwerich Tetra syndrome, Richter syndrome (RS), acute liver failure, diabetes, Kennedy disease, seborrheic alopecia, hirsutism, skin disease, cardiovascular disease, dysfunctional uterine bleeding , anemia, aplastic anemia in children, endometriosis, transplant rejection, polycystic ovary syndrome, and thyroid disease, the method comprising administering a therapeutically effective amount of a compound of formula (III) or Salts, enantiomers, stereoisomers, solvates, isotopically enriched analogs, prodrugs or poly
- Figure 1 shows that the compound of the present invention can effectively inhibit the proliferation of tumor cell line DU-145, and the inhibitory effect is better than that of the positive control drug enzalutamide.
- Figure 2 shows the degradative ability of the compounds of the present invention to full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) proteins in human prostate cancer cell 22RV1 detected by Western-blot.
- AR-FL full-length androgen receptor
- AR-V7 androgen receptor splice variant 7
- Fig. 3 shows the ability of the compound of the present invention to degrade the full-length androgen receptor (AR-FL) protein in human prostate cancer cell C4-2 detected by Western-blot.
- the present disclosure provides a compound of formula (I) or its salt (including pharmaceutically acceptable salt), stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph Model:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for the compound of formula (I).
- R 1 , R 2 , R 3 and R 4 of the compound of formula (I) are the same or different and each independently represent hydrogen, deuterium, halogen (such as fluorine, chlorine, bromine or iodine), optionally deuterium Substituted C 1-6 alkyl (such as optionally deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl) , optionally deuterated C 1-6 alkoxy (such as optionally deuterated C 1-4 alkoxy, such as methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy group, butoxy, sec-butyloxy or tert-butyloxy), or halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH
- R 1 , R 2 , R 3 and R 4 of the compound of formula (I) are the same or different and each independently represent hydrogen or deuterium.
- R 1 , R 2 , R 3 and R 4 of the compound of formula (I) represent hydrogen.
- a of the compound of formula (I) represents CO.
- a of the compound of formula (I) represents CH2 .
- a of the compound of formula (I) represents CD2 .
- the formula (I) compounds are optionally partially deuterated, for example carrying 1 to 20 (eg 1-15, 1-10, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) deuterium, or the compound of formula (I) is optionally fully deuterated.
- the number of deuterium atoms is in principle not subject to any restrictions or is automatically limited by the size of the building blocks.
- R 9 when only one of R 5 , R 6 , R 7 and R 8 of a compound of formula (I) represents R 9 , said compound of formula (I) is partially deuterated, for example carrying 1 to 15 (eg, 1-10, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) deuterium, or the compound of formula (I) is fully deuterated.
- the number of deuterium atoms is in principle not subject to any restrictions or is automatically limited by the size of the building blocks.
- R 5 of the compound of formula (I) represents R 9
- R 6 , R 7 and R 8 are the same or different and independently represent hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, amino , cyano, optional deuterated C 1-6 alkyl, optional deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 Alkynyl.
- R 6 of the compound of formula (I) represents R 9
- R 5 , R 7 and R 8 are the same or different and independently represent hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, amino , cyano, optional deuterated C 1-6 alkyl, optional deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 Alkynyl.
- R 7 of the compound of formula (I) represents R 9
- R 5 , R 6 and R 8 are the same or different and independently represent hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, amino , cyano, optional deuterated C 1-6 alkyl, optional deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 Alkynyl.
- R 8 of the compound of formula (I) represents R 9
- R 5 , R 6 and R 7 are the same or different and independently represent hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, amino , cyano, optional deuterated C 1-6 alkyl, optional deuterated C 1-6 alkoxy, halogenated C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 Alkynyl.
- R 5 , R 6 , R 7 and R 8 in a compound of formula (I) represents R 9 and said compound of formula (I) is not deuterated
- R represents When the optionally substituted nitrogen-containing bridged heterocyclic group, the compound of formula (I) does not include the following compounds:
- R 5 , R 6 , R 7 and R 8 in a compound of formula (I) represents R 9 and said compound of formula (I) is not deuterated
- A represents CO
- the group R represents a substituted nitrogen-containing monocyclic heterocyclic group
- the other of R 6 and R 7 , R 5 and R 8 each independently represent hydrogen , halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl (such as C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), C 1-6 alkoxy (e.g.
- C 1-4 alkoxy e.g. methoxy, ethoxy, propoxy, isopropoxy , butoxy, sec-butyloxy or tert-butyloxy
- halogenated C 1-6 alkyl such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH -, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), C 2-6
- alkenyl such as vinyl, propenyl or butynyl
- C 2-6 alkynyl such as ethynyl, propynyl or butynyl
- the other of R6 and R7 , R 1 to 3 (eg 1, 2 or 3) of 5 and R 8 represent halogen, and the nitrogen-containing monocyclic heterocyclic group is replaced by one
- R 6 and R 7 and R 8 in a compound of formula (I) represents R 9 and said compound of formula (I) is not deuterated
- A represents One of CO and R 6 and R 7 represents R 9
- the other of R 6 and R 7 represents hydrogen, halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl (such as C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl or tert-butyl), C 1-6 alkoxy (such as C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyl oxy or tert-butyloxy), halogenated C 1-6
- R and R each independently represent halogen (such as fluorine, chlorine, bromine or iodine).
- R 5 , R 6 , R 7 and R 8 in a compound of formula (I) represents R 9 and said compound of formula (I) is not deuterated
- A represents CO
- one of R 5 and R 8 represents R 9
- the group R represents a substituted nitrogen-containing monocyclic heterocyclic group
- the other of R 5 and R 8 , R 6 and R 7 each independently represent hydrogen , halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl (such as C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), C 1-6 alkoxy (e.g.
- C 1-4 alkoxy e.g. methoxy, ethoxy, propoxy, isopropoxy , butoxy, sec-butyloxy or tert-butyloxy
- halogenated C 1-6 alkyl such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH -, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), C 2-6
- alkenyl such as vinyl, propenyl or butynyl
- C 2-6 alkynyl such as ethynyl, propynyl or butynyl
- the other of R 5 and R 8 , R 1 to 3 (eg 1, 2 or 3) of 6 and R 7 represent halogen (eg fluorine, chlorine, bromine or iodine
- R 5 , R 6 , R 7 and R 8 in a compound of formula (I) represents R 9 and said compound of formula (I) is not deuterated
- A represents CO and one of R 5 and R 8 represents R 9
- the other of R 5 and R 8 and/or R 7 each independently represents a halogen
- R represents hydrogen, halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl (such as C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), C 1-6 alkoxy (e.g.
- C 1-4 alkoxy e.g. methoxy, ethoxy, propoxy group, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy
- halogenated C 1-6 alkyl eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -
- C 2-6 alkenyl eg vinyl, propenyl or butenyl
- C 2-6 alkynyl eg ethynyl, propynyl or butynyl.
- R 5 , R 6 , R 7 and R 8 in a compound of formula (I) represents R 9 and said compound of formula (I) is not deuterated
- A represents CH 2 and one of R 6 and R 7 represent R 9
- the group R represents a substituted nitrogen-containing monocyclic heterocyclic group
- the other of R 6 and R 7 , R 5 and R 8 each independently represent Hydrogen, halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl (such as C 1-4 alkyl, such as methyl, ethyl, propyl , isopropyl, butyl, sec-butyl or tert-butyl), C 1-6 alkoxy (such as C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy butoxy, sec-butyloxy or tert-butyl
- 1-6 e.g. 1, 2, 3, 4, 5 or 6) substituents selected from the group consisting of hydroxy, amino, mercapto, nitro, halogen (e.g. fluorine, chlorine, bromine or iodine), CHO, cyano, C 1-6 alkyl (e.g. C 1-4 alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1 -6 alkyl (e.g.
- halogenated C 1-4 alkyl such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), C 3-6 cycloalkyl (eg cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C 1-6 alkoxy (e.g. C1-4 alkoxy, e.g.
- C 1-6 alkyl-NH- such as C 1-3 alkyl NH-, such as CH 3 NH-, CH 3 CH 2 NH- or CH 3 CH 2 CH 2 NH-
- NH 2 -C 1- 6 alkylene eg NH 2 -C 1-3 alkylene-, eg NH 2 CH 2 -, NH 2 CH 2 CH 2 - and NH 2 CH 2 CH 2 CH 2 -
- C 1-6 alkyl -NHC(O)- such as CH 3 -NHC(O)-, CH 3 CH 2 -NHC(O)-, and CH 3 CH 2 CH 2 -NHC(O)-
- C 1-6 alkyl- C(O)NH- eg, CH3 -C( O )NH-, CH3CH2 -C(O)NH-, and CH3CH2CH2 - C
- R 5 represents halogen (such as fluorine, chlorine, bromine or iodine)
- R 6 and The other in R 7 and/or R 8 each independently represent halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl (such as C 1-6 4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), C 1-6 alkoxy (such as C 1-4 alkoxy, such as methoxy ethoxy, propoxy, iso
- R 5 , R 6 , R 7 and R 8 in a compound of formula (I) represents R 9 and said compound of formula (I) is not deuterated
- A represents CH 2 and one of R 5 and R 8 represent R 9
- the group R represents a substituted nitrogen-containing monocyclic heterocyclic group
- the other of R 5 and R 8 , R 6 and R 7 each independently represent Hydrogen, halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl (such as C 1-4 alkyl, such as methyl, ethyl, propyl , isopropyl, butyl, sec-butyl or tert-butyl), C 1-6 alkoxy (such as C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy butoxy, sec-butyloxy or tert-butyl
- R 5 , R 6 , R 7 and R 8 in a compound of formula (I) represents R 9 and said compound of formula (I) is not deuterated
- A represents One of CH 2 and R 5 and R 8 represents R 9
- the group R represents an unsubstituted nitrogen-containing monocyclic heterocyclic group
- the other of R 5 and R 8 , R 6 and R 7 are each independently Represents hydrogen, halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, mercapto, nitro, amino, cyano, C 1-6 alkyl (such as C 1-4 alkyl, such as methyl, ethyl, propyl radical, isopropyl, butyl, sec-butyl or tert-butyl), C 1-6 alkoxy (such as C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropyl oxy, butoxy, sec-butyl
- the group R of the compound of formula (I) R 9 represents an optionally substituted nitrogen-containing heterocyclic group, and the optionally substituted nitrogen-containing heterocyclic group is an optionally substituted nitrogen-containing mono Ring heterocyclyl or optionally substituted nitrogen-containing bridged heterocyclyl.
- the nitrogen-containing monocyclic heterocyclyl is a 4- to 10-membered monocyclic heterocyclyl containing one nitrogen atom and optionally a heteroatom selected from nitrogen, oxygen and sulfur, including but Not limited to the following groups: piperidinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, thiomorpholine radical, azepanyl, diazepanyl, azacyclooctyl or diazepanyl.
- the nitrogen-containing bridged heterocyclic group is a C5-20 bridged heterocyclic group containing a nitrogen atom and optionally a heteroatom selected from nitrogen, oxygen and sulfur, including but not limited to the following Group: azabicyclo[3.1.1]heptyl, azabicyclo[2.2.1]heptyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl , diazabicyclo[3.1.1]heptyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.2.1]octyl or diazabicyclo[2.2.2]octane Alkyl, for example, represents the following groups:
- the nitrogen-containing monocyclic heterocyclic group and the nitrogen-containing bridging heterocyclic group are optionally substituted.
- the nitrogen-containing monocyclic heterocyclic group and the nitrogen-containing bridging heterocyclic group are optionally replaced by one or more (for example, 1-10, 1-8 or 1-6, For example 1, 2, 3, 4, 5 or 6) are substituted with substituents selected from the group consisting of deuterium, hydroxyl, amino, mercapto, nitro, halogen (eg fluorine, chlorine, bromine or iodine), cyano, CHO, Optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert butyl), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C-
- the group R of the compound of formula (I) represents the following groups:
- the compound of formula (I) is also a compound of formula (I-1) or formula (I-2):
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined above for the compound of formula (I).
- the compound of formula (I) is also a compound of formula (I-3), formula (I-4), or formula (I-5):
- the present disclosure provides a compound of formula (II) or its salt (including pharmaceutically acceptable salt), stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph Model:
- R 1 , R 2 , R 3 and R 4 of the compound of formula (II) are the same or different and each independently represent hydrogen, deuterium, halogen (such as fluorine, chlorine, bromine or iodine), optionally deuterium Substituted C 1-6 alkyl (such as optionally deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl) , optionally deuterated C 1-6 alkoxy (such as optionally deuterated C 1-4 alkoxy, such as methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy group, butoxy, sec-butyloxy or tert-butyloxy), or halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, Cl
- R 1 , R 2 , R 3 and R 4 of the compound of formula (II) are the same or different and each independently represents hydrogen or deuterium.
- R 1 , R 2 , R 3 and R 4 of the compound of formula (II) represent hydrogen.
- a of the compound of formula (II) represents CO.
- a of the compound of formula (II) represents CH2 .
- a of the compound of formula (II) represents CD2 .
- n of the compound of formula (II) represents the integer 1
- n represents the integer 0, 1, 2, or 3.
- n of the compound of formula (II) represents the integer 2
- n represents the integer 0, 1 or 2.
- LIN represents a bond, optionally substituted methylene, or optionally substituted linear or branched C 2-30 alkylene, wherein one or more (such as 1-10, 1-8 or 1- 6, such as 1, 2, 3, 4, 5 or 6) groups R e and/or one or more (such as 1-10, 1-8 or 1-6, such as 1, 2, 3, 4, 5 or 6) groups R f or one or more (for example 1-10, 1-8 or 1-6, for example 1, 2, 3, 4, 5 or 6) groups Any combination of the group Re and R f , the group Re , R f or the combination of the group Re and R f will be one or more pairs of the main carbon chain (such as 1-10 pairs,
- W represents an optionally substituted nitrogen-containing monocyclic heterocyclic group
- W represents an optionally substituted nitrogen-containing monocyclic heterocyclic group
- LIN represents a bond, an optionally substituted methylene group, or an optional Substituted linear or branched C 2-30 alkylene, wherein one or more (for example 1-10 one, 1-8 or 1-6, for example 1, 2, 3, 4, 5 or 6) groups R e and/or one or more (for example 1-10, 1-8 or 1 -6, eg 1,2,3,4,5 or 6) groups R f or one or more (eg 1-10, 1-8 or 1-6, eg 1,2,3 , 4, 5 or 6) any combination of groups Re and R f , the group Re ,
- optionally deuterated C 1-4 alkoxy such as methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy
- optionally deuterated C 1-6 alkyl-NH- such as optionally deuterated C 1-3 alkyl NH-, such as CH 3 NH-, CH 3 CH 2 NH- or CH 3 CH 2 CH 2 NH-
- halogenated C 1-6 alkyl eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -
- NH 2 -C 1-6 alkylene eg NH 2 -C 1-3 alkylene-, such as NH 2 CH 2 -
- methylene group and the linear or branched C2-30 alkylene group are optionally replaced by one or more (for example 1-10, 1-8 or 1-6, for example 1, 2, 3, 4, 5 or 6) are substituted with substituents selected from the group consisting of deuterium, hydroxyl, amino, mercapto, nitro, halogen (eg fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 alkyl (e.g.
- optionally deuterated C 1-4 alkyl such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl
- halogen Substituted C 1-6 alkyl such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -
- optionally deuterated C 3-6 cycloalkyl such as optionally perdeuterated cyclopropyl , optional perdeuterated cyclobutyl, optional perdeuterated cyclopentyl or optional perdeuterated cyclohexyl
- optionally deuterated C 1-6 alkoxy such as optionally deuterated C 1-4 alkoxy, such
- LIN represents optionally substituted methylene, or optionally substituted linear or branched C 2-30 alkylene, wherein the linear or branched One or more (such as 1-10, 1-8 or 1-6, such as 1, 2, 3, 4, 5 or 6) can optionally be inserted into the main carbon chain of C 2-30 alkylene ) group R e and/or one or more (for example 1-10, 1-8 or 1-6, for example 1, 2, 3, 4, 5 or 6) groups R f or one or Any combination of multiple (for example 1-10, 1-8 or 1-6, for example 1, 2, 3, 4, 5 or 6) groups R e and R f , said group R e , R f or the combination of group R e and R f will be one or more pairs
- C 1-6 alkoxy e.g. optionally deuterated C 1-4 alkoxy, e.g. methoxy, CD 3 -O-, ethoxy, propoxy , isopropoxy, butoxy, sec-butyloxy or tert-butyloxy
- optionally deuterated C 1-6 alkyl-NH- such as optionally deuterated C 1-3 alkane -NH-, such as CH 3 NH-, CH 3 CH 2 NH- or CH 3 CH 2 CH 2 NH-
- halogenated C 1-6 alkyl such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -
- NH- optionally deuterated C 1-6 alkyl-NH-
- LIN represents optionally substituted methylene, or optionally substituted linear or branched C 2-30 alkylene, wherein One or more (such as 1-10, 1-8 or 1-6, such as 1, 2, 3 , 4, 5 or 6) groups R e and/or one or more (for example 1-10, 1-8 or 1-6, for example 1, 2, 3, 4, 5 or 6) Group R f or any combination of one or more (eg 1-10, 1-8 or 1-6, eg 1, 2, 3, 4, 5 or 6) groups R e and R f , the group R e , R f or the combination of the group R e and R f combine one or more pairs of the main carbon chain (for example 1-10 pairs
- deuterated C 1-4 alkyl such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl
- deuterated C 3-6 Cycloalkyl e.g.
- methylene group and the linear or branched C2-30 alkylene group are optionally replaced by one or more (for example 1-10, 1-8 or 1-6, for example 1, 2, 3, 4, 5 or 6) are substituted with substituents selected from the group consisting of deuterium, hydroxyl, amino, mercapto, nitro, halogen (eg fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 alkyl (e.g.
- optionally deuterated C 1-4 alkyl such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl
- halogen Substituted C 1-6 alkyl such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -
- optionally deuterated C 3-6 cycloalkyl such as optionally perdeuterated cyclopropyl , optional perdeuterated cyclobutyl, optional perdeuterated cyclopentyl or optional perdeuterated cyclohexyl
- optionally deuterated C 1-6 alkoxy such as optionally deuterated C 1-4 alkoxy, such
- LIN represents optionally substituted methylene
- W represents optionally substituted nitrogen-containing monocyclic heterocyclyl or optionally substituted nitrogen-containing monocyclic heterocyclyl or Nitrogen-bridged heterocyclyl
- methylene group is optionally substituted by one or more (eg 1 or 2) substituents selected from the group consisting of deuterium, hydroxyl, amino, mercapto, nitro, halogen (eg fluorine, chlorine, bromine or iodine ), cyano, optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH -, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), optionally deuterated C 1-6 al
- optionally deuterated C 1-4 alkoxy e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy
- optionally deuterated C 1-6 alkyl-NH- such as optionally deuterated C 1-3 alkyl-NH-, such as CH 3 NH-, CH 3 CH 2 NH- or CH 3 CH 2 CH 2 NH-
- NH 2 -C 1-6 alkylene eg NH 2 -C 1-3 alkylene-, eg NH 2 CH 2 -, NH 2 CH 2 CH 2 - and NH 2 CH 2 CH 2 CH 2 -
- optionally deuterated C 1-6 alkyl-NHC(O)- such as optionally deuterated C 1-4 alkyl-NHC(O)-,
- R represents piperazinyl
- W represents optionally substituted nitrogen-containing mono
- the piperazinyl is substituted.
- the piperazinyl represented by R c is substituted with 1-4 (eg 1-3 or 1-2, eg 1, 2, 3 or 4) substituents selected from the group consisting of deuterium, Hydroxy, amino, mercapto, nitro, halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, CHO, optionally deuterated C1-6 alkyl (e.g.
- optionally deuterated C1-4 alkyl such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl
- halogenated C 1-6 alkyl such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -
- optionally deuterated C 3-6 cycloalkyl such as optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl
- optionally deuterated C 1-6 alkoxy such as optionally deuterated C 1-4 alkoxy, such as me
- the methylene represented by LIN is optionally substituted with one or more (e.g., 1 or 2) substituents selected from the group consisting of deuterium, hydroxyl, amino, mercapto, nitro, halogen (e.g., fluoro , chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 alkyl (e.g.
- optionally deuterated C 1-4 alkyl such as methyl, CD 3 , ethyl, propyl, iso propyl, butyl, sec-butyl or tert-butyl
- halogenated C 1-6 alkyl eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -
- optionally deuterated C 3 -6 cycloalkyl such as optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl
- optionally deuterated Substituted C 1-6 alkoxy such as optionally deuterated C
- the nitrogen-containing monocyclic heterocyclic group represented by W is optionally replaced by one or more (such as 1-10, 1-8 or 1-6, such as 1, 2, 3, 4, 5 or 6) substituents selected from the group consisting of deuterium, hydroxyl, amino, mercapto, nitro, halogen (eg fluorine, chlorine, bromine or iodine), cyano, CHO, COOH, N 3 , methanesulfonyloxy Base, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally substituted C 3-8 Cycloalkyl (such as one or more, such as 1-6, such as 1, 2, 3, 4, 5 or 6, selected from deuterium, halogen, amino, hydroxyl, mercapto, cyano, CHO, COOH, Substituents of N 3
- R c of the compound of formula (II) represents the following groups:
- a monocyclic C3-10 heterocyclylene containing a nitrogen atom and optionally a heteroatom selected from nitrogen, oxygen and sulfur for example, piperidinylene, piperazinylene, morpholinylene, nitrogenous Heterocyclobutyl, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinyl, thiazolidinylene, thiomorpholinyl, azepanylidene, diazepine Heptylidene, azacyclooctylene or diazacyclooctylene; or
- azabicyclo[3.1.1]heptaneylidene azabicyclo[2.2 .1] heptaneylidene, azabicyclo[3.2.1]octanylidene, azabicyclo[2.2.2]octanylidene, diazabicyclo[3.1.1]heptaneylidene, diazo Heterobicyclo[2.2.1]heptaneylidene, diazabicyclo[3.2.1]octanylidene or diazabicyclo[2.2.2]octanylidene, for example the following groups:
- the monocyclic C 3-10 heterocyclylene and the C 5-20 bridged heterocyclylene are each independently optionally replaced by one or more (for example 1-10, 1-8 or 1-6, for example 1, 2, 3, 4, 5 or 6) are substituted with substituents selected from the group consisting of deuterium, hydroxyl, amino, mercapto, nitro, halogen (such as fluorine, chlorine, bromine or iodine), cyano, CHO, Deuterated C 1-6 alkyl (such as optionally deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl group), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CH
- R c of the compound of formula (II) represents the following groups:
- W of the compound of formula (II) represents the following groups:
- a monocyclic C3-10 heterocyclic group containing a nitrogen atom and optionally a heteroatom selected from nitrogen, oxygen and sulfur for example, piperidinyl, piperazinyl, morpholinyl, azetidinyl, Pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, thiomorpholinyl, azepanyl, diazepanyl, azacyclooctyl, or diazepine Cyclooctyl; or
- a C5-20 bridged heterocyclic group containing a nitrogen atom and optionally a heteroatom selected from nitrogen, oxygen and sulfur for example, azabicyclo[3.1.1]heptanyl, azabicyclo[2.2.1 ]heptyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, diazabicyclo[3.1.1]heptanyl, diazabicyclo[2.2.1] ]heptyl, diazabicyclo[3.2.1]octyl or diazabicyclo[2.2.2]octyl, such as the following groups:
- Saturated or partially unsaturated monocyclic or bicyclic or polycyclic C 3-20 cycloalkyl for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl , cyclooctyl, decahydronaphthyl, octahydrocyclopentadienyl, octahydro-1H-indenyl, C 7-11 spirocycloalkyl, adamantyl, noradamantyl, bornyl, bicyclic [2.2.1]heptyl or bicyclo[2.2.1]heptenyl; or
- Heteroaryl for example, a 5- to 20-membered monocyclic ring containing 1 or more (eg 1-4, eg 1, 2, 3 or 4) heteroatoms independently selected from oxygen, nitrogen and sulfur or Bicyclic C5-20 aromatic ring groups, for example, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazole Base, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuryl, isobenzofuryl, benzothienyl, indole Azolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl
- C5-14 aryl optionally comprising one or more (eg 1-3, eg 1, 2 or 3) fused rings, eg, phenyl or naphthyl or fluorenyl; and
- the monocyclic C 3-10 heterocyclic group, the C 5-20 bridged heterocyclic group, the C 3-20 cycloalkyl, the heteroaryl and the C 5-14 aryl are each independently Optionally substituted with one or more (e.g. 1-10, 1-8 or 1-6, e.g.
- perdeuterated C 1-3 alkyl-NH- such as CD 3 NH-, CD 3 CD 2 NH- or CD 3 CD 2 CD 2 NH-
- NH 2 -C 1-6 alkylene eg NH 2 -C 1-3 alkylene-, eg NH 2 CH 2 -, NH 2 CH 2 CH 2 - and NH 2 CH 2 CH 2 CH 2 -
- deuterated C 1-6 alkyl-NHC(O)- such as perdeuterated C 1-4 alkyl-NHC(O)-, such as CD 3 -NHC(O)-, CD 3 CD 2 - NHC(O)-, and CD 3 CD 2 CD 2 -NHC(O)-
- the LIN of the compound of formula (II) represents the structure of the following formula:
- each group R e is selected from O, N(R g ), C(O), C(O)O, OC(O), S(O), S(O) 2 , S(O) 2 NH , NHS(O) 2 , C(O)N(R g ), N(R g )C(O), or N(R g )C(O)N(R g ), wherein each R g independently represents H or C 1-6 alkyl; each group R is selected from cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene, alkenylene or any combination thereof, wherein The cycloalkylene group, the arylene group, the heterocyclylene group and the heteroarylene group are independently of each other optionally further selected from deuterium, an optionally deuterated C 1-6 alkyl group (such as may be deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropy
- One or more (eg 1-30 ) CH hydrogens of the C 1-30 alkylene group are optionally further replaced by substituents selected from: deuterium, hydroxyl, amino, mercapto, nitro, halogen (such as fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl group, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH -, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), optionally deuterated
- optionally deuterated C 1-4 alkoxy e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy , butoxy, sec-butyloxy or tert-butyloxy
- optionally deuterated C 1-6 alkyl-NH- such as optionally deuterated C 1-3 alkyl-NH-, such as CH 3 NH-, CH 3 CH 2 NH- or CH 3 CH 2 CH 2 NH-
- NH 2 -C 1-6 alkylene eg NH 2 -C 1-3 alkylene-, eg NH 2 CH 2 -, NH 2 CH 2 CH 2 - and NH 2 CH 2 CH 2 CH 2 -
- optionally deuterated C 1-6 alkyl-NHC(O)- such as optionally deuterated C 1-4 Alkyl-NHC(O)-, such as CH3 -NHC(O)-, CH3CH2 - NHC(O)-, and CH3CH2CH2 -
- R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 and R a8 independently represent H, deuterium, hydroxyl, amino, mercapto, nitro, halogen (such as fluorine, chlorine, bromine or iodine) ), cyano, optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH -, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH
- optionally deuterated C 1-4 alkoxy e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy
- optionally deuterated C 1-6 alkyl-NH- such as optionally deuterated C 1-3 alkyl-NH-, such as CH 3 NH-, CH 3 CH 2 NH- or CH 3 CH 2 CH 2 NH-
- NH 2 -C 1-6 alkylene eg NH 2 -C 1-3 alkylene-, eg NH 2 CH 2 -, NH 2 CH 2 CH 2 - and NH 2 CH 2 CH 2 CH 2 -
- optionally deuterated C 1-6 alkyl-NHC(O)- such as optionally deuterated C 1-4 alkyl-NHC(O)-,
- the symbol # indicates the point of attachment to the group U ;
- n1, n2, n3, n4, m1, m2, m3 are each independently selected from integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
- the LIN of the compound of formula (II) represents the structure of the following formula:
- each R independently represents H or C 1-6 alkyl (such as C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl) ;
- the cycloalkylene group, the arylene group, the heterocyclylene group and the heteroarylene group are independently of each other optionally further selected from deuterium, optionally deuterated C 1-6 alkyl (for example optionally deuterated C 1-4 alkyl such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 3- 6 Cycloalkyl (eg, optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl, or optionally perdeuterated cyclohexyl), hydroxyl, amino, Mercapto, halogen (such as fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 alkoxy (such as optionally deuterated C 1-4 alkoxy, such as methoxy, CD 3 -O -, eth
- R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 and R a8 independently represent H, deuterium, hydroxyl, amino, mercapto, nitro, halogen (such as fluorine, chlorine, bromine or iodine) ), cyano, optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH -, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH
- optionally deuterated C 1-4 alkoxy e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy
- optionally deuterated C 1-6 alkyl-NH- such as optionally deuterated C 1-3 alkyl-NH-, such as CH 3 NH-, CH 3 CH 2 NH- or CH 3 CH 2 CH 2 NH-
- NH 2 -C 1-6 alkylene eg NH 2 -C 1-3 alkylene-, eg NH 2 CH 2 -, NH 2 CH 2 CH 2 - and NH 2 CH 2 CH 2 CH 2 -
- optionally deuterated C 1-6 alkyl-NHC(O)- such as optionally deuterated C 1-4 alkyl-NHC(O)-,
- the symbol # indicates the point of attachment to the group U ;
- n1, n2, n3, n4, m1, m2, m3 are each independently selected from integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
- LIN of the compound of formula (II) represents the following group:
- the piperidinylene and the piperazinylene are independently from each other optionally further selected from deuterium, optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-4 alkane group, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 3-6 cycloalkyl (such as optionally perdeuterated cyclopropyl, optionally perdeuterated cyclobutyl, optionally perdeuterated cyclopentyl or optionally perdeuterated cyclohexyl), hydroxyl, amino, mercapto, halogen (such as fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 alkoxy (such as optionally deuterated C 1-4 alkoxy, such as methoxy, CD 3 -O-, ethoxy, propoxy, iso propoxy, but
- Each R independently represents H or C 1-6 alkyl (such as C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl);
- the symbol # indicates the point of attachment to the group U ;
- n1, n2, n3, n4, m1, m2, m3 are each independently selected from integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
- R of the compound of formula (II) represents the following groups:
- the compound of formula (II) is also a compound of formula (II-1) or formula (II-2):
- R 1 , R 2 , R 3 , R 4 , (R b ) n and (R a ) m are as defined above for compounds of formula (II) and embodiments thereof.
- the compound of formula (II) is also a compound of formula (II-3) or formula (II-4):
- the compound of formula (II) is also a compound of formula (II-5), formula (II-6), formula (II-7), or formula (II-8):
- R 1 , R 2 , R 3 , R 4 , (R b ) n and Ra are as defined above for compounds of formula (II) and embodiments thereof.
- A represents CO, CH2 or CD2 ;
- R 1 , R 2 , R 3 and R 4 are the same or different and independently represent hydrogen, deuterium, halogen (such as fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 alkyl (such as optional Deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 1-6 alkoxy (e.g.
- C 1-4 alkoxy such as methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy
- halogenated C 1-6 alkyl such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH- , CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -);
- R b n means that the benzene ring is substituted by n R b , and each R b is the same or different and independently represents hydrogen, deuterium, halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, mercapto, nitro , amino, cyano, optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl , sec-butyl or tert-butyl), optionally deuterated C 1-6 alkoxy (such as optionally deuterated C 1-4 alkoxy, such as methoxy, CD 3 -O-, ethoxy radical, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as
- n represents the integer 0, 1, 2, or 3;
- R a represents the structure of the following formula:
- U 1 and U 2 are the same or different and each independently represents a bond, N(R d ) or O, wherein R d represents H or optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-6 4 alkyl, such as methyl, CD3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl);
- R d represents H or optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-6 4 alkyl, such as methyl, CD3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl);
- R c represents an optionally substituted nitrogen-containing monocyclic heterocyclic group or an optionally substituted nitrogen-containing bridging heterocyclic group
- W represents hydrogen, an optionally substituted nitrogen-containing monocyclic heterocyclic group, an optionally substituted nitrogen-containing bridging heterocyclic group, an optionally substituted cycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted aryl group, C 2-6 alkenyl (such as vinyl, propenyl or butenyl), C 2-6 alkynyl (such as ethynyl, propynyl or butynyl), leaving group, CHO, COOH, NH 2 , hydroxyl or mercapto; and
- W represents an optionally substituted nitrogen-containing monocyclic heterocyclic group, an optionally substituted nitrogen-containing bridged heterocyclic group, an optionally substituted cycloalkyl group, an optionally substituted heteroaryl group or an optionally substituted aryl group
- LIN represents a bond, an optionally substituted methylene group, or an optionally substituted linear or branched C 2-30 alkylene group, wherein the main carbon of the linear or branched C 2-30 alkylene group is One or more (for example 1-10, 1-8 or 1-6, for example 1, 2, 3, 4, 5 or 6) groups Re and/or one or Multiple (for example 1-10, 1-8 or 1-6, for example 1, 2, 3, 4, 5 or 6) groups R f or one or more (for example 1-10, 1 - any combination of 8 or 1-6, eg 1, 2, 3, 4, 5 or 6) groups R e and R f , said groups R e , R f or groups R e and R The combination of f combines one or more pairs (such
- each group R e is not directly connected to each other; each group R f is selected from Cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene, alkenylene or any combination thereof, wherein the cycloalkylene, the arylene, the heterocycle
- the radical and the heteroarylene group are independently of each other optionally further selected from deuterium, optionally deuterated C 1-6 alkyl (for example optionally deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optional deuterated C 3-6 cycloalkyl
- LIN represents optionally substituted methylene, or optionally substituted A linear or branched C 2-30 alkylene group, wherein the main carbon chain of the linear or branched C 2-30 alkylene group is optionally inserted with one or more (such as 1-10 , 1-8 or 1-6, eg 1, 2, 3, 4, 5 or 6) groups R e and/or one or more (eg 1-10, 1-8 or 1- 6, such as 1, 2, 3, 4, 5 or 6) groups R f or one or more (such as 1-10, 1-8 or 1-6, such as 1, 2, 3, 4, 5 or 6) any combination of groups Re and R f , the group Re , R f or the combination of groups Re and R f will combine one or more pairs of the main carbon chain (for example 1-10 pairs, 1-8 pairs or 1-6 pairs, such as 1, 2, 3, 4, 5 or 6 pairs)
- optionally deuterated C 1-4 alkyl-NHC(O)- such as CH 3 -NHC(O)-, CH 3 CH 2 -NHC(O)-, and CH 3 CH 2 CH 2 -NHC (O)-
- optionally deuterated C 1-6 alkyl-C(O)NH- such as optionally deuterated C 1-4 alkyl-C(O)NH-, such as CH 3 -C substituents of (O)NH-, CH3CH2 -C(O)NH-, and CH3CH2CH2 - C(O)NH-
- cyano or any combination thereof ; or
- LIN represents an optionally substituted methylene group
- W represents an optionally substituted nitrogen-containing monocyclic heterocyclic group or an optionally substituted nitrogen-containing bridging heterocyclic group
- the nitrogen-containing monocyclic heterocyclic group, the nitrogen-containing bridged heterocyclyl group, the nitrogen-containing monocyclic heterocyclyl group, the nitrogen-containing bridged heterocyclyl group, the cycloalkyl group, the heterocyclic group Aryl and said aryl are each independently optionally selected by one or more (for example 1-10, 1-8 or 1-6, for example 1, 2, 3, 4, 5 or 6) Substitution from the following substituents: deuterium, hydroxy, amino, mercapto, nitro, halogen (eg fluorine, chlorine, bromine or iodine), cyano, CHO, COOH, N3 , methanesulfonyloxy, trifluoromethanesulfonate Acyloxy, p-toluenesulfonyloxy, C 1-6 alkyl (for example C 1-4 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or
- C 1-4 alkoxy e.g. methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyl Oxygen
- deuterated C 1-6 alkyl-O- C 1-6 alkyl-NH- (such as C 1-3 alkyl-NH-, such as CH 3 NH-, CH 3 CH 2 NH- or CH 3 CH 2 CH 2 NH-), deuterated C 1-6 alkyl-NH- (for example perdeuterated C 1-3 alkyl-NH-, for example CD 3 NH-, CD 3 CD 2 NH- or CD 3 CD 2 CD 2 NH-), NH 2 -C 1-6 alkylene (eg NH 2 -C 1-3 alkylene-, eg NH 2 CH 2 -, NH 2 CH 2 CH 2 - and NH 2 CH 2 CH 2 CH 2 -), C 1-6 alkyl-NHC(O)- (eg C 1-4 alkyl
- the present disclosure provides a compound of formula (III) or its salt (including pharmaceutically acceptable salt), stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph Model:
- R 1 represents a bond
- W 1 represents a piperidinylene group
- LIN represents a methylene group
- R c represents a piperazinylene group, 2,5-diazabicyclo[2.2.1]heptane Alkylidene, 8-azabicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3.1]nonaneylidene
- R b represents Fluorine
- n represents the integer 1, 2 or 3
- U1 and U2 are the same or different and each independently represents a bond, NH or O; or
- R 1 represents a bond
- W 1 represents a piperazinylene group
- LIN represents a methylene group
- R c represents a piperidinylene group, 2,5-diazabicyclo[2.2.1]heptane Alkylidene, 8-azabicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3.1]nonaneylidene
- R b represents Fluorine
- n represents an integer of 1, 2 or 3
- U1 and U2 are the same or different and each independently represents a bond, NH or O.
- R 1 represents a bond
- W 1 represents piperidinylene
- LIN represents methylene
- R c represents piperazinylene, 2,5-diazabicyclo[2.2.1]heptane Alkylidene, 8-azabicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3.1]nonaneylidene
- R b represents Fluorine
- n represents an integer 1, 2 or 3
- U1 and U2 are the same or different and each independently represents a bond, NH or O; or
- R 1 represents a bond
- W 1 represents a piperazinylene group
- LIN represents a methylene group
- R c represents a piperidinylene group, 2,5-diazabicyclo[2.2.1]heptane Alkylidene, 8-azabicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3.1]nonaneylidene
- R b represents fluorine
- n represents an integer 1, 2 or 3
- U1 and U2 are the same or different and each independently represents a bond, NH or O.
- R 1 represents a bond or -O-CH 2 -CH 2 -
- W 1 represents piperidinylene
- LIN represents methylene
- R c represents piperazinylene, 2,5- Diazabicyclo[2.2.1]heptaneylidene, 8-azabicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3.
- R b represents hydrogen, and U 1 and U 2 are identical or different and independently represent a bond, NH or O; or in formula (IV-3), R 1 represents a bond or -O- CH 2 -CH 2 -, W 1 means piperazinylene, LIN means methylene, R c means piperidinylene, 2,5-diazabicyclo[2.2.1]heptane, 8-aza Heterobicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3.1]nonaneylidene, R b represents hydrogen, and U 1 and U 2 are the same or different and each independently represents a bond, NH or O.
- R 1 represents a bond or represents -O-CH 2 -CH 2 -
- W 1 represents piperidinylene
- LIN represents methylene
- R c represents piperazinylene, 2,5 -diazabicyclo[2.2.1]heptaneylidene, 8-azabicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3 .1]
- Nonaneylidene R b represents hydrogen
- U 1 and U 2 are the same or different and each independently represents a bond, NH or O; or
- R 1 represents a bond or represents -O-CH 2 -CH 2 -
- W 1 represents piperazinylene
- LIN represents methylene
- R c represents piperidinylene, 2,5 -diazabicyclo[2.2.1]heptaneylidene, 8-azabicyclo[3.2.1]octanylidene or 9-ethyl-3-methyl-3,9-diazabicyclo[3.3 .1]
- Nonaneylidene R b represents hydrogen
- U 1 and U 2 are the same or different and each independently represents a bond, NH or O.
- the compound of formula (III) of the present disclosure or its salt (including pharmaceutically acceptable salt), stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph can bind target protein, recruit target protein to E3 ubiquitin ligase for ubiquitination labeling and degradation.
- the compound of formula (III) in the present disclosure can specifically target a specific target protein class or family, and exhibit a wide range of pharmacological activities by degrading/inhibiting various target protein classes or families.
- specific target proteins include, but are not limited to, the target proteins in Table 3 below:
- the PBM is a small molecule ligand targeting a specific target protein, including but not limited to, a small molecule ligand targeting EGFR, a small molecule ligand targeting CDK4/6, a small molecule ligand targeting ALK Ligands, small molecule ligands targeting RET, small molecule ligands targeting FAK, small molecule ligands targeting BCR-ABL, small molecule ligands targeting BTK, small molecule ligands targeting AR, Small molecule ligands targeting ER or small molecule ligands targeting BET.
- a small molecule ligand targeting a specific target protein including but not limited to, a small molecule ligand targeting EGFR, a small molecule ligand targeting CDK4/6, a small molecule ligand targeting ALK Ligands, small molecule ligands targeting RET, small molecule ligands targeting FAK, small molecule ligands targeting BCR-ABL, small molecule ligands targeting
- the PBM comprises a structure selected from the following formulae:
- R 2 p1 represents that the benzene ring of the formula (PBM-1) is substituted by p1 R 2 , each R 2 is the same or different and each independently represents halogen or halogenated C 1-6 alkyl;
- R 3 p2 represents that the quinazoline ring of formula (PBM-1) is substituted by p2 R 3 , each R 3 is the same or different and each independently represents C 1-10 alkyl, deuterated C 1-10 Alkyl, C 1-10 alkoxy, heterocyclyloxy, or -NHC(O)R 4 , wherein R 4 is C 1-10 alkyl or C 2-10 alkenyl, for example R 3 represents methyl , Methoxy, For example
- p1 represents an integer 1, 2, 3, 4 or 5;
- p2 represents an integer 1, 2, or 3;
- R 5 p3 represents that the benzene ring of the formula (PBM-2) is substituted by p3 R 5 , each R 5 is the same or different and each independently represents a C 1-10 alkyl group, a deuterated C 1-10 alkyl group , C 1-10 alkoxy or -NHC(O)R 4 , wherein R 4 is C 1-10 alkyl , deuterated C 1-10 alkyl or C 2-10 alkenyl, for example R 5 represents methyl , methoxy or
- p3 represents an integer 1, 2, 3 or 4;
- R 6 p4 represents that the 1H-indole ring of the formula (PBM-2) is substituted by p4 R 6 , each R 6 is the same or different and each independently represents C 1-10 alkyl or deuterated C 1- 10 alkyl;
- p4 represents an integer 0, 1, 2 or 3;
- R 7 p5 represents that the benzene ring of the formula (PBM-3) is substituted by p5 R 7 , each R 7 is the same or different and each independently represents halogen, hydroxyl, C 1-6 alkyl, halogenated C 1 -6 alkyl, deuterated C 1-6 alkyl, NO 2 , NH 2 , or cyano,
- p5 represents the integer 2, 3, 4 or 5;
- R 8 represents a C 6-10 aryl group, or a heteroaryl group comprising 1 or 2 5- to 7-membered rings and 1-4 heteroatoms selected from N, O and S, wherein the C 6-10 Aryl and the heteroaryl are each optionally substituted by one or more R 4a , and each R 4a is the same or different and each independently is halogen, hydroxyl, cyano, amino, nitro, C alkane Base, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, or halogenated C 1-6 alkoxy;
- R 9 represents C 1-10 alkyl (such as ) or deuterated C 1-10 alkyl
- R 10 means Wherein (R 5a ) p6 means that the piperidine ring is substituted by p6 R 5a , each R 5a is the same or different and each independently represents deuterium, halogen, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkane group , deuterated C 1-6 alkyl, C 1-6 alkoxy, deuterated C 1-6 alkoxy, NO 2 , NH 2 , or cyano, p6 represents an integer 1, 2, 3, 4 or 5;
- R 11 represents that the benzene ring and pyridine ring of the formula (PBM-5) are each optionally substituted by p7 R 11 , each R 11 is the same or different and each independently represents halogen, C 1-6 alkyl , halogenated C 1-6 alkyl, or deuterated C 1-6 alkyl, p7 represents an integer of 0, 1, 2 or 3;
- Ring A of the formula (PBM-6) represents a C 6-10 aryl group or a heteroaryl group comprising 1 or 2 5- to 7-membered rings and 1-4 heteroatoms selected from N, O and S, so The ring A is optionally substituted by one or more R 6a , and each R 6a is the same or different and is independently deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl, halo C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 2-6 alkenyl, or C 2-6 alkynyl;
- Ring B of the formula (PBM-6) represents a C 3-15 cycloalkyl group or a heterocyclic group comprising 1 or 2 3- to 7-membered rings and 1-4 heteroatoms selected from N, O and S, wherein the ring B is optionally substituted by one or more R 7a , and each R 7a is the same or different and is independently deuterium, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterium Substituted C 1-6 alkyl, C 1-6 alkoxy, or halogenated C 1-6 alkoxy;
- the ring C of the formula (PBM-6) represents a heteroaryl group comprising 1 or 2 5- to 7-membered rings and 1-4 heteroatoms selected from N, O and S, and the ring C is optionally replaced by One or more R 8a are substituted, and each R 8a is the same or different and is independently deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, or halogenated C 1-6 alkoxy;
- X 1 of formula (PBM-7) represents N or CR 12 , wherein R 12 is hydrogen or represents a bond, and X 2 represents CH or N;
- R 13 is hydrogen or represents a bond, wherein when R 13 represents a bond, X 1 represents N or CH, and the ring atom N connected to R 13 is directly connected to R 1 ; or when R 13 is hydrogen, X 1 represents CR 12 , wherein R 12 represents a bond, and the ring atom C connected to R 12 is directly connected to R 1 ;
- R 14 represents -O-aryl, -O-heteroaryl, -C 1-3 alkylene-NHC(O)-heteroaryl, or -C 1-3 alkylene-C(O)NH- Heteroaryl, said aryl and heteroaryl are each independently optionally substituted by one or more R 9a , and each R 9a is the same or different and each independently is deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, or halogenated C 1-6 alkoxy;
- R 15 represents deuterium, hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl or -NHC(O)R 17 , wherein R 17 is C 1-10 Alkyl or C 2-10 alkenyl, for example R 15 represents hydrogen, methyl, or
- R 16 represents hydrogen, cyano, or amino
- X 3 of formula (PBM-8) represents CR 21 or a fragment
- the symbol ## represents the point of attachment of N adjacent to X 3
- the symbol ### represents the point of attachment to X 4
- R represents deuterium, hydrogen, halogen, C 1-6 alkyl, halogenated C 1- 6 alkyl, deuterated C 1-6 alkyl, -C(O)-C 1-6 alkyl, -C(O)-deuterated C 1-6 alkyl or -C(O)NR 22 R 23
- R 22 and R 23 are the same or different and independently represent hydrogen, C 1-6 alkyl or deuterated C 1-6 alkyl, and R 22 and R 23 are not hydrogen at the same time;
- X 4 of formula (PBM-8) represents N or CR 24 , wherein R 24 represents hydrogen, deuterium, halogen, C 1-6 alkyl, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl;
- X 5 and X 6 each independently represent CH or N;
- R 18 represents a bond or an optionally substituted heteroarylene (such as a halogen substituted heteroarylene);
- R 19 represents hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, or optionally substituted C 3-7 cycloalkyl;
- R 20 and R 25 are the same or different and each independently represents hydrogen, halogen, C 1-6 alkyl, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl;
- R 26 represents hydrogen, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, or deuterated C 1-6 alkyl;
- R 27 represents hydrogen, cyano, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, or deuterated C 1-6 alkyl;
- R 28 p8 represents that the benzene ring of the formula (PBM-10) is substituted by p8 R 28 , each R 28 is the same or different and each independently represents halogen, C 1-6 alkyl, halogenated C 1-6 Alkyl, or deuterated C 1-6 alkyl;
- p8 represents an integer 1, 2, 3 or 4;
- R 29 represents NR 30 R 31 , wherein R 30 and R 31 are the same or different and independently represent hydrogen, C 1-6 alkyl or deuterated C 1-6 alkyl;
- X 7 , X 8 and X 9 of the formula (PBM-11) are the same or different and independently represent N or CH;
- R 32 p9 represents that the six-membered ring containing X 8 and X 9 of formula (PBM-11) is optionally substituted by p9 R 32 , each R 32 is the same or different and each independently represents halogen, C 1 -6 alkoxy, C 1-6 alkyl, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl;
- p9 represents an integer 0, 1, 2, 3 or 4;
- R 33 represents halogen, C 1-6 alkoxy, C 1-6 alkyl, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl;
- R 34 represents -C(O)NHR 35 , -NHC(O)-R 35 , -S(O) 2 NHR 35 , -S(O) 2 R 35 or -P(O)(R 35 ) 2 , wherein Each R 35 is the same or different and each independently represents C 1-6 alkyl or deuterated C 1-6 alkyl;
- R 36 p10 represents that the benzene ring of the formula (PBM-12) is optionally substituted by p10 R 36 , each R 36 is the same or different and each independently represents halogen, C 1-6 alkoxy, C 1 -6 alkyl, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl;
- p10 represents the integer 0, 1, 2, 3 or 4;
- R 37 represents that the benzene ring of the formula (PBM-13) is substituted by p11 R 37 , each R 37 is the same or different and each independently represents halogen, C 1-6 alkoxy, C 1-6 alkane Base, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl;
- p11 represents an integer 0, 1, 2, 3 or 4;
- R 38 p12 represents that the benzene ring of the formula (PBM-14) is substituted by p12 R 38 , each R 38 is the same or different and each independently represents halogen, C 1-6 alkoxy, C 1-6 alkane Base, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl;
- p12 represents an integer 0, 1, 2, 3 or 4;
- R 39 p13 represents that the 4-oxo-3,4-dihydroquinazoline ring of the formula (PBM-14) is substituted by p13 R 39 , each R 39 is the same or different and each independently represents a halogen, C 1-6 alkoxy, C 1-6 alkyl, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl;
- p13 represents an integer 1, 2, 3 or 4;
- R 40 p14 represents that the benzene ring of the formula (PBM-15) is substituted by p14 R 40 , each R 40 is the same or different and each independently represents halogen, C 1-6 alkoxy, C 1-6 alkane Base, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl;
- p14 represents an integer 1, 2, 3 or 4;
- R 41 represents halogen, C 1-6 alkyl, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl;
- R 42 p15 represents that the quinoline ring of the formula (PBM-16) is substituted by p15 R 42 , each R 42 is the same or different and each independently represents halogen, cyano, C 1-6 alkoxy, C 1-6 alkyl, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl;
- p15 represents the integer 2, 3 or 4;
- R 43 p16 represents that the benzene ring of the formula (PBM-16) is substituted by p16 R 43 , each R 43 is the same or different and each independently represents halogen, C 1-6 alkoxy, C 1-6 alkane Base, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl;
- p16 represents an integer 3 or 4;
- R 44 p17 represents that the benzene ring, pyrimidine ring and pyridine ring of the formula (PBM-17) are each optionally substituted by p17 R 44 , each R 44 is the same or different and each independently represents halogen, C 1-6 alkane Oxygen, C 1-6 alkyl, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl;
- p17 represents an integer 0, 1, 2, 3 or 4;
- R 45 , R 46 , R 47 and R 48 represents a bond, and the remaining three are the same or different and independently represent hydrogen, halogen, or hydroxyl, wherein when R 45 , R 46 , R 47 and R 48 When one of them represents a bond, the benzene ring or methylene group in the formula (PBM-18) to which the bond is connected is directly connected to R 1 ;
- R 49 represents that the 1,2,3,4-tetrahydronaphthalene ring of the formula (PBM-19) is substituted by p18 R 49 , each R 49 is the same or different and each independently represents hydrogen, hydroxyl, halogen, C 1-6 alkyl, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl;
- p18 represents the integer 0, 1, 2, 3 or 4;
- R 50 and R 51 represents a bond, and the other represents hydrogen, halogen, C 1-6 alkyl, deuterated C 1-6 alkyl or halogenated C 1-6 alkyl, wherein when R 50 and R When one of 51 represents a bond, the benzene ring in the formula (PBM-19) to which the bond is connected is directly connected to R 1 .
- PBM represents a small molecule ligand targeting EGFR, including but not limited to representing the following formula (PBM-1-1A), formula (PBM-1-1B), formula (PBM-1-1C) or The structure of formula (PBM-1-1D):
- R 2 p1 means that the benzene ring of formula (PBM-1-1A), formula (PBM-1-1B), formula (PBM-1-1C) or formula (PBM-1-1D) is covered by p1 R 2 is substituted, each R 2 is the same or different and each independently represents halogen (such as fluorine, chlorine, bromine or iodine) or halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C- , FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 -, or CH 2 ClCH 2- );
- halogen such as fluorine, chlorine, bromine or iodine
- halogenated C 1-6 alkyl such as halogenated C 1-4 alkyl, such as F 3 C- , FCH 2
- R 3 p2 represents that the quinazoline ring of formula (PBM-1-1A), formula (PBM-1-1B), formula (PBM-1-1C) or formula (PBM-1-1D) is covered by p2 R 3 is substituted, each R 3 is the same or different and each independently represents a C 1-10 alkyl group (such as a C 1-8 alkyl group, a C 1-6 alkyl group or a C 1-4 alkyl group, such as methyl, ethyl, etc.
- a C 1-10 alkyl group such as a C 1-8 alkyl group, a C 1-6 alkyl group or a C 1-4 alkyl group, such as methyl, ethyl, etc.
- propyl isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl), deuterated C 1-10 alkyl (e.g.
- perdeuterated C 1-8 alkane group perdeuterated C 1-6 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.
- C 1-10 alkoxy Such as C 1-8 alkoxy, C 1-6 alkoxy or C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyl Oxygen or tert-butyloxy), heterocyclyloxy (wherein heterocyclyl is for example containing one or more, for example 1-4 or 1, 2, 3 or 4, selected from nitrogen, oxygen and sulfur 4- to 20-membered monocyclic or bicyclic heterocyclic group), or -NHC(O)R 4 , wherein R 4 is C 1-10 alkyl (for example, C 1-8 alkyl, C 1- 6 Alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl,
- p1 represents the integer 1, 2, 3, 4 or 5;
- p2 represents an integer 1, 2, or 3;
- R 3 represents heterocyclyl-O-, which is a group containing one or more (for example 1-4 or 1, 2, 3 or 4) selected from nitrogen, oxygen and sulfur 4- to 20-membered (e.g., 4-15, 4-12, 4-10, 4-7, or 4-6) monocyclic or bicyclic heterocyclyl of heteroatoms, including but not limited to nitrogen Heterocyclobutyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazole Alkyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, azepanyl, diazepanyl (e.g.
- 1,4-diazepanyl Alkyl-1-yl 1,4-diazepanyl Alkyl-1-yl), azacyclooctyl, diazacyclooctyl, azabicyclo[3.1.1]heptyl, azabicyclo[2.2.1]heptanyl, azabicyclo[3.2.
- R represents:
- -NHC(O)-C 2-10 alkenyl for example -NHC(O)-ethenyl, -NHC(O)-propenyl or -NHC(O)-butenyl; or
- the PBM represents a structure of Formula (PBM-1-1), Formula (PBM-1-2), Formula (PBM-1-3), or Formula (PBM-1-4):
- PBM represents a small molecule ligand targeting EGFR, including but not limited to representing the following formula (PBM-2-1A), formula (PBM-2-1B), formula (PBM-2-1C) or The structure of formula (PBM-2-1D):
- R 5 p3 represents that the benzene ring of formula (PBM-2-1A), formula (PBM-2-1B), formula (PBM-2-1C) or formula (PBM-2-1D) is covered by p3 R 5 is substituted, each R 5 is the same or different and each independently represents a C 1-10 alkyl group (such as a C 1-8 alkyl group, a C 1-6 alkyl group or a C 1-4 alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl), deuterated C 1-10 alkyl (e.g.
- Perdeuterated C 1-6 alkyl or perdeuterated C 1-4 alkyl such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.
- C 1-10 alkoxy such as C 1-8 alkoxy, C 1-6 alkoxy or C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy
- R 4 is C 1-10 alkyl (such as C 1-8 alkyl, C 1-6 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl), deuterated C 1-10 alkyl (e.g.
- perdeuterated C 1-8 alkyl perdeuterated C 1-6 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.
- C 2-10 Alkenyl such as C 2-6 alkenyl or C 2-4 alkenyl, such as vinyl, propenyl, butenyl or pentenyl
- R represents methyl, methoxy or
- p3 represents an integer 1, 2, 3 or 4;
- R 6 p4 represents the 1H-indole ring of formula (PBM-2-1A), formula (PBM-2-1B), formula (PBM-2-1C) or formula (PBM-2-1D) p4 R 6 substitutions, each R 6 is the same or different and each independently represents a C 1-10 alkyl group (such as a C 1-8 alkyl group, a C 1-6 alkyl group or a C 1-4 alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl) or deuterated C 1-10 alkyl (e.g. perdeuterated C 1-8 Alkyl, perdeuterated C 1-6 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.); and
- p4 represents the integer 0, 1, 2 or 3.
- the PBM represents the structure of the following formula (PBM-2-1):
- PBM represents a small molecule ligand targeting EGFR, including but not limited to representing the following formula (PBM-3-1A), formula (PBM-3-1B), formula (PBM-3-1C) or The structure of formula (PBM-3-1D):
- R 7 represents that the benzene ring of formula (PBM-3-1A), formula (PBM-3-1B), formula (PBM-3-1C) or formula (PBM-3-1D) is covered by p5 R 7 is substituted, each R 7 is the same or different and each independently represents halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, C 1-6 alkyl (such as C 1-8 alkyl, C 1-6 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl), halogenated C 1-6 Alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -,
- perdeuterated C 1-6 alkyl perdeuterated C 1-5 alkane or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.), NO 2 , NH 2 , or cyano,
- p5 represents the integer 2, 3, 4 or 5;
- R 8 represents a C 6-10 aryl group, or a heteroaryl group comprising 1 or 2 5- to 7-membered rings and 1-4 heteroatoms selected from N, O and S, wherein the C 6-10 Aryl and said heteroaryl are each optionally substituted by one or more (e.g. 1-6, e.g.
- R 4a is the same or different and Each independently is halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, cyano, amino, nitro, C 1-6 alkyl (such as C 1-8 alkyl, C 1-6 alkyl or C 1 -4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl), halogenated C1-6 alkyl (e.g.
- halogenated C 1-4 alkyl such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), deuterated C 1-6 alkyl (such as per deuterated C 1-6 alkyl, per deuterated C 1-5 alkyl or Perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.), C 1-6 alkoxy (such as C 1-4 alkoxy, such as methoxy ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), or halogenated C 1-6 alkoxy (such as halogenated C 1-4 Alkoxy, eg F 3 CO-, FCH 2 -O-, F 2 CH
- R represents C 6-10 aryl, such as but not limited to phenyl or naphthyl, and each of phenyl or naphthyl is optionally replaced by one or more (such as 1-6, such as 1, 2, 3, 4, 5 or 6) R 4a substitution as defined above.
- R represents heteroaryl comprising 1 or 2 5- to 7-membered rings and 1-4 heteroatoms selected from N, O and S.
- R represents 1 or more (such as 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) independently selected from oxygen, nitrogen and sulfur A heteroatomic 5- to 14-membered monocyclic or bicyclic aromatic ring group.
- heteroaryl examples include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl , imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuryl, isobenzofuryl, benzothienyl , indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxa Oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazol
- the PBM represents the structure of the following formula (PBM-3-1):
- PBM represents a small molecule ligand targeting EGFR, including, but not limited to, a structure representing the following formula (PBM-4):
- R 9 represents C 1-10 alkyl (such as C 1-8 alkyl, C 1-6 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl) or deuterated C 1-10 alkyl (such as per deuterated C 1-8 alkyl, per deuterated C 1-6 Alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.); and
- R 10 means Wherein (R 5a ) p6 means that the piperidine ring is substituted by p6 R 5a , each R 5a is the same or different and each independently represents deuterium, halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, C 1-6 Alkyl (such as C 1-8 alkyl, C 1-6 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl), halogenated C 1-6 alkyl, deuterated C 1-6 alkyl (such as per deuterated C 1-6 alkyl, per deuterated C 1-5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.), C 1-6 al
- perdeuterated C 1-6 4 alkoxy such as CD 3 -O-, CD 3 CD 2 -O-, or CD 3 CD 2 CD 2 -O-), NO 2 , NH 2 , or cyano
- p6 represents an integer 1, 2, 3 , 4 or 5.
- the PBM represents the structure of the following formula (PBM-4-1) or formula (PBM-4-2):
- PBM represents a small molecule ligand targeting EGFR, including but not limited to representing the following formula (PBM-5-1A), formula (PBM-5-1B), formula (PBM-5-1C) or The structure of formula (PBM-5-1D):
- each R 11 is the same or different and each independently represents halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkyl (such as C 1-6 alkyl, C 1 -5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkane group (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CH
- the PBM represents the structure of the following formula (PBM-5-1):
- a PBM represents a small molecule ligand targeting AR, including but not limited to a structure representing the following formula (PBM-6-1A):
- Ring A of the formula (PBM-6-1A) represents a C 6-10 aryl group or a 5- to 20-membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S,
- the ring A is optionally substituted by t1 (for example 1-6, for example 1, 2, 3, 4, 5 or 6) R 6a , and each R 6a is the same or different and each independently is deuterium, halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, cyano, amino, nitro, C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, For example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (for example halogenated C 1-4 alkyl, For example, F
- C 1-4 alkoxy e.g. methoxy, ethoxy, propoxy, iso propoxy, butoxy, sec-butyloxy or tert-butyloxy
- halogenated C 1-6 alkoxy eg halogenated C 1-4 alkoxy, eg F 3 CO-, FCH 2 -O-, F 2 CH-O-, ClCH 2 -O-, Cl 2 CH-O-, CF 3 CF 2 -O-, CF 3 CHF-O-, CHF 2 CF 2 -O-, CHF 2 CHF -O-, CF 3 CH 2 -O- or CH 2 ClCH 2 -O-
- C 2-6 alkenyl such as vinyl, propenyl or butenyl
- C 2-6 alkynyl such as acetylene group, propynyl or butynyl
- Ring B of the formula (PBM-6-1A) represents a C 3-15 cycloalkyl group or a 3 to 20-membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S, wherein the ring B can be optionally substituted by t2 (for example 1-6, for example 1, 2, 3, 4, 5 or 6) R 7a , and each R 7a is the same or different and each independently is deuterium, halogen (for example fluorine, chlorine , bromine or iodine), C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl , such as methyl, ethyl, propyl, isopropyl, butyl group, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-
- the ring C of the formula (PBM-6-1A) represents a 5- to 20-membered monocyclic or bicyclic heteroaryl group containing 1-4 heteroatoms selected from N, O and S, and the ring C is optionally Substituted by t3 (for example 1-6, for example 1, 2, 3, 4, 5 or 6) R 8a , and each R 8a is the same or different and each independently is deuterium, halogen (for example fluorine, chlorine, bromine or iodine), hydroxyl, cyano, amino, C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -
- C 1-4 alkoxy e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyl yloxy or tert-butyloxy
- halogenated C 1-6 alkoxy such as halogenated C 1-4 alkoxy, such as F 3 CO-, FCH 2 -O-, F 2 CH-O -, ClCH 2 -O-, Cl 2 CH-O-, CF 3 CF 2 -O-, CF 3 CHF-O-, CHF 2 CF 2 -O-, CHF 2 CHF-O-, CF 3 CH 2 - O- or CH 2 ClCH 2 -O-);
- t1 represents an integer 1, 2, 3, 4, 5 or 6;
- t2 represents the integer 1, 2, 3, 4, 5 or 6;
- t3 represents an integer 1, 2, 3, 4, 5 or 6.
- the PBM represents the structure of the following formula (PBM-6-1A-1):
- R 6a t1 represents that the benzene ring of the formula (PBM-6-1A-1) is optionally substituted by t1 R 6a , each R 6a is the same or different and each independently is deuterium, halogen (such as fluorine, chlorine , bromine or iodine), hydroxyl, cyano, amino, nitro, C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl radical, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C- , FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -
- C 1-4 alkoxy e.g. methoxy, ethoxy, propoxy, isopropoxy, butane oxy, sec-butyloxy or tert-butyloxy
- halogenated C 1-6 alkoxy such as halogenated C 1-4 alkoxy, such as F 3 CO-, FCH 2 -O-, F 2 CH-O-, ClCH 2 -O-, Cl 2 CH-O-, CF 3 CF 2 -O-, CF 3 CHF-O-, CHF 2 CF 2 -O-, CHF 2 CHF-O-, CF 3 CH 2 -O- or CH 2 ClCH 2 -O-
- C 2-6 alkenyl such as vinyl, propenyl or butenyl
- C 2-6 alkynyl such as ethynyl, propynyl or butynyl
- C 2-6 alkenyl such as vinyl, propenyl or butenyl
- Ring B of the formula (PBM-6-1A-1) represents a C 3-15 cycloalkyl group or a 3 to 20-membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S, wherein the ring B is optionally substituted with t2 R 7a , and each R 7a is the same or different and each independently is deuterium, halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkyl (such as C 1-6 alkane C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -
- Q 1 represents N or CH
- R 8a t3 represents the nitrogen-containing heteroaryl group of the formula (PBM-6-1A-1) optionally substituted by t3 R 8a , each R 8a is the same or different and each independently is deuterium, halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, cyano, amino, C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-
- C 1-4 alkoxy e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy , sec-butyloxy or tert-butyloxy
- halogenated C 1-6 alkoxy such as halogenated C 1-4 alkoxy, such as F 3 CO-, FCH 2 -O-, F 2 CH-O-, ClCH 2 -O-, Cl 2 CH-O-, CF 3 CF 2 -O-, CF 3 CHF-O-, CHF 2 CF 2 -O-, CHF 2 CHF-O-, CF 3 CH2 - O- or CH2ClCH2 - O-);
- t1 represents an integer 1, 2, 3, 4, 5 or 6;
- t2 represents the integer 1, 2, 3, 4, 5 or 6;
- t3 represents an integer 1 or 2.
- Q represents N. In some embodiments, Q represents CH.
- the PBM represents a structure of the following formula (PBM-6-1), formula (PBM-6-2), or formula (PBM-6-3):
- PBMs represent small molecule ligands targeting BTK, including but not limited to those representing the following formula (PBM-7-1A), formula (PBM-7-1B) or formula (PBM-7-1C) structure:
- X2 represents CH or N
- R 14 represents -O-aryl, -O-heteroaryl, -C 1-3 alkylene-NHC(O)-heteroaryl, or -C 1-3 alkylene-C(O)NH- Heteroaryl, said aryl and heteroaryl are each independently optionally substituted by one or more (eg 1-5, eg 1, 2, 3, 4 or 5) R 9a , and each R 9a
- R 9a The same or different and each independently deuterium, halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, cyano, amino, C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (such as halo C 1-4
- R 15 represents deuterium, hydrogen, halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl radical, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), deuterated C 1-6 alkyl (such as perdeuterated C 1-6 alkyl, perdeuterated C 1-5 alkyl or perdeuterated C 1-4
- R 16 represents hydrogen, cyano, or amino.
- R 14 represents -O-aryl, -O-heteroaryl, -C 1-3 alkylene-NHC(O)-heteroaryl, or -C 1-3 alkylene- C(O)NH-heteroaryl, wherein aryl can be optionally substituted C 6-10 aryl, such as but not limited to phenyl or naphthyl, and heteroaryl can be optionally substituted containing 1 or more 5- to 14-membered monocyclic or bicyclic 5- to 14-membered heteroatoms (eg 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) independently selected from oxygen, nitrogen and sulfur aromatic ring group.
- aryl can be optionally substituted C 6-10 aryl, such as but not limited to phenyl or naphthyl
- heteroaryl can be optionally substituted containing 1 or more 5- to 14-membered monocyclic or bicyclic 5- to 14-membered heteroatoms (eg 1 to 6, or 1 to 5, or
- R 14 represents -O-phenyl or -O-naphthyl, phenyl or naphthyl is optionally replaced by one or more (for example 1-5, for example 1, 2, 3, 4 or 5)
- R 9a is substituted, and each R 9a is the same or different and is independently deuterium, halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, cyano, amino, C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl) , halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-
- perdeuterated C 1-6 alkyl perdeuterated C 1-6 alkyl, perdeuterated C 1-6 alkyl, per Deuterated C 1-5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.
- C 1-6 alkoxy such as C 1 -4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy
- halogenated C1-6 alkoxy group such as halogenated C 1-4 alkoxy, such as F 3 CO-, FCH 2 -O-, F 2 CH-O-, ClCH 2 -O-, Cl 2 CH-O-, CF 3 CF 2 - O-, CF 3 CHF-O-, CHF 2 CF 2 -O-, CHF 2 CHF-O-, CF 3 CH 2 -O- or CH 2 ClCH 2 -O-
- R 14 represents -O-heteroaryl, -C 1-3 alkylene-NHC(O)-heteroaryl, or -C 1-3 alkylene-C(O)NH -heteroaryl
- heteroaryl is optionally substituted by one or more (for example 1-5, for example 1, 2, 3, 4 or 5) R 9a
- each R 9a is the same or different and each independently is deuterium, halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, cyano, amino, C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl , such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl , such
- the PBM represents the structure of the following formula (PBM-7-1) or formula (PBM-7-2):
- PBM represents a small molecule ligand targeting CDK4/6, including but not limited to representing the following formula (PBM-8-1A), formula (PBM-8-1B), formula (PBM-8-1C ) or the structure of formula (PBM-8-1D):
- R 21 represents deuterium, hydrogen, halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl radical, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), deuterated C 1-6 alkyl (such as perdeuterated C 1-6 alkyl, perdeuterated C 1-5 alkyl or perdeuterated C 1-4
- perdeuterated C 1-6 alkyl perdeuterated C 1-5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.), and R 22 and R 23 are not at the same time hydrogen;
- X 4 represents N or CR 24 , wherein R 24 represents hydrogen, deuterium, halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (such as perdeuterium Substituted C 1-6 alkyl, perdeuterated C 1-5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.) or halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF
- X 5 and X 6 each independently represent CH or N;
- Ring D represents an optionally substituted heteroarylene (eg, a halogen-substituted heteroarylene);
- R 19 represents hydrogen, C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl , sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), deuterated C 1-6 alkane (such as perdeuterated C 1-6 alkyl, perdeuterated C 1-5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -
- R 20 and R 25 are the same or different and independently represent hydrogen, halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (such as perdeuterated C 1-6 alkyl, perdeuterated C 1-5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.) or halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF
- ring D represents optionally substituted heteroarylene, for example optionally substituted containing 1 or more (eg 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) 5- to 20-membered monocyclic or bicyclic heteroarylene of heteroatoms independently selected from oxygen, nitrogen and sulfur.
- heteroarylene examples include, but are not limited to, furylylene, oxazolylene, isoxazolylene, oxadiazolylidene, thienylene, thiazolylylene, isothiazolylene, thiadiazolylylene, Pyrrolene, imidazolyl, pyrazolylene, triazolylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzo Furyl, isobenzofuryl, benzothienyl, indazolyl, benzimidazolylene, benzoxazolylene, benzoisoxazolylene, benzothiazolyl, phenylene Aisothiazolyl, benzotriazolylene, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2, 3] Thiadiazolyl, quinolin
- Heteroarylene is optionally substituted with one or more (eg 1-5, eg 1, 2, 3, 4 or 5) substituents selected from the group consisting of halogen (eg fluorine, chlorine, bromine or iodine) , hydroxy, cyano, amino, C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl , butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH -, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2
- perdeuterated C 1-6 alkyl perdeuterated C 1-5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 ⁇ , CD 3 CD 2 CD 2 - etc.
- C 1-6 alkoxy e.g. C 1-4 alkoxy, e.g.
- halogenated C 1-6 alkoxy such as halogenated C 1-4 alkoxy, such as F 3 CO-, FCH 2 -O-, F 2 CH-O-, ClCH 2 -O-, Cl 2 CH-O-, CF 3 CF 2 -O-, CF 3 CHF-O-, CHF 2 CF 2 -O-, CHF 2 CHF-O-, CF 3 CH 2 -O- or CH2ClCH2 - O-).
- the PBM represents a structure of the following formula (PBM-8-1), formula (PBM-8-2), or formula (PBM-8-3):
- PBM represents a small molecule ligand targeting ALK, including but not limited to representing the following formula (PBM-9-1A), formula (PBM-9-1B), formula (PBM-9-1C) or The structure of formula (PBM-9-1D):
- R 26 represents hydrogen, halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C -, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 -, or CH 2 ClCH 2 -), or deuterated C 1-6 alkyl (such as per deuterated C 1-6 alkyl, per deuterated C 1-5 alkyl or per deuterated C 1-4 alky
- R 27 represents hydrogen, cyano, halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (for example halogenated C 1-4 alkyl, for example F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), or deuterated C 1-6 alkyl (such as per deuterated C 1-6 alkyl, per deuterated C 1-5 alkyl or per deuterated C 1-4 al
- the PBM represents the structure of the following formula (PBM-9-1):
- PBM represents a small molecule ligand targeting ALK, including but not limited to representing a structure of the following formula (PBM-10):
- R 28 p8 represents that the benzene ring of the formula (PBM-10) is substituted by p8 R 28 , each R 28 is the same or different and each independently represents a halogen (such as fluorine, chlorine, bromine or iodine), C 1- 6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl , pentyl or hexyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), or de
- p8 represents the integer 1, 2, 3 or 4;
- R 29 represents NR 30 R 31 , wherein R 30 and R 31 are the same or different and independently represent hydrogen, C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl) or deuterated C 1-6 alkyl (such as perdeuterated C 1-6 6 alkyl, perdeuterated C 1-5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.).
- C 1-6 alkyl such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or
- the PBM represents the structure of the following formula (PBM-10-1):
- the PBM represents a structure of Formula (PBM-11-1A), Formula (PBM-11-1B), or Formula (PBM-11-1C):
- X 7 , X 8 and X 9 are the same or different and independently represent N or CH;
- R 32 p9 represents that the six-membered ring containing X 8 and X 9 is optionally substituted by p9 R 32 , each R 32 is the same or different and each independently represents a halogen (such as fluorine, chlorine, bromine or iodine) , C 1-6 alkoxy (such as C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy base ) , C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (such as per deuterated C 1-6 alkyl, per deuterated C 1-5 alkyl or per deuterated C 1-4
- p9 represents an integer 0, 1, 2, 3 or 4;
- R 33 represents halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkoxy, C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkane group, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (such as perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.) or halogenated C 1-6 alkane group (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CH
- R 34 represents -C(O)NHR 35 , -NHC(O)-R 35 , -S(O) 2 NHR 35 , -S(O) 2 R 35 or -P(O)(R 35 ) 2 , wherein Each R 35 is the same or different and each independently represents a C 1-6 alkyl group (such as a C 1-6 alkyl group, a C 1-5 alkyl group or a C 1-4 alkyl group, such as a methyl group, an ethyl group, a propyl group , isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl) or deuterated C 1-6 alkyl (such as per deuterated C 1-6 alkyl, per deuterated C 1-5 alkane group or perdeuterated C 1-4 alkyl group, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.).
- a PBM represents a small molecule ligand targeting ALK, including but not limited to a ligand representing the following formula (PBM-11-1D), formula (PBM-11-1E) or formula (PBM-11-1F) structure:
- X 8 and X 9 are the same or different and each independently represents N or CH;
- R 32 p9 means that the six-membered ring containing X 8 and X 9 is optionally substituted by p9 R 32 , each R 32 is the same or different and each independently represents a halogen (such as fluorine, chlorine, bromine or iodine) , C 1-6 alkoxy (such as C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy base ) , C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (such as per deuterated C 1-6 alkyl, per deuterated C 1-5 alkyl or per deuterated C 1-4
- p9 represents the integer 0, 1, 2, 3 or 4;
- R 34 represents -C(O)NHR 35 , -NHC(O)-R 35 , -S(O) 2 NHR 35 , -S(O) 2 R 35 or -P(O)(R 35 ) 2 , wherein Each R 35 is the same or different and each independently represents a C 1-6 alkyl group (such as a C 1-6 alkyl group, a C 1-5 alkyl group or a C 1-4 alkyl group, such as a methyl group, an ethyl group, a propyl group , isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl) or deuterated C 1-6 alkyl (such as per deuterated C 1-6 alkyl, per deuterated C 1-5 alkane group or perdeuterated C 1-4 alkyl group, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.).
- a PBM represents a small molecule ligand targeting ALK, including but not limited to a structure representing the following formula (PBM-11-1) or formula (PBM-11-2):
- PBMs represent small molecule ligands targeting FAK, including but not limited to those representing the following formula (PBM-11-1G), formula (PBM-11-1H) or formula (PBM-11-1I) structure:
- X 8 and X 9 are the same or different and each independently represents N or CH;
- R 32 p9 means that the six-membered ring containing X 8 and X 9 is optionally substituted by p9 R 32 , each R 32 is the same or different and each independently represents a halogen (such as fluorine, chlorine, bromine or iodine) , C 1-6 alkoxy (such as C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy base ) , C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (such as per deuterated C 1-6 alkyl, per deuterated C 1-5 alkyl or per deuterated C 1-4
- p9 represents the integer 0, 1, 2, 3 or 4;
- R 34 represents -C(O)NHR 35 , -NHC(O)-R 35 , -S(O) 2 NHR 35 , -S(O) 2 R 35 or -P(O)(R 35 ) 2 , wherein Each R 35 is the same or different and each independently represents a C 1-6 alkyl group (such as a C 1-6 alkyl group, a C 1-5 alkyl group or a C 1-4 alkyl group, such as a methyl group, an ethyl group, a propyl group , isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl) or deuterated C 1-6 alkyl (such as per deuterated C 1-6 alkyl, per deuterated C 1-5 alkane group or perdeuterated C 1-4 alkyl group, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.).
- PBMs represent small molecule ligands targeting FAK, including but not limited to those representing the following formula (PBM-11-1G), formula (PBM-11-1H) or formula (PBM-11-1I) structure:
- PBM represents a small molecule ligand targeting RET, including, but not limited to, those representing the following formula (PBM-11-1J), formula (PBM-11-1K) or formula (PBM-11-1L) structure:
- X 8 and X 9 are the same or different and each independently represents N or CH;
- R 32 p9 means that the six-membered ring containing X 8 and X 9 is optionally substituted by p9 R 32 , each R 32 is the same or different and each independently represents a halogen (such as fluorine, chlorine, bromine or iodine) , C 1-6 alkoxy (such as C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy base ) , C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (such as per deuterated C 1-6 alkyl, per deuterated C 1-5 alkyl or per deuterated C 1-4
- p9 represents the integer 0, 1, 2, 3 or 4;
- R 34 represents -C(O)NHR 35 , -NHC(O)-R 35 , -S(O) 2 NHR 35 , -S(O) 2 R 35 or -P(O)(R 35 ) 2 , wherein Each R 35 is the same or different and each independently represents a C 1-6 alkyl group (such as a C 1-6 alkyl group, a C 1-5 alkyl group or a C 1-4 alkyl group, such as a methyl group, an ethyl group, a propyl group , isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl) or deuterated C 1-6 alkyl (such as per deuterated C 1-6 alkyl, per deuterated C 1-5 alkane group or perdeuterated C 1-4 alkyl group, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.).
- a PBM represents a small molecule ligand targeting RET, including, but not limited to, a structure representing the following formula (PBM-11-4) or formula (PBM-11-5):
- PBM represents a small molecule ligand targeting RET, including but not limited to representing the following formula (PBM-12-1A), formula (PBM-12-1B), formula (PBM-12-1C), The structure of formula (PBM-12-1D) or formula (PBM-12-1E):
- each R 36 is the same or different and each independently represents halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkoxy (such as C 1- 4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 alkyl (such as C 1 -6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), Deuterated C 1-6 alkyl (such as perdeuterated
- p10 represents the integer 0, 1, 2, 3 or 4;
- a PBM represents a small molecule ligand targeting RET, including, but not limited to, a structure representing the following formula (PBM-12-1):
- PBM represents a small molecule ligand targeting BET, including, but not limited to, a structure representing the following formula (PBM-13):
- R 37 p11 represents that the benzene ring of the formula (PBM-13) is substituted by p11 R 37 , each R 37 is the same or different and each independently represents a halogen (such as fluorine, chlorine, bromine or iodine), C 1- 6 alkoxy (such as C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert butyl, pentyl or hexyl), deuterated C 1-6 alkyl (such as per deuterated C 1-6 alkyl, per deuterated C 1-5 alkyl or per deuterated C 1-4 alkyl, such as CD 3 ,
- p11 represents the integer 0, 1, 2, 3 or 4.
- PBM represents a small molecule ligand targeting BET, including, but not limited to, a structure representing the following formula (PBM-13):
- PBM represents a small molecule ligand targeting BET, including but not limited to representing the following formula (PBM-14-1A), formula (PBM-14-1B), formula (PBM-14-1C), The structure of formula (PBM-14-1D) or formula (PBM-14-1E):
- each R 38 is the same or different and each independently represents halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkoxy (such as C 1-4 alkoxy group, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 alkyl (such as C 1-6 alk C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (such as perdeuterated C 1-6 alkyl
- p12 represents an integer 0, 1, 2, 3 or 4;
- R 39 p13 means formula (PBM-14-1A), formula (PBM-14-1B), formula (PBM-14-1C), formula (PBM-14-1D) or formula (PBM-14-1E)
- the 4-oxo-3,4-dihydroquinazoline ring is substituted by p13 R 39 , each R 39 is the same or different and each independently represents a halogen (such as fluorine, chlorine, bromine or iodine), C 1 -6 alkoxy (for example C 1-4 alkoxy, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C
- p13 represents the integer 1, 2, 3 or 4.
- a PBM represents a small molecule ligand targeting BET, including but not limited to a structure representing the following formula (PBM-14-1):
- a PBM represents a small molecule ligand that targets BCR-ABL, including but not limited to structures representing the following formula (PBM-15-1A) or formula (PBM-15-1B):
- R 40 p14 represents that the benzene ring of formula (PBM-15-1A) or formula (PBM-15-1B) is substituted by p14 R 40 , each R 40 is the same or different and each independently represents a halogen (such as fluorine , chlorine, bromine or iodine), C 1-6 alkoxy (such as C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyl Oxygen or tert-butyloxy), C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, iso propyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (such as per deuterated C 1-6 alkyl, per deuterated C 1-5 alkyl or Perdeuter
- p14 represents the integer 1, 2, 3 or 4;
- R 41 represents halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl , propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (such as perdeuterated C 1-6 alkyl, perdeuterated C 1 -5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.) or halogenated C 1-6 alkyl (such as halogenated C 1- 4Alkyl , such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2
- a PBM represents a small molecule ligand targeting BCR-ABL, including but not limited to a structure representing the following formula (PBM-15-1):
- PBM represents a small molecule ligand targeting BCR-ABL, including but not limited to representing the following formula (PBM-16-1A), formula (PBM-16-1B), formula (PBM-16-1C ) or the structure of formula (PBM-16-1D):
- R 42 p15 represents that the quinoline ring of formula (PBM-16-1A), formula (PBM-16-1B), formula (PBM-16-1C) or formula (PBM-16-1D) is covered by p15 R 42 is substituted, each R 42 is the same or different and each independently represents halogen (such as fluorine, chlorine, bromine or iodine), cyano, C 1-6 alkoxy (such as C 1-4 alkoxy, such as methoxy ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 alkyl (such as C 1-6 alkyl, C 1- 5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (such as perdeuterated C 1-6 alkyl,
- halogenated C 1-6 alkyl eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 - , CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -);
- p15 represents the integer 2, 3 or 4;
- R 43 p16 means that the benzene ring of formula (PBM-16-1A), formula (PBM-16-1B), formula (PBM-16-1C) or formula (PBM-16-1D) is covered by p16 R 43 is substituted, each R 43 is the same or different and each independently represents halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkoxy (such as C 1-4 alkoxy, such as methoxy, ethoxy group, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (such as perdeuterium Substituted C 1-6
- p16 represents the integer 3 or 4.
- a PBM represents a small molecule ligand targeting BCR-ABL, including but not limited to a structure representing the following formula (PBM-16-1):
- PBM represents a small molecule ligand targeting BCR-ABL, including but not limited to representing the following formula (PBM-17-1A), formula (PBM-17-1B), formula (PBM-17-1C ), the structure of formula (PBM-17-1D) or formula (PBM-17-1E):
- R 44 p17 means formula (PBM-17-1A), formula (PBM-17-1B), formula (PBM-17-1C), formula (PBM-17-1D) or formula (PBM-17-1E)
- the benzene ring, pyrimidine ring and pyridine ring are each optionally substituted by p17 R 44 , each R 44 is the same or different and each independently represents halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkoxy (e.g.
- C 1-4 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy
- C 1-6 alkoxy such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl , ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl group or hexyl
- deuterated C 1-6 alkyl such as perdeuterated C 1-6 alkyl, perdeuterated C 1-5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.
- halogenated C 1-6 alkyl eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3
- p17 represents the integer 0, 1, 2, 3 or 4.
- a PBM represents a small molecule ligand targeting BCR-ABL, including but not limited to a structure representing the following formula (PBM-17-1):
- PBM represents a small molecule ligand targeting ER, including but not limited to representing the following formula (PBM-18-1A), formula (PBM-18-1B), formula (PBM-18-1C) or The structure of formula (PBM-18-1D):
- R 45 , R 46 , R 47 and R 48 are the same or different and each independently represents hydrogen, halogen (such as fluorine, chlorine, bromine or iodine), or hydroxyl; and
- PBM represents a small molecule ligand targeting ER, including but not limited to representing the following formula (PBM-18-1), formula (PBM-18-2), formula (PBM-18-3), The structure of formula (PBM-18-4), formula (PBM-18-5) or formula (PBM-18-6):
- a PBM represents a small molecule ligand targeting ER, including but not limited to a structure representing the following formula (PBM-19-1A) or formula (PBM-19-1B):
- R 49 represents that the 1,2,3,4-tetrahydronaphthalene ring of formula (PBM-19-1A) or formula (PBM-19-1B) is replaced by p18 R 49 , each R 49 is the same or different and Each independently represents hydrogen, hydroxyl, halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (e.g.
- perdeuterated C 1-6 alkyl Perdeuterated C 1-5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.
- halogenated C 1-6 alkyl such as Halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -);
- p18 represents the integer 0, 1, 2, 3 or 4;
- R 50 and R 51 each independently represent hydrogen, halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkane group, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), deuterated C 1-6 alkyl (such as perdeuterated C 1-6 Alkyl, perdeuterated C 1-5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -, etc.) or halogenated C 1-6 alkane group (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CH
- PBM represents a small molecule ligand targeting ER, including but not limited to representing a structure of the following formula (PBM-19-1):
- said R 1 represents a structure of the following formula:
- Bond, -O-, C 1-6 alkylene optionally substituted by a substituent selected from halogen and C 1-3 alkyl e.g., methylene, ethylene, propylene, isopropylidene , butylene, tert-butylene, pentylene, and hexylene
- -N(R 1a )-R 2a -*** eg -N(CH 3 )-CH 2 CH 2 -***, - NH-CH 2 CH 2 -***
- -OR 2a -*** eg -O-(CH 2 ) 3 -***, -O-CH 2 -*** and -O-(CH 2 ) 2 -***
- -C(O)NH-R 2a -***(eg -C(O)NH-(CH 2 ) 2 -***, -C(O)NH-(CH 2 ) 3 -***, -C(O)NH-CH CH-CH 2 -***
- Phenylene or naphthylene wherein each of said phenylene or naphthylene is independently optionally substituted by one or more R 3a , and each R 3a is the same or different and each independently is halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, cyano, amino, nitro, C 1-6 alkyl (such as C 1-6 alkyl, C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C -, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-
- the W 1 is t connected rings W 2 represented by the following structural formula:
- each ring W 2 is the same or different and each independently is the following groups:
- Monocyclic C 3-10 heterocyclylenes containing one nitrogen atom and optionally heteroatoms selected from nitrogen, oxygen and sulfur for example represent the following groups: piperidinylene, piperazinylene, morpholine group, azetidinyl group, pyrrolidinyl group, imidazolidinyl group, pyrazolidinyl group, oxazolidinyl group, thiazolidinyl group, thiomorpholinyl group, azepanylidene group, Diazepanylidene, azacyclooctylene or diazepanylidene; or
- a C5-20 bridged heterocyclylene group containing a nitrogen atom and optionally a heteroatom selected from nitrogen, oxygen and sulfur for example represents the following groups: azabicyclo[3.1.1]heptaneylidene, nitrogen Heterobicyclo[2.2.1]heptane, azabicyclo[3.2.1]octane, azabicyclo[2.2.2]octane, diazabicyclo[3.1.1]heptane group, diazabicyclo[2.2.1]heptaneylidene, diazabicyclo[3.2.1]octaneylidene or diazabicyclo[2.2.2]octaneylidene, for example representing the following groups:
- Cycloalkylene for example, represents the following groups: cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene , cyclooctylene, decahydronaphthylene, octahydropentalene, octahydro-1H-indenylene, C 5-15 spirocyclylene, adamantyl, noradamantyl , bornylidene, bicyclo[2.2.1]heptaneylidene, or bicyclo[2.2.1]heptenylidene;
- the monocyclic C 3-10 heterocyclylene, the C 5-20 bridged heterocyclylene and the C 3-15 cycloalkylene are each independently optionally selected from one or more of the following Substituent substitution: deuterium, hydroxyl, amino, mercapto, nitro, halogen (such as fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkane group (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), optionally deuterated C 3-6 cycloalkyl (such as optionally deuterated cyclopropyl, cyclobutyl, cyclopentyl or
- C 1-4 alkoxy e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy
- optionally deuterated C 1-6 alkyl-NH- NH 2 -C 1-6 alkylene
- optionally deuterated C 1-6 alkyl -NHC(O)- optionally deuterated C 1-6 alkyl-C(O)NH- or any combination thereof
- C 1-4 alkoxy e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy
- optionally deuterated C 1-6 alkyl-NH- NH 2 -C 1-6 alkylene
- optionally deuterated C 1-6 alkyl -NHC(O)- optionally deuterated C 1-6 alkyl-C(O)NH- or any combination thereof
- t represents the integer 1 or 2.
- said W represents the following groups:
- the group is optionally further selected from one or more groups selected from deuterium, halogen (such as fluorine, chlorine, bromine or iodine), cyano, amino, C 1-6 alkyl (such as C 1-6 alkyl , C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1 -6 alkyl (e.g.
- halogenated C 1-4 alkyl such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), deuterated C 1-6 alkyl (such as perdeuterated C 1-6 alkyl, perdeuterated C 1-6 5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -), C 1-6 alkoxy (such as C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), haloC1-6alkoxy (e.g.
- haloC1 -4 alkoxy such as F 3 CO-, FCH 2 -O-, F 2 CH-O-, ClCH 2 -O-, Cl 2 CH-O-, CF 3 CF 2 -O-, CF 3 CHF- O-, CHF 2 CF 2 -O-, CHF 2 CHF-O-, CF 3 CH 2 -O- or CH 2 ClCH 2 -O-), deuterated C 1-6 alkoxy or any combination thereof base substitution.
- the R 1 -W 1 represents the following groups:
- the group is optionally further selected from one or more groups selected from deuterium, halogen (such as fluorine, chlorine, bromine or iodine), cyano, amino, C 1-6 alkyl (such as C 1-6 alkyl , C 1-5 alkyl or C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl or hexyl), halogenated C 1 -6 alkyl (e.g.
- halogenated C 1-4 alkyl such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), deuterated C 1-6 alkyl (such as perdeuterated C 1-6 alkyl, perdeuterated C 1-6 5 alkyl or perdeuterated C 1-4 alkyl, such as CD 3 , CD 3 CD 2 -, CD 3 CD 2 CD 2 -), C 1-6 alkoxy (such as C 1-4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), haloC1-6alkoxy (e.g.
- haloC1 -4 alkoxy such as F 3 CO-, FCH 2 -O-, F 2 CH-O-, ClCH 2 -O-, Cl 2 CH-O-, CF 3 CF 2 -O-, CF 3 CHF- O-, CHF 2 CF 2 -O-, CHF 2 CHF-O-, CF 3 CH 2 -O- or CH 2 ClCH 2 -O-), deuterated C 1-6 alkoxy or any combination thereof base substitution.
- the ULM represents the following formula (ULM-1), formula (ULM-2), formula (ULM-3), formula (ULM-4), formula (ULM-5), formula (ULM- 6), the structure of formula (ULM-7), formula (ULM-8), formula (ULM-9), or formula (ULM-10):
- A represents CO, CH2 or CD2 ;
- R 1 , R 2 , R 3 and R 4 are the same or different and independently represent hydrogen, deuterium, halogen (such as fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 alkyl (such as optional Deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 1-6 alkoxy (e.g.
- C 1-4 alkoxy such as methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy
- halogenated C 1-6 alkyl such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH- , CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -);
- R b n means that the benzene ring is optionally substituted by n R b , each R b is the same or different and each independently represents hydrogen, deuterium, halogen (such as fluorine, chlorine, bromine or iodine), hydroxyl, mercapto , nitro, amino, cyano, optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl , butyl, sec-butyl or tert-butyl), optionally deuterated C 1-6 alkoxy (such as optionally deuterated C 1-4 alkoxy, such as methoxy, CD 3 -O- , ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl,
- n represents the integer 0, 1, 2 or 3;
- U 1 and U 2 are the same or different and each independently represents a bond, N(R d ) or O, wherein R d represents H or optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-6 4 alkyl, such as methyl, CD3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl);
- R d represents H or optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-6 4 alkyl, such as methyl, CD3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl);
- R c represents an optionally substituted monocyclic C 3-10 heterocyclylene containing a nitrogen atom and optionally a heteroatom selected from nitrogen, oxygen and sulfur, for example representing the following groups: piperidinylene, Piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, thiomorpholinyl, Azepanylidene, diazepanylidene, azacyclooctylene or diazepanylidene; or
- R c represents an optionally substituted C5-20 bridged heterocyclylene containing a nitrogen atom and optionally a heteroatom selected from nitrogen, oxygen and sulfur, for example representing the following group: azabicyclo[3.1.1 ]heptane, azabicyclo[2.2.1]heptane, azabicyclo[3.2.1]octane, azabicyclo[2.2.2]octane, diazabicyclo[ 3.1.1]heptaneylidene, diazabicyclo[2.2.1]heptaneylidene, diazabicyclo[3.2.1]octanylidene or diazabicyclo[2.2.2]octanylidene , for example representing the following groups:
- the monocyclic C 3-10 heterocyclylene and the C 5-20 bridging heterocyclylene are each independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, hydroxyl, amino , mercapto, nitro, halogen (such as fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 -, or
- optionally deuterated C 1-4 alkoxy such as methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert Butyloxy
- optionally deuterated C 1-6 alkyl-NH- NH 2 -C 1-6 alkylene
- optionally deuterated C 1-6 alkyl-NHC(O)- optionally deuterated C 1-6 alkyl-C(O)NH- or any combination thereof.
- said R c represents the following groups:
- the ULM represents the following formula (ULM-11), formula (ULM-12), formula (ULM-13), formula (ULM-14), formula (ULM-15), formula (ULM- 16), the structure of formula (ULM-17), formula (ULM-18), formula (ULM-19), formula (ULM-20), formula (ULM-21) or formula (ULM-22):
- the ULM represents a structure of the formula:
- the LIN represents the structure of the formula:
- each group R e is selected from O, N(R g ), C(O), C(O)O, OC(O), S(O), S(O) 2 , S(O) 2 NH , NHS(O) 2 , C(O)N(R g ), N(R g )C(O), or N(R g )C(O)N(R g ), wherein each R g independently represents H or C 1-6 alkyl (such as C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl); each group R is selected from Cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene, alkenylene or any combination thereof, wherein the cycloalkylene, the arylene, the heterocycle
- the radical and the heteroarylene group are independently of each other optionally further selected from deuterium, optionally deuterated C
- the hydrogen of one or more CH of the C 1-30 alkylene group is optionally further replaced by a substituent selected from: deuterium, hydroxyl, amino, mercapto, nitro, halogen (such as fluorine, chlorine, bromine or iodine), cyano, optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl group, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C- , FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), optionally deuterated C 3-6 cycl
- R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 and R a8 independently represent H, deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, optional deuterated C 1-6 alkyl (e.g.
- C 1-4 alkyl such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl
- halogen Substituted C 1-6 alkyl such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -
- optionally deuterated C 3-6 cycloalkyl such as optionally deuterated cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
- optionally deuterated C 1-6 alkoxy optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 alkylene , optional deuterated
- the symbol # indicates the point of attachment to the group U ;
- n1, n2, n3, n4, m1, m2, m3 are each independently selected from integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
- the LIN represents the structure of the formula:
- each R independently represents H or C 1-6 alkyl
- the cycloalkylene group, the arylene group, the heterocyclylene group and the heteroarylene group are independently of each other optionally further selected from deuterium, optionally deuterated C 1-6 alkyl (for example optionally deuterated C 1-4 alkyl such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 3- 6 Cycloalkyl (such as optionally deuterated cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxyl, amino, mercapto, halogen (such as fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 alkoxy, optionally deuterated C 1-6 alkyl-NH-, halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -
- R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 and R a8 independently represent H, deuterium, hydroxyl, amino, mercapto, nitro, halogen (such as fluorine, chlorine, bromine or iodine) ), cyano, optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (eg halogenated C 1-4 alkyl, eg F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH -, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH
- the symbol # indicates the point of attachment to the group U ;
- n1, n2, n3, n4, m1, m2, m3 are each independently selected from integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
- the LIN represents the following groups:
- the piperidinylene and the piperazinylene are independently from each other optionally further selected from deuterium, optionally deuterated C 1-6 alkyl (such as optionally deuterated C 1-4 alkane such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), optionally deuterated C 3-6 cycloalkyl (such as optionally deuterated cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxyl, amino, mercapto, halogen (such as fluorine, chlorine, bromine or iodine), optionally deuterated C 1-6 alkoxy (such as optional Deuterated C 1-4 alkoxy, such as methoxy, CD 3 -O-, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy ), optionally deuterated
- Each R independently represents H or C 1-6 alkyl
- the symbol # indicates the point of attachment to the group U ;
- n1, n2, n3, n4, m1, m2, m3 are each independently selected from integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
- the -W 1 -LIN-U 2 -R c -U 1 - represents the following groups:
- the group is optionally further selected from deuterium, Halogen (such as fluorine, chlorine, bromine or iodine), cyano, amino, C 1-6 alkyl (such as C 1-4 alkyl, such as methyl, CD 3 , ethyl, propyl, isopropyl, butyl group, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), deuterated C 1-6 alkyl (eg per Deuterated C 1-4 alkyl, such as perdeuterated methyl (CD 3 ), perdeuterated ethyl, perdeuterated propyl,
- the compound of formula (III) is also composed of the following formula (III-1), formula (III-2), formula (III-3), formula (III-4), formula (III-5), formula (III-6), formula (III-7), formula (III-8), formula (III-9), formula (III-10), formula (III-11), formula (III-12), formula ( III-13), formula (III-14), formula (III-15), formula (III-16), formula (III-17), formula (III-18), formula (III-19), formula (III -20), formula (III-21), formula (III-22), formula (III-23) or the structural representation of formula (III-24):
- ULM represents the structure of the following formula (ULM):
- W 1 represents optionally substituted piperidinylene
- R c represents optionally substituted piperidinylene
- U 1 represents a bond
- A, R 1 , R 2 , R 3 , R 4 , (R b ) n , U 2 , LIN, R 1 , (R 6a ) t1 , ring B, (R 7a ) t2 , (R 8a ) t3 , Q 1 are as defined above in the compound of formula (III) and its subembodiments, wherein W 1 and the substituents of the piperidinylene represented by R c are each independently as defined herein.
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Abstract
Description
化合物编号 | HTRF IC 50(μM) | 化合物编号 | HTRF IC 50(μM) |
Lena-NH 2 | 2.38 | GT-03100 | 9.80 |
GT-03106 | 4.04 | GT-03075 | 5.09 |
GT-03109 | 3.55 | GT-03210 | 2.69 |
GT-03077 | 5.20 | GT-03211 | 9.80 |
GT-03108 | 8.75 | GT-03076 | 0.65 |
化合物编号/名称 | SW620 |
瑞博西尼 | >10000 |
GT-03651 | B |
化合物编号/名称 | Daudi | Kasumi-1 | SU-DHL-6 | TMD8 |
达沙替尼 | B | A+ | A+ | A+ |
GT-03630 | - | A+ | B | - |
GT-03628 | - | B | - | - |
GT-03631 | B | B | A+ | - |
GT-03538 | B | B | A+ | A+ |
GT-03629 | - | B | B | - |
GT-03627 | - | B | B | - |
GT-03632 | A | A+ | A+ | - |
GT-03537 | B | A | A+ | A+ |
Claims (62)
- 式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物:其中A表示CO、CH 2或CD 2;R 1、R 2、R 3和R 4相同或不同且各自独立地表示氢、氘、卤素、可选氘代的C 1-6烷基、可选氘代的C 1-6烷氧基、或卤代C 1-6烷基;R 5、R 6、R 7和R 8相同或不同且各自独立地表示R 9、氢、氘、卤素、羟基、巯基、硝基、氨基、氰基、可选氘代的C 1-6烷基、可选氘代的C 1-6烷氧基、卤代C 1-6烷基、C 2-6烯基、或C 2- 6炔基,其中R 5、R 6、R 7和R 8中的1至3个表示R 9;R 9表示基团R-U-,其中,U表示键,或U表示N(R 10)或O,其中R 10表示H、或可选氘代的C 1-6烷基;R表示可选取代的含氮杂环基,所述可选取代的含氮杂环基是可选取代的含氮单环杂环基或可选取代的含氮桥杂环基;其中当R 5、R 6、R 7和R 8中的2至4个独立地表示R 9时,所述式(I)化合物可选地被部分氘化或完全氘化,或当R 5、R 6、R 7和R 8中仅1个表示R 9时,所述式(I)化合物可选地被部分氘化或完全氘化,其中在R 5、R 6、R 7和R 8中仅1个表示R 9并且所述式(I)化合物未被氘化的情况下:当R表示所述可选取代的含氮桥杂环基时,式(I)化合物不包括以下化合物:5-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;3-(5-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(8-氮杂双环[3.2.1]辛烷-3-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;和3-(5-(9-乙基-3-甲基-3,9-二氮杂双环[3.3.1]壬烷-7-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;或当A表示CO以及R 6和R 7中的一个表示R 9,其中基团R表示取代的含氮单环杂环基,并且R 6和R 7中的另一个、R 5和R 8各自独立地表示氢、卤素、羟基、巯基、硝基、氨基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、C 2-6烯基、或C 2-6炔基时,所述R 6和R 7中的另一个、R 5和R 8三者中的1至3个表示卤素,以及所述含氮单环杂环基被一或多个选自以下的取代基取代:羟基、氨基、巯基、硝基、卤素、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、NH 2-C 1-6亚烷基、C 1-6烷基-NH-、C 1-6烷基-NHC(O)-、C 1-6烷基-C(O)NH-或其任意组合;当A表示CO以及R 6和R 7中的一个表示R 9,其中基团R表示未取代的含氮单环杂环基时,R 6和R 7中的另一个表示氢、卤素、羟基、巯基、硝基、氨基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、C 2-6烯基、或C 2-6炔基,以及R 5和R 8各自独立地表示卤素;当A表示CO以及R 5和R 8中的一个表示R 9,其中基团R表示取代的含氮单环杂环基,并且R 5和R 8中的另一个、R 6和R 7各自独立地表示氢、卤素、羟基、巯基、硝基、氨基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、C 2-6烯基、或C 2-6炔基时,所述R 5和R 8中的另一个、R 6和R 7三者中的1至3个表示卤素,以及所述含氮单环杂环基被一或多个选自以下的取代基取代:羟基、氨基、巯基、硝基、卤素、氰基、CHO、C 1-6烷基、卤代C 1- 6烷基、C 3-6环烷基、C 1-6烷氧基、C 1-6烷基-NH-、NH 2-C 1-6亚烷基、C 1-6烷基-NHC(O)-、C 1- 6烷基-C(O)NH-或其任意组合;当A表示CO以及R 5和R 8中的一个表示R 9,其中基团R表示未取代的含氮单环杂环基时,R 5和R 8中的另一个和/或R 7各自独立地表示卤素,以及R 6表示氢、卤素、羟基、巯基、硝基、氨基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、C 2-6烯基、或C 2-6炔基;当A表示CH 2以及R 6和R 7中的一个表示R 9,其中基团R表示取代的含氮单环杂环基,并且R 6和R 7中的另一个、R 5和R 8各自独立地表示氢、卤素、羟基、巯基、硝基、氨基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、C 2-6烯基、或C 2-6炔基时,所述R 6和R 7中的另一个、R 5和R 8三者中的1至3个表示卤素,以及所述含氮单环杂环基被一或多个选自以下的取代基取代:羟基、氨基、巯基、硝基、卤素、CHO、氰基、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 1-6烷基-NH-、NH 2-C 1-6亚烷基、C 1-6烷基-NHC(O)-、C 1-6烷基-C(O)NH-或其任意组合;当A表示CH 2以及R 6和R 7中的一个表示R 9,其中基团R表示未取代的含氮单环杂环基时,R 5表示卤素,R 6和R 7中的另一个和/或R 8各自独立地表示卤素、羟基、巯基、硝基、氨基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、C 2-6烯基、或C 2-6炔基;当A表示CH 2以及R 5和R 8中的一个表示R 9,其中基团R表示取代的含氮单环杂环基,并且R 5和R 8中的另一个、R 6和R 7各自独立地表示氢、卤素、羟基、巯基、硝基、氨基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、C 2-6烯基、或C 2-6炔基时,所述R 5和R 8中的另一个、R 6和R 7中的1至3个表示卤素,以及所述含氮单环杂环基被一或多个选自以下的取代基取代:羟基、氨基、巯基、硝基、卤素、CHO、氰基、C 1-6烷基、卤代C 1-6 烷基、C 3-6环烷基、C 1-6烷氧基、C 1-6烷基-NH-、NH 2-C 1-6亚烷基、C 1-6烷基-NHC(O)-、C 1- 6烷基-C(O)NH-或其任意组合;或当A表示CH 2以及R 5和R 8中的一个表示R 9,其中基团R表示未取代的含氮单环杂环基,并且R 5和R 8中的另一个、R 6和R 7各自独立地表示氢、卤素、羟基、巯基、硝基、氨基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、C 2-6烯基、或C 2-6炔基时,所述R 5和R 8中的另一个、R 6和R 7三者不同时为氢,并且当R 6为卤素时,所述R 5和R 8中的另一个以及R 7不同时为氢。
- 如权利要求1或2所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中当R 5、R 6、R 7和R 8中的2至4个独立地表示R 9时,所述式(I)化合物可选地被部分氘化,例如携带有1至20个氘,或者所述式(I)化合物可选地被完全氘化。
- 如权利要求1或2所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中当R 5、R 6、R 7和R 8中仅1个表示R 9时,所述式(I)化合物被部分氘化,例如携带有1至15个氘,或者所述式(I)化合物被完全氘化。
- 如权利要求1或2所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中所述含氮单环杂环基和所述含氮桥杂环基可选地被一或多个选自以下的取代基取代:氘、羟基、氨基、巯基、硝基、卤素、氰基、CHO、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合。
- 如权利要求1或2所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中所述含氮单环杂环基是含有一个氮原子和可选地含有选自氮、氧和硫的杂原子的4元至10元单环杂环基,例如表示以下基团:哌啶基、哌嗪基、吗啉基、氮杂环丁基、吡咯烷基、咪唑烷基、吡唑烷基、噁唑烷基、噻唑烷基、硫代吗啉基、氮杂环庚基、二氮杂环庚基、氮杂环辛基或二氮杂环辛基;或所述含氮桥杂环基是含有一个氮原子和可选地含有选自氮、氧和硫的杂原子的C 5-20桥杂环基,例如表示以下基团:氮杂双环[3.1.1]庚烷基、氮杂双环[2.2.1]庚烷基、氮杂双环 [3.2.1]辛烷基、氮杂双环[2.2.2]辛烷基、二氮杂双环[3.1.1]庚烷基、二氮杂双环[2.2.1]庚烷基、二氮杂双环[3.2.1]辛烷基或二氮杂双环[2.2.2]辛烷基,例如表示以下基团:其中所述含氮单环杂环基和所述含氮桥杂环基可选地被一或多个选自以下的取代基取代:氘、羟基、氨基、巯基、硝基、卤素、氰基、CHO、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 3-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合。
- 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其选自:5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;5-(3-氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(2-氮杂双环[2.2.1]庚烷-5-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(2-氮杂双环[2.2.2]辛烷-5-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-5-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-6-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,7-二氟-5-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,6-二氟-5-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5-二氟-6-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5,7-三氟-6-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;6-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;6-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;5-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;6-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;5-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5,7-三氟-6-(哌嗪-1-基)异吲哚啉-1,3-二酮;6-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;5-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;6-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;5-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;6-(2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;5-(2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;6-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;5-(3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-((1R,4R)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-((1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(1-氧代-5-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3-氮杂双环[3.1.1]庚烷-6-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(6-氮杂双环[3.1.1]庚烷-3-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3-氮杂双环[3.2.1]辛烷-8-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,6-二甲基哌嗪-1-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,5-二甲基哌嗪-1-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(6-氟-1-氧代-5-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-氟-1-氧代-5-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,6-二甲基哌嗪-1-基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,5-二甲基哌嗪-1-基)-4-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(7-氟-1-氧代-5-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,6-二甲基哌嗪-1-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,5-二甲基哌嗪-1-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(6,7-二氟-1-氧代-5-(哌嗪-1-基)异吲哚啉-2-基)哌啶-2,6-二酮;3-(4,7-二氟-1-氧代-5-(哌嗪-1-基)异吲哚啉-2-基)哌啶-2,6-二酮;3-(4,6,7-三氟-1-氧代-5-(哌嗪-1-基)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-4,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-4,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-4,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-4,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-4,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-4,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-4,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-4,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-4,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-4,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-4,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-4,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-4,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-4,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-4,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-4,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-4,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-4,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(7-氟-1-氧代-5-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(6,7-二氟-1-氧代-5-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(4,7-二氟-1-氧代-5-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(4,6-二氟-1-氧代-5-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(4,6,7-三氟-1-氧代-5-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,6-二甲基哌嗪-1-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,6-二甲基哌嗪-1-基)-4,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,6-二甲基哌嗪-1-基)-4,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(2,6-二甲基哌嗪-1-基)-4,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,5-二甲基哌嗪-1-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,5-二甲基哌嗪-1-基)-4,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,5-二甲基哌嗪-1-基)-4,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-(3,5-二甲基哌嗪-1-基)-4,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-4-(哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-7-(哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5-二氟-7-(哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5,6-二氟-4-(哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5,7-二氟-4-(哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5,6-三氟-7-(哌嗪-1-基)异吲哚啉-1,3-二酮;4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮;4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-7-氟异吲哚啉-1,3-二酮;7-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮;4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-5,7-二氟异吲哚啉-1,3-二酮;4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-5,6,7-三氟异吲哚啉-1,3-二酮;4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮;4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-7-氟异吲哚啉-1,3-二酮;7-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮;4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-5,7-二氟异吲哚啉-1,3-二酮;4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-5,6,7-三氟异吲哚啉-1,3-二酮;4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮;4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-7-氟异吲哚啉-1,3-二酮;7-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮;4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-5,7-二氟异吲哚啉-1,3-二酮;4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-5,6,7-三氟异吲哚啉-1,3-二酮;4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮;4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-7-氟异吲哚啉-1,3-二酮;7-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮;4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-5,7-二氟异吲哚啉-1,3-二酮;4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-5,6,7-三氟异吲哚啉-1,3-二酮;4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮;4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-7-氟异吲哚啉-1,3-二酮;7-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮;4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-5,7-二氟异吲哚啉-1,3-二酮;4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-5,6,7-三氟异吲哚啉-1,3-二酮;4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮;4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-7-氟异吲哚啉-1,3-二酮;7-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮;4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-5,7-二氟异吲哚啉-1,3-二酮;4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-5,6,7-三氟异吲哚啉-1,3-二酮;4-(2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮;4-(2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;4-(2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-7-氟异吲哚啉-1,3-二酮;7-(2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;4-(2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮;4-(2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-5,7-二氟异吲哚啉-1,3-二酮;4-(2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-5,6,7-三氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-4-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-6-氟-4-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-7-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5-二氟-7-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5,7-二氟-4-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5,6-二氟-4-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5,6-三氟-7-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-4-(哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-7-(哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5-二氟-7-(哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5,6-二氟-4-(哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5,7-二氟-4-(哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5,6-三氟-7-(哌啶-4-基)异吲哚啉-1,3-二酮;4-(3-氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮;4-(3-氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;4-(3-氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-7-氟异吲哚啉-1,3-二酮;7-(3-氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;4-(3-氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮;4-(3-氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-5,7-二氟异吲哚啉-1,3-二酮;4-(3-氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-5,6,7-三氟异吲哚啉-1,3-二酮;4-(6-氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮;4-(6-氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;4-(6-氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-7-氟异吲哚啉-1,3-二酮;7-(6-氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;4-(6-氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮;4-(6-氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-5,7-二氟异吲哚啉-1,3-二酮;4-(6-氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-5,6,7-三氟异吲哚啉-1,3-二酮;4-((1R,5S,8r)-3-氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮;4-((1R,5S,8r)-3-氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;4-((1R,5S,8r)-3-氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-7-氟异吲哚啉-1,3-二酮;7-((1R,5S,8r)-3-氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;4-((1R,5S,8r)-3-氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮;4-((1R,5S,8r)-3-氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-5,7-二氟异吲哚啉-1,3-二酮;4-((1R,5S,8r)-3-氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-5,6,7-三氟异吲哚啉-1,3-二酮;4-(3,5-二甲基哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮;4-(3,5-二甲基哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;4-(3,5-二甲基哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-7-氟异吲哚啉-1,3-二酮;7-(3,5-二甲基哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;4-(3,5-二甲基哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-5,6-二氟异吲哚啉-1,3-二酮;4-(3,5-二甲基哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-5,7-二氟异吲哚啉-1,3-二酮;4-(3,5-二甲基哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-5,6,7-三氟异吲哚啉-1,3-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(1-氧代-4-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-氟-1-氧代-4-(哌嗪-1-基)异吲哚啉-2-基)哌啶-2,6-二酮;3-(7-氟-1-氧代-4-(哌嗪-1-基)异吲哚啉-2-基)哌啶-2,6-二酮;3-(6,7-二氟-1-氧代-4-(哌嗪-1-基)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5,6-二氟-1-氧代-4-(哌嗪-1-基)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5,7-二氟-1-氧代-4-(哌嗪-1-基)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5,6,7-三氟-1-氧代-4-(哌嗪-1-基)异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-5-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-5,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-5,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-6-基)-5,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-5-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-5,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-5,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,6-二氮杂双环[3.1.1]庚烷-3-基)-5,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-5-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-5,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-5,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-5,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-5-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-5,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-5,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-5,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-5-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-5,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-5,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.1]庚烷-2-基)-5,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-5-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-5,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-5,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,5-二氮杂双环[2.2.2]辛烷-2-基)-5,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,6-二甲基哌嗪-1-基)-5-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,6-二甲基哌嗪-1-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,6-二甲基哌嗪-1-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,6-二甲基哌嗪-1-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,6-二甲基哌嗪-1-基)-5,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,6-二甲基哌嗪-1-基)-5,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(2,6-二甲基哌嗪-1-基)-5,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-氟-1-氧代-4-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(6-氟-1-氧代-4-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(7-氟-1-氧代-4-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(6,7-二氟-1-氧代-4-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5,7-二氟-1-氧代-4-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5,6-二氟-1-氧代-4-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5,6,7-三氟-1-氧代-4-(哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5-氟-1-氧代-4-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮;3-(7-氟-1-氧代-4-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮;3-(6,7-二氟-1-氧代-4-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5,6-二氟-1-氧代-4-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5,7-二氟-1-氧代-4-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮;3-(5,6,7-三氟-1-氧代-4-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3-氮杂双环[3.1.1]庚烷-6-基)-5-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3-氮杂双环[3.1.1]庚烷-6-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3-氮杂双环[3.1.1]庚烷-6-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3-氮杂双环[3.1.1]庚烷-6-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3-氮杂双环[3.1.1]庚烷-6-基)-5,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3-氮杂双环[3.1.1]庚烷-6-基)-5,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3-氮杂双环[3.1.1]庚烷-6-基)-5,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(6-氮杂双环[3.1.1]庚烷-3-基)-5-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(6-氮杂双环[3.1.1]庚烷-3-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(6-氮杂双环[3.1.1]庚烷-3-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(6-氮杂双环[3.1.1]庚烷-3-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(6-氮杂双环[3.1.1]庚烷-3-基)-5,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;;3-(4-(6-氮杂双环[3.1.1]庚烷-3-基)-5,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(6-氮杂双环[3.1.1]庚烷-3-基)-5,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S,8r)-3-氮杂双环[3.2.1]辛烷-8-基)-5-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S,8r)-3-氮杂双环[3.2.1]辛烷-8-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S,8r)-3-氮杂双环[3.2.1]辛烷-8-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S,8r)-3-氮杂双环[3.2.1]辛烷-8-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S,8r)-3-氮杂双环[3.2.1]辛烷-8-基)-5,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S,8r)-3-氮杂双环[3.2.1]辛烷-8-基)-5,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-((1R,5S,8r)-3-氮杂双环[3.2.1]辛烷-8-基)-5,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,5-二甲基哌啶-4-基)-5-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,5-二甲基哌啶-4-基)-6-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,5-二甲基哌啶-4-基)-7-氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,5-二甲基哌啶-4-基)-6,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,5-二甲基哌啶-4-基)-5,6-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;3-(4-(3,5-二甲基哌啶-4-基)-5,7-二氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮;和3-(4-(3,5-二甲基哌啶-4-基)-5,6,7-三氟-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮。
- 式(II)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物:其中A表示CO、CH 2或CD 2;R 1、R 2、R 3和R 4相同或不同且各自独立地表示氢、氘、卤素、可选氘代的C 1-6烷基、可选氘代的C 1-6烷氧基、或卤代C 1-6烷基;(R b) n表示所述苯环被n个R b取代,各R b相同或不同且各自独立地表示氢、氘、卤素、羟基、巯基、硝基、氨基、氰基、可选氘代的C 1-6烷基、可选氘代的C 1-6烷氧基、卤代C 1-6烷基、C 2-6烯基、或C 2-6炔基;(R a) m表示所述苯环被m个R a取代,各R a相同或不同且各自独立地表示下式结构:W-LIN-U 2-R c-U 1-,其中U 1和U 2相同或不同且各自独立地表示键、N(R d)或O,其中R d表示H或可选氘代的C 1-6烷基;R c表示可选取代的含氮单环亚杂环基或可选取代的含氮亚桥杂环基;W表示氢、可选取代的含氮单环杂环基、可选取代的含氮桥杂环基、可选取代的环烷基、可选取代的杂芳基、可选取代的芳基、C 2-6烯基、C 2-6炔基、离去基团、CHO、COOH、NH 2、羟基或巯基;和其中,在所述式(II)化合物被部分氘化或完全氘化的情况下,当W表示可选取代的含氮单环杂环基、可选取代的含氮桥杂环基、可选取代的环烷基、可选取代的杂芳基或可选取代的芳基时,LIN表示键、可选取代的亚甲基、或可选取代的直链或支链的C 2-30亚烷基,其中所述直链或支链的C 2-30亚烷基的主碳链中可选地插入有一或多个基团R e和/或一或多个基团R f或者一或多个基团R e与R f的任意组合,所述基团R e、R f或者基团R e与R f的组合将所述主碳链的一或多对相邻碳原子之间的碳-碳键间断开;各基团R e选自O、N(R g)、C(O)、C(O)O、OC(O)、S(O)、S(O) 2、S(O) 2NH、NHS(O) 2、C(O)N(R g)、N(R g)C(O)、或N(R g)C(O)N(R g),其中各R g独立地表示H或C 1-6烷基,以及当所述直链或支链C 2-30亚烷基的主碳链中插入有两个以上基团R e时,各基团R e彼此不直接相连接;各基团R f选自亚环烷基、亚芳基、亚杂环基、亚杂芳基、亚炔基、亚烯基或其任意组合,其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自氘、可选氘代的C 1-6烷基、可选氘代的C 3-6环烷基、羟基、氨基、巯基、卤素、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、卤代C 1-6烷基、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-、氰基或其任意组合的取代基取代;或当W表示氢、C 2-6烯基、C 2-6炔基、离去基团、CHO、COOH、NH 2、羟基或巯基时,LIN表示可选取代的亚甲基、或可选取代的直链或支链的C 2-30亚烷基,其中所述直链或支链的C 2-30亚烷基的主碳链中可选地插入有一或多个基团R e和/或一或多个基团R f或者一或多个基团R e与R f的任意组合,所述基团R e、R f或者基团R e与R f的组合将所述主碳链的一或多对相邻碳原子之间的碳-碳键间断开;各基团R e选自O、N(R g)、C(O)、C(O)O、OC(O)、S(O)、S(O) 2、S(O) 2NH、NHS(O) 2、C(O)N(R g)、N(R g)C(O)、或N(R g)C(O)N(R g),其中各R g独立地表示H或C 1-6烷基,以及当所述直链或支链C 2-30亚烷基的主碳链中插入有两个以上基团R e时,各基团R e彼此不直接相连接;各基团R f选自亚环烷基、亚芳基、亚杂环基、亚杂芳基、亚炔基、亚烯基或其任意组合,其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自氘、可选氘代的C 1-6烷基、可选氘代的C 3-6环烷基、羟基、氨基、巯基、卤素、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、卤代C 1-6烷基、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-、氰基或其任意组合的取代基取代;或当所述式(II)化合物未被氘化时,LIN表示可选取代的亚甲基,以及W表示可选取代的含氮单环杂环基或可选取代的含氮桥杂环基;以及m表示整数1、2、3或4,n表示整数0、1、2、或3,且m和n之和是整数1、2、3或4;条件是,当所述式(II)化合物未被氘化时,所述式(II)化合物不是以下化合物:3-(4,6-二氟-1-氧代-5-(4-(哌啶-4-基甲基)哌嗪-1-基)异吲哚啉-2-基)哌啶-2,6-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-(哌啶-4-基甲基)哌嗪-1-基)异吲哚啉-1,3-二酮;3-(4-氯-1-氧代-5-(4-(哌啶-4-基甲基)哌啶-1-基)异吲哚啉-2-基)哌啶-2,6-二酮;5-(4-(氮杂环丁烷-3-基甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;和2-(2,6-二氧代哌啶-3-基)-5-(3-(哌嗪-1-基甲基)氮杂环丁烷-1-基)异吲哚啉-1,3-二酮。
- 如权利要求9或10所述的式(II)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中当所述式(II)化合物被部分氘化(例如携带有1至20个氘)或者被完全氘化,且W表示可选取代的含氮单环杂环基、可选取代的含氮桥杂环基、可选取代的环烷基、可选取代的杂芳基、或可选取代的芳基时,LIN表示键、可选取代的亚甲基、或可选取代的直链或支链的C 2-30亚烷基,其中所述直链或支链的C 2-30亚烷基的主碳链中可选地插入有一或多个基团R e和/或一或多个基团R f或者一或多个基团R e与R f的任意组合,所述基团R e、R f或者基团R e与R f的组合将所述主碳链的一或多对相邻碳原子之间的碳-碳键间断开;各基团R e选自O、N(R g)、C(O)、C(O)O、S(O)、S(O) 2、S(O) 2NH、NHS(O) 2、OC(O)、C(O)N(R g)、N(R g)C(O)、或N(R g)C(O)N(R g),其中各R g独立地表示H或C 1-6烷基,以及当所述直链或支链C 2-30亚烷基的主碳链中插入有两个以上基团R e时,各基团R e彼此不直接相连接;各基团R f选自亚环烷基、亚芳基、亚杂环基、亚杂芳基、亚炔基、亚烯基或其任意组合,其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自氘、可选氘代的C 1-6烷基、可选氘代的C 3-6环烷基、羟基、氨基、巯基、卤素、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、卤代C 1-6烷基、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-、氰基或其任意组合的取代基取代;或当所述式(II)化合物被部分氘化(例如携带有1至20个氘)或者被完全氘化且W表示氢、C 2-6烯基、C 2-6炔基、离去基团、CHO、COOH、NH 2、羟基或巯基时,LIN表示可选取代的亚甲基、或可选取代的直链或支链的C 2-30亚烷基,其中所述直链或支链的C 2-30亚烷基的主碳链中可选地插入有一或多个基团R e和/或一或多个基团R f或者一或多个基团R e与R f的任意组合,所述基团R e、R f或者基团R e与R f的组合将所述主碳链的一或多对相邻碳原子之间的碳-碳键间断开;各基团R e选自O、N(R g)、C(O)、C(O)O、S(O)、S(O) 2、S(O) 2NH、NHS(O) 2、OC(O)、C(O)N(R g)、N(R g)C(O)、或N(R g)C(O)N(R g),其中各R g独立地表示H或C 1-6烷基,以及当所述直链或支链C 2-30亚烷基的主碳链中插入有两个以上基团R e时,各基团R e彼此不直接相连 接;各基团R f选自亚环烷基、亚芳基、亚杂环基、亚杂芳基、亚炔基、亚烯基或其任意组合,其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自氘、可选氘代的C 1-6烷基、可选氘代的C 3-6环烷基、羟基、氨基、巯基、卤素、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、卤代C 1-6烷基、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-、氰基或其任意组合的取代基取代;或当所述式(II)化合物未被氘化时,LIN表示可选取代的亚甲基,以及W表示可选取代的含氮单环杂环基或可选取代的含氮桥杂环基;其中所述亚甲基和所述直链或支链的C 2-30亚烷基可选地被一或多个选自以下的取代基取代:氘、羟基、氨基、巯基、硝基、卤素、氰基、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合。
- 如权利要求9或10所述的式(II)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中R c表示以下基团:含有一个氮原子和可选地含有选自氮、氧和硫的杂原子的单环C 3-10亚杂环基,例如,亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚噁唑烷基、亚噻唑烷基、亚硫代吗啉基、氮杂环庚亚基、二氮杂环庚亚基、氮杂环辛亚基或二氮杂环辛亚基;或含有一个氮原子和可选地含有选自氮、氧和硫的杂原子的C 5-20亚桥杂环基,例如,氮杂双环[3.1.1]庚烷亚基、氮杂双环[2.2.1]庚烷亚基、氮杂双环[3.2.1]辛烷亚基、氮杂双环[2.2.2]辛烷亚基、二氮杂双环[3.1.1]庚烷亚基、二氮杂双环[2.2.1]庚烷亚基、二氮杂双环[3.2.1]辛烷亚基或二氮杂双环[2.2.2]辛烷亚基,例如以下基团:其中符号*表示与基团U 1的连接点,其中所述单环C 3-10亚杂环基和所述C 5-20亚桥杂环基各自独立地可选地被一或多个选自以下的取代基取代:氘、羟基、氨基、巯基、硝基、卤素、氰基、CHO、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合。
- 如权利要求9或10所述的式(II)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中W表示以下基团:含有一个氮原子和可选地含有选自氮、氧和硫的杂原子的单环C 3-10杂环基,例如,哌啶基、哌嗪基、吗啉基、氮杂环丁基、吡咯烷基、咪唑烷基、吡唑烷基、噁唑烷基、噻唑烷基、硫代吗啉基、氮杂环庚基、二氮杂环庚基、氮杂环辛基或二氮杂环辛基;或含有一个氮原子和可选地含有选自氮、氧和硫的杂原子的C 5-20桥杂环基,例如,氮杂双环[3.1.1]庚烷基、氮杂双环[2.2.1]庚烷基、氮杂双环[3.2.1]辛烷基、氮杂双环[2.2.2]辛烷基、二氮杂双环[3.1.1]庚烷基、二氮杂双环[2.2.1]庚烷基、二氮杂双环[3.2.1]辛烷基或二氮杂双环[2.2.2]辛烷基,例如以下基团:饱和或部分不饱和的单环或双环或多环C 3-20环烃基,例如,环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环辛基、十氢萘基、八氢并环戊二烯基、八氢-1H-茚基、C 7-11螺环烷基、金刚烷基、降金刚烷基、冰片基、二环[2.2.1]庚烷基或二环[2.2.1]庚烯基;或杂芳基,例如,含有1个或多个独立选自氧、氮和硫的杂原子的5-至20-元单环或二环的C 5-20芳香环基团,例如,呋喃基、噁唑基、异噁唑基、噁二唑基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、咪唑基、吡唑基、三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吲哚基、异吲哚基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、吲唑基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、苯并[2,1,3]噁二唑基、苯并[2,1,3]噻二唑基、苯并[1,2,3]噻二唑基、喹啉基、异喹啉基、萘啶基、噌啉基、喹唑啉基、喹喔啉基、酞嗪基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-a]吡啶基、1H-吡咯并[3,2-b]吡啶基、1H-吡咯并[2,3-b]吡啶基、4H-氟[3,2-b]吡咯基、吡咯并[2,1-b]噻唑基或咪唑并[2,1-b]噻唑基;或可选地包含一个或多个稠合环的C 5-14芳基,例如,苯基或萘基或芴基;以及其中所述单环C 3-10杂环基、所述C 5-20桥杂环基、所述C 3-20环烃基、所述杂芳基和所述C 5- 14芳基各自独立地可选地被一或多个选自以下的取代基取代:氘、羟基、氨基、巯基、硝基、卤素、氰基、CHO、COOH、N 3、甲磺酰氧基、三氟甲磺酰氧基、对甲苯磺酰氧基、C 1-6烷基、氘代C 1-6烷基、卤代C 1-6烷基、可选取代的C 3-8环烷基(例如被一或多个选自氘、卤素、氨基、羟基、巯基、氰基、CHO、COOH、N 3、甲磺酰氧基、三氟甲磺酰氧基、对甲苯磺酰氧基的取代基取代)、可选取代的4元至9元杂环基(例如被一或多个选自氘、卤素、氨基、羟基、巯基、氰基、CHO、COOH、N 3、甲磺酰氧基、三氟甲磺酰氧基、对甲苯磺酰氧基的取代基取代)、C 1-6烷氧基、氘代C 1-6烷基-O-、C 1-6烷基-NH-、氘代C 1-6烷基-NH-、NH 2-C 1-6亚烷基、C 1-6烷基-NHC(O)-、氘代C 1-6烷基-NHC(O)-、C 1-6烷基-C(O)NH-、氘代C 1-6烷基-C(O)NH-或其任意组合。
- 如权利要求9或10所述的式(II)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中LIN表示以下式的结构:#-C 1-30亚烷基-;#-(C(R a1)(R a2)) n1-(R e(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(R e(C(R a3)(R a4)) n2) m1-(R e(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(R e(C(R a3)(R a4)) n2) m1-(R e(C(R a5)(R a6)) n3) m2-(R e(C(R a7)(R a8)) n4) m3-;#-(C(R a1)(R a2)) n1-(R f(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(R f(C(R a3)(R a4)) n2) m1-(R f(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(R f(C(R a3)(R a4)) n2) m1-(R f(C(R a5)(R a6)) n3) m2-(R f(C(R a7)(R a8)) n4) m3-;#-(C(R a1)(R a2)) n1-(R e-R f-(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(R e(C(R a3)(R a4)) n2) m1-(R f(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(R f-R e-(C(R a3)(R a4)) n2) m1-;或#-(C(R a1)(R a2)) n1-(R f(C(R a3)(R a4)) n2) m1-(R e(C(R a5)(R a6)) n3) m2-;其中,各基团R e选自O、N(R g)、C(O)、C(O)O、OC(O)、S(O)、S(O) 2、S(O) 2NH、NHS(O) 2、C(O)N(R g)、N(R g)C(O)、或N(R g)C(O)N(R g),其中各R g独立地表示H或C 1-6烷基;各基团R f选自亚环烷基、亚芳基、亚杂环基、亚杂芳基、亚炔基、亚烯基或其任意组合,其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自氘、可选氘代的C 1-6烷基、可选氘代的C 3-6环烷基、羟基、氨基、巯基、卤素、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、卤代C 1-6烷基、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-、氰基或其任意组合的取代基取代;所述C 1-30亚烷基的一或多个CH 2的氢可选地进一步被选自以下的取代基替代:氘、羟基、氨基、巯基、硝基、卤素、氰基、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合;R a1、R a2、R a3、R a4、R a5、R a6、R a7和R a8分别独立地表示H、氘、羟基、氨基、巯基、硝基、卤素、氰基、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合;符号#表示与基团U 2的连接点;和n1、n2、n3、n4、m1、m2、m3分别独立地选自整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、或15。
- 如权利要求9或10所述的式(II)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中LIN表示以下式的结构:#-(C(R a1)(R a2)) n1-(O(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(O(C(R a3)(R a4)) n2) m1-(O(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(O(C(R a3)(R a4)) n2) m1-(O(C(R a5)(R a6)) n3) m2-(O(C(R a7)(R a8)) n4) m3-;#-(C(R a1)(R a2)) n1-(N(R g)(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(N(R g)(C(R a3)(R a4)) n2) m1-(N(R g)(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(N(R g)(C(R a3)(R a4)) n2) m1-(N(R g)(C(R a5)(R a6)) n3) m2-(N(R g)(C(R a7)(R a8)) n4) m3-;#-(C(R a1)(R a2)) n1-(C(O)N(R g)-(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(C(O)N(R g)-(C(R a3)(R a4)) n2) m1-(C(O)N(R g)-(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(C(O)N(R g)-(C(R a3)(R a4)) n2) m1-(C(O)N(R g)-(C(R a5)(R a6)) n3) m2-(C(O)N(R g)-(C(R a7)(R a8)) n4) m3-;#-(C(R a1)(R a2)) n1-(C(O)N(R g)-(C(R a3)(R a4)) n2) m1-(O-(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-C(O)N(R g)-(C(R a3)(R a4)) n2-(O(C(R a5)(R a6)) n3) m1-;#-(C(R a1)(R a2)) n1-(N(R g)C(O)-(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(N(R g)C(O)-(C(R a3)(R a4)) n2) m1-(O-(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(N(R g)C(O)-(C(R a3)(R a4)) n2) m1-(O-(C(R a5)(R a6)) n3) m2-(O-(C(R g)(R a8)) n4) m3-;#-(C(R a1)(R a2)) n1-N(R g)C(O)-(C(R a3)(R a4)) n2-(O(C(R a5)(R a6)) n3) m1-;#-(C(R a1)(R a2)) n1-N(R g)C(O)N(R g)-(C(R a3)(R a4)) n2-;#-(C(R a1)(R a2)) n1-C(O)-(C(R a3)(R a4)) n2-;#-(C(R a1)(R a2)) n1-(亚芳基-(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(亚芳基-(C(R a3)(R a4)) n2) m1-亚芳基-(C(R a5)(R a6)) n3-;#-(C(R a1)(R a2)) n1-(亚杂环基-(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(亚杂环基-(C(R a3)(R a4)) n2) m1-(亚杂环基-(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(亚杂芳基-(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(亚杂芳基-(C(R a3)(R a4)) n2) m1-(亚杂芳基-(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(亚环烷基-(C(R a3)(R a4)) n2) m1-;或#-(C(R a1)(R a2)) n1-(亚环烷基-(C(R a3)(R a4)) n2) m1-(亚环烷基-(C(R a5)(R a6)) n3) m2-;其中,各R g独立地表示H或C 1-6烷基;所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自氘、可选氘代的C 1-6烷基、可选氘代的C 3-6环烷基、羟基、氨基、巯基、卤素、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、卤代C 1-6烷基、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-、氰基或其任意组合的取代基取代;R a1、R a2、R a3、R a4、R a5、R a6、R a7和R a8分别独立地表示H、氘、羟基、氨基、巯基、硝基、卤素、氰基、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合;符号#表示与基团U 2的连接点;和n1、n2、n3、n4、m1、m2、m3分别独立地选自整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、或15。
- 如权利要求9或10所述的式(II)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中LIN表示以下基团:#-CH 2-、#-(CH 2) 2-、#-(CH 2) 3-、#-(CH 2) 4-、#-(CH 2) 5-、#-(CH 2) 6-、#-(CH 2) 7-、#-(CH 2) 8-、#-(CH 2) 9-、#-(CH 2) 10-、#-(CH 2) 11-、#-(CH 2) 12-、#-(CH 2) 13-、#-(CH 2) 14-、#-(CH 2) 15-、#-(CH 2) 16-、#-(CH 2) 17-、#-(CH 2) 18-、#-(CH 2) 19-、#-(CH 2) 20-、#-(CH 2) 21-、#-(CH 2) 22-、#-(CH 2) 25-、或#-(CH 2) 30-;#-CH 2-O-CH 2-、#-CH 2-O-(CH 2) 2-、#-(CH 2) 1-O-(CH 2) 3-、#-(CH 2) 1-O-(CH 2) 4-、#-(CH 2) 1-O-(CH 2) 5-、#-(CH 2) 1-O-(CH 2) 6-、#-(CH 2) 1-O-(CH 2) 7-、#-(CH 2) 1-O-(CH 2) 8-、#-(CH 2) 1-O- (CH 2) 9-、#-(CH 2) 1-O-(CH 2) 10-、#-(CH 2) 2-O-(CH 2) 1-、#-(CH 2) 2-O-(CH 2) 2-、#-(CH 2) 2-O-(CH 2) 3-、#-(CH 2) 2-O-(CH 2) 4-、#-(CH 2) 2-O-(CH 2) 5-、#-(CH 2) 2-O-(CH 2) 6-、#-(CH 2) 2-O-(CH 2) 7-、#-(CH 2) 2-O-(CH 2) 8-、#-(CH 2) 2-O-(CH 2) 9-、#-(CH 2) 2-O-(CH 2) 10-、#-(CH 2) 2-O-(CH 2) 11-、#-(CH 2) 2-O-(CH 2) 12-、#-(CH 2) 3-O-(CH 2) 1-、#-(CH 2) 3-O-(CH 2) 2-、#-(CH 2) 3-O-(CH 2) 3-、#-(CH 2) 3-O-(CH 2) 4-、#-(CH 2) 3-O-(CH 2) 5-、#-(CH 2) 3-O-(CH 2) 6-、#-(CH 2) 3-O-(CH 2) 7-、#-(CH 2) 4-O-(CH 2) 1-、#-(CH 2) 4-O-(CH 2) 2-、#-(CH 2) 4-O-(CH 2) 3-、#-(CH 2) 4-O-(CH 2) 4-、#-(CH 2) 4-O-(CH 2) 5-、#-(CH 2) 4-O-(CH 2) 6-、#-(CH 2) 5-O-(CH 2) 1-、#-(CH 2) 5-O-(CH 2) 2-、#-(CH 2) 5-O-(CH 2) 3-、#-(CH 2) 5-O-(CH 2) 4-、#-(CH 2) 5-O-(CH 2) 5-、#-(CH 2) 6-O-(CH 2) 1-、#-(CH 2) 6-O-(CH 2) 2-、#-(CH 2) 6-O-(CH 2) 3-、#-(CH 2) 6-O-(CH 2) 4-、#-(CH 2) 7-O-(CH 2) 1-、#-(CH 2) 7-O-(CH 2) 2-、#-(CH 2) 7-O-(CH 2) 3-、#-(CH 2) 8-O-(CH 2) 1-、#-(CH 2) 8-O-(CH 2) 2-、#-CH(CH 3)-O-(CH 2) 1-、#-CH(CH 3)-O-(CH 2) 2-、#-CH(CH 3)-O-(CH 2) 3-、#-CH(CH 3)-O-(CH 2) 4-、#-CH(CH 3)-O-(CH 2) 5-、#-CH(CH 3)-O-(CH 2) 6-、#-CH(CH 3)-O-(CH 2) 7-、#-CH(CH 3)-O-(CH 2) 8-、#-CH(CH 3)-O-(CH 2) 9-、#-CH(CH 3)-O-(CH 2) 10-、#-CH 2-(O(CH 2) 2) 2-、#-CH 2-(O(CH 2) 2) 3-、#-CH 2-(O(CH 2) 2) 4-、#-CH 2-(O(CH 2) 2) 5-、#-CH 2-(O(CH 2) 2) 6-、#-CH 2-(O(CH 2) 2) 7-、#-CH 2-(O(CH 2) 2) 8-、#-CH 2-(O(CH 2) 2) 9-、#-CH 2-(O(CH 2) 2) 10-、#-CH 2-(O(CH 2) 2) 1-OCH 2-、#-CH 2-(O(CH 2) 2) 2-OCH 2-、#-CH 2-(O(CH 2) 2) 3-OCH 2-、#-CH 2-(O(CH 2) 2) 4-OCH 2-、#-CH 2-(O(CH 2) 2) 5-OCH 2-、#-CH 2-(O(CH 2) 2) 6-OCH 2-、#-CH 2-(O(CH 2) 2) 7-OCH 2-、#-CH 2-(O(CH 2) 2) 8-OCH 2-、#-CH 2-(O(CH 2) 2) 9-OCH 2-、#-CH 2-(O(CH 2) 2) 10-OCH 2-、#-(CH 2) 2-(O(CH 2) 2) 2-、#-(CH 2) 2-(O(CH 2) 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 4-、#-(CH 2) 2-(O(CH 2) 2) 5-、#-(CH 2) 2-(O(CH 2) 2) 6-、#-(CH 2) 2-(O(CH 2) 2) 7-、#-(CH 2) 2-(O(CH 2) 2) 8-、#-(CH 2) 2-(O(CH 2) 2) 9-、#-(CH 2) 2-(O(CH 2) 2) 10-、#-(CH 2) 3-(O(CH 2) 2) 2-、#-(CH 2) 3-(O(CH 2) 2) 3-、#-(CH 2) 3-(O(CH 2) 2) 4-、#-(CH 2) 3-(O(CH 2) 2) 5-、#-(CH 2) 3-(O(CH 2) 2) 6-、#-(CH 2) 3-(O(CH 2) 2) 7-、#-(CH 2) 3-(O(CH 2) 2) 8-、#-(CH 2) 3-(O(CH 2) 2) 9-、#-(CH 2) 3-(O(CH 2) 2) 10-、#-(CH 2) 4-(O(CH 2) 2) 2-、#-(CH 2) 4-(O(CH 2) 2) 3-、#-(CH 2) 4-(O(CH 2) 2) 4-、#-(CH 2) 4-(O(CH 2) 2) 5-、#-(CH 2) 4-(O(CH 2) 2) 6-、#-(CH 2) 4-(O(CH 2) 2) 7-、#-(CH 2) 4-(O(CH 2) 2) 8-、#-(CH 2) 4-(O(CH 2) 2) 9-、#-(CH 2) 4-(O(CH 2) 2) 10-、#-CH 2-(O(CH 2) 3) 2-、#-CH 2-(O(CH 2) 3) 3-、#-CH 2-(O(CH 2) 3) 4-、#-CH 2-(O(CH 2) 3) 5-、#-CH 2-(O(CH 2) 3) 6-、#-CH 2-(O(CH 2) 3) 7-、#-CH 2-(O(CH 2) 3) 8-、#-CH 2-(O(CH 2) 3) 9-、#-CH 2-(O(CH 2) 3) 10-、#-(CH 2) 2-(O(CH 2) 3) 2-、#-(CH 2) 2-(O(CH 2) 3) 3-、#-(CH 2) 2-(O(CH 2) 3) 4-、#-(CH 2) 2-(O(CH 2) 3) 5-、#-(CH 2) 2-(O(CH 2) 3) 6-、#-(CH 2) 2-(O(CH 2) 3) 7-、#-(CH 2) 2-(O(CH 2) 3) 8-、#-(CH 2) 2-(O(CH 2) 3) 9-、#-(CH 2) 2-(O(CH 2) 3) 10-、#-(CH 2) 3-(O(CH 2) 3) 2-、#-(CH 2) 3-(O(CH 2) 3) 3-、#-(CH 2) 3-(O(CH 2) 3) 4-、#-(CH 2) 3-(O(CH 2) 3) 5-、#-(CH 2) 3-(O(CH 2) 3) 6-、#-(CH 2) 3-(O(CH 2) 3) 7-、#-(CH 2) 3-(O(CH 2) 3) 8-、#-(CH 2) 3-(O(CH 2) 3) 9-、#-(CH 2) 3-(O(CH 2) 3) 10-、#-CH 2-O-(CH 2) 2-O-(CH 2) 3-、#-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、#-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、#-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、#-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、#-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、#-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、#-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、#-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、#-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、#-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、#-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、#-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、#-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、#-(CH 2) 3-(O(CH 2) 2) 4- (O(CH 2) 3) 4-、#-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、#-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、#-CH 2-O-(CH 2) 3-O-(CH 2) 2-、#-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、#-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、#-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、#-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、#-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、#-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、#-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、#-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、#-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、#-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、#-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、#-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、#-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、#-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、#-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、#-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、#-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、#-CH 2-O-(CH 2) 2-O-CH 2-、#-(CH 2) 2-O-(CH 2) 2-O-CH 2-、#-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、#-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、#-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-、#-(CH 2) 1-N(R g)-(CH 2) 1-、#-(CH 2) 1-N(R g)-(CH 2) 2-、#-(CH 2) 1-N(R g)-(CH 2) 3-、#-(CH 2) 1-N(R g)-(CH 2) 4-、#-(CH 2) 1-N(R g)-(CH 2) 5-、#-(CH 2) 1-N(R g)-(CH 2) 6-、#-(CH 2) 1-N(R g)-(CH 2) 7-、#-(CH 2) 1-N(R g)-(CH 2) 8-、#-(CH 2) 1-N(R g)-(CH 2) 9-、#-(CH 2) 1-N(R g)-(CH 2) 10-、#-(CH 2) 2-N(R g)-(CH 2) 1-、#-(CH 2) 2-N(R g)-(CH 2) 2-、#-(CH 2) 2-N(R g)-(CH 2) 3-、#-(CH 2) 2-N(R g)-(CH 2) 4-、#-(CH 2) 2-N(R g)-(CH 2) 5-、#-(CH 2) 2-N(R g)-(CH 2) 6-、#-(CH 2) 2-N(R g)-(CH 2) 7-、#-(CH 2) 2-N(R g)-(CH 2) 8-、#-(CH 2) 2-N(R g)-(CH 2) 9-、#-(CH 2) 2-N(R g)-(CH 2) 10-、#-(CH 2) 2-N(R g)-(CH 2) 11-、#-(CH 2) 2-N(R g)-(CH 2) 12-、#-(CH 2) 3-N(R g)-(CH 2) 1-、#-(CH 2) 3-N(R g)-(CH 2) 2-、#-(CH 2) 3-N(R g)-(CH 2) 3-、#-(CH 2) 4-N(R g)-(CH 2) 1-、#-(CH 2) 4-N(R g)-(CH 2) 2-、#-(CH 2) 4-N(R g)-(CH 2) 3-、#-(CH 2) 4-N(R g)-(CH 2) 4-、#-(CH 2) 5-N(R g)-(CH 2) 1-、#-(CH 2) 5-N(R g)-(CH 2) 2-、#-(CH 2) 5-N(R g)-(CH 2) 3-、#-(CH 2) 5-N(R g)-(CH 2) 4-、#-(CH 2) 5-N(R g)-(CH 2) 5-、#-(CH 2) 6-N(R g)-(CH 2) 1-、#-(CH 2) 6-N(R g)-(CH 2) 2-、#-(CH 2) 6-N(R g)-(CH 2) 3-、#-(CH 2) 7-N(R g)-(CH 2) 1-、#-(CH 2) 7-N(R g)-(CH 2) 2-、#-(CH 2) 7-N(R g)-(CH 2) 3-、#-(CH 2) 8-N(R g)-(CH 2) 1-、#-(CH 2) 8-N(R g)-(CH 2) 2-、#-(CH 2) 8-N(R g)-(CH 2) 3-、#-CH(CH 3)-N(R g)-(CH 2) 1-、#-CH(CH 3)-N(R g)-(CH 2) 2-、#-CH(CH 3)-N(R g)-(CH 2) 3-、#-CH(CH 3)-N(R g)-(CH 2) 4-、#-CH(CH 3)-N(R g)-(CH 2) 5-、#-CH(CH 3)-N(R g)-(CH 2) 6-、#-CH(CH 3)-N(R g)-(CH 2) 7-、#-CH(CH 3)-N(R g)-(CH 2) 8-、#-CH(CH 3)-N(R g)-(CH 2) 9-、#-CH(CH 3)-N(R g)-(CH 2) 10-、#-CH 2C(O)NHCH 2-、#-(CH 2) 2C(O)NH(CH 2) 2-、#-(CH 2) 2C(O)NH(CH 2) 3-、#-(CH 2) 2C(O)NH(CH 2) 4-、#-(CH 2) 2C(O)NH(CH 2) 5-、#-(CH 2) 3C(O)NH(CH 2) 3-、#-(CH 2) 3C(O)NH(CH 2) 4-、#-(CH 2) 4C(O)NH(CH 2) 4-、#-(CH 2) 5C(O)NH(CH 2) 5-、#-(CH 2) 6C(O)NH(CH 2) 7-、#-(CH 2) 6C(O)NH(CH 2) 6-、#-(CH 2) 7C(O)NH(CH 2) 7-、#-(CH 2) 8C(O)NH(CH 2) 8、U-(CH 2) 9C(O)NH(CH 2) 9-、#-(CH 2) 10C(O)NH(CH 2) 10-、#-(CH 2) 2C(O)NH(CH 2) 2-O-(CH 2) 2-、#-CH 2NHC(O)CH 2-、#-(CH 2) 2NHC(O)(CH 2) 2-、#-(CH 2) 2NHC(O)(CH 2) 3-、#-(CH 2) 2NHC(O)(CH 2) 4-、#-(CH 2) 2NHC(O)(CH 2) 5-、#-(CH 2) 3NHC(O)(CH 2) 3-、#-(CH 2) 3NHC(O)(CH 2) 4-、#-(CH 2) 4NHC(O)(CH 2) 4-、#-(CH 2) 5NHC(O)(CH 2) 5-、#-(CH 2) 6NHC(O)(CH 2) 7-、#-(CH 2) 6NHC(O)(CH 2) 6-、#-(CH 2) 7NHC(O)(CH 2) 7-、#-(CH 2) 8NHC(O)(CH 2) 8、#-(CH 2) 9NHC(O)(CH 2) 9-、#-(CH 2) 10NHC(O)(CH 2) 10-、#-(CH 2) 4NHC(O)(CH 2) 8-、#-(CH 2) 2NHC(O)(CH 2) 2-O-(CH 2) 2-、#- (CH 2) 4NHC(O)CH 2-、#-CH 2-亚哌啶基-CH 2-、#-CH 2-亚哌啶基-(CH 2) 2-、#-CH 2-亚哌啶基-(CH 2) 3-、#-CH 2-亚哌啶基-(CH 2) 4-、#-CH 2-亚哌啶基-(CH 2) 5-、#-CH 2-亚哌啶基-(CH 2) 6-、#-CH 2-亚哌啶基-(CH 2) 7-、#-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 2-亚哌啶基-(CH 2) 1-、#-(CH 2) 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 2-亚哌啶基-(CH 2) 4-、#-(CH 2) 2-亚哌啶基-(CH 2) 5-、#-(CH 2) 2-亚哌啶基-(CH 2) 6-、#-(CH 2) 2-亚哌啶基-(CH 2) 7-、#-(CH 2) 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 3-亚哌啶基-CH 2-、#-(CH 2) 3-亚哌啶基-(CH 2) 2-、#-(CH 2) 3-亚哌啶基-(CH 2) 3-、#-(CH 2) 3-亚哌啶基-(CH 2) 4-、#-(CH 2) 3-亚哌啶基-(CH 2) 5-、#-(CH 2) 3-亚哌啶基-(CH 2) 6-、#-(CH 2) 3-亚哌啶基-(CH 2) 7-、#-(CH 2) 3-亚哌啶基-(CH 2) 8-、#-(CH 2) 4-亚哌啶基-CH 2-、#-(CH 2) 4-亚哌啶基-(CH 2) 2-、#-(CH 2) 4-亚哌啶基-(CH 2) 3-、#-(CH 2) 4-亚哌啶基-(CH 2) 4-、#-(CH 2) 4-亚哌啶基-(CH 2) 5-、#-(CH 2) 4-亚哌啶基-(CH 2) 6-、#-(CH 2) 4-亚哌啶基-(CH 2) 7-、#-(CH 2) 4-亚哌啶基-(CH 2) 8-、#-(CH 2) 5-亚哌啶基-(CH 2) 1-、#-(CH 2) 5-亚哌啶基-(CH 2) 2-、#-(CH 2) 5-亚哌啶基-(CH 2) 3-、#-(CH 2) 5-亚哌啶基-(CH 2) 4-、#-(CH 2) 5-亚哌啶基-(CH 2) 5-、#-(CH 2) 5-亚哌啶基-(CH 2) 6-、#-(CH 2) 5-亚哌啶基-(CH 2) 7-、#-(CH 2) 5-亚哌啶基-(CH 2) 8-、#-(CH 2) 6-亚哌啶基-(CH 2) 1-、#-(CH 2) 6-亚哌啶基-(CH 2) 2-、#-(CH 2) 6-亚哌啶基-(CH 2) 3-、#-(CH 2) 6-亚哌啶基-(CH 2) 4-、#-(CH 2) 6-亚哌啶基-(CH 2) 5-、#-(CH 2) 6-亚哌啶基-(CH 2) 6-、#-(CH 2) 6-亚哌啶基-(CH 2) 7-、#-(CH 2) 6-亚哌啶基-(CH 2) 8-、#-(CH 2) 7-亚哌啶基-(CH 2) 1-、#-(CH 2) 7-亚哌啶基-(CH 2) 2-、#-(CH 2) 7-亚哌啶基-(CH 2) 3-、#-(CH 2) 7-亚哌啶基-(CH 2) 4-、#-(CH 2) 7-亚哌啶基-(CH 2) 8-、#-(CH 2) 8-亚哌啶基-CH 2-、#-(CH 2) 8-亚哌啶基-(CH 2) 2-、#-(CH 2) 8-亚哌啶基-(CH 2) 3-、#-(CH 2) 8-亚哌啶基-(CH 2) 4-、#-(CH 2) 8-亚哌啶基-(CH 2) 5-、#-(CH 2) 8-亚哌啶基-(CH 2) 6-、#-(CH 2) 8-亚哌啶基-(CH 2) 7-、#-(CH 2) 8-亚哌啶基-(CH 2) 8-、#-CH 2-N(R g)-CH 2-亚哌啶基-CH 2-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 4-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 5-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 6-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 7-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-CH 2-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 2-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 3-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 4-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 5-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 6-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 7-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 4-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 5-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 6-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 7-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 5-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 5-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 6-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 6-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 7-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 7-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 8-N(R g)-CH 2- 亚哌啶基-(CH 2) 2-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 4-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 5-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 6-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 7-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-CH 2-亚哌嗪基-CH 2-、#-CH 2-亚哌嗪基-(CH 2) 2-、#-CH 2-亚哌嗪基-(CH 2) 3-、#-CH 2-亚哌嗪基-(CH 2) 4-、#-CH 2-亚哌嗪基-(CH 2) 5-、#-CH 2-亚哌嗪基-(CH 2) 6-、#-CH 2-亚哌嗪基-(CH 2) 7-、#-CH 2-亚哌嗪基-(CH 2) 8-、#-(CH 2) 2-亚哌嗪基-(CH 2) 1-、#-(CH 2) 2-亚哌嗪基-(CH 2) 2-、#-(CH 2) 2-亚哌嗪基-(CH 2) 3-、#-(CH 2) 2-亚哌嗪基-(CH 2) 4-、#-(CH 2) 2-亚哌嗪基-(CH 2) 5-、#-(CH 2) 2-亚哌嗪基-(CH 2) 6-、#-(CH 2) 2-亚哌嗪基-(CH 2) 7-、#-(CH 2) 2-亚哌嗪基-(CH 2) 8-、#-(CH 2) 3-亚哌嗪基-CH 2-、#-(CH 2) 3-亚哌嗪基-(CH 2) 2-、#-(CH 2) 3-亚哌嗪基-(CH 2) 3-、#-(CH 2) 3-亚哌嗪基-(CH 2) 4-、#-(CH 2) 3-亚哌嗪基-(CH 2) 5-、#-(CH 2) 3-亚哌嗪基-(CH 2) 6-、#-(CH 2) 3-亚哌嗪基-(CH 2) 7-、#-(CH 2) 3-亚哌嗪基-(CH 2) 8-、#-(CH 2) 4-亚哌嗪基-CH 2-、#-(CH 2) 4-亚哌嗪基-(CH 2) 2-、#-(CH 2) 4-亚哌嗪基-(CH 2) 3-、#-(CH 2) 4-亚哌嗪基-(CH 2) 4-、#-(CH 2) 4-亚哌嗪基-(CH 2) 5-、#-(CH 2) 4-亚哌嗪基-(CH 2) 6-、#-(CH 2) 4-亚哌嗪基-(CH 2) 7-、#-(CH 2) 4-亚哌嗪基-(CH 2) 8-、#-(CH 2) 5-亚哌嗪基-(CH 2) 1-、#-(CH 2) 5-亚哌嗪基-(CH 2) 2-、#-(CH 2) 5-亚哌嗪基-(CH 2) 3-、#-(CH 2) 5-亚哌嗪基-(CH 2) 4-、#-(CH 2) 5-亚哌嗪基-(CH 2) 5-、#-(CH 2) 5-亚哌嗪基-(CH 2) 6-、#-(CH 2) 5-亚哌嗪基-(CH 2) 7-、#-(CH 2) 5-亚哌嗪基-(CH 2) 8-、#-(CH 2) 6-亚哌嗪基-(CH 2) 1-、#-(CH 2) 6-亚哌嗪基-(CH 2) 2-、#-(CH 2) 6-亚哌嗪基-(CH 2) 3-、#-(CH 2) 6-亚哌嗪基-(CH 2) 4-、#-(CH 2) 6-亚哌嗪基-(CH 2) 5-、#-(CH 2) 6-亚哌嗪基-(CH 2) 6-、#-(CH 2) 6-亚哌嗪基-(CH 2) 7-、#-(CH 2) 6-亚哌嗪基-(CH 2) 8-、#-(CH 2) 7-亚哌嗪基-(CH 2) 1-、#-(CH 2) 7-亚哌嗪基-(CH 2) 2-、#-(CH 2) 7-亚哌嗪基-(CH 2) 3-、#-(CH 2) 7-亚哌嗪基-(CH 2) 4-、#-(CH 2) 7-亚哌嗪基-(CH 2) 8-、#-(CH 2) 8-亚哌嗪基-CH 2-、#-(CH 2) 8-亚哌嗪基-(CH 2) 2-、#-(CH 2) 8-亚哌嗪基-(CH 2) 3-、#-(CH 2) 8-亚哌嗪基-(CH 2) 4-、#-(CH 2) 8-亚哌嗪基-(CH 2) 5-、#-(CH 2) 8-亚哌嗪基-(CH 2) 6-、#-(CH 2) 8-亚哌嗪基-(CH 2) 7-、或#-(CH 2) 8-亚哌嗪基-(CH 2) 8-;其中,所述亚哌啶基和所述亚哌嗪基彼此独立地可选地进一步被选自氘、可选氘代的C 1-6烷基、可选氘代的C 3-6环烷基、羟基、氨基、巯基、卤素、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、卤代C 1-6烷基、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-、氰基或其任意组合的取代基取代;各R g独立地表示H或C 1-6烷基;符号#表示与基团U 2的连接点;和n1、n2、n3、n4、m1、m2、m3分别独立地选自整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、或15。
- 如权利要求9所述的式(II)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其选自:2-(2,6-二氧代哌啶-3-基)-5-(3-(哌啶-4-基甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-(哌啶-4-基甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(6-(哌啶-4-基甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(6-(哌啶-4-基甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-(哌啶-4-基甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-(哌啶-4-基甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(8-(哌啶-4-基甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(8-(哌啶-4-基甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(5-(哌啶-4-基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-(哌啶-4-基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((1R,4R)-5-(哌啶-4-基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-((1R,4R)-5-(哌啶-4-基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((1S,4S)-5-(哌啶-4-基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-((1S,4S)-5-(哌啶-4-基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(5-(哌啶-4-基甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-(哌啶-4-基甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-(哌啶-4-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-(哌啶-4-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-6-(4-(哌啶-4-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-5-(4-(哌啶-4-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,6-二氟-5-(4-(哌啶-4-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,7-二氟-5-(4-(哌啶-4-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5-二氟-6-(4-(哌啶-4-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5,7-三氟-6-(4-(哌啶-4-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;5-(2,6-二甲基-4-(哌啶-4-基甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(2,6-二甲基-4-(哌啶-4-基甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3,5-二甲基-4-(哌啶-4-基甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3,5-二甲基-4-(哌啶-4-基甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(1-(哌啶-4-基甲基)哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(1-(哌啶-4-基甲基)哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((R)-3-((哌啶-4-基甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((S)-3-((哌啶-4-基甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((S)-1-(哌啶-4-基甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((R)-1-(哌啶-4-基甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;5-(3-(氮杂环丁烷-3-基甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-(氮杂环丁烷-3-基甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(6-(氮杂环丁烷-3-基甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-(氮杂环丁烷-3-基甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-(氮杂环丁烷-3-基甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-(氮杂环丁烷-3-基甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(8-(氮杂环丁烷-3-基甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(8-(哌啶-4-基甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;5-(5-(氮杂环丁烷-3-基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-(氮杂环丁烷-3-基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((1R,4R)-5-(氮杂环丁烷-3-基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((1R,4R)-5-(氮杂环丁烷-3-基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((1S,4S)-5-(氮杂环丁烷-3-基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((1S,4S)-5-(氮杂环丁烷-3-基甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-(氮杂环丁烷-3-基甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-(氮杂环丁烷-3-基甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-(氮杂环丁烷-3-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-(氮杂环丁烷-3-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;6-(4-(氮杂环丁烷-3-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-(氮杂环丁烷-3-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-(氮杂环丁烷-3-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-(氮杂环丁烷-3-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;6-(4-(氮杂环丁烷-3-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(4-(氮杂环丁烷-3-基甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-(氮杂环丁烷-3-基甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-(氮杂环丁烷-3-基甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-(氮杂环丁烷-3-基甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-(氮杂环丁烷-3-基甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-(氮杂环丁烷-3-基甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-(氮杂环丁烷-3-基甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((R)-3-((氮杂环丁烷-3-基甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-((氮杂环丁烷-3-基甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-(氮杂环丁烷-3-基甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;和5-(((R)-1-(氮杂环丁烷-3-基甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮。
- 式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物:PBM-R 1-W 1-LIN-ULM式(III)其中PBM-R 1-W 1-表示能够结合蛋白的靶向部分,ULM表示能够结合E3泛素连接酶的配体部分,LIN为连接部分,PBM-R 1-W 1-通过基团LIN共价连接ULM;ULM表示以下式(ULM)的结构:其中A表示CO、CH 2或CD 2;R 1、R 2、R 3和R 4相同或不同且各自独立地表示氢、氘、卤素、可选氘代的C 1-6烷基、可选氘代的C 1-6烷氧基、或卤代C 1-6烷基;(R b) n表示所述苯环可选地被n个R b取代,各R b相同或不同且各自独立地表示氢、氘、卤素、羟基、巯基、硝基、氨基、氰基、可选氘代的C 1-6烷基、可选氘代的C 1-6烷氧基、卤代C 1- 6烷基、C 2-6烯基、或C 2-6炔基;n表示整数0、1、2或3;U 1和U 2相同或不同且各自独立地表示键、N(R d)或O,其中R d表示H或可选氘代的C 1-6烷基;R c表示可选取代的含氮单环亚杂环基或可选取代的含氮亚桥杂环基;LIN表示键、可选取代的亚甲基、或可选取代的直链或支链的C 2-30亚烷基,其中所述直链或支链的C 2-30亚烷基的主碳链中可选地插入有一或多个基团R e和/或一或多个基团R f或者一或多个基团R e与R f的任意组合,所述基团R e、R f或者基团R e与R f的组合将所述主碳链的一或多对相邻碳原子之间的碳-碳键间断开;各基团R e选自O、N(R g)、C(O)、C(O)O、OC(O)、S(O)、S(O) 2、S(O) 2NH、NHS(O) 2、C(O)N(R g)、N(R g)C(O)、或N(R g)C(O)N(R g),其中各R g独立地表示H或C 1-6烷基,以及当所述直链或支链C 2-30亚烷基的主碳链中插入有两个以上基团R e时,各基团R e彼此不直接相连接;各基团R f选自亚环烷基、亚芳基、亚杂环基、亚杂芳基、 亚炔基、亚烯基或其任意组合,其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自氘、可选氘代的C 1-6烷基、可选氘代的C 3-6环烷基、羟基、氨基、巯基、卤素、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、卤代C 1-6烷基、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-、氰基或其任意组合的取代基取代;W 1是由以下结构式表示的t个相连的环W 2:各环W 2相同或不同且各自独立地是可选取代的含氮单环亚杂环基、可选取代的含氮亚桥杂环基、或可选取代的亚环烷基,和t表示整数1或2;以及R 1表示:键、-O-、可选取代的C 1-6亚烷基(例如亚甲基)、-N(R 1a)-R 2a-***(例如 )、-O-R 2a-***(例如 )、-C(O)NH-R 2a-***、或-NHC(O)-R 2a-***(例如 ),其中符号***表示与W 1的连接点,R 1a是氢或C 1-6烷基,以及R 2a是可选取代的C 1-6亚烷基或可选取代的C 1-6亚烯基;或C 6-10芳基或包含1或2个5-至7-元环和1-4个选自N、O和S的杂原子的杂芳基,其中所述C 6-10芳基和所述杂芳基各自可选地被一或多个R 3a取代,以及各R 3a相同或不同且各自独立地是卤素、羟基、氰基、氨基、硝基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、或卤代C 1-6烷氧基;其中,式(III)化合物的一或多个氢可选地被氘取代;其中,当式(III)化合物未被氘取代时,式(III)化合物不包括以下化合物:在式(IV-1)中,R 1表示键,W 1表示亚哌啶基,LIN表示亚甲基,R c表示亚哌嗪基、2,5-二氮杂双环[2.2.1]庚烷亚基、8-氮杂双环[3.2.1]辛烷亚基或9-乙基-3-甲基-3,9-二氮杂双环[3.3.1]壬烷亚基,R b表示氟,n表示整数1、2或3,以及U 1和U 2相同或不同且各自独立地表示键、NH或O;或在式(IV-1)中,R 1表示键,W 1表示亚哌嗪基,LIN表示亚甲基,R c表示亚哌啶基、2,5-二氮杂双环[2.2.1]庚烷亚基、8-氮杂双环[3.2.1]辛烷亚基或9-乙基-3-甲基-3,9-二氮杂双环[3.3.1]壬 烷亚基,R b表示氟,n表示整数1、2或3,以及U 1和U 2相同或不同且各自独立地表示键、NH或O;在式(IV-2)中,R 1表示键,W 1表示亚哌啶基,LIN表示亚甲基,R c表示亚哌嗪基、2,5-二氮杂双环[2.2.1]庚烷亚基、8-氮杂双环[3.2.1]辛烷亚基或9-乙基-3-甲基-3,9-二氮杂双环[3.3.1]壬烷亚基,R b表示氟,和n表示整数1、2或3,以及U 1和U 2相同或不同且各自独立地表示键、NH或O;或在式(IV-2)中,R 1表示键,W 1表示亚哌嗪基,LIN表示亚甲基,R c表示亚哌啶基、2,5-二氮杂双环[2.2.1]庚烷亚基、8-氮杂双环[3.2.1]辛烷亚基或9-乙基-3-甲基-3,9-二氮杂双环[3.3.1]壬烷亚基,R b表示氟,和n表示整数1、2或3,以及U 1和U 2相同或不同且各自独立地表示键、NH或O;在式(IV-3)中,R 1表示键或-O-CH 2-CH 2-,W 1表示亚哌啶基,LIN表示亚甲基,R c表示亚哌嗪基、2,5-二氮杂双环[2.2.1]庚烷亚基、8-氮杂双环[3.2.1]辛烷亚基或9-乙基-3-甲基-3,9-二氮杂双环[3.3.1]壬烷亚基,R b表示氢,以及U 1和U 2相同或不同且各自独立地表示键、NH或O;或在式(IV-3)中,R 1表示键或-O-CH 2-CH 2-,W 1表示亚哌嗪基,LIN表示亚甲基,R c表示亚哌啶基、2,5-二氮杂双环[2.2.1]庚烷亚基、8-氮杂双环[3.2.1]辛烷亚基或9-乙基-3-甲基-3,9-二氮杂双环[3.3.1]壬烷亚基,R b表示氢,以及U 1和U 2相同或不同且各自独立地表示键、NH或O;以及在式(IV-4)中,R 1表示键或表示-O-CH 2-CH 2-,W 1表示亚哌啶基,LIN表示亚甲基,R c表示亚哌嗪基、2,5-二氮杂双环[2.2.1]庚烷亚基、8-氮杂双环[3.2.1]辛烷亚基或9-乙基-3-甲基-3,9-二氮杂双环[3.3.1]壬烷亚基,R b表示氢,以及U 1和U 2相同或不同且各自独立地表示键、NH或O;或在式(IV-4)中,R 1表示键或表示-O-CH 2-CH 2-,W 1表示亚哌嗪基,LIN表示亚甲基,R c表示亚哌啶基、2,5-二氮杂双环[2.2.1]庚烷亚基、8-氮杂双环[3.2.1]辛烷亚基或9-乙基-3-甲基-3,9-二氮杂双环[3.3.1]壬烷亚基,R b表示氢,以及U 1和U 2相同或不同且各自独立地表示键、NH或O。
- 如权利要求20所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中所述PBM是靶向EGFR的小分子配体、靶向CDK4/6的小分子配体、靶向ALK的小分子配体、靶向RET的小分子配体、靶向FAK的小分子配体、靶向BCR-ABL的小分子配体、靶向BTK的小分子配体、靶向AR的小分子配体、靶向ER的小分子配体或靶向BET的小分子配体。
- 如权利要求21所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中所述PBM包括选自以下式的结构:其中(R 2) p1表示式(PBM-1)的所述苯环被p1个R 2取代,各R 2相同或不同且各自独立地表示卤素或卤代C 1-6烷基;(R 3) p2表示式(PBM-1)的所述喹唑啉环被p2个R 3取代,各R 3相同或不同且各自独立地表示C 1-10烷基、氘代C 1-10烷基、C 1-10烷氧基、杂环基氧基、或-NHC(O)R 4,其中R 4是C 1-10烷基或C 2-10烯基,例如R 3表示甲基、甲氧基、 例如p1表示整数1、2、3、4或5;p2表示整数1、2、或3;(R 5) p3表示式(PBM-2)的所述苯环被p3个R 5取代,各R 5相同或不同且各自独立地表示C 1- 10烷基、氘代C 1-10烷基、C 1-10烷氧基或-NHC(O)R 4,其中R 4是C 1-10烷基、氘代C 1-10烷基或C 2- 10烯基,例如R 5表示甲基、甲氧基或p3表示整数1、2、3或4;(R 6) p4表示式(PBM-2)的所述1H-吲哚环被p4个R 6取代,各R 6相同或不同且各自独立地表示C 1-10烷基或氘代C 1-10烷基;p4表示整数0、1、2或3;(R 7) p5表示式(PBM-3)的所述苯环被p5个R 7取代,各R 7相同或不同且各自独立地表示卤素、羟基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、NO 2、NH 2、或氰基,p5表示整数2、3、4或5;R 8表示C 6-10芳基,或包含1或2个5-至7-元环和1-4个选自N、O和S的杂原子的杂芳基,其中所述C 6-10芳基和所述杂芳基各自可选地被一或多个R 4a取代,以及各R 4a相同或不同且各自独立地是卤素、羟基、氰基、氨基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、或卤代C 1-6烷氧基;R 10表示 其中(R 5a) p6表示所述哌啶环被p6个R 5a取代,各R 5a相同或不同且各自独立地表示氘、卤素、羟基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1- 6烷氧基、氘代C 1-6烷氧基、NO 2、NH 2、或氰基,p6表示整数1、2、3、4或5;(R 11) p7表示式(PBM-5)的所述苯环和吡啶环各自可选地被p7个R 11取代,各R 11相同或不同且各自独立地表示卤素、C 1-6烷基、卤代C 1-6烷基、或氘代C 1-6烷基,p7表示整数0、1、2或3;式(PBM-6)的环A表示C 6-10芳基或含有1-4个选自N、O和S的杂原子的5-至20-元单环或二环杂芳基,所述环A可选地被一或多个R 6a取代,以及各R 6a相同或不同且各自独立地是氘、卤素、羟基、氰基、氨基、硝基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 2-6烯基、或C 2-6炔基;式(PBM-6)的环B表示C 3-15环烷基或含有1-4个选自N、O和S的杂原子的3至20元杂环基,其中所述环B可选地被一或多个R 7a取代,以及各R 7a相同或不同且各自独立地是氘、卤素、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、或卤代C 1-6烷氧基;式(PBM-6)的环C表示含有1-4个选自N、O和S的杂原子的5-至20-元单环或二环杂芳基,所述环C可选地被一或多个R 8a取代,以及各R 8a相同或不同且各自独立地是氘、卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、或卤代C 1-6烷氧基;式(PBM-7)的X 1表示N或CR 12,其中R 12是氢或表示键,以及X 2表示CH或N;R 13是氢或表示键,其中当R 13表示键时,X 1表示N或CH,且与R 13连接的环原子N直接连接R 1;或当R 13是氢时,X 1表示CR 12,其中R 12表示键,以及与R 12连接的环原子C直接连接R 1;R 14表示-O-芳基、-O-杂芳基、-C 1-3亚烷基-NHC(O)-杂芳基、或-C 1-3亚烷基-C(O)NH-杂芳基,所述芳基和杂芳基各自独立地可选地被一或多个R 9a取代,以及各R 9a相同或不同且各自独立地是氘、卤素、羟基、氰基、氨基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、或卤代C 1-6烷氧基;R 16表示氢、氰基、或氨基;式(PBM-8)的X 3表示CR 21或片段 其中符号##表示与X 3相邻的N的连接点,符号###表示与X 4的连接点,和R 21表示氘、氢、卤素、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、-C(O)-C 1-6烷基、-C(O)-氘代C 1-6烷基或-C(O)NR 22R 23,其中R 22、R 23相同或不同且各自独立地表示氢、C 1-6烷基或氘代C 1-6烷基,且R 22、R 23不同时为氢;式(PBM-8)的X 4表示N或CR 24,其中R 24表示氢、氘、卤素、C 1-6烷基、氘代C 1-6烷基或卤代C 1-6烷基;X 5和X 6各自独立地表示CH或N;R 18表示键或可选取代的亚杂芳基(例如卤素取代的亚杂芳基);R 19表示氢、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、或可选取代的C 3-7环烷基;R 20和R 25相同或不同且各自独立地表示氢、卤素、C 1-6烷基、氘代C 1-6烷基或卤代C 1-6烷基;R 26表示氢、卤素、C 1-6烷基、卤代C 1-6烷基、或氘代C 1-6烷基;R 27表示氢、氰基、卤素、C 1-6烷基、卤代C 1-6烷基、或氘代C 1-6烷基;(R 28) p8表示式(PBM-10)的所述苯环被p8个R 28取代,各R 28相同或不同且各自独立地表示卤素、C 1-6烷基、卤代C 1-6烷基、或氘代C 1-6烷基;p8表示整数1、2、3或4;R 29表示NR 30R 31,其中R 30、R 31相同或不同且各自独立地表示氢、C 1-6烷基或氘代C 1-6烷基;式(PBM-11)的X 7、X 8和X 9相同或不同且各自独立地表示N或CH;(R 32) p9表示式(PBM-11)的所述含有X 8和X 9的六元环可选地被p9个R 32取代,各R 32相同或不同且各自独立地表示卤素、C 1-6烷氧基、C 1-6烷基、氘代C 1-6烷基或卤代C 1-6烷基;p9表示整数0、1、2、3或4;R 33表示卤素、C 1-6烷氧基、C 1-6烷基、氘代C 1-6烷基或卤代C 1-6烷基;R 34表示-C(O)NHR 35、-NHC(O)-R 35、-S(O) 2NHR 35、-S(O) 2R 35或-P(O)(R 35) 2,其中各R 35相同或不同且各自独立地表示表示C 1-6烷基或氘代C 1-6烷基;(R 36) p10表示式(PBM-12)的所述苯环可选地被p10个R 36取代,各R 36相同或不同且各自独立地表示卤素、C 1-6烷氧基、C 1-6烷基、氘代C 1-6烷基或卤代C 1-6烷基;p10表示整数0、1、2、3或4;(R 37) p11表示式(PBM-13)的所述苯环被p11个R 37取代,各R 37相同或不同且各自独立地表示卤素、C 1-6烷氧基、C 1-6烷基、氘代C 1-6烷基或卤代C 1-6烷基;p11表示整数0、1、2、3或4;(R 38) p12表示式(PBM-14)的所述苯环被p12个R 38取代,各R 38相同或不同且各自独立地表示卤素、C 1-6烷氧基、C 1-6烷基、氘代C 1-6烷基或卤代C 1-6烷基;p12表示整数0、1、2、3或4;(R 39) p13表示式(PBM-14)的所述4-氧代-3,4-二氢喹唑啉环被p13个R 39取代,各R 39相同或不同且各自独立地表示卤素、C 1-6烷氧基、C 1-6烷基、氘代C 1-6烷基或卤代C 1-6烷基;p13表示整数1、2、3或4;(R 40) p14表示式(PBM-15)的所述苯环被p14个R 40取代,各R 40相同或不同且各自独立地表示卤素、C 1-6烷氧基、C 1-6烷基、氘代C 1-6烷基或卤代C 1-6烷基;p14表示整数1、2、3或4;R 41表示卤素、C 1-6烷基、氘代C 1-6烷基或卤代C 1-6烷基;(R 42) p15表示式(PBM-16)的所述喹啉环被p15个R 42取代,各R 42相同或不同且各自独立地表示卤素、氰基、C 1-6烷氧基、C 1-6烷基、氘代C 1-6烷基或卤代C 1-6烷基;p15表示整数2、3或4;(R 43) p16表示式(PBM-16)的所述苯环被p16个R 43取代,各R 43相同或不同且各自独立地表示卤素、C 1-6烷氧基、C 1-6烷基、氘代C 1-6烷基或卤代C 1-6烷基;p16表示整数3或4;(R 44) p17表示式(PBM-17)的苯环、嘧啶环和吡啶环各自可选地被p17个R 44取代,各R 44相同或不同且各自独立地表示卤素、C 1-6烷氧基、C 1-6烷基、氘代C 1-6烷基或卤代C 1-6烷基;p17表示整数0、1、2、3或4;R 45、R 46、R 47和R 48中之一表示键,且剩余的三个相同或不同且各自独立地表示氢、卤素、或羟基,其中当R 45、R 46、R 47和R 48中之一表示键时,所述键所连接的式(PBM-18)中的所述苯环或亚甲基直接连接R 1;(R 49) p18表示式(PBM-19)的1,2,3,4-四氢萘环被p18个R 49取代,各R 49相同或不同且各自独立地表示氢、羟基、卤素、C 1-6烷基、氘代C 1-6烷基或卤代C 1-6烷基;p18表示整数0、1、2、3或4;以及R 50和R 51中之一表示键,且另一个表示氢、卤素、C 1-6烷基、氘代C 1-6烷基或卤代C 1-6烷基,其中当R 50和R 51中之一表示键时,所述键所连接的式(PBM-19)中的所述苯环直接连接R 1。
- 如权利要求20所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中所述R 1表示以下式的结构:键、-O-、可选取代的C 1-6亚烷基(例如亚甲基、亚乙基、亚丙基、亚异丙基、亚丁基、亚叔丁基、亚戊基、和亚己基)、-N(R 1a)-R 2a-***(例如-N(CH 3)-CH 2CH 2-***,-NH-CH 2CH 2-***)、-O-R 2a-***(例如-O-(CH 2) 3-***,-O-CH 2-***和-O-(CH 2) 2-***)、-C(O)NH-R 2a-***(例如-C(O)NH-(CH 2) 2-***,-C(O)NH-(CH 2) 3-***,-C(O)NH-CH=CH-CH 2-***,和-C(O)NH-CH 2-CH=CH-CH 2-***,)、或-NHC(O)-R 2a-***(例如-NHC(O)-CH=CH-CH 2-***,-NHC(O)-CH 2-CH=CH-CH 2-***,-NHC(O)-(CH 2) 2-***,和-NHC(O)-(CH 2) 3-***),其中符号***表示与W 1的连接点,R 1a是氢或C 1-6烷基,以及R 2a是可选取代的C 1-6亚烷基或可选取代的C 2-6亚烯基;或亚苯基或亚萘基,其中所述亚苯基或亚萘基独立地可选地被一或多个R 3a取代,以及各R 3a相同或不同且各自独立地是卤素、羟基、氰基、氨基、硝基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、或卤代C 1-6烷氧基;或亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚三唑基、亚吡啶基、亚嘧啶基、亚哒嗪基、亚吡嗪基、亚吲哚基、亚异吲哚基、亚苯并呋喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并[2,1,3]噁二唑基、亚苯并[2,1,3]噻二唑基、亚苯并[1,2,3]噻二唑基、亚喹啉基、亚异喹啉基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、亚酞嗪基、吡唑并[1,5-a]吡啶亚基、吡唑并[1,5-a]嘧啶亚基、咪唑并[1,2-a]吡啶亚基、1H-吡咯并[3,2-b]吡啶亚基、1H-吡咯并[2,3-b]吡啶亚基、4H-氟[3,2-b]吡咯亚基、吡咯并[2,1-b]噻唑亚基、或咪唑并[2,1-b]噻唑亚基,各基团独立地可选地被一或多个R 3a取代,以及各R 3a相同或不同且各自独立地是卤素、羟基、氰基、氨基、硝基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、或卤代C 1-6烷氧基。
- 如权利要求20所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中所述W 1是由以下结构式表示的t个相连的环W 2:其中各环W 2相同或不同且各自独立地是以下基团:含有一个氮原子和可选地含有选自氮、氧和硫的杂原子的单环C 3-10亚杂环基,例如表示以下基团:亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚噁唑烷基、亚噻唑烷基、亚硫代吗啉基、氮杂环庚亚基、二氮杂环庚亚基、氮杂环辛亚基或二氮杂环辛亚基;或含有一个氮原子和可选地含有选自氮、氧和硫的杂原子的C 5-20亚桥杂环基,例如表示以下基团:氮杂双环[3.1.1]庚烷亚基、氮杂双环[2.2.1]庚烷亚基、氮杂双环[3.2.1]辛烷亚基、氮杂双环[2.2.2]辛烷亚基、二氮杂双环[3.1.1]庚烷亚基、二氮杂双环[2.2.1]庚烷亚基、二氮杂双环[3.2.1]辛烷亚基或二氮杂双环[2.2.2]辛烷亚基,例如表示以下基团:C 3-15亚环烷基,例如表示以下基团:亚环丙基、亚环丁基、亚环戊基、亚环戊烯基、亚环己基、亚环己烯基、亚环庚基、亚环辛基、亚十氢萘基、八氢并环戊二烯亚基、八氢-1H-茚亚基、C 5-15亚螺环基、亚金刚烷基、亚降金刚烷基、亚冰片基、二环[2.2.1]庚烷亚基、或二环[2.2.1]庚烯亚基;其中所述单环C 3-10亚杂环基、所述C 5-20亚桥杂环基和所述C 3-15亚环烷基各自独立地可选地被一或多个选自以下的取代基取代:氘、羟基、氨基、巯基、硝基、卤素、氰基、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合;以及t表示整数1或2。
- 如权利要求20所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中所述ULM表示以下式(ULM-1)、式(ULM-2)、式(ULM-3)、式(ULM-4)、式(ULM-5)、式(ULM-6)、式(ULM-7)、式(ULM-8)、式(ULM-9)、或式(ULM-10)的结构:其中A表示CO、CH 2或CD 2;R 1、R 2、R 3和R 4相同或不同且各自独立地表示氢、氘、卤素、可选氘代的C 1-6烷基、可选氘代的C 1-6烷氧基、或卤代C 1-6烷基;(R b) n表示所述苯环可选地被n个R b取代,各R b相同或不同且各自独立地表示氢、氘、卤素、羟基、巯基、硝基、氨基、氰基、可选氘代的C 1-6烷基、可选氘代的C 1-6烷氧基、卤代C 1- 6烷基、C 2-6烯基、或C 2-6炔基;n表示整数0、1、2或3;U 1和U 2相同或不同且各自独立地表示键、N(R d)或O,其中R d表示H或可选氘代的C 1-6烷基;R c表示含有一个氮原子和可选地含有选自氮、氧和硫的杂原子的可选取代的单环C 3-10亚杂环基,例如表示以下基团:亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚噁唑烷基、亚噻唑烷基、亚硫代吗啉基、氮杂环庚亚基、二氮杂环庚亚基、氮杂环辛亚基或二氮杂环辛亚基;或R c表示含有一个氮原子和可选地含有选自氮、氧和硫的杂原子的可选取代的C 5-20亚桥杂环基,例如表示以下基团:氮杂双环[3.1.1]庚烷亚基、氮杂双环[2.2.1]庚烷亚基、氮杂双环[3.2.1]辛烷亚基、氮杂双环[2.2.2]辛烷亚基、二氮杂双环[3.1.1]庚烷亚基、二氮杂双环[2.2.1]庚烷亚基、二氮杂双环[3.2.1]辛烷亚基或二氮杂双环[2.2.2]辛烷亚基,例如表示以下基团:其中所述单环C 3-10亚杂环基和所述C 5-20亚桥杂环基各自独立地可选地进一步被一或多个选自以下的取代基取代:氘、羟基、氨基、巯基、硝基、卤素、氰基、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合。
- 如权利要求20-31中任一项所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中所述LIN表示以下式:#-C 1-30亚烷基-;#-(C(R a1)(R a2)) n1-(R e(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(R e(C(R a3)(R a4)) n2) m1-(R e(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(R e(C(R a3)(R a4)) n2) m1-(R e(C(R a5)(R a6)) n3) m2-(R e(C(R a7)(R a8)) n4) m3-;#-(C(R a1)(R a2)) n1-(R f(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(R f(C(R a3)(R a4)) n2) m1-(R f(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(R f(C(R a3)(R a4)) n2) m1-(R f(C(R a5)(R a6)) n3) m2-(R f(C(R a7)(R a8)) n4) m3-;#-(C(R a1)(R a2)) n1-(R e-R f-(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(R e(C(R a3)(R a4)) n2) m1-(R f(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(R f-R e-(C(R a3)(R a4)) n2) m1-;或#-(C(R a1)(R a2)) n1-(R f(C(R a3)(R a4)) n2) m1-(R e(C(R a5)(R a6)) n3) m2-;其中,各基团R e选自O、N(R g)、C(O)、C(O)O、OC(O)、S(O)、S(O) 2、S(O) 2NH、NHS(O) 2、C(O)N(R g)、N(R g)C(O)、或N(R g)C(O)N(R g),其中各R g独立地表示H或C 1-6烷基;各基团R f选自亚环烷基、亚芳基、亚杂环基、亚杂芳基、亚炔基、亚烯基或其任意组合,其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自氘、可选氘代的C 1-6烷基、可选氘代的C 3-6环烷基、羟基、氨基、巯基、卤素、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、卤代C 1-6烷基、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-、氰基或其任意组合的取代基取代;所述C 1-30亚烷基的一或多个CH 2的氢可选地进一步被选自以下的取代基替代:氘、羟基、氨基、巯基、硝基、卤素、氰基、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合;R a1、R a2、R a3、R a4、R a5、R a6、R a7和R a8分别独立地表示H、氘、羟基、氨基、巯基、硝基、卤素、氰基、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合;符号#表示与基团U 2的连接点;和n1、n2、n3、n4、m1、m2、m3分别独立地选自整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、或15。
- 如权利要求20-31中任一项所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中所述LIN表示以下式的结构:#-(C(R a1)(R a2)) n1-(O(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(O(C(R a3)(R a4)) n2) m1-(O(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(O(C(R a3)(R a4)) n2) m1-(O(C(R a5)(R a6)) n3) m2-(O(C(R a7)(R a8)) n4) m3-;#-(C(R a1)(R a2)) n1-(N(R g)(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(N(R g)(C(R a3)(R a4)) n2) m1-(N(R g)(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(N(R g)(C(R a3)(R a4)) n2) m1-(N(R g)(C(R a5)(R a6)) n3) m2-(N(R g)(C(R a7)(R a8)) n4) m3-;#-(C(R a1)(R a2)) n1-(C(O)N(R g)-(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(C(O)N(R g)-(C(R a3)(R a4)) n2) m1-(C(O)N(R g)-(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(C(O)N(R g)-(C(R a3)(R a4)) n2) m1-(C(O)N(R g)-(C(R a5)(R a6)) n3) m2-(C(O)N(R g)-(C(R a7)(R a8)) n4) m3-;#-(C(R a1)(R a2)) n1-(C(O)N(R g)-(C(R a3)(R a4)) n2) m1-(O-(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-C(O)N(R g)-(C(R a3)(R a4)) n2-(O(C(R a5)(R a6)) n3) m1-;#-(C(R a1)(R a2)) n1-(N(R g)C(O)-(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(N(R g)C(O)-(C(R a3)(R a4)) n2) m1-(O-(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(N(R g)C(O)-(C(R a3)(R a4)) n2) m1-(O-(C(R a5)(R a6)) n3) m2-(O-(C(R g)(R a8)) n4) m3-;#-(C(R a1)(R a2)) n1-N(R g)C(O)-(C(R a3)(R a4)) n2-(O(C(R a5)(R a6)) n3) m1-;#-(C(R a1)(R a2)) n1-N(R g)C(O)N(R g)-(C(R a3)(R a4)) n2-;#-(C(R a1)(R a2)) n1-C(O)-(C(R a3)(R a4)) n2-;#-(C(R a1)(R a2)) n1-(亚芳基-(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(亚芳基-(C(R a3)(R a4)) n2) m1-亚芳基-(C(R a5)(R a6)) n3-;#-(C(R a1)(R a2)) n1-(亚杂环基-(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(亚杂环基-(C(R a3)(R a4)) n2) m1-(亚杂环基-(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(亚杂芳基-(C(R a3)(R a4)) n2) m1-;#-(C(R a1)(R a2)) n1-(亚杂芳基-(C(R a3)(R a4)) n2) m1-(亚杂芳基-(C(R a5)(R a6)) n3) m2-;#-(C(R a1)(R a2)) n1-(亚环烷基-(C(R a3)(R a4)) n2) m1-;或#-(C(R a1)(R a2)) n1-(亚环烷基-(C(R a3)(R a4)) n2) m1-(亚环烷基-(C(R a5)(R a6)) n3) m2-;其中,各R g独立地表示H或C 1-6烷基;所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自氘、可选氘代的C 1-6烷基、可选氘代的C 3-6环烷基、羟基、氨基、巯基、卤素、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、卤代C 1-6烷基、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-、氰基或其任意组合的取代基取代;R a1、R a2、R a3、R a4、R a5、R a6、R a7和R a8分别独立地表示H、氘、羟基、氨基、巯基、硝基、卤素、氰基、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合;符号#表示与基团U 2的连接点;和n1、n2、n3、n4、m1、m2、m3分别独立地选自整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、或15。
- 如权利要求20-31中任一项所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中所述LIN表示以下基团:#-CH 2-、#-(CH 2) 2-、#-(CH 2) 3-、#-(CH 2) 4-、#-(CH 2) 5-、#-(CH 2) 6-、#-(CH 2) 7-、#-(CH 2) 8-、#-(CH 2) 9-、#-(CH 2) 10-、#-(CH 2) 11-、#-(CH 2) 12-、#-(CH 2) 13-、#-(CH 2) 14-、#-(CH 2) 15-、#-(CH 2) 16-、#-(CH 2) 17-、#-(CH 2) 18-、#-(CH 2) 19-、#-(CH 2) 20-、#-(CH 2) 21-、#-(CH 2) 22-、#-(CH 2) 25-、或#-(CH 2) 30-;#-CH 2-O-CH 2-、#-CH 2-O-(CH 2) 2-、#-(CH 2) 1-O-(CH 2) 3-、#-(CH 2) 1-O-(CH 2) 4-、#-(CH 2) 1-O-(CH 2) 5-、#-(CH 2) 1-O-(CH 2) 6-、#-(CH 2) 1-O-(CH 2) 7-、#-(CH 2) 1-O-(CH 2) 8-、#-(CH 2) 1-O-(CH 2) 9-、#-(CH 2) 1-O-(CH 2) 10-、#-(CH 2) 2-O-(CH 2) 1-、#-(CH 2) 2-O-(CH 2) 2-、#-(CH 2) 2-O-(CH 2) 3-、#-(CH 2) 2-O-(CH 2) 4-、#-(CH 2) 2-O-(CH 2) 5-、#-(CH 2) 2-O-(CH 2) 6-、#-(CH 2) 2-O-(CH 2) 7-、#-(CH 2) 2-O-(CH 2) 8-、#-(CH 2) 2-O-(CH 2) 9-、#-(CH 2) 2-O-(CH 2) 10-、#-(CH 2) 2-O-(CH 2) 11-、#-(CH 2) 2-O-(CH 2) 12-、#-(CH 2) 3-O-(CH 2) 1-、#-(CH 2) 3-O-(CH 2) 2-、#-(CH 2) 3-O-(CH 2) 3-、#-(CH 2) 3-O-(CH 2) 4-、#-(CH 2) 3-O-(CH 2) 5-、#-(CH 2) 3-O-(CH 2) 6-、#-(CH 2) 3-O-(CH 2) 7-、#-(CH 2) 4-O-(CH 2) 1-、#-(CH 2) 4-O-(CH 2) 2-、#-(CH 2) 4-O-(CH 2) 3-、#-(CH 2) 4-O-(CH 2) 4-、#-(CH 2) 4-O-(CH 2) 5-、#-(CH 2) 4-O-(CH 2) 6-、#-(CH 2) 5-O-(CH 2) 1-、#-(CH 2) 5-O-(CH 2) 2-、#-(CH 2) 5-O-(CH 2) 3-、#-(CH 2) 5-O-(CH 2) 4-、#-(CH 2) 5-O-(CH 2) 5-、#-(CH 2) 6-O-(CH 2) 1-、#-(CH 2) 6-O-(CH 2) 2-、#-(CH 2) 6-O-(CH 2) 3-、#-(CH 2) 6-O-(CH 2) 4-、#-(CH 2) 7-O-(CH 2) 1-、#-(CH 2) 7-O-(CH 2) 2-、#-(CH 2) 7-O-(CH 2) 3-、#-(CH 2) 8-O-(CH 2) 1-、#-(CH 2) 8-O-(CH 2) 2-、#-CH(CH 3)-O-(CH 2) 1-、#-CH(CH 3)-O-(CH 2) 2-、#-CH(CH 3)-O-(CH 2) 3-、#-CH(CH 3)-O-(CH 2) 4-、#-CH(CH 3)-O-(CH 2) 5-、#-CH(CH 3)-O-(CH 2) 6-、#-CH(CH 3)-O-(CH 2) 7-、#-CH(CH 3)-O-(CH 2) 8-、#-CH(CH 3)-O-(CH 2) 9-、#-CH(CH 3)-O-(CH 2) 10-、#-CH 2-(O(CH 2) 2) 2-、#-CH 2-(O(CH 2) 2) 3-、#-CH 2-(O(CH 2) 2) 4-、#-CH 2-(O(CH 2) 2) 5-、#-CH 2-(O(CH 2) 2) 6-、#-CH 2-(O(CH 2) 2) 7-、#-CH 2-(O(CH 2) 2) 8-、#-CH 2-(O(CH 2) 2) 9-、#-CH 2-(O(CH 2) 2) 10-、#-CH 2-(O(CH 2) 2) 1-OCH 2-、#-CH 2-(O(CH 2) 2) 2-OCH 2-、#-CH 2-(O(CH 2) 2) 3-OCH 2-、#-CH 2-(O(CH 2) 2) 4-OCH 2-、#-CH 2-(O(CH 2) 2) 5-OCH 2-、#-CH 2-(O(CH 2) 2) 6-OCH 2-、#-CH 2-(O(CH 2) 2) 7-OCH 2-、#-CH 2-(O(CH 2) 2) 8-OCH 2-、#-CH 2-(O(CH 2) 2) 9- OCH 2-、#-CH 2-(O(CH 2) 2) 10-OCH 2-、#-(CH 2) 2-(O(CH 2) 2) 2-、#-(CH 2) 2-(O(CH 2) 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 4-、#-(CH 2) 2-(O(CH 2) 2) 5-、#-(CH 2) 2-(O(CH 2) 2) 6-、#-(CH 2) 2-(O(CH 2) 2) 7-、#-(CH 2) 2-(O(CH 2) 2) 8-、#-(CH 2) 2-(O(CH 2) 2) 9-、#-(CH 2) 2-(O(CH 2) 2) 10-、#-(CH 2) 3-(O(CH 2) 2) 2-、#-(CH 2) 3-(O(CH 2) 2) 3-、#-(CH 2) 3-(O(CH 2) 2) 4-、#-(CH 2) 3-(O(CH 2) 2) 5-、#-(CH 2) 3-(O(CH 2) 2) 6-、#-(CH 2) 3-(O(CH 2) 2) 7-、#-(CH 2) 3-(O(CH 2) 2) 8-、#-(CH 2) 3-(O(CH 2) 2) 9-、#-(CH 2) 3-(O(CH 2) 2) 10-、#-(CH 2) 4-(O(CH 2) 2) 2-、#-(CH 2) 4-(O(CH 2) 2) 3-、#-(CH 2) 4-(O(CH 2) 2) 4-、#-(CH 2) 4-(O(CH 2) 2) 5-、#-(CH 2) 4-(O(CH 2) 2) 6-、#-(CH 2) 4-(O(CH 2) 2) 7-、#-(CH 2) 4-(O(CH 2) 2) 8-、#-(CH 2) 4-(O(CH 2) 2) 9-、#-(CH 2) 4-(O(CH 2) 2) 10-、#-CH 2-(O(CH 2) 3) 2-、#-CH 2-(O(CH 2) 3) 3-、#-CH 2-(O(CH 2) 3) 4-、#-CH 2-(O(CH 2) 3) 5-、#-CH 2-(O(CH 2) 3) 6-、#-CH 2-(O(CH 2) 3) 7-、#-CH 2-(O(CH 2) 3) 8-、#-CH 2-(O(CH 2) 3) 9-、#-CH 2-(O(CH 2) 3) 10-、#-(CH 2) 2-(O(CH 2) 3) 2-、#-(CH 2) 2-(O(CH 2) 3) 3-、#-(CH 2) 2-(O(CH 2) 3) 4-、#-(CH 2) 2-(O(CH 2) 3) 5-、#-(CH 2) 2-(O(CH 2) 3) 6-、#-(CH 2) 2-(O(CH 2) 3) 7-、#-(CH 2) 2-(O(CH 2) 3) 8-、#-(CH 2) 2-(O(CH 2) 3) 9-、#-(CH 2) 2-(O(CH 2) 3) 10-、#-(CH 2) 3-(O(CH 2) 3) 2-、#-(CH 2) 3-(O(CH 2) 3) 3-、#-(CH 2) 3-(O(CH 2) 3) 4-、#-(CH 2) 3-(O(CH 2) 3) 5-、#-(CH 2) 3-(O(CH 2) 3) 6-、#-(CH 2) 3-(O(CH 2) 3) 7-、#-(CH 2) 3-(O(CH 2) 3) 8-、#-(CH 2) 3-(O(CH 2) 3) 9-、#-(CH 2) 3-(O(CH 2) 3) 10-、#-CH 2-O-(CH 2) 2-O-(CH 2) 3-、#-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、#-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、#-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、#-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、#-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、#-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、#-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、#-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、#-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、#-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、#-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、#-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、#-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、#-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、#-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、#-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、#-CH 2-O-(CH 2) 3-O-(CH 2) 2-、#-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、#-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、#-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、#-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、#-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、#-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、#-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、#-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、#-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、#-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、#-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、#-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、#-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、#-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、#-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、#-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、#-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、#-CH 2-O-(CH 2) 2-O-CH 2-、#-(CH 2) 2-O-(CH 2) 2-O-CH 2-、#-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、#-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、#-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-、#-(CH 2) 1-N(R g)-(CH 2) 1-、#-(CH 2) 1-N(R g)-(CH 2) 2-、#-(CH 2) 1-N(R g)-(CH 2) 3-、#-(CH 2) 1-N(R g)-(CH 2) 4-、#-(CH 2) 1-N(R g)-(CH 2) 5-、#-(CH 2) 1-N(R g)-(CH 2) 6-、#-(CH 2) 1-N(R g)-(CH 2) 7-、#-(CH 2) 1-N(R g)-(CH 2) 8-、#-(CH 2) 1-N(R g)-(CH 2) 9-、#-(CH 2) 1-N(R g)-(CH 2) 10-、#-(CH 2) 2-N(R g)-(CH 2) 1-、#-(CH 2) 2-N(R g)-(CH 2) 2-、#-(CH 2) 2-N(R g)-(CH 2) 3-、#-(CH 2) 2-N(R g)-(CH 2) 4-、#-(CH 2) 2-N(R g)-(CH 2) 5-、#-(CH 2) 2-N(R g)-(CH 2) 6-、#-(CH 2) 2-N(R g)-(CH 2) 7-、#-(CH 2) 2-N(R g)-(CH 2) 8-、#-(CH 2) 2-N(R g)-(CH 2) 9-、#-(CH 2) 2-N(R g)-(CH 2) 10-、#-(CH 2) 2-N(R g)-(CH 2) 11-、#-(CH 2) 2-N(R g)-(CH 2) 12-、#-(CH 2) 3-N(R g)-(CH 2) 1-、#-(CH 2) 3- N(R g)-(CH 2) 2-、#-(CH 2) 3-N(R g)-(CH 2) 3-、#-(CH 2) 4-N(R g)-(CH 2) 1-、#-(CH 2) 4-N(R g)-(CH 2) 2-、#-(CH 2) 4-N(R g)-(CH 2) 3-、#-(CH 2) 4-N(R g)-(CH 2) 4-、#-(CH 2) 5-N(R g)-(CH 2) 1-、#-(CH 2) 5-N(R g)-(CH 2) 2-、#-(CH 2) 5-N(R g)-(CH 2) 3-、#-(CH 2) 5-N(R g)-(CH 2) 4-、#-(CH 2) 5-N(R g)-(CH 2) 5-、#-(CH 2) 6-N(R g)-(CH 2) 1-、#-(CH 2) 6-N(R g)-(CH 2) 2-、#-(CH 2) 6-N(R g)-(CH 2) 3-、#-(CH 2) 7-N(R g)-(CH 2) 1-、#-(CH 2) 7-N(R g)-(CH 2) 2-、#-(CH 2) 7-N(R g)-(CH 2) 3-、#-(CH 2) 8-N(R g)-(CH 2) 1-、#-(CH 2) 8-N(R g)-(CH 2) 2-、#-(CH 2) 8-N(R g)-(CH 2) 3-、#-CH(CH 3)-N(R g)-(CH 2) 1-、#-CH(CH 3)-N(R g)-(CH 2) 2-、#-CH(CH 3)-N(R g)-(CH 2) 3-、#-CH(CH 3)-N(R g)-(CH 2) 4-、#-CH(CH 3)-N(R g)-(CH 2) 5-、#-CH(CH 3)-N(R g)-(CH 2) 6-、#-CH(CH 3)-N(R g)-(CH 2) 7-、#-CH(CH 3)-N(R g)-(CH 2) 8-、#-CH(CH 3)-N(R g)-(CH 2) 9-、#-CH(CH 3)-N(R g)-(CH 2) 10-、#-CH 2C(O)NHCH 2-、#-(CH 2) 2C(O)NH(CH 2) 2-、#-(CH 2) 2C(O)NH(CH 2) 3-、#-(CH 2) 2C(O)NH(CH 2) 4-、#-(CH 2) 2C(O)NH(CH 2) 5-、#-(CH 2) 3C(O)NH(CH 2) 3-、#-(CH 2) 3C(O)NH(CH 2) 4-、#-(CH 2) 4C(O)NH(CH 2) 4-、#-(CH 2) 5C(O)NH(CH 2) 5-、#-(CH 2) 6C(O)NH(CH 2) 7-、#-(CH 2) 6C(O)NH(CH 2) 6-、#-(CH 2) 7C(O)NH(CH 2) 7-、#-(CH 2) 8C(O)NH(CH 2) 8、U-(CH 2) 9C(O)NH(CH 2) 9-、#-(CH 2) 10C(O)NH(CH 2) 10-、#-(CH 2) 2C(O)NH(CH 2) 2-O-(CH 2) 2-、#-CH 2NHC(O)CH 2-、#-(CH 2) 2NHC(O)(CH 2) 2-、#-(CH 2) 2NHC(O)(CH 2) 3-、#-(CH 2) 2NHC(O)(CH 2) 4-、#-(CH 2) 2NHC(O)(CH 2) 5-、#-(CH 2) 3NHC(O)(CH 2) 3-、#-(CH 2) 3NHC(O)(CH 2) 4-、#-(CH 2) 4NHC(O)(CH 2) 4-、#-(CH 2) 5NHC(O)(CH 2) 5-、#-(CH 2) 6NHC(O)(CH 2) 7-、#-(CH 2) 6NHC(O)(CH 2) 6-、#-(CH 2) 7NHC(O)(CH 2) 7-、#-(CH 2) 8NHC(O)(CH 2) 8、#-(CH 2) 9NHC(O)(CH 2) 9-、#-(CH 2) 10NHC(O)(CH 2) 10-、#-(CH 2) 4NHC(O)(CH 2) 8-、#-(CH 2) 2NHC(O)(CH 2) 2-O-(CH 2) 2-、#-(CH 2) 4NHC(O)CH 2-、#-CH 2-亚哌啶基-CH 2-、#-CH 2-亚哌啶基-(CH 2) 2-、#-CH 2-亚哌啶基-(CH 2) 3-、#-CH 2-亚哌啶基-(CH 2) 4-、#-CH 2-亚哌啶基-(CH 2) 5-、#-CH 2-亚哌啶基-(CH 2) 6-、#-CH 2-亚哌啶基-(CH 2) 7-、#-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 2-亚哌啶基-(CH 2) 1-、#-(CH 2) 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 2-亚哌啶基-(CH 2) 4-、#-(CH 2) 2-亚哌啶基-(CH 2) 5-、#-(CH 2) 2-亚哌啶基-(CH 2) 6-、#-(CH 2) 2-亚哌啶基-(CH 2) 7-、#-(CH 2) 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 3-亚哌啶基-CH 2-、#-(CH 2) 3-亚哌啶基-(CH 2) 2-、#-(CH 2) 3-亚哌啶基-(CH 2) 3-、#-(CH 2) 3-亚哌啶基-(CH 2) 4-、#-(CH 2) 3-亚哌啶基-(CH 2) 5-、#-(CH 2) 3-亚哌啶基-(CH 2) 6-、#-(CH 2) 3-亚哌啶基-(CH 2) 7-、#-(CH 2) 3-亚哌啶基-(CH 2) 8-、#-(CH 2) 4-亚哌啶基-CH 2-、#-(CH 2) 4-亚哌啶基-(CH 2) 2-、#-(CH 2) 4-亚哌啶基-(CH 2) 3-、#-(CH 2) 4-亚哌啶基-(CH 2) 4-、#-(CH 2) 4-亚哌啶基-(CH 2) 5-、#-(CH 2) 4-亚哌啶基-(CH 2) 6-、#-(CH 2) 4-亚哌啶基-(CH 2) 7-、#-(CH 2) 4-亚哌啶基-(CH 2) 8-、#-(CH 2) 5-亚哌啶基-(CH 2) 1-、#-(CH 2) 5-亚哌啶基-(CH 2) 2-、#-(CH 2) 5-亚哌啶基-(CH 2) 3-、#-(CH 2) 5-亚哌啶基-(CH 2) 4-、#-(CH 2) 5-亚哌啶基-(CH 2) 5-、#-(CH 2) 5-亚哌啶基-(CH 2) 6-、#-(CH 2) 5-亚哌啶基-(CH 2) 7-、#-(CH 2) 5-亚哌啶基-(CH 2) 8-、#-(CH 2) 6-亚哌啶基-(CH 2) 1-、#-(CH 2) 6-亚哌啶基-(CH 2) 2-、#-(CH 2) 6-亚哌啶基-(CH 2) 3-、#-(CH 2) 6-亚哌啶基-(CH 2) 4-、#-(CH 2) 6-亚哌啶基-(CH 2) 5-、#-(CH 2) 6-亚哌啶基-(CH 2) 6-、#-(CH 2) 6-亚哌啶基-(CH 2) 7-、#-(CH 2) 6-亚哌啶基-(CH 2) 8-、#-(CH 2) 7-亚哌啶基-(CH 2) 1-、#-(CH 2) 7-亚哌啶基-(CH 2) 2-、#-(CH 2) 7-亚哌啶基-(CH 2) 3-、#-(CH 2) 7-亚哌啶基-(CH 2) 4-、#-(CH 2) 7-亚哌啶基-(CH 2) 8-、 #-(CH 2) 8-亚哌啶基-CH 2-、#-(CH 2) 8-亚哌啶基-(CH 2) 2-、#-(CH 2) 8-亚哌啶基-(CH 2) 3-、#-(CH 2) 8-亚哌啶基-(CH 2) 4-、#-(CH 2) 8-亚哌啶基-(CH 2) 5-、#-(CH 2) 8-亚哌啶基-(CH 2) 6-、#-(CH 2) 8-亚哌啶基-(CH 2) 7-、#-(CH 2) 8-亚哌啶基-(CH 2) 8-、#-CH 2-N(R g)-CH 2-亚哌啶基-CH 2-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 4-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 5-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 6-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 7-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-CH 2-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 2-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 3-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 4-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 5-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 6-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 7-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 4-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 5-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 6-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 7-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 5-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 5-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 6-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 6-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 7-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 7-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 4-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 5-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 6-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 7-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-CH 2-亚哌嗪基-CH 2-、#-CH 2-亚哌嗪基-(CH 2) 2-、#-CH 2-亚哌嗪基-(CH 2) 3-、#-CH 2-亚哌嗪基-(CH 2) 4-、#-CH 2-亚哌嗪基-(CH 2) 5-、#-CH 2-亚哌嗪基-(CH 2) 6-、#-CH 2-亚哌嗪基-(CH 2) 7-、#-CH 2-亚哌嗪基-(CH 2) 8-、#-(CH 2) 2-亚哌嗪基-(CH 2) 1-、#-(CH 2) 2-亚哌嗪基-(CH 2) 2-、#-(CH 2) 2-亚哌嗪基-(CH 2) 3-、#-(CH 2) 2-亚哌嗪基-(CH 2) 4-、#-(CH 2) 2-亚哌嗪基-(CH 2) 5-、#-(CH 2) 2-亚哌嗪基-(CH 2) 6-、#-(CH 2) 2-亚哌嗪基-(CH 2) 7-、#-(CH 2) 2-亚哌嗪基-(CH 2) 8-、#-(CH 2) 3-亚哌嗪基-CH 2-、#-(CH 2) 3-亚哌嗪基-(CH 2) 2-、#-(CH 2) 3-亚哌嗪基-(CH 2) 3-、#-(CH 2) 3-亚哌嗪基-(CH 2) 4-、#-(CH 2) 3-亚哌嗪基-(CH 2) 5-、#-(CH 2) 3-亚哌嗪基-(CH 2) 6-、#-(CH 2) 3-亚哌嗪基-(CH 2) 7-、#-(CH 2) 3-亚哌嗪基-(CH 2) 8-、#-(CH 2) 4-亚哌嗪基-CH 2-、#-(CH 2) 4-亚哌嗪基-(CH 2) 2-、#-(CH 2) 4-亚哌嗪基-(CH 2) 3-、#-(CH 2) 4-亚哌嗪基-(CH 2) 4-、#-(CH 2) 4-亚哌嗪基-(CH 2) 5-、#-(CH 2) 4-亚哌嗪基-(CH 2) 6-、#-(CH 2) 4-亚哌嗪基-(CH 2) 7-、#-(CH 2) 4-亚哌嗪基-(CH 2) 8-、#-(CH 2) 5-亚哌嗪基-(CH 2) 1-、#-(CH 2) 5-亚哌嗪基-(CH 2) 2-、#-(CH 2) 5-亚哌嗪基-(CH 2) 3-、#-(CH 2) 5-亚哌嗪基-(CH 2) 4-、#-(CH 2) 5-亚哌嗪基-(CH 2) 5-、#-(CH 2) 5-亚哌嗪基-(CH 2) 6-、#-(CH 2) 5-亚哌嗪基-(CH 2) 7-、#-(CH 2) 5-亚哌嗪基-(CH 2) 8-、#-(CH 2) 6-亚哌嗪基-(CH 2) 1-、#-(CH 2) 6-亚哌嗪基-(CH 2) 2-、#-(CH 2) 6-亚哌嗪基-(CH 2) 3-、#-(CH 2) 6-亚哌嗪基-(CH 2) 4-、#-(CH 2) 6-亚哌嗪基 -(CH 2) 5-、#-(CH 2) 6-亚哌嗪基-(CH 2) 6-、#-(CH 2) 6-亚哌嗪基-(CH 2) 7-、#-(CH 2) 6-亚哌嗪基-(CH 2) 8-、#-(CH 2) 7-亚哌嗪基-(CH 2) 1-、#-(CH 2) 7-亚哌嗪基-(CH 2) 2-、#-(CH 2) 7-亚哌嗪基-(CH 2) 3-、#-(CH 2) 7-亚哌嗪基-(CH 2) 4-、#-(CH 2) 7-亚哌嗪基-(CH 2) 8-、#-(CH 2) 8-亚哌嗪基-CH 2-、#-(CH 2) 8-亚哌嗪基-(CH 2) 2-、#-(CH 2) 8-亚哌嗪基-(CH 2) 3-、#-(CH 2) 8-亚哌嗪基-(CH 2) 4-、#-(CH 2) 8-亚哌嗪基-(CH 2) 5-、#-(CH 2) 8-亚哌嗪基-(CH 2) 6-、#-(CH 2) 8-亚哌嗪基-(CH 2) 7-、或#-(CH 2) 8-亚哌嗪基-(CH 2) 8-;其中,所述亚哌啶基和所述亚哌嗪基彼此独立地可选地进一步被选自氘、可选氘代的C 1-6烷基、可选氘代的C 3-6环烷基、羟基、氨基、巯基、卤素、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、卤代C 1-6烷基、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-、氰基或其任意组合的取代基取代;各R g独立地表示H或C 1-6烷基;符号#表示与基团U 2的连接点;和n1、n2、n3、n4、m1、m2、m3分别独立地选自整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、或15。
- 如权利要求20所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其也是由以下式(III-1)、式(III-2)、式(III-3)、式(III-4)、式(III-5)、式(III-6)、式(III-7)、式(III-8)、式(III-9)、式(III-10)、式(III-11)、式(III-12)、式(III-13)、式(III-14)、式(III-15)、式(III-16)、式(III-17)、式(III-18)、式(III-19)、式(III-20)、式(III-21)、式(III-22)、式(III-23)或式(III-24)的结构表示:其中,A、R 1、R 2、R 3、R 4、(R b) n、U 1、U 2、R c、LIN、W 1、R 1、(R 2) p1、(R 3) p2、(R 5) p3、(R 6) p4、(R 7) p5、R 8、R 9、R 10、(R 11) p7、环A、环B、环C、X 1、X 2、R 14、R 15、R 16、X 3、X 4、X 5、X 6、R 18、R 19、R 20、R 25、R 26、R 27、(R 28) p8、R 29、X 7、X 8、X 9、(R 32) p9、R 33、R 34、(R 36) p10、(R 37) p11、(R 38) p12、(R 39) p13、(R 40) p14、R 41、(R 42) p15、(R 43) p16、(R 44) p17、R 45、R 46、R 47、R 48、(R 49) p18、R 50、R 51如权利要求22中所定义。
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如权利要求20所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其选自:N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-(((1S,4S)-5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-(((1R,4R)-5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((((3R)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((((3S)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-(((3S)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-(((3R)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(3-((1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(8-((1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(3-((1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(6-((1-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)哒嗪-3-甲酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3S)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-(((1S,4S)-5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3R)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-(((1R,4R)-5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)烟酰胺;N-((1r,3R)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((((3R)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)烟酰胺;N-((1r,3S)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((((3S)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-(((3S)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-(((3R)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((1S,4S)-5-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((1S,4S)-5-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((1R,4R)-5-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((1R,4R)-5-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(6-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(6-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(8-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(8-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((1S,4S)-5-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((1S,4S)-5-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((1R,4R)-5-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((1R,4R)-5-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;6-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;6-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;6-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-((R)-3-(((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((3R)-3-(((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-(((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((3S)-3-(((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((3S)-1-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((R)-1-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)环己基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((3R)-1-((4-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)-3-氟环己基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-(((1S,4S)-5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-(((1R,4R)-5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-(((1S,4S)-5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-(((1R,4R)-5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((((3R)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-((((3S)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-(((3S)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;3-(叔丁基)-N-(4-(5-(4-(4-(((3R)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)苯基)-1H-吲唑-3-基)-2-甲基苄基)-1,2,4-噁二唑-5-甲酰胺;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(6-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(6-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(8-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(8-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((1S,4S)-5-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-((1S,4S)-5-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((1R,4R)-5-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-((1R,4R)-5-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(5-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-5-(4-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-6-(4-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5-二氟-6-(4-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,7-二氟-5-(4-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,6-二氟-5-(4-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5,7-三氟-6-(4-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(1-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(1-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((R)-3-(((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((S)-3-(((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((R)-1-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((S)-1-((1-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌啶-4-基)甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-(((1R,4R)-5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-(((1S,4S)-5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-(((1S,4S)-5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-(((1R,4R)-5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((((3R)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-((((3S)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-(((3S)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;7-环戊基-2-((5-(4-(((3R)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;5-(4-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;6-(4-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;6-(4-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(4-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((R)-3-(((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-(((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((R)-1-((1-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;6-(4-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;6-(4-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((R)-3-(((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-(((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((R)-1-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;6-(4-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;6-(4-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((R)-3-(((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-(((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((R)-1-((1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;8-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈;5-(4-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(6-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(8-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(4-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(4-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(4-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;5-(4-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((R)-3-(((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-(((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((R)-1-((4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)环己基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((((3R)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-((((3S)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(((3S)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)-4-(4-(((3R)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((((3R)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-((((3S)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(((3S)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;N-(4-((3-氯-4-氟苯基)氨基)-7-(3-(4-(((3R)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)丙氧基)喹唑啉-6-基)丙烯酰胺;5-(4-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(6-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(8-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;6-(4-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;6-(4-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(4-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((4-((4-((3,4-二氯-2-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)环己基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(6-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(8-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;6-(4-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;6-(4-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(4-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((R)-3-(((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-(((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((R)-1-((1-(3-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)丙基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((((3R)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-((((3S)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-(((3S)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;N-(2-((2-(4-(((3R)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((((3R)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-((((3S)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-(((3S)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;(E)-N-(4-((3-氯-4-氟苯基)氨基)-7-(((S)-四氢呋喃-3-基)氧基)喹唑啉-6-基)-4-(4-(((3R)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)丁-2-烯酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((((3R)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-((((3S)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-(((3S)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(6-(6-(4-(((3R)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)哒嗪-3-基)-1-氧代异吲哚啉-2-基)-2-(5-氟-2-羟基苯基)-N-(噻唑-2-基)乙酰胺;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(6-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(6-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(8-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(8-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(5-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(5-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-6-(4-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-5-(4-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,6-二氟-5-(4-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,7-二氟-5-(4-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5-二氟-6-(4-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5,7-三氟-6-(4-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;5-(2,6-二甲基-4-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(2,6-二甲基-4-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3,5-二甲基-4-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3,5-二甲基-4-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(1-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(1-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((R)-3-(((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((S)-3-(((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((S)-1-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((R)-1-((1-(((R,E)-1 1,2 6,7-三甲基-3-氧代-5 2,5 3-二氢-1 1H,5 1H-11-氧杂-4-氮杂-5(2,1)-苯并[d]咪唑杂-2(2,4)-吡啶杂-1(4,5)-吡唑杂环十一蕃-5 6-基)甲基)哌啶-4-基)甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;5-(4-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(6-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;6-(4-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;6-(4-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(4-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((R)-3-(((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-(((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((R)-1-((1-(6-((2-(1-(环丙基磺酰基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-异丙基-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(6-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(6-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(8-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(8-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(5-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(5-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-6-(4-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-5-(4-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,6-二氟-5-(4-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,7-二氟-5-(4-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5-二氟-6-(4-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5,7-三氟-6-(4-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(1-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(1-((1-(1-异丙基-6-((2-(4-甲氧基哌啶-1-基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-3-基)哌啶-4-基)甲基)哌啶-4-基)异吲哚啉-1,3-二酮;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((((3R)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-((((3S)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-(((3S)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;N-(叔丁基)-3-((2-((4-(2-(4-(((3R)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)乙氧基)苯基)氨基)-5-甲基嘧啶-4-基)氨基)苯磺酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((((3R)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-((((3S)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-(((3S)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;4-(4-(((3R)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)-N-(5-((R)-2-甲氧基-2-苯基乙酰基)-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)苯甲酰胺;5-(4-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(6-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;6-(3-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(8-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;6-(4-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;6-(4-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(4-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((R)-3-(((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-(((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((R)-1-((1-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚熳-6-基)乙酰基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(6-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;6-(4-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;6-(4-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((R)-3-(((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-(((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((R)-1-((1-(4-(5,7-二甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((((3R)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((((3S)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-(((3S)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-(((3R)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((((3R)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-((((3S)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(((3S)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(((3R)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((((3R)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-((((3S)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-(((3S)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;4-((4-(((3R)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((6-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((8-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((5-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6,7-二氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟-1,3-二氧代异吲哚啉-5-基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-3,5-二甲基哌嗪-1-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)-2,6-二甲基哌嗪-1-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((4-(2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((((3R)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-((((3S)-1-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)哌啶-3-基)氨基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-(((3S)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;2-((2-((4-(4-(((3R)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)吡啶-4-基)氨基)-N-甲基苯甲酰胺;5-(4-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(6-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(6-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(6-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(8-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(8-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(8-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;6-(4-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(4-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;6-(4-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;6-(4-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;6-(4-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;6-(4-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((R)-3-(((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((R)-3-(((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((R)-3-(((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-(((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-(((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-(((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((R)-1-((1-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((R)-1-((1-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((R)-1-((1-(2-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(6-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(8-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;6-(4-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;6-(4-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((R)-3-(((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-(((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((R)-1-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(6-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(8-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;6-(4-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;6-(4-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((R)-3-(((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-(((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((R)-1-((1-(4-(4-氯-1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(6-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(6-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(6-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(6-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;5-(3-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(8-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(8-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(8-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(8-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(5-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(5-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(5-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(5-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(5-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;5-(5-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-6-(4-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-4-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-6-(4-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;6-(4-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-4-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-5-(4-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-4,6-二氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,6-二氟-5-(4-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-4,7-二氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,7-二氟-5-(4-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-6-(4-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-4,5-二氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5-二氟-6-(4-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;6-(4-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-4,6,7-三氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5,7-三氟-6-(4-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;5-(4-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(1-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(1-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)异吲哚啉-1,3-二酮;5-(1-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(1-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(1-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)异吲哚啉-1,3-二酮;5-(1-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((R)-3-(((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((R)-3-(((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;5-((R)-3-(((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((S)-3-(((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((S)-3-(((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;5-((S)-3-(((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((S)-1-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((S)-1-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;5-(((S)-1-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((R)-1-((1-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((R)-1-((1-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;5-(((R)-1-((1-(2-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(6-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(6-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(8-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(8-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(5-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(5-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-6-(4-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-5-(4-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,6-二氟-5-(4-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,7-二氟-5-(4-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5-二氟-6-(4-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5,7-三氟-6-(4-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(1-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(1-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((R)-3-(((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((S)-3-(((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((S)-1-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((R)-1-((1-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(6-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(6-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(3-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(3-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(8-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(8-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(5-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(5-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;6-(4-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6-二氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,7-二氟异吲哚啉-1,3-二酮;6-(4-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,5-二氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)-2-(2,6-二氧代哌啶-3-基)-4,6,7-三氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(4-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(4-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-(1-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(1-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-4-基)-2-(2,6-二氧代哌啶-3-基)-6-氟异吲哚啉-1,3-二酮;5-((R)-3-(((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-((S)-3-(((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((S)-1-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;5-(((R)-1-((1-(4-(1,2-双(4-羟基苯基)丁-1-烯-1-基)苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(6-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(6-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(8-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(8-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(5-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-6-(4-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-5-(4-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,6-二氟-5-(4-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,7-二氟-5-(4-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5-二氟-6-(4-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5,7-三氟-6-(4-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(1-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(1-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((R)-3-(((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((S)-3-(((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((S)-1-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((R)-1-((1-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯基)哌啶-4-基)甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-6-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(6-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(6-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(3-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(3-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(8-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(8-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(5-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,5-二氮杂双环[2.2.2]辛烷-2-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-6-(4-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4-氟-5-(4-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,6-二氟-5-(4-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,7-二氟-5-(4-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5-二氟-6-(4-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-4,5,7-三氟-6-(4-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌嗪-1-基-2,2,3,3,5,5,6,6-d 8)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)-2,6-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(4-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(4-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)-3,5-二甲基哌嗪-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(1-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-氟-6-(1-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((R)-3-(((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-((S)-3-(((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)氨基)哌啶-1-基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((S)-1-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;2-(2,6-二氧代哌啶-3-基)-5-(((R)-1-((1-(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)哌啶-4-基)甲基)哌啶-3-基)氨基)异吲哚啉-1,3-二酮;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((8-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-(((3S,4S)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)-3,4-二羟基哌啶-1-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)-3,6-二氢吡啶-1(2H)-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1-氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-4-氟-1-氧代异吲哚啉-5-基)-3,6-二氢吡啶-1(2H)-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,4r)-4-(3-氯-4-氰基苯氧基)环己基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-7-氟-1-氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)哒嗪-3-甲酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)烟酰胺;N-((1r,3r)-3-(3-氯-4-氰基苯氧基)-2,2,4,4-四甲基环丁基)-6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)-3,6-二氢吡啶-1(2H)-基)甲基)哌啶-1-基)烟酰胺;7-环戊基-2-((5-(4-((4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)氨基)哌啶-1-基)甲基)哌啶-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺;N-(2-氯-6-甲基苯基)-2-((6-(4-((4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)哌啶-1-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺;和N-(2-氯-6-甲基苯基)-2-((6-(4-(((3S,4S)-4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)-3,4-二羟基哌啶-1-基)甲基)哌啶-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺。
- 如权利要求20至37中任一项所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物,其是式(III)化合物的氢卤酸盐(包括盐酸盐、氢溴酸盐)、硫酸盐、马来酸盐、磺酸盐、柠檬酸盐/枸橼酸盐、乳酸盐、乳糖酸盐、L-酒石酸盐、富马酸盐、L-苹果酸盐、L-乳酸盐、α-酮戊二酸盐、马尿酸盐、D-葡萄糖醛酸盐、D-葡萄糖酸盐、α-D-葡庚糖酸盐、乙醇酸盐、粘酸盐、L-抗坏血酸盐、乳清酸盐、苦味酸盐、甘氨酸盐、丙氨酸盐、精氨酸盐、肉桂酸盐、月桂酸盐、帕莫酸盐、癸二酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、乙二磺酸盐、甲酸盐、乙酸盐、2,2-二氯乙酸盐、三甲基乙酸盐、丙酸盐、戊酸盐、棕榈酸盐、三苯基乙酸盐、2-乙基-丁二酸盐、碘酸盐、烟酸盐、L-焦谷氨酸盐、L-脯氨酸盐、阿魏酸盐、2-羟基乙磺酸盐、硝酸盐、龙胆酸盐、胆酸盐、水杨酸盐、对苯二酸盐、戊二酸盐、己二酸盐、硬脂酸盐、油酸盐、十一烯酸盐、樟脑酸盐、樟脑磺酸盐、十二基磺酸盐、磷酸盐、硫氰酸盐、二氢磷酸盐、焦磷酸盐、偏磷酸盐、草酸盐、碳酸盐、丙二酸盐、苯甲酸盐、扁桃酸盐、琥珀酸盐、三氟乙酸盐、丙酮酸盐、对氯苯磺酸盐、1,5-萘二磺酸盐、3-羟基-2-萘甲酸盐、1-羟基-2-萘甲酸盐、2-萘磺酸盐、羟乙酸盐或对甲苯磺酸盐。
- 药物组合物,其包含作为活性成分的如权利要求1至8中任一项所述的式(I)化合物、或如权利要求9至19中任一项所述的式(II)化合物、或其药学上可接受的盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,及至少一种药学上可接受的载体。
- 如权利要求39所述的药物组合物,进一步包括至少一种额外的治疗剂。
- 药物组合物,其包含作为活性成分的如权利要求20至37中任一项所述的式(III)化合物或其药学上可接受的盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,及至少一种药学上可接受的载体。
- 如权利要求41所述的药物组合物,进一步包括至少一种额外的治疗剂,例如抗癌剂。
- 一种药盒或试剂盒,其包含:如权利要求1至8中任一项所述的式(I)化合物或其药学上可接受的盐或如权利要求39或40所述的药物组合物;或如权利要求9至19中任一项所述的式(II)化合物或其药学上可接受的盐或如权利要求39或40所述的药物组合物;或如权利要求20至37中任一项所述的式(II)化合物或其药学上可接受的盐或如权利要求41或42所述的药物组合物。
- 如权利要求1至8中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,或者如权利要求9至19中任一项所述的式(II)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,用于制备如权利要求20所述的式(III)化合物的用途。
- 如权利要求44所述的用途,其中所述式(III)化合物能用于治疗和/或预防选自以下的疾病或病症:肿瘤、感染性疾病、自身炎症性疾病、炎症性疾病、自身免疫性疾病、神经疾病、呼吸系统疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、充血性心力衰竭、心肌梗塞、翁韦里希特综合征、里希特氏综合征(Richter syndrome,RS)、急性肝功能衰竭、糖尿病、肯尼迪病(Kennedy disease)、脂溢性脱发、多毛症、皮肤疾病、心血管疾病、功能性子宫出血、贫血、小儿再生障碍性贫血、子宫内膜异位症、移植排斥反应、多囊卵巢综合征和甲状腺疾病。
- 如权利要求1至8中任一项所述的式(I)化合物、如权利要求9至19中任一项所述的式(II)化合物、或它们的盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物用于制备用于治疗或预防cereblon蛋白介导的疾病或病症的药物的用途。
- 如权利要求46所述的用途,其中所述cereblon蛋白介导的疾病或病症包括:肿瘤、感染性疾病、自身炎症性疾病、炎症性疾病、自身免疫性疾病、神经疾病、呼吸系统疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、充血性心力衰竭、心肌梗塞、翁韦里希特综合征、里希特氏综合征(Richter syndrome,RS)、急性肝功能衰竭和糖尿病。
- 如权利要求46所述的用途,其中所述cereblon蛋白介导的疾病或病症选自由以下组成的群组:骨髓瘤,包括多发性骨髓瘤、浆细胞骨髓瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤;骨髓纤维化;骨髓疾病;骨髓增生异常综合征(MDS);既往治疗的骨髓增生异常综合征;移植相关的癌症;中性粒细胞减少症;白血病,包括急性髓细胞白血病、慢性粒细胞白血病、B细胞慢性淋巴细胞白血病、与白血病相关的贫血、急性髓性白血病(AML);淋巴瘤,包括弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、间变性淋巴瘤、间变性大细胞淋巴瘤、CD20阳性淋巴瘤、套细胞淋巴瘤、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性纵隔(胸腺)大B细胞淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞淋巴瘤、难治性转化的非霍奇金淋巴瘤;甲状腺癌;黑色素瘤;肺癌;炎症性肌纤维母细胞瘤;结直肠癌;脑胶质瘤;星形胶质母细胞瘤;卵巢癌;支气管癌;前列腺癌;乳腺癌,包括三阴性乳腺癌、偶发性乳腺癌和考登病患者;胰腺癌;神经母细胞瘤;髓外浆细胞瘤;浆细胞瘤;胃癌;胃肠道间质瘤;食道癌;大肠腺癌;食管鳞状细胞癌;肝癌;肾细胞癌;膀胱癌;子宫内膜癌;脑癌;口腔癌;肉瘤,包括横纹肌肉瘤、各种脂肪源性肿瘤、尤文肉瘤/原始神经外胚层瘤(Ewing/PNETs)、和平滑肌肉瘤;尿路上皮癌;基底细胞癌;口腔鳞状细胞癌;胆管癌;骨癌;宫颈癌;皮肤癌;翁韦里希特综合征;里希特氏综合征(Richter syndrome,RS);脓毒综合征;自身免疫性疾病,包括类风湿性关节炎、自身免疫性脑脊髓炎、强直性脊柱炎、银屑病、系统性红斑狼疮、多发性硬化症、复发性口腔溃疡、川崎病、多发性肌炎/皮肌炎、干燥综合征、特应性皮炎;角结膜干燥症;自身炎症性疾病,包括痛风等;炎症性疾病,包括克罗恩病和溃疡性结肠炎、肺炎、骨关节炎、滑膜炎、全身炎症反应综合征、气道炎症、支气管炎;脑型疟疾;感染性疾病,包括病毒性肺炎、艾滋病(AIDS)、COVID-19新型冠状病毒感染、革兰氏阴性菌感染、革兰氏阳性菌感染、结核病等;感染性休克;细菌性脑膜炎;慢性阻塞性肺疾病;哮喘;出血性休克;器官(包括肾、心脏、肺)或组织移植排斥反应;糖尿病;类肉瘤病;成人呼吸窘迫综合征;充血性心力衰竭;心肌梗塞;恶病质和败血症休克所致的多器官功能衰竭;和急性肝功能衰竭。
- 如权利要求20至37中任一项所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物用于制备治疗和/或预防选自以下的疾病或病症的药物的用途:肿瘤、感染性疾病、自身炎症性疾病、炎症性疾病、自身免疫性疾病、神经疾病、呼吸系统疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、充血性心力衰竭、心肌梗塞、翁韦里希特综合征、里希特氏综合征(Richter syndrome,RS)、急性肝功能衰竭、糖尿病、肯尼迪病(Kennedy disease)、脂溢性脱发、多毛症、皮肤疾病、心血管疾病、功能性子宫出血、贫血、小儿再生障碍性贫血、子宫内膜异位症、移植排斥反应、多囊卵巢综合征和甲状腺疾病。
- 如权利要求49所述的用途,其中所述疾病或病症选自由以下组成的群组:骨髓瘤,包括多 发性骨髓瘤、浆细胞骨髓瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤;骨髓纤维化;骨髓疾病;骨髓增生异常综合征(MDS);既往治疗的骨髓增生异常综合征;移植相关的癌症;中性粒细胞减少症;白血病,包括急性髓细胞白血病、慢性粒细胞白血病、B细胞慢性淋巴细胞白血病、与白血病相关的贫血、急性髓性白血病(AML);淋巴瘤,包括弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、间变性淋巴瘤、间变性大细胞淋巴瘤、CD20阳性淋巴瘤、套细胞淋巴瘤、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性纵隔(胸腺)大B细胞淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞淋巴瘤、难治性转化的非霍奇金淋巴瘤;甲状腺癌;黑色素瘤;肺癌,包括肺腺癌、肺鳞癌;炎症性肌纤维母细胞瘤;结直肠癌;脑胶质瘤;星形胶质母细胞瘤;卵巢癌;支气管癌;前列腺癌;乳腺癌,包括三阴性乳腺癌、偶发性乳腺癌和考登病患者;胰腺癌;神经母细胞瘤;髓外浆细胞瘤;浆细胞瘤;胃癌;胃肠道间质瘤;食道癌;大肠腺癌;食管鳞状细胞癌;肝癌;肾细胞癌;膀胱癌;子宫内膜癌;脑癌;口腔癌;肉瘤,包括横纹肌肉瘤、各种脂肪源性肿瘤、尤文肉瘤/原始神经外胚层瘤(Ewing/PNETs)、及平滑肌肉瘤;尿路上皮癌;基底细胞癌;口腔鳞状细胞癌;胆管癌;骨癌;宫颈癌;皮肤癌;翁韦里希特综合征;里希特氏综合征(Richter syndrome,RS);脓毒综合征;自身免疫性疾病,包括类风湿性关节炎、自身免疫性脑脊髓炎、强直性脊柱炎、银屑病、系统性红斑狼疮、多发性硬化症、复发性口腔溃疡、川崎病、多发性肌炎/皮肌炎、干燥综合征、特应性皮炎;角结膜干燥症;自身炎症性疾病,包括痛风等;炎症性疾病,包括克罗恩病和溃疡性结肠炎、肺炎、骨关节炎、滑膜炎、全身炎症反应综合征、气道炎症、支气管炎;脑型疟疾;感染性疾病,包括病毒性肺炎、艾滋病(AIDS)、COVID-19新型冠状病毒感染、革兰氏阴性菌感染、革兰氏阳性菌感染、结核病等;感染性休克;细菌性脑膜炎;慢性阻塞性肺疾病;哮喘;出血性休克;器官(包括肾、心脏、肺)或组织移植排斥反应;糖尿病;类肉瘤病;成人呼吸窘迫综合征;恶病质和败血症休克所致的多器官功能衰竭;急性肝功能衰竭;功能性子宫出血;贫血;小儿再生障碍性贫血;子宫内膜异位症;多囊卵巢综合征;甲状腺疾病;心血管疾病(例如冠心病、充血性心力衰竭、心肌梗塞、动脉粥样硬化症);皮肤疾病(例如痤疮);肯尼迪病(Kennedy disease);脂溢性脱发;和多毛症。
- 如权利要求1至8中任一项所述的式(I)化合物、如权利要求9至19中任一项所述的式(II)化合物、或它们的盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其用于治疗和/或预防cereblon蛋白介导的疾病或病症。
- 如权利要求51所述的式(I)化合物、式(II)化合物、或它们的盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中所述cereblon蛋白介导的疾病或病症包括:肿瘤、感染性疾病、自身炎症性疾病、炎症性疾病、自身免疫性疾病、神经疾病、呼吸系统疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉 瘤病、成人呼吸窘迫综合征、充血性心力衰竭、心肌梗塞、翁韦里希特综合征、里希特氏综合征(Richter syndrome,RS)、急性肝功能衰竭和糖尿病。
- 如权利要求52所述的式(I)化合物、式(II)化合物、或它们的盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中所述cereblon蛋白介导的疾病或病症选自由以下组成的群组:骨髓瘤,包括多发性骨髓瘤、浆细胞骨髓瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤;骨髓纤维化;骨髓疾病;骨髓增生异常综合征(MDS);既往治疗的骨髓增生异常综合征;移植相关的癌症;中性粒细胞减少症;白血病,包括急性髓细胞白血病、慢性粒细胞白血病、B细胞慢性淋巴细胞白血病、与白血病相关的贫血、急性髓性白血病(AML);淋巴瘤,包括弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、间变性淋巴瘤、间变性大细胞淋巴瘤、CD20阳性淋巴瘤、套细胞淋巴瘤、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性纵隔(胸腺)大B细胞淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞淋巴瘤、难治性转化的非霍奇金淋巴瘤;甲状腺癌;黑色素瘤;肺癌;炎症性肌纤维母细胞瘤;结直肠癌;脑胶质瘤;星形胶质母细胞瘤;卵巢癌;支气管癌;前列腺癌;乳腺癌,包括三阴性乳腺癌、偶发性乳腺癌和考登病患者;胰腺癌;神经母细胞瘤;髓外浆细胞瘤;浆细胞瘤;胃癌;胃肠道间质瘤;食道癌;大肠腺癌;食管鳞状细胞癌;肝癌;肾细胞癌;膀胱癌;子宫内膜癌;脑癌;口腔癌;肉瘤,包括横纹肌肉瘤、各种脂肪源性肿瘤、尤文肉瘤/原始神经外胚层瘤(Ewing/PNETs)、和平滑肌肉瘤;尿路上皮癌;基底细胞癌;口腔鳞状细胞癌;胆管癌;骨癌;宫颈癌;皮肤癌;翁韦里希特综合征;里希特氏综合征(Richter syndrome,RS);脓毒综合征;自身免疫性疾病,包括类风湿性关节炎、自身免疫性脑脊髓炎、强直性脊柱炎、银屑病、系统性红斑狼疮、多发性硬化症、复发性口腔溃疡、川崎病、多发性肌炎/皮肌炎、干燥综合征、特应性皮炎;角结膜干燥症;自身炎症性疾病,包括痛风等;炎症性疾病,包括克罗恩病和溃疡性结肠炎、肺炎、骨关节炎、滑膜炎、全身炎症反应综合征、气道炎症、支气管炎;脑型疟疾;感染性疾病,包括病毒性肺炎、艾滋病(AIDS)、COVID-19新型冠状病毒感染、革兰氏阴性菌感染、革兰氏阳性菌感染、结核病等;感染性休克;细菌性脑膜炎;慢性阻塞性肺疾病;哮喘;出血性休克;器官(包括肾、心脏、肺)或组织移植排斥反应;糖尿病;类肉瘤病;成人呼吸窘迫综合征;充血性心力衰竭;心肌梗塞;恶病质和败血症休克所致的多器官功能衰竭;和急性肝功能衰竭。
- 如权利要求20至37中任一项所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其用于治疗和/或预防选自以下的疾病或病症:肿瘤、感染性疾病、自身炎症性疾病、炎症性疾病、自身免疫性疾病、神经疾病、呼吸系统疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、充血性心力衰竭、心肌梗塞、翁韦里希特综合征、里希特氏综合征 (Richter syndrome,RS)、急性肝功能衰竭、糖尿病、肯尼迪病(Kennedy disease)、脂溢性脱发、多毛症、皮肤疾病、心血管疾病、功能性子宫出血、贫血、小儿再生障碍性贫血、子宫内膜异位症、移植排斥反应、多囊卵巢综合征和甲状腺疾病。
- 如权利要求54所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,其中所述靶蛋白介导或与其相关的疾病或病症选自由以下组成的群组:骨髓瘤,包括多发性骨髓瘤、浆细胞骨髓瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤;骨髓纤维化;骨髓疾病;骨髓增生异常综合征(MDS);既往治疗的骨髓增生异常综合征;移植相关的癌症;中性粒细胞减少症;白血病,包括急性髓细胞白血病、慢性粒细胞白血病、B细胞慢性淋巴细胞白血病、与白血病相关的贫血、急性髓性白血病(AML);淋巴瘤,包括弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、间变性淋巴瘤、间变性大细胞淋巴瘤、CD20阳性淋巴瘤、套细胞淋巴瘤、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性纵隔(胸腺)大B细胞淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞淋巴瘤、难治性转化的非霍奇金淋巴瘤;甲状腺癌;黑色素瘤;肺癌,包括肺腺癌、肺鳞癌;炎症性肌纤维母细胞瘤;结直肠癌;脑胶质瘤;星形胶质母细胞瘤;卵巢癌;支气管癌;前列腺癌;乳腺癌,包括三阴性乳腺癌、偶发性乳腺癌和考登病患者;胰腺癌;神经母细胞瘤;髓外浆细胞瘤;浆细胞瘤;胃癌;胃肠道间质瘤;食道癌;大肠腺癌;食管鳞状细胞癌;肝癌;肾细胞癌;膀胱癌;子宫内膜癌;脑癌;口腔癌;肉瘤,包括横纹肌肉瘤、各种脂肪源性肿瘤、尤文肉瘤/原始神经外胚层瘤(Ewing/PNETs)、及平滑肌肉瘤;尿路上皮癌;基底细胞癌;口腔鳞状细胞癌;胆管癌;骨癌;宫颈癌;皮肤癌;翁韦里希特综合征;里希特氏综合征(Richter syndrome,RS);脓毒综合征;自身免疫性疾病,包括类风湿性关节炎、自身免疫性脑脊髓炎、强直性脊柱炎、银屑病、系统性红斑狼疮、多发性硬化症、复发性口腔溃疡、川崎病、多发性肌炎/皮肌炎、干燥综合征、特应性皮炎;角结膜干燥症;自身炎症性疾病,包括痛风等;炎症性疾病,包括克罗恩病和溃疡性结肠炎、肺炎、骨关节炎、滑膜炎、全身炎症反应综合征、气道炎症、支气管炎;脑型疟疾;感染性疾病,包括病毒性肺炎、艾滋病(AIDS)、COVID-19新型冠状病毒感染、革兰氏阴性菌感染、革兰氏阳性菌感染、结核病等;感染性休克;细菌性脑膜炎;慢性阻塞性肺疾病;哮喘;出血性休克;器官(包括肾、心脏、肺)或组织移植排斥反应;糖尿病;类肉瘤病;成人呼吸窘迫综合征;恶病质和败血症休克所致的多器官功能衰竭;急性肝功能衰竭;功能性子宫出血;贫血;小儿再生障碍性贫血;子宫内膜异位症;多囊卵巢综合征;甲状腺疾病;心血管疾病(例如冠心病、充血性心力衰竭、心肌梗塞、动脉粥样硬化症);皮肤疾病(例如痤疮);肯尼迪病(Kennedy disease);脂溢性脱发;和多毛症。
- 一种治疗或预防受试者中的cereblon蛋白介导的疾病或病症的方法,其包括向所述受试者施用治疗有效量的如权利要求1至8中任一项所述的式(I)化合物、如权利要求9至19中任 一项所述的式(II)化合物、或它们的盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,或如权利要求39或40所述的药物组合物。
- 如权利要求56所述的方法,其中所述cereblon蛋白介导的疾病或病症包括:肿瘤、感染性疾病、自身炎症性疾病、炎症性疾病、自身免疫性疾病、神经疾病、呼吸系统疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、充血性心力衰竭、心肌梗塞、翁韦里希特综合征、里希特氏综合征(Richter syndrome,RS)、急性肝功能衰竭和糖尿病。
- 如权利要求57所述的方法,其中所述cereblon蛋白介导的疾病或病症选自由以下组成的群组:骨髓瘤,包括多发性骨髓瘤、浆细胞骨髓瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤;骨髓纤维化;骨髓疾病;骨髓增生异常综合征(MDS);既往治疗的骨髓增生异常综合征;移植相关的癌症;中性粒细胞减少症;白血病,包括急性髓细胞白血病、慢性粒细胞白血病、B细胞慢性淋巴细胞白血病、与白血病相关的贫血、急性髓性白血病(AML);淋巴瘤,包括弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、间变性淋巴瘤、间变性大细胞淋巴瘤、CD20阳性淋巴瘤、套细胞淋巴瘤、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性纵隔(胸腺)大B细胞淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞淋巴瘤、难治性转化的非霍奇金淋巴瘤;甲状腺癌;黑色素瘤;肺癌;炎症性肌纤维母细胞瘤;结直肠癌;脑胶质瘤;星形胶质母细胞瘤;卵巢癌;支气管癌;前列腺癌;乳腺癌,包括三阴性乳腺癌、偶发性乳腺癌和考登病患者;胰腺癌;神经母细胞瘤;髓外浆细胞瘤;浆细胞瘤;胃癌;胃肠道间质瘤;食道癌;大肠腺癌;食管鳞状细胞癌;肝癌;肾细胞癌;膀胱癌;子宫内膜癌;脑癌;口腔癌;肉瘤,包括横纹肌肉瘤、各种脂肪源性肿瘤、尤文肉瘤/原始神经外胚层瘤(Ewing/PNETs)、和平滑肌肉瘤;尿路上皮癌;基底细胞癌;口腔鳞状细胞癌;胆管癌;骨癌;宫颈癌;皮肤癌;翁韦里希特综合征;里希特氏综合征(Richter syndrome,RS);脓毒综合征;自身免疫性疾病,包括类风湿性关节炎、自身免疫性脑脊髓炎、强直性脊柱炎、银屑病、系统性红斑狼疮、多发性硬化症、复发性口腔溃疡、川崎病、多发性肌炎/皮肌炎、干燥综合征、特应性皮炎;角结膜干燥症;自身炎症性疾病,包括痛风等;炎症性疾病,包括克罗恩病和溃疡性结肠炎、肺炎、骨关节炎、滑膜炎、全身炎症反应综合征、气道炎症、支气管炎;脑型疟疾;感染性疾病,包括病毒性肺炎、艾滋病(AIDS)、COVID-19新型冠状病毒感染、革兰氏阴性菌感染、革兰氏阳性菌感染、结核病等;感染性休克;细菌性脑膜炎;慢性阻塞性肺疾病;哮喘;出血性休克;器官(包括肾、心脏、肺)或组织移植排斥反应;糖尿病;类肉瘤病;成人呼吸窘迫综合征;充血性心力衰竭;心肌梗塞;恶病质和败血症休克所致的多器官功能衰竭;和急性肝功能衰竭。
- 如权利要求56-58中任一项所述的方法,其中通过至少一种选自鼻腔给药、吸入给药、局部给药、口服给药、口腔粘膜给药、直肠给药、胸膜腔给药、腹膜给药、阴道给药、肌内 给药、皮下给药、经皮给药、硬膜外腔给药、鞘内给药和静脉给药的给药方式将所述的式(I)化合物或其药学上可接受的盐、或所述的式(II)化合物或其药学上可接受的盐、或所述的药物组合物施用至所述受试者。
- 一种治疗或预防受试者的疾病或病症的方法,其中所述疾病或病症包括肿瘤、感染性疾病、自身炎症性疾病、炎症性疾病、自身免疫性疾病、神经疾病、呼吸系统疾病、贫血、出血性休克、移植排斥反应、多器官功能障碍综合征(MODS)、类肉瘤病、成人呼吸窘迫综合征、充血性心力衰竭、心肌梗塞、翁韦里希特综合征、里希特氏综合征(Richter syndrome,RS)、急性肝功能衰竭、糖尿病、肯尼迪病(Kennedy disease)、脂溢性脱发、多毛症、皮肤疾病、心血管疾病、功能性子宫出血、贫血、小儿再生障碍性贫血、子宫内膜异位症、移植排斥反应、多囊卵巢综合征和甲状腺疾病,所述方法包括向所述受试者施用治疗有效量的如权利要求20至37中任一项所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物,或如权利要求41或42所述的药物组合物。
- 如权利要求60所述的方法,其中所述疾病或病症选自由以下组成的群组:骨髓瘤,包括多发性骨髓瘤、浆细胞骨髓瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤;骨髓纤维化;骨髓疾病;骨髓增生异常综合征(MDS);既往治疗的骨髓增生异常综合征;移植相关的癌症;中性粒细胞减少症;白血病,包括急性髓细胞白血病、慢性粒细胞白血病、B细胞慢性淋巴细胞白血病、与白血病相关的贫血、急性髓性白血病(AML);淋巴瘤,包括弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、间变性淋巴瘤、间变性大细胞淋巴瘤、CD20阳性淋巴瘤、套细胞淋巴瘤、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性纵隔(胸腺)大B细胞淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞淋巴瘤、难治性转化的非霍奇金淋巴瘤;甲状腺癌;黑色素瘤;肺癌,包括肺腺癌、肺鳞癌;炎症性肌纤维母细胞瘤;结直肠癌;脑胶质瘤;星形胶质母细胞瘤;卵巢癌;支气管癌;前列腺癌;乳腺癌,包括三阴性乳腺癌、偶发性乳腺癌和考登病患者;胰腺癌;神经母细胞瘤;髓外浆细胞瘤;浆细胞瘤;胃癌;胃肠道间质瘤;食道癌;大肠腺癌;食管鳞状细胞癌;肝癌;肾细胞癌;膀胱癌;子宫内膜癌;脑癌;口腔癌;肉瘤,包括横纹肌肉瘤、各种脂肪源性肿瘤、尤文肉瘤/原始神经外胚层瘤(Ewing/PNETs)、及平滑肌肉瘤;尿路上皮癌;基底细胞癌;口腔鳞状细胞癌;胆管癌;骨癌;宫颈癌;皮肤癌;翁韦里希特综合征;里希特氏综合征(Richter syndrome,RS);脓毒综合征;自身免疫性疾病,包括类风湿性关节炎、自身免疫性脑脊髓炎、强直性脊柱炎、银屑病、系统性红斑狼疮、多发性硬化症、复发性口腔溃疡、川崎病、多发性肌炎/皮肌炎、干燥综合征、特应性皮炎;角结膜干燥症;自身炎症性疾病,包括痛风等;炎症性疾病,包括克罗恩病和溃疡性结肠炎、肺炎、骨关节炎、滑膜炎、全身炎症反应综合征、气道炎症、支气管炎;脑型疟疾;感染性疾病,包括病毒性肺炎、艾滋病(AIDS)、COVID-19新型冠状病毒感染、革兰氏阴性菌感染、革兰氏阳性菌感染、结核 病等;感染性休克;细菌性脑膜炎;慢性阻塞性肺疾病;哮喘;出血性休克;器官(包括肾、心脏、肺)或组织移植排斥反应;糖尿病;类肉瘤病;成人呼吸窘迫综合征;恶病质和败血症休克所致的多器官功能衰竭;急性肝功能衰竭;功能性子宫出血;贫血;小儿再生障碍性贫血;子宫内膜异位症;多囊卵巢综合征;甲状腺疾病;心血管疾病(例如冠心病、充血性心力衰竭、心肌梗塞、动脉粥样硬化症);皮肤疾病(例如痤疮);肯尼迪病(Kennedy disease);脂溢性脱发;和多毛症。
- 如权利要求60或61所述的方法,其中通过至少一种选自鼻腔给药、吸入给药、局部给药、口服给药、口腔粘膜给药、直肠给药、胸膜腔给药、腹膜给药、阴道给药、肌内给药、皮下给药、经皮给药、硬膜外腔给药、鞘内给药和静脉给药的给药方式将所述的式(III)化合物或其药学上可接受的盐、或所述的药物组合物施用至所述受试者。
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DATABASE Registry CAS; 19 October 2021 (2021-10-19), ANONYMOUS : "1H-Isoindole-1,3(2H)-dio ne, 2-(2,6-dioxo-3-pi peridinyl)-5-[4-[[1-[2- [4-[6- [5-(1-methylethoxy)- 1H-indazol-3-yl]-4-p yrimidinyl]-1-piperaz inyl]ethyl]-4- piperidinyl]methyl]- 1-piperidinyl]-", XP093059855, Database accession no. 2714476-17-0 * |
DATABASE Registry CAS; 23 June 2022 (2022-06-23), ANONYMOUS : "Benzonitrile, 3-chloro-5- [1-[4-[[2-[4-[1-[1-[2- (2,6-dioxo-3-piperidi nyl)- 2,3-dihydro-1,3-diox o-1H-isoindol-5-yl]-3 -piperidinyl]-3-azetid inyl]-1- piperazinyl]-4-pyrimi dinyl]methoxy]phen yl]-1-methylethyl]-", XP093059863, Database accession no. 2776896-94-5 * |
DATABASE Registry CAS; 30 September 2021 (2021-09-30), ANONYMOUS : "1H-Isoindole-1,3(2H)-dio ne, 5-[2-(2-aminoeth yl)-3-methyl-1-piperi dinyl]-2- (2,6-dioxo-3-piperidi nyl)-", XP093059849, Database accession no. 2703770-66-3 * |
DEGORCE SÉBASTIEN L., TAVANA OMID, BANKS ERICA, CRAFTER CLAIRE, GINGIPALLI LAKSHMAIAH, KOUVCHINOV DAVID, MAO YUMENG, PACHL FIONA, : "Discovery of Proteolysis-Targeting Chimera Molecules that Selectively Degrade the IRAK3 Pseudokinase", JOURNAL OF MEDICINAL CHEMISTRY, vol. 63, no. 18, 24 September 2020 (2020-09-24), US , pages 10460 - 10473, XP093059781, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.0c01125 * |
HAN XIN, ZHAO LIJIE, XIANG WEIGUO, QIN CHONG, MIAO BUKEYAN, MCEACHERN DONNA, WANG YU, METWALLY HODA, WANG LU, MATVEKAS ALEKSAS, WE: "Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer", JOURNAL OF MEDICINAL CHEMISTRY, vol. 64, no. 17, 9 September 2021 (2021-09-09), US , pages 12831 - 12854, XP093059787, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.1c00882 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024015412A1 (en) * | 2022-07-12 | 2024-01-18 | Regents Of The University Of Michigan | Tetrahydronaphthalene derivatives as estrogen receptor degraders |
WO2024032600A1 (zh) * | 2022-08-08 | 2024-02-15 | 西藏海思科制药有限公司 | 一种杂环衍生物及其组合物和药学上的应用 |
WO2024173646A1 (en) * | 2023-02-16 | 2024-08-22 | Innovo Therapeutics, Inc. | Cyclin-dependent kinase degrading compounds |
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KR20240110576A (ko) | 2024-07-15 |
AU2022370021A1 (en) | 2024-05-09 |
CN116003418A (zh) | 2023-04-25 |
EP4421071A1 (en) | 2024-08-28 |
CA3235512A1 (en) | 2023-04-27 |
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