CN117586253A - Protein degradation agent, preparation method thereof and application thereof in pharmacy - Google Patents

Protein degradation agent, preparation method thereof and application thereof in pharmacy Download PDF

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CN117586253A
CN117586253A CN202311010353.5A CN202311010353A CN117586253A CN 117586253 A CN117586253 A CN 117586253A CN 202311010353 A CN202311010353 A CN 202311010353A CN 117586253 A CN117586253 A CN 117586253A
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independently selected
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汪信锋
杜书奇
段书冬
秦继红
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Shanghai Huilun Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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Abstract

The invention discloses a protein degradation agent, a preparation method thereof and application thereof in pharmacy. In particular to a compound shown in a general formula (I), a preparation method and a pharmaceutical composition thereof, and the application of the compound as a protein degradation agent in preparing medicines for treating or preventing tumor-related diseases.

Description

Protein degradation agent, preparation method thereof and application thereof in pharmacy
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a protein degradation agent, a preparation method thereof and application thereof in pharmacy.
Background
PARP, which is known as poly-ADP-ribose polymerase, i.e., poly ADP ribose polymerase, is involved in a number of cellular processes including DNA repair, genomic stability, etc.; the protein family consists of 18 members including PARP1, PARP2, etc. PARP inhibitors, through binding to the catalytic site of PARP1 or PARP2, result in the inability of PARP proteins to shed from the DNA damage site. PARP tethered to DNA can arrest DNA replication during DNA replication, further resulting in BER limitation. At this point, the cell will trigger homologous recombination repair, and BRCA1, BRCA2 and other proteins known as "BRCA-like" play an important role in homologous repeat repair. Therefore, in BRCA mutated cancer cells, homologous recombination repair cannot be performed. In addition, the function of PARP is inhibited, so that cancer cells can only carry out a DNA double-strand repair mode which is easy to make mistakes, and the cancer cells die.
PARP inhibitors are an effective means of treating cancer at present, and are hot spots and important points in the development of antitumor drugs. With the continued depth of PARP inhibitor research, some problems that are unfavorable for the application of PARP inhibitors are also found clinically, and further research and explanation are needed. Firstly, the safety problem of long-term use of the medicine. Out of the 4 PAPR inhibitors currently on the market, the remaining 3 require 300-600mg of drug to be ingested every day, except Talazoparib. PARP inhibitors have a short half-life and require frequent dosing. The PARP inhibitor taken in a large amount for a long time in the treatment process not only has a killing effect on tumor cells, but also has a certain killing effect on normal cells. Although PARP inhibitors exhibit some tumor tissue selectivity, this selectivity cannot be maintained for further observation over long-term massive drug action. In combination, it is also an important aspect to ensure therapeutic efficacy while reducing adverse effects, and therefore, a suitable dosing range must be established for PARP inhibitors. And secondly, the mechanism of action of the medicine is not completely clear. Third, PARP is prone to the development of tumor resistance over long periods of time, thereby reducing efficacy. How to generate drug resistance and overcome and improve the drug resistance problem needs to be solved. The development of resistance to PARP inhibitors is a complex process, where it is widely accepted that secondary mutations in the BRCA1/2 gene restore its protein function and are thus resistant to PARP inhibitors. In addition, deletion of 53BP1 expression and multidrug resistance and the like also allow the recovery of the HR functional moiety. Cancer cells may also have other mechanisms of drug resistance to be further investigated, and more elaborate treatment regimens should be set for different patients to delay and avoid the development of drug resistance. The clinical efficacy of PARP inhibitors has also led us to further develop PARP inhibitors and new strategies for treating tumors with greater confidence.
Treatment of diseases by degradation of target pathogenic proteins is a new model in the current drug discovery field, with protein degradation targeting chimera (Proteolysis Targeting Chimera, PROTAC) technology being a representative technology currently used for tumor targeted therapy. PRTOAC is a bifunctional molecule consisting of 3 parts, including a ligand that binds to a target protein, a ligand that binds to E3 ubiquitin ligase, and a Linker that links them. Target proteins are multimerized by recruiting target proteins and E3 ubiquitin protein ligase, which are in turn degraded by the intracellular ubiquitin protease system. The procac compounds have unique advantages over traditional small molecule inhibitors. Using the PROTAC technology, we have developed a number of PROTAC compounds that efficiently degrade pathogenic proteins in vivo and in vitro. ProTAC compounds have also been introduced into clinical studies. The invention designs the PARP degradation agent by utilizing the PROTAC technology, so as to provide a novel method for PARP-dependent tumor targeted therapy while overcoming the defects of small molecule PARP inhibitors.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a protein degradation agent and application thereof in anti-tumor drugs, and provides a compound capable of effectively inhibiting proliferation activity of tumor cells and degrading PARP1 protein.
In order to achieve the above purpose, the technical scheme adopted by the invention for solving the technical problems is as follows:
the invention provides a compound shown in a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein:
selected from:Ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
L 1 selected from-L 11 -L 12 -L 13 -L 14 -L 15 -L 16 -L 17 -L 18 -L 19 -；
L 11 、L 12 、L 13 、L 14 、L 15 、L 16 、L 17 、L 18 And L 19 Each independently selected from the group consisting of bond, - (CH) 2 ) n1 -、-NH-、-O-、-S-、-C(O)NH-、-C(O)-、-CH 2 -NH-、-CH 2 -N(CH 3 ) -, cycloalkylene, heterocyclylene, arylene or heteroarylene; the- (CH) 2 ) n1 -、-NH-、-C(O)NH-、-CH 2 -NH-、-CH 2 -N(CH 3 ) -, cycloalkylene, heterocyclylene, arylene, and heteroarylene, optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; l (L) 2 Selected from the group consisting of bond, alkylene, -O-, -NH-, -C (O) -, -CH 2 -NH-or-S-;
R a each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R b each group is independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, alkyl, alkoxy, haloalkyl, Haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;
R c each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R d each group is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
u is VHL or CRBN E3 ubiquitin ligase ligand selected from VHL or its derivative, pomalidomide or its derivative, lenalidomide or its derivative, or thalidomide or its derivative;
m is selected from 0, 1, 2 or 3;
x, y, z and o are each independently integers selected from 0 to 5; and is also provided with
n1 is an integer from 0 to 20.
In a preferred embodiment of the present invention, the ring B is selected from C 5-7 Cycloalkyl, 5-7 membered mono-heterocyclyl, 7-10 membered di-heterocyclyl; preferably cyclohexyl,
In a preferred embodiment of the present invention, the above U is selected from
Wherein:
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 R 21 R 22 R 23 and R is 24 Each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl; and is also provided with
p1 to p24 are each independently selected from 0, 1, 2, 3 or 4.
In a further preferred embodiment of the present invention, the above compound, stereoisomer thereof or pharmaceutically acceptable salt thereof is represented by the general formula (II):
wherein:
ring a is selected from aryl, 5-8 membered mono-heteroaryl, 8-14 membered di-heteroaryl;
preferably phenyl group,
L 1 Selected from-L 11 -L 12 -L 13 -L 14 -L 15 -L 16 -L 17 -L 18 -L 19 -；
L 11 、L 12 、L 13 、L 14 、L 15 、L 16 、L 17 、L 18 And L 19 Each independently selected from the group consisting of bond, - (CH) 2 ) n1 -、-NH-、-O-、-S-、-C(O)NH-、-C(O)-、-CH 2 -NH-、-CH 2 -N(CH 3 ) -, piperidinyl, piperazinyl, phenylene, pyrimidinyl, pyrazolyl, pyridazinyl, pyrazinyl, pyrrolopyrrolyl, bipyridylAzaspiro [5.5 ]]Undecyl, azaspiro [5.5 ]]Undecyl, benzidine, azetidine, diazepine, pyrrolidinylene, azaspiro [3.5 ]]Nonylalkyl, diazaspiro [3.5]Nonylalkyl, diazabicyclo [3.1.1]Heptyl or diazaspiro [2.5]An octyl group; the- (CH) 2 ) n1 -、-NH-、-C(O)NH-、-CH 2 -NH-、-CH 2 -N(CH 3 ) -, piperidinyl, piperazinyl, phenylene, pyrimidinyl, pyrazolyl, pyridazinyl, pyrazinyl, pyrrolopyrrolyl, diazaspiro [5.5 ]]Undecyl, azaspiro [5.5 ]]Undecyl, benzidine, azetidine, diazepine, pyrrolidinylene, azaspiro [3.5 ] ]Nonylalkyl, diazaspiro [3.5]Nonylalkyl, diazabicyclo [3.1.1]Heptyl and diazaspiro [2.5]Octyl optionally further substituted with deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, amino, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 One or more substituents in the haloalkoxy group;
u is selected from
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 R 21 R 22 R 23 And R is 24 Each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-5 Cycloalkyl or 3-5 membered heterocyclyl;
p1 to p24 are each independently selected from 0, 1, 2, 3 or 4;
R a each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 3-5 Cycloalkyl;
x is selected from 0, 1, 2 or 3; and is also provided with
n1 is an integer from 0 to 20.
In a further preferred embodiment of the present invention, L is as defined above 1 Selected from-L 11 -L 12 -L 13 -L 14 -L 15 -L 16 -L 17 -L 18 -L 19 -；
L 11 、L 12 、L 13 、L 14 、L 15 、L 16 、L 17 、L 18 And L 19 Each independently selected from the group consisting of bond, - (CH) 2 ) n1 -、-NH-、-O-、-S-、-C(O)NH-、-C(O)-、-CH 2 -NH-、-CH 2 -N(CH 3 )-、 The- (CH) 2 ) n1 -、-NH-、-C(O)NH-、-CH 2 -NH-、-CH 2 -N(CH 3 )-、 Optionally further substituted with deuterium, fluorine, chlorine, bromine, hydroxy, cyano, amino, nitro, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 One or more substituents in the haloalkoxy group;
n1 is an integer from 0 to 20.
In a further preferred embodiment of the present invention, the above compound, stereoisomer thereof or pharmaceutically acceptable salt thereof is represented by the general formula (III) or the general formula (III-A):
wherein:
L 1 selected from-L 11 -L 12 -L 13 -L 14 -L 15 -L 16 -L 17 -L 18 -L 19 -；
L 11 、L 12 、L 13 、L 14 、L 15 、L 16 、L 17 、L 18 And L 19 Each independently selected from the group consisting of bond, - (CH) 2 ) n1 -、-NH-、-O-、-S-、-C(O)NH-、-C(O)-、-CH 2 -NH-、-CH 2 -N(CH 3 )-、 The- (CH) 2 ) n1 -、-NH-、-C(O)NH-、-CH 2 -NH-、-CH 2 -N(CH 3 )-、 Optionally further substituted with deuterium, fluorine, chlorine, bromine, hydroxy, cyano, amino, nitro, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 One or more substituents in the haloalkoxy group;
u is selected from
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 R 21 R 22 R 23 And R is 24 Each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-5 Cycloalkyl or 3-5 membered heterocyclyl;
p1 to p24 are each independently selected from 0, 1, 2, 3 or 4; and is also provided with
n1 is an integer from 0 to 20.
In a further preferred embodiment of the present invention, L is as defined above 1 Selected from- (CH) 2 ) m1 -C(O)NR a1 (CH 2 ) 2 NR a2 -、-C(O)-(CH 2 ) m2 C(O)N R a1 (CH 2 ) 2 NR a2 -、 -(CH 2 ) m7 -C(O)NH-(CH 2 ) 2 -O-、-O-(CH 2 ) m8 C(O)NR a1 (CH 2 ) m9 NR a2 -、
The- (CH) 2 ) m1 -C(O)NR a1 (CH 2 ) 2 NR a2 -、-C(O)-(CH 2 ) m2 C(O)NR a1 (CH 2 ) 2 NR a2 -、 -(CH 2 ) m7 -C(O)NH-(CH 2 ) 2 -O-、-O-(CH 2 ) m8 C(O)NR a1 (CH 2 ) m9 NR a2 -、
Optionally further substituted with deuterium, halogen, hydroxy, amino, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 One or more substituents in the alkoxy group;
R a1 and R is a2 Each independently selected from hydrogen, deuterium, halogen or C 1-3 An alkyl group;
alternatively, R a1 And R is a2 And linked together with the carbon atom to which it is attached to form a 5-8 membered heterocyclic group, said 5-8 membered heterocyclic group optionally being further substituted with deuterium, halogen, C 1-3 One or more substituents in the alkyl group; preferably, R a1 And R is a2 Forming a piperazinyl group with the carbon atom to which it is attached; and is also provided with
m1 to m9 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.
In a further preferred embodiment of the present invention, the above compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of each of the compounds of formula (I) and stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers.
The invention also provides a preferable scheme, and relates to application of the compounds shown in the general formulas and stereoisomers or pharmaceutically acceptable salts thereof or the medicinal composition in preparing PARP related diseases.
The invention also provides a preferable scheme, and relates to application of the compounds in the general formulas and stereoisomers or pharmaceutically acceptable salts thereof or the pharmaceutical composition in preparation of medicines for treating or preventing tumor-related diseases.
The invention also relates to a method of treating or preventing a tumor-associated disease comprising administering to a mammal an effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, prodrug, solvate or hydrate thereof.
Detailed description of the invention
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 8 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms, and most preferably an alkyl group containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, with methyl, ethyl, isopropyl, t-butyl, haloalkyl, deuteroalkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl being preferred.
The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means-CH 2-, and "ethylene" means- (CH 2) 2-, "propylene" means- (CH 2) 3-, and "butylene" means- (CH 2) 4-, etc.
The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "alkenylene" means that one hydrogen atom of the alkenyl group is further substituted, for example: "vinylidene" means- (CH) 2-.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "cycloalkylene" refers to a cyclic alkyl group having one hydrogen atom further substituted.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, C (O), S (O) (=nh) or S (O) m (where m is an integer from 0 to 2), but excluding the ring portion of-O-, -O-S-, or-S-, the remaining ring atoms being carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; most preferably containing 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetane, thietane, azetidine, tetrahydropyranyl, azepanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetane, thietane, azetidine, tetrahydrofuranyl, tetrahydropyranyl, 1-aminosubunit-1-oxothiopyran, azepanyl, piperidinyl, and piperazinyl being preferred. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups; the heterocyclic groups of the spiro ring, the condensed ring and the bridged ring are optionally connected with other groups through single bonds, or are further connected with other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring in a parallel ring mode. The heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from hydrogen, alkyl, hydroxyalkyl, amino, imino, cyano, oxo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "heterocyclylene" refers to a heterocyclic group in which one hydrogen atom is further substituted, non-limiting examples of which include: piperidylene, piperazinylene, pyrrolopyrrolidene, diazaspiro [5.5 ]]Undecyl, azaspiro [5.5 ]]Undecyl, benzidine, azetidine, diazepine, pyrrolidinylene, azaspiro [3.5 ]]Nonylalkyl, diazaspiro [3.5]Nonylalkyl, diazabicyclo [3.1.1]Heptyl, azaspiro [2.5 ]]Octyl group,
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.
Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "arylene" refers to an aryl group having one hydrogen atom further substituted, non-limiting examples of which include:
the term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5-8 membered mono-heteroaryl or 8-14 membered di-heteroaryl, more preferably 5-membered mono-heteroaryl, 6-membered mono-heteroaryl or 9-membered di-heteroaryl, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyridoimidazolyl, pyrimidoimidazolyl, and the like, preferably pyridoimidazolyl, pyrimidoimidazolyl.
Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "heteroarylene" refers to a heteroaryl group in which one hydrogen atom is further substituted, non-limiting examples of which include:
a pyridylene group, a pyrimidinylene group, a pyrazolylene group, a pyridazinylene group, a pyrazinylene group,
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" refers to-NH 2.
"cyano" refers to-CN.
"nitro" means-NO 2.
"carboxy" means-C (O) OH.
"THF" refers to tetrahydrofuran.
"EtOAc" refers to ethyl acetate.
"MeOH" refers to methanol.
"DMF" refers to N, N-dimethylformamide.
"TFA" refers to trifluoroacetic acid.
"MeCN" refers to acetonitrile.
"DMA" refers to N, N-dimethylacetamide.
"Et2O" refers to diethyl ether.
"DCE" refers to 1,2 dichloroethane.
"DIPEA" refers to N, N-diisopropylethylamine.
"NBS" refers to N-bromosuccinimide.
"NIS" refers to N-iodosuccinimide.
"Cbz-Cl" refers to benzyl chloroformate.
"Pd2 (dba) 3" refers to tris (dibenzylideneacetone) dipalladium.
"Dppf" refers to 1,1' -bis-diphenylphosphino ferrocene.
"HATU" refers to 2- (7-oxo-benzotriazol) -N, N' -tetramethylurea hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"LiHMDS" refers to lithium bis (trimethylsilylamide).
"MeLi" refers to lithium-based.
"n-BuLi" refers to n-butyllithium.
"NaBH (OAc) 3" refers to sodium triacetoxyborohydride.
"NMP" refers to N-methylpyrrolidone.
"EDCI" refers to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
"TEA" refers to triethylamine.
"EA" refers to ethyl acetate.
"DCM" refers to dichloromethane.
"DMAP" refers to 4-dimethylaminopyridine.
"NMO" refers to N-methylmorpholine oxide.
"DIBAL-H" refers to diisobutylaluminum hydride.
"T3P" refers to 1-propylphosphoric anhydride.
"DMP" refers to dimethyl phthalate.
"Dess-Martin" refers to Dess-Martin oxidizer.
"Ruphos" refers to 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl.
"Ruphos Pd G3" refers to sulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II).
"LDA" refers to lithium diisopropylamide.
"SEMCl" refers to 2- (trimethylsilyl) ethoxymethyl chloride.
"wt%" refers to mass percent.
The terms "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C", etc. all express the same meaning, that is, X may be any one or several of A, B, C.
The hydrogen in the invention can be replaced by the isotope deuterium, and any hydrogen in the compound of the embodiment of the invention can be replaced by deuterium atoms.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
Detailed Description
The examples of the present invention are for understanding the present invention, and the scope of the present invention is not limited to the following examples. Unless otherwise specified, compounds, reagents, laboratory animals, and the like used in the examples of the present invention were purchased from commercial suppliers. Some of the compounds may be synthesized by the methods described in WO2016/165655A 1.
Example 1
N- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -15- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoylpiperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) pentamide (1)
Step 1:4- (6-amino-5-nitropyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (1 b)
To a solution of 6-chloro-3-nitropyridin-2-amine (5 g,28.8 mmol) in DMF (50 mL) was added DIPEA (4.8 mL,28.8 mmol) and piperazine-1-carboxylic acid tert-butyl ester (6.4 g,34.6 mmol) at room temperature. The mixture was reacted at 85℃for 2h. The reaction mixture was poured into ice water and stirred for 10 minutes. The suspension was filtered and the filter cake was dried in vacuo to give the title compound as a yellow solid (9 g, 96.6%).
1 H NMR(400MHz,CDCl 3 )δ8.20(d,J＝9.4Hz,1H),6.07(d,J＝9.5Hz,1H),3.77-3.67(m,4H),3.57-3.49(m,4H),1.48(s,9H).
LC/MS(ESI)m/z:324(M+H) + .
Step 2:4- (5, 6-diaminopyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (1 c)
Pd/C (300 mg,10 wt%) was added to a solution of compound 1b (9 g,27.83 mmol) in methanol under nitrogen at room temperature. The mixture was de-aerated three times under a hydrogen atmosphere and reacted at 40 ℃ for 2h under a hydrogen balloon. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give the title compound as a pale yellow solid (3.5 g, yield 42.9%).
1 H NMR(400MHz,CDCl 3 )δ6.88(d,J＝8.1Hz,1H),5.96(d,J＝8.1Hz,1H),3.58-3.47(m,5H),3.34-3.21(m,4H),1.47(s,9H).
LC/MS(ESI)m/z:294(M+H) + .
Step 3:4- (5-amino-6- (16- (tert-butoxy) -16-oxohexadecylamido) pyridin-2-yl) piperazine-1-carboxylic acid ester (1 d)
To a solution of compound 1c (1.2 g,4.09 mmol) and 16- (tert-butoxy) -16-oxohexadecanoic acid (1.4 g,4.09 mmol) in DCM (18 mL) under nitrogen at room temperature was added EDCI (0.94 g,4.91 mmol) and TEA (0.90 mL,6.14 mmol) and the mixture was reacted for 3h. After the reaction was completed, it was diluted with water and extracted three times with ethyl acetate, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product obtained was subjected to flash column chromatography (silica gel, etOAc: pe=0-60%) to give the title compound as a green solid (1.5 g, 59.4% yield).
1 H NMR(400MHz,CDCl 3 )δ7.18(d,J＝8.5Hz,1H),6.76(s,1H),6.03(d,J＝8.5Hz,1H),4.47-4.40(m,2H),3.55-3.41(m,8H),2.35(t,J＝7.5Hz,2H),2.20(t,J＝7.5Hz,2H),1.77-1.67(m,2H),1.62-1.57(m,2H),1.48(s,9H),1.44(s,9H),1.33-1.93(m,20H).
LC/MS(ESI)m/z:618(M+H) + .
Step 4:15- (5- (4- (tert-Butoxycarbonyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) pentadecanoic acid (1 e)
A30 wt% sodium methoxide solution (6 mL) was added to a mixed solution of compound 1d (730 mg,1.18 mmol) in methanol (3.5 mL) and t-butanol (7 mL) at room temperature, and the reaction was stirred at 90℃for 16h. The mixture was concentrated under reduced pressure and the crude product was acidified to a pH of about 5 with 1N dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Flash column chromatography of the crude product (silica gel, meOH: DCM)
=0-10%) to give the title compound as a grey solid (270 mg, 38.10% yield).
1 H NMR(400MHz,CDCl 3 )δ7.86(d,J＝8.8Hz,1H),6.61(d,J＝9.1Hz,1H),3.62-3.41(m,8H),2.89(d,J＝7.5Hz,2H),2.41-2.35(m,2H),1.86-1.76(m,2H),1.71-1.61(m,2H),1.49(s,9H),1.36-1.20(m,20H).
LC/MS(ESI)m/z:544(M+H) + .
Step 5:4- (2- (15- (2- (2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) amino) -15-oxopentadecadecyl) -3H-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carboxylic acid ester (1 g)
To a solution of compound 1e (240 mg,0.44 mmol) and compound 1f (140 mg,0.44 mmol) in DCM (3 mL) under nitrogen was added EDCI (254 mg,1.32 mmol) and TEA (0.10 mL,0.53 mmol). The reaction was carried out at room temperature for 3 hours. After the reaction was completed, it was diluted with water and extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Flash column chromatography of the crude product (silica gel, meOH: dcm=0-5%) afforded the title compound as a yellow solid (300 mg, 80.7% yield).
LC/MS(ESI)m/z:842(M+H) + .
Step 6: n- (2- (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) ethyl) -15- (5- (piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) glutaramide hydrochloride (1H)
Hydrogen chloride in methanol (5 mL, 2M) was slowly added to 1g (200 mg,0.24 mmol) of the compound and the reaction was stirred at room temperature for 2h. The mixture was concentrated under reduced pressure to give the title compound as a yellow oil (180 mg, yield 100%) which was used directly in the next reaction.
LC/MS(ESI)m/z:742(M+H) + .
Step 7: n- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -15- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoylpiperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) pentamide (1)
EDCI (93 mg,0.49 mmol) and TEA (0.20 mL,1.21 mmol) were added to a solution of compound 1k (synthesized as reported in WO2016/165655A 1) (120 mg,0.40 mmol) and compound 1h (300 mg,0.40 mmol) in DCM at room temperature under nitrogen. After 2h of reaction, the mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, meOH: dcm=0-20%) and further purified by preparative HPLC (C18, 50-60% acetonitrile in distilled water with 0.1% formic acid) to give the title compound as a yellow solid (25.8 mg, yield 6.24%).
1 H NMR(400MHz,CD 3 OD)δ8.37(d,J＝7.6Hz,1H),7.96(d,J＝7.7Hz,1H),7.91-7.79(m,2H),7.70(d,J＝8.8Hz,1H),7.56-7.46(m,2H),7.39(d,J＝6.3Hz,1H),7.17(t,J＝8.9Hz,1H),7.10(d,J＝8.6Hz,1H),7.03(d,J＝7.0Hz,1H),6.75(d,J＝8.9Hz,1H),5.07-5.00(m,1H),4.39(s,2H),3.92-3.81(m,2H),3.65-3.59(m,2H),3.48-3.37(m,8H),2.87-2.78(m,3H),2.76-2.66(m,2H),2.16(t,J＝7.4Hz,2H),2.11-2.04(m,1H),1.84-1.75(m,2H),1.59-1.52(m,2H),1.34-1.21(m,20H).
LC/MS(ESI)m/z:1022(M+H) + .
Example 2
N- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -14- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b]Pyridin-2-yl) tetradecanamide (2)
Step 1: 15-methoxy-15-oxododecanoic acid (2 b)
Barium hydroxide (1.7 g,9.99 mmol) was added to a solution of dimethyl 1, 15-dimethylpentadecanedioate (5 g,16.6 mmol) in methanol (100 mL) at room temperature and the reaction stirred at 55deg.C for 1h. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was acidified to pH of about 3 with 1N diluted hydrochloric acid, extracted three times with ethyl acetate, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-5%) to give the title compound as a yellow solid (1.1 g, yield 23.1%).
1 H NMR(400MHz,CDCl 3 )δ3.67(s,3H),2.33(m,4H),1.63(m,5H),1.27(m,18H).
LC/MS(ESI)m/z:285(M-H) - .
Step 2:4- (5-amino-6- (15-methoxy-15-oxopentadecylamido) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (2 c)
To a solution of tert-butyl 4- (5, 6-diaminopyridin-2-yl) piperazine-1-carboxylate (1.4 g,4.77 mmol) in DCM (14 mL) under nitrogen was added compound 2b (1.4 g,4.77 mmol), EDCI (1.1 g,5.73 mmol) and TEA (0.99 mL,7.16 mmol) and the mixture was stirred at room temperature for 2h. The reaction mixture was diluted with water and extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, meOH: dcm=0-10%) to give the title compound as a white solid (1.5 g, yield 55.9%).
Step 3:14- (5- (4-Acetylpiperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) tetradecanoic acid methyl ester (2 d)
Compound 2c (1.5 g,2.67 mmol) was dissolved in acetic acid (15 mL) and stirred overnight at 120deg.C. The mixture was then concentrated under reduced pressure. Flash column chromatography of the crude product (silica gel, meOH: dcm=0-10%) afforded the title compound as a white solid (680 mg, 52.4% yield).
1 H NMR(400MHz,CDCl 3 )δ7.81(d,J＝8.8Hz,1H),6.61(d,J＝8.8Hz,1H),3.83-3.77(m,2H),3.67(s,3H),3.65-3.61(m,2H),3.50-3.49(m,4H),2.87-2.83(m,2H),2.33-2.24(m,2H),2.10(s,3H),2.18-2.09(m,4H),1.30-1.20(m,18H).
LC/MS(ESI)m/z:486(M+H) + .
Step 4:14- (5-piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) tetradecanoic acid methyl ester (2 e)
Concentrated sulfuric acid (0.6 mL) was added to a solution of compound 2d (680 mg,1.40 mmol) in methanol (6 mL). Stir at 80 ℃ overnight. The mixture was concentrated under reduced pressure. The residue was basified with saturated sodium bicarbonate solution to a pH of about 8 at 0 ℃, and the mixture was concentrated under reduced pressure. The residue was triturated with DCM and filtered. The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound as a yellow solid (370 mg, yield 59.6%).
1 H NMR(400MHz,CDCl 3 )δ7.76(s,1H),6.60(d,J＝8.8Hz,1H),3.67(d,J＝1.9Hz,5H),3.54-3.46(m,4H),3.05-2.99(m,4H),2.89-2.79(m,2H),2.33-2.24(m,2H),1.64-1.58(m,2H),1.44-1.28(m,18H).
LC/MS(ESI)m/z:444(M+H) + .
Step 5:14- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) tetradecanoic acid methyl ester (2 f)
To a mixture of compound 2e (350 mg,0.79 mmol) and compound 1k (235 mg,0.79 mmol) in DMF (4 mL) was added HATU (360 mg,0.95 mmol) and TEA (0.14 mL,0.95 mmol) under a nitrogen atmosphere at room temperature. The reaction was stirred at room temperature for 2h, the mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by flash column chromatography (silica gel, meOH: dcm=0-5%) to give the title compound as a yellow solid (540 mg, 94.6% yield).
LC/MS(ESI)m/z:724(M+H) + .
Step 6:14- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) tetradecanoic acid (2 g)
To a solution of compound 2f (200 mg,0.28 mmol) in THF (2 mL) and distilled water (1 mL) was added lithium hydroxide monohydrate (115.9 mg,2.76 mmol) at 0 ℃. The mixture was stirred at 30 ℃ for 1h, concentrated to dryness under reduced pressure, the residue diluted with water and acidified with 1N diluted hydrochloric acid to pH about 3. The mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound (130 mg, yield 66.3%).
1 H NMR(400MHz,DMSO-d 6 )δ8.28(d,J＝6.8Hz,1H),7.99(d,J＝7.8Hz,1H),7.88(d,J＝8.4Hz,3H),7.50-7.44(m,1H),7.42-7.37(m,1H),7.27(t,J＝9.0Hz,1H),6.97(d,J＝9.1Hz,1H),4.39-4.29(m,2H),4.09-3.97(m,1H),3.80-3.61(d,J＝45.5Hz,4H),3.50-3.45(m,3H),2.93(t,J＝7.5Hz,2H),2.18(t,J＝7.3Hz,2H),1.83-1.71(m,2H),1.55-1.43(m,2H),1.32-1.12(m,18H).
LC/MS(ESI)m/z:710(M+H) + .
Step 7: n- (2- (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -14- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) tetradecanamide (2)
To a solution of 2g (120 mg,0.17 mmol) of the compound and 4- ((2-aminoethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione hydrochloride (60 mg,0.17 mmol) in DMF was added HATU (64 mg,0.17 mmol) and DIPEA (0.08 mL,0.51 mmol) under nitrogen at room temperature. The mixture was stirred at room temperature for 1h, diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. Purification by preparative HPLC (C18, 50-60% acetonitrile in distilled water with 0.1% formic acid) afforded the title compound as a white solid (15.7 mg, 9.24% yield).
1 H NMR(400MHz,CD 3 OD)δ8.36(d,J＝7.6Hz,1H),7.95(d,J＝7.9Hz,1H),7.90-7.79(m,2H),7.70(d,J＝8.8Hz,1H),7.53-7.48(m,2H),7.38(d,J＝4.3Hz,1H),7.16(t,J＝8.9Hz,1H),7.09(d,J＝8.6Hz,1H),7.02(d,J＝7.1Hz,1H),6.75(d,J＝8.8Hz,1H),5.03(d,J＝12.5,5.4Hz,1H),4.38(s,2H),3.87(s,2H),3.63(s,2H),3.42(m,8H),2.91-2.77(m,3H),2.76-2.64(m,2H),2.15(t,J＝7.5Hz,2H),2.11-2.03(m,1H),1.84-1.76(m,2H),1.59-1.52(m,2H),1.33-1.21(m,19H).
LC/MS(ESI)m/z:1008(M+H) + .
Example 3
N- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -13- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoylpiperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) tridecanamide (3)
The title compound (32 mg) was obtained as a yellow solid by substituting 1, 14-tetradecanedioic acid dimethyl ester for compound 2a, referring to the synthetic method for compound 2.
1 H NMR(400MHz,CD 3 OD)δ8.37(d,J＝7.5Hz,1H),7.96(d,J＝7.7Hz,1H),7.91-7.80(m,2H),7.70(d,J＝8.8Hz,1H),7.55-7.46(m,2H),7.39(d,J＝6.2Hz,1H),7.17(t,J＝8.9Hz,1H),7.10(d,J＝8.5Hz,1H),7.02(d,J＝7.1Hz,1H),6.76(d,J＝8.9Hz,1H),5.06-4.99(m,1H),4.39(s,2H),3.88(s,2H),3.64(s,2H),3.46-3.41(m,8H),2.88-2.79(m,3H),2.75-2.65(m,2H),2.16(t,J＝7.5Hz,2H),2.12-2.04(m,1H),1.83-1.75(m,2H),1.60-1.52(m,2H),1.40-1.18(m,18H).
LC/MS(ESI)m/z:994(M+H) + .
Example 4
N- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -12- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoylpiperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) dodecanamide (4)
The title compound (5.6 mg) was obtained as a yellow solid by substituting 1, 13-tridecanedioic acid dimethyl ester for compound 2a, referring to the synthetic method of compound 2.
1 H NMR(400MHz,CD 3 OD)δ8.37(d,J＝7.6Hz,1H),7.96(d,J＝8.2Hz,1H),7.90-7.80(m,2H),7.76(d,J＝9.0Hz,1H),7.55-7.45(m,2H),7.38(d,J＝4.4Hz,1H),7.17(t,J＝8.9Hz,1H),7.10(d,J＝8.6Hz,1H),7.02(d,J＝7.1Hz,1H),6.84(d,J＝9.1Hz,1H),5.02(dd,J＝12.5,5.5Hz,1H),4.39(s,2H),3.87(s,2H),3.67(s,2H),3.52-3.38(m,8H),2.92-2.89(m,2H),2.83-2.62(m,3H),2.15(t,J＝7.4Hz,2H),2.08-2.03(m,1H),1.86-1.76(m,2H),1.62-1.54(m,2H),1.34-1.23(m,14H).
LC/MS(ESI)m/z:980(M+H) + .
Example 5
N- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -2- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) acetamide (5)
The title compound (12.5 mg) was obtained as a yellow solid by substituting 1, 12-dodecanedioic acid dimethyl ester for compound 2a, referring to the synthetic method of compound 2.
1 H NMR(400MHz,CD 3 OD)δ8.36(d,J＝7.4Hz,1H),7.96(d,J＝8.4Hz,1H),7.90-7.81(m,2H),7.69(d,J＝9.1Hz,1H),7.55-7.46(m,2H),7.38(d,J＝6.2Hz,1H),7.17(t,J＝9.0Hz,1H),7.09(d,J＝8.7Hz,1H),7.02(d,J＝7.2Hz,1H),6.74(d,J＝8.9Hz,1H),5.03(dd,J＝12.5,5.3Hz,1H),4.39(s,2H),3.91-3.82(m,2H),3.65-3.61(m,2H),3.44-3.40(m,8H),2.84-2.81(m,3H),2.75-2.66(m,2H),2.20-2.12(m,2H),2.08-2.03(m,1H),1.80-1.77(m,2H),1.59-1.51(m,2H),1.31-1.24(m,12H).
LC/MS(ESI)m/z:966(M+H) + .
Example 6
N- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -10- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methylbenzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) decanoamide (6)
The title compound (5 mg) was obtained as a yellow solid by substituting 1, 11-undecanedioic acid dimethyl ester for compound 2a, referring to the preparation of compound 2.
1 H NMR(400MHz,CD 3 OD)δ8.37(dd,J＝7.7,0.9Hz,1H),7.96(d,J＝7.5Hz,1H),7.90-7.82(m,3H),7.55-7.48(m,2H),7.38(dd,J＝6.2,1.8Hz,1H),7.18(t,J＝8.9Hz,1H),7.10(d,J＝8.5Hz,1H),7.01(t,J＝7.1Hz,2H),5.03-4.98(m,1H),4.39(s,2H),3.90-3.85(m,2H),3.79-3.73(m,2H),3.59-3.54(m,2H),3.46-3.41(m,6H),3.05(t,J＝7.4Hz,2H),2.88-2.78(m,1H),2.73-2.66(m,2H),2.15(t,J＝7.3Hz,2H),2.09-2.00(m,1H),1.86-1.80(m,2H),1.57-1.51(m,2H),1.33-1.24(m,10H).
LC/MS(ESI)m/z:952(M+H) + .
Example 7
N- (2- (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -9- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) nonanamide (7)
The title compound (30 mg) was obtained as a yellow solid by substituting 1, 10-dodecanedioic acid dimethyl ester for compound 2a, referring to the preparation of compound 2.
1 H NMR(400MHz,CD 3 OD)δ8.36(d,J＝7.4Hz,1H),7.95(d,J＝7.5Hz,1H),7.90-7.80(m,2H),7.69(d,J＝8.8Hz,1H),7.54-7.44(m,2H),7.38(d,J＝6.3Hz,1H),7.16(t,J＝8.9Hz,1H),7.08(d,J＝8.5Hz,1H),7.02(d,J＝7.0Hz,1H),6.74(d,J＝8.9Hz,1H),5.06-4.98(m,1H),4.39(s,2H),3.87(s,2H),3.62(s,2H),3.45-3.37(m,8H),2.85-2.78(m,3H),2.73-2.60(m,2H),2.14(t,J＝7.4Hz,2H),2.09-2.02(m,1H),1.77(t,J＝9.5Hz,2H),1.58-1.52(m,2H),1.30-1.27(m,9H).
LC/MS(ESI)m/z:938(M+H) + .
Example 8
N- (2- (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) ethyl) -12- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) dodecanamide (8)
The steps are as follows: n- (2- (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) ethyl) -12- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) dodecanamide (8)
To a solution of 12- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) dodecanoic acid 8b (synthesized with reference to compound 2 g) (120 mg,0.18 mmol) and 4- (2-aminoethoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione hydrochloride (8 a) (84 mg,0.26 mmol) in DMF (1.2 mL) under a nitrogen atmosphere was added HATU (100 mg,0.26 mmol) and DIPEA (0.09 mL,0.53 mmol), stirred for 2H, the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, meOH: dcm=0-60%) and further purified by preparative HPLC (C18, 50-60% acetonitrile in distilled water and 0.1% formic acid) to give the title compound 8 as a white solid (15 mg, yield 8.72%).
1 H NMR(400MHz,CD 3 OD)δ8.39(d,J＝7.6Hz,1H),7.97(d,J＝7.5Hz,1H),7.93-7.89(m,2H),7.92-7.81(m,1H),7.80-7.75(m,1H),7.55-7.50(m,1H),7.49-7.44(m,2H),7.39(d,J＝4.3Hz,1H),7.20(t,J＝9.0Hz,1H),7.08(d,J＝9.2Hz,1H),5.12-5.08(m,1H),4.41(s,2H),4.29(t,J＝5.2Hz,2H),3.89(s,2H),3.80(d,J＝5.3Hz,2H),3.65-3.60(m,4H),3.44(d,J＝5.1Hz,2H),3.10(t,J＝7.6Hz,2H),2.79-2.67(m,2H),2.21(t,J＝7.3Hz,2H),1.93-1.83(m,2H),1.62-1.55(m,2H),1.45-1.18(m,16H).
LC/MS(ESI)m/z:981(M+H) + .
Example 9
2- (2, 6-Dioxopiperidin-3-yl) -4- (4- (12- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) dodecylpiperazin-1-yl) isoindoline-1, 3-dione (9)
Step 1:2- (2, 6-Dioxopiperidin-3-yl) -4- (4- (12- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) dodecylpiperazin-1-yl) isoindoline-1, 3-dione (9)
DIPEA (0.10 mL,0.66 mmol) and HATU (84 mg,0.22 mmol) were added to a solution of compound 8b (150 mg,0.22 mmol) and 2- (2, 6-dioxopiperidin-3-yl) -4- (piperazin-1-yl) -2, 3-dihydro-1H-isoindole-1, 3-dione 9a (75 mg,0.22 mmol) in DCM under a nitrogen atmosphere at room temperature and the mixture stirred for 3H. Dilute with water and extract three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-5%) and further purified by preparative HPLC (C18, 50-60% acetonitrile in distilled water with 0.1% formic acid) to give the title compound as a yellow solid (11 mg, yield 4.97%).
1 H NMR(400MHz,CD 3 OD)δ8.39-8.33(m,1H),7.96(d,J＝7.3Hz,1H),7.90-7.80(m,2H),7.74-7.62(m,2H),7.52-7.46(m,1H),7.41-7.36(m,2H),7.30(d,J＝8.3Hz,1H),7.17(t,J＝8.9Hz,1H),6.77(d,J＝8.9Hz,1H),5.15-5.05(m,1H),4.39(s,2H),3.92-3.83(m,2H),3.80-3.71(m,4H),3.68-3.60(m,2H),3.50-3.37(m,4H),3.36-3.33(m,2H),3.29-3.26(m,2H),2.88-2.81(m,3H),2.79-2.68(m,2H),2.43(t,J＝7.6Hz,2H),2.15-2.07(m,1H),1.85-1.75(m,2H),1.64-1.58(m,2H),1.36-1.28(m,14H).
LC/MS(ESI)(m/z):1006(M+H) + .
Example 10
N- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-4-amino) ethyl) -2- (5- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) hexyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) acetamide (10)
Step 1:5- (2-benzyloxy) -2-oxoethyl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (10 b)
To a mixture of tert-butyl octahydropyrrolo [3,4-c ] pyrrole-2-carboxylate 10a (3 g,14.1 mmol) and benzyl 2-bromoacetate (2.25 mL,14.1 mmol) was added potassium carbonate (5.86 g,42.4 mmol), stirred at 50℃for 3h, quenched with water, and extracted three times with ethyl acetate. The combined organic layers were washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, etOAc: pe=0-25%) to give the title compound (2 g, 39.3% yield) as a colourless oil.
1 H NMR(400MHz,CDCl 3 )δ7.39-7.30(m,5H),5.15(s,2H),3.59-3.44(m,2H),3.35(s,2H),3.32-3.18(m,2H),2.97-2.89(m,2H),2.87-2.78(m,2H),2.51-2.39(m,2H),1.44(s,9H).
LC/MS(ESI)(m/z):361(M+H) + .
Step 2: benzyl 2- (hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) acetate hydrochloride (10 c)
A solution of hydrogen chloride in methanol (20 mL, 4M) was added to compound 10b (2 g,5.55 mmol) and stirred at room temperature for 3h. The mixture was concentrated to dryness under reduced pressure to give the title compound as a yellow oily substance (2 g, crude yield 138.5%) which was used directly in the next step.
1 H NMR(400MHz,CD 3 OD)δ7.45-7.33(m,5H),5.30(s,2H),4.38(s,2H),3.65-3.38(m,9H),3.35(s,1H).
LC/MS(ESI)(m/z):261(M+H) + .
Step 3:4- (2- (hept-6-en-1-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carboxylic acid tert-butyl ester (10 e)
A mixture of tert-butyl 4- (5, 6-diaminopyridin-2-yl) piperazine-1-carboxylate (8.5 g,29.1 mmol), octa-7-enal 10d (5.5 g,43.6 mmol) and elemental iodine (0.74 g,2.91 mmol) was stirred at room temperature for 1h. The mixture was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-3%) to give the title compound as a black oil (3.5 g, yield 30.2%).
1 H NMR(400MHz,CDCl 3 )δ7.77(d,J＝8.5Hz,1H),6.60(d,J＝8.8Hz,1H),5.83-5.72(m,1H),5.01-4.89(m,3H),3.61-3.40(m,8H),2.86(t,J＝8Hz,2H),2.06-2.01(m,2H),1.87-1.80(m,2H),1.51(s,9H),1.44-1.39(m,4H).
LC/MS(ESI)(m/z):400(M+H) + .
Step 4:5- (4-Boc) piperazin-1-yl) -2- (hept-6-en-1-yl) -3H-imidazo [4,5-b ] pyridine-3-carboxylic acid tert-butyl ester (10 f)
Compound 10e (2 g,5.01 mmol), (Boc) 2 A mixture of O (1.31 g,6.01 mmol) and DMAP (0.06 g,0.50 mmol) in DCM (20 mL) was stirred at 30deg.C for 1h. The mixture was concentrated to dryness under reduced pressure. Flash column chromatography (silica gel, etOAc: pe=0-35%) purification of the residue afforded the title compound The title compound was a yellow oil (2 g, 80.0% yield).
1 H NMR(400MHz,CDCl 3 )δ7.94(d,J＝8.9Hz,1H),6.62(t,J＝8.7Hz,1H),5.80-5.73(m,1H),4.95-4.88(m,2H),3.59-3.52(m,8H),3.19-3.05(m,2H),2.07-2.04(m,2H),1.95-1.87(m,2H),1.68(s,9H),1.48(s,9H),1.46-1.42(m,4H).
LC/MS(ESI)(m/z):500(M+H) + .
Step 5:5- (4-Boc) piperazin-1-yl) -2- (6-oxohexyl) -3H-imidazo [4,5-b ] pyridine-3-carboxylic acid tert-butyl ester (10 g)
To a mixture of compound 10f (2 g,4.0 mmol) and 4-methylmorpholine N-oxide (0.70 g,6.0 mmol) in THF (20 mL), tert-butanol (20 mL) and distilled water (10 mL) was added OsO 4 (0.1 g,0.40 mmol) and the mixture was stirred at 30℃for 30 minutes, then NaIO was added 4 (4.28 g,20.01 mmol) and the mixture was stirred at 30℃for a further 1h. The mixture was diluted with DCM, washed with saturated sodium thiosulfate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound as a brown oil (1.8 g, yield 90.0%).
LC/MS(ESI)(m/z):502(M+H) + .
Step 6:2- (6- (5- (2- (benzyloxy) -2-oxoethyl) hexahydropyrrolo [3,4-c ] pyrrolidin-2 (1H) -yl) hexyl) -5- (4- (tert-butoxycarbonyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridine-3-carboxylic acid ester (10H)
To a mixture of 10g (900 mg,1.79 mmol) of the compound and 2- { octahydropyrrolo [3,4-c ] pyrrol-2-yl } acetate (560 mg,2.15 mmol) was added acetic acid (0.1 mL,0.18 mmol) at room temperature, and after stirring for 20 minutes, sodium cyanoborohydride (112 mg,1.79 mmol) was added. After stirring at 30 ℃ for 2h, the mixture was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-5%) to give the title compound as a yellow oil (440 mg, yield 32.9%).
LC/MS(ESI)(m/z):746(M+H) + .
Step 7: benzyl 2- (5- (6- (5-piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) hexyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) yl) acetate (10 i)
TFA (2 mL) was added to a solution of compound 10h (430 mg,0.58 mmol) in DCM at 0deg.C, and the mixture was stirred at 20deg.C for 2h and concentrated to dryness under reduced pressure to give the title compound as a brown oil (350 mg, 100% yield) which was used directly in the next step.
LC/MS(ESI)(m/z):546(M+H) + .
Step 8: benzyl 2- (5- (6- (5- (4-) (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) hexyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) acetate (10 j)
To a solution of compound 10i (170 mg,0.31 mmol), 2-fluoro-5- [ (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl ] benzoic acid (93 mg,0.31 mmol) and DIPEA (120 mg,0.94 mmol) in DMF (2 mL) was added HATU (177 mg,0.47 mmol) under a nitrogen atmosphere at room temperature. Stir at room temperature for 2h. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-5%) to give the title compound as a yellow oil (200 mg, yield 77.7%).
LC/MS(ESI)m/z:826(M+H) + .
Step 9: n- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-amino) ethyl) -2- (5- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) hexyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) acetamide (10 k)
Lithium hydroxide monohydrate (7.6 mg,0.18 mmol) was added to a mixed solution of compound 10j (50 mg,0.06 mmol) in methanol (1 mL), THF (1 mL) and water (0.5 mL) at room temperature, and stirred at room temperature for 1h. The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in water and acidified to pH of about 3 with 1N diluted hydrochloric acid and the mixture concentrated to dryness under reduced pressure to give the title compound as a yellow solid (70 mg) which was used directly in the next step without further purification.
LC/MS(ESI)m/z:736(M+H) + .
Step 10: n- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-4-amino) ethyl) -2- (5- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) hexyl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) acetamide (10)
To compound 10k (150 mg,0.20 mmol) and 4- [ (2-aminoethyl) amino at room temperature ]To a mixture of (E) -2- (2, 6-dioxopiperidin-3-yl) -2, 3-dihydropyrrole-1H-isoindole-1, 3-dione (77 mg,0.25 mL) was added DIPEA (0.1 mL,0.60 mmol) and T 3 P (98 mg,0.31mmol,50wt% DMF solution) was stirred at 30℃for 1h. The mixture was concentrated to dryness under reduced pressure, and the residue was further purified by flash column chromatography (silica gel, meOH: dcm=0 to 60%) and preparative HPLC (C18, 50-60% acetonitrile in distilled water with 0.1% formic acid) to give a yellow solid (3.94 mg, yield 1.87%).
1 H NMR(400MHz,CD 3 OD)δ8.36(d,J＝8.4Hz,1H),7.96(d,J＝8.0Hz,1H),7.91-7.75(m,3H),7.57-7.46(m,2H),7.41-7.35(m,1H),7.17(t,J＝8.9Hz,1H),7.11(d,J＝7.3Hz,1H),7.04(d,J＝6.7Hz,1H),6.86(s,1H),5.07-4.96(m,1H),4.39(s,2H),3.87(s,2H),3.68(s,2H),3.56-3.49(m,4H),3.41(s,2H),3.11-2.96(m,5H),2.86-2.78(m,1H),2.76-2.65(m,2H),2.14-2.04(m,2H),1.94-1.83(m,2H),1.75-1.65(m,6H),1.49-1.41(m,2H),1.36-1.26(m,2H),1.05-0.92(m,8H).
LC/MS(ESI)(m/z):1034(M+H) + .
Example 11
N- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-4-amino) ethyl) -2- (4- (7- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydrobenzozin-1-yl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) heptyl) piperazin-1-yl) acetamide (11)
Step 1:5- (4- (tert-Butoxycarbonyl) piperazin-1-yl) -2- (octadecyl-7-en-1-yl) -3H-imidazo [4,5-b ] pyridine-3-carboxylic acid tert-butyl ester (11 b)
Will (Boc) 2 A solution of O (260 mg,1.20 mmol) in DCM (2 mL) was added to compound 11a (prepared as described for compound 10 e) (400 mg,0.97 mmol) and DMAP (25 mg,0.19 mmol) in DCM (10 mL) and stirred at room temperature for 3h. The mixture was diluted with DCM (30 mL), washed with 1N hydrochloric acid solution and brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, etOAc: pe=0-50%) to give the title compound as a yellow solid (400 mg, yield 80.5%).
LC/MS(ESI)m/z:514(M+H) + .
Step 2:5- (4-Boc) piperazin-1-yl) -2- (7-oxoheptyl) -3H-imidazo [4,5-b ] pyridine-3-carboxylic acid tert-butyl ester (11 c)
4-methylmorpholine 4-oxide (110 mg,0.94 mmol) was added to a mixture of compound 11b (400 mg,0.78 mmol) in THF (10 mL), t-butanol (5 mL) and water (5 mL) at room temperature, followed by OsO 4 (10 mg,0.05 mmol). Stirring at room temperature for 2h, then adding NaIO 4 (840 mg,3.91 mmol) and stirred at room temperature for a further 2h. The mixture was diluted with ethyl acetate, the organic phase was washed with saturated sodium thiosulfate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, etOAc: pe=0-25%) to give the title compound as a colorless oil (320 mg, yield 79.7%).
LC/MS(ESI)m/z:516(M+H) +
Step 3:5- (4-Boc) piperazin-1-yl) -2- (7- (4- (2-ethoxy-2-oxoethyl) piperazin-1-yl) heptyl) -3H-imidazo [4,5-b ] pyridine-3-carboxylate (11 d)
To a solution of compound 11c (300 mg,0.58 mmol) and ethyl 2- (piperazin-1-yl) acetate (120 mg,0.70 mmol) in methanol (10 mL) at 0deg.C was added sodium cyanoborohydride (60 mg,0.95 mmol) and acetic acid (60 mg,1.00 mmol), and the mixture was stirred at room temperature for 2h. The reaction was quenched with ice water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-10%) to give the title compound as a colorless oil (260 mg, yield 66.3%).
1 H NMR(400MHz,CDCl 3 )δ7.86(m,1H),6.64(t,J＝8.0Hz,1H),4.20(q,J＝7.1Hz,2H),3.64-3.49(m,9H),3.23-3.07(m,4H),3.01-2.89(m,4H),2.85(d,J＝8.9Hz,2H),1.93-1.85(m,2H),1.83-1.72(m,4H),1.70(s,9H),1.49(d,J＝1.8Hz,9H),1.45-1.34(m,7H),1.29(t,J＝7.1Hz,3H).
LC/MS(ESI)m/z:672(M+H) + .
Step 4: ethyl 2- (4- (7- (5-piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) heptyl) piperazin-1-yl) acetate trifluoroacetate (11 e)
TFA (0.5 mL) was added to a solution of compound 11d (260 mg,0.39 mmol) in DCM (1 mL) at 0deg.C under nitrogen and stirred at room temperature for 3h. The mixture was concentrated to dryness to give the title compound as a colorless oil (240 mg, yield 100%) which was used directly in the next reaction.
LC/MS(ESI)m/z:472(M+H) + .
Step 5: ethyl 2- (4- (7- (5- (4-fluoro-5-) (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoylpiperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) heptylpiperazin-1-yl) acetate (11 f)
DIPEA (140 mg,0.45 mmol) and HATU (150 mg,0.41 mmol) were added to a solution of compound 11e (240 mg,0.39 mmol) and 2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoic acid (140 mg,0.45 mmol) in DCM under nitrogen at room temperature and stirred for 3h at room temperature. The mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-10%) to give the title compound as a yellow solid (230 mg, yield 80.2%).
1 H NMR(400MHz,CDCl 3 )δ11.65(s,1H),8.54(d,J＝7.8Hz,1H),7.85(dt,J＝10.9,3.9Hz,4H),7.58-7.51(m,1H),7.33-7.29(m,1H),7.07(t,J＝8.7Hz,1H),6.74(d,J＝8.8Hz,1H),4.30(s,2H),4.18(q,J＝7.1Hz,2H),3.56-3.44(m,3H),3.38-3.33(m,2H),3.20(s,2H),2.92(t,J＝7.7Hz,2H),2.71-2.44(m,8H),2.39-2.31(m,2H),1.95-1.85(m,2H),1.54-1.36(m,8H),1.31(d,J＝7.3Hz,2H),1.26(dd,J＝9.2,5.1Hz,4H).
LC/MS(ESI)m/z:752(M+H) + .
Step 6:2- (4- (7- (5- (4-fluoro-2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) heptylpiperazin-1-yl) acetic acid (11 g)
Lithium hydroxide monohydrate (42 mg,1.0 mmol) was added to a solution of compound 11f (230 mg,0.29 mmol) in ethanol (5 mL) and water (2 mL) and stirred at room temperature for 2h. The mixture was concentrated to dryness. The residue was diluted with water and washed twice with ethyl acetate. The aqueous layer was acidified to pH about 7 with 1N dilute hydrochloric acid and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound as a white solid (130 mg, yield 58.7%).
LC/MS(ESI)m/z:724(M+1) + .
Step 7: ethyl 2- (4- (7- (5- (4-fluoro-5-) (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoylpiperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) heptylpiperazin-1-yl) acetate (11)
To a mixture of 11g (130 mg,0.18 mmol) of the compound, 4- (2-aminoethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (65 mg,0.18 mmol) and DIPEA (140 mg,0.45 mol) was added HATU (76 mg,0.19 mmol) and stirred at room temperature for 2h. The mixture was poured into ice water, and the precipitate was filtered. The filter cake was purified by preparative HPLC (C18, 10-80% acetonitrile in distilled water with 0.1% formic acid) to give the title compound as a white solid (7.9 mg, yield 4.6%).
1 H NMR(400MHz,DMSO)δ12.59(s,1H),12.29(s,1H),11.10(s,1H),8.26(d,J＝7.9Hz,1H),8.15(s,1H),8.01-7.97(m,1H),7.93-7.82(m,3H),7.72-7.65(m,1H),7.64-7.54(m,1H),7.47-7.38(m,2H),7.29-7.15(m,2H),7.03(d,J＝7.4Hz,1H),6.69(d,J＝8.3Hz,2H),6.53(s,1H),5.17-4.95(m,1H),4.34(s,2H),3.79-3.72(m,2H),3.64-3.50(m,4H),2.91-2.83(m,3H),2.81-2.64(m,4H),2.41-2.31(m,8H),2.28-2.17(m,3H),2.06-1.96(m,1H),1.81-1.64(m,3H),1.42-1.19(m,10H).
LC/MS(ESI)m/z:1022(M+H) + .
Example 12
2- (2, 6-Dioxopiperidin-3-yl) -4- (2- (2- (2- (4- (4- (4- (3-) 5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) propyl) piperidine-4-carbonyl) piperazin-1-yl) ethyl) amino) isoindoline-1, 3-dione (12)
Step 1:4- (1- (benzyloxy) carbonyl) piperidine-4-carbonyl) piperazine-1-carboxylic acid tert-butyl ester (12 b)
To a mixture of 1- (benzyloxy) carbonyl) piperidine-4-carboxylic acid (3 g,13.1 mmol) and tert-butylpiperazine-1-carboxylic acid ester (2.9 g,13.1 mmol) in DCM (30 mL) at 0deg.C was added EDCI (3 g,15.7 mmol) and TEA (2.7 mL,19.6 mmol) and stirred at room temperature for 2h. The reaction was quenched with water and extracted twice with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-5%) to give the title compound as a colorless solid (2.1 g, yield 37.5%).
1 H NMR(400MHz,CDCl 3 )δ7.40-7.30(m,5H),5.15(s,2H),4.22-4.08(m,2H),3.65-3.44(m,8H),2.79-2.72(m,2H),2.62-2.57(m,1H),1.79-1.62(m,4H),1.45(s,9H).
LC/MS(ESI)m/z:432(M+H) + .
Step 2:4- (piperidine-4-carbonyl) piperazine-1-carboxylic acid benzyl ester hydrochloride (12 c)
A solution of hydrogen chloride in methanol (20 mL, 4M) was added to 12b (2.1 g,4.87 mmol). Stirred at room temperature for 2h, the mixture was concentrated to dryness under reduced pressure to give the title compound as a white solid (1.9 g, yield 100%), which was used directly in the next step without further purification.
1 H NMR(400MHz,DMSO-d 6 )δ9.06-8.93(m,1H),8.69-8.55(m,1H),7.42-7.29(m,5H),5.10(s,2H),3.58-3.31(m,8H),3.27-3.23(m,1H),3.13-2.81(m,4H),1.81-1.66(m,4H).
LC/MS(ESI)m/z:332(M+H) + .
Step 3:2- (2, 6-Dioxopiperidin-3-yl) -4- (2-hydroxyethoxyethyl) amino) isoindoline-1, 3-dione (12 d)
To a solution of 2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione (2 g,7.2 mmol) in DMSO (20 mL) of 2- (2-aminoethoxy) ethane-1-ol (760 mg,7.2 mmol) was added DIPEA (3.6 mL,21.6 mmol) under nitrogen at room temperature and the mixture was stirred overnight at 70 ℃. The mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-5%) to give the title compound as a green oil (1.9 g, 73.1% yield).
1 H NMR(400MHz,CDCl 3 )δ7.46(dd,J＝8.2,7.4Hz,1H),7.07(d,J＝7.0Hz,1H),6.89(d,J＝8.5Hz,1H),4.91-4.85(m,1H),3.72(dd,J＝9.3,4.1Hz,4H),3.59(dd,J＝5.7,3.3Hz,2H),3.45(q,J＝5.4Hz,2H),2.87-2.65(m,3H),2.07(dd,J＝9.7,4.5Hz,2H).
LC/MS(ESI)m/z:362(M+H) + .
Step 4:2- (2, 6-Dioxopiperidin-3-yl) -1, 3-Dioxoisoindolin-4-yl) amino) ethoxy) ethylmethanesulfonate (12 e)
To a solution of 12d (500 mg,1.38 mmol) in DCM (5 mL) under nitrogen at room temperature was added TEA (0.6 mL,4.14 mmol) and methanesulfonyl chloride (238 mg,2.07 mmol) and the mixture was stirred at room temperature for 1h. The mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness by filtration to give the title compound as a yellow oil (324 mg, yield 53.2%).
1 H NMR(400MHz,CDCl 3 )δ7.51(dd,J＝9.9,5.7Hz,1H),7.12(d,J＝7.1Hz,1H),6.93(d,J＝8.5Hz,1H),6.49(t,J＝5.4Hz,1H),4.95-4.86(m,1H),4.40-4.34(m,2H),3.80-3.73(m,4H),3.49(dt,J＝7.0,3.5Hz,2H),3.04(s,3H),2.92-2.66(m,4H).
LC/MS(ESI)m/z:441(M+H) + .
Step 5: 4-pentenal (12 g)
To a solution of pent-4-en-1-ol (5 g,58.1 mmol) in DCM (50 mL) under nitrogen at room temperature was added pyridinium chlorochromate (18.8 g,87.1 mmol). After stirring the reaction for 2h, the filter cake was filtered and washed twice with DCM, the filtrate was washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness by filtration to give the title compound as a yellow oil (1.4 g, 28.7% yield) for the next reaction without further purification.
Step 6:4- (2-but-3-en-1-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carboxylic acid tert-butyl ester (12H)
To a mixture of tert-butyl 4- (5, 6-diaminopyridin-2-yl) piperazine-1-carboxylate (2.5 g,8.52 mmol) and 12g (1.4 g,16.6 mmol) acetic acid (25 mL) at room temperature was added elemental iodine (0.42 g,1.65 mmol), the reaction was stirred for 1h and then concentrated to dryness under reduced pressure, the residue was diluted with ethyl acetate, the mixture was washed with saturated sodium thiosulfate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-5%) to give the title compound as a yellow oil (700 mg, yield 23.0%).
LC/MS(ESI)(m/z):358(M+H) + .
Step 7:2- (but-3-en-1-yl) -5- (4-t-butoxycarbonyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridine-3-carboxylic acid tert-butyl ester (12 i)
Will (Boc) 2 O (513 mg,2.35 mmol) and DMAP (24 mg,0.20 mmol) were added to a mixture of 12h (700 mg,1.96 mmol) and DCM (7 mL) and stirred at 30deg.C for 1h. The mixture was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, etOAc: pe=0-35%) to give the title compound as a yellow oil (730 mg, yield 81.5%).
LC/MS(ESI)(m/z):458(M+H) + .
Step 8:5- (4-Boc) piperazin-1-yl) -2- (3-oxopropyl) -3H-imidazo [4,5-b ] pyridine-3-carboxylic acid tert-butyl ester (12 j)
To a mixed solution of 12i (600 mg,1.31 mmol) and N-methylmorpholine oxide (184 mg,1.57 mmol) in THF (3 mL), t-butanol (3 mL) and distilled water (1.5 mL) was added OsO 4 (3 mg,0.01 mmol) and at 30Stirred at C for 0.5h. Then NaIO is added 4 (1.4 g,6.55 mmol) was stirred at 30℃for 1h, then diluted with DCM, washed with saturated sodium thiosulfate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound as a brown oil (553 mg, 75.6% yield).
LC/MS(ESI)(m/z):460(M+H) + .
Step 9:2- (3- (4- (benzyloxy) carbonyl) piperazine-1-carbonyl) piperidin-1-yl) propyl) -5- (4-tert-butoxycarbonyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridine-3-carboxylate (12 k)
Acetic acid (0.14 mL,2.40 mmol) was added to a mixture of 12j (553 mg,1.20 mmol) and tert-butyl 4- (piperidine-4-carbonyl) piperazine-1-carboxylate (560 mg,1.44 mmol) at room temperature, after stirring for 20 min, sodium cyanoborohydride (151 mg,2.40 mmol) was added and stirred at 30℃for 2h. The reaction mixture was quenched with ice water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-5%) to give the title compound as a yellow solid (335 mg, yield 35.9%).
1 H NMR(400MHz,CDCl 3 )δ7.97(d,J＝9.0Hz,1H),7.39-7.32(m,5H),6.69(d,J＝
9.0Hz,1H),3.97(t,J＝4.8Hz,1H),3.66-3.44(m,26H),2.49-2.28(m,4H),1.71(s,9H),1.47(s,9H).
LC/MS(ESI)(m/z):775(M+H) + .
Step 10: benzyl 4- (1- (3- (5-piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) propyl) piperidine-4-carbonyl) piperazine-1-carboxylate (12 l)
TFA (1 mL) was added to a solution of 12k (335 mg,0.43 mmol) in DCM (2 mL) and the system stirred for 2h. Concentrated to dryness under reduced pressure to give the title compound as a yellow oil (310 mg, yield 100%) which was used directly in the next reaction.
LC/MS(ESI)(m/z):575(M+H) + .
Step 11:4- (1- (3- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) propyl) piperidine-4-carbonyl) piperazine-1-carboxylic acid benzyl ester (12 m)
To a solution of 12l (247 mg,0.43 mmol), 2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoic acid (129 mg,0.43 mmol) in DMF (3 mL) were added HATU (164 mg,0.43 mmol) and DIPEA (0.22 mL,1.29 mmol) under nitrogen at room temperature and the reaction was stirred for 2h. The mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-5%) to give the title compound as a yellow solid (173 mg, yield 46.9%).
1 H NMR(400MHz,DMSO-d 6 )δ8.27(d,J＝7.9Hz,1H),7.99(d,J＝7.8Hz,1H),7.91(t,J＝6.9Hz,1H),7.85(t,J＝7.5Hz,1H),7.70(d,J＝8.1Hz,1H),7.47-7.42(m,1H),7.41-7.35(m,5H),7.35-7.30(m,1H),7.25(t,J＝9.0Hz,1H),6.70(d,J＝8.8Hz,1H),5.10(s,2H),4.35(s,2H),3.76(s,2H),3.58-3.38(m,12H),3.18(d,J＝5.2Hz,3H),2.90(s,2H),2.75(d,J＝7.5Hz,2H),2.34(s,2H),2.02-1.85(m,4H),1.63-1.54(m,4H).
LC/MS(ESI)m/z:855(M+H) + .
Step 12:4- (4-fluoro-3- (4- (2- (3- (4-piperazine-1-carbonyl) piperidin-1-yl) propyl) -3H-imidazo [4,5-b ] pyridin-5-ylpiperazine-1-carbonyl) benzyl) phthalazin-1 (2H) -one (12 n)
A mixture of palladium hydroxide (15 mg,0.1 mmol) and 12m (150 mg,0.17 mmol) was degassed three times under a nitrogen atmosphere, and a methanol solution was added under a hydrogen balloon, and the reaction system was stirred at 90℃for 1h. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound as a brown oil (144 mg, yield 100%) which was used directly in the next reaction.
1 H NMR(400MHz,DMSO-d 6 )δ8.26(d,J＝7.8Hz,1H),7.99(d,J＝7.9Hz,1H),7.93-7.81(m,2H),7.69(d,J＝8.6Hz,1H),7.47-7.36(m,2H),7.25(t,J＝9.0Hz,1H),6.69(d,J＝8.8Hz,1H),4.12(s,1H),3.83-3.68(m,2H),3.59-3.48(m,3H),3.47-3.34(m,10H),2.90-2.81(m,2H),2.78-2.70(m,2H),2.69-2.56(m,2H),2.35-2.23(m,3H),1.95
-1.80(m,4H),1.56-1.53(m,4H).
LC/MS(ESI)m/z:721(M+H) + .
Step 13:2- (2, 6-Dioxopiperidin-3-yl) -4- (2- (2- (2- (4- (4- (4- (3-) 5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) propyl) piperidine-4-carbonyl) piperazin-1-yl) ethyl) amino) isoindoline-1, 3-dione (12)
To a solution of 12n (100 mg,0.14 mmol), ethyl 2- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) methanesulfonate (120 mg,0.28 mmol) in acetonitrile (1 mL) was added DIPEA (0.07 mL,0.42 mmol) and stirred at 90℃for 1h at room temperature. The mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-60%) and further purified by preparative HPLC (C18, 50-60% acetonitrile in distilled water with 0.1% formic acid) to give the title compound as a yellow solid (9.5 mg, yield 6.5%).
1 H NMR(400MHz,CD 3 OD)δ8.38(d,J＝7.5Hz,1H),7.97(d,J＝7.9Hz,1H),7.91-7.83(m,3H),7.62-7.57(m,1H),7.52(s,1H),7.38(d,J＝6.4Hz,1H),7.22-7.08(m,3H),6.92(d,J＝9.0Hz,1H),5.13-5.09(m,1H),4.40(s,2H),3.95-3.38(m,25H),3.22-3.07(m,6H),2.90-2.68(m,3H),2.38-1.97(m,8H).
LC/MS(ESI)m/z:1064(M+H) + .
Example 13
2- (2, 6-Dioxopiperidin-3-yl) -4- (3- (4- (4- (2- (5-) 4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) ethyl) amino) methyl) benzyl) piperidin-1-yl) -3-oxopropyl) amino) isoindoline-1, 3-dione (13)
Step 1:4- (2- (2- (benzyloxy) carbonylamino) ethyl) -3H-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carboxylic acid tert-butyl ester (13 b)
To a solution of tert-butyl 4- (5, 6-diaminopyridin-2-yl) piperazine-1-carboxylate (1 g,3.41 mmol) in acetic acid (15 mL) was added benzyl (3-oxopropyl) carbamate (780 mg,3.75 mmol) and elemental iodine (90 mg,0.34 mmol) at room temperature. Stirred at 30℃for 1h. Dilute with ethyl acetate, wash with saturated sodium thiosulfate solution and brine, dry over anhydrous sodium sulfate, filter and concentrate to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-5%) to give the title compound as a yellow solid (340 mg, yield 20.8%).
LC/MS(ESI)(m/z):481(M+H) + .
Step 2: benzyl (2- (5-piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) ethyl) carbamate hydrochloride (13 c)
A solution of hydrogen chloride in methanol (3 mL, 4M) was added to a solution of 13b (340 mg,0.71 mmol) in methanol (3 mL) and stirred at room temperature for 2h. The mixture was concentrated to dryness under reduced pressure to give the title compound as a yellow oil (320 mg, yield 100%).
LC/MS(ESI)(m/z):381(M+H) + .
Step 3:2- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) ethyl) carbamate (13 d)
To a solution of 13c (320 mg,0.77 mmol) and 2-fluoro-5- [ (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl ] benzoic acid (229 mg,0.77 mmol) in DMF (3 mL) under nitrogen at room temperature was added HATU (350 mg,0.92 mmol) and DIPEA (0.27 mL,1.54 mmol) and the mixture stirred for 2h. Ethyl acetate diluted water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-10%) to give the title compound as a yellow solid (400 mg, yield 78.9%).
LC/MS(ESI)(m/z):661(M+H) + .
Step 4:4- (3- (4- (2- (2-aminoethyl) -3H-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carbonyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (13 e)
To a solution of 13d (180 mg,0.27 mmol) in ethanol (2 mL) was added palladium on carbon (20 mg,10 wt%) and the mixture was degassed three times under nitrogen and stirred overnight at 80℃under a hydrogen balloon. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound as a pale yellow oil (100 mg, yield 69.7%).
1 H NMR(400MHz,DMSO-d 6 )δ12.60(s,1H),8.27(d,J＝7.8Hz,1H),8.07(d,J＝9.2Hz,2H),7.99(d,J＝7.9Hz,1H),7.94-7.82(m,2H),7.48(s,1H),7.39(d,J＝4.2Hz,1H),7.29-7.24(m,1H),7.13-7.08(m,1H),6.74(s,2H),3.73(d,J＝20.0Hz,4H),3.54-3.52(s,2H),3.43-3.29(m,6H),2.89-2.89(s,2H).
LC/MS(ESI)(m/z):527(M+H) + .
Step 5:4- (4- (methoxycarbonyl) benzyl) piperidine-1-carboxylic acid tert-butyl ester (13 g)
To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (2 g,9.38 mmol) in 1, 4-dioxane (20 mL) was added p-toluenesulfonyl hydrazide (1.8 g,9.66 mmol) at room temperature, and stirred at 80℃for 1.5h. Then, 4- (methoxycarbonyl) phenyl ] boronic acid (1.9 g,10.3 mmol) and potassium carbonate (1.4 g,10.3 mmol) were added to the mixture, which was stirred under nitrogen at 80℃for 3h. The mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, etOAc: pe=0-20%) to give the title compound as a colorless oil (720 mg, yield 23.0%).
1 H NMR(400MHz,CDCl 3 )δ7.96(d,J＝8.2Hz,2H),7.20(d,J＝8.2Hz,2H),4.15-3.98(m,2H),3.90(s,3H),2.72-2.53(m,4H),1.74-1.65(m,1H),1.59(d,J＝11.4Hz,2H),1.45(s,9H),1.21-1.08(m,2H).
LC/MS(ESI)(m/z):334(M+H) + .
Step 6:4- (4-hydroxymethyl benzyl) piperidine-1-carboxylic acid tert-butyl ester (13 h)
To a solution of 13g (700 mg,2.09 mmol) of 1, 4-dioxane (7 mL) was added lithium borohydride (91 mg,4.19 mmol) at room temperature. After stirring at 80 ℃ for 2h, the reaction was cooled to room temperature and the mixture was quenched with saturated ammonium chloride solution. Ethyl acetate was extracted twice. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, etOAc: pe=0-50%) to give the title compound as a white oil (460 mg, 71.7% yield).
1 H NMR(400MHz,CDCl 3 )δ7.25(d,J＝7.9Hz,2H),7.09(d,J＝8.0Hz,2H),4.60(s,2H),4.10-3.96(m,2H),2.80-2.63(m,2H),2.51(d,J＝6.9Hz,2H),1.70-1.53(m,3H),1.45(m,9H),1.16-1.04(m,2H).
LC/MS(ESI)(m/z):306(M+H) + .
Step 7:4- (piperidin-4-ylmethyl) phenyl methoxide hydrochloride (13 i)
A solution of hydrogen chloride in methanol (2 mL, 4M) was added to 13h (340 mg,1.11 mmol) at room temperature and stirred for 2h. The mixture was concentrated to dryness under reduced pressure to give the title compound as a colorless oil (330 mg, yield 100%).
LC/MS(ESI)(m/z):206(M+H) + .
Step 8:2- (2, 6-Dioxopiperidin-3-yl) -4- (3- (4- (4-hydroxymethyl benzyl) piperidin-1-yl) -3-oxopropyl) amino) isoindoline-1, 3-dione (13 j)
To a solution of 3- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) propionic acid (13 a) (200 mg,0.58 mmol) and 13i (140 mg,0.58 mmol) in DCM (5 mL) at room temperature were added EDCI (133 mg,0.69m mol) and TEA (0.24 mL,1.74 mmol), and the reaction was stirred for 2h. The mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-10%) to give the title compound as a yellow solid (80 mg, yield 25.9%).
LC/MS(ESI)(m/z):533(M+H) + .
Step 9:4- (1- (3- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propionylpiperidin-4-yl) methylbenzaldehyde (13 k)
To a solution of 13j (280 mg,0.53 mmol) in DCM (2 mL) and THF (2 mL) was added dessert-martin oxidant (267.1 mg,0.63 mmol), and after stirring at room temperature for 2h, the mixture was diluted with DCM, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give the title compound as a yellow solid (200 mg, 71.7% yield).
1 H NMR(400MHz,CDCl 3 )δ9.97(s,1H),8.87(s,1H),7.84-7.76(m,2H),7.54-7.44(m,1H),7.31-7.27(m,2H),7.10-7.02(m,1H),6.95(d,J＝8.6Hz,1H),6.55(t,J＝6.1Hz,1H),4.99-4.86(m,1H),4.61(t,J＝14.2Hz,1H),4.17-4.08(m,1H),3.80(d,J＝13.5Hz,1H),3.72-3.60(m,1H),3.41-3.36(m,1H),3.04-2.91(m,1H),2.68-2.58(m,4H),2.54-2.46(m,1H),2.38(t,J＝8.1Hz,1H),1.85-1.72(m,1H),1.66(d,J＝12.4Hz,2H),1.30-1.22(m,2H),1.20-1.07(m,2H).
LC/MS(ESI)m/z:531(M+H) + .
Step 10:2- (2, 6-Dioxopiperidin-3-yl) -4- (3- (4- (4- (2- (5-) 4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) ethyl) amino) methyl) benzyl) piperidin-1-yl) -3-oxopropyl) amino) isoindoline-1, 3-dione (13)
To 13k (30 mg,0.06 mmol) and 13e (29.8 mg,0.06 mmol) of DMF (1 mL) were added acetic acid (0.01 mL) at room temperature, and after stirring the mixture for 20 minutes, sodium borohydride acetate (3.8 mg,0.12 mmol) was added and the mixture was stirred at room temperature for 16h. The mixture was diluted with water and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C18, 50-60% acetonitrile in distilled water with 0.1% formic acid) to give the title compound as a yellow solid (4.0 mg, yield 6.8%).
1 H NMR(400MHz,CD 3 OD)δ8.47(s,1H),8.36(d,J＝6.5Hz,1H),7.95(d,J＝7.5Hz,1H),7.91-7.81(m,2H),7.75(d,J＝8.9Hz,1H),7.57-7.47(m,2H),7.41-7.34(m,3H),7.23-7.15(m,2H),7.11-7.02(m,2H),6.80(d,J＝8.9Hz,1H),4.58(s,2H),4.39(s,2H),4.16(s,2H),3.94-3.81(m,3H),3.68-3.58(m,4H),3.48-3.38(m,6H),3.23-3.18(m,2H),2.81-2.50(m,8H),1.63-1.53(m,3H),1.36-1.25(m,5H),0.92-0.84(m,3H).
LC/MS(ESI)m/z:1041(M+H) + .
Example 14
N- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-4-amido) ethyl) -2- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) methyl) -3, 9-diazaspiro [5.5] undec-3-yl) pyrimidine-5-carboxamide (14)
Step 1: 5-chloro-3- (2-trimethylsilylethoxy) methyl-3H-imidazo [4,5-b ] pyridine (14 b)
Sodium hydrogen (1.02 g,25.5mmol,60% dispersed in mineral oil) was added to a solution of 5-chloro-3H-imidazo [4,5-b ] pyridine 14a (3 g,19.6 mmol) in DMF (30 mL) at 0deg.C, after stirring at that temperature for 30 min, 2- (trimethylsilyl) ethoxymethyl chloride (3.92 g,23.5 mmol) was added and stirring at room temperature for 3H. After cooling to 0 ℃, the reaction was quenched with ice water and extracted three times with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. Flash column chromatography of the residue (silica gel, etOAc: pe=0-50%) afforded the title compound as a yellow oil (4.8 g, 86.5% yield).
LC/MS(ESI)m/z:284(M+H) + .
Step 2:4- (3- (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carboxylic acid tert-butyl ester (14 c)
To a mixture of 14b (4.8G, 17.0 mmol) and tert-butylpiperazine-1-carboxylate (3.79G, 20.4 mmol) was added sodium tert-butoxide (3.26G, 34.0 mmol), ruphos (0.79G, 1.70 mmol) and Rupos Pd G3 (2.85G, 3.40 mmol) at room temperature, the mixture was degassed three times under nitrogen atmosphere, stirred at 85 ℃ for 3h, the mixture was cooled to room temperature, diluted with ice water, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, etOAc: pe=0-60%) to give the title compound as a brown oil (5.0 g, yield 68.1%).
LC/MS(ESI)m/z:434(M+H) + .
Step 3:4- (2-formyl-3- (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carboxylic acid tert-butyl ester (14 d)
To a solution of 14c (5.0 g,11.5 mmol) in THF (50 mL) at-78deg.C was added dropwise a 2M solution of LDA in THF (11.5 mL,23.0 mmol), stirred at that temperature for 1h, then DMF (1.26 g,17.3 mmol) was added dropwise, and the mixture was allowed to react at-78deg.C for 1h, then cooled to room temperature and stirred for 30 min. The reaction mixture was cooled to 0 ℃, quenched with ice water, extracted 3 times with ethyl acetate, the organic layer was washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, etOAc: pe=)
0-80%) to give the title compound as a brown oil (4.5 g, 84.6% yield).
LC/MS(ESI)m/z:462(M+H) + .
Step 4: ethyl 2- (9- (5- (4-t-butoxycarbonyl) piperazin-1-yl) -3- (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4,5-b ] pyridin-2-yl) methyl) -3, 9-diazaspiro [5.5] undec-3-yl) pyrimidine-5-carboxylate (14 e)
To a solution of 14d (100 mg,0.22 mmol) and methyl 2- (3, 9-diazaspiro [5.5] undec-3-yl) pyrimidine-5-carboxylate (75.5 mg,0.26 mmol) in methanol (3 mL) at room temperature was added acetic acid (0.01 mL,0.02 mmol), and the mixture was stirred at room temperature for 30 min. Sodium borohydride acetate (93 mg,0.44 mmol) was then added and the reaction stirred for 4h. The reaction mixture was quenched with ice water and extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-10%) to give the title compound as a brown oil (100 mg, yield 61.7%).
LC/MS(ESI)m/z:750(M+H) + .
Step 5:2- (9- (5- (4-t-Butoxycarbonyl) piperazin-1-yl) -3- (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4,5-b ] pyridin-2-yl) methyl) -3, 9-diazaspiro [5.5] undec-3-yl) pyrimidine-5-carboxylic acid (14 f)
To a mixed solution of 14e (100 mg,0.13 mmol) in THF (1 mL), methanol (1 mL) and distilled water (1 mL) at room temperature was added lithium hydroxide monohydrate (16.8 mg,0.40 mmol), and the mixture was stirred at 30℃for 2h. The mixture was concentrated to dryness under reduced pressure, and the residue was diluted with water. The mixture was washed twice with ethyl acetate, acidified to a pH of about 3 with 1N diluted hydrochloric acid and extracted 3 times with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound (90 mg, yield 96.1%).
LC/MS(ESI)m/z:722(M+H) + .
Step 6: tert-butyl 4- (2- (9- (5- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-amino) ethylcarbamoyl) pyrimidin-2-yl) -3, 9-diazaspiro [5.5] undec-3-yl) methyl) -3- (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carboxylate (14 g)
To a solution of 14f (90 mg,0.12 mmol) and 1f (66 mg,0.19 mmol) in DMF (2 mL) under nitrogen at room temperature was added HATU (68.4 mg,0.19 mmol) and DIPEA (0.06 mL,0.36 mmol) and the mixture was stirred at room temperature for 2h. Dilute with water and extract three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-10%) to give the title compound as a brown oil (120 mg, yield 94.5%).
LC/MS(ESI)m/z:1021(M+H) + .
Step 7: n- (2- (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) ethyl) -2- (9- (5-piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) methyl) -3, 9-diazaspiro [5.5] undec-3-yl) pyrimidine-5-carboxamide hydrochloride (14H)
To 14g (120 mg,0.12 mmol) of a solution of hydrogen chloride in methanol (5 mL, 2M) was added at room temperature and stirred for 1h. The mixture was concentrated to dryness under reduced pressure to give the title compound as a yellow solid (120 mg,100% yield) which was used directly in the next reaction.
LC/MS(ESI)m/z:790(M+H) + .
Step 8N- (2- (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-4-amido) ethyl) -2- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) benzoyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-2-yl) methyl) -3, 9-diazaspiro [5.5] undec-3-yl) pyrimidine-5-carboxamide (14)
DIPEA (0.10 mL,0.60 mmol) and T were added to a solution of 14h (112 mg,0.12 mmol) and 2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoic acid (35.8 mg,0.12 mmol) in DMF (2 mL) under a nitrogen atmosphere at room temperature 3 P (114 mg,0.18mmol,50wt% DMF), the mixture was stirred for 1h. The mixture was concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography (silica gel, meOH: dcm=0-25%) and further purified by preparative HPLC (C18, 50-60% acetonitrile in distilled water with 0.1% formic acid). The title compound was obtained as a yellow solid (6.2 mg, yield 4.83%).
1 H NMR(400MHz,CD 3 OD)δ8.72(s,2H),8.39-8.34(m,1H),8.15(d,J＝9.3Hz,1H),7.97(d,J＝7.6Hz,1H),7.91-7.82(m,2H),7.56-7.50(m,2H),7.42-7.38(m,1H),7.22-7.12(m,3H),7.04(d,J＝7.0Hz,1H),5.04(dd,J＝12.4,5.5Hz,1H),4.71(s,2H),4.40(s,2H),3.96-3.90(m,6H),3.87-3.82(m,2H),3.70-3.65(m,2H),3.59(s,4H),3.55-3.46(m,6H),2.90-2.61(m,3H),2.12-2.05(m,1H),2.03-1.84(m,4H),1.72-1.61(m,4H).
LC/MS(ESI)m/z:1070(M+H) + .
Example 15
N- (2- (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -13- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-7-yl) oxy) tridecanamide (15)
Step 1:5, 7-dichloro-3- (2-trimethylsilylethoxy) methyl-3H-imidazo [4,5-b ] pyridine (15 b)
To a solution of compound 15a (19.0 g,101.1 mmol) and SEMCl (20.0 g,121.3 mmol) in DMF (190 mL) was added DIPEA (15.6 g,121.3 mmol). The reaction mixture was stirred at room temperature for 2h. Water (150 mL) was then added to the mixture and extracted with EtOAc (100 mL. Times.3). The combined organic phases were washed with water (50 ml×2) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. Purification by flash column chromatography (silica gel, PE: etoac=20:1) afforded the title compound 15b (23.0 g, 71.5%).
1 H NMR(400MHz,CDCl 3 ):δ8.21(s,1H),7.35(s,1H),5.63(s,2H),3.62(t,J＝8.0Hz,2H),0.94(t,J＝8.0Hz,2H),0.04(s,9H).
LC/MS(ESI)m/z:318.0(M+H) + .
Step 2: 5-chloro-7- (4-methoxybenzyloxy) -3- (2-trimethylsilylethoxy) methyl) -3H-imidazo [4,5-b ] pyridine (15 c)
To a solution of compound 15b (26.5 g,83.3 mmol) in THF (550 mL) was added NaH (3.7 g,91.6mmol, 60%). Stirred at room temperature for 0.5h. 15-Crown-5 (18.3 g,83.3 mmol) and (4-methoxyphenyl) methanol (11.5 g,83.3 mmol) were then added to the reaction mixture. After stirring at room temperature for 3h, water (200 mL) was added to the mixture and extracted with EtOAc (100 mL. Times.3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash column chromatography (silica gel, PE: etoac=20:1) to give the title compound 15c (8.0 g, 22.9%) as a white solid.
1 H NMR(400MHz,CDCl 3 ):δ8.04(s,1H),7.42(d,J＝8.4Hz,2H),6.91(d,J＝8.4Hz,2H),6.79(s,1H),5.60(s,2H),5.48(s,2H),3.82(s,3H),3.61(t,J＝8.0Hz,2H),0.93(t,J＝8.0Hz,2H),0.04(s,9H).
LC/MS(ESI)m/z:420.1(M+H) + .
Step 3:4- (7- (4-methoxybenzyloxy) -3- (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carboxylic acid tert-butyl ester (15 d)
To the reaction flask was added compound 15c (8.0G, 19.0 mmol), tert-butyl piperazine-1-carboxylate (4.3G, 22.9 mmol), ruphos (890 mg,1.9 mmol), ruphos Pd G3 (1.9G, 2.28 mmol) and t-BuONa (2.2G, 22.8 mmol), and after the mixture was purged three times with nitrogen, THF (154 mL) was added. The reaction mixture was heated to 80 ℃ for 3h, tlc indicated the reaction was complete. To the mixture was added water (100 mL) and extracted with EtOAc (100 mL. Times.3). The combined organic phases were washed with brine (150 mL), dried over anhydrous sodium sulfate and concentrated. Flash column chromatography of the crude product (silica gel, PE: etoac=5:1) afforded the title compound 15d (8.4 g, 78.4%) as a white solid.
1 H NMR(400MHz,CDCl 3 ):δ7.84(s,1H),7.42(d,J＝8.0Hz,2H),6.90(d,J＝7.2Hz,2H),6.14(s,1H),5.52(d,J＝4.0Hz,4H),3.81(s,3H),3.64-3.53(m,10H),1.49(s,9H),0.93(t,J＝8.0Hz,2H),0.05(s,9H).
LC/MS(ESI)m/z:570.3(M+H) + .
Step 4:4- (7-hydroxy-3- (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carboxylic acid tert-butyl ester (15 e)
To a solution of compound 15d (8.5 g,14.7 mmol) in MeOH (120 mL) was added Pd/C (4.0 g,10 wt%). The reaction mixture was stirred under a hydrogen atmosphere at 30 ℃ for 6h, hplc showed the reaction to be complete. The mixture was filtered through a pad of celite and the filtrate was concentrated to dryness. Flash column chromatography of the residue (silica gel, PE: etoac=3:1) afforded the title compound 15e (5.7 g, 86.2%) as a white solid.
1 H NMR(400MHz,CDCl 3 ):δ7.94(s,1H),6.22(s,1H),5.55(s,2H),3.64(t,J＝11.2Hz,2H),.356(s,8H),1.49(s,9H),0.93(t,J＝11.2Hz,2H),0.05(s,9H).
LC/MS(ESI)m/z:450.3(M+H) + .
Step 5:4- (7- (13-ethoxy-13-oxotridecyl) oxy) -3- (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carboxylic acid tert-butyl ester (15 f)
Compound 15e (90 mg,0.2 mol) and 13-bromotridecanoic acid ethyl ester (96 mg,0.3 mol) were dissolved in DMF (3 mL), potassium carbonate (41 mg,0.3 mmol) was added, after stirring at 80 ℃ for 3h, cooled to room temperature, quenched with water, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure, and the crude product was flash column chromatographed (silica gel, PE: etoac=1:2) to give the title compound 15f (0.122 g, 88.7%) as a pale yellow solid.
LC/MS(ESI)m/z:690.5(M+H) + .
Step 6:13- (5- (4-Boc) piperazin-1-yl) -3- (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4,5-b ] pyridin-7-yl) oxy tridecanoic acid (15 g)
To a mixed solvent of methanol (4.5 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (75 mg,1.78 mmol) to which was dissolved compound 15f (122 mg,0.178 mmol), the reaction system was stirred at 50℃for 2 hours, then water was added after concentrating under reduced pressure, pH was adjusted to about 3 with 1N diluted hydrochloric acid, ethyl acetate was used for extraction, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give the title compound (100 mg, 85%) which was used directly in the next step without purification.
LC/MS(ESI)m/z:662.4(M+H) + .
Step 7:4- (7- (13- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) amino) -13-oxotridecyl) oxy) -3- (2- (trimethylsilyl) ethoxy) methyl) -3H-imidazo [4,5-b ] pyridin-5-yl) piperazine-1-carboxylate (15H)
To a solution of 15g (100 mg,0.15 mmol) of the compound and 4- ((2-aminoethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione hydrochloride (60 mg,0.17 mmol) in DMF was added HATU (64 mg,0.17 mmol) and DIPEA (0.08 mL,0.51 mmol) under nitrogen at room temperature. The mixture was stirred at room temperature for 1h, diluted with water and extracted three times with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. Flash column chromatography purification (silica gel, DCM: meoh=20:1) afforded the title compound as a pale yellow solid (85 mg, 58% yield).
LC/MS(ESI)m/z:960.5(M+H) + .
Step 8: n- (2- (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -13- (5-piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-7-yl) oxy) tridecanamide (15 i)
1, 4-Dioxahexacyclic solution of hydrogen chloride (2 mL, 4M) was added to compound 15h (85 mg,0.088 mmol) at room temperature, and after stirring for 2h, concentrated to dryness under reduced pressure to give the title compound 15i (65 mg, yield 100%) which was used in the next step without purification.
LC/MS(ESI)m/z:730.4(M+H) + .
Step 9: n- (2- (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -13- (5- (4- (2-fluoro-5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) piperazin-1-yl) -3H-imidazo [4,5-b ] pyridin-7-yl) oxy) tridecanamide (15)
To a mixture of compound 15i (65 mg,0.088 mmol) and compound 1k (27 mg,0.088 mmol) in DMF (3 mL) was added HATU (34 mg,0.088 mmol) and TEA (0.014 mL,0.088 mmol) under a nitrogen atmosphere at room temperature. The reaction was stirred at room temperature for 2h, the mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by flash column chromatography (silica gel, meOH: dcm=0-20%) to give the title compound as a yellow solid (60 mg, 67% yield).
1 H NMR(400MHz,DMSO-d 6 )δ12.59(s,1H),11.09(s,1H),9.83(s,1H),8.24(d,J＝8.0Hz,1H),8.01(s,1H),7.97(d,J＝8.1Hz,1H),7.90(dd,J＝14.3,6.0Hz,2H),7.83(d,J＝7.6Hz,1H),7.58-7.50(m,1H),7.43(s,1H),7.38(d,J＝4.7Hz,1H),7.23(t,J＝9.0Hz,1H),7.15(d,J＝8.7Hz,1H),7.00(d,J＝7.0Hz,1H),6.70(s,1H),6.25(s,1H),5.03(dd,J＝12.8,5.5Hz,1H),4.31(d,J＝10.0Hz,3H),4.09(s,1H),3.72(s,2H),3.55(s,2H),3.38(s,2H),3.27(s,2H),3.21(d,J＝5.9Hz,2H),3.15(s,2H),3.10-2.99(m,2H),2.87(m,1H),2.54(m,1H),2.01(t,J＝7.3Hz,2H),1.73(d,J＝6.8Hz,2H),1.42(m,2H),1.34-1.11(m,16H).
LC/MS(ESI)m/z:1010.5(M+H) + .
Biological test evaluation
The invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.
Test column 1PARP1 protein degradation experiments
Colon cancer cells SW620 were cultured in leibeovitz's L-15 (Gibco). Transfection of HiBiT-PARP1 plasmid into cells using Lipofectamine 2000 (Thermo Fisher) in the absence of CO 2 Is constant at 37 DEG CCulturing in an incubator for 24 hours. Cells were collected and frozen at-80℃in tubes with 10% DMSO and 90% FBS. One branch of frozen SW620/HiBiT-PARP1 cells is taken and rapidly placed in a water bath kettle at 37 ℃ until the cells are completely dissolved. After centrifugation, the cells were resuspended in Leibovitz's L-15 medium to adjust the cell density to 5.0x10 4 cells/mL. mu.L of cells were added to 384-well compound plates containing 20. Mu.L of compound using Multidrop combi (Thermo Scientific). The cell density was 1000 cells/well. In the absence of CO 2 Incubate in a 37℃incubator for 24h. After equilibration for 10 minutes at room temperature, 20nL of Nano-Glo HiBiT (Promega) lysis reagent was added with Multidrop Combi. Incubate at room temperature for 10 min and read signal values using EnVision (Perkin Elmer).
Envision read the collected fluorescence signal value (RFU), the maximum RFU value was taken, and the compound degradation effect value for each well on the experimental plate was calculated according to the following formula: % effect=100× (Value-ZPE)/(HPE-ZPE). Wherein,% Effect is the compound degradation Effect Value of the corresponding experimental hole, value is the signal Value of the experimental hole, ZPE is the signal mean Value of the negative control experimental hole, and HPE is the signal mean Value of the positive control experimental hole. The positive control was 1 μm SK575. The concentration of the compound to be detected is diluted by 3.162 times by a reaction system, the 11 concentrations are 10 mu M to 0.1nM, and the DC of the compound is calculated by using XLFIT to fit the percent degradation rate of the compound and the 11 point concentration data to a parameter nonlinear logic formula 50 Values.
The experimental results are shown in table 1:
examples DC 50 (nM)
1 26.4
2 10.2
3 7.2
4 5.8
5 6.8
6 12.3
7 10
8 13.2
9 6.3
11 47.7
14 13.4
15 16.3
TABLE 1 PARP1 protein degradation Activity of the Compounds of the invention
By referring to the experimental method to test other compounds of the invention, the obtained DC with PARP1 protein degradation activity 50 (nM) values between 0.1 and 100 nM; preferably less than 50nM.
Conclusion of experiment:
the compound has good degradation activity on PARP1 protein.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the application. Thus, the present application is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein, and any modifications, equivalent alterations, improvements, etc., within the spirit and principles of the present invention are to be included within the scope of the present invention.

Claims (10)

1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Wherein:
selected from:
Ring a and ring B are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
L 1 selected from-L 11 -L 12 -L 13 -L 14 -L 15 -L 16 -L 17 -L 18 -L 19 -；
L 11 、L 12 、L 13 、L 14 、L 15 、L 16 、L 17 、L 18 And L 19 Each independently selected from the group consisting of bond, - (CH) 2 ) n1 -、-NH-、-O-、-S-、-C(O)NH-、-C(O)-、-CH 2 -NH-、-CH 2 -N(CH 3 ) -, cycloalkylene, heterocyclylene, arylene or heteroarylene; the- (CH) 2 ) n1 -、-NH-、-C(O)NH-、-CH 2 -NH-、-CH 2 -N(CH 3 ) -, cycloalkylene, heterocyclylene, arylene, and heteroarylene, optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
L 2 selected from the group consisting of bond, alkylene, -O-, -NH-, -C (O) -, -CH 2 -NH-or-S-;
R a 、R b 、R c and R is d Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
u is VHL or CRBN E3 ubiquitin ligase ligand selected from VHL or its derivative, pomalidomide or its derivative, lenalidomide or its derivative, or thalidomide or its derivative;
m is selected from 0, 1, 2 or 3;
x, y, z and o are each independently integers selected from 0 to 5; and is also provided with
n1 is an integer from 0 to 20.
2. The compound of claim 1, a stereoisomer or pharmaceutically acceptable salt thereof, wherein ring B is selected from C 5-7 Cycloalkyl, 5-7 membered mono-heterocyclyl, 7-10 membered di-heterocyclyl; preferably cyclohexyl,
3. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein U is selected from the group consisting of U
Wherein:
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 R 21 R 22 R 23 and R is 24 Each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl; and is also provided with
p1 to p24 are each independently selected from 0, 1, 2, 3 or 4.
4. A compound according to any one of claims 1 to 3, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (II):
wherein:
ring a is selected from aryl, 5-8 membered mono-heteroaryl, 8-14 membered di-heteroaryl;
preferably phenyl group,
L 1 Selected from-L 11 -L 12 -L 13 -L 14 -L 15 -L 16 -L 17 -L 18 -L 19 -；
L 11 、L 12 、L 13 、L 14 、L 15 、L 16 、L 17 、L 18 And L 19 Each independently selected from the group consisting of bond, - (CH) 2 ) n1 -、-NH-、-O-、-S-、-C(O)NH-、-C(O)-、-CH 2 -NH-、-CH 2 -N(CH 3 ) -, piperidinyl, piperazinyl, phenylene, pyrimidinyl, pyrazolyl, pyridazinyl, pyrazinyl, pyrrolopyrrolyl, diazaspiro [5.5 ]]Undecyl, azaspiro [5.5 ]]Undecyl, benzidine, azetidine, diazepine, pyrrolidinylene, azaspiro [3.5 ] ]Nonylalkyl, diazaspiro [3.5]Nonylalkyl, diazabicyclo [3.1.1]Heptyl or diazaspiro [2.5]An octyl group; the- (CH) 2 ) n1 -、-NH-、-C(O)NH-、-CH 2 -NH-、-CH 2 -N(CH 3 ) -, piperidinyl, piperazinyl, phenylene, pyrimidinyl, pyrazolyl, pyridazinyl, pyrazinyl, pyrrolopyrrolyl, diazaspiro [5.5 ]]Undecyl, azaspiro [5.5 ]]Undecyl, benzidine, azetidine, diazepine, pyrrolidinylene, azaspiro [3.5 ]]Nonylalkyl, diazaspiro [3.5]Nonylalkyl, diazabicyclo [3.1.1]Heptyl and diazaspiro [2.5]Octyl optionally further substituted with deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, amino, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 One or more substituents in the haloalkoxy group;
u is selected from
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 R 21 R 22 R 23 And R is 24 Each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-5 Cycloalkyl or 3-5 membered heterocyclyl;
p1 to p24 are each independently selected from 0, 1, 2, 3 or 4;
R a each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 3-5 Cycloalkyl;
x is selected from 0, 1, 2 or 3; and n1 is an integer from 0 to 20.
5. The compound according to any one of claims 1 to 4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the general formula (III) or the general formula (III-a):
wherein:
L 1 selected from-L 11 -L 12 -L 13 -L 14 -L 15 -L 16 -L 17 -L 18 -L 19 -；
L 11 、L 12 、L 13 、L 14 、L 15 、L 16 、L 17 、L 18 And L 19 Each independently selected from the group consisting of bond, - (CH) 2 ) n1 -、-NH-、-O-、-S-、-C(O)NH-、-C(O)-、-CH 2 -NH-、-CH 2 -N(CH 3 )-、 The- (CH) 2 ) n1 -、-NH-、-C(O)NH-、-CH 2 -NH-、-CH 2 -N(CH 3 )-、 Optionally further substituted with deuterium, fluorine, chlorine, bromine, hydroxy, cyano, amino, nitro, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 One or more substituents in the haloalkoxy group;
u is selected from
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 R 21 R 22 R 23 And R is 24 Each independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-5 Cycloalkyl or 3-5 membered heterocyclyl;
p1 to p24 are each independently selected from 0, 1, 2, 3 or 4; and n1 is an integer from 0 to 20.
6. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein L 1 Selected from- (CH) 2 ) m1 -C(O)NR a1 (CH 2 ) 2 NR a2 -、-C(O)-(CH 2 ) m2 C(O)N R a1 (CH 2 ) 2 NR a2 -、 -(CH 2 ) m7 -C(O)NH-(CH 2 ) 2 -O-、-O-(CH 2 ) m8 C(O)NR a1 (CH 2 ) m9 NR a2 -、 The- (CH) 2 ) m1 -C(O)NR a1 (CH 2 ) 2 NR a2 -、-C(O)-(CH 2 ) m2 C(O)NR a1 (CH 2 ) 2 NR a2 -、 -(CH 2 ) m7 -C(O)NH-(CH 2 ) 2 -O-、-O-(CH 2 ) m8 C(O)NR a1 (CH 2 ) m9 NR a2 -、 Optionally further substituted with deuterium, halogen, hydroxy, amino, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 One or more substituents in the alkoxy group;
R a1 and R is a2 Each independently selected from hydrogen, deuterium, halogen or C 1-3 An alkyl group;
alternatively, R a1 And R is a2 And linked together with the carbon atom to which it is attached to form a 5-8 membered heterocyclic group, said 5-8 membered heterocyclic group optionally being further substituted with deuterium, halogen, C 1-3 One or more substituents in the alkyl group; preferably, R a1 And R is a2 Forming a piperazinyl group with the carbon atom to which it is attached; and m1 to m9 are each independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.
7. The compound according to any one of claims 1-6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
8. a pharmaceutical composition comprising a therapeutically effective dose of a compound of any one of claims 1-7, or a stereoisomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
9. Use of a compound according to any one of claims 1-7, or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for PARP-related diseases.
10. Use of a compound according to any one of claims 1-7, or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, in the manufacture of a medicament for the treatment or prevention of a tumor-associated disease.
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