CN117069716A - Selective PARP1 inhibitors - Google Patents
Selective PARP1 inhibitors Download PDFInfo
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- CN117069716A CN117069716A CN202310550859.9A CN202310550859A CN117069716A CN 117069716 A CN117069716 A CN 117069716A CN 202310550859 A CN202310550859 A CN 202310550859A CN 117069716 A CN117069716 A CN 117069716A
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- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
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- 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
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Abstract
The present invention provides selective PARP1 inhibitors. Specifically, the invention provides a compound or pharmaceutically acceptable salt or solvate thereof, wherein the compound is shown as a formula A, and each group is defined in the specification; and a preparation method and application of the compound.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a selective poly (ADP-ribose) polymerase 1 (PARP 1) inhibitor and application thereof in preventing or treating PARP1 related diseases. .
Background
Poly (a) ribose diphosphate polymerase (PARP) is a monomeric protease that is widely found in most eukaryotic nuclei. During poly ADP glycosylation, PARP enzymes are involved in certain processes, such as regulating cell death, cell cycle progression, gene transcription, intracellular DNA repair, and the like. The PARP family has at least 18 members and has a certain homology among the members. PARP1 and PARP2 are two main types of enzymes in the PARP family, wherein PARP1 plays more than 90% of functions, and the substrate selectivity of the two types of enzymes is different. Improved PARPl selectivity may have improved efficacy and reduced toxicity compared to other commercially available PARP1/2 inhibitors. Thus, there is an unmet medical need for effective and safe PARP inhibitors, in particular highly selective PARP1 inhibitors. The selective PARP1 inhibitors described herein have surprisingly high selectivity (e.g., selectivity over PARP 2).
In view of the foregoing, there is a great need in the art to develop a novel PARP1 selective inhibitor.
Disclosure of Invention
It is an object of the present invention to provide a highly selective inhibitor of poly (ADP-ribose) polymerase 1 (PARP 1). It is a further object of the present invention to provide the use of said inhibitors in the prevention or treatment of diseases associated with PARP 1.
In a first aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is of formula A
Wherein,
W 1 and W is 2 Each independently is- (CH) 2 ) -or- (CH) 2 ) 2 -;
X 1 Is CR (CR) a2 Or N;
X 2 is CR (CR) a3 Or N;
R 1 selected from the group consisting of: substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl;
R 2 selected from the group consisting of: H. halogen, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl;
R 3 selected from the group consisting of: H. substituted or unsubstituted C 1-3 An alkyl group;
R 4 and R is 5 Each independently selecting the following group: H. halogen, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl;
R 6 selected from the group consisting of: H. substituted or unsubstituted C 1-3 An alkyl group;
R a1 、R a2 、R a3 、R c1 and R is c2 Each independently selected from the group consisting of: H. substituted or unsubstituted C 1-4 An alkyl group;
unless otherwise specified, the substitution means that one or more (e.g., 1, 2, or 3) hydrogens in the group are replaced with a substituent selected from the group consisting of: deuterium (D), halogen, C 1-4 Alkyl, C 1-4 A haloalkyl group.
In another preferred embodiment, the compound is represented by formula A1 or A2;
in another preferred embodiment, W 1 And W is 2 One is- (CH) 2 ) 2 -, the other is- (CH) 2 ) -; or W 1 And W is 2 Are all- (CH) 2 )-。
In another preferred embodiment, W 1 And W is 2 Are all- (CH) 2 )-。
In another preferred embodiment, W 1 And W is 2 One is- (CH) 2 ) 2 -, the other is- (CH) 2 )-。
In another preferred embodiment, the compound is represented by formula B-1
In another preferred embodiment, R a1 、R a2 、R a3 、R c1 And R is c2 All are H.
In another preferred embodiment, the compound is represented by formula B-1
In another preferred embodiment, R a1 、R a2 、R a3 、R c1 And R is c2 All are H.
In another preferred embodiment, the compound is represented by formula I-1
Wherein,
X 1 CH or N;
X 2 CH or N;
R 1 selected from the group consisting of: substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl;
R 2 selected from the group consisting of: H. halogen, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl;
R 3 selected from the group consisting of: H. substituted or unsubstituted C 1-3 An alkyl group;
R 4 and R is 5 Each independently selecting the following group: H. halogen, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl;
R 6 selected from the group consisting of: H. substituted or unsubstituted C 1-3 An alkyl group;
unless otherwise specified, the substitution means that one or more (e.g., 1, 2, or 3) hydrogens in the group are replaced with a substituent selected from the group consisting of: deuterium, halogen, C 1-4 Alkyl, C 1-4 Halogenated compoundsAn alkyl group.
In another preferred embodiment, the compound is represented by formula I-2
Wherein,
X 1 、X 2 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 as defined in formula I-1.
In another preferred embodiment, R 1 Is substituted or unsubstituted C 1-6 An alkyl group.
In another preferred embodiment, R 1 Is substituted or unsubstituted C 1-4 An alkyl group.
In another preferred embodiment, R 1 Selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; preferably, R 1 Selected from the group consisting of: methyl, ethyl, n-propyl. In another preferred embodiment, R 1 Is ethyl.
In another preferred embodiment, R 2 Selected from the group consisting of: H. halogen, substituted or unsubstituted C 1-3 An alkyl group.
In another preferred embodiment, R 2 Selected from the group consisting of: H. halogen. In another preferred embodiment, R 2 Selected from the group consisting of: H. f, cl. In another preferred embodiment, R 2 H or F.
In another preferred embodiment, R 3 Is substituted or unsubstituted C 1-3 An alkyl group.
In another preferred embodiment, R 3 Is C 1-3 Alkyl or deuterated C 1-3 An alkyl group.
In another preferred embodiment, R 3 Is methyl or-CD 3 。
In another preferred embodiment, R 4 And R is 5 Each independently selecting the following group: H. halogen, substituted or unsubstituted C 1-3 An alkyl group. In another preferred embodiment, R 4 And R is 5 Each independently selecting the following group: H. halogen. In another preferred embodiment In the example, R 4 And R is 5 Each independently selecting the following group: H. halogen. In another preferred embodiment, R 4 And R is 5 Each independently selecting the following group: H. f, cl. In another preferred embodiment, R 4 And R is 5 Each independently is H or F.
In another preferred embodiment, R 4 And R is 5 Each independently is H. In another preferred embodiment, R 4 And R is 5 Each independently is halogen (e.g., F). In another preferred embodiment, R 4 Is H and R 5 Halogen (e.g., F). In another preferred embodiment, R 4 Is halogen (e.g. F) and R 5 H.
In another preferred embodiment, R 6 Selected from the group consisting of: H. methyl, ethyl.
In another preferred embodiment, X 1 、X 2 、R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 Are the corresponding groups in the specific compounds in the examples (such as the compounds shown in tables A and B).
In another preferred embodiment, the compound is selected from the group consisting of the compounds of tables a and B:
table A
Table B
In a second aspect of the present invention, there is provided a process for the preparation of a compound as described in the first aspect, comprising the steps of:
(a)
reacting the intermediate of formula 1 with the intermediate of formula 2-1 or 2-2 to obtain a compound represented by formula I-1 or I-2;
in the formulae, R H Is a reactive group (e.g. -CH 2 Cl、-CH 2 Br、-C(O)H);X 1 、X 2 、R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 As previously defined.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising:
(i) The compound of the first aspect or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier or excipient.
In another preferred embodiment, the pharmaceutical composition further comprises an additional antineoplastic agent.
In a fourth aspect of the present invention there is provided a compound as described in the first aspect in the manufacture of (i) a medicament for the treatment, amelioration or prophylaxis of diseases associated with PARP1 and/or diseases mediated by PARP 1; and/or (ii) a PARP1 inhibitor; and/or (iii) an antineoplastic agent; and/or (iv) use in a tumor drug sensitizer.
In another preferred embodiment, the compounds treat, ameliorate or prevent a disease associated with PARP1 and/or mediated by PARP1 by selectively inhibiting PARP 1.
In another preferred embodiment, the PARP 1-related and/or PARP 1-mediated disease comprises: cardiovascular disease, inflammatory disease, sepsis, fibrotic disease (such as scar, etc.), diabetes, fatty liver, cranial nerve disease, parkinson, senile dementia, osteoporosis, eye disease, virus, skin inflammatory disease, pulmonary hypertension, asthma, cerebral apoplexy, arthritis, enteritis, organ transplantation, and anti-shrink host disease.
In another preferred embodiment, the PARP 1-related and/or PARP 1-mediated disease comprises: tumors (e.g., cancers).
In another preferred embodiment, the PARP 1-related and/or PARP 1-mediated disease comprises: breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, leukemia, brain tumor, sarcoma, gastrointestinal cancer (such as gastric and colorectal cancer), or lung cancer, or a combination thereof.
In another preferred embodiment, the PARP1 inhibitor is a selective PARP1 inhibitor.
In another preferred embodiment, the tumor is a cancer; preferably, it includes: breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, leukemia, gastrointestinal cancer (e.g., gastric and colorectal) or lung cancer or combinations thereof
In another preferred embodiment, the gastrointestinal cancer comprises: gastric cancer, colorectal cancer.
In another preferred embodiment, the neoplastic drug sensitizer is used in combination with at least one additional antineoplastic drug.
In a fifth aspect of the present invention, there is provided a pharmaceutical combination comprising:
(a) The compound of the first aspect or a pharmaceutically acceptable salt or solvate thereof; and
(b) At least one additional antineoplastic agent.
In a sixth aspect of the present invention, there is provided a method of selectively inhibiting PARP1, the method comprising:
Contacting a subject with a compound according to the first aspect, thereby inhibiting PARP1 activity in the subject.
In another preferred embodiment, the subject is a cell or a PARP1 enzyme.
In another preferred embodiment, the inhibition is selective inhibition of PARP 1.
In another preferred embodiment, the method is non-therapeutic in vitro.
In a seventh aspect of the present invention, there is provided a method of treating, ameliorating or preventing (i) a PARP 1-related disease and/or a PARP 1-mediated disease or (ii) a tumor, comprising the steps of:
administering to a subject in need thereof a therapeutically effective amount of a compound according to the first aspect or a pharmaceutical composition according to the fourth aspect, thereby treating, ameliorating or preventing (i) a PARP 1-related disease and/or a PARP 1-mediated disease or (ii) a tumor.
In another preferred embodiment, the subject is a mammal, preferably a human.
In another preferred embodiment, the compounds treat, ameliorate or prevent a disease associated with PARP1 and/or mediated by PARP1 by selectively inhibiting PARP 1.
In another preferred embodiment, the PARP 1-associated and/or PARP 1-mediated disease is as described in the fourth aspect
In another preferred embodiment, the method further comprises administering to a subject in need thereof a therapeutically effective amount of an additional anti-tumor agent.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The inventors have conducted extensive and intensive studies to find that a class of compounds having a novel structure have significantly more excellent PARP1 inhibitory activity and surprisingly high selectivity for PARP1, for example, that such compounds have significantly higher PARP1 inhibitory activity than other PARP family members such as PARP2, thereby rendering such compounds less toxic. Based on this, the inventors completed the present invention.
Terminology
As used herein, the term "halogen" refers to F, cl, br or I. Accordingly, "halo" means that a hydrogen atom in a group is replaced with F, cl, br or I.
Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a straight or branched hydrocarbon radical having the indicated number of carbon atoms (i.e., C 1-6 Representing 1-6 carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
The term "cycloalkyl" refers to a compound having a specified number of ring atoms (e.g,C 3-6 Cycloalkyl has 3-6 ring atoms) and is a fully saturated hydrocarbon ring. "cycloalkyl" also refers to bicyclic and polycyclic hydrocarbon rings, e.g., bicyclo [2.2.1 ]]Heptane, bicyclo [2.2.2]Octane, and the like.
Substituents for alkyl groups (including those commonly referred to as alkylene, alkenyl, alkynyl and cycloalkyl) may be various groups selected from the group consisting of: halogen, alkyl (e.g. C 1-4 Alkyl), haloalkyl (e.g. C 1-4 Haloalkyl).
For the compounds provided herein, a bond from a substituent (typically an R group) to the center of the ring will be understood to refer to a bond attached to any available vertex of the ring.
As used herein, the terms "comprising," "including," or "comprising" mean that the various ingredients can be used together in a mixture or composition of the invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "containing.
As used herein, the term "pharmaceutically acceptable" ingredient refers to a substance that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response), commensurate with a reasonable benefit/risk ratio.
Unless otherwise indicated, all compounds present in the present invention are intended to include all possible optical isomers, such as single chiral compounds, or mixtures of various chiral compounds (i.e., racemates). Among all the compounds of the invention, each chiral carbon atom may optionally be in the R configuration or in the S configuration, or in a mixture of R and S configurations.
As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S).
Certain compounds of the application possess an asymmetric carbon atom (optical center) or double bond; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., isolated enantiomers) are all intended to be included within the scope of the present application. When compounds provided herein have a defined stereochemistry (denoted R or S, or indicated with dashed or wedge-shaped bonds), those compounds will be understood by those skilled in the art to be substantially free of other isomers (e.g., at least 80%,90%,95%,98%,99% and up to 100% free of other isomers).
The compounds of the present application may also contain non-natural proportions of atomic isotopes at one or more of the isotopic atoms constituting such compounds. The unnatural proportion of an isotope can be defined as from the naturally found amount of the atom in question to 100% of the amount of that atom. For example, the compounds may incorporate radioactive isotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) Or C-14% 14 C) Or non-radioactive isotopes, e.g. deuterium @, of 2 H) Or C-13% 13 C) A. The application relates to a method for producing a fibre-reinforced plastic composite Such isotopic variants may provide additional uses beyond those described herein. For example, isotopic variants of the compounds of the present application can have additional uses including, but not limited to, as diagnostic and/or imaging agents, or as cytotoxic/radiotherapeutic agents. In addition, isotopic variations of the compounds of the present application can have altered pharmacokinetic and pharmacodynamic characteristics to facilitate increased safety, tolerability, or efficacy during treatment. All isotopic variations of the compounds of the present application, whether radioactive or not, are intended to be encompassed within the scope of the present application.
Active ingredient
As used herein, the term "compound of the present invention" or "compound of the present invention" refers to a compound represented by formula (a), formula (A1), formula (A2), formula (B) or formula (I) herein (particularly a compound represented by formula (I)). The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (a) or formula (I).
Wherein the term "pharmaceutically acceptable salt" refers to salts of the compounds of the invention with acids or bases that are suitable for use as medicaments. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is the salts of the compounds of the present invention with acids. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and the like; amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred class of salts are salts of the compounds of the invention with bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butylamine, ethylenediamine, hydroxyethylamine, dihydroxyethylamine, and triethylamine salts, and amine salts formed from morpholine, piperazine, lysine, respectively.
The term "solvate" refers to a complex of the compound of the invention coordinated to a solvent molecule to form a specific ratio. "hydrate" refers to a complex of the compound of the present invention coordinated to water.
In addition, the compounds of the present invention also include prodrugs of compounds of formula (a) or formula (I). The term "prodrug" includes a class of compounds which may themselves be biologically active or inactive, and which upon administration by an appropriate method undergo a metabolic or chemical reaction in the human body to convert to a compound of formula (a) or formula (I), or a salt or solution of a compound of formula (a) or formula (I). The prodrugs include, but are not limited to, carboxylic acid esters, carbonic acid esters, phosphoric acid esters, nitric acid esters, sulfuric acid esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and the like of the compound.
Preparation method
The process for preparing the compounds of the structures of formula (a), formula (A1), formula (A2), formula (B) or formula (I) according to the present invention is specifically described herein, but these specific processes do not constitute any limitation to the present invention. The compounds of the present invention may also be conveniently prepared by optionally combining the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present invention pertains.
Pharmaceutical compositions and methods of administration
Since the compounds of the present invention have excellent selective inhibitory activity and antitumor activity against PARP1, the compounds of the present invention and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compounds of the present invention as a main active ingredient are useful for the treatment, prevention and amelioration of diseases associated with PARP1 or mediated by PARP1 or for the treatment, prevention and amelioration of tumors. According to the prior art, the compounds of the invention are useful for the treatment of: cancer, cardiovascular disease, inflammatory disease, sepsis, fibrotic disease (such as scar, etc.), diabetes, fatty liver, cerebral nerve disease, parkinson's disease, senile dementia, osteoporosis, eye disease, virus, skin inflammatory disease, pulmonary hypertension, asthma, cerebral apoplexy, arthritis, enteritis, organ transplantation and anti-shrink primary disease. The cancer may be breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, leukemia, brain tumor, sarcoma, gastrointestinal cancer (e.g., gastric and colorectal cancer), or lung cancer.
Herein, the term "selective" refers to a higher activity or potency (e.g., inhibitory activity) for a given target (e.g., PARP 1) than for other targets (e.g., PARP 2); for example, the activity or potency (e.g., inhibitory activity) against a given target (e.g., PARP 1) is at least 100-fold greater than the activity or potency (e.g., inhibitory activity) against other targets (e.g., PARP 2). For example, when the enzyme inhibitory activity is quantified by IC50 value, the IC50 Others /IC50 PARP1 >50 (> 100, > 500), where IC50 PARP1 Refers to the IC50 (e.g., IC50 values measured by the method of test example 1 herein) of the compounds of the invention for enzymatic inhibition of PARP1, IC50 Others Refers to the inhibitory activity IC50 (nM) of the compounds of the invention against one or more of the following enzymes: PARP2.
The pharmaceutical compositions of the present invention comprise a safe and effective amount or range of therapeutically effective amounts of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 0.01 to 100mg of the compound of the invention per dose, more preferably 0.01 to 50mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g. ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds. For example, the compounds of the present invention may be administered as sensitizers for antitumor drugs in combination with at least one additional antitumor drug. The additional antineoplastic agents may be targeted agents or chemotherapy and radiotherapy agents (e.g., carboplatin, paclitaxel, temozolomide, etc.), and proton therapy.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 0.01 to 100mg, preferably 0.01 to 50mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The main advantages of the invention include:
1. the compounds of the present invention have excellent selectivity. The compounds of the present invention have more excellent inhibitory activity against PARP1 than PARP 2. Thus, the compounds of the present invention have lower toxicity and superior safety.
2. The compounds of the present invention have excellent inhibitory activity while having excellent selectivity
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
A. Preparation example
Example 1: synthesis of Compound 1
Step A
Compound 1a (5 g,13.1 mmol), silver difluoride (11.8 g,80.6 mmol) was added sequentially to a round bottom flask containing 100mL of acetonitrile, nitrogen protected, and stirred at room temperature in the dark for 20 hours. LCMS was monitored, after completion of the reaction, filtered and the filtrate concentrated. 200mL of ethyl acetate was added, the organic phase was washed with water (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (eluent: ethyl acetate/petroleum ether, 1/10, v/v) to give compound 1b (3.6 g, 59.7%) as a white solid. 1H NMR (400 MHz, CDCl 3): delta ppm 8.12 (t, J=8.1 Hz, 1H), 7.90 (dd, J=7.9, 1.3Hz, 1H), 3.98 (s, 3H): LCMS:233.9,235.9
[M+H]+.
Step B
Compound 1b (1 g,4.32 mmol), compound 1c (0.83 g,4.8 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (0.3 g,0.48 mmol), tris (dibenzylideneacetone) dipalladium (0.44 g,0.48 mmol), cesium carbonate (1.88 g,5.76 mmol) were added sequentially to a round bottom flask containing 1, 4-dioxane (30 mL), nitrogen protected, and stirred at 100deg.C for 16 hours. After completion of the reaction, LCMS was monitored, concentrated under reduced pressure, diluted with water (100 mL), extracted with ethyl acetate (80 mL. Times.3), combined extracts, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (eluent: petroleum ether/ethyl acetate, 5/1, v/v) to give compound 1d (0.9 g, 54.2%) as a white solid. LCMS 326.1[ m+h ] +.
Step C
Compound 1d (800 mg,2.45 mmol) was added to a round bottom flask containing methanol (3 mL) and tetrahydrofuran (4 mL), and 2N aqueous sodium hydroxide solution (30 mL) was added with stirring and stirred at room temperature for 16 hours. LCMS monitored, after completion of the reaction, the reaction was concentrated, diluted with 10mL of water, and ph=4 with 3M HCl. Ethyl acetate extraction (100 ml×3), combined extracts, washing with saturated brine, drying over anhydrous sodium sulfate, and concentrating under reduced pressure gave compound 1e (750 mg, 88.17%) as a white solid. 1H NMR (400 MHz, CD3 OD): delta ppm 7.88 (dd, J=8.1, 1.2Hz, 1H), 6.97 (dd, J=10.2, 8.2Hz, 1H), 4.46-4.17 (m, 3H), 3.85 (dd, J=7.9, 3.8Hz, 2H), 1.42 (s, 9H). LCMS:256.0[ M-56] +.
Step D:
compound 1e (750 mg,2.4 mmol), formamide hydrochloride (194.6 mg,2.88 mmol), HATU (1.09 g,2.88 mmol), N, N-diisopropylethylamine (620.7 mg,4.80 mmol) was added sequentially to a round bottom flask containing N, N-dimethylformamide (30 mL) and stirred at 70℃for 16 h. After completion of the reaction, LCMS was monitored, diluted with water (50 mL), extracted with ethyl acetate (80 mL. Times.3), combined extracts, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (eluent: petroleum ether/ethyl acetate, 2/3, v/v) to give compound 1f as a white solid (800 mg, 92.1%). LCMS 325.1[ M+H ] +.
Step E:
compound 1f (800 mg,2.46 mmol) was added to a round bottom flask containing 20mL of dichloromethane, trifluoroacetic acid (3 mL) was added with stirring at room temperature, and stirring was performed at room temperature for 16 hours. The LCMS was monitored and the temperature was monitored,
after completion of the reaction, concentration was performed under reduced pressure to obtain 1g (600 mg, 97.9%) of a pale yellow solid compound. LCMS 225.1[ m+h ] +.
Step F:
compound 1h (5 g,23.2 mmol), N-dimethylformamide dimethyl acetal (31.5 mL) was added sequentially to a round bottom flask containing 50mL of N, N-dimethylformamide and stirred at 90 ℃ for 5 hours.
LCMS was monitored, and after completion of the reaction, concentrated under reduced pressure and isolated by medium pressure flash chromatography (eluent: petroleum ether/ethyl acetate, 10/1, v/v) to afford compound 1i as a yellow solid (5.8 g, 93.5%). 1H NMR (400 MHz, CDCl 3): delta ppm 8.40 (d, J=2.0 Hz, 1H), 8.34 (d, J=2.4 Hz, 1H), 8.18
–8.15(m,1H),6.15(d,J=12.4Hz,1H),3.05(s,6H).
Step G:
/>
compound 1i (5.8 g,21.4 mmol) and sodium periodate (13.7 g,64.0 mmol) were added sequentially to a round bottom flask containing 100mL of tetrahydrofuran and 100mL of water and stirred at room temperature for 14 hours. LCMS monitored, after completion of the reaction, a 10% sodium bisulfite solution was quenched, extracted with ethyl acetate (100 ml×3), the combined extracts dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium pressure flash chromatography (eluent: petroleum ether/ethyl acetate, 10/1, v/v) to give compound 1j (3.1 g, 63.3%) as a yellow solid. 1H NMR (400 MHz, CDCl 3): delta ppm 10.20 (s, 1H), 9.02 (d, J=2.0 Hz, 1H), 8.36 (d, J=1.6 Hz, 1H).
Step H:
sodium hydride (60%, 644.1mg,16.1 mmol) was dispersed in dry tetrahydrofuran (50 mL), nitrogen was purged, and compound 1k (4.1 g,16.3 mmol) was added dropwise at 0deg.C and stirred at 0deg.C for 1 hour. Then, a solution of Compound 1j (3.1 g,13.5 mmol) in 30mL of tetrahydrofuran was added dropwise at 0℃and stirred at room temperature for 16 hours. After completion of the reaction, LCMS was monitored, quenched with water (20 mL), extracted with ethyl acetate (50 mL. Times.2), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and isolated by medium pressure flash chromatography (eluent: petroleum ether/ethyl acetate, 10/1, v/v) to give compound 1l (1.8 g, 40.7%) as a yellow solid. 1H NMR (400 MHz, CDCl 3): delta ppm 8.87 (d, J=2.0 Hz, 1H), 8.40 (d, J=2.0 Hz, 1H), 7.70 (s, 1H), 4.23 (q, J=7.2 Hz, 2H), 2.53 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H), 1.03 (t, J=7.2 Hz, 3H): LCMS:329.0,331.1[ M+H ] +.
Step I:
compound 1l (1.8 g,5.5 mmol), iron powder (1.5 g,26.8 mmol), ammonium chloride (1.45 g,28.3 mmol) were added sequentially to a round bottom flask containing ethanol/water (30 mL,4/1, v/v) and stirred at 70℃for 3 hours. LCMS was monitored, after completion of the reaction, filtration, concentration of the filtrate, dilution with water (30 mL), extraction with dichloromethane (50 ml×2), combined extracts, drying over anhydrous sodium sulfate, concentration under reduced pressure, separation by medium pressure flash chromatography (eluent: petroleum ether/ethyl acetate, 3/1, v/v) to give compound 1m (150 mg, 10.9%) as a yellow solid. LCMS 252.7,254.7[ M+H ] +.
Step J:
/>
compound 1m (150 mg,0.60 mmol), triethylamine (180 mg,1.78 mmol), triethylsilane (137.8 mg,1.19 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (48.4 mg,0.059 mmol) were successively added to a high-pressure reaction vessel containing 5mL of N, N-dimethylformamide, carbon monoxide (1 MPa) was charged, and stirred at 100℃for 16 hours. After completion of the reaction, LCMS was monitored, cooled to room temperature, filtered, the filtrate was concentrated, diluted with 20mL of water, extracted with ethyl acetate (30 mL. Times.3), the combined extracts dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to medium pressure flash preparative chromatography (eluent: ethyl acetate/petroleum ether, 1/10-3/1, v/v) to give compound 1n (88 mg, 73.3%) as a yellow solid. 1H NMR (400 MHz, CDCl 3): delta ppm 11.19 (s, 1H), 10.21 (s, 1H), 8.99 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 2.79 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.4 Hz, 3H): LCMS:203.1[ M+H ] +.
Step K:
compound 1n (88 mg,0.44 mmol), compound 1g (96 mg,0.43 mmol), glacial acetic acid (0.05 mL) are added sequentially to a round bottom flask containing 10mL of methanol and stirred at room temperature for 16 hours, followed by sodium cyanoborohydride (55 mg,0.88 mmol) and stirring at room temperature for 2 hours. LCMS was monitored, after completion of the reaction, quenched with water (20 mL), extracted with ethyl acetate (30 mL. Times.2), the combined extracts washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium pressure flash chromatography (eluent: dichloromethane/methanol, 10/1, v/v) to give compound 1 as an off-white solid (50 mg, 28%).
1H NMR(400MHz,CD3OD)δppm 8.55(d,J=1.7Hz,1H),7.82(t,J=7.2Hz,3H),7.08(t,J=9.0Hz,1H),4.72–4.49(m,5H),4.31–4.17(m,2H),2.87(s,3H),2.71–
2.60(m,2H),1.26(t,J=7.4Hz,3H).LCMS:411.1[M+H]+.
Example 2: synthesis of Compound 2
Step A
Compound 1d (400 mg,1.23 mmol) was added to a round-bottomed flask containing 20mL of N, N-dimethylformamide, sodium hydride (35.3 mg,1.47 mmol) was added under stirring at 0℃and after stirring for 30 minutes, methyl iodide (208.8 mg,1.47 mmol) was added dropwise and stirring was carried out at room temperature for 1 hour. LCMS monitored, and after completion of the reaction, the reaction was quenched by addition of 1mL of saturated sodium chloride. Diluting with water (30 mL), extracting with ethyl acetate (30 mL. Times.3), combining the extracts, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (eluent: petroleum ether/ethyl acetate, 3/2, v/v) to give compound 2a (400 mg, 86.3%) as a white solid. LCMS 284.1[ M-56] +.
Step B
Compound 2a (600 mg,1.76 mmol) was added to a round bottom flask containing 10mL of methanol, a solution of methylamine in tetrahydrofuran (8.8 mL,17.3 mmol) was added and stirred in the greenhouse for 16 hours. LCMS monitored, and after completion of the reaction, the filtrate was concentrated. 10mL of water was added, extraction was performed with ethyl acetate (30 mL. Times.3), and the extracts were combined and dried over anhydrous sodium sulfate to give compound 2b (600 mg, 90%) as a yellow oil. LCMS 238.1[ M-56] +.
Step C
Compound 2b (400 mg,1.77 mmol) was added to a round bottom flask containing 20mL of dichloromethane and trifluoroacetic acid (3 mL) was added with stirring at room temperature and stirred for 16 h. LCMS monitored, after completion of the reaction, concentrated under reduced pressure to give compound 2c (450 mg, 96.2%) as a yellow oil. LCMS 239.1[ M+H ] +.
Step D
Compound 1n (88 mg,0.44 mmol), compound 2c (100 mg,0.42 mmol), and glacial acetic acid (0.05 mL) were added sequentially to a round-bottomed flask containing 10mL of methanol, stirred at room temperature for 16 hours, followed by sodium cyanoborohydride (55 mg,0.88 mmol) and stirring at room temperature was continued for 2 hours. LCMS was monitored, after completion of the reaction, quenched with water (20 mL), extracted with ethyl acetate (30 ml×2), the combined extracts washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and isolated by medium pressure flash chromatography (eluent: dichloromethane/methanol, 10/1, v/v) to give compound 2 as an off-white solid (60 mg, 32%).
1H NMR(400MHz,CD3OD)δppm 8.43(s,1H),7.88–7.75(m,2H),7.68(s,1H),7.32–7.21(m,1H),4.30–4.18(m,1H),3.96(s,2H),3.87(t,J=7.4Hz,2H),3.39(t,J=7.4Hz,2H),2.88(d,J=1.7Hz,6H),2.63(q,J=7.3Hz,2H),1.25(t,J=7.4Hz,3H).LCMS:425.1[M+H]+.
Example 3: synthesis of Compound 3
Step A
Compound 1a (1.25 g,5.8 mmol), compound 1c (1 g,5.8 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (0.36 g,5.8 mmol), tris (dibenzylideneacetone) dipalladium (0.53 g,0.58 mmol), cesium carbonate (2.27 g,6.96 mmol) were added sequentially to a round bottom flask containing 100mL of 1, 4-dioxane, nitrogen protected, and stirred at 100℃for 16 hours. LCMS monitored, after completion of the reaction, cooled to room temperature. Diluting with water (100 mL), extracting with ethyl acetate (200 mL. Times.3), combining the extracts, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (eluent: petroleum ether/ethyl acetate, 2/3, v/v) to obtain pale yellow solid compound 3a (0.9 g, 44.83%). LCMS 308.1[ m+h ] +.
Step B
Compound 3a (400 mg,1.30 mmol) was added to a round bottom flask containing methanol (3 mL) and tetrahydrofuran (4 mL), and 2N aqueous sodium hydroxide solution (3 mL) was added with stirring and stirred at room temperature for 16 hours. LCMS monitored, after completion of the reaction, the reaction was concentrated, diluted with 10mL of water, and ph=4 with 3M HCl. Ethyl acetate extraction (50 ml×3), combined extracts, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 3b (350 mg, 82.50%) as a pale yellow solid. LCMS 294.1[ m+h ] +.
Step C
Compound 3b (400 mg,1.36 mmol), methochloride (110.11 mg,1.63 mmol), HATU (620.08 mg,1.63 mmol), N, N-diisopropylethylamine (351.27 mg,2.72 mmol) were added sequentially to a round bottom flask containing 20mL of N, N-dimethylformamide and stirred in the greenhouse for 16 hours. After completion of the reaction, the LCMS was monitored, diluted with 40mL of water, extracted with ethyl acetate (30 mL. Times.3), the combined extracts dried over anhydrous sodium sulfate, and separated by column chromatography (eluent: petroleum ether/ethyl acetate, 1/5, v/v) to give compound 3c (400 mg, 86.2%) as a white solid. LCMS 307.2[ m+h ] +.
Step D
Compound 3c (400 mg,1.30 mmol) was added to a round bottom flask containing 20mL of dichloromethane and trifluoroacetic acid (4 mL) was added with stirring at room temperature and stirred at room temperature for 16 hours. LCMS monitored, after completion of the reaction, concentrated under reduced pressure to give compound 3d (270 mg, 90.5%) as a yellow oil. LCMS 207.2[ M+H ] +.
Step E
Compound 3d (92.7 mg,0.45 mmol), compound 3e (100 mg,0.37 mmol), potassium iodide (74.6 mg,0.45 mmol), N, N-diisopropylethylamine (96.8 mg,0.75 mmol) were added sequentially to a round bottom flask containing 10mL of acetonitrile and stirred at 70℃for 4 hours. After completion of the reaction, LCMS was monitored, concentrated under reduced pressure, extracted with 30mL of water, ethyl acetate (30 mL. Times.3), the combined extracts dried over anhydrous sodium sulfate, and separated by column chromatography (eluent: dichloromethane/methanol, 1/10, v/v) to give compound 3 (73 mg, 44.7%) as a white solid. 1H NMR (400 MHz, CD3 OD) delta ppm 8.46 (s, 1H), 8.18 (s, 1H), 7.92 (d, J=2.3 Hz, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.72 (s, 1H), 6.92 (dd, J=8.6, 2.5Hz, 1H), 4.31 (dd, J=12.9, 6.4Hz, 1H), 4.21-4.01 (m, 4H), 3.49 (d, J=5.9 Hz, 2H), 2.89 (s, 3H), 2.63 (q, J=7.3 Hz, 2H), 1.25 (t, J=7.4 Hz, 3H) S:393.1[ M+H ] +.
Example 4: synthesis of Compound 4
Step A
Compound 3a (500 mg,1.62 mmol) was added to a round bottom flask containing 20mL of N, N-dimethylformamide, sodium hydride (60%, 74.7mg,1.95 mmol) was added under stirring at 0℃and after stirring for 30 minutes, ethyl iodide (303.45 mg,1.95 mmol) was added dropwise and stirring was carried out at room temperature for 1 hour. LCMS monitored, and after completion of the reaction, the reaction was quenched by addition of 1mL of saturated sodium chloride. Diluting with water (30 mL), extracting with ethyl acetate (30 mL. Times.3), combining the extracts, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (eluent: petroleum ether/ethyl acetate, 3/2, v/v) to give compound 4a (450 mg, 70.1%) as a white solid. LCMS 336.1[ m+h ] +.
Step B
Compound 4a (400 mg,1.19 mmol) was added to a round bottom flask containing methanol (3 mL) and tetrahydrofuran (4 mL), and 2N aqueous sodium hydroxide solution (3 mL) was added with stirring and stirred at room temperature for 16 hours. After completion of LCMS monitoring the reaction, the reaction was concentrated, diluted with 10mL of water and ph=4 with 3M HCl. Ethyl acetate extraction (50 ml×3), combined extracts, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 4b (370 mg, 86.9%) as a white solid. LCMS 321.9[ m+h ] +.
Step C
Compound 4b (370 mg,1.15 mmol), methochloride (93.0 mg,1.38 mmol), HATU (523.7 mg,1.38 mmol), N, N-diisopropylethylamine (296.7 mg,2.29 mmol) were added sequentially to a round bottom flask containing 20mL of N, N-dimethylformamide and stirred in the greenhouse for 16 hours. After completion of the reaction, the LCMS was monitored, diluted with 40mL of water, extracted with ethyl acetate (30 mL. Times.3), the combined extracts dried over anhydrous sodium sulfate, and separated by column chromatography (eluent: petroleum ether/ethyl acetate, 1/5, v/v) to give compound 4c (350 mg, 81.8%) as a white solid. LCMS 335.1[ m+h ] +.
Step D
Compound 4c (300 mg,0.89 mmol) was added to a round bottom flask containing 20mL of dichloromethane and trifluoroacetic acid (4 mL) was added with stirring at room temperature and stirred at room temperature for 16 hours. LCMS monitored, after completion of the reaction, concentrated under reduced pressure to give compound 4d (200 mg, 85.9%) as a yellow oil. LCMS 235.1[ m+h ] +.
Step E
Compound 4c (92.7 mg,0.45 mmol), compound 3e (100 mg,0.37 mmol), potassium iodide (74.6 mg,0.45 mmol) and N, N-diisopropylethylamine (96.8 mg,0.75 mmol) were added sequentially to a round bottom flask containing 10mL of acetonitrile and stirred at 70℃for 4 hours. After completion of the reaction, LCMS was monitored, concentrated under reduced pressure, extracted with 30mL of water, ethyl acetate (30 mL. Times.3), the combined extracts dried over anhydrous sodium sulfate, and separated by column chromatography (eluent: dichloromethane/methanol, 1/10, v/v) to give compound 4 (73 mg, 44.7%) as a white solid. 1H NMR (400 MHz, CD3 OD) delta ppm 8.45 (d, J=1.1 Hz, 1H), 8.03 (s, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.11 (dd, J=8.8, 2.0Hz, 1H), 4.38-4.32 (m, 1H), 3.94-3.91 (m, 4H), 3.54 (q, J=7.0 Hz, 2H), 3.34 (t, J=7.6 Hz, 2H), 2.90 (s, 3H), 2.72-2.54 (m, 2H), 1.25 (t, J=7.4 Hz, 3H), 1.10 (t, J=7.0 Hz, 3H) S:421.1
[M+H]+.
Example 5: synthesis of Compound 5
Step A
Compound 5a (5.0 g,21 mmol) and compound 5b (3.23 g,21 mmol) were added to DMF (60 mL) followed by slow dropwise addition of N, N-diisopropylethylamine (8.14 g,63 mmol) and stirring on ice for 4 hours. After completion of the reaction, LCMS was monitored, diluted with water (200 mL), extracted with ethyl acetate (200 ml×3), combined extracts, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give yellow oily compound 5c (6.1 g), crude, which was used directly in the next step without purification. LCMS 334.9,337.0[ M+H ] +.
Step B
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Compound 5c (6.1 g, crude) was added sequentially to a round bottom flask containing methanol (120 mL), and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered, potassium carbonate (5.1 g,36.4 mmol) was added to the filtrate, stirred at room temperature for 4 hours, diluted with water (200 mL), extracted with ethyl acetate (200 mL. Times.3), the extracts were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=1:1) to give compound 5d (3.0 g, 52.3% in two steps) as a yellow solid. 1H NMR (400 MHz, CDCl 3): δppm 9.17 (s, 1H), 6.87 (d, J=6.4 Hz, 1H), 6.47 (d, J=9.2 Hz, 1H), 3.88 (dd, J=7.6, 4.8Hz, 1H), 1.85-1.78 (m, 2H), 1.01 ((t, J=7.6 Hz, 3H). LCMS:272.9,274.9[ M+H ] +.
Step C
Compound 5d (3.0 g,11.0 mmol) was dissolved in dichloromethane (80 mL), and 2, 3-dichloro-5, 6-dicyanobenzoquinone (3.25 g,14.3 mmol) was added under nitrogen and reacted at room temperature for 3 hours. The reaction solution was filtered, and the cake was slurried with methanol, and filtered to give compound 5e (2.3 g, 77.3%) as a yellow solid. LCMS 270.9,272.9[ m+h ] +.
Step D
Compound 5e (2.3 g,8.5 mmol), compound 5f (3.56 g,11.0 mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (0.67 g,0.85 mmol) was added to dioxane (60 mL), nitrogen-protected, and stirred at 80℃for 4 hours. After completion of the reaction, the crude product was concentrated under reduced pressure, slurried with methylene chloride and filtered to give 5g (1.4 g, 72.9%) of a yellow solid compound. 1H NMR (400 MHz, DMSO-d 6) delta ppm 12.38 (s, 1H), 7.49 (d, J=10.4 Hz, 1H), 7.41 (d, J=10.8 Hz, 1H), 5.51 (t, J=5.6 Hz, 1H), 4.63 (d, J=5.6 Hz, 2H), 2.83-2.7 (m, 2H), 1.21 (t, J=5.6 Hz, 3H) LCMS 223.1[ M+H ] +.
Step E
5g (0.5 g,2.2 mmol) of the compound was added to dry dichloromethane (20 mL), and phosphorus tribromide (1.78 g,6.6 mmol) was added dropwise at 0deg.C under nitrogen and stirred at room temperature for 16 hours. LCMS monitored, after completion of the reaction, filtration, cake rinsing with dichloromethane (30 mL) and drying gave compound as a yellow solid for 5h (0.47 g, 75.5%). LCMS 285.1,287.1[ M+H ] +.
Step F
Compound 5h (102 mg,0.36 mmol), compound 1g (80 mg,0.36 mmol) and potassium iodide (18 mg,0.11 mmol) were dissolved in acetonitrile (10 mL), nitrogen blanketed, and diisopropylethylamine (138 mg,1.07 mmol) was then added and stirred at 70℃for 5 hours. LCMS was monitored, after completion of the reaction, diluted with water (20 mL), extracted with ethyl acetate (20 ml×3), combined extracts, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative chromatography [ (Gemini-C18 column, 5 μ silica, 21mm diameter, 150mm long), water (0.1% TFA) and MeCN as eluents (50-90%) ] to give compound 5 (30 mg, 18.3%) as a white solid. 1H NMR (400 MHz, CD3 OD): delta ppm 7.80 (d, J=8.0 Hz, 1H), 7.64 (d, J=10.4 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.09 (t, J=8.8 Hz, 1H), 4.64-4.60 (m, 5H), 4.25-4.24 (m, 2H), 2.89-2.86 (m, 5H), 1.28 (t, J=7.2 Hz, 3H): LCMS:429.0[ M+H ] +.
Example 6: synthesis of Compound 6
Compound 5h (71.8 mg,0.25 mmol), compound 2c (50 mg,0.21 mmol), potassium iodide (41.8 mg,0.25 mmol), N, N-diisopropylethylamine (54.2 mg,0.42 mmol) were added sequentially to a round bottom flask containing 10mL of acetonitrile and stirred at 70℃for 16 h. After completion of the reaction, LCMS was monitored, diluted with water (20 mL), extracted with ethyl acetate (30 mL. Times.3), the extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (eluent: dichloromethane/methanol, 10/1, v/v) to give compound 6 (9 mg, 8.8%) as a white solid. 1H NMR (400 MHz, DMSO-d 6) delta ppm 12.29 (s, 1H), 8.39 (d, J=4.8 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.52 (d, J=10.4 Hz, 1H), 7.39-7.28 (m, 2H), 4.19-4.05 (m, 1H), 3.72 (s, 2H), 3.65 (t, J=6.9 Hz, 2H), 3.06 (t, J=6.8 Hz, 2H), 2.86 (s, 3H), 2.82-2.74 (m, 5H), 1.20 (t, J=7.4 Hz, 3H) & LCMS 443.1[ M+H ] +.
Example 7: synthesis of Compound 7
Step A
Compound 7a (10.0 g,42 mmol) and compound 5b (6.45 g,42 mmol) were added to DMF (100 mL) followed by slow dropwise addition of N, N-diisopropylethylamine (16.3 g,126 mmol) and stirring on ice for 4 hours. After completion of the reaction, LCMS was monitored, diluted with water (200 mL), extracted with ethyl acetate (200 ml×3), combined extracts, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 7b (18 g) as a yellow oily compound, crude, which was used directly in the next step without purification. LCMS 334.9,337.0[ M+H ] +.
Step B
Compound 7b (18 g, crude), ammonium chloride (22.98 g,429 mmol) and zinc powder (15.8 g,242 mmol) were added sequentially to a round bottom flask containing methanol (200 mL) and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered, potassium carbonate (6 g,44 mmol) was added to the filtrate, stirred at room temperature for 4 hours, diluted with water (200 mL), extracted with ethyl acetate (200 mL. Times.3), the extracts were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was separated by column chromatography (eluent: petroleum ether/ethyl acetate=1:1) to give compound 7c (3 g, 26.2% in two steps) as a yellow solid.
1H NMR(400MHz,DMSO-d6):δppm 10.47(s,1H),7.01–6.97(m,1H),6.53–6.51(m,2H),3.74–3.71(m,1H),1.68–1.57(m,2H),0.92((t,J=7.6Hz,3H).LCMS:273.1,275.1[M+H]+.
Step C
Compound 7c (2.8 g,10.3 mmol) was dissolved in dichloromethane (30 mL), and 2, 3-dichloro-5, 6-dicyanobenzoquinone (2.8 g,12.4 mmol) was added under nitrogen and reacted at room temperature for 3 hours. The reaction solution was filtered, and the cake was slurried with methanol, and filtered to give compound 7d (2.3 g, 77.8%) as a yellow solid. LCMS 270.8,272.8[ m+h ] +.
Step D
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Compound 7d (2.3 g,8.5 mmol), compound 5f (3.3 g,10.2 mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (0.47 g,0.60 mmol) was added to dioxane (60 mL), nitrogen-protected, and stirred at 80℃for 4 hours. After completion of the reaction, the crude product was concentrated under reduced pressure, slurried with dichloromethane and filtered to give compound 7e (1.5 g, 71.76%) as a yellow solid. 1H NMR (400 MHz, DMSO-d 6) delta ppm 12.42 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.32 (t, J=15.6 Hz, 1H), 4.63 (d, J=5.2 Hz, 2H), 2.84-2.78 (m, 2H), 1.21 (t, J=14.8 Hz, 3H). LCMS:223.1[ M+H ] +.
Step E
Compound 7e (0.6 g,2.7 mmol) was added to dry dichloromethane (30 mL), nitrogen blanketed, and phosphorus tribromide (2.19 g,8.1 mmol) was added dropwise at 0deg.C and stirred at room temperature for 16 hours. LCMS monitored, after completion of the reaction, filtration, filter cake eluting with dichloromethane (30 mL) and drying gave compound 7f (0.6 g, 70.37%) as a yellow solid. LCMS 285.0,287.0[ M+H ] +.
Step F
Compound 7f (71.8 mg,0.25 mmol), compound 2c (50 mg,0.21 mmol), potassium iodide (41.8 mg,0.25 mmol) and N, N-diisopropylethylamine (54.2 mg,0.42 mmol) were added sequentially to a round-bottomed flask containing 10mL of acetonitrile and stirred at 70℃for 16 hours. After completion of the reaction, LCMS was monitored, diluted with water (20 mL), extracted with ethyl acetate (30 mL. Times.3), combined extracts, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (eluent: dichloromethane/methanol, 10/1, v/v) to give compound 7 (20 mg, 19.8%) as a white solid. 1H NMR (400 MHz, CD3 OD) delta ppm 7.85 (d, J=7.7 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.41-7.28 (m, 2H), 4.64 (s, 2H), 4.56-
4.46(m,3H),4.27(dd,J=10.5,6.0Hz,2H),2.92(s,3H),2.91–2.85(m,5H),1.28(t,J=7.4Hz,3H).LCMS:443.1[M+H]+.
Example 8: synthesis of Compound 8
Compound 7f (102 mg,0.36 mmol), compound 1g (80 mg,0.36 mmol) and potassium iodide (18 mg,0.11 mmol) were dissolved in acetonitrile (10 mL), nitrogen blanketed, followed by diisopropylethylamine (185 mg,1.42 mmol) and stirred at 70℃for 5 hours. LCMS monitored, after completion of the reaction, diluted with water (20 mL), extracted with ethyl acetate (20 ml×3), combined extracts, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative chromatography [ (Gemini-C18 column, 5 μ silica, 21mm diameter, 150mm long), water (0.1% TFA) and MeCN as eluent (50-90%) ] gave compound 8 (14 mg, 8.61%) as a white solid. 1H NMR (400 MHz, CD3 OD): delta 7.80 (d, J=8.0 Hz, 1H), 7.67 (d, J=7.2 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.09 (t, J=8.0 Hz, 1H), 4.65-4.60 (m, 5H), 4.27-4.21 (m, 2H), 2.93-2.87 (m, 5H), 1.29 (t, J=7.2 Hz, 3H): LCMS 429.0[ M+H ] +.
Example 9: synthesis of Compound 9
Step A
Compound 9a (2 g,10.7 mmol), compound 1a (2 g,9.3 mmol), cesium carbonate (9 g,27.62 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (1.7 g,2.73 mmol) and tris (dibenzylideneacetone) dipalladium (850 mg,0.93 mmol) were added sequentially to 1, 4-dioxane (50 mL), nitrogen protected, and stirred at 100deg.C for 16 hours. After completion of the reaction, LCMS was monitored, concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with water (50 mL. Times.2), saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (eluent: petroleum ether/ethyl acetate, 1/4to 1/1, v/v) to give compound 9b (2.2 g, 73.9%) as a pale yellow solid. 1H NMR (400 MHz, CDCl 3): delta ppm:8.16 (d, J=3.2 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 6.98 (dd, J=8.8, 3.2Hz, 1H), 4.64-4.54 (m, 1H), 4.29-4.22 (m, 2H), 4.05-3.99 (m, 2H), 3.96 (s, 3H), 3.09 (s, 3H), 1.46 (s, 9H). LCMS:322.1[ M+H ] +.
Step B
Compound 9b (2.2 g,6.85 mmol) and sodium hydroxide (1.1 g,27.38 mmol) were dissolved in methanol (40 mL) and water (10 mL) and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was diluted with water (50 mL), the pH was adjusted to 4 with 1N diluted hydrochloric acid, and the mixture was filtered to give Compound 9c (1.8 g, 85.5%) as a pale yellow solid. 1H NMR (400 MHz, CDCl 3): delta ppm:8.11 (d, J=2 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.09 (dd, J=8.4, 2.4Hz, 1H), 4.70-4.60 (m, 1H), 4.33-4.28 (m, 2H), 4.06-4.00 (m, 2H), 3.13 (s, 3H), 1.46 (s, 9H).
Step C
Compound 9c (250 mg,0.81 mmol), methylamine hydrochloride (82 mg,1.21 mmol), HATU (370 mg,0.97 mmol) and N, N-diisopropylethylamine (420 mg,3.25 mmol) were added sequentially to N, N-dimethylformamide (10 mL) and stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 mL), washed with water (30 mL. Times.2), saturated aqueous sodium chloride (30 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (eluent: petroleum ether/ethyl acetate, 1/1, v/v) to give compound 9d (200 mg, 76.7%) as a pale yellow solid. LCMS 321.1[ M+H ]
Step D
Compound 9d (200 mg,0.62 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (3 mL) was added dropwise. Stirred at room temperature for 2 hours. After completion of the reaction, LCMS was monitored and concentrated under reduced pressure to give compound 9e (100 mg) as a white solid, crude product, which was used directly in the next reaction without purification. LCMS 221.2[ m+h ] +.
Step E
Compound 9e (100 mg,0.43 mmol), compound 3e (145 mg,0.54 mmol), potassium iodide (75 mg,0.45 mmol) and N, N-diisopropylethylamine (235 mg,1.82 mmol) were added to acetonitrile (10 mL), nitrogen blanket, and stirred at 70℃for 2 hours. After completion of the reaction, LCMS was monitored, concentrated under reduced pressure, the residue was diluted with water (20 mL), extracted with ethyl acetate (20 ml×2), washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to hplc separation [ (Gemini-C18 column, 5 μ silica, 21mm diameter, 150mm length), water (0.1% TFA) and MeCN (10-30%) as eluent to give compound 9 (20 mg, 11.4%) as an off-white solid. 1H NMR (400 MHz, CD3 OD): δppm 8.62 (d, J=2.0 Hz, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 7.88 (s, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.31 (dd, J=8.8, 2.8Hz, 1H), 4.68 (s, 2H), 4.57-4.33 (m, 4H), 4.00 (s, 1H), 3.13 (s, 3H), 2.95 (s, 3H), 2.74-2.66 (m, 2H), 1.31 (t, J=7.6 Hz, 3H): S:407.2[ M+H ] +.
Example 10: synthesis of Compound 10
Step A:
compound 9c (250 mg,0.81 mmol), deuterated methylamine hydrochloride (86 mg,1.22 mmol), HATU (370 mg,0.97 mmol) and N, N-diisopropylethylamine (420 mg,3.25 mmol) were added sequentially to N, N-dimethylformamide (10 mL) and stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 mL), washed with water (30 mL. Times.2), saturated aqueous sodium chloride (30 mL. Times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on column (eluent: petroleum ether/ethyl acetate, 1/1, v/v) to give compound 10a as a pale yellow solid (210 mg, 79.8%). LCMS 324.1[ m+h ] +.
Step B
Compound 10a (210 mg,0.65 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, LCMS was monitored and concentrated under reduced pressure to give compound 10b (100 mg) as a white solid, crude product, which was used directly in the next reaction without purification. LCMS 224.2[ m+h ] +.
Step C
/>
Compound 10b (100 mg,0.45 mmol), compound 3e (145 mg,0.54 mmol), potassium iodide (75 mg,0.45 mmol) and N, N-diisopropylethylamine (230 mg,1.78 mmol) were added sequentially to acetonitrile (10 mL), and stirred at 70℃for 2 hours under nitrogen. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was diluted with water (20 mL), extracted with ethyl acetate (20 mL. Times.2), washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to HPLC (high performance liquid chromatography) to obtain off-white solid compound 10 (22 mg, 12.0%) as eluent (10-30%) from [ (Gemini-C18 column, 5. Mu. Silica, 21mm in diameter, 150mm long), water (0.1% TFA), and MeCN). 1H NMR (400 MHz, CD3 OD): δppm 8.62 (d, J=1.6 Hz, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 7.89 (s, 1H), 7.86 (s, 1H), 7.30 (dd, J=8.8, 2.8Hz, 1H), 4.68 (s, 2H), 4.58-4.43 (m, 4H), 4.00 (s, 1H), 3.13 (s, 3H), 2.76-2.66 (m, 2H), 1.30 (t, J=7.6 Hz, 3H): LCMS:410.3
[M+H]+.
Example 11: synthesis of Compound 11
Step A
Compound 1a (500 mg,2.31 mmol), compound 11a (431 mg,2.31 mmol), tris (dibenzylideneacetone) dipalladium (100 mg,0.11 mmol) and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (1.73 g,2.78 mmol) were dissolved in 1, 4-dioxane (30 mL), followed by cesium carbonate (1.51 g,4.63 mmol), nitrogen blanket, and stirred at 100℃for 6 hours. LCMS monitored the reaction. After the completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL) and filtered off to remove insoluble materials under reduced pressure. The filtrate was washed with water (50 mL. Times.2), saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. Purification by medium pressure flash chromatography (eluent: petroleum ether/ethyl acetate=1:1) afforded compound 11b as a white solid (600 mg, 80.67%). LCMS 322.1[ M+H ] +.
Step B
Compound 11b (600 mg,1.87 mmol) was dissolved in a methanol/tetrahydrofuran mixed solvent (1:1, 8 mL), and a 2N aqueous sodium hydroxide solution (4 mL,8 mmol) was added at 0deg.C and stirred at room temperature for 2 hours. The reaction was monitored by TLC and concentrated under reduced pressure after completion of the reaction. The residue was diluted with water (10 mL) and washed with diethyl ether (10 mL. Times.2). Dilute hydrochloric acid (0.5M) was added dropwise to the aqueous phase to adjust the pH to 5-6, and the mixture was filtered under reduced pressure to give compound 11c (500 mg, 87.14%) as a white solid. The reaction mixture was used in the next reaction without purification. LCMS 308.2[ m+h ] +.
Step C
Compound 11c (500 mg,1.63 mmol), methylamine hydrochloride (165 mg,2.44 mmol), HATU (750 mg,1.97 mmol) were dissolved in N, N-dimethylformamide (20 mL), followed by N, N-diisopropylethylamine (1.05 g,8.13 mmol) and stirred at room temperature for 4 hours. LCMS monitored the reaction and after completion of the reaction concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL), washed with water (20 mL. Times.2), washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. Purification by medium pressure flash chromatography (eluent: petroleum ether/ethyl acetate=2:3) afforded compound 11d as a white solid (460 mg, 88.25%). LCMS 321.1[ m+h ] +.
Step D
Compound 11d (460 mg,1.44 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added at 0deg.C, and the mixture was stirred at room temperature for 2 hours under nitrogen. LCMS monitored the reaction and after completion of the reaction concentrated under reduced pressure to give 400mg of a white solid, trifluoroacetate salt. The reaction mixture was used in the next reaction without purification. LCMS 221.2[ m+h ] +.
Step E
Compound 5h (100 mg,0.35 mmol), compound 11e (250 mg, crude), potassium iodide (58 mg,0.35 mmol) and N, N-diisopropylethylamine (225 mg,1.74 mmol) were added sequentially to acetonitrile (5 mL) and stirred at 70℃for 4 h. LCMS monitored reaction, after completion of reaction concentrated under reduced pressure, HPLC separation [ (Gemini-C18 column, 5. Mu. Silica, diameter 21mm, length 150 mm), water (0.1% TFA) and MeCN as eluent (5-40%) ] afforded compound 11 (34 mg, 22.84%) as an off-white solid. 1H NMR (400 MHz, CD3 OD): delta ppm 7.96 (d, J=2.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.55 (d, J=10 Hz, 1H), 7.41 (d, J=6.8 Hz, 1H), 6.99 (dd, J=8.8, 2.8Hz, 1H), 4.21-4.12 (m, 1H), 4.06 (s, 2H), 3.27 (dd, J=10, 6.8Hz, 1H), 3.10-3.02 (m, 1H), 2.97-2.86 (m, 6H), 2.81 (dd, J=10.4, 4.4Hz, 1H), 2.51-2.39 (m, 1H), 1.91-1.81 (m, 1H), 1.32 (t, J=7.4 Hz,3 S+1.425 [ M ].
Example 12: synthesis of Compound 12
Step A
Compound 1a (500 mg,2.31 mmol), compound 12a (431 mg,2.31 mmol), tris (dibenzylideneacetone) dipalladium (100 mg,0.11 mmol) and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (1.73 g,2.78 mmol) were dissolved in 1, 4-dioxane (30 mL), followed by cesium carbonate (1.51 g,4.63 mmol), nitrogen blanket, and stirred at 100℃for 6 hours. LCMS monitored the reaction. After the completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL) and filtered off to remove insoluble materials under reduced pressure. The filtrate was washed with water (50 mL. Times.2), saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. Purification by medium pressure flash chromatography (eluent: petroleum ether/ethyl acetate=1:1) afforded compound 12b as a white solid (650 mg, 87.39%). LCMS 322.2[ M+H ] +.
Step B
Compound 12b (650 mg,1.87 mmol) was dissolved in a methanol/tetrahydrofuran mixed solvent (1:1, 8 mL), and a 2N aqueous sodium hydroxide solution (4 mL,8 mmol) was added at 0deg.C and stirred at room temperature for 2 hours. The reaction was monitored by TLC and concentrated under reduced pressure after completion of the reaction. The residue was diluted with water (10 mL) and washed with diethyl ether (10 mL. Times.2). Dilute hydrochloric acid (0.5M) was added dropwise to the aqueous phase to adjust the pH to 5-6, and the mixture was filtered under reduced pressure to give compound 12c (460 mg, 74.00%) as a white solid. The reaction mixture was used in the next reaction without purification. LCMS 308.1[ m+h ] +.
Step C
Compound 12c (460 mg,1.50 mmol), methylamine hydrochloride (151 mg,2.24 mmol), HATU (683 mg,1.80 mmol) was dissolved in N, N-dimethylformamide (20 mL), followed by the addition of N, N-diisopropylethylamine (967 mg,7.48 mmol) and stirring at room temperature for 4 hours. LCMS monitored the reaction and after completion of the reaction concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL), washed with water (20 mL. Times.2), washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. Purification by medium pressure flash chromatography (eluent: petroleum ether/ethyl acetate=2:3) afforded compound 12d (430 mg, 89.67%) as a white solid. LCMS 321.1[ m+h ] +.
Step D
Compound 12d (430 mg,1.34 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added at 0deg.C, and the mixture was stirred at room temperature for 2 hours under nitrogen. LCMS monitored the reaction and after completion of the reaction concentrated under reduced pressure to give compound 12e (400 mg, trifluoroacetate) as a white solid. The reaction mixture was used in the next reaction without purification. LCMS 221.1[ m+h ] +.
Step E
Compound 5h (100 mg,0.35 mmol), compound 11e (250 mg, crude), potassium iodide (58 mg,0.35 mmol) and N, N-diisopropylethylamine (225 mg,1.74 mmol) were added sequentially to acetonitrile (5 mL) and stirred at 70℃for 4 h. LCMS monitored reaction, concentrated under reduced pressure after completion of reaction, and HPLC separating [ (Gemini-C18 column, 5. Mu. Silica, diameter 21mm, length 150 mm), water (0.1% TFA) and MeCN as eluents (5-40%) ] to give off-white solid compound 12 (28 mg, 18.84%). 1H NMR (400 MHz, CD3 OD): delta ppm 7.96 (d, J=2.4 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.55 (d, J=10.4 Hz, 1H), 7.41 (d, J=6.8 Hz, 1H), 6.99 (dd, J=8.8, 2.8Hz, 1H), 4.20-4.10 (m, 1H), 4.03 (s, 2H), 3.24 (dd, J=10.4, 6.8Hz, 1H), 3.07-2.99 (m, 1H), 2.95-2.86 (m, 6H), 2.78 (dd, J=10.4, 4.4Hz, 1H), 2.50-2.39 (m, 1H), 1.90-1.79 (m, 1H), 1.32 (t, J=7.4, 6.8Hz, 1H): 3.07-2.99 (m, 1H) (+. 425M).
B. Test examples
Test example 1: PARP enzyme Activity test experiments
1. Experimental materials:
PARP chemofluorescence detection kit was purchased from BPS Bioscience; enVision Multi-tag Analyzer (Perkinelmer).
2. The experimental steps are as follows:
and (3) preparation of a reagent:
preparing PBST buffer solution: the 1xPBS contains 0.05% Tween-20, i.e. 5. Mu.L 100% Tween-20 is added into 10mL PBS
1X test buffer preparation: 10 xPIP test buffer was diluted 10-fold with double distilled water
Compound preparation:
compound solution preparation: test compounds were diluted 5-fold to 8 th concentration, i.e. from 1000 μm to 12.8nM, with 100% dmso. The internal control compound was diluted 5-fold to 8 th concentration, i.e. from 200 μm to 2.56nM, using 100% dmso. The test compounds were then serially diluted with 1x assay buffer to working solution with 10% DMSO.
The experimental method comprises the following steps:
a) Diluting the histone solution in the kit by 5 times with 1xPBS, taking 25 mu L/hole diluent into a micro-pore plate, and standing at 4 ℃ for overnight incubation;
b) After the incubation is finished, discarding the liquid in the wells, taking 100 mu L/well PBST wash plate for 3 times, discarding the residual liquid in the wells;
c) Taking 100 mu L/hole sealing liquid into a micro-pore plate, and placing the micro-pore plate at 25 ℃ for incubation for 90 minutes; after the incubation is finished, discarding the liquid in the wells, taking 100 mu L/well PBST wash plate for 3 times, discarding the residual liquid in the wells;
d) Taking 2.5 mu L/hole compound working solution to a micro-pore plate, and setting a double-hole experiment;
e) Diluting PARP enzyme to 2 ng/mu L, adding 10 mu L/hole to a micro-pore plate, wherein the final concentration gradient of a compound to be detected is 10 mu M to 0.128nM, the final concentration gradient of an internal control compound is 2 mu M to 0.0256nM, PARP (20 ng/hole) is added, and the reaction system is incubated at 25 ℃ for 60 minutes;
f) 12.5. Mu.L/well bottom mix (1.25. Mu.L 10 xPIP test buffer; 1.25 μl of 10 xPIRP test mix; 2.5 μl Activated DNA;7.5 μl of double distilled water) to the microplate;
g) After the incubation is finished, discarding the liquid in the wells, taking 100 mu L/well PBST wash plate for 3 times, discarding the residual liquid in the wells;
h) 50-fold dilution of strepavidin-HRP with blocking solution, and then taking 25 mu L/well to the microplate, and incubating at 25 ℃ for 30 minutes;
i) After the incubation is finished, discarding the liquid in the wells, taking 100 mu L/well PBST wash plate for 3 times, discarding the residual liquid in the wells;
j) ELISA ECL substrate A and ELISA ECL substrate B were mixed 1:1 (v/v) and 50. Mu.L/well was applied to the microplate and chemiluminescent values were read.
3. Experimental data processing method
The raw data was converted to enzyme activity using the equation (Sample-Min)/(Max-Min)/(100%), and the IC50 values were obtained by curve fitting four parameters (log (inhibitor) vs. response-Variable slope model in GraphPad Prism).
Max: mixed solution containing 1% DMSO, PARP and substrate
Min: does not contain PARP enzyme.
The results of the test are shown in table 1, table 1 providing the enzymatic inhibition of PARP by the compounds of the present invention.
Test example 2: inhibition Activity test on DLD1-BRCA2 KO cells
Experimental materials:
DLD-1 cells were purchased from Nanjac, a. Bailo; DLD1-BRCA2 KO cells are self-constructed by Wuhan He research biomedical technology Co., ltd; 1640 medium was purchased from Biological Industries; fetal bovine serum was purchased from Biosera and cell viability chemiluminescent detection reagents were purchased from Promega corporation.
The experimental method comprises the following steps:
cell antiproliferation assay:
DLD1 or DLD1 BRCA2 KO cells were seeded in a white 96-well plate, 80 μl of cell suspension per well, containing 1000 DLD1 or DLD1 BRCA2 KO cells. Cell plates were placed in a carbon dioxide incubator overnight for culture. The test compounds were diluted 5-fold to the 8 th concentration, i.e. from 2mM to 0.0256. Mu.M, using a row gun and a double multiplex well experiment was set up. 78. Mu.L of medium was added to the intermediate plate, and 2. Mu.L of the gradient diluted compound per well was transferred to the intermediate plate at the corresponding position, and 20. Mu.L of the gradient diluted compound per well was transferred to the cell plate after mixing. The concentration of compound transferred into the cell plate ranged from 10. Mu.M to 0.128nM. The cell plates were placed in a carbon dioxide incubator for 7 days. A cell plate was also prepared and the signal value read on the day of dosing as the maximum value (Max value in the following equation) was used in the data analysis. To this plate, 25. Mu.L of cell viability chemiluminescent detection reagent was added per well and incubated at room temperature for 10 minutes to stabilize the luminescent signal. Multiple marker analyzer readings were used. After incubation of the cell plates with the compounds, 25 μl of cell viability chemiluminescent detection reagent per well was added to the cell plates and incubated at room temperature for 10 minutes to stabilize the luminescent signal. Multiple marker analyzer readings were used.
Data analysis:
the raw data was converted to inhibition rate using the equation (Sample-Min)/(Max-Min) ×100%, and the IC50 values were obtained by curve fitting four parameters (obtained in the "log (inhibitor) vs. response-Variable slope" mode in GraphPad Prism). The results of the test are shown in Table 1, table 1 provides the inhibitory activity of the compounds of the application against DLD-1BRCA2 KO cells.
TABLE 1
Numbering of compounds | PARP1(nM) | PARP2(nM) | BRCA2 DLD-1(nM) |
1 | 3.91 | 103 | 6.17 |
2 | 3.23 | 150 | 502 |
3 | 2.54 | 77.7 | 7.17 |
4 | 8.4 | 333 | 3500 |
5 | 6.45 | 553 | 238 |
6 | 37.35 | 1000 | 1000 |
7 | 36.71 | 1000 | 1000 |
8 | 7.96 | 243 | 460 |
9 | 5.4 | 268 | 126 |
10 | 5.21 | 310 | 160 |
11 | 6.49 | NA | NA |
12 | 40.54 | NA | NA |
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (10)
1. A compound or pharmaceutically acceptable salt or solvate thereof, wherein the compound is shown as formula A
Wherein,
W 1 and W is 2 Each independently is- (CH) 2 ) -or- (CH) 2 ) 2 -;
X 1 Is CR (CR) a2 Or N;
X 2 is CR (CR) a3 Or N;
R 1 selected from the group consisting of: substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl;
R 2 selected from the group consisting of: H. halogen, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl;
R 3 selected from the group consisting of: H. substituted or unsubstituted C 1-3 An alkyl group;
R 4 and R is 5 Each independently selecting the following group: H. halogen, substituted or substitutedUnsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl;
R 6 selected from the group consisting of: H. substituted or unsubstituted C 1-3 An alkyl group;
R a1 、R a2 、R a3 、R c1 and R is c2 Each independently selected from the group consisting of: H. substituted or unsubstituted C 1-4 An alkyl group;
unless otherwise specified, the substitution means that one or more (e.g., 1, 2, or 3) hydrogens in the group are replaced with a substituent selected from the group consisting of: deuterium (D), halogen, C 1-4 Alkyl, C 1-4 A haloalkyl group.
2. The compound according to claim 1, wherein the compound is represented by formula B-1 or B-2
3. The compound according to claim 1, wherein the compound is represented by formula I
Wherein,
X 1 CH or N;
X 2 CH or N;
R 1 selected from the group consisting of: substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl;
R 2 selected from the group consisting of: H. halogen, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl;
R 3 selected from the group consisting of: H. substituted or unsubstituted C 1-3 An alkyl group;
R 4 and R is 5 Each independently selecting the following group: H. halogen, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl;
R 6 selected from the group consisting of: H. substituted or unsubstituted C 1-3 An alkyl group;
unless otherwise specified, the substitution refers to the substitution of one or more hydrogens in the group with a substituent selected from the group consisting of: deuterium, halogen, C 1-4 Alkyl, C 1-4 A haloalkyl group.
4. A compound according to claim 3 wherein,
R 1 is substituted or unsubstituted C 1-4 An alkyl group; and/or
R 2 Is H or F; and/or
R 3 Is C 1-3 Alkyl or deuterated C 1-3 An alkyl group; and/or
R 4 And R is 5 Each independently is H or F; and/or
R 6 Selected from the group consisting of: H. methyl, ethyl.
5. The compound of claim 1 or 2, wherein the compound is selected from the group consisting of compounds of table a and table B:
table A
Table B
6. A process for the preparation of a compound as claimed in claim 3, comprising the steps of: (a)
Reacting the intermediate of formula 1 with the intermediate of formula 2-1 or 2-2 to obtain a compound represented by formula I-1 or I-2;
in the formulae, R H Is a reactive group (e.g. -CH 2 Cl、-CH 2 Br、-C(O)H);X 1 、X 2 、R 1 、R 2 、R 3 、R 4 、R 5 And R is 6 As defined in claim 3.
7. A pharmaceutical composition comprising:
(i) The compound of claim 1, or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier or excipient.
8. A compound as claimed in claim 1 in the manufacture of (i) a medicament for the treatment, amelioration or prophylaxis of diseases associated with PARP1 and/or mediated by PARP 1; and/or (ii) a PARP1 inhibitor; and/or (iii) an antineoplastic agent; and/or (iv) use in a tumor drug sensitizer.
9. The use according to claim 8, wherein,
the diseases related to PARP1 and/or mediated by PARP1 include: cardiovascular disease, inflammatory disease, sepsis, fibrotic disease, diabetes, fatty liver, cerebral nerve disease, parkinson, senile dementia, osteoporosis, eye disease, virus, skin inflammatory disease, pulmonary arterial hypertension, asthma, cerebral apoplexy, arthritis, enteritis, organ transplantation anti-shrink host disease; and/or
The diseases related to PARP1 and/or mediated by PARP1 include: a tumor.
10. The use according to claim 8, wherein the PARP 1-related and/or PARP 1-mediated disease comprises: breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, leukemia, brain tumor, sarcoma, gastrointestinal cancer, or lung cancer, or a combination thereof.
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