CN113636970B - Isoindolone compound, preparation method and application thereof - Google Patents
Isoindolone compound, preparation method and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention provides an isoindolone compound, a preparation method and application thereof, wherein the general formula of the compound or pharmaceutically acceptable salt thereof is shown as (I); wherein R is 1 And R is 2 Independently selected from H, alkanes, substituted aromatic ring groups, alkylamides or arylamides; n is 0 or 1. The compound or the pharmaceutically acceptable salt thereof has the efficient and reversible effect of inhibiting the PARP1 protease activity and is expected to relieve the toxic and side effects of the medicine.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an isoindolone compound, a preparation method and application thereof.
Background
Malignant tumor is one of the major diseases threatening the life safety of human beings. At present, the treatment means of malignant tumors mainly comprise surgery, radiotherapy and chemotherapy. The traditional antitumor drug has the defect of large toxic and side effects and the like, so that the traditional antitumor drug is prevented from being further applied in clinic. In recent years, the rapid development of small molecule targeted drugs has provided a new option for the treatment of tumors
The abnormality of the DNA damage response pathway is an important factor in the development and progression of tumors. It can promote the rapid growth of tumor cells by promoting the mutation accumulation of tumor driving genes, the generation of tumor heterogeneity, the escape of apoptosis and other approaches. At present, small molecule targeted drugs aiming at key proteins of DNA damage response have been developed in preclinical research and clinical application processes. Among them, the inhibitor of poly (adenosine diphosphate) ribose polymerase (PARP) develops most rapidly.
PARP inhibitors are a cancer therapy that targets poly (apyrase). It is the first successful use of synthetic lethal concepts to obtain approved anticancer drugs for clinical use. Synthetic lethality simply refers to the fact that two different genes or proteins change simultaneously, resulting in cell death, while if only one of the two genes or proteins is abnormal, it does not. PARP1 functions by binding to DNA damage sites and catalysing the synthesis of poly ADP-ribose chains on protein substrates. Furthermore, PARP1 is able to recruit other DNA repair proteins to the site of injury to co-repair DNA damage. PARP inhibitors, through binding to the catalytic site of PARP1 or PARP2, result in the inability of PARP proteins to shed from the site of DNA damage. PRAP bound to DNA can cause DNA replication fork arrest and DNA replication failure to proceed smoothly during DNA replication. At this time, the cells typically initiate a repair process called Homologous Repeat Repair (HRR) to repair the error. BRCA1 and BRCA2 play an important role in HRR, and when these proteins are impaired in function leading to HRR dysfunction, other DNA repair methods employed by cells often introduce large-scale genomic recombination, leading to cell death.
PARP inhibitors were originally developed for use with other therapies that cause DNA damage to tumor cells, enhancing the efficacy of other therapies by impairing the ability of cancer cells to repair DNA damage. But in 2005 researchers found that tumor cells carrying BRCA mutations were 1000 times more sensitive to PARP inhibitors than tumor cells carrying wild-type BRCA genes. Because of this property, the efficacy of PARP inhibitors is expected to extend to other tumors carrying the same DNA repair defects. For this reason, the development of PARP inhibitors has become a hotspot in the anticancer field.
From the 70 s of the 20 th century, the development of PARP inhibitors has undergone three generations. The first generation PARP inhibitors were analogues of the metabolite nicotinamide of PARP catalyzed nad+ and represented the drug 3-aminobenzamide. The drugs are quickly replaced by the second generation PARP inhibitors due to the defects of low activity, poor selectivity and the like. The second generation PARP inhibitor is based on the structure-activity relationship, and the activity and the selectivity are obviously improved compared with the first generation PARP inhibitor. In recent years, with research on the structure of PARP inhibitors and their mode of action with PARP1, research on efficient and low-toxicity third generation PARP inhibitors has been rapidly developed. Currently, 5 PARP inhibitors are marketed and are used for the treatment of malignant tumors such as ovarian cancer, breast cancer, pancreatic cancer and prostate cancer. However, the limitation of PARP inhibitors on HRR repair deficient tumor application and the generation of drug resistance have prevented their further clinical development while achieving good therapeutic effect.
Disclosure of Invention
In view of the above, the present invention provides an isoindolone compound, a preparation method thereof, and applications thereof in preparing a drug for treating and/or preventing cancer and preparing a reversible PARP1 inhibitor drug; the isoindolone compounds are used as novel PARP inhibitors for inhibiting PARP1 protease activity, and aim to solve the drug resistance problem faced by the current PARP inhibitors.
Specifically, the invention provides an isoindolone compound, and the technical scheme is realized as follows:
a compound of the general formula (I) or a pharmaceutically acceptable salt thereof:
wherein R is 1 And R is 2 Independently selected from H, alkanes, substituted aromatic ring groups, alkylamides or arylamides; n is 0 or 1.
Further, the compound is any one of the following:
in another aspect, the present invention provides a method for preparing a compound of formula (I) or formula 1-29, wherein the compound has two synthetic routes, namely the following synthetic route one or synthetic route two:
the first synthetic route comprises the following steps:
(1) The compound A-1 (4-bromoisoindoline-1-ketone) and the compound A-2 (5-amino-2-fluorobenzoic acid methyl ester) react in a solvent in the presence of a catalyst, alkali and a ligand to obtain a compound A-3;
(2) Compound A-3 is prepared in the presence of base in THF, meOH and H 2 Hydrolyzing the mixed solvent of O to generate a compound A-4;
(3) Condensing the compound A-4 with amine in a solvent in the presence of alkali and a condensing agent to obtain a compound A;
the second synthesis route comprises the following steps:
(1) Reacting a compound B-1 (4-aminoisoindoline-1-one) with a compound B-2 (2-fluoro-5-formylbenzoic acid methyl ester) in a solvent in the presence of a reducing agent and an acid to obtain a compound B-3;
(2) Compound B-3 is prepared in THF, meOH and H under the action of a base 2 Hydrolyzing the mixed solvent of O to generate a compound B-4;
(3) Condensing the compound B-4 with amine in a solvent in the presence of a base and a condensing agent to obtain the compound B.
Further, in scheme one:
in the step (1), the catalyst is a palladium catalyst selected from Pd 2 (dba) 3 、Pd(OAc) 2 、Pd(PPh 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 Or Pd (dppf) Cl 2 The method comprises the steps of carrying out a first treatment on the surface of the The alkali is K 3 PO 4 、K 2 CO 3 、Cs 2 CO 3 、KO t Bu or Na 2 CO 3 The method comprises the steps of carrying out a first treatment on the surface of the The ligand is brettphos, XPhos, SPhos, xantPhos, ruPhos or PPh 3 The method comprises the steps of carrying out a first treatment on the surface of the The solvent is dioxane, H 2 O, THF, DMF, toluene, one or both;
in the step (2), the alkali is LiOH, naOH or KOH;
in the step (3), the amine is alkylamine, aryl substituted amine, alkylamide or arylamide; the alkali is TEA, DIPEA, DABCO, DBU or tetramethyl ethylenediamine; condensing agent is HATU, HBTU, DCC, EDC or EDCI; the solvent is DCM, DMF, DMSO, THF or dioxane;
in the second synthesis route:
in the (1), the reducing agent is sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride; the acid is acetic acid, hydrochloric acid, sulfuric acid or phosphoric acid; solvent dioxane, THF, DMF, DMSO, toluene or MeOH;
in the step (2), the alkali is LiOH, naOH or KOH;
in the step (3), the amine is alkylamine, aryl substituted amine, alkylamide or arylamide; the alkali is TEA, DIPEA, DABCO, DBU or tetramethyl ethylenediamine; condensing agent is HATU, HBTU, DCC, EDC or EDCI; the solvent is DCM, DMF, DMSO, THF or dioxane.
In yet another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or formulas 1-29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
Further, the dosage form of the pharmaceutical composition is any pharmaceutically acceptable dosage form.
In a further aspect, the invention provides the use of a compound of formula (I) or formulae 1 to 29, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
Further, the cancer is a cancer associated with an abnormality of poly (adenosine diphosphate) ribose polymerase (PARP 1).
Further, the cancer is breast cancer, prostate cancer, ovarian cancer, bladder cancer, liver cancer, taste cancer, lung cancer, neuroblastoma or leukemia.
In a further aspect, the invention also provides the use of a compound of formula (I) or formulae 1-29, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in the manufacture of a medicament for use in the treatment of reversible PARP1 inhibitors.
Compared with the prior art, the isoindolone compound, the preparation method and the application thereof have the following advantages:
the invention provides a novel PARP inhibitor for inhibiting the activity of PARP1 protease, which can solve the drug resistance problem faced by the current PARP inhibitor; the compound or the pharmaceutically acceptable salt thereof has high-efficiency reversible effect of inhibiting PARP1 protease activity and is expected to relieve toxic and side effects of medicines.
Detailed Description
Unless defined otherwise, technical terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified.
The present invention will be described in detail with reference to examples.
Synthetic route one (synthetic route one employed in examples 1 to 14):
in the presence of a ligand, reacting in a solvent to obtain a compound A-3; wherein the palladium catalyst is Pd 2 (dba) 3 、Pd(OAc) 2 、Pd(PPh 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 Or Pd (dppf) Cl 2 The method comprises the steps of carrying out a first treatment on the surface of the The alkali is K 3 PO 4 、K 2 CO 3 、Cs 2 CO 3 、KO t Bu or Na 2 CO 3 The method comprises the steps of carrying out a first treatment on the surface of the The ligand is brettphos, XPhos, SPhos, xantPhos, ruPhos or PPh 3 The method comprises the steps of carrying out a first treatment on the surface of the The solvent is dioxane, H 2 O, THF, DMF, toluene, one or both;
(2) Compound A-3 is prepared in the presence of base in THF, meOH and H 2 Hydrolyzing the mixed solvent of O to generate a compound A-4; wherein the alkali is LiOH, naOH or KOH;
(3) Condensing the compound A-4 with amine in a solvent in the presence of alkali and a condensing agent to obtain a compound A; wherein the amine is alkylamine, aryl substituted amine, alkylamide or arylamide; the alkali is TEA, DIPEA, DABCO, DBU or tetramethyl ethylenediamine; condensing agent is HATU, HBTU, DCC, EDC or EDCI; the solvent is DCM, DMF, DMSO, THF or dioxane.
Example 1
Preparation of the target product Compound 1
The preparation method comprises the following steps:
1) Preparation of Compound A-3
4-bromoisoindolin-1-one (743 mg,3.50 mmol) was dissolved in dioxane (35.0 mL) and H 2 To O (3.50 mL) was added methyl 5-amino-2-fluorobenzoate (800 mg,4.73 mmol), pd, respectively 2 (dba) 3 (160mg，0.180mmol)，K 3 PO 4 (2.60 g,12.3 mmol) and brettphos (188 mg,0.350 mmol) were reacted at 100℃for 15h. After the reaction solution was cooled to room temperature, it was then filtered through celite, washed with ethyl acetate, dried and concentrated, and purified by column chromatography (dichloromethane: methanol=20:1) to give compound a-3 (white solid, 840mg, 80%).
The compound A-3 was tested as follows: 1 H NMR(400MHz,DMSO-d 6 )δ8.52(s,1H),8.13(s,1H),7.56(dd,J＝6.1,3.0Hz,1H),7.41–6.83(m,5H),4.27(s,2H),3.85(s,3H). 13 C NMR(100MHz,DMSO)δ170.6,164.6,164.5,155.8(d,J F-C ＝250.7Hz),139.7,139.2,134.7,133.4,129.4,124.4(d,J F-C ＝8.6Hz),120.5,118.8(d,J F-C ＝11.8Hz),118.3(d,J F-C ＝23.3Hz),118.1,115.5,52.8,44.2. 19 F NMR(376MHz,DMSO)δ-120.6.HRMS(ESI):m/z calcd for C 16 H 13 FN 2 NaO 3 + [M+Na] + :323.0802；found 323.0801。
2) Preparation of Compound A-4
Compound A-3 (84mg, 2.80 mmol) was added to THF (6.00 mL), meOH (2.00 mL) and H 2 To a mixed solution of O (2.00 mL), lithium hydroxide monohydrate (587 mg,14.0 mmol) was added and the mixture was reacted at room temperature for 4 hours. The reaction solution was dried and concentrated, then acidified with 5% diluted hydrochloric acid solution, extracted with ethyl acetate, and concentrated by organic phase drying to give crude compound A-4 (white solid, 800mg, 100%).
3) Preparation of Compound 1
The crude compound A-4 was used in the next step without further purification, and cyclopropyl (piperazin-1-yl) methanone (25.7 mg,0.170 mmol) was added to DMF (1.50 mL), HATU (72.4 mg,0.190 mmol), TEA (66.0. Mu.L, 0.480 mmol) and reacted at room temperature for 12h. The reaction mixture was treated with H 2 O-washing, ethyl acetate extraction, saturated saline back extraction, organic phase drying concentration, column chromatography purification (dichloromethane: methanol=20:1) to obtain the target product compound 1 (white solid, 48.8mg, 68%).
Compound 1 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ8.07(s,1H),7.99(d,J＝8.5Hz,1H),7.82(q,J＝8.9Hz,1H),7.67–7.53(m,2H),7.49–7.42(m,2H),7.15–6.91(m,1H),4.50(s,2H),3.90–3.03(m,8H),1.25–1.24(m,1H),0.90(d,J＝7.5Hz,4H). 13 C NMR(100MHz,CDCl 3 )δ172.3,171.0,163.0,137.4(d,J F-C ＝3.2Hz),133.4,131.2(d,J F-C ＝8.1Hz),131.0,130.6(d,J F-C ＝3.2Hz),129.0,128.9,128.1,127.8,125.9,124.8(d,J F-C ＝17.5Hz),124.3(d,J F-C ＝23.1Hz),43.5,29.8,28.4,10.9,8.0. 19 F NMR(376MHz,CDCl 3 )δ-115.5.HRMS(ESI):m/z calcd for C 23 H 23 FN 4 NaO 3 + [M+Na] + :422.1754；found 422.1751。
example 2
Preparation of the target product Compound 2
The preparation method comprises the following steps:
1) Preparation of Compound A-3: the same procedure as in preparation of A-3 of example 1 gave compound A-3.
2) Preparation of Compound A-4: the same procedure as in preparation of A-4 of example 1 gave compound A-4.
3) Preparation of Compound 2
On the basis of example 1, in contrast to the amine used in example 1, which was cyclobutyl (piperazin-1-yl) methanone (27.4 mg,0.170 mmol), the title compound 2 was obtained following the synthesis procedure described in example 1. Flash column chromatography (dichloromethane: methanol=20:1) afforded compound 2 (53.4 mg,72%, white solid).
Compound 2 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ8.17(s,1H),7.89(d,J＝8.5Hz,1H),7.83(q,J＝8.9Hz,1H),7.67–7.56(m,2H),7.49–7.43(m,2H),7.15–6.92(m,1H),4.65(s,2H),3.89–3.12(m,8H),1.25–1.24(m,1H),0.96–0.87(m,6H). 13 C NMR(100MHz,CDCl 3 )δ172.3,171.0,163.0,137.4(d,J F-C ＝3.2Hz),133.4,131.2(d,J F-C ＝8.1Hz),131.1,130.6(d,J F-C ＝3.2Hz),129.8,128.9,128.1,127.8,125.9,124.8(d,J F-C ＝17.5Hz),124.1(d,J F-C ＝23.1Hz),43.5,29.7,29.4,13.3,10.9,8.1. 19 F NMR(376MHz,CDCl 3 )δ-123.6.HRMS(ESI):m/z calcd for C 24 H 25 FN 4 NaO 3 + [M+Na] + :459.1803；found 459.1808。
example 3
Preparation of the target product Compound 3
The preparation method comprises the following steps:
1) Preparation of Compound A-3
The same procedure as in preparation of A-3 of example 1 gave compound A-3.
2) Preparation of Compound A-4
The same procedure as in preparation of A-4 of example 1 gave compound A-4.
3) Preparation of Compound 3
On the basis of example 1, in contrast to the amine used in example 1, which was cyclopentyl (piperazin-1-yl) methanone (28.8 mg,0.170 mmol), the synthesis procedure described in example 1 was followed to obtain the title compound 3. Flash column chromatography (dichloromethane: methanol=20:1) afforded compound 3 (53.6 mg,70%, white solid).
Compound 3 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ8.11(s,1H),7.99(d,J＝7.5Hz,1H),7.81(q,J＝8.9Hz,1H),7.67–7.56(m,2H),7.48–7.43(m,2H),7.15–6.95(m,1H),4.65(s,2H),4.01–3.39(m,8H),1.25–1.24(m,1H),0.96–0.85(m,8H). 13 C NMR(100MHz,CDCl 3 )δ172.3,171.0,163.0,137.4(d,J F-C ＝3.2Hz),133.4,131.2(d,J F-C ＝8.1Hz),131.1,130.6(d,J F-C ＝3.2Hz),129.8,128.9,128.1,127.8,125.9,124.8(d,J F-C ＝17.5Hz),124.1(d,J F-C ＝23.1Hz),43.5,29.7,29.4,13.3,10.9,8.1. 19 F NMR(376MHz,CDCl 3 )δ-115.6.HRMS(ESI):m/z calcd for C 25 H 27 FN 4 NaO 3 + [M+Na] + :473.1959；found 473.1962。
example 4
Preparation of the target product Compound 4
The preparation method comprises the following steps:
1) Preparation of Compound A-3: the same procedure as in preparation of A-3 of example 1 gave compound A-3.
2) Preparation of Compound A-4: the same procedure as in preparation of A-4 of example 1 gave compound A-4.
3) Preparation of Compound 4
On the basis of example 1, in contrast to the amine employed in example 1, piperazin-1-yl (tetrahydrofuran-3-yl) methanone (31.3 mg,0.170 mmol) was employed to afford the title compound 4 following the synthetic procedure described in example 1. Flash column chromatography (dichloromethane: methanol=20:1) afforded compound 4 (50.8 mg,66%, white solid).
Compound 4 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ8.12(s,1H),7.95(d,J＝7.9Hz,1H),7.81(q,J＝7.9Hz,1H),7.67–7.56(m,2H),7.48–7.43(m,2H),7.25–7.05(m,1H),4.65(s,2H),3.89–3.21(m,8H),2.96–2.81(m,4H),1.25–1.24(m,1H),0.96–0.92(m,2H). 13 C NMR(100MHz,CDCl 3 )δ171.6,170.0,163.6,136.4(d,J F-C ＝4.1Hz),133.4,131.2(d,J F-C ＝8.1Hz),131.1,130.6(d,J F-C ＝4.1Hz),129.8,128.9,128.1,127.8,125.9,124.8(d,J F-C ＝17.5Hz),124.1(d,J F-C ＝23.1Hz),52.6,51.7,46.5,36.5,25.7,22.7,8.0. 19 F NMR(376MHz,CDCl 3 )δ-117.1.HRMS(ESI):m/z calcd for C 24 H 25 FN 4 NaO 4 + [M+Na] + :475.1752；found 475.1755。
example 5
Preparation of the target product Compound 5
The preparation method comprises the following steps:
1) Preparation of Compound A-3: the same procedure as in preparation of A-3 of example 1 gave compound A-3.
2) Preparation of Compound A-4: the same procedure as in preparation of A-4 of example 1 gave compound A-4.
3) Preparation of Compound 5
On the basis of example 1, in contrast to the amine used in example 1, ethyl (piperazin-1-yl) methanone (20.0 mg,0.170 mmol) was used in this example to obtain the title compound 5 following the synthetic procedure described in example 1. Flash column chromatography (dichloromethane: methanol=20:1) afforded compound 5 (50.5 mg,75%, white solid).
Compound 5 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ8.11(s,1H),7.99(d,J＝7.5Hz,1H),7.81(q,J＝8.9Hz,1H),7.67–7.56(m,2H),7.48–7.43(m,2H),7.15–6.95(m,1H),4.65(s,2H),3.99(d,J＝9.5Hz,2H),3.70(q,J＝16.6Hz,2H),3.21(d,J＝7.5Hz,4H),2.62(s,3H). 13 C NMR(100MHz,CDCl 3 )δ172.3,171.0,163.0,137.4(d,J F-C ＝3.2Hz),133.4,131.2(d,J F-C ＝8.1Hz),131.1,130.6(d,J F-C ＝3.2Hz),129.3,128.9,127.5,126.8,125.9,123.8(d,J F-C ＝17.5Hz),122.1(d,J F-C ＝23.1Hz),45.5,29.7,23.4,15.3. 19 F NMR(376MHz,CDCl 3 )δ-114.6.HRMS(ESI):m/z calcd for C 21 H 21 FN 4 NaO 3 + [M+Na] + :419.1490；found 419.1491。
example 6
Preparation of the target product Compound 6
The preparation method comprises the following steps:
1) Preparation of Compound A-3: the same procedure as in preparation of A-3 of example 1 gave compound A-3.
2) Preparation of Compound A-4: the same procedure as in preparation of A-4 of example 1 gave compound A-4.
3) Preparation of Compound 6
On the basis of example 1, in contrast to the amine employed in example 1, piperazin-1-yl (thiophen-2-yl) methanone (33.4 mg,0.170 mmol) was employed in this example to afford the title compound 6 following the synthetic procedure described in example 1. Flash column chromatography (dichloromethane: methanol=20:1) afforded compound 6 (43.4 mg,55%, white solid).
Compound 6 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ7.53–7.45(m,2H),7.38(t,J＝7.7Hz,1H),7.33–7.27(m,2H),7.04(dtd,J＝8.5,5.2,3.3Hz,5H),5.96(s,1H),4.29(s,2H),3.94–3.71(m,6H),3.44(d,J＝11.4Hz,2H). 13 C NMR(100MHz,CDCl 3 )δ172.1,165.0,160.1,139.3,135.8,133.6(d,J F-C ＝3.0Hz),133.0,132.9(d,J F-C ＝7.2Hz),129.3(d,J F-C ＝3.1Hz),125.9,124.7(d,J F-C ＝187.5Hz),123.4,122.0,119.3,119.1,118.6,116.7(d,J F-C ＝24.6Hz),116.1,56.8,44.2,38.6. 19 F NMR(376MHz,CDCl 3 )δ-124.21.HRMS(ESI):m/z calcd for C 24 H 21 FN 4 NaO 3 S + [M+Na] + :487.1211；found 487.1215。
example 7
Preparation of the target product Compound 7
The preparation method comprises the following steps:
1) Preparation of Compound A-3: the same procedure as in preparation of A-3 of example 1 gave compound A-3.
2) Preparation of Compound A-4: the same procedure as in preparation of A-4 of example 1 gave compound A-4.
3) Preparation of Compound 7
On the basis of example 1, in contrast to the amine employed in example 1, piperazin-1-yl (pyridin-2-yl) methanone (35.5 mg,0.170 mmol) was employed to afford the title compound 7 following the synthetic procedure described in example 1. Flash column chromatography (dichloromethane: methanol=20:1) afforded compound 7 (53.5 mg,73%, white solid).
Compound 7 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ7.60(s,1H),7.46–7.39(m,3H),7.32(t,J＝7.6Hz,1H),7.25(s,1H),7.05–6.98(m,4H),6.94(t,J＝8.6Hz,1H),6.49(s,1H),4.27(s,2H),3.81–3.07(m,8H). 13 C NMR(100MHz,CDCl 3 )δ172.1,165.0,160.1,139.3,138.8,135.8,133.6(d,J F-C ＝3.0Hz),133.0,132.9(d,J F-C ＝8.2Hz),129.3(d,J F-C ＝3.0Hz),124.9,124.7(d,J F-C ＝17.5Hz),123.4,121.0,119.3,119.0,118.6,116.5(d,J F-C ＝24.6Hz),116.3,55.8,44.2,38.2. 19 F NMR(376MHz,CDCl 3 )δ-120.8.HRMS(ESI):m/z calcd for C 24 H 22 FN 5 NaO 2 + [M+Na] + :454.1650；found 454.1654。
example 8
Preparation of the target product Compound 8
The preparation method comprises the following steps:
1) Preparation of Compound A-3: the same procedure as in preparation of A-3 of example 1 gave compound A-3.
2) Preparation of Compound A-4: the same procedure as in preparation of A-4 of example 1 gave compound A-4.
3) Preparation of Compound 8
On the basis of example 1, in contrast to example 1, which used 4-methoxypiperidine (19.6 mg,0.170 mmol) in this example, the synthesis procedure described in example 1 was followed to give the title compound 8. Flash column chromatography (dichloromethane: methanol=20:1) afforded compound 8 (37.8 mg,58%, white solid).
Compound 8 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ7.60(s,1H),7.46–7.39(m,1H),7.32(t,J＝7.6Hz,1H),7.25(s,1H),7.05–6.98(m,2H),6.94(t,J＝8.6Hz,1H),6.49(s,1H),4.27(s,2H),3.96(s,1H),3.69–3.41(m,3H),3.36(d,J＝1.2Hz,2H),3.20(d,J＝17.3Hz,2H),2.11–1.36(m,4H). 13 C NMR(100MHz,CDCl 3 )δ172.1,165.0,139.3,138.8,133.6(d,J F-C ＝3.0Hz),132.9(d,J F-C ＝8.2Hz),129.3(d,J F-C ＝3.0Hz),124.9,124.7(d,J F-C ＝17.5Hz),121.0,119.3,118.6,116.5(d,J F-C ＝24.6Hz),116.3,55.8,44.2,38.2,31.0,30.1. 19 F NMR(376MHz,CDCl 3 )δ-124.8.HRMS(ESI):m/z calcd for C 21 H 22 FN 3 NaO 3 + [M+Na] + :406.1537；found 406.1531。
example 9
Preparation of the target product Compound 9
The preparation method comprises the following steps:
1) Preparation of Compound A-3: the same procedure as in preparation of A-3 of example 1 gave compound A-3.
2) Preparation of Compound A-4: the same procedure as in preparation of A-4 of example 1 gave compound A-4.
3) Preparation of Compound 9
On the basis of example 1, in contrast to example 1, which used 4-hydroxypiperidine (16.9 mg,0.170 mmol) was used as the amine, the title compound 9 was obtained following the synthesis procedure described in example 1. Flash column chromatography (dichloromethane: methanol=20:1) afforded compound 9 (20.7 mg,33%, white solid).
Compound 9 was tested as follows: 1 H NMR(400MHz,Methanol-d 4 )δ7.90(s,1H),7.51(ddd,J＝7.9,4.9,2.1Hz,1H),7.36(d,J＝6.3Hz,1H),7.25–7.12(m,2H),7.06(d,J＝7.5Hz,1H),6.65(d,J＝8.0Hz,1H),4.48(s,2H),4.16(d,J＝13.7Hz,1H),3.85(q,J＝4.3Hz,1H),3.49–3.33(m,2H),3.10(s,1H),1.92(d,J＝13.7Hz,1H),1.71(d,J＝15.0Hz,1H),1.53(dq,J＝8.6,4.5Hz,1H),1.35(m,1H). 13 C NMR(100MHz,CDCl 3 )δ170.5,167.6,136.4(d,J F-C ＝3.2Hz),133.4,131.2(d,J F-C ＝8.1Hz),131.1,130.6(d,J F-C ＝3.2Hz),129.8,128.7,128.0,127.68,125.8,124.8(d,J F-C ＝17.5Hz),124.1(d,J F-C ＝23.1Hz),53.9,44.5,35.7,16.1. 19 F NMR(376MHz,CDCl 3 )δ-116.8.HRMS(ESI):m/z calcd for C 20 H 20 FN 3 NaO 3 + [M+Na] + :392.1381；found 392.1384。
example 10
Preparation of the target product Compound 10
The preparation method comprises the following steps:
1) Preparation of Compound A-3: the same procedure as in preparation of A-3 of example 1 gave compound A-3.
2) Preparation of Compound A-4: the same procedure as in preparation of A-4 of example 1 gave compound A-4.
3) Preparation of Compound 10
On the basis of example 1, in the present example, 6-azaspiro [2.5] octane (18.9 mg,0.170 mmol) was used in a manner different from example 1 in terms of amine used, and the objective compound 10 was obtained according to the synthetic procedure described in example 1. Flash column chromatography (dichloromethane: methanol=20:1) afforded compound 10 (40.6 mg,63%, white solid).
Compound 10 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ8.12(s,1H),7.95(d,J＝7.9Hz,1H),7.81(q,J＝7.9Hz,1H),7.67–7.56(m,2H),7.48–7.43(m,2H),7.25–7.05(m,1H),4.65(s,2H),3.99(d,J＝9.5Hz,2H),3.70(q,J＝16.6Hz,2H),3.21(d,J＝7.5Hz,4H),1.25–1.24(m,1H),1.06–0.92(m,3H). 13 C NMR(100MHz,CDCl 3 )δ170.5,167.6,136.4(d,J F-C ＝3.2Hz),133.4,131.2(d,J F-C ＝8.1Hz),131.1,130.6(d,J F-C ＝3.2Hz),129.8,128.7,128.0,127.68,125.8,124.8(d,J F-C ＝17.5Hz),124.1(d,J F-C ＝23.1Hz),44.5,35.7,16.1,10.2,8.0. 19 F NMR(376MHz,CDCl 3 )δ-114.8.HRMS(ESI):m/z calcd for C 22 H 22 FN 3 NaO 2 + [M+Na] + :402.1588；found 402.1591。
example 11
Preparation of the target product Compound 11
The preparation method comprises the following steps:
1) Preparation of Compound A-3: the same procedure as in preparation of A-3 of example 1 gave compound A-3.
2) Preparation of Compound A-4: the same procedure as in preparation of A-4 of example 1 gave compound A-4.
3) Preparation of Compound 11
On the basis of example 1, in contrast to example 1, which used tert-butyl 1, 4-diazine-1-carboxylate (34.1 mg,0.170 mmol) was used, the title compound 11 was obtained according to the synthesis procedure described in example 1. Flash column chromatography (dichloromethane: methanol=20:1) afforded compound 11 (56.5 mg,71%, white solid).
Compound 11 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ8.17(s,1H),7.89(d,J＝8.5Hz,1H),7.83(q,J＝8.9Hz,1H),7.67–7.56(m,2H),7.49–7.43(m,2H),7.15–6.92(m,1H),4.65(s,2H),3.99(d,J＝7.5Hz,2H),3.70(q,J＝16.6Hz,2H),3.21(d,J＝7.5Hz,4H),2.91(s,9H),0.96–0.87(m,9H). 13 C NMR(100MHz,CDCl 3 )δ172.3,171.0,163.0,137.4(d,J F-C ＝3.2Hz),133.4,131.2(d,J F-C ＝8.1Hz),131.1,130.6(d,J F-C ＝3.2Hz),129.8,128.6,128.1,127.1,125.6,124.4(d,J F-C ＝18.5Hz),121.1(d,J F-C ＝33.1Hz),46.5,32.6,29.9,29.4,22.1,13.3,8.1. 19 F NMR(376MHz,CDCl 3 )δ-123.6.HRMS(ESI):m/z calcd for C 25 H 29 FN 4 NaO 4 + [M+Na] + :491.2065；found 491.2066。
example 12
Preparation of the target product Compound 12
The preparation method comprises the following steps:
1) Preparation of Compound A-3: the same procedure as in preparation of A-3 of example 1 gave compound A-3.
2) Preparation of Compound A-4: the same procedure as in preparation of A-4 of example 1 gave compound A-4.
3) Preparation of Compound 12
On the basis of example 1, in contrast to example 1, which employed cyclopropyl (1, 4-diaza-1-yl) methanone (28.6 mg,0.170 mmol) was used, the synthesis procedure described in example 1 was followed to obtain the title compound 12. Flash column chromatography (dichloromethane: methanol=20:1) afforded compound 12 (48.2 mg,65%, white solid).
Compound 12 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ7.55–7.46(m,1H),7.39(dt,J＝12.3,7.7Hz,1H),7.26(s,1H),7.02(ddd,J＝6.3,4.3,1.5Hz,2H),6.99–6.86(m,1H),6.51(d,J＝10.8Hz,1H),5.72(d,J＝5.2Hz,1H),4.28(d,J＝6.9Hz,2H),3.92(s,1H),3.85–3.68(m,3H),3.65–3.38(m,4H),2.08(d,J＝6.0Hz,1H),1.78–1.60(m,2H),1.05–0.74(m,4H). 13 C NMR(100MHz,DMSO)δ175.2,170.0,164.8,157.7,144.1,140.0,136.3,133.4,129.37,123.2,123.1,116.9,112.0,110.8,92.8,55.3,49.5,48.7,47.1,45.7,44.0,22.6,14.4,7.5. 19 F NMR(376MHz,DMSO)δ-119.6.HRMS(ESI):m/z calcd for C 24 H 25 FN 4 NaO 3 + [M+Na] + :459.1803；found 459.1808。
example 13
Preparation of the target product Compound 13
The preparation method comprises the following steps:
1) Preparation of Compound A-3: the same procedure as in preparation of A-3 of example 1 gave compound A-3.
2) Preparation of Compound A-4: the same procedure as in preparation of A-4 of example 1 gave compound A-4.
3) Preparation of Compound 13
On the basis of example 1, unlike example 1, which used an amine, ethyl (1, 4-diaza-1-yl) methanone (25.2 mg,0.170 mmol) was used, the synthesis procedure described in example 1 was followed to obtain the title compound 13. Flash column chromatography (dichloromethane: methanol=20:1) afforded compound 13 (37.0 mg,53%, white solid).
Compound 13 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ8.11(s,1H),7.86(d,J＝8.7Hz,1H),7.83(q,J＝8.8Hz,1H),7.67–7.56(m,2H),7.49–7.43(m,2H),7.15–6.92(m,1H),4.65(s,2H),3.99(d,J＝7.5Hz,2H),3.70(q,J＝16.6Hz,2H),3.21(d,J＝7.5Hz,4H),2.71(s,3H),0.96–0.87(m,9H). 13 C NMR(100MHz,CDCl 3 )δ172.1,170.0,165.0,136.4(d,J F-C ＝3.2Hz),134.4,131.2(d,J F-C ＝8.1Hz),131.1,130.6(d,J F-C ＝3.2Hz),129.8,128.6,128.1,127.1,125.6,124.4(d,J F-C ＝18.5Hz),121.1(d,J F-C ＝33.1Hz),46.5,32.6,29.9,29.4,22.1,8.1. 19 F NMR(376MHz,CDCl 3 )δ-125.6.HRMS(ESI):m/z calcd for C 22 H 23 FN 4 NaO 3 + [M+Na] + :433.1646；found 433.1649。
example 14
Preparation of the target product Compound 14
The preparation method comprises the following steps:
1) Preparation of Compound A-3: the same procedure as in preparation of A-3 of example 1 gave compound A-3.
2) Preparation of Compound A-4: the same procedure as in preparation of A-4 of example 1 gave compound A-4.
3) Preparation of Compound 14
On the basis of example 1, in contrast to example 1, which used 1- (ethylsulfonyl) -1, 4-diazane (32.4 mg,0.170 mmol) in this example, the synthesis procedure described in example 1 was followed to give the title compound 14. Flash column chromatography (dichloromethane: methanol=20:1) afforded compound 14 (33.7 mg,43%, white solid).
Compound 14 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.96(d,J＝7.8Hz,1H),7.88(q,J＝8.9Hz,1H),7.67–7.56(m,2H),7.49–7.43(m,2H),7.15–6.92(m,1H),4.65(s,2H),3.99(d,J＝7.5Hz,2H),3.70(q,J＝16.6Hz,2H),3.21(d,J＝7.5Hz,4H),2.51(q,J＝5.8Hz,2H),1.62(t,J＝9.8Hz,3H),0.96–0.87(m,9H). 13 C NMR(100MHz,CDCl 3 )δ173.3,171.7,164.0,138.4(d,J F-C ＝3.2Hz),135.4,134.2(d,J F-C ＝8.1Hz),132.1,130.6(d,J F-C ＝3.2Hz),129.8,128.6,128.1,127.1,125.6,124.4(d,J F-C ＝18.5Hz),121.1(d,J F-C ＝33.1Hz),47.5,33.6,31.0,29.4,22.1,16.3,8.1. 19 F NMR(376MHz,CDCl 3 )δ-121.6.HRMS(ESI):m/z calcd for C 22 H 25 FN 4 NaO 4 S + [M+Na] + :483.1473；found 483.1469。
synthetic route two (synthetic route two used in examples 15 to 29):
(1) Reacting a compound B-1 (4-aminoisoindoline-1-one) with a compound B-2 (2-fluoro-5-formylbenzoic acid methyl ester) in a solvent in the presence of a reducing agent and an acid to obtain a compound B-3; wherein, the reducing agent is sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride; the acid is acetic acid, hydrochloric acid, sulfuric acid or phosphoric acid; solvent dioxane, THF, DMF, DMSO, toluene or MeOH;
(2) Compound B-3 is prepared in THF, meOH and H under the action of a base 2 Hydrolyzing the mixed solvent of O to generate a compound B-4; wherein the alkali is LiOH, naOH or KOH;
(3) Condensing the compound B-4 with amine in a solvent in the presence of alkali and a condensing agent to obtain a compound B; wherein the amine is alkylamine, aryl substituted amine, alkylamide or arylamide; the alkali is TEA, DIPEA, DABCO, DBU or tetramethyl ethylenediamine; condensing agent is HATU, HBTU, DCC, EDC or EDCI; the solvent is DCM, DMF, DMSO, THF or dioxane.
Example 15
Preparation of the target product Compound 15
The preparation method comprises the following steps:
1) Preparation of Compound B-3
Methyl 2-fluoro-5-formylbenzoate (1.00 g,5.40 mmol) was dissolved in DMF (5.00 mL), stirred at room temperature for 10 min, followed by addition of a solution of 4-aminoisoindolin-1-one (400 mg,2.70 mmol) in DMF (5.00 mL), stirring was continued for 1h, the reaction was cooled to room temperature, then sodium triacetoxyborohydride (4.58 g,21.6 mmol) was added, after 30 min, warmed to room temperature and stirred overnight. The reaction solution was extracted with ethyl acetate and saturated sodium bicarbonate solution, dried and concentrated, then ethanol (50.0 mL) was added, warmed to 50 ℃, then the solids were removed by suction filtration, dried and concentrated, and purified by column chromatography (dichloromethane: methanol=80:1-40:1) to give compound B-3 (white solid, 764mg, 90%).
The compound B-3 was tested as follows: 1 H NMR(400MHz,DMSO-d 6 )δ8.40(s,1H),7.91(d,J＝7.0Hz,1H),7.80–7.58(m,1H),7.30(dd,J＝10.9,8.6Hz,1H),7.16(t,J＝7.7Hz,1H),6.88(d,J＝7.4Hz,1H),6.58(d,J＝7.9Hz,1H),6.40(s,1H),4.43(s,2H),4.22(s,2H),3.84(d,J＝1.8Hz,3H). 13 C NMR(101MHz,DMSO)δ171.1,164.7,161.6,158.9(d,J F-C ＝236.7Hz),143.69,136.93,134.20,134.10,133.62,130.57,129.35(d,J F-C ＝6.3Hz),118.41(d,J F-C ＝13.3Hz),117.47(d,J F-C ＝22.2Hz),112.28,52.83,45.49,43.99. 19 F NMR(376MHz,DMSO)δ-113.5.HRMS(ESI):m/z calcd for C 17 H 15 FN 2 NaO 3 + [M+Na] + :337.0959；found 337.0958。
2) Preparation of Compound B-4
Compound B-3 (764 mg,2.43 mmol) was added to THF (6.00 mL), meOH (2.00 mL) and H 2 To a mixture of O (2.00 mL) was added lithium hydroxide monohydrate (512 mg,12.2 mmol) and the mixture was reacted at room temperature for 4 hours. The reaction solution was dried and concentrated, then acidified with 5% diluted hydrochloric acid solution, extracted with ethyl acetate, and concentrated by organic phase drying to give crude compound B-4 (white solid, 729mg, 100%).
3) Preparation of Compound 15
It was used in the next step without further purification. Crude compound B-4 (60.0 mg,0.200 mmol), cyclopropyl (piperazin-1-yl) methanone (28.0 mg,0.200 mmol) was added to DMF (1.50 mL), HATU (82.9 mg,0.220 mmol), TEA (76.0. Mu.L, 0.540 mmol) was added separately and reacted at room temperature for 12h. The reaction mixture was treated with H 2 O-washing, ethyl acetate extraction, brine stripping, organic phase drying and concentration, column chromatography purification (dichloromethane: methanol=30:1) to obtain compound 15 (white solid, 70.0mg, 80%).
Compound 15 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ8.02(s,1H),7.89(d,J＝8.5Hz,1H),7.83(q,J＝8.9Hz,1H),7.67–7.56(m,2H),7.49–7.43(m,2H),7.15–6.92(m,1H),4.61(s,2H),4.53(s,2H),3.79–3.04(m,8H),,1.25–1.24(m,1H),0.99–0.89(m,4H). 13 C NMR(100MHz,CDCl 3 )δ172.3,171.0,163.0,137.4(d,J F-C ＝3.2Hz),132.4,131.2(d,J F-C ＝8.1Hz),131.0,130.6(d,J F-C ＝3.2Hz),129.0,128.9,128.1,127.5,125.9,124.8(d,J F-C ＝17.5Hz),124.3(d,J F-C ＝23.1Hz),52.7,43.5,29.8,28.4,12.3,8.0. 19 F NMR(376MHz,CDCl 3 )δ-116.7.HRMS(ESI):m/z calcd for C 24 H 25 FN 4 NaO 3 + [M+Na] + :459.1803；found 459.1807。
example 16
Preparation of the target product Compound 16
The preparation method comprises the following steps:
1) Preparation of Compound B-3: in the same manner as in the preparation of B-3 in example 15, compound B-3 was obtained.
2) Preparation of Compound B-4: in the same manner as in the preparation of B-4 in example 15, compound B-4 was obtained.
3) Preparation of Compound 16
On the basis of example 15, in contrast to the amine used in example 15, which was cyclopentyl (piperazin-1-yl) methanone (33.4 mg,0.200 mmol), the synthesis procedure described in example 15 was followed to obtain the title compound 16. Flash column chromatography (dichloromethane: methanol=30:1) afforded compound 16 (70.6 mg,76%, white solid).
Compound 16 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ7.50(m,2H),7.43(dd,J＝13.6,5.7Hz,1H),7.31(d,J＝7.2Hz,1H),7.27(s,1H),7.25(d,J＝7.3Hz,1H),7.09(t,J＝8.8Hz,1H),6.70(d,J＝7.6Hz,1H),4.43(s,2H),4.28(s,2H),3.93–3.19(m,8H),2.98–2.75(m,1H),1.86–1.80(m,4H),1.76–1.71(m,2H),1.68–1.52(m,2H). 13 C NMR(100MHz,CDCl 3 )δ175.1,172.7,164.8,158.5,155.9,142.8,135.8,132.9,130.7,129.7,128.9,128.2,116.6,116.3,113.2,47.1,45.3,43.5,42.1,41.2,30.3,26.2. 19 F NMR(376MHz,DMSO)δ-119.44.HRMS(ESI):m/z calcd for C 26 H 29 FN 4 NaO 3 + [M+Na] + :487.2116；found 487.2114。
example 17
Preparation of the target product Compound 17
The preparation method comprises the following steps:
1) Preparation of Compound B-3: in the same manner as in the preparation of B-3 in example 15, compound B-3 was obtained.
2) Preparation of Compound B-4: in the same manner as in the preparation of B-4 in example 15, compound B-4 was obtained.
3) Preparation of Compound 17
On the basis of example 15, in contrast to the amine used in example 15, piperazin-1-yl (tetrahydrofuran-3-yl) methanone (33.9 mg,0.200 mmol) was used in this example to obtain the title compound 17 following the synthetic procedure described in example 15. Flash column chromatography (dichloromethane: methanol=30:1) afforded compound 17 (66.2 mg, 71%) as a white solid.
Compound 17 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ7.42(p,J＝4.7Hz,2H),7.34–7.19(m,3H),7.10(t,J＝8.6Hz,1H),6.68(t,J＝7.3Hz,1H),4.43(s,2H),4.28(s,2H),4.22–4.09(m,1H),4.06–3.74(m,1H),3.65–3.58(m,5H),3.46–3.11(m,6H),2.28–2.17(m,1H),1.33–1.21(m,2H). 13 C NMR(100MHz,CDCl 3 )δ172.3,171.9,165.9,158.5,156.2,141.8,135.6,132.7,130.7,129.5,128.7,128.0,123.4,116.2,113.0,70.4,67.3,47.1,45.1,43.5,42.1,40.0,30.1. 19 F NMR(376MHz,CDCl 3 )δ-116.78.HRMS(ESI):m/z calcd for C 25 H 27 FN 4 NaO 4 + [M+Na] + :489.1909；found 489.1908。
example 18
Preparation of the target product Compound 18
The preparation method comprises the following steps:
1) Preparation of Compound B-3: in the same manner as in the preparation of B-3 in example 15, compound B-3 was obtained.
2) Preparation of Compound B-4: in the same manner as in the preparation of B-4 in example 15, compound B-4 was obtained.
3) Preparation of Compound 18
On the basis of example 15, in contrast to the amine used in example 15, ethyl (piperazin-1-yl) methanone (25.9 mg,0.200 mmol) was used in this example to obtain the title compound 18 following the synthetic procedure described in example 15. Flash column chromatography (dichloromethane: methanol=30:1) afforded compound 18 (59.1 mg,72%, white solid).
Compound 18 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ8.11(s,1H),7.99(d,J＝7.5Hz,1H),7.81(q,J＝8.9Hz,1H),7.67–7.56(m,2H),7.48–7.43(m,2H),7.15–6.95(m,1H),4.65(s,2H),4.32(s,2H),3.99–3.19(m,8H),2.62(s,3H). 13 C NMR(100MHz,CDCl 3 )δ172.3,171.0,163.0,137.4(d,J F-C ＝3.2Hz),133.4,131.2(d,J F-C ＝8.1Hz),131.1,130.6(d,J F-C ＝3.2Hz),129.3,128.9,127.5,126.8,125.9,123.8(d,J F-C ＝17.5Hz),122.1(d,J F-C ＝23.1Hz),45.5,42.1,29.7,23.4,15.3. 19 F NMR(376MHz,CDCl 3 )δ-112.6.HRMS(ESI):m/z calcd for C 22 H 23 FN 4 NaO 3 + [M+Na] + :433.1646；found 433.1647。
example 19
Preparation of the target product Compound 19
The preparation method comprises the following steps:
1) Preparation of Compound B-3: in the same manner as in the preparation of B-3 in example 15, compound B-3 was obtained.
2) Preparation of Compound B-4: in the same manner as in the preparation of B-4 in example 15, compound B-4 was obtained.
3) Preparation of Compound 19
On the basis of example 15, in contrast to the amine used in example 15, piperazin-1-yl (thiophen-2-yl) methanone (35.9 mg,0.200 mmol) was used in this example to obtain the title compound 19 following the synthetic procedure described in example 15. Flash column chromatography (dichloromethane: methanol=30:1) afforded compound 19 (71.8 mg,75%, white solid).
Compound 19 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ7.48(dd,J＝5.0,1.1Hz,1H),7.46–7.40(m,2H),7.35–7.26(m,3H),7.15–7.03(m,2H),6.95(s,1H),6.71(dd,J＝7.5,1.3Hz,1H),4.44(s,2H),4.29(s,2H),3.85(s,4H),3.73(t,J＝5.2Hz,2H),3.40(s,2H). 13 C NMR(100MHz,CDCl 3 )δ172.1,165.0,160.1,139.3,135.8,133.6(d,J F-C ＝3.0Hz),133.0,132.9(d,J F-C ＝7.2Hz),129.3(d,J F-C ＝3.1Hz),125.9,124.7(d,J F-C ＝187.5Hz),123.4,122.0,119.3,119.1,118.6,116.7(d,J F-C ＝24.6Hz),116.1,56.8,53.0,44.2,38.6. 19 F NMR(376MHz,CDCl 3 )δ-116.6.HRMS(ESI):m/z calcd for C 25 H 23 FN 4 NaO 3 S + [M+Na] + :501.1367；found 501.1363。
example 20
Preparation of the target product Compound 20
The preparation method comprises the following steps:
1) Preparation of Compound B-3: in the same manner as in the preparation of B-3 in example 15, compound B-3 was obtained.
2) Preparation of Compound B-4: in the same manner as in the preparation of B-4 in example 15, compound B-4 was obtained.
3) Preparation of Compound 20
On the basis of example 15, in contrast to the amine used in example 15, piperazin-1-yl (pyridin-2-yl) methanone (37.7 mg,0.200 mmol) was used in this example to obtain the title compound 20 following the synthetic procedure described in example 15. Flash column chromatography (dichloromethane: methanol=30:1) afforded compound 20 (68.2 mg,72%, white solid).
Compound 20 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ7.63(s,1H),7.46–7.39(m,3H),7.32(t,J＝7.6Hz,1H),7.25(s,1H),7.05–6.98(m,4H),6.94(t,J＝8.6Hz,1H),6.49(s,1H),4.65(s,2H),4.27(s,2H),3.96–3.21(m,8H). 13 C NMR(100MHz,CDCl 3 )δ172.1,165.0,160.1,139.3,138.8,135.8,133.6(d,J F-C ＝3.0Hz),133.0,132.9(d,J F-C ＝7.2Hz),129.3(d,J F-C ＝3.1Hz),125.9,124.7(d,J F-C ＝187.5Hz),123.4,122.0,119.3,119.1,118.6,116.7(d,J F-C ＝24.6Hz),116.1,56.8,53.0,44.2,38.6. 19 F NMR(376MHz,CDCl 3 )δ-116.5.HRMS(ESI):m/z calcd for C 25 H 24 FN 5 NaO 2 + [M+Na] + :468.1806；found 468.1808。
example 21
Preparation of the target product Compound 21
The preparation method comprises the following steps:
1) Preparation of Compound B-3: in the same manner as in the preparation of B-3 in example 15, compound B-3 was obtained.
2) Preparation of Compound B-4: in the same manner as in the preparation of B-4 in example 15, compound B-4 was obtained.
3) Preparation of Compound 21
On the basis of example 15, in contrast to the amine used in example 15, 4-methoxypiperidine (21.6 mg,0.200 mmol) was used in this example, and target compound 21 was obtained according to the synthesis procedure described in example 15. Flash column chromatography (dichloromethane: methanol=30:1) afforded compound 21 (49.3 mg,62%, white solid).
Compound 21 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ7.56(s,1H),7.46–7.39(m,1H),7.32(t,J＝7.6Hz,1H),7.25(s,1H),7.05–6.98(m,2H),6.94(t,J＝8.6Hz,1H),6.49(s,1H),4.61(s,2H),4.29(s,2H),3.90(s,1H),3.69–3.41(m,3H),3.26(d,J＝1.2Hz,2H),3.20(d,J＝17.3Hz,2H),2.11–1.36(m,4H). 13 C NMR(100MHz,CDCl 3 )δ172.1,165.0,139.3,138.8,133.6(d,J F-C ＝3.0Hz),132.9(d,J F-C ＝8.2Hz),129.3(d,J F-C ＝3.0Hz),124.9,124.7(d,J F-C ＝16.5Hz),121.0,119.3,118.6,117.5(d,J F-C ＝23.6Hz),112.3,55.8,52.2,47.1,36.2,31.0,30.1. 19 F NMR(376MHz,CDCl 3 )δ-117.0.HRMS(ESI):m/z calcd for C 22 H 24 FN 3 NaO 3 + [M+Na] + :420.1694；found 420.1692。
example 22
Preparation of the target product Compound 22
The preparation method comprises the following steps:
1) Preparation of Compound B-3: in the same manner as in the preparation of B-3 in example 15, compound B-3 was obtained.
2) Preparation of Compound B-4: in the same manner as in the preparation of B-4 in example 15, compound B-4 was obtained.
3) Preparation of Compound 22
On the basis of example 15, in contrast to the amine used in example 15, 4-hydroxypiperidine (20.6 mg,0.200 mmol) was used in this example to obtain the title compound 22 following the synthesis procedure described in example 15. Flash column chromatography (dichloromethane: methanol=30:1) afforded compound 22 (34.5 mg,45%, white solid).
Compound 22 was tested as follows: 1 H NMR(400MHz,Methanol-d 4 )δ7.90(s,1H),7.51(ddd,J＝7.9,4.9,2.1Hz,1H),7.36(d,J＝6.3Hz,1H),7.25–7.12(m,2H),7.06(d,J＝7.5Hz,1H),6.65(d,J＝8.0Hz,1H),4.48(s,2H),4.33(s,2H),4.16(d,J＝13.7Hz,1H),3.85(q,J＝4.3Hz,1H),3.49–3.33(m,2H),3.10(s,1H),1.92(d,J＝13.7Hz,1H),1.71(d,J＝15.0Hz,1H),1.53(dq,J＝8.6,4.5Hz,1H),1.35(m,1H). 13 C NMR(100MHz,CDCl 3 )δ170.5,167.6,136.4(d,J F-C ＝3.2Hz),133.4,131.2(d,J F-C ＝8.1Hz),131.1,130.6(d,J F-C ＝3.2Hz),129.8,128.7,128.0,127.68,125.8,124.8(d,J F-C ＝17.5Hz),124.1(d,J F-C ＝23.1Hz),53.9,48.7,44.5,35.7,16.1. 19 F NMR(376MHz,CDCl 3 )δ-117.1.HRMS(ESI):m/z calcd for C 21 H 22 FN 3 NaO 3 + [M+Na] + :406.1537；found 406.1535。
example 23
Preparation of the target product Compound 23
The preparation method comprises the following steps:
1) Preparation of Compound B-3: in the same manner as in the preparation of B-3 in example 15, compound B-3 was obtained.
2) Preparation of Compound B-4: in the same manner as in the preparation of B-4 in example 15, compound B-4 was obtained.
3) Preparation of Compound 23
On the basis of example 15, in contrast to the amine used in example 15, 6-azaspiro [2.5] octane (21.6 mg,0.200 mmol) was used in this example to obtain the title compound 23 following the synthetic procedure described in example 15. Flash column chromatography (dichloromethane: methanol=30:1) afforded compound 23 (59.0 mg,75%, white solid).
Compound 23 was tested as follows: 1 H NMR(400MHz,DMSO-d 6 )δ8.41(s,1H),7.51–7.43(m,1H),7.36(dd,J＝6.5,2.3Hz,1H),7.24(t,J＝9.0Hz,1H),7.14(t,J＝7.7Hz,1H),6.86(d,J＝7.4Hz,1H),6.56(d,J＝8.0Hz,1H),6.37(t,J＝6.2Hz,1H),4.41(s,2H),3.79–3.47(m,2H),3.14(d,J＝5.7Hz,2H),1.47–1.01(m,4H),0.39–0.25(m,4H). 13 C NMR(100MHz,DMSO)δ171.1,164.6,158.9,155.7,143.6,137.0,133.9,130.1,129.3,127.9,124.6,116.0,112.3,110.8,47.1,45.5,43.9,41.8,18.0,11.5. 19 F NMR(376MHz,DMSO)δ-119.95.HRMS(ESI):m/z calcd for C 23 H 24 FN 3 NaO 2 + [M+Na] + :416.1745；found 416.1748。
example 24
Preparation of the target product Compound 24
The preparation method comprises the following steps:
1) Preparation of Compound B-3: in the same manner as in the preparation of B-3 in example 15, compound B-3 was obtained.
2) Preparation of Compound B-4: in the same manner as in the preparation of B-4 in example 15, compound B-4 was obtained.
3) Preparation of Compound 24
Based on example 15, in the present example, tert-butyl 1, 4-diazine-1-carboxylate (36.6 mg,0.200 mmol) was used in a manner different from the amine used in example 15, and the objective compound 24 was obtained according to the synthetic procedure described in example 15. Flash column chromatography (dichloromethane: methanol=30:1) afforded compound 24 (68.5 mg,71%, white solid).
Compound 24 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ8.14(s,1H),7.89(d,J＝8.1Hz,1H),7.83(q,J＝8.1Hz,1H),7.67–7.56(m,2H),7.49–7.41(m,2H),7.15–6.92(m,1H),4.65(s,2H),4.38(s,2H),3.99(d,J＝7.5Hz,2H),3.70(q,J＝16.6Hz,2H),3.21(d,J＝7.5Hz,4H),2.91(s,9H),0.96–0.87(m,9H). 13 C NMR(100MHz,CDCl 3 )δ172.3,171.0,163.0,137.4(d,J F-C ＝3.2Hz),133.4,131.2(d,J F-C ＝8.1Hz),131.1,130.6(d,J F-C ＝3.2Hz),129.8,129.6,128.1,127.1,125.6,124.4(d,J F-C ＝18.5Hz),121.1(d,J F-C ＝33.1Hz),48.8,46.5,32.6,29.9,29.4,22.1,13.3,8.1. 19 F NMR(376MHz,CDCl 3 )δ-122.9.HRMS(ESI):m/z calcd for C 26 H 31 FN 4 NaO 4 + [M+Na] + :505.2222；found 505.2219。
example 25
Preparation of the target product Compound 25
The preparation method comprises the following steps:
1) Preparation of Compound B-3: in the same manner as in the preparation of B-3 in example 15, compound B-3 was obtained.
2) Preparation of Compound B-4: in the same manner as in the preparation of B-4 in example 15, compound B-4 was obtained.
3) Preparation of Compound 25
On the basis of example 15, in contrast to the amine used in example 15, homopiperazine (15.1 mg,0.200 mmol) was used in this example to obtain the target compound 25 according to the synthetic procedure described in example 15. Flash column chromatography (dichloromethane: methanol=30:1) afforded compound 25 (25.3 mg,33%, white solid).
Compound 25 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ8.14(s,1H),7.89(d,J＝8.1Hz,1H),7.83(q,J＝8.1Hz,1H),7.67–7.56(m,2H),7.49–7.41(m,2H),7.15–6.92(m,1H),4.65(s,2H),4.38(s,2H),3.99(d,J＝7.5Hz,2H),3.70(q,J＝16.6Hz,2H),3.21(d,J＝7.5Hz,4H),0.96–0.87(m,9H). 13 C NMR(100MHz,CDCl 3 )δ172.3,163.0,137.4(d,J F-C ＝3.2Hz),133.4,131.2(d,J F-C ＝8.1Hz),131.1,130.6(d,J F-C ＝3.2Hz),129.8,129.6,128.1,127.1,125.6,124.4(d,J F-C ＝18.5Hz),121.1(d,J F-C ＝33.1Hz),48.8,46.5,32.6,29.4,23.1,8.4. 19 F NMR(376MHz,CDCl 3 )δ-123.0.HRMS(ESI):m/z calcd for C 21 H 23 FN 4 NaO 2 + [M+Na] + :405.1697；found 405.1699。
example 26
Preparation of the target product Compound 26
The preparation method comprises the following steps:
1) Preparation of Compound B-3: in the same manner as in the preparation of B-3 in example 15, compound B-3 was obtained.
2) Preparation of Compound B-4: in the same manner as in the preparation of B-4 in example 15, compound B-4 was obtained.
3) Preparation of Compound 26
On the basis of example 15, in contrast to the amine used in example 15, which was cyclopropyl (1, 4-diaza-1-yl) methanone (31.1 mg,0.200 mmol), the title compound 26 was obtained following the synthetic procedure described in example 15. Flash column chromatography (dichloromethane: methanol=30:1) afforded compound 26 (65.8 mg,73%, white solid).
Compound 26 was tested as follows: 1 H NMR(400MHz,DMSO-d 6 )δ8.39(s,1H),7.49–7.45(m,1H),7.32–7.12(m,1H),6.86(dd,J＝7.5,3.7Hz,3H),6.62–6.50(m,1H),6.43–6.35(m,1H),4.39(s,2H),4.22(s,2H),3.74–3.56(m,4H),3.44–3.36(m,2H),3.29–3.06(m,2H),1.96–1.84(m,1H),1.69(q,J＝6.3Hz,1H),0.85(t,J＝6.6Hz,1H),0.69(dd,J＝14.3,5.5Hz,4H). 13 C NMR(100MHz,DMSO)δ175.2,170.0,164.7,157.0,144.5,140.0,136.2,133.4,129.2,123.1,123.1,116.8,111.9,110.8,92.8,55.3,49.5,48.7,47.0,45.7,43.9,22.5,14.4,7.5. 19 F NMR(376MHz,DMSO)δ-119.59.HRMS(ESI):m/z calcd for C 25 H 27 FN 4 NaO 3 + [M+Na] + :473.1959；found 473.1958。
example 27
Preparation of the target product Compound 27
The preparation method comprises the following steps:
1) Preparation of Compound B-3: in the same manner as in the preparation of B-3 in example 15, compound B-3 was obtained.
2) Preparation of Compound B-4: in the same manner as in the preparation of B-4 in example 15, compound B-4 was obtained.
3) Preparation of Compound 27
On the basis of example 15, in contrast to the amine used in example 15, ethyl (1, 4-diaza-1-yl) methanone (28.2 mg,0.200 mmol) was used in this example to obtain the title compound 27 following the synthetic procedure described in example 15. Flash column chromatography (dichloromethane: methanol=30:1) afforded compound 27 (58.6 mg,69%, white solid).
Compound 27 was tested as follows: 1 H NMR(400MHz,DMSO-d 6 )δ8.39(s,1H),7.49–7.45(m,1H),7.32–7.12(m,1H),6.86(dd,J＝7.5,3.7Hz,3H),6.62–6.50(m,1H),6.43–6.35(m,1H),4.39(s,2H),4.22(s,2H),3.74–3.56(m,4H),3.44–3.36(m,2H),3.29–3.06(m,2H),2.85(s,3H),1.96–1.84(m,1H),1.69(q,J＝6.3Hz,1H). 13 C NMR(100MHz,DMSO)δ175.2,170.0,164.7,157.0,144.5,140.0,136.2,133.4,129.2,123.1,123.1,116.8,111.9,110.8,92.8,52.4,49.5,48.7,47.0,45.7,43.9,22.5,7.5. 19 F NMR(376MHz,CDCl 3 )δ-111.10.HRMS(ESI):m/z calcd for C 23 H 25 FN 4 NaO 3 + [M+Na] + :447.1803；found 447.1801。
example 28
Preparation of the target product Compound 28
The preparation method comprises the following steps:
1) Preparation of Compound B-3: in the same manner as in the preparation of B-3 in example 15, compound B-3 was obtained.
2) Preparation of Compound B-4: in the same manner as in the preparation of B-4 in example 15, compound B-4 was obtained.
3) Preparation of Compound 28
On the basis of example 15, in contrast to the amine used in example 15, 1- (ethylsulfonyl) -1, 4-diazane (34.2 mg,0.200 mmol) was used in this example to give the title compound 28 according to the synthetic procedure described in example 15. Flash column chromatography (dichloromethane: methanol=30:1) afforded compound 28 (46.5 mg,49%, white solid).
Compound 28 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ7.49(d,J＝6.3Hz,1H),7.40–7.26(m,3H),7.25–7.16(m,2H),7.06(q,J＝9.0Hz,1H),6.63(dd,J＝18.8,7.6Hz,1H),4.39(s,2H),4.27(s,2H),3.83(m,J＝5.3Hz,2H),3.53–3.26(m,6H),2.97(dd,J＝14.8,7.4Hz,2H),2.08–1.85(m,2H),1.36–1.24(t,3H). 13 C NMR(100MHz,CDCl 3 )δ171.8,165.7,142.7,135.5,132.7,129.9,129.4,128.9,127.5,126.8,124.4,116.3,113.0,112.7,51.3,50.0,48.0,46.8,45.8,44.8,43.7,26.8,8.1. 19 F NMR(376MHz,CDCl 3 )δ-117.68.HRMS(ESI):m/z calcd for C 23 H 27 FN 4 NaO 4 S + [M+Na] + :497.1629；found 497.1632。
example 29
Preparation of the target product Compound 29
The preparation method comprises the following steps:
1) Preparation of Compound B-3: in the same manner as in the preparation of B-3 in example 15, compound B-3 was obtained.
2) Preparation of Compound B-4: in the same manner as in the preparation of B-4 in example 15, compound B-4 was obtained.
3) Preparation of Compound 29
On the basis of example 15, in contrast to the amine used in example 15, 8-aminoquinoline (28.9 mg,0.200 mmol) was used in this example to obtain the title compound 29 following the synthetic procedure described in example 15. Flash column chromatography (dichloromethane: methanol=30:1) afforded compound 29 (54.6 mg,64%, white solid).
Compound 29 was tested as follows: 1 H NMR(400MHz,Chloroform-d)δ7.60(s,1H),7.46–7.39(m,4H),7.32(t,J＝7.6Hz,1H),7.25(s,1H),7.23–7.19(m,2H),7.05–6.98(m,4H),6.94(t,J＝8.6Hz,1H),6.49(s,1H),4.27(s,2H). 13 C NMR(100MHz,CDCl 3 )δ172.1,170.2,165.0,160.1,158.4,153.2,147.3,139.3,138.8,135.8,133.6(d,J F-C ＝3.0Hz),133.0,132.9(d,J F-C ＝8.2Hz),129.3(d,J F-C ＝3.0Hz),124.9,124.7(d,J F-C ＝17.5Hz),123.4,121.0,119.3,119.0,118.6,116.5(d,J F-C ＝24.6Hz),116.3,44.2. 19 F NMR(376MHz,CDCl 3 )δ-120.8.HRMS(ESI):m/z calcd for C 24 H 17 FN 4 NaO 2 + [M+Na] + :435.1228；found 435.1229。
performance test:
enzyme activity test: the enzyme activity test was carried out using a kit of Trevigen PARP1 (PARP in vivo Pharmacodynamic Assay 2nd Generation,Item No.4520-096-k. Purchased from AmyJet Scientific inc.) for the detection of compounds 1 to 29 of the target products prepared in examples 1 to 29 described above, the detection results being shown in the following table:
| compounds of formula (I) | PARP1 enzyme activity IC 50 /nM |
| 1 | 45.3 |
| 2 | 98.2 |
| 3 | 12.1 |
| 4 | 112.9 |
| 5 | 194.2 |
| 6 | 69.8 |
| 7 | 79.1 |
| 8 | 83.9 |
| 9 | 41.6 |
| 10 | 14.9 |
| 11 | 34.4 |
| 12 | 64.2 |
| 13 | 41.0 |
| 14 | 234.2 |
| 15 | 8.8 |
| 16 | 18.7 |
| 17 | 21.6 |
| 18 | 30.2 |
| 19 | 90.3 |
| 20 | 142.3 |
| 21 | 35.2 |
| 22 | 39.7 |
| 23 | 46.3 |
| 24 | 11.2 |
| 25 | 40.7 |
| 26 | 52.5 |
| 27 | 31.1 |
| 28 | 34.0 |
| 29 | 52.3 |
As can be seen from the data in the above table, the objective compounds 1 to 29 prepared in examples 1 to 29 have highly effective and reversible effects of inhibiting PARP1 protease activity.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (8)
1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:
the compound is any one of the following:
2. a process for the preparation of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: the compound has two synthetic routes, namely the following synthetic route one or the synthetic route two:
the first synthetic route comprises the following steps:
(1) The compound A-1 and the compound A-2 react in a solvent in the presence of a catalyst, alkali and a ligand to obtain a compound A-3;
(2) Compound A-3 is prepared in the presence of base in THF, meOH and H 2 Hydrolyzing the mixed solvent of O to generate a compound A-4;
(3) Condensing the compound A-4 with amine in a solvent in the presence of alkali and a condensing agent to obtain a compound A;
the second synthesis route comprises the following steps:
(1) Reacting the compound B-1 with the compound B-2 in a solvent in the presence of a reducing agent and acid to obtain a compound B-3;
(2) Compound B-3 is prepared in THF, meOH and H under the action of a base 2 Hydrolyzing the mixed solvent of O to generate a compound B-4;
(3) Condensing the compound B-4 with amine in a solvent in the presence of alkali and a condensing agent to obtain a compound B;
wherein the radicals R in the first and second synthetic routes 1 And R is 2 As claimed in claim 1.
3. A process for the preparation of a compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein:
in the first synthesis route:
in the step (1), the catalyst is a palladium catalyst selected from Pd 2 (dba) 3 、Pd(OAc) 2 、Pd(PPh 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 Or Pd (dppf) Cl 2 The method comprises the steps of carrying out a first treatment on the surface of the The alkali is K 3 PO 4 、K 2 CO 3 、Cs 2 CO 3 、KO t Bu or Na 2 CO 3 The method comprises the steps of carrying out a first treatment on the surface of the The ligand is brettphos, XPhos, SPhos, xantPhos, ruPhos or PPh 3 The method comprises the steps of carrying out a first treatment on the surface of the The solvent is 2, 6-dioxane, H 2 O, THF, DMF, toluene, or both;
in the step (2), the alkali is LiOH, naOH or KOH;
in the step (3), the alkali is TEA, DIPEA, DABCO, DBU or tetramethyl ethylenediamine; condensing agent is HATU, HBTU, DCC, EDC or EDCI; the solvent is DCM, DMF, DMSO, THF or 2, 6-dioxane;
in the second synthesis route:
in the (1), the reducing agent is sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride; the acid is acetic acid, hydrochloric acid, sulfuric acid or phosphoric acid; the solvent is 2, 6-dioxane, THF, DMF, DMSO, toluene or MeOH;
in the step (2), the alkali is LiOH, naOH or KOH;
in the step (3), the alkali is TEA, DIPEA, DABCO, DBU or tetramethyl ethylenediamine; condensing agent is HATU, HBTU, DCC, EDC or EDCI; the solvent is DCM, DMF, DMSO, THF or 2, 6-dioxane.
4. A pharmaceutical composition characterized by: a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
5. The pharmaceutical composition according to claim 4, wherein: the dosage form of the pharmaceutical composition is any pharmaceutically acceptable dosage form.
6. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 or 5 as a reversible PARP1 inhibitor for the manufacture of a medicament for the treatment and/or prevention of cancer.
7. Use according to claim 6, characterized in that: the cancer is breast cancer, prostatic cancer, ovarian cancer, bladder cancer, liver cancer, lung cancer, neuroblastoma or leukemia.
8. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 or 5 for the preparation of a reversible PARP1 inhibitor medicament.
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