CN107286174B - Substituted 2,4- (1H,3H) pyrimidinedione as PARP inhibitor and application thereof - Google Patents

Substituted 2,4- (1H,3H) pyrimidinedione as PARP inhibitor and application thereof Download PDF

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CN107286174B
CN107286174B CN201610220259.6A CN201610220259A CN107286174B CN 107286174 B CN107286174 B CN 107286174B CN 201610220259 A CN201610220259 A CN 201610220259A CN 107286174 B CN107286174 B CN 107286174B
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pyrimidine
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郑永勇
金华
周峰
黄美花
孟欣
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Shanghai Xunhe Pharmaceutical Technology Co Ltd
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Abstract

The present invention relates to a class of substituted 2,4- (1H,3H) pyrimidinedione derivatives and their use as therapeutically effective poly (ADP-ribose) polymerase (PARP) inhibitors. Specifically, the invention relates to a novel substituted 2,4- (1H,3H) pyrimidinedione derivative shown in a general formula (I) and a pharmaceutical composition thereof, and application of the derivative as a selective PARP-1/2 inhibitor in preventing or treating PARP-1/2 related diseases.

Description

Substituted 2,4- (1H,3H) pyrimidinedione as PARP inhibitor and application thereof
Technical Field
The present invention relates to substituted 2,4- (1H,3H) pyrimidinediones and their use as therapeutically effective inhibitors of poly (ADP-ribose) polymerase (PARP).
Background
PARP is a short name for poly (ADP-ribose) polymerase, a ribozyme closely related to single-stranded DNA damage repair, and plays a key role in repairing DNA damage and maintaining genome integrity. PARP is a large family, including 18 subtypes (Ame, j.c., c. spenhauer, and g.de murcia. bioessays 26: 882-93.). Among PARP, only PARP-1 and PARP-2 are involved in the repair of DNA single strand breaks. Among them, PARP-1 is most abundant in eukaryotic cells, and the functional study thereof is also most intensive. PARP-1 mediated DNA repair plays a multiple molecular biological role: on one hand, PARP can repair DNA damage caused by oxidation or chemotherapeutic drugs and is an important factor causing chemotherapy or radiotherapy drug resistance; on the other hand, according to synthetic lethality theory, if synthetic lethality exists between two genes, Cell survival is not affected when either gene is inhibited or mutated alone, but inhibition of both genes simultaneously results in apoptosis (Kraus W.L.and Lis, J.T. (2003). Cell 113: 677-683; Ame, J.C., C.Spenlehuer, and G.de Murcia.Bioessays 26: 882-93.).
PARP-1/2 is recruited to the site of DNA damage and is activated following DNA binding by its zinc finger, and then poly (ADP-ribose) on histone glutamate residues. This generates highly negatively charged ADP-ribose chains, which in turn lead to unwinding and repair of damaged DNA by base excision repair mechanisms. PARP-1 is responsible for most of the DNA damage (> 90%) associated with PARP activity. Due to its multifunctional role, activation of PARP-1/2 has played a role in a variety of human diseases, such as cancer, stroke, myocardial infarction, inflammation, hypertension, atherosclerosis, and diabetes.
Radiation and chemotherapy are two important therapeutic approaches for cancer treatment. Ionizing radiation and DNA-methylating agents kill cancer cells by mechanisms involving the breaking of single strands of DNA. However, single strand breaks activate PARP-1 and initiate base excision repair mechanisms to repair the damage, resulting in reduced efficacy or development of drug resistance. When PARP-1 activity is inhibited, single-stranded DNA becomes persistent, which leads to genomic abnormalities and apoptosis, ultimately leading to cell death (Dantzer, f., g.de La Rubia, et al.biochemistry 2000; 39: 7559-69). Thus, PARP-1 inhibitors may be used as adjunctive anti-Cancer agents to potentiate the clinical effects of radiation and chemotherapy (Plummer R, Jones C, et al. Clin Cancer Res.2008Dec 1; 14 (23): 7917-23).
Breast and ovarian cancer are the major diseases causing death in women. Mutations BRCA1 or BRCA2 account for 3-5% of all breast cancers in breast cancer and up to 5% or more in ovarian cancer (R.Wooster and B.L. Weber (2003). N.Engl. J.Med.348 (23): 2339-2347). Triple negative breast cancer refers to breast cancer that lacks both estrogen and progestin receptors and does not express HER2, representing approximately 15% of all breast cancers, and which is unresponsive to current estrogen therapy and HER2 targeted therapies and has no standard treatment regimen. BRCA1/2 plays an essential role in the repair of DNA double strand breaks by a mechanism known as homologous recombination. BRCA1/2 gene-deficient cells are unable to repair DNA double strand breaks, but rely primarily on PARP-1/2-mediated base excision repair to maintain genetic integrity. Inhibition of PARP-1 activity results in synthetic lethality in BRCA1/2 gene-deficient cancer cells (Bryant, H.E., N.Schultz, H.D.Thomas, et al (2005). Nature.434: 913-917). Thus, PARP-1/2 inhibitors can be engineered as single agents for cancer treatment through defective DNA repair.
Currently, there are several selective PARP-1/2 inhibitors currently in clinical stage (e.g. AZD2281, ABT-888, and AG014699, etc.). Clinical evaluation of these drugs includes breast cancer, ovarian cancer, prostate cancer, colorectal cancer, pancreatic cancer, liver cancer, melanoma, gastric cancer, solid tumors, and the like.
In conclusion, PARP inhibitors are theoretically not only sensitizers for chemotherapy and radiotherapy, but also have inhibitory effects on tumors with gene mutation (BRCA1/2 mutation) or HR deficiency when used alone.
Disclosure of Invention
The invention aims to provide a novel substituted 2,4- (1H,3H) pyrimidinedione compound and a derivative or a pharmaceutically acceptable salt thereof.
The invention also aims to provide application of the compound serving as a novel high-selectivity PARP-1/2 inhibitor in preparing medicines for preventing or treating PARP enzyme-related diseases, wherein the PARP enzyme-related diseases comprise cancers (such as breast cancer, ovarian cancer, prostate cancer, colorectal cancer, pancreatic cancer, liver cancer, melanoma, gastric cancer, solid tumors and the like), various ischemic diseases and neurodegenerative diseases (such as Parkinson's disease, Alzheimer's disease and the like).
In order to achieve the above objects, the present invention provides substituted 2,4- (1H,3H) pyrimidinediones represented by the following general formula I:
Figure BSA0000128603490000031
wherein:
R1，R2each represents hydrogen and C1-C3Alkyl of (C)1-C3Alkoxy, halogen, trifluoromethyl or cyano of (a);
or R1，R2Together with the carbon atoms to which they are attached form a substituted or unsubstituted 5-to 6-membered aliphatic ring, a substituted or unsubstituted benzene ring;
R3，R4，R5，R6each represents hydrogen and C1-C3Alkyl of (C)1-C3Alkoxy, halogen, trifluoromethyl or cyano of (a);
R7，R8independently selected from hydrogen,
Figure BSA0000128603490000032
Or R7，R8Together with the nitrogen atom to which they are attached form a substituted or unsubstituted 5-to 7-membered aliphatic ring which may contain 1N or O or S, and which may be substituted on N by R9Substitution;
R9represents hydrogen, C1-C4Alkyl, phenyl, R1Substituted phenyl, C5-C6Heteroaryl, acyl, sulfonyl of (a);
wherein acyl is-C (═ O) R10，R10Is an acyl substituent, said substituent being C1-C3Alkyl radical, C3-C7Cycloalkyl, phenyl, R1A substituted phenyl group;
wherein sulfonyl is-S (═ O)2R10，R10Is an acyl substituent, said substituent being C1-C3Alkyl radical, C3-C7Cycloalkyl, phenyl, R1A substituted phenyl group;
x represents S, O, N;
y represents H, O;
a represents
Figure BSA0000128603490000041
Figure BSA0000128603490000042
n is 1, 2, 3;
Figure BSA0000128603490000043
represents a single bond or a double bond.
The present invention also provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier, and at least one compound of formula (I) and pharmaceutically acceptable salts thereof as described herein for use as PARP inhibitors.
As described in this application "C1-C3The "alkyl group" of (a) means a methyl group, an ethyl group, an n-propyl group or an isopropyl group; said "C1-C3The "alkoxy group" of (a) means a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group; the halogen refers to F, Cl, Br and I; said "C3-C7Cycloalkyl "means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; said "C5-C6By heteroaryl is meant a 5 to 6 membered aromatic monocyclic ring comprising 1-3 heteroatoms selected from N, O, S, the remaining ring atoms being carbon.
Typical compounds of the present invention include, but are not limited to, the following compounds of table 1:
Figure BSA0000128603490000044
Figure BSA0000128603490000051
Figure BSA0000128603490000061
Figure BSA0000128603490000071
Figure BSA0000128603490000081
or a pharmaceutically acceptable salt thereof.
Examples of pharmaceutically acceptable salts include inorganic and organic salts, such as hydrochloride, hydrobromide, sulfate, phosphate, citrate, tartrate, succinate, maleate, fumarate, tonsil and oxalate salts.
Part of the compounds of the invention can be prepared by the following general synthesis method one:
Figure BSA0000128603490000082
according to S Goto, H Tsuboi et al at org.&Procedure reported in Dev.2003, pp700 preparation I4I.e. substituted 2,4- (1H,3H) pyrimidinediones (I)1) With Hexamethyldisilazane (HMDS) under acidic conditions to give intermediate I2，I2And I3Preparing an ester intermediate I through substitution reaction4，I4The target product I is prepared through hydrolysis and amidation reactions.
Part of the compounds of the invention can be prepared by the following general synthesis method II:
Figure BSA0000128603490000091
I2and I7Preparing an intermediate I through substitution reaction8，I8And I6And (4) carrying out amination reaction to obtain a target product I.
The invention relates to a substituted 2,4- (1H,3H) pyrimidinedione derivative which is a PARP-1/2 inhibitor, and the compound can be used for treating various clinical diseases, such as cancers, caused by abnormal activity of PARP-1/2. Such diseases include, but are not limited to, breast cancer, ovarian cancer, prostate cancer, colorectal cancer, liver cancer, melanoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, lung cancer, gastric cancer, pancreatic cancer.
Meanwhile, the invention also comprises the application of the compound in treating other diseases caused by abnormal PARP-1/2 activity, such as central nervous system diseases such as apoplexy and neurodegenerative diseases.
The derivative can be formed into a composition for treating related cancers and other diseases by oral administration, injection and the like in the process of treating diseases.
The composition comprises a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The mentioned carriers refer to the carriers conventional in the pharmaceutical field, such as: diluents, excipients such as water, etc.; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.; fillers such as starch and the like; disintegrating agents such as calcium carbonate, sodium bicarbonate; in addition, other adjuvants such as flavoring agents and sweeteners may also be added to the composition.
For oral administration, it can be prepared into conventional solid preparations such as tablet, powder or capsule; for injection, it can be prepared into injection.
The various dosage forms of the composition of the present invention can be prepared by conventional methods in the medical field, wherein the content of the active ingredient is 0.1-99.5% (by weight).
The administration amount of the present invention may vary depending on the route of administration, age, body weight of the patient, type and severity of the disease to be treated, etc., and the daily dose thereof is 0.005 to 30mg/kg body weight (oral administration) or 0.005 to 30mg/kg body weight (injection).
Examples
The present invention is further illustrated below with reference to specific examples, which are not intended to limit the scope of the invention.
Example 1
The compound (I-1)1- (3- (4-cyclopropylcarbonylpiperazine-1-carbonyl) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Step 1: thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione (0.5g, 2.98mmol), HMDS (1.2g, 7.44mmol), and toluene (8mL) were charged to a reaction flask, concentrated sulfuric acid (20mg) was added with stirring, and the reaction was refluxed with stirring for 12 hours. The solvent was concentrated to dryness under reduced pressure.
Step 2: methyl 3-bromomethylbenzoate (1.02g, 4.46mmol) and DMF (1mL) were added to the residue in step 1 in this order, and the reaction was stirred for 5h at 130 ℃ and 135 ℃. Cooling to 90-100 deg.C, adding 1, 4-dioxane (3mL) under stirring, further cooling to 60-70 deg.C, adding methanol (5mL), and stirring for 30 min. Concentrating the solvent to dryness, adding ethanol (10mL) into the residue, and recrystallizing to obtain white solid intermediate 1- (3-methoxycarbonylbenzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (0.5g, two-step yield 53.2%), MS (m/z): 317[ M + H ]]+。
And step 3: 1- (3-methoxycarbonylbenzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (0.5g, 1.58mmol), methanol (3 mL)/tetrahydrofuran (3mL), and water (3mL) were added to a reaction flask, and sodium hydroxide (0.1g, 2.37mmol) was added with stirring, followed by reaction at 40-50 ℃ for 2H. 1N diluted hydrochloric acid solution is added dropwise to adjust the pH value to 2-3, and the mixture is stirred for 1 hour. Filtering, adding ethanol (3mL) into the solid for recrystallization to obtain a white solid intermediate 1- (3-carboxyl benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (0.45g, yield 94.2%), MS (m/z): 303[ M + H]+。
And 4, step 4: 1- (3-carboxybenzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (0.2g, 0.66mmol), trispyrrolidinyl phosphonium bromide hexafluorophosphate (PyBrOP, 0.46g, 0.99mmol), 1-cyclopropylformylpiperazine (0.1g, 0.66mmol), N-diisopropylethylamine (DIPEA, 0.17g, 1.32mmol), and dichloromethane (5mL) were added to the reaction flask and stirred at room temperature overnight. Dichloromethane (5mL) and water (5mL) were added to the reaction mixture, followed by extraction, and the organic layer was washed with water (3mL), dried, filtered, and concentrated to give a crude product. The crude product was chromatographed on silica gel column (mobile phase CH)2Cl2/CH3OH 50/1) to obtain the final product 1- (3- (4-cyclopropyl carbonyl piperazine-1-carbonyl) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-1), white solid (0.2g, yield 68.9%), MS (m/z): 461[ M + Na ]]+。1H NMR(DMSO-d6)：：11.60(br，1H)，7.47-7.35 (m，4H)，7.22-7.20(d，J＝8.0Hz，1H)，7.18-7.16(d，J＝8.0Hz，1H)，5.16(s，2H)， 3.73-3.43(m，8H)，1.26-1.21(m，1H)，0.73-0.70(m，4H)。
Example 2
The compound (I-2)1- (4-fluoro-3- (4-cyclopropylcarbonylpiperazine-1-carbonyl) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Step 1: thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione (0.5g, 2.98mmol), HMDS (1.2g, 7.44mmol), and toluene (8mL) were charged to a reaction flask, concentrated sulfuric acid (20mg) was added with stirring, and the reaction was refluxed with stirring for 12 hours. The solvent was concentrated to dryness under reduced pressure.
Step 2: the residue in step 1 was added with methyl 2-fluoro-5-bromomethylbenzoate (1.1g, 4.46mmol) and DMF (1mL) in this order, heated to 130-. Cooling to 90-100 deg.C, adding 1, 4-dioxane (3mL) under stirring, further cooling to 60-70 deg.C, adding methanol (5mL), and stirring for 30 min. Concentrating the solvent to dryness, adding ethanol (10mL) into the residue, and recrystallizing to obtain white solid intermediate 1- (4-fluoro-3-methoxycarbonylbenzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (0.6g, yield 60.4%), MS (m/z): 335[ M + H ]]+。
And step 3: 1- (4-fluoro-3-methoxycarbonylbenzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (0.6g, 1.8mmol), methanol (3 mL)/tetrahydrofuran (3mL), and water (3mL) were added to a reaction flask, and sodium hydroxide (0.1g, 2.37mmol) was added with stirring, followed by reaction at 40-50 ℃ for 2H. 1N diluted hydrochloric acid solution is added dropwise to adjust the pH value to 2-3, and the mixture is stirred for 1 hour. Filtering, adding ethanol (3mL) into the solid for recrystallization to obtain a white solid intermediate 1- (4-fluoro-3-carboxyl benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (0.48g, yield 83.5%), MS (m/z): 321[ M + H [ ]]+。
And 4, step 4: 1- (4-fluoro-3-carboxybenzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (0.21g, 0.66mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (PyBrOP, 0.46g, 0.99mmol), 1-cyclopropylformylpiperazine (0.1g, 0.66mmol), N-diisopropylethylamine (DIPEA, 0.17g, 1.32mmol), dichloromethane (5mL) were added to the reaction flask, stirred at room temperature and filteredAnd (4) at night. Dichloromethane (5mL) and water (5mL) were added to the reaction mixture, followed by extraction, and the organic layer was washed with water (3mL), dried, filtered, and concentrated to give a crude product. The crude product was chromatographed on silica gel column (mobile phase CH)2Cl2/CH3OH 50/1) to obtain the final product 1- (4-fluoro-3- (4-cyclopropylcarbonylpiperazine-1-carbonyl) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-2), white solid (0.19g, yield 63.3%), MS (m/z): 478[ M + Na ]]+。1H NMR(DMSO-d6)：：11.58(br，1H)， 7.45-7.35(m，3H)，7.21-7.19(d，J＝8.0Hz，1H)，7.17-7.15(d，J＝8.0Hz，1H)，5.17(s， 2H)，3.70-3.42(m，8H)，1.27-1.24(m，1H)，0.74-0.70(m，4H)。
Example 3
The compound (I-3)1- (3- (4-methylpiperazine-1-methyl) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Step 1: thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione (0.5g, 2.98mmol), HMDS (1.2g, 7.44mmol), and toluene (8mL) were charged to a reaction flask, concentrated sulfuric acid (20mg) was added with stirring, and the reaction was refluxed with stirring for 12 hours. The solvent was concentrated to dryness under reduced pressure.
Step 2: step 1 the residue was added with m-dibromide benzyl (1.18g, 4.46mmol) and DMF (1mL) in sequence, heated to 130 ℃ and stirred at 135 ℃ for reaction for 5 h. Cooling to 90-100 deg.C, adding 1, 4-dioxane (3mL) under stirring, further cooling to 60-70 deg.C, adding methanol (5mL), and stirring for 30 min. Concentrating the solvent to dryness, adding ethanol (10mL) into the residue, and recrystallizing to obtain white solid intermediate 1- (3-bromobenzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (0.6g, 57.7% two-step yield), MS (m/z): 352[ M + H]+. And step 3: 1- (3-bromobenzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (0.2g, 0.57mmol), 1-methylpiperazine (0.06g, 0.63mmol), N-dimethylformamide (DMF, 4mL), DIPEA (0.15g, 1.14mmol) were added to the reaction flask, and the reaction was stirred at room temperature for 5H. Dichloromethane (10mL) and water (5mL) were added to the reaction mixture, followed by extraction, and the organic layer was washed with water (3mL), dried, filtered, and concentrated to give a crude product. The crude product was chromatographed on silica gel column (mobile phase CH)2Cl2/CH3OH 30/1) to obtain the final product 1- (3- (4-methylpiperazine-1-methyl) benzylYl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-3), white solid (0.15g, yield 71.1%), MS (m/z): 371[ M + H]+。1H NMR(DMSO-d6)：：11.58(br，1H)， 7.32-7.15(m，6H)，5.11(s，2H)，5.11(s，2H)，3.43(s，2H)，2.33(m，8H)，2.16(s，3H)。
Example 4
The compound (I-4)1- (3- (4-hydroxypiperidine-1-methyl) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-4 was carried out as in example 3 starting from 1- (3-bromobenzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and 4-hydroxypiperidine. To obtain a final product 1- (3- (4-hydroxypiperidine-1-methyl) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-4), white solid. MS (m/z): 372[ M + H ]]+。1H NMR(DMSO-d6)：：11.56(br，1H)，7.32-7.13(m，6H)，5.13(s，2H)，4.32(br，1H)， 3.42(s，2H)，3.38(m，1H)，2.52(m，2H)，1.92(m，2H)，1.67(m，2H)，1.32(m，2H)。
Example 5
The compound (I-5)1- (4-fluoro-3- (4-hydroxypiperidine-1-carbonyl) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-5 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) thieno [2, 3-D ]]Pyrimidine-2, 4(1H, 3H) -dione and 4-hydroxypiperidine. To obtain a final product 1- (4-fluoro-3- (4-hydroxypiperidine-1-carbonyl) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-5), white solid. MS (m/z): 426[ M + Na ]]+。1HNMR(DMSO-d6)：：11.59(br，1H)，7.35-7.13(m，6H)，5.11(s， 2H)，4.30(br，1H)，3.37(m，1H)，2.51(m，2H)，1.94(m，2H)，1.68(m，2H)，1.33(m， 2H)。
Example 6
The compound (I-6)1- (4-fluoro-3- (4-methylpiperazine-1-carbonyl) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
The synthesis of compound I-6 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) thieno [2,3-D]pyrimidine-2, 4(1H, 3H) -dione and 1-methylpiperazine. To obtain a final product 1- (4-fluoro-3- (4-methylpiperazine-1-carbonyl) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-6), white solid. MS (m/z): 403[ M + H ]]+。1H NMR(DMSO-d6)：：11.61(br，1H)，7.49-7.18(m，6H)，5.13(s，2H)， 3.66(m，2H)，3.37(m，2H)，2.42(m，2H)，2.36(m，2H)，2.29(s，3H)。
Example 7
Compound (I-7)1- ((N- (3-morpholinopropyl) benzamide) methyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-7 was carried out as in example 1 starting from 1- (3-carboxybenzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and 3-morpholinopropylamine. Obtaining a final product 1- ((N- (3-morpholine propyl) benzamide) methyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-7), white solid. MS (m/z): 429 [ M + H]+。1H NMR(DMSO-d6)：：11.60(br，1H)，8.52(br，1H)，7.76-7.74(m，2H)， 7.45-7.43(m，2H)，7.21-7.19(d，J＝8.0Hz，1H)，7.15-7.13(d，J＝8.0Hz，1H)，5.15(s， 2H)，3.55-3.53(m，4H)，3.27-3.22(m，2H)，2.30(m，6H)，1.68-1.63(m，2H)。
Example 8
The compound (I-8)1- (4-fluoro-3- (4- (2-pyridyl) piperazine-1-carbonyl) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-8 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) thieno [2, 3-D ]]Pyrimidine-2, 4(1H, 3H) -dione and 1- (2-pyridyl) piperazine. To obtain the final product 1- (4-fluoro-3- (4- (2-pyridyl) piperazine-1-carbonyl) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-8), white solid. MS (m/z): 466[ M + H]+。1H NMR(DMSO-d6)：：11.59(br，1H)，7.89(m， 1H)，7.76-7.45(m，6H)，7.22-7.20(d，J＝8.0Hz，1H)，7.15-7.13(d，J＝8.0Hz，1H)， 5.13(s，2H)，3.57-3.53(m，4H)，3.27-3.21(m，4H)。
Example 9
The compound (I-9)1- (4-fluoro-3- (4- (2-pyridyl) piperazine-1-carbonyl) benzyl) benzo [4, 5] thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-9 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) benzo [4, 5]]Thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (synthesis analogous to examples 1 and 2, starting from benzo [4, 5] benzo]Thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and methyl 2-fluoro-5-bromomethylbenzoate) and 1- (2-pyridyl) piperazine. To obtain the final product 1- (4-fluoro-3- (4- (2-pyridyl) piperazine-1-carbonyl) benzyl) benzo [4, 5]Thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-9), white solid. MS (m/z): 516[ M + H]+。1H NMR(DMSO-d6)：：11.61(br，1H)，7.92(m，3H)，7.73-7.53(m，6H)，7.35-7.30 (m，2H)，5.11(s，2H)，3.58-3.55(m，4H)，3.29-3.22(m，4H)。
Example 10
The compound (I-10)1- (4-fluoro-3- (4- (3-trifluoromethylphenyl) piperazine-1-carbonyl) benzyl) indolo [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-10 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) indolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (synthesis analogous to examples 1 and 2, starting from indolo [2, 3-D)]Pyrimidine-2, 4(1H, 3H) -dione and methyl 2-fluoro-5-bromomethylbenzoate) and 1- (3-trifluoromethylphenyl) piperazine. To obtain a final product 1- (4-fluoro-3- (4- (3-trifluoromethylphenyl) piperazine-1-carbonyl) benzyl) indolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-10), white solid. MS (m/z): 566[ M + H]+。1H NMR (DMSO-d6)：：12.10(br，1H)，11.58(br，1H)，7.91-7.88(m，3H)，7.73-7.65(m，5H)， 7.35-7.25(m，3H)，5.12(s，2H)，3.56-3.53(m，4H)，3.27-3.21(m，4H)。
Example 11
The compound (I-11)1- (4-fluoro-3- (4-cyclopropylcarbonylpiperazine-1-carbonyl) benzyl) furo [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-11 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl)Yl) furo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (synthesis analogous to examples 1 and 2, starting from furo [2, 3-D)]Pyrimidine-2, 4(1H, 3H) -dione and methyl 2-fluoro-5-bromomethylbenzoate) and 1- (3-trifluoromethylphenyl) piperazine. To obtain the final product 1- (4-fluoro-3- (4-cyclopropyl carbonyl piperazine-1-carbonyl) benzyl) furo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-11), white solid. MS (m/z): 441[ M + H]+。1H NMR (DMSO-d6)：：11.58(br，1H)，7.46-7.37(m，3H)，7.25-7.20(m，1H)，7.17-7.15(d，J ＝8.0Hz，1H)，5.13(s，2H)，3.69-3.39(m，8H)，1.26-1.24(m，1H)，0.75-0.71(m，4H)。
Example 12
The compound (I-12)1- (4-fluoro-3- (4-cyclopropylcarbonylpiperazine-1-carbonyl) benzyl) pyrrolo [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-12 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) pyrrolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (synthesis analogous to examples 1 and 2, starting from pyrrolo [2, 3-D)]Pyrimidine-2, 4(1H, 3H) -dione and methyl 2-fluoro-5-bromomethylbenzoate) and 1- (3-trifluoromethylphenyl) piperazine. To obtain the final product 1- (4-fluoro-3- (4-cyclopropyl carbonyl piperazine-1-carbonyl) benzyl) pyrrolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-12), white solid. MS (m/z): 440[ M + H ]]+。1H NMR (DMSO-d6)：：11.60(br，1H)，7.45-7.35(m，3H)，7.21-7.19(d，J＝8.0Hz，1H)， 7.17-7.15(d，J＝8.0Hz，1H)，5.23(br，1H)，5.11(s，2H)，3.67-3.42(m，8H)，1.27-1.24 (m，1H)，0.76-0.71(m，4H)。
Example 13
The compound (I-13)1- (4-fluoro-3- (4- (p-tolyl) piperazine-1-carbonyl) benzyl) furo [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-13 by the method of example 2, starting with 1- (4-fluoro-3-carboxybenzyl) furo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and 1- (p-tolyl) piperazine. To obtain the final product 1- (4-fluoro-3- (4- (p-tolyl) piperazine-1-carbonyl) benzyl) furo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -diones(I-13), a white solid. MS (m/z): 463[ M + H]+。1H NMR(DMSO-d6)：：11.59(br，1H)，7.43-7.35 (m，3H)，7.27-7.24(m，2H)，7.19-7.14(m，4H)，5.13(s，2H)，3.65-3.40(m，8H)，2.17 (s，3H)。
Example 14
The compound (I-14)1- (4-fluoro-3- (4- (methanesulfonyl) piperazine-1-carbonyl) benzyl) pyrrolo [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-14 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) pyrrolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and 1-methanesulfonylpiperazine. To obtain the final product 1- (4-fluoro-3- (4- (methane sulfonyl) piperazine-1-carbonyl) benzyl) pyrrolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-14), white solid. MS (m/z): 450[ M + H ]]+。1H NMR(DMSO-d6)：：11.59(br，1H)，7.43-7.31(m，3H)， 7.21-7.19(d，J＝8.0Hz，1H)，7.18-7.16(d，J＝8.0Hz，1H)，5.22(br，1H)，5.13(s，2H)， 3.68-3.57(m，4H)，2.97(s，3H)，2.65-2.60(m，4H)。
Example 15
The compound (I-15)1- (4-fluoro-3- (piperazine-1-carbonyl) benzyl) -5-isopropyl-pyrrolo [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-15 by the method of example 2 starting from 1- (4-fluoro-3-carboxybenzyl) -5-isopropyl-pyrrolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (synthesis analogous to examples 1 and 2, starting from 5-isopropyl-pyrrolo [2, 3-D)]Pyrimidine-2, 4(1H, 3H) -dione and methyl 2-fluoro-5-bromomethylbenzoate) and piperazine. To obtain the final product 1- (4-fluoro-3- (piperazine-1-carbonyl) benzyl) -5-isopropyl-pyrrolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-15), white solid. MS (m/z): 414[ M + H]+。1H NMR(DMSO-d6)：：11.58(br，1H)，7.42-7.31(m，3H)，7.19(s，1H)，5.21(br，1H)，5.11(s，2H)， 3.69-3.59(m，4H)，2.66-2.60(m，5H)，1.91(m，1H)，1.25-1.23(m，6H)。
Example 16
The compound (I-16)1- (4-fluoro-3- (4- (2-pyrimidinyl) piperazine-1-carbonyl) benzyl) pyrrolo [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-16 by the method of example 2, starting with 1- (4-fluoro-3-carboxybenzyl) pyrrolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and 1- (2-pyrimidinyl) piperazine. To obtain the final product 1- (4-fluoro-3- (4- (2-pyrimidinyl) piperazine-1-carbonyl) benzyl) pyrrolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-16), white solid. MS (m/z): 450[ M + H ]]+。1H NMR(DMSO-d6)：：11.58(br，1H)，8.52-5.50 (m，2H)，7.78-7.55(m，3H)，7.13-7.10(m，2H)，6.95-6.93(d，J＝8.0Hz，1H)，5.21(br， 1H)，5.13(s，2H)，3.56-3.53(m，4H)，3.26-3.21(m，4H)。
Example 17
The compound (I-17)1- (4-fluoro-3- (4- (2' -picolinoyl) piperazine-1-methyl) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-17 was carried out as in example 3 starting from 1- (4-fluoro-3-bromobenzyl) thieno [2, 3-D ]]Pyrimidine-2, 4(1H, 3H) -dione and N- (2' -picolinoyl) piperazine. To obtain the final product 1- (4-fluoro-3- (4- (2' -pyridine formyl) piperazine-1-methyl) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-17), white solid. MS (m/z): 480[ M + H ]]+。1H NMR(DMSO-d6)：：11.59(br，1H)， 8.70-8.65(m，2H)，8.02-7.93(m，2H)，7.32-7.13(m，5H)，5.11(s，2H)，3.51-3.47(m， 4H)，3.43(s，2H)，3.25-3.20(m，4H)。
Example 18
The compound (I-18)1- (4-fluoro-3- (4- (2' -pyridyl) piperazin-1-methyl) benzyl) -5-cyano-pyrrolo [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-18 was carried out as in example 3 starting from 1- (4-fluoro-3-bromobenzyl) -5-cyano-pyrrolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and 1- (2-pyridyl) piperazine. To obtain the final product 1- (4-fluoro-3- (4- (2' -pyridyl) piperazine-1-methyl) benzyl) -5-cyano-pyrrolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-18), white solid. MS (m/z): 460[ M + H ]]+。1H NMR(DMSO-d6)：：11.60(br，1H)， 8.53-8.47(m，2H)，8.01-7.95(m，2H)，7.33-7.11(m，4H)，5.13(s，2H)，3.50-3.47(m， 4H)，3.45(s，2H)，2.65-2.58(m，4H)。
Example 19
The compound (I-19)1- (4-fluoro-3- (4- (3-furyl) piperazine-1-carbonyl) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-19 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) thieno [2, 3-D ]]Pyrimidine-2, 4(1H, 3H) -dione and 1- (3-furyl) piperazine. To obtain the final product 1- (4-fluoro-3- (4- (3-furyl) piperazine-1-carbonyl) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-19), white solid. MS (m/z): 455[ M + H]+。1H NMR(DMSO-d6)：：11.59(br，1H)，7.88-7.85 (m，3H)，7.76-7.52(m，2H)，7.23-7.17(m，3H)，5.11(s，2H)，3.55-3.51(m，4H)， 3.26-3.20(m，4H)。
Example 20
The compound (I-20)1- (2-trifluoromethyl-4-fluoro-3- (4- (cyclobutylcarbonyl) piperazine-1-methyl) benzyl) -5-isopropyl-6-iodo-thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-20 was carried out as in example 3 starting from 1- (2-trifluoromethyl-4-fluoro-3-bromobenzyl) -5-isopropyl-6-iodo-thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and 1-cyclobutylformylpiperazine. To obtain a final product 1- (2-trifluoromethyl-4-fluoro-3- (4- (cyclobutyl carbonyl) piperazine-1-methyl) benzyl) -5-isopropyl-6-iodine-thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-20), white solid. MS (m/z): 709[ M + H]+。1H NMR(DMSO-d6)：：11.59(br，1H)，7.02(s，1H)，6.95(s，1H)，5.11(s，2H)，4.21 (m，1H)，3.53(s，2H)，3.43-3.38(m，4H)，2.95-2.81(m，11H)，1.29-1.27(m，6H)。
Example 21
The compound (I-21)1- (2-methyl-5- (4-phenylpiperazine-1-carbonyl) benzyl) -5, 6-dihydro-4H-cyclopentyl [ B ] thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-21The procedure is as in example 2, starting from 1- (2-methyl-5-carboxybenzyl) -5, 6-dihydro-4H-cyclopentyl [ B ]]Thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and 1-phenylpiperazine. To obtain a final product 1- (2-methyl-5- (4-phenylpiperazine-1-carbonyl) benzyl) -5, 6-dihydro-4H-cyclopentyl [ B]Thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-21), white solid. MS (m/z): 501[ M + H [ ]]+。1H NMR (DMSO-d6)：：11.60(br，1H)，7.75-7.58(m，3H)，7.08-6，93(m，5H)，5.11(s，2H)， 3.56-3.42(m，8H)，3.02-2.88(m，4H)，2.42-2.38(m，2H)，2.25(s，3H)。
Example 22
The compound (I-22)1- (2, 6-dimethyl-3- (4-benzoylpiperazine-1-carbonyl) benzyl) -5-cyano-furo [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-22 by the method of example 2, starting with 1- (2, 6-dimethyl-3-carboxybenzyl) -5-cyano-furo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and benzoylpiperazine. To obtain the final product 1- (2, 6-dimethyl-3- (4-benzoyl piperazine-1-carbonyl) benzyl) -5-cyano-furo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-22), white solid. MS (m/z): 512[ M + H]+。1H NMR(DMSO-d6)：：11.59(br，1H)，8.15(s，1H)，8.02-7.97(m，3H)，7.65-7.53(m，3H)，7.15-7.13(m， 1H)，5.11(s，2H)，3.67-3.37(m，8H)，2.35(s，3H)，2.20(s，3H)。
Example 23
The compound (I-23)1- (4-fluoro-2-isopropoxy-5- (4- (3-fluorophenyl) piperazine-1-carbonyl) benzyl) -6-fluoroindolo [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-23 by the method of example 2, starting with 1- (4-fluoro-2-isopropoxy-5-carboxybenzyl) -6-fluoroindolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione) and 1- (3-fluorophenyl) piperazine. To obtain the final product 1- (4-fluoro-2-isopropoxy-5- (4- (3-fluorophenyl) piperazine-1-carbonyl) benzyl) -6-fluoroindolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-23), white solid. MS (m/z): 592[ M + H]+。1H NMR (DMSO-d6)：：12.11(br，1H)，11.59(br，1H)，7.65-7.55(m，3H)，7.25-7.19(m，3H)，6.70-6.59(m，3H)，5.12(s，2H)，4.83(m，1H)，3.57-3.51(m，4H)，3.26-3.21(m，4H)， 1.28-1.26(m，6H)。
Example 24
The compound (I-24)1- (3- (4- (m-toluenesulfonyl) piperazine-1-carbonyl) benzyl) -7-methyl-indolo [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-24 by the method of example 1, starting from 1- (3-carboxybenzyl) -7-methyl-indolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione) and 1- (m-toluenesulfonyl) piperazine. To obtain a final product 1- (3- (4- (m-toluenesulfonyl) piperazine-1-carbonyl) benzyl) -7-methyl-indolo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-24), white solid. MS (m/z): 572[ M + H]+。1H NMR(DMSO-d6)：：12.10(br， 1H)，11.60(br，1H)，7.89-7.54(m，6H)，7.35-7.23(m，3H)，6.93-6.85(m，2H)，5.11(s， 2H)，3.58-3.51(m，4H)，3.27-3.20(m，4H)，2.35(s，3H)，2.33(s，3H)。
Example 25
The compound (I-25)1- (3-bromo-5- (thiazolidine-1-carbonyl) benzyl) -5-chlorothieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-25 was carried out as in example 2 starting from 1- (3-bromo-5-carboxybenzyl) -5-chlorothieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and thiazolidine. To obtain a final product 1- (3-bromine-5- (tetrahydrothiazole-1-carbonyl) benzyl) -5-chlorothieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-25), white solid. MS (m/z): 488[ M + H]+。1H NMR(DMSO-d6)：：11.59(br，1H)，8.03(s，1H)，7.69(s，1H)，7.63 (s，1H)，6.21(s，1H)，5.11(s，2H)，4.35-4.31(m，4H)，2.80-2.75(m，2H)。
Example 26
The compound (I-26)1- (4-chloro-3- (4-ethylpiperazine-1-carbonyl) benzyl) -5, 6-dimethylfuro [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
The synthesis of compound I-26 was carried out as in example 2 starting from 1- (4-chloro-3-carboxybenzyl) -5-chlorothieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and 1-ethyl homopiperazine. To obtain a final product 1- (4-chloro-3- (4-ethyl homopiperazine-1-carbonyl) benzyl) -5, 6-dimethyl furo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-26), white solid. MS (m/z): 460[ M + H ]]+。1H NMR(DMSO-d6)：：11.59(br，1H)，7.68-7.54 (m，3H)，5.11(s，2H)，3.45-3.39(m，4H)，3.02-2.93(m，4H)，2.68(m，2H)，2.31(s， 3H)，1.97(s，3H)，1.78(m，2H)，1.03-1.00(t，J＝4.0Hz，3H)。
Example 27
The compound (I-27)1- (2-methoxy-4-fluoro-5- (4- (cyclohexylcarbonyl) piperazine-1-carbonyl) benzyl) -5-methoxy-thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-27 by the method of example 2 starting from 1- (2-methoxy-4-fluoro-5-carboxybenzyl) -5-methoxy-thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and 1-cyclohexanecarboxylpiperazine. To obtain the final product 1- (2-methoxy-4-fluoro-5- (4- (cyclohexylcarbonyl) piperazine-1-carbonyl) benzyl) -5-methoxy-thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-27), white solid. MS (m/z): 559[ M + H ]]+。1H NMR (DMSO-d6)：：11.59(br，1H)，7.62(s，1H)，7.21(s，1H)，5.91(s，1H)，5.11(s，2H)， 3.82(s，6H)，3.67-3.59(m，8H)，2.35-2.30(m，1H)，1.49-1.27(m，10H)。
Example 28
The compound (I-28)1- (3-cyano-5- (4- (cyclopentylsulfonyl) piperazine-1-methyl) benzyl) -5-trifluoromethyl-6-bromo-thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-28 by the method of example 3, starting with 1- (3-cyano-5-bromobenzyl) -5-trifluoromethyl-6-bromo-thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and 1-cyclopentylsulfonylpiperazine. To obtain a final product 1- (3-cyano-5- (4- (cyclopentylsulfonyl) piperazine-1-methyl) benzyl) -5-trifluoromethyl-6-bromo-thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-28), white solid. MS (m/z): 661[ M + H]+。1H NMR (DMSO-d6)：：11.59(br，1H)，7.69(s，1H)，7.67(s，1H)，7.38(s，1H)，5.11(s，2H)， 3.67(s，2H)，3.01(m，1H)，2.90-2.76(m，8H)，1.95-1.45(m，8H)。
Example 29
The compound (I-29)1- (4-fluoro-3- (2-pyridylpiperazine-1-carbonyl) benzyl) -5, 6, 7, 8-tetrahydrobenzo [4, 5] thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-29 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) -5, 6, 7, 8-tetrahydrobenzo [4, 5]]Thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and 1- (2-pyridyl) piperazine. To obtain the final product 1- (4-fluoro-3- (2-pyridylpiperazine-1-carbonyl) benzyl) -5, 6, 7, 8-tetrahydrobenzo [4, 5]]Thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-29), white solid. MS (m/z): 520[ M + H ]]+。1H NMR (DMSO-d6)：：11.58(br，1H)，7.89(m，1H)，7.65-7.55(m，4H)，7.20-7.16(m，2H)， 5.15(s，2H)，3.57-3.53(m，4H)，3.27-3.21(m，4H)，2.69-2.65(m，4H)，1.89-1.84(m， 4H)。
Example 30
The compound (I-30)1- (4-fluoro-3- (N- (1-piperidinylmethyl) carboxamide) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-30 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) thieno [2, 3-D ]]Pyrimidine-2, 4(1H, 3H) -dione and piperidine-1-methylamine. To obtain a final product 1- (4-fluoro-3- (N- (1-piperidylmethyl) formamide) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-30), white solid. MS (m/z): 417[ M + H ]]+。1H NMR(DMSO-d6)：：11.60(br，1H)，8.53(br，1H)， 7.77-7.74(m，2H)，7.43-7.42(m，1H)，7.21-7.19(d，J＝8.0Hz，1H)，7.15-7.13(d，J＝ 8.0Hz，1H)，5.16(s，2H)，4.78(s，2H)，3.12-3.08(m，4H)，2.15-2.09(m，6H)。
Example 31
The compound (I-31)1- (4-fluoro-3- (N- (1-thiomorpholinethyl) carboxamide) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-31 according to example 2The method is carried out by taking 1- (4-fluoro-3-carboxyl benzyl) thieno [2, 3-D as the initial raw material]Pyrimidine-2, 4(1H, 3H) -dione and 4- (2-aminoethyl) thiomorpholine. To obtain the final product 1- (4-fluoro-3- (N- (1-thiomorpholinethyl) formamide) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-31), white solid. MS (m/z): 449[ M + H ]]+。1H NMR(DMSO-d6)：：11.59(br，1H)，8.52(br， 1H)，7.78-7.74(m，2H)，7.43-7.42(m，1H)，7.20-7.18(d，J＝8.0Hz，1H)，7.15-7.13(d， J＝8.0Hz，1H)，5.17(s，2H)，4.16-4.08(m，2H)，3.13-2.88(m，10H)。
Example 32
The compound (I-32)1- (4-fluoro-3- (N- (4-hydroxypiperidine-1-ethyl) carboxamide) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-32 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) thieno [2, 3-D ]]Pyrimidine-2, 4(1H, 3H) -dione and 4- (2-aminoethyl) piperidinol. To obtain a final product 1- (4-fluoro-3- (N- (4-hydroxypiperidine-1-ethyl) formamide) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-32), white solid. MS (m/z): 447[ M + H]+。1H NMR(DMSO-d6)：：11.63(br，1H)， 8.53(br，1H)，7.79-7.74(m，2H)，7.44-7.42(m，1H)，7.20-7.18(d，J＝8.0Hz，1H)， 7.16-7.14(d，J＝8.0Hz，1H)，5.19(s，2H)，4.21-4.08(m，4H)，3.12-3.04(m，6H)， 2.32-2.25(m，4H)。
Example 33
The compound (I-33)1- (4-fluoro-3- (N- (morpholine-1-ethyl) carboxamide) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-33 by the method of example 2, starting with 1- (4-fluoro-3-carboxybenzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and N- (2-aminoethyl) morpholine. To obtain the final product 1- (4-fluoro-3- (N- (morpholine-1-ethyl) formamide) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-33), white solid. MS (m/z): 433[ M + H ]]+。1H NMR(DMSO-d6)：：11.62(br，1H)，8.52(br， 1H)，7.78-7.74(m，2H)，7.45-7.44(m，1H)，7.19-7.17(d，J＝8.0Hz，1H)，7.17-7.15(d， J＝8.0Hz，1H)，5.18(s，2H)，4.22-4.08(m，6H)，3.13-3.04(m，6H)。
Example 34
The compound (I-34)1- (4-fluoro-3- (N- (4-aminopiperidine-1-ethyl) carboxamide) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-34 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) thieno [2, 3-D ]]Pyrimidine-2, 4(1H, 3H) -dione and 4- (2-aminoethyl) piperidineamine. To obtain a final product 1- (4-fluoro-3- (N- (4-aminopiperidine-1-ethyl) formamide) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-34), white solid. MS (m/z): 446[ M + H [ ]]+。1H NMR(DMSO-d6)：：11.59(br，1H)，8.52(br，1H)，7.78-7.74(m，2H)，7.43-7.42(m，1H)，7.19-7.17(d，J＝8.0Hz，1H)， 7.13-7.11(d，J＝8.0Hz，1H)，5.18(s，2H)，4.13-4.08(m，2H)，3.13-3.04(m，7H)， 2.33-2.25(m，4H)。
Example 35
The compound (I-35)1- (4-fluoro-3- (N- (4-dimethylaminopiperidine-1-ethyl) carboxamide) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-35 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) thieno [2, 3-D ]]Pyrimidine-2, 4(1H, 3H) -dione and 4- (2-aminoethyl) dimethylaminopiperidine. To obtain a final product 1- (4-fluoro-3- (N- (4-dimethylamino piperidine-1-ethyl) formamide) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-35), white solid. MS (m/z): 474[ M + H]+。1H NMR(DMSO-d6)：：11.58(br， 1H)，8.53(br，1H)，7.79-7.74(m，2H)，7.43-7.42(m，1H)，7.18-7.16(d，J＝8.0Hz， 1H)，7.13-7.11(d，J＝8.0Hz，1H)，5.19(s，2H)，4.15-4.11(m，2H)，3.15-3.04(m，7H)， 2.42(s，6H)，2.32-2.25(m，4H)。
Example 36
The compound (I-36)1- (4-fluoro-3- (N- (4-methylaminopiperidine-1-ethyl) carboxamide) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-36 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) thieno [2, 3-D ]]Pyrimidine-2, 4(1H, 3H) -dione and 4- (2-aminoethyl) methylaminopiperidine. To obtain a final product 1- (4-fluoro-3- (N- (4-methylaminopiperidine-1-ethyl) formamide) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-36), white solid. MS (m/z): 460[ M + H ]]+。1H NMR(DMSO-d6)：：11.59(br，1H)， 8.52(br，1H)，7.78-7.74(m，2H)，7.42-7.40(m，1H)，7.18-7.16(d，J＝8.0Hz，1H)， 7.14-7.12(d，J＝8.0Hz，1H)，5.18(s，2H)，4.13-4.11(m，2H)，3.82(s，3H)，3.16-3.04 (m，7H)，2.30-2.25(m，4H)。
Example 37
The compound (I-37)1- (4-fluoro-3- (N- (piperazine-1-ethyl) carboxamide) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-34 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) thieno [2, 3-D ]]Pyrimidine-2, 4(1H, 3H) -dione and N-aminoethylpiperazine. To obtain a final product 1- (4-fluoro-3- (N- (piperazine-1-ethyl) formamide) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-37), white solid. MS (m/z): 432[ M + H]+。1H NMR(DMSO-d6)：：11.58(br，1H)，8.53(br，1H)， 7.79-7.74(m，2H)，7.46-7.44(m，1H)，7.19-7.17(d，J＝8.0Hz，1H)，7.13-7.11(d，J＝ 8.0Hz，1H)，5.19(s，2H)，4.14-4.11(m，2H)，3.16-3.04(m，10H)。
Example 38
The compound (I-38)1- (4-fluoro-3- (N- (4-methylpiperazine-1-ethyl) carboxamide) benzyl) thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-38 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) thieno [2, 3-D ]]Pyrimidine-2, 4(1H, 3H) -dione and 4-methyl-1-piperazineethanolamine. To obtain a final product 1- (4-fluoro-3- (N- (4-methylpiperazine-1-ethyl) formamide) benzyl) thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-38), white solid. MS (m/z): 446[ M + H [ ]]+。1H NMR(DMSO-d6)：：11.59(br，1H)， 8.54(br，1H)，7.79-7.73(m，2H)，7.45-7.44(m，1H)，7.20-7.18(d，J＝8.0Hz，1H)， 7.14-7.12(d，J＝8.0Hz，1H)，5.21(s，2H)，4.15-4.11(m，2H)，3.15-2.97(m，10H)， 2.35(s，3H)。
Example 39
The compound (I-39)1- (4-fluoro-3- (4- (cycloheptylcarbonyl) piperazine-1-carbonyl) benzyl) -thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-39 the procedure of example 2 was followed, starting from 1- (4-fluoro-3-carboxybenzyl) thieno [2, 3-D ]]Pyrimidine-2, 4(1H, 3H) -dione and 1-cycloheptylpiperazine. To obtain the final product 1- (4-fluoro-3- (4- (cycloheptylcarbonyl) piperazine-1-carbonyl) benzyl) -thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-39), white solid. MS (m/z): 513[ M + H]+。1H NMR(DMSO-d6)：：11.58(br，1H)，7.62-7.58 (m，2H)，7.45-7.43(m，1H)，7.21-7.19(d，J＝8.0Hz，1H)，7.13-7.11(d，J＝8.0Hz， 1H)，5.11(s，2H)，3.67-3.59(m，8H)，2.33-2.28(m，1H)，1.59-1.37(m，12H)。
Example 40
The compound (I-40)1- (4-fluoro-3- (4-propionylpiperazine-1-carbonyl) benzyl) -thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-40 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) thieno [2, 3-D ]]Pyrimidine-2, 4(1H, 3H) -dione and 1-propionyl piperazine. To obtain the final product 1- (4-fluoro-3- (4-propionyl piperazine-1-carbonyl) benzyl) -thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-40), white solid. MS (m/z): 445[ M + H ]]+。1H NMR(DMSO-d6)：：11.59(br，1H)，7.63-7.58(m，2H)， 7.46-7.44(m，1H)，7.19-7.17(d，J＝8.0Hz，1H)，7.12-7.10(d，J＝8.0Hz，1H)，5.13(s， 2H)，3.66-3.59(m，8H)，1.98-1.95(q，J＝4.0Hz，2H)，1.25-1.23(t，J＝4.0Hz，3H)。
EXAMPLE 41
The compound (I-41)1- (4-fluoro-3- (4- (4-fluorobenzoyl) piperazine-1-carbonyl) benzyl) -thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-41 by the method of example 2, starting with 1- (4-fluoro-3-carboxybenzyl) -furo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and 1- (4-fluorobenzoyl) piperazine. To obtain the final product 1- (4-fluoro-3- (4- (4-fluorobenzoyl) piperazine-1-carbonyl) benzyl) -thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-41), white solid. MS (m/z): 511[ M + H]+。1H NMR(DMSO-d6)：：11.58(br，1H)， 8.36-8.32(m，2H)，8.15-8.12(m，2H)，8.02-7.97(m，3H)，7.18-7.16(d，J＝8.0Hz， 1H)，7.12-7.10(d，J＝8.0Hz，1H)，5.13(s，2H)，3.65-3.40(m，8H)。
Example 42
The compound (I-42)1- (4-fluoro-3- (4- (3-trifluoromethylbenzoyl) piperazine-1-carbonyl) benzyl) -thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-42 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) -furo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and 1- (3-trifluoromethylbenzoyl) piperazine. To obtain a final product 1- (4-fluoro-3- (4- (3-trifluoromethyl benzoyl) piperazine-1-carbonyl) benzyl) -thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-42), white solid. MS (m/z): 561[ M + H ]]+。1H NMR(DMSO-d6)：：11.57(br，1H)，8.38-8.35(m，2H)，8.17-8.15(m，2H)，8.03-7.97(m，3H)，7.21-7.19 (d，J＝8.0Hz，1H)，7.13-7.11(d，J＝8.0Hz，1H)，5.12(s，2H)，3.63-3.41(m，8H)。
Example 43
The compound (I-43)1- (4-fluoro-3- (4-isobutyrylpiperazine-1-carbonyl) benzyl) -thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-43 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) thieno [2, 3-D ]]Pyrimidine-2, 4(1H, 3H) -dione and 1-isobutyrylpiperazine. To obtain the final product 1- (4-fluoro-3- (4-isobutyrylpiperazine-1-carbonyl) benzyl) -thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-43), white solid. MS (m/z): 459[ M + H ]]+。1H NMR(DMSO-d6)：：11.58(br，1H)，7.62-7.58(m， 2H)，7.45-7.44(m，1H)，7.17-7.15(d，J＝8.0Hz，1H)，7.12-7.10(d，J＝8.0Hz，1H)， 5.15(s，2H)，3.67-3.59(m，8H)，2.37-2.33(m，1H)，1.33-1.28(m，6H)。
Example 44
The compound (I-44)1- (4-fluoro-3- (4- (3-cyanobenzoyl) piperazine-1-carbonyl) benzyl) -thieno [2, 3-D ] pyrimidine-2, 4(1H, 3H) -dione
Synthesis of Compound I-44 was carried out as in example 2 starting from 1- (4-fluoro-3-carboxybenzyl) -furo [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione and 1- (3-cyanobenzoyl) piperazine. To obtain the final product 1- (4-fluoro-3- (4- (3-cyanobenzoyl) piperazine-1-carbonyl) benzyl) -thieno [2, 3-D]Pyrimidine-2, 4(1H, 3H) -dione (I-44), white solid. MS (m/z): 518[ M + H]+。1H NMR(DMSO-d6)：：11.58(br， 1H)，8.37-8.34(m，2H)，8.17-8.14(m，2H)，8.02-7.98(m，3H)，7.20-7.18(d，J＝ 8.0Hz，1H)，7.13-7.11(d，J＝8.0Hz，1H)，5.13(s，2H)，3.62-3.41(m，8H)。
Example 45
Biological assay
PARP-1 Activity assay: PARP-1 activity was determined using the HT Universal chemiluminescent PARP assay kit (Trevigen, Gaithersburg, Md., USA). Assay incorporation of biotin poly (ADP-ribose) into histone catalyzed by PARP-1 after activation of the measured DNA was measured. The experimental procedure was performed according to the instructions provided with the assay kit. That is, in histone-coated wells, PARP-1(0.5 units/well) was incubated with activated DNA and NAD + in reaction buffer for 45 minutes at 25 ℃ in the presence or absence of test article. After incubation, the wells were washed with PBS containing 0.1% Triton X-100 and incubated with Strep-HRP for 60 minutes at 25 ℃. Immediately after addition of PeroxyGlowTM to the wells, chemiluminescence was measured with a VictorX52030 Multilabel Reader (Perkin Elmer). IC calculation Using the Medium-Effect method (Chou, T.C. (2006); Pharmacol. Rev.58 (3): 621-50The value is obtained. IC of the example Compounds50The values are shown in table 2.
PARP-2 Activity assay: PARP-2 activity assays were performed according to the PARP-1 assay.
Cell proliferation assay: MDA-MB-436 cells were purchased from American Type Culture Collection (USA). Cells were maintained at 37 ℃ and 5% CO2In a humid atmosphere. For proliferation assays, MDA-MB-436 cells were seeded at low density in 96-well plates in RPMI-1640 medium supplemented with 10% FBS and at 37 ℃ in 5% CO2Incubated for 24h in a humid atmosphere. Cells were incubated for a further 7 days at 37 ℃ in fresh medium in the presence or absence of test article. By using
Figure BSA0000128603490000261
Aqueous phase nonradioactive cell proliferation kit (Promega) cell proliferation was measured by 3- (4, 5-dimethylthiazol-2-yl) -5- (-3-hydroxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazole (MTS) assay. Absorbance at 490nm was determined by Victor X52030 Multilabel Reader (Perkin Elmer) (A490). EC was calculated using the mesogenic method (Chou, T.C. (2006). Pharmacol. Rev.58 (3): 621-Bu 681)50The value is obtained. EC of the Compounds of examples50The values are shown in table 2.
Table 2. test results:
Figure BSA0000128603490000271
Figure BSA0000128603490000281
note: a is more than 500nM, B is more than 100nM and more than or equal to 500nM, C is more than or equal to 100nM and more than or equal to 20nM, and D is less than or equal to 20 nM.

Claims (7)

1. A substituted 2,4- (1H,3H) pyrimidinedione derivative is characterized by being a compound shown as the following general formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0002475509420000011
wherein:
R1，R2each represents hydrogen,C1-C3Alkyl of (C)1-C3Alkoxy, halogen, trifluoromethyl or cyano of (a);
or R1，R2Together with the carbon atoms to which they are attached form an unsubstituted 5-to 6-membered aliphatic ring, an unsubstituted benzene ring;
R3，R4，R5，R6each represents hydrogen and C1-C3Alkyl of (C)1-C3Alkoxy, halogen, trifluoromethyl or cyano of (a);
R7，R8independently selected from hydrogen,
Figure FDA0002475509420000012
Or R7，R8Together with the nitrogen atom to which they are attached form an unsubstituted 5-to 7-membered aliphatic ring, or 1C on the aliphatic ring may be substituted by N, O or S, and N may be substituted by R9Substitution;
R9represents hydrogen, C1-C4Alkyl, phenyl, R1Substituted phenyl, C5-C6Heteroaryl, acyl, sulfonyl of (a);
wherein acyl is-C (═ O) R10，R10Is an acyl substituent, said substituent being C1-C2Alkyl radical, C3-C7Cycloalkyl, phenyl, R1A substituted phenyl group;
wherein sulfonyl is-S (═ O)2R10，R10Is an acyl substituent, said substituent being C1-C2Alkyl radical, C3-C7Cycloalkyl, phenyl, R1A substituted phenyl group;
x represents S, O, N;
y represents H, O;
a represents
Figure FDA0002475509420000013
Figure FDA0002475509420000014
n is 1, 2, 3;
Figure FDA0002475509420000015
represents a single bond or a double bond.
2. The substituted 2,4- (1H,3H) pyrimidinedione derivative according to claim 1, wherein C is1-C3Alkyl of (a) is methyl, ethyl, n-propyl or isopropyl; said C1-C3The alkoxy of (A) is methoxy, ethoxy, n-propoxy or isopropoxy.
3. The substituted 2,4- (1H,3H) pyrimidinedione derivative according to claim 1, wherein C is3-C7Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; said C5-C6The heteroaryl of (a) is a 5 to 6 membered aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, S, the remaining ring atoms being carbon; the halogen refers to F, Cl, Br and I.
4. A substituted 2,4- (1H,3H) pyrimidinedione derivative is characterized by being a compound selected from the following group:
Figure FDA0002475509420000021
Figure FDA0002475509420000031
Figure FDA0002475509420000041
Figure FDA0002475509420000051
or a pharmaceutically acceptable salt thereof.
5. Use of the substituted 2,4- (1H,3H) pyrimidinedione derivatives and pharmaceutically acceptable salts thereof as PARP-1/2 inhibitors in the preparation of a medicament for preventing or treating PARP-1/2 related diseases.
6. The use of claim 5 wherein the PARP-1/2 related disease is a PARP-1/2 related cancer.
7. A pharmaceutical composition comprising a therapeutically effective amount of a substituted 2,4- (1H,3H) pyrimidinedione derivative according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier or excipient.
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