CN107286166B - Substituted 1,3,4, 5-tetrahydro-6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one derivatives - Google Patents
Substituted 1,3,4, 5-tetrahydro-6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one derivatives Download PDFInfo
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to a substituted 1,3,4, 5-tetrahydro-6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one derivatives, and their use as therapeutically effective poly (ADP-ribose) polymerase (PARP) inhibitors. In particular, the invention relates to a novel substituted 1,3,4, 5-tetrahydro-6H-pyrrolo [4,3,2-EF ] compound shown as a general formula (I)][2]Benzazepine-6-one derivatives, and pharmaceutical compositions thereof, as selective PARP-1/2 inhibitors, for use in preventing or treating PARP-1/2 related diseases.
Description
Technical Field
The present invention relates to substituted 1,3,4, 5-tetrahydro-6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-ones and their use as therapeutically effective poly (ADP-ribose) polymerase (PARP) inhibitors.
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 single-strand breaks in D NA. 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-1/2 inhibitor is not only a sensitizer for chemotherapy and radiotherapy, but also has inhibitory effect on the gene mutation (BRCA1/2 mutation) or HR defect tumor when used alone.
Disclosure of Invention
The invention aims to provide a novel substituted 1,3,4, 5-tetrahydro-6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-ketone compound, a derivative thereof 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 1,3,4, 5-tetrahydro-6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-ones represented by the following general formula I:
wherein:
R1，R2，R3，R4，R5，R6each represents hydrogen and C1-C3Alkyl of (C)1-C3Alkoxy, halogen, trifluoromethyl or cyano of (a);
R7，R8one of them is-COA;
R7，R8the other represents hydrogen, C1-C3Alkyl of (C)1-C3Alkoxy, halogen, trifluoromethyl, cyano of (a);
a is one of the following groups:
R9represents hydrogen, methyl, halogen, hydroxyl, cyano, amino, trifluoromethyl;
n is 0, 1, 2;
R10represents hydrogen, methyl, halogen, hydroxyl, cyano, trifluoromethyl;
x and Y respectively represent C, N;
R11represents hydrogen, C1-C3Alkyl, phenyl, R1Substituted phenyl, C5-C6Heteroaryl, acyl, sulfonyl of (a);
wherein acyl is-C (═ O) R12，R12Is an acyl substituent, said substituent being C1-C3Alkyl radical, C3-C7Cycloalkyl, phenyl, R1Substituted phenyl, C5-C6An aromatic hetero group of (a);
wherein sulfonyl is-S (═ O)2R12，R12Is an acyl substituent, said substituent being C1-C3Alkyl radical, C3-C7Cycloalkyl, phenyl, R1Substituted phenyl, C5-C6The heteroaryl of (1).
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:
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:
starting materials I1And I2(orI5) Preparing an intermediate I by Suzuki coupling reaction3(or I)6) Intermediates I3(or I)6) Hydrolyzing to obtain acid intermediate I4(or I)7) The acid intermediate is condensed with an amine (A) to produce the final product I.
Wherein the raw material I1Pro.res AT org, according to AT Gillmore, M Badland et al.&Prepared according to the procedure reported in dev.2012, pp 1897.
The invention relates to substituted 1,3,4, 5-tetrahydro-6H-pyrrolo [4,3,2-EF ] [2] benzazepine-6-one derivatives which are PARP-1/2 inhibitors, and the compounds 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) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4- (4- (cyclopropanoyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Step 1: 2-bromo-8-fluoro-1, 3,4, 5-tetrahydro-6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (400mg, 1.41mmol), 4-methoxycarbonylphenylboronic acid (305mg, 1.69mmol), Pd (dppf) Cl2(103mg, 0.14mmol) and sodium carbonate (300mg, 2.83mmol) were added DMF (8mL)/H2In O (2mL), N2Heating to 80-90 ℃ under protection and reacting for 3 h. The reaction solution was cooled to room temperature and H was added2O (20mL) and dichloromethane (30mL), drying and concentrating to dryness to obtain 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-methoxycarbonylphenyl) -6H-pyrrolo [4,3,2-EF][2]The crude benzazepin-6-one was used for the next reaction.
Step 2: step 1 product tetrahydrofuran (10mL)/H was added2To a solution of O (5mL), sodium hydroxide (282mg, 7.05mmol) was added and the mixture was heated to 70 ℃ for reaction for 3 hours. Cooling the reaction solution to room temperature, adjusting pH to 2 with 1N dilute hydrochloric acid, stirring for 30min, filtering, and vacuum drying to obtain 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (0.33g, two-step yield 73.3%), MS (m/z): 325[ M + H ]]+。
And step 3: 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (100mg, 0.31mmol), benzotriazol-N, N' -tetramethyluronium hexafluorophosphate (HBTU, 129mg, 0.34mmol), 1-cyclopropylformylpiperazine (52mg, 0.34mmol), N-diisopropylethylamine (DIPEA,80mg, 0.62mmol), DMF (3mL) was added to the reaction flask and stirred at room temperature for 2 h. Dropwise addition of H2O (5mL), stirring, solid precipitation, filtration to give a grey solid, recrystallization from methanol (10mL) to give 8-fluoro-1, 3,4, 5-tetrahydro-2- (4- (4- (cyclopropanoyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-1), white solid (70mg, yield 49.3%). MS (m/z): 461[ M + Na ]]+。1H NMR(DMSO-d6)：δ：11.38(br，1H)，8.12-7.97(m，5H)，7.76(s，1H)，7.32(s，1H)，3.75-3.42(m，10H)，2.72-2.69(m，2H)，1.26-1.21(m，1H)，0.73-0.70(m，4H)。
Example 2
The compound (I-2) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4- (4-hydroxypiperidine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
The synthesis of compound I-2 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 4-hydroxypiperidines. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4- (4-hydroxypiperidine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-2), white solid. MS (m/z): 430[ M + Na ]]+。1HNMR(DMSO-d6)：δ：11.39(br，1H)，8.11-7.97(m，5H)，7.77(s，1H)，7.32(s，1H)，4.29(br，1H)，3.72-3.38(m，7H)，2.70-2.66(m，2H)，1.86-1.67(m，4H)。
Example 3
The compound (I-3) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (2-pyridinyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-3 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (synthesis analogous to example 1, starting from 2-bromo-8-fluoro-1, 3,4, 5-tetrahydro-6H-pyrrolo [4,3, 2-EF)][2]Benzazepin-6-one and 3-methoxycarbonyl-4-fluorobenzeneboronic acid) and (2-pyridyl) piperazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (2-pyridyl) piperazine-1-carbonyl) Phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-3), white solid. MS (m/z): 488[ M + H]+。1H NMR(DMSO-d6)：δ：11.39(br，1H)，8.59(s，1H)，8.39(m，1H)，8.01-7.87(m，3H)，7.52-7.35(m，3H)，6.72-6.66(m，2H)，3.89-3.81(m，4H)，3.60-3.50(m，6H)，2.73-2.69(t，J＝5.6Hz，2H)。
Example 4
The compound (I-4) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (3-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [4, 3-A ] pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-4 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 3-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]A pyrazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (3-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]Pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-4), white solid. MS (m/z): 463[ M + H]+。1H NMR(DMSO-d6)：δ：11.38(br，1H)，8.58(s，1H)，8.40(m，1H)，8.02-7.89(m，2H)，7.48-7.39(m，2H)，4.46(s，2H)，4.32-4.25(m，2H)，3.68-3.54(m，4H)，2.73-2.69(t，J＝5.6Hz，2H)，2.45(s，3H)。
Example 5
The compound (I-5) 8-fluoro-1, 3,4, 5-tetrahydro-2- (3-methyl-4- (4-methylpiperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-5 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (3-methyl-4-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (synthesis analogous to example 1, starting from 2-bromo-8-fluoro-1, 3,4, 5-tetrahydro-6H-pyrrolo [4,3, 2-EF)][2]Benzazepin-6-one and 4-methoxycarbonyl-3-methylbenzeneboronic acid) and 1-methylpiperazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (3-methyl-4- (4-methylpiperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-5), white solid. MS (m/z): 421[ M + H]+。1H NMR(DMSO-d6)：δ：11.38(br，1H)，8.01-7.97(m，3H)，7.79-7.77(m，2H)，7.32(s，1H)，3.49-3.45(m，6H)，2.70-2.66(m，2H)，2.47(s，3H)，2.32-2.25(m，7H)。
Example 6
The compound (I-6) 8-cyano-9-methyl-1, 3,4, 5-tetrahydro-2- (5-methoxy-3- (4-trifluoromethylpiperidine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-6 was carried out as in example 1 starting from 8-cyano-9-methyl-1, 3,4, 5-tetrahydro-2- (5-methoxy-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (synthesis analogous to example 1, starting from 2-bromo-8-cyano-9-methyl-1, 3,4, 5-tetrahydro-6H-pyrrolo [4,3, 2-EF)][2]Benzazepin-6-one and 3-methoxycarbonyl-5-methoxyphenylboronic acid) and 4-trifluoromethylpiperidine. To obtain a final product 8-cyano-9-methyl-1, 3,4, 5-tetrahydro-2- (5-methoxy-3- (4-trifluoromethylpiperidine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-6), white solid. MS (m/z): 511[ M + H]+。1H NMR(DMSO-d6)：δ：11.39(br，1H)，8.19-8.17(m，2H)，8.01(br，1H)，7.62(s，1H)，6.39(s，1H)，3.85(s，3H)，3.47-3.42(m，6H)，2.73-2.69(t，J＝5.6Hz，2H)，2.34-2.31(m，4H)，1.69-1.55(m，4H)。
Example 7
The compound (I-7)7, 9-dimethoxy-1, 3,4, 5-tetrahydro-2- (4-trifluoromethyl-3- (3-methylpiperidine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
The synthesis of compound I-7 was carried out as in example 1 starting from 7, 9-dimethoxy-1, 3,4, 5-tetrahydro-2- (4-trifluoromethyl-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (synthesis analogous to example 1, starting from 2-bromo-7, 9-dimethoxy-1, 3,4, 5-tetrahydro-6H-pyrrolo [4,3, 2-EF)][2]Benzazepin-6-one and 3-methoxycarbonyl-4-trifluoromethylphenylboronic acid) and 4-methylpiperidine. Obtaining the final product7, 9-dimethoxy-1, 3,4, 5-tetrahydro-2- (4-trifluoromethyl-3- (3-methylpiperidine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-7), white solid. MS (m/z): 516[ M + H]+。1H NMR(DMSO-d6)：δ：11.37(br，1H)，8.54(s，1H)，8.01-7.98(m，2H)，7.86-7.84(m，1H)，6.58(s，1H)，3.85(s，6H)，3.49-3.43(m，6H)，2.75-2.71(m，2H)，1.69-1.45(m，5H)，0.95-0.93(d，J＝8.0Hz，3H)。
Example 8
The compound (I-8) 8-chloro-1, 3,4, 5-tetrahydro-2- (2, 4, 6-trimethyl-3- (4-phenylpiperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-8 was carried out as in example 1 starting from 8-chloro-1, 3,4, 5-tetrahydro-2- (2, 4, 6-trimethyl-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (synthesis analogous to example 1, starting from 2-bromo-8-chloro-1, 3,4, 5-tetrahydro-6H-pyrrolo [4,3, 2-EF)][2]Benzazepin-6-one and 3-methoxycarbonyl-2, 4, 6-trimethylbenzeneboronic acid) and 1-phenylpiperazine. To obtain the final product 8-chloro-1, 3,4, 5-tetrahydro-2- (2, 4, 6-trimethyl-3- (4-phenylpiperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-8), white solid. MS (m/z): 528[ M + H ]]+。1H NMR(DMSO-d6)：δ：11.38(br，1H)，8.03-8.01(m，2H)，7.68(s，1H)，7.25-7.19(m，3H)，6.90-6.82(m，3H)，3.52-3.43(m，10H)，2.75-2.73(m，2H)，2.45(s，3H)，2.42(s，3H)，2.38(s，3H)。
Example 9
The compound (I-9) 8-fluoro-1, 3,4, 5-tetrahydro-2- (2-methoxy-4- (4- (2-pyridinyloxy) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-9 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (2-methoxy-4-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (synthesis analogous to example 1, starting from 2-bromo-8-fluoro-1, 3,4, 5-tetrahydro-6H-pyrrolo [4,3, 2-EF)][2]Benzo (b) isAza-6-one and 4-methoxycarbonyl-2-methoxyphenylboronic acid) and (2-pyridinoyl) piperazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (2-methoxy-4- (4- (2-pyridine acyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-9), white solid. MS (m/z): 528[ M + H ]]+。1H NMR(DMSO-d6)：δ：11.39(br，1H)，8.72(m，1H)，8.36(m，1H)，8.02-7.88(m，4H)，7.66(m，2H)，7.32(s，1H)，3.82(s，3H)，3.60-3.49(m，10H)，2.70-2.66(m，2H)。
Example 10
The compound (I-10) 8-isopropoxy-1, 3,4, 5-tetrahydro-2- (3-chloro-4- (4- (cyclobutanoyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-10 was carried out as in example 1 starting from 8-isopropoxy-1, 3,4, 5-tetrahydro-2- (3-chloro-4-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (synthesis analogous to example 1, starting from 2-bromo-8-isopropoxy-1, 3,4, 5-tetrahydro-6H-pyrrolo [4,3, 2-EF)][2]Benzazepin-6-one and 4-methoxycarbonyl-3-chlorobenzeneboronic acid) and 1-cyclobutylformylpiperazine. To obtain the final product 8-isopropoxy-1, 3,4, 5-tetrahydro-2- (3-chloro-4- (4- (cyclobutyryl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepine-6- (I-10), white solid. MS (m/z): 550[ M + H ]]+。1HNMR(DMSO-d6)：δ：11.38(br，1H)，8.19(s，1H)，8.36(m，1H)，8.03-7.88(m，3H)，7.58(s，1H)，7.15(s，1H)，4.85(m，1H)，3.63-3.49(m，10H)，2.88-2.75(m，3H)，2.31-2.15(m，6H)，1.35(s，6H)。
Example 11
The compound (I-11) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (3-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [4, 3-A ] pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-11 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 3-trifluoromethyl-5, 6,7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]A pyrazine. To obtain a final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (3-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]Pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-11), white solid. MS (m/z): 517[ M + H]+。1HNMR(DMSO-d6)：δ：11.39(br，1H)，8.59(s，1H)，8.41(m，1H)，8.01-7.89(m，2H)，7.47-7.39(m，2H)，4.47(s，2H)，4.31-4.27(m，2H)，3.66-3.54(m，4H)，2.72-2.69(t，J＝5.6Hz，2H)。
Example 12
The compound (I-12) 8-trifluoromethyl-1, 3,4, 5-tetrahydro-2- (4-bromo-3- (3-cyano-5, 6, 7, 8-tetrahydroimidazo [1, 5-a ] pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-12 was carried out as in example 1 starting from 8-trifluoromethyl-1, 3,4, 5-tetrahydro-2- (4-bromo-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 3-cyano-5, 6, 7, 8-tetrahydroimidazo [1, 5-a ]]A pyrazine. To obtain a final product 8-trifluoromethyl-1, 3,4, 5-tetrahydro-2- (4-bromo-3- (3-cyano-5, 6, 7, 8-tetrahydroimidazo [1, 5-a ]]Pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-12), white solid. MS (m/z): 584[ M + H ]]+。1H NMR(DMSO-d6)：δ：11.39(br，1H)，8.49(s，1H)，8.25(s，1H)，8.02-7.89(m，3H)，7.58(s，1H)，7.43(s，1H)，4.38-4.35(m，4H)，3.62-3.59(m，4H)，3.66-3.54(m，4H)，2.73-2.69(t，J＝5.6Hz，2H)。
Example 13
The compound (I-13) 8-isopropyl-1, 3,4, 5-tetrahydro-2- (4-cyano-3- (6-chloro-1, 2, 3, 4-tetrahydropyrrolo [1, 2-a ] pyrazine-2-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-13 was carried out as in example 1 starting from 8-isopropyl-1, 3,4, 5-tetrahydro-2- (4-cyano-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 6-chloro-1, 2, 3, 4-tetrahydropyrrolo [1, 2-a ]]A pyrazine. To obtain the final product 8-isoPropyl-1, 3,4, 5-tetrahydro-2- (4-cyano-3- (6-chloro-1, 2, 3, 4-tetrahydropyrrolo [1, 2-a)]Pyrazine-2-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-13), white solid. MS (m/z): 513[ M + H]+。1H NMR(DMSO-d6)：δ：11.37(br，1H)，8.78(s，1H)，8.22(m，1H)，7.99-7.89(m，3H)，7.26(s，1H)，6.05-6.03(d，J＝8.0Hz，1H)，5.73-5.71(d，J＝8.0Hz，1H)，4.48-4.42(m，4H)，3.64-3.59(m，4H)，2.87-2.75(m，3H)，1.29(s，6H)。
Example 14
The compound (I-14)1, 3,4, 5-tetrahydro-2- (4-methoxy-3- (4-amino-3, 5-dimethylpiperidine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-14 was carried out as in example 1 starting from 1,3,4, 5-tetrahydro-2- (4-methoxy-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (synthesis analogous to example 1, starting from 2-bromo-1, 3,4, 5-tetrahydro-6H-pyrrolo [4,3, 2-EF)][2]Benzazepin-6-one and 3-methoxycarbonyl-4-methoxyphenylboronic acid) and 4-amino-3, 5-dimethylpiperidine. To obtain the final product 1,3,4, 5-tetrahydro-2- (4-methoxyl-3- (4-amino-3, 5-dimethylpiperidine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-14), white solid. MS (m/z): 511[ M + H]+。1H NMR(DMSO-d6)：δ：11.39(br，1H)，8.49(s，1H)，8.01(br，1H)，7.81-7.69(m，3H)，7.27-7.24(m，2H)，5.09(br，2H)，3.85(s，3H)，3.47-3.42(m，6H)，2.73-2.69(m，3H)，1.92(m，2H)，0.95(m，6H)。
Example 15
The compound (I-15) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-isopropoxy-3- (4-cyanopiperidine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-15 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-isopropoxy-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 4-cyanopiperidines. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-iso)Propoxy-3- (4-cyanopiperidine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-15), white solid. MS (m/z): 475[ M + H ]]+。1H NMR(DMSO-d6)：δ：11.37(br，1H)，8.49(s，1H)，8.02(br，1H)，7.80-7.77(m，2H)，7.33-7.27(m，2H)，4.69-4.65(m，1H)，3.47-3.41(m，6H)，2.71-2.62(m，3H)，2.35-2.31(m，4H)，1.29(s，6H)。
Example 16
The compound (I-16) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [4, 3-A ] pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-16 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]A pyrazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [4, 3-A ]]Pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-16), white solid. MS (m/z): 449[ M + H ]]+。1H NMR(DMSO-d6)：δ：11.38(br，1H)，8.58(s，1H)，8.41-8.39(m，2H)，8.01-7.90(m，2H)，7.47-7.39(m，2H)，4.45(s，2H)，4.31-4.28(m，2H)，3.66-3.54(m，4H)，2.71-2.69(m，2H)。
Example 17
The compound (I-17) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-17 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and piperazines. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-17), white solid. MS (m/z): 410[ M + H]+。1H NMR(DMSO-d6)：δ：11.37(br，1H)，8.58(s，1H)，8.40(m，1H)，8.01-7.87(m，2H)，7.48-7.33(m，2H)，3.48-3.46(m，6H)，2.83-2.75(m，6H)，1.92(br，1H)。
Example 18
The compound (I-18) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (cycloheptylsulfonyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-18 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one and 1- (cycloheptylsulfonyl) piperazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (cycloheptylsulfonyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-18), white solid. MS (m/z): 571[ M + H]+。1H NMR(DMSO-d6)：δ：11.37(br，1H)，8.58(s，1H)，8.39(m，1H)，8.01-7.89(m，2H)，7.48-7.35(m，2H)，3.48-3.46(m，6H)，2.93-2.77(m，7H)，2.03-1.67(m，12H)。
Example 19
The compound (I-19) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (cyclohexanoyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-19 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 1- (cyclohexanoyl) piperazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (cyclohexanoyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-19), white solid. MS (m/z): 521[ M + H]+。1H NMR(DMSO-d6)：δ：11.38(br，1H)，8.57(s，1H)，8.41(m，1H)，8.01(br，1H)，7.78(s，1H)，7.48-7.36(m，2H)，3.65-3.50(m，10H)，2.73-2.65(m，3H)，1.90-1.82(m，10H)。
Example 20
The compound (I-20) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- ((2-pyrimidinyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-20Example 1 the procedure was carried out starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and (2-pyrimidinyl) piperazines. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- ((2-pyrimidinyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-20), white solid. MS (m/z): 489[ M + H ]]+。1H NMR(DMSO-d6)：δ：11.39(br，1H)，8.57-8.46(m，4H)，8.01(br，1H)，8.39(m，1H)，7.87(m，1H)，7.49-7.36(m，2H)，6.92(m，1H)，3.57-3.41(m，10H)，2.73-2.69(t，J＝5.6Hz，2H)。
Example 21
The compound (I-21) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (n-propylpiperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-21 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one and n-propylpiperazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (n-propylpiperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-21), white solid. MS (m/z): 453[ M + H ]]+。1H NMR(DMSO-d6)：δ：11.39(br，1H)，8.57(s，1H)，8.40(m，1H)，8.01-7.89(m，2H)，7.46-7.34(m，2H)，3.48-3.42(m，6H)，2.73-2.57(m，8H)，1.45-1.42(m，2H)，0.93-0.89(t，J＝5.6Hz，3H)。
Example 22
The compound (I-22) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (benzoyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-22 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 1- (benzoyl) piperazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (benzoyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-22), white solid. MS (m/z): 515[ M + H]+。1H NMR(DMSO-d6)：δ：11.39(br，1H)，8.58(s，1H)，8.41(m，1H)，8.03-8.00(m，3H)，7.73-7.65(m，4H)，7.47-7.34(m，2H)，3.63-3.43(m，10H)，2.73-2.70(m，2H)。
Example 23
The compound (I-23) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (2-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [1, 5-A ] pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-23 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 2-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]A pyrazine. To obtain a final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (2-trifluoromethyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]Pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-23), white solid. MS (m/z): 517[ M + H]+。1H NMR(DMSO-d6)：δ：11.38(br，1H)，8.58(s，1H)，8.41(m，1H)，8.01-7.88(m，2H)，7.46-7.39(m，2H)，4.45(s，2H)，4.02-3.97(m，2H)，3.64-3.54(m，4H)，2.72-2.69(m，2H)。
Example 24
The compound (I-24) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (2-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [1, 5-A ] pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-24 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 2-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]A pyrazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (2-methyl-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]Pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-24), white solid. MS (m/z): 463[ M + H]+。1H NMR(DMSO-d6)：δ：11.39(br，1H)，8.57(s，1H)，8.40(m，1H)，8.00-7.89(m，2H)，7.49-7.37(m，2H)，4.45(s，2H)，4.03-4.00(m，2H)，3.68-3.49(m，4H)，2.73-2.69(t，J＝5.6Hz，2H)，2.44(s，3H)。
Example 25
The compound (I-25) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [1, 5-A ] pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-25 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]A pyrazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]Pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-25), white solid. MS (m/z): 449[ M + H ]]+。1H NMR(DMSO-d6)：δ：11.39(br，1H)，8.59(s，1H)，8.41-8.39(m，1H)，8.01-7.90(m，3H)，7.47-7.36(m，2H)，4.45(s，2H)，4.05-4.01(m，2H)，3.68-3.54(m，4H)，2.70-2.67(m，2H)。
Example 26
The compound (I-26) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (3-hydroxy-5, 6, 7, 8-tetrahydroimidazo [1, 2-a ] pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
The synthesis of compound I-26 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 3-hydroxy-5, 6, 7, 8-tetrahydroimidazo [1, 2-a ]]A pyrazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (3-hydroxy-5, 6, 7, 8-tetrahydroimidazo [1, 2-a ]]Pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-26), white solid. MS (m/z): 464[ M + H ]]+。1H NMR(DMSO-d6)：δ：11.54(br，1H)，11.39(br，1H)，8.58(s，1H)，8.40-8.39(m，1H)，8.01-7.92(m，2H)，7.45-7.36(m，2H)，7.01(s，1H)，4.45-4.35(m，4H)，4.05-4.01(m，2H)，3.65-3.55(m，4H)，2.74-2.69(t，J＝5.6Hz，2H)。
Example 27
The compound (I-27) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (2-cyano-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [1, 5-A ] pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-27 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 2-cyano-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]A pyrazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (2-cyano-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazole [1, 5-A ]]Pyrazine-7-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-27), white solid. MS (m/z): 474[ M + H]+。1H NMR(DMSO-d6)：δ：11.39(br，1H)，8.58(s，1H)，8.40(m，1H)，8.01-7.88(m，2H)，7.45-7.37(m，2H)，4.46(s，2H)，4.03-4.01(m，2H)，3.63-3.54(m，4H)，2.71-2.69(m，2H)。
Example 28
The compound (I-28) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (7-fluoro-1, 2, 3, 4-tetrahydropyrrolo [1, 2-a ] pyrazine-2-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-28 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 7-fluoro-1, 2, 3, 4-tetrahydropyrrolo [1, 2-a ]]A pyrazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (7-fluoro-1, 2, 3, 4-tetrahydropyrrolo [1, 2-a ]]Pyrazine-2-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-28), white solid. MS (m/z): 465[ M + H]+。1H NMR(DMSO-d6)：δ：11.36(br，1H)，8.57(s，1H)，8.40(m，1H)，8.01-7.88(m，2H)，7.47-7.36(m，2H)，6.86(s，1H)，5.88(s，1H)，4.48-4.42(m，4H)，3.65-3.54(m，4H)，2.71-2.68(m，2H)。
Example 29
The compound (I-29) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (2-thienyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-29 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and (2-thienyl) piperazines. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (2-thienyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-29), white solid. MS (m/z): 493[ M + H ]]+。1H NMR(DMSO-d6)：δ：11.38(br，1H)，8.58(s，1H)，8.41(m，1H)，8.12(br，1H)，8.02-7.89(m，3H)，7.53-7.41(m，3H)，6.65-6.63(m，1H)，3.82-3.67(m，10H)，2.72-2.68(t，J＝8.0Hz，2H)。
Example 30
The compound (I-30) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (2-furyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-30 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and (2-furyl) piperazines. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (2-furyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-30), white solid. MS (m/z): 477[ M + H ]]+。1H NMR(DMSO-d6)：δ：11.39(br，1H)，8.59(s，1H)，8.42(m，1H)，8.11(br，1H)，8.01-7.89(m，3H)，7.52-7.44(m，3H)，6.66-6.65(m，1H)，3.83-3.67(m，10H)，2.70-2.66(t，J＝8.0Hz，2H)。
Example 31
The compound (I-31) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (4-pyridinyloxy) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
The synthesis of compound I-31 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]benzazepin-6-one and 1- (4-pyridinoyl) piperazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (4-pyridine acyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-31), white solid. MS (m/z): 516[ M + H]+。1H NMR(DMSO-d6)：δ：11.38(br，1H)，8.93(m，1H)，8.58(s，1H)，8.42(m，1H)，8.03-7.98(m，4H)，7.72-7.67(m，3H)，3.63-3.42(m，10H)，2.73-2.70(m，2H)。
Example 32
The compound (I-32) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (2-thiophenoyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-32 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones and 1- (2-thiophenoyl) piperazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (2-thiophenoyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-32), white solid. MS (m/z): 521[ M + H]+。1H NMR(DMSO-d6)：δ：11.39(br，1H)，8.59(s，1H)，8.42-8.38(m，2H)，8.01-7.98(m，3H)，7.71-7.67(m，3H)，3.64-3.47(m，10H)，2.70-2.66(t，J＝8.0Hz，2H)。
Example 33
The compound (I-33) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (2-furoyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-33 by the method of example 1, starting with 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one and 1- (2-furoyl) piperazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (2-furoyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-33), white solid. MS (m/z): 505[ M + H]+。1H NMR(DMSO-d6)：δ：11.38(br，1H)，8.59(s，1H)，8.43-8.38(m，2H)，8.04-7.99(m，3H)，7.72-7.67(m，3H)，3.63-3.45(m，10H)，2.71-2.67(t，J＝8.0Hz，2H)。
Example 34
The compound (I-34) 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (2-thiophenesulfonyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one
Synthesis of Compound I-34 was carried out as in example 1 starting from 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3-carboxyphenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one and 1- (2-thiophenesulfonyl) piperazine. To obtain the final product 8-fluoro-1, 3,4, 5-tetrahydro-2- (4-fluoro-3- (4- (2-thiophenesulfonyl) piperazine-1-carbonyl) phenyl) -6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-one (I-34), white solid. MS (m/z): 557[ M + H ]]+。1H NMR(DMSO-d6)：δ：11.37(br，1H)，8.58(s，1H)，8.42-8.39(m，2H)，8.03-7.99(m，3H)，7.73-7.67(m，3H)，3.62-3.46(m，10H)，2.71-2.67(t，J＝8.0Hz，2H)。
Example 35
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 proliferationAnd (3) cloning analysis: 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
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:
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 1,3,4, 5-tetrahydro-6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one derivative is characterized by being a compound shown as the following general formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R1，R2，R3，R4，R5，R6each represents hydrogen and C1-C3Alkyl of (C)1-C3Alkoxy, halogen, trifluoromethyl or cyano of (a);
R7，R8one of them is-COA;
R7，R8the other represents hydrogen, C1-C3Alkyl of (C)1-C3Alkoxy, halogen, trifluoromethyl, cyano of (a);
a is one of the following groups:
R10represents hydrogen, methyl, halogen, hydroxyl, cyano, trifluoromethyl;
x and Y represent C, N.
2. The substituted 1,3,4, 5-tetrahydro-6H-pyrrolo [4,3,2-EF ] of claim 1][2]Benzazepin-6-one derivatives characterized by the fact that 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 1,3,4, 5-tetrahydro-6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one derivative according to claim 1, characterized by a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
4. Use of substituted 1,3,4, 5-tetrahydro-6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one derivatives according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof as PARP-1/2 inhibitors for the preparation of a medicament for the prevention or treatment of a disease associated with PARP-1/2.
5. The use as claimed in claim 4 wherein the PARP-1/2 related disease is PARP-1/2 related cancer.
6. A pharmaceutical composition comprising a therapeutically effective amount of a substituted 1,3,4, 5-tetrahydro-6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one derivative according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.
7. A pharmaceutical composition comprising a therapeutically effective amount of a substituted 1,3,4, 5-tetrahydro-6H-pyrrolo [4,3,2-EF ] [2] benzazepin-6-one derivative according to any one of claims 1 to 3 and a pharmaceutically acceptable excipient.
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