WO2022166749A1 - 三并杂环类化合物、其制备方法及其应用 - Google Patents
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- TYEWRRJIQQGORS-UHFFFAOYSA-N pyrido[3,2-b][1,4]oxazepine Chemical compound O1C=CC=NC2=NC=CC=C12 TYEWRRJIQQGORS-UHFFFAOYSA-N 0.000 description 1
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- 235000005713 safflower oil Nutrition 0.000 description 1
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- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
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- 239000010703 silicon Substances 0.000 description 1
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- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007886 soft shell capsule Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
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- 235000012222 talc Nutrition 0.000 description 1
- NSILYQWHARROMG-UHFFFAOYSA-N tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNC(CO)C1 NSILYQWHARROMG-UHFFFAOYSA-N 0.000 description 1
- PDAFIZPRSXHMCO-LURJTMIESA-N tert-butyl n-[(2s)-1-hydroxypropan-2-yl]carbamate Chemical compound OC[C@H](C)NC(=O)OC(C)(C)C PDAFIZPRSXHMCO-LURJTMIESA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
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- 230000001988 toxicity Effects 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical compound CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
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- 150000003751 zinc Chemical class 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/12—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 three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/14—Ortho-condensed systems
Definitions
- Aryl hydrocarbon receptors are coordination-activated transcription factors involved in the regulation of various cellular functions, including pro-inflammatory responses and biological metabolism (S.Feng, Z.Cao, X.Wang, Role of arylhydrocarbon receptor in cancer. Biochim Biophys Acta 1836, 197-210 (2013); and B. Stockinger, P. Di Meglio, M. Gialitakis, J. H. Duarte, The aryl hydrocarbon receptor: multitasking in the immune system. Annu Rev Immunol 32, 403-432 (2014 )).
- AHR can be activated by a number of ligands, including metabolically produced endogenous tryptophan such as kynurenine and certain polycyclic aromatic hydrocarbons (C.A. Opitz et al., An endogenous tumor-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197-203 (2011)). Activation of AHR induces the expression of target genes, including genes involved in metabolism, such as cytochromes P4501A1 and P4501B1. Activation also resulted in an increase in the AHR target gene TCDD-induced poly(ADP-ribose) polymerase (TIPARP). Like PARP7, functions as a negative regulator of some AHR transcriptional targets (L. MacPherson et al., Aryl hydrocarbon receptor repressor and TIPARP (ARTD14) use similar, but also distinct mechanisms to repress aryl hydrocarbon receptor signaling. Int J Mot Sci 15, 7939-7957 (2014).
- AHR-induced PARP7 can interact with TBK1, a major kinase that is activated during pathogen-associated molecular pattern pathway initiation, resulting in Type I interferon response and activation of antiviral immunity (T. Yamada et al., Constitutive aryl hydrocarbon receptor signaling constraints Type I interferon-mediated antiviral innate defense Nat Immunol 17687-604 (2016)).
- PARP7 has the ability to ribosylate TBK1 ADP Activation of TBK1 inactivates TBK1, thereby inhibiting the response of type I interferon.
- the present invention solves the above technical problems through the following technical solutions.
- R 2 , R 4 are independently halogen, CN, SF 5 , C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 2a , C 1-6 substituted by one or more R 2b 6 alkyl-S-; when there are multiple substituents, the same or different;
- X is independently C(R 3a ), C or N;
- Q is independently C(R 3a ) or N;
- T is independently C(R 3b ) or N;
- Y is independently C(R 3c ) or N;
- Z is independently C(R 3d ) or N;
- R 4a , R 4b and R 4c are independently H, C 1-6 alkyl or C 1-6 alkyl substituted by one or more R a1 ; when there are multiple substituents, they are the same or different;
- R 6d is independently H, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R a3 , C 3-6 cycloalkyl or -CN; when there are multiple substituents, the same or different;
- R 7 and R 8 are independently H, C 1-6 alkyl or C 1-6 alkyl substituted with OR 7a ;
- R 7a is selected from C 1-6 alkyl groups and C 1-6 alkyl groups in C 1-6 haloalkyl groups, and said C 1-6 alkyl groups are independently methyl groups , ethyl, n-propyl or isopropyl.
- R7 and R8 are independently H or methyl; eg, one of R7 and R8 is H and the other is methyl.
- R 1a is independently halogen, CN, OH;
- R 2 and R 4 are independently halogen, CN, C 1-6 alkyl, C 1-6 alkyl substituted with one or more R 2a , C 1-6 alkyl substituted with one or more R 2b -S-; when there are multiple substituents, the same or different;
- Q is independently C(R 3a ) or N;
- T is independently C(R 3b ) or N;
- Y is independently C(R 3c ) or N;
- Z is independently C(R 3d ) or N;
- R 3a , R 3b , R 3c , R 3d are independently H, halogen, CN, NH 2 , C 1-6 alkyl, C 1-6 alkyl substituted with one or more R a4 , or C 1-6 alkoxy;
- R 4a , R 4b and R 4c are independently H, C 1-6 alkyl or C 1-6 alkyl substituted by one or more R a1 ; when there are multiple substituents, they are the same or different;
- a 2 is independently C(R 5a ), C(R 5b R 5c ), connection key;
- R 6d is independently H, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R a3 , C 3-6 cycloalkyl or -CN; when there are multiple substituents, the same or different;
- R 5a , R 5b , R 5c , R 5d are independently H, C 1-6 alkyl or C 1-6 alkyl substituted with one or more R a2 ;
- R 6d is independently H, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R a3 , C 3-6 cycloalkyl; when there are multiple substituents, they are the same or different;
- R 1 and R 1' are H.
- R 3 and R 3' is H, and the other is H or C 1-6 alkyl;
- R 3 and R 3' are H.
- R 5 and R 5' are H.
- R 1 , R 1' , R 3 , R 3' , R 5 , and R 5' is H or C 1-6 alkyl, and the rest are H;
- halogen C 1-6 alkyl substituted with one or more R 2a ;
- R4 is independently halogen, CN, C1-6 alkyl substituted by one or more R2a ;
- halogen C 1-6 alkyl substituted with one or more R 2a ;
- X is independently N.
- T is independently N.
- R 3c is H, CN, NH 2 or C 1-6 alkyl
- Y is independently C(R 3c );
- R 4a , R 4b , R 4c are independently H or C 1-6 alkyl
- Another example is methyl.
- R 3a , R 3b , R 3c and R 3d are independently halogen
- the halogen is F, Cl, Br, I;
- T is independently N or CH.
- Z is independently CH, N, C(CN), C( NH2 ); eg, CH, N.
- R 1 , R 1' are independently H or C 1-6 alkyl
- R 3 , R 3' , R 5 , R 5' are independently H;
- Z is independently C(R 3d ) or N;
- X and T are independently N;
- Z is independently CH or N
- R 1 , R 1' , R 3 , R 3' , R 5 , R 5' are independently H;
- Y is independently C(R 3c );
- a 1 is independently C(R 4b R 4c );
- B is independently O or S
- R 1 , R 1' , R 3 , R 3' , R 5 , R 5' are independently H;
- Y and Z are independently CH;
- R 2 , R 4 are independently halogen, CN, C 1-6 alkyl substituted by one or more halogens;
- R 3b is H
- Y is C(R 3c );
- R 3c is H, C 1-6 alkyl or C 1-6 alkoxy substituted by one or more R a4 ;
- Z is C(R 3d );
- R 3d is H, C 1-6 alkyl or C 1-6 alkyl substituted by one or more R a4 ;
- R 4a , R 4b , R 4c are independently H or C 1-6 alkyl
- R 6a is H
- R a3 is halogen or -OH
- R 2 is CN, C 1-6 alkyl substituted with one or more halogens
- R 4 is C 1-6 alkyl substituted with one or more halogens
- X is N
- T is C(R 3b ) or N; R 3b is H;
- R 6d is H, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R a3 , C 3-6 cycloalkyl, CN;
- R 5d is H, C 1-6 alkyl
- R 1 , R 1' are independently H or C 1-6 alkyl
- R 3 , R 3' , R 5 , R 5' are independently H;
- Y is independently C(R 3c ); R 3c is H;
- a 2 is independently O, N(R 5d ) or a linkage
- R 5b , R 5c are independently H
- R 6d is H, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R a3 , C 3-6 cycloalkyl;
- X and T are independently N;
- Y is independently C(R 3c ); R 3c is H;
- Z is independently C(R 3d ) or N; R 3d is H;
- a 2 is independently C(R 5b R 5c ) or a connecting bond
- a 2 is independently O, N(R 5d ) or a linkage
- a 2 is independently O, N(R 5d ) or C(R 5b R 5c );
- R 5b , R 5c are independently H
- R 6b , R 6c are independently H
- the described tri-heterocyclic compound as shown in formula IA is any of the following structures:
- the bond represents a mixture of R and S configurations.
- the tri-heterocyclic compound represented by the formula IA can also be prepared by the tri-heterocyclic compound represented by the formula I', using conventional methods in the art, After peripheral modification, other tri-heterocyclic compounds represented by formula IA can be obtained.
- the described preparation method of the triheterocyclic compound shown in formula IA comprises the steps:
- W, L, R 7 , R 8 , R 1 , R 1' , R 2 , R 3 , R 3' , R 4 , R 5 , R 5' , X, T, Y, Z, A 1 , B, A 2 , Q, and * are as defined in any of the above scenarios;
- the preparation method thereof comprises the following steps:
- R 1 , R 1' , R 3 , R 3' , R 5 , R 5' , R 2 , R 4 , X, T, Y, Z, A 1 , B, A 2 , Q, and * are as defined above;
- X' is a leaving group such as halogen (eg Cl) or OH;
- R 1 , R 1' , R 3 , R 3' , R 5 , R 5' , R 2 , R 4 , X, T, Y, Z, A 1 , B, A 2 , Q, and * are defined as above.
- Described solvent is DMF, dichloromethane DCM.
- the base is diisopropylethylamine or K 2 CO 3 .
- the molar ratio of the base to the compound represented by formula II is 1:1.
- Described condensing agent is propyl phosphoric anhydride T3P, for example, 50% ethyl acetate solution is used.
- the molar ratio of the condensing agent to the compound represented by formula II is 1:1.
- the molar ratio of the compound represented by formula IIA to the compound represented by formula IIIA is 1:1.
- the amidation reaction was carried out under nitrogen protection.
- the temperature of the amidation reaction is 0°C to 60°C.
- the necessary starting materials or reagents for the preparation of compounds such as those of Formula IA are either commercially available or prepared by synthetic methods known in the art.
- Compounds of the invention can be prepared as free bases or as acid salts thereof as described in the experimental section below.
- the term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein, and which possesses all of the pharmaceutically activity of the parent compound.
- Pharmaceutically acceptable salts can be prepared by treating the organic base in a suitable organic solvent with the corresponding acid according to conventional methods.
- salt formation examples include: salt formation with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts formed with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethyl acetate Sulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-Naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid or trimethylacetic acid.
- inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phospho
- the tri-heterocyclic compounds represented by formula IA may have one or more chiral carbon atoms, so they can be separated into optically pure isomers, such as pure enantiomers, or racemates, or mixed isomer. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts, or chiral preparative column separation.
- the chemicals used in the synthetic route described in this patent include solvents, reagents, catalysts and protecting groups, deprotecting groups, protecting groups.
- the above methods may additionally include steps before or after the steps specifically described herein, where appropriate protecting groups may be added or removed to obtain the target compound. Additionally, various synthetic steps can be performed alternately or sequentially to obtain the final target product.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the above-mentioned triheterocyclic compound represented by formula IA or a pharmaceutically acceptable salt thereof, and (one or more) pharmaceutical excipients.
- the amount of the triheterocyclic compound represented by formula IA or a pharmaceutically acceptable salt thereof may be a therapeutically effective amount.
- the present invention also provides the use of the tri-heterocyclic compound represented by formula IA or a pharmaceutically acceptable salt thereof in the preparation of a PARP inhibitor.
- the PARP can be PARP7.
- the PARP inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as: providing comparison as a standard sample or a control sample, or preparing according to conventional methods in the art A kit is provided to provide rapid detection of the inhibitory effect of PARP.
- the present invention also provides a use of the triheterocyclic compound represented by formula IA or a pharmaceutically acceptable salt thereof in the preparation of a medicine; the medicine is used for the prevention and/or treatment of PARP related disease or PARP-mediated disease.
- the PARP can be PARP7.
- the PARP-related or PARP-mediated diseases may include abnormal proliferative diseases or other diseases related to the targets of this series of compounds; the abnormal proliferative diseases include but are not limited to cancer, the Cancers such as lung cancer (e.g.
- lung squamous tumor H1373 lung cancer cell
- colon cancer colorectal cancer
- pancreatic cancer kidney cancer
- stomach cancer esophagus cancer
- ovarian cancer breast cancer
- cervical cancer head and neck cancer (upper aerodigestive tract)
- bladder cancer melanoma
- fibrosarcoma glioblastoma.
- the amount of the triheterocyclic compound represented by formula IA or a pharmaceutically acceptable salt thereof can be a therapeutically effective amount.
- the present invention also provides the use of the triheterocyclic compound represented by formula IA or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same in preparing a medicine; the medicine is used for Prevention and/or treatment of dysproliferative diseases.
- the dysproliferative diseases include, but are not limited to, cancers such as lung cancer (eg, lung squamous tumor, H1373 lung cancer cell), colon cancer, colorectal cancer, pancreatic cancer, kidney cancer, gastric cancer, esophageal cancer, ovarian cancer , breast, cervical and head and neck (upper aerodigestive tract), bladder, melanoma, fibrosarcoma, glioblastoma.
- the amount of the triheterocyclic compound represented by formula IA or a pharmaceutically acceptable salt thereof can be a therapeutically effective amount.
- Another aspect of the present invention relates to a method of treating, preventing and/or treating dysproliferative diseases, comprising administering to a patient a therapeutically effective dose of the triheterocyclic compound represented by formula IA or a pharmaceutically acceptable amount thereof.
- An acceptable salt or a pharmaceutical composition comprising the same; wherein, the abnormal proliferative disease includes, but is not limited to, the cancer such as lung cancer (for example, lung squamous tumor, H1373 lung cancer cell), colon cancer, colorectal cancer, Pancreatic, renal, gastric, esophageal, ovarian, breast, cervical and head and neck (upper aerodigestive), bladder, melanoma, fibrosarcoma, glioblastoma.
- lung cancer for example, lung squamous tumor, H1373 lung cancer cell
- colon cancer colorectal cancer
- Another aspect of the present invention relates to a medicine for inhibiting PARP7, which comprises the triheterocyclic compound represented by formula IA or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
- the present invention provides a triheterocyclic compound as shown in formula I or a pharmaceutically acceptable salt thereof,
- R 2a , R 2b are independently halogen
- T is independently C(R 3b ) or N;
- Y is independently C(R 3c ) or N;
- Z is independently C(R 3d ) or N;
- R 3a , R 3b , R 3c , R 3d are independently H, halogen, CN, NH 2 or C 1-6 alkyl;
- R 4a , R 4b and R 4c are independently H, C 1-6 alkyl or C 1-6 alkyl substituted by one or more R a1 ; when there are multiple substituents, they are the same or different;
- a 2 is independently C(R 5a ), C(R 5b R 5c ) or a connecting bond;
- R 5a , R 5b , R 5c , R 5d are independently H, C 1-6 alkyl or C 1-6 alkyl substituted with one or more R a2 ;
- one of R 1 and R 1' is H, and the other is H, C 1-6 alkyl or C 1-6 alkyl substituted by one or more R 1a ;
- R 1 and R 1' are H, and the other is H or C 1-6 alkyl;
- R 1 and R 1' are H.
- one of R 3 and R 3' is H, and the other is H, C 1-6 alkyl or C 1-6 alkyl substituted by one or more R 1a ;
- R 3 and R 3' are H.
- one of R 5 and R 5' is H, and the other is H, C 1-6 alkyl or C 1-6 alkyl substituted by one or more R 1a ;
- R 5 and R 5' are H, and the other is H or C 1-6 alkyl;
- R 5 and R 5' are H.
- one of R 1 , R 1' , R 3 , R 3' , R 5 , R 5' is H, C 1-6 alkyl or substituted with one or more R 1a of C 1-6 alkyl, the rest are H;
- R 1 , R 1' , R 3 , R 3' , R 5 , and R 5' is H or C 1-6 alkyl, and the rest are H;
- R 1 , R 1' , R 3 , R 3' , R 5 , R 5' are H.
- the carbon to which R 3 and R 3' are attached is a chiral carbon, it is in S configuration or R configuration.
- halogen C 1-6 alkyl substituted with one or more R 2a ;
- Another example is a C 1-6 alkyl substituted with one or more halogens.
- R4 is independently halogen, CN, C1-6 alkyl substituted by one or more R2a ;
- Another example is C 1-6 alkyl substituted with one or more halogens.
- R 2 and R 4 are independently C 1-6 alkyl substituted by one or more R 2a ;
- X is independently N.
- T is independently N.
- R 3c is H, CN, NH 2 or C 1-6 alkyl
- Y is independently C(R 3c );
- R 3d is H, halogen, CN or C 1-6 alkyl
- R 4a , R 4b , R 4c are independently H or C 1-6 alkyl
- R 5a , R 5b , R 5c , R 5d are independently H or C 1-6 alkyl
- R 5b and R 5c are H, the other is H or C 1-6 alkyl;
- R 5b and R 5c are H.
- a 2 is C(R 5b R 5c ) and the carbon is a chiral carbon
- its configuration is S configuration, R configuration or a mixture thereof.
- a 2 is independently C(R 5b R 5c ) or a linkage.
- R 6a , R 6b , R 6c are independently H or halogen
- R 6b and R 6c are independently H.
- B is independently C(R 6b R 6c ).
- R 6a , R 6b , R 6c and R 6d are independently C 3-6 cycloalkyl
- the C 3-6 cycloalkyl is cyclopropyl, cyclobutyl base, cyclopentyl, cyclohexyl;
- R 3 , R 3' , R 5 , R 5' are independently H;
- B is independently O, S, N or N(R 6d ), and A 2 is independently C(R 5b R 5c ) or a connecting bond;
- R 2 and R 4 are independently CF 3 ;
- Y is independently CH;
- R 1 , R 1' , R 3 , R 3' , R 5 , R 5' are independently H;
- R 2 , R 4 are independently C 1-6 alkyl substituted by one or more halogens
- X and T are independently N;
- Y is independently C(R 3c );
- a 1 is independently C(R 4b R 4c );
- B is independently O or S
- a 2 is independently C(R 5b R 5c ) or a connecting bond
- a 1 is independently CH 2 ;
- B is independently O or S
- a 2 is independently CH 2 or a connecting bond
- the described tri-heterocyclic compound shown in formula I is any of the following structures:
- the triheterocyclic compounds represented by formula I or their pharmaceutically acceptable salts according to the present invention can be synthesized by methods similar to those known in the chemical field, and the steps and conditions can refer to the steps of similar reactions in the art and conditions, especially syntheses as described herein.
- Starting materials are typically from commercial sources such as Aldrich or can be readily prepared using methods well known to those skilled in the art (obtained via SciFinder, Reaxys online database).
- the tri-heterocyclic compounds shown in formula I can also be prepared by using the tri-heterocyclic compounds shown in formula I by using conventional methods in the art. Peripheral modification further obtains other described tri-heterocyclic compounds represented by formula I.
- the compounds of the present invention can be prepared by the methods described in the present invention, wherein the substituents are as defined in formula I unless otherwise specified.
- the following reaction schemes and examples serve to further illustrate the content of the present invention.
- the described preparation method of the tri-heterocyclic compound shown in formula I comprises the steps:
- R 1 , R 1' , R 3 , R 3' , R 5 , R 5' , R 2 , R 4 , X, T, Y, Z, A 1 , B, A 2 and * are defined as above.
- the conditions and operations of the amidation reaction can be conventional conditions and operations in this type of reaction in the art.
- the present invention preferably as follows:
- Described solvent is DMF, dichloromethane DCM.
- the base is diisopropylethylamine or K 2 CO 3 .
- the molar ratio of the base to the compound represented by formula II is 1:1.
- Described condensing agent is propyl phosphoric anhydride T3P, for example, 50% ethyl acetate solution is used.
- the molar ratio of the condensing agent to the compound represented by formula II is 1:1.
- the necessary starting materials or reagents for the preparation of compounds such as those of formula I are either commercially available or prepared by synthetic methods known in the art.
- Compounds of the invention can be prepared as free bases or as acid salts thereof as described in the experimental section below.
- the term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein, and which possesses all of the pharmaceutically activity of the parent compound.
- Pharmaceutically acceptable salts can be prepared by treating the organic base in a suitable organic solvent with the corresponding acid according to conventional methods.
- salt formation examples include: salt formation with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts formed with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethyl acetate Sulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-Naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid or trimethylacetic acid.
- inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phospho
- the tri-heterocyclic compounds represented by formula I may have one or more chiral carbon atoms, so they can be separated into optically pure isomers, such as pure enantiomers, or racemates, or mixed isomer. Pure single isomers can be obtained by separation methods in the art, such as chiral crystallization into salts, or chiral preparative column separation.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the above-mentioned triheterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, and (one or more) pharmaceutical excipients.
- the amount of the triheterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof may be a therapeutically effective amount.
- the present invention also provides the use of the tri-heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a PARP inhibitor.
- the PARP can be PARP7.
- the PARP inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as: providing comparison as a standard sample or a control sample, or preparing according to conventional methods in the art A kit is provided to provide rapid detection of the inhibitory effect of PARP.
- the present invention also provides a use of the triheterocyclic compound shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicine; the medicine is used for the prevention and/or treatment of PARP related or PARP-mediated disease.
- the PARP can be PARP7.
- the PARP-related or PARP-mediated diseases may include abnormal proliferative diseases or other diseases related to the targets of this series of compounds; the abnormal proliferative diseases include but are not limited to cancer, the Cancers such as lung cancer (e.g.
- lung squamous tumor H1373 lung cancer cell
- colon cancer colorectal cancer
- pancreatic cancer kidney cancer
- stomach cancer esophagus cancer
- ovarian cancer breast cancer
- cervical cancer head and neck cancer (upper aerodigestive tract)
- bladder cancer melanoma
- fibrosarcoma glioblastoma.
- the amount of the triheterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof can be a therapeutically effective amount.
- the present invention also provides the use of the triheterocyclic compound shown in formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same in preparing a medicine; the medicine is used for Prevention and/or treatment of dysproliferative diseases.
- the dysproliferative diseases include, but are not limited to, cancers such as lung cancer (eg, lung squamous tumor, H1373 lung cancer cell), colon cancer, colorectal cancer, pancreatic cancer, kidney cancer, gastric cancer, esophageal cancer, ovarian cancer , breast, cervical and head and neck (upper aerodigestive tract), bladder, melanoma, fibrosarcoma, glioblastoma.
- the described triheterocyclic compound as shown in formula I or its pharmaceutically acceptable salt can be used in a therapeutically effective amount
- Another aspect of the present invention relates to a method for preventing and/or treating PARP7-related or PARP-mediated diseases, comprising administering to a patient a therapeutically effective dose of the triheterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
- Another aspect of the present invention relates to a method for treating, preventing and/or treating abnormal proliferative diseases, comprising administering to a patient a therapeutically effective dose of the triheterocyclic compound represented by formula I or a pharmaceutically acceptable amount thereof.
- An acceptable salt or a pharmaceutical composition comprising the same; wherein, the abnormal proliferative disease includes, but is not limited to, the cancer such as lung cancer (for example, lung squamous tumor, H1373 lung cancer cell), colon cancer, colorectal cancer, Pancreatic, renal, gastric, esophageal, ovarian, breast, cervical and head and neck (upper aerodigestive), bladder, melanoma, fibrosarcoma, glioblastoma.
- lung cancer for example, lung squamous tumor, H1373 lung cancer cell
- colon cancer colorectal cancer
- Another aspect of the present invention relates to a medicine for inhibiting PARP7, which comprises the triheterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
- the effective amount of the compound, pharmaceutical composition or medicament of the present invention depends on the species, body weight, age, individual condition, individual pharmacokinetic parameters, disease to be treated and mode of administration of the mammal.
- An effective amount of a compound, pharmaceutical composition or medicament of the present invention can be readily determined by routine experimentation, as can the most effective and convenient route of administration and the most appropriate formulation.
- the pharmaceutical excipients can be those widely used in the field of pharmaceutical production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to enable the subject to dissolve the active ingredient at a desired rate after administration, or to promote the activity of the subject after the composition is administered. The ingredients are effectively absorbed.
- the pharmaceutical excipients can be inert fillers, or provide some function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.
- Described pharmaceutical adjuvants may include one or more of the following adjuvants: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, anti-sticking agents Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors and sweeteners.
- adjuvants may include one or more of the following adjuvants: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, anti-sticking agents Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors and sweeten
- Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbic acid Potassium acid, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidones, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; adjuvants
- compositions of the present invention can be prepared in light of the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, attenuating, encapsulating, entrapping or lyophilizing processes.
- compositions of the present invention may be administered topically or systemically, for example, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals, especially humans, and include those according to the present invention.
- enteral administration such as rectal or oral administration
- parenteral administration to mammals, especially humans, and include those according to the present invention.
- the therapeutically effective amount of the active ingredient is as defined above and below, and depends on the species of mammal, body weight, age, individual condition, individual pharmacokinetic parameters, the disease to be treated and the mode of administration.
- enteral administration such as oral administration
- the compounds of the present invention can be formulated into a wide variety of dosage forms.
- compositions and dosage forms may contain, as an active ingredient, one or more compounds of the present invention, or one or more pharmaceutically acceptable salts thereof.
- Pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, lozenges, capsules, suppositories and dispersible granules. A solid carrier can also be one or more substances that act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is usually a finely divided solid which is in admixture with the finely divided active component.
- the active component is usually mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
- suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like .
- the formulation of the active compound can include as carrier an encapsulating material providing a capsule in which the active component, with or without carriers, is surrounded by a carrier in association with it.
- liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.
- Emulsions can be prepared in solutions, such as aqueous propylene glycol, or can contain emulsifying agents, such as lecithin, sorbitan monooleate, or acacia.
- Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, fragrances, stabilizers and thickening agents.
- Exemplary combinations for rectal administration include suppositories, which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic glycerides, or polyethylene glycols, which are solid at ordinary temperatures, but in the rectal cavity Melt and/or dissolve to release drug.
- suitable non-irritating excipients such as cocoa butter, synthetic glycerides, or polyethylene glycols, which are solid at ordinary temperatures, but in the rectal cavity Melt and/or dissolve to release drug.
- the compounds of the invention may also be administered parenterally, eg, by inhalation, injection or infusion, such as by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, extraventricular, intrasynovial, intrasternal, intrathecal Intra, intralesional, intracranial, intratumoral, intradermal and subcutaneous injection or infusion.
- the pharmaceutical compositions of the present invention may be in the form of sterile injectable or infusible injectable preparations, eg, as sterile aqueous or oily suspensions.
- This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg, Tween 80) and suspending agents.
- the sterile injectable or infusible preparation may also be a sterile injectable or infusible solution or suspension in a nontoxic parenterally acceptable diluent or solvent.
- the pharmaceutical composition can be a solution in 1,3-butanediol.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono- or diglycerides.
- Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
- Suitable stabilizers include antioxidants such as sodium bisulfate, sodium sulfite or ascorbic acid, citric acid and salts thereof and sodium EDTA, alone or in combination.
- Suitable stabilizers include antioxidants such as sodium bisulfate, sodium sulfite or ascorbic acid, citric acid and salts thereof and sodium EDTA, alone or in combination.
- Parenteral solutions may also contain preservatives such as benzalkonium chloride, paraben or propyl paraben, and chlorobutanol.
- suitable pharmaceutical formulations include particles, aerosols, powders, mists or droplets, eg, with an average size of about 10 microns in diameter or less.
- compositions for inhalation can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and/or other enhancers known in the art solvent or dispersant.
- compositions of the present invention may also be administered topically to the skin or mucous membranes.
- the pharmaceutical composition may be, for example, a lotion, gel, paste, tincture, transdermal patch, gel for transmucosal delivery.
- the pharmaceutical composition may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in a carrier.
- Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
- the pharmaceutical compositions may be formulated in a suitable lotion or emulsion containing the active compound suspended or solvent in a carrier.
- Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- a therapeutically effective dose can first be estimated using various methods well known in the art. Initial doses for animal studies can be based on effective concentrations established in cell culture assays. Dosage ranges suitable for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the present invention can be prepared as medicaments for oral administration.
- an effective or therapeutically effective amount or dose of an agent refers to the amount of the agent or compound that results in an improvement in symptoms or prolonged survival in an individual.
- Toxicity and therapeutic efficacy of the molecule can be determined in cell cultures or experimental animals by standard medical procedures, for example by measuring the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). dose).
- the dose ratio of toxic to therapeutic effects is the therapeutic index and can be expressed as LD50 / ED50 . Agents that exhibit high therapeutic indices are preferred.
- An effective or therapeutically effective amount is the amount of a compound or pharmaceutical composition that will elicit a biological or medical response in a tissue, system, animal or human being sought by a researcher, veterinarian, physician or other clinician.
- the dosage lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
- the dosage may vary within this range depending upon the dosage form employed and/or the route of administration employed.
- the correct formulation, route of administration, dosage and dosing interval should be selected according to methods known in the art, taking into account the particularities of the individual situation.
- MEC minimal effective concentration
- the amount of the agent or composition administered may depend on various factors, including the sex, age and weight of the individual being treated, the severity of the affliction, the mode of administration and the judgment of the prescribing physician.
- compositions of the present invention can be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient, as required.
- the package or device may comprise metal or plastic foil (eg, blister packs) or glass and rubber stoppers, as in vials.
- the pack or dispenser device may be accompanied by instructions for use.
- Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
- C1 - C6 alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms.
- the total number of carbon atoms in the simplified notation does not include carbons that may be present in the substituents of the group.
- substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable .
- substituted means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent.
- the substituents are independent of each other, that is, the one or more substituents may be different from each other or the same of.
- a substituent group may be substituted at various substitutable positions of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents can be substituted identically or differently at each position.
- “Pharmaceutically acceptable” means that which can be used in the preparation of pharmaceutical combinations, is generally safe and non-toxic, and is not biologically and otherwise undesirable, and includes both for veterinary and human pharmaceutical use acceptable situation.
- Step 3 (S)-5,5-Difluoro-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a ][1,8]Naphthyridine and (R)-5,5-difluoro-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[ Synthesis of 1,2-a][1,8]naphthyridine
- the fourth step synthesis of 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[ 1,2-d]pyridin[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl) Pyridazin-3(2H)-one (Compound 1)
- the crude product of compound 2 was prepared with a preparative liquid phase (column: XBridge Prep OBD C18, 30 ⁇ 150 mm 5um, mobile phase A: water (add 10 mol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 mL/min, Elution gradient: mobile phase B increased from 20% to 52% in 8 minutes, detection wavelength: 220 nm, retention time: 7.28 min) and purified to obtain the target product as a white solid (50 mg, 0.091 mmol, yield: 23.00%).
- a preparative liquid phase column: XBridge Prep OBD C18, 30 ⁇ 150 mm 5um
- mobile phase A water (add 10 mol/L ammonium bicarbonate)
- mobile phase B acetonitrile
- flow rate 60 mL/min
- Elution gradient mobile phase B increased from 20% to 52% in 8 minutes
- detection wavelength 220 nm
- retention time 7.28 min
- the third step Synthesis of (R)-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) Amino)propoxy)propionyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazine[2,1-c]pyridine[2,3 -e][1,4]oxazin-5-one (compound 3)
- reaction solution was poured into ice water (20 mL), the aqueous phase was extracted three times with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, anhydrous sodium sulfate was irritated, and anhydrous sulfuric acid was removed by filtration Sodium, the filtrate was spin-dried to obtain the crude product.
- the crude product was eluted with a preparative liquid phase (column: XBridge Prep OBD C18, 30 ⁇ 150mm 5um, mobile phase A: water (add 10 mol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 ml/min Gradient: mobile phase B increased from 20% to 52% in 8 minutes, detection wavelength: 220 nm, retention time: 6.95 min) and purified to obtain the target product as a white solid (52 mg, 0.090 mmol, yield: 25.01%).
- a preparative liquid phase columnumn: XBridge Prep OBD C18, 30 ⁇ 150mm 5um, mobile phase A: water (add 10 mol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 ml/min Gradient: mobile phase B increased from 20% to 52% in 8 minutes, detection wavelength: 220 nm, retention time: 6.95 min) and purified to obtain the target product as a white solid
- the synthetic method is the same as in Example 3, except that (3S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester is used to replace the raw material (3R)-3-(hydroxymethyl)piperazine in the first step reaction -1-carboxylate tert-butyl ester reacts.
- the crude product of compound 4 was separated and purified by high performance liquid chromatography (column: XBridge Prep OBD C18, 30 ⁇ 150mm 5um, mobile phase A: water (add 10 mol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 ml /min, elution gradient: mobile phase B increased from 20% to 52% in 8 minutes, detection wavelength: 220nm, retention time: 7.13min) and purified white solid target product (20mg, 0.035mmol, yield: 53%) ).
- Example 5 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyridine Azino[2,1-c]pyridin[2,3-e][1,4]oxapine-9(7H)-yl)propoxy)propan-2-yl)amino)-4-(tris Synthesis of Fluoromethyl)pyridazin-3(2H)-one (Compound 5)
- the third step synthesis of 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H- Pyrazino[2,1-c]pyridin[2,3-e][1,4]oxapine-9(7H)-yl)propoxy)propan-2-yl)amino)-4-( Trifluoromethyl)pyridazin-3(2H)-one (Compound 5)
- the reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography (column: XBridge Prep OBD C18, 30 ⁇ 150 mm, 5um; mobile phase A: water (10mmol/L sodium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: mobile phase B increased from 20% to 52% in 8 minutes, detection wavelength: 220 nm; retention time: 6.85 minutes) to obtain the target product as a white solid (11 mg, 0.019 mmol, yield: 59%).
- high performance liquid chromatography columnumn: XBridge Prep OBD C18, 30 ⁇ 150 mm, 5um; mobile phase A: water (10mmol/L sodium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: mobile phase B increased from 20% to 52% in 8 minutes, detection wavelength: 220 nm; retention time: 6.85 minutes
- the synthetic route is the same as that of Example 5, except (S)-5-oxo-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c] Pyridine[2,3-e][1,4]oxazoline-9(7H)-carboxylate tert-butyl ester (6-1) replaced the raw material (R)-5-oxo-3- in the first step reaction (Trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][1,4]oxazoline-9(7H )-tert-butyl formate (3-2) was reacted.
- the crude product of compound 6 was purified by high performance liquid chromatography (column: XBridge Prep OBD C18, 30 ⁇ 150mm, 5um; mobile phase A: water (10mmol/L sodium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL/min; Gradient: mobile phase B increased from 20% to 52% in 8 minutes, detection wavelength: 220 nm; retention time: 6.90 minutes), the target product (11 mg, 0.019 mmol, yield: 59%) was obtained as a white solid.
- the reaction solution was concentrated under reduced pressure, water (10 mL) was added to the crude product, the pH value was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate (10 mL ⁇ 3).
- the organic phase was dried over anhydrous sodium sulfate, the anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to dry the crude product.
- LCMS MS (ESI) m/z: 273 [M+H] + .
- the reaction solution was diluted with dichloromethane (100 mL), and the organic phase was washed three times with water (30 mL ⁇ 3) and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by high performance liquid chromatography ((column: YMC-Actus Triart C18, 30mm ⁇ 150mm, 5um, mobile phase A: water (add 0.05% trifluoroacetic acid) , mobile phase B: acetonitrile, flow rate: 60 ml/min, elution gradient: mobile phase B increased from 5% to 45% in 8 minutes, detection wavelength: 220nm, retention time: 7.05min)) After purification, a white solid target was obtained The product (59.61 mg, yield: 19%).
- Example 8 (S)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino )propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2-e]pyrazine Synthesis of -6(6aH)-one (Compound 8)
- the second step Synthesis of (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3, 2-e]pyrazine(9-2)
- Example 10 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyridine Azin[1,2-a]pyridin[3,2-f][1,4]diazepin-9(5H)-yl)propoxy)propanol-2-yl)amino)-4-( Synthesis of Trifluoromethyl)piperazin-3(2H)-one (Compound 10)
- the third step Synthesis of tert-butoxycarbonyl-(R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazine[1,2-a]pyridine[3, 2-f][1,4]diazepin-5(6H)-one (10-5)
- Diazepin-5(6H)-one (500 mg, 1.29 mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0 °C, and solid sodium borohydride (50 mg, 1.295 mmol) was added. ), boron trifluoride-diethyl ether complex (185mg, 1.292mmol) was added dropwise under stirring conditions. After the dropwise addition, the reaction mixture was stirred at room temperature for 2 hours.
- 6-phenyl 9-(tert-butyl)(S)-3-(trifluoromethyl)-7a,8,10,11-hexahydropyrazine[1,2-a]pyridine[3,2- f][1,4]piperazine-6,9(5H,7H)-dicarboxylic acid (10-7) (500 mg, 0.986 mmol) was dissolved in dichloromethane (5 mL), then trifluoroacetic acid (3 mL) was added, The reaction mixture was stirred at room temperature for 2 hours.
- the reaction solution was concentrated under reduced pressure, the crude product was diluted with water (30 mL), the pH was adjusted to 8-9 with sodium bicarbonate, extracted three times with dichloromethane (20 mL ⁇ 3), and the combined extracts were spin-dried under reduced pressure to obtain the crude product.
- the target product 300 mg, 1.157 mmol, yield: 83%) was obtained as a white solid, LCMS: MS (ESI) m/z: 407 [M+H] + .
- Step 7 Synthesis of (R)-9-(3-((S)-2-((6-oxygen-5-(trifluoromethyl)-1,6-hexahydropyrazin-4-yl)amino )propoxy)propanol)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazine[1,2-a]pyridine[3,2-f][ 1,4] Benzyl piperazine-6(5H)-carboxylate (10-9)
- reaction solution was poured into ice water (20 mL), the aqueous phase was extracted three times with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, anhydrous sodium sulfate was irritated, and anhydrous sulfuric acid was removed by filtration Sodium, the filtrate was spin-dried to obtain the crude product.
- the crude product was eluted with a preparative liquid phase (column: XBridge Prep OBD C18, 30 ⁇ 150mm 5um, mobile phase A: water (add 10 mol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 ml/min Gradient: mobile phase B increased from 20% to 52% in 8 minutes, detection wavelength: 220 nm, retention time: 7.12 min) and purified to obtain the target product as a white solid (50 mg, 0.091 mmol, yield: 28.09%).
- a preparative liquid phase columnumn: XBridge Prep OBD C18, 30 ⁇ 150mm 5um, mobile phase A: water (add 10 mol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 ml/min Gradient: mobile phase B increased from 20% to 52% in 8 minutes, detection wavelength: 220 nm, retention time: 7.12 min) and purified to obtain the target product as a white solid
- reaction solution was poured into ice water (20 mL), the aqueous phase was extracted three times with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, anhydrous sodium sulfate was irritated, and anhydrous sulfuric acid was removed by filtration Sodium, the filtrate was spin-dried to obtain the crude product.
- the crude product was prepared with a reverse prep liquid phase (column: XBridge Prep OBD C18, 30 ⁇ 150mm 5um, mobile phase A: water (add 10 mol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 ml/min, Elution gradient: mobile phase B increased from 20% to 52% in 8 minutes, detection wavelength: 220 nm, retention time: 7.09 min) and purified to obtain the white solid target product (50 mg, 0.091 mmol, yield: 28.09%).
- Example 12 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H-pyridine Azino[2,1-c]pyrido[2,3-e][1,4]thiazin-9(7H)-yl)propoxy)propan-2-yl)amino)-4-(tris Synthesis of Fluoromethyl)pyridazin-3(2H)-one (Compound 12)
- Step 2 Synthesis of 1-benzyl 4-(tert-butyl)(R)-2-((((2-chloro-5-(trifluoromethyl)pyridin-3-yl)methyl)thio) Methyl)piperazine-1,4-dicarboxylate (12-4)
- the fourth step Synthesis of (R)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyrido[2, 3-e][1,4]thiazoline (12-6)
- the fifth step Synthesis of 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-7a,8,10,11-tetrahydro-5H- Pyrazino[2,1-c]pyrido[2,3-e][1,4]thiazin-9(7H)-yl)propoxy)propan-2-yl)amino)-4-( Trifluoromethyl)pyridazin-3(2H)-one (Compound 12)
- the fifth step Synthesis of (R)-5-methyl-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a] Pyrido[3,2-e]pyrazine (13-7)
- Step 6 Synthesis of 5-(((S)-1-(3-(S)-5-methyl-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro -8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(tris Fluoromethyl)pyridazin-3(2H)-one (Compound 13)
- reaction solution was stirred at room temperature for 0.5 hour. After the completion of the reaction, add water to quench, extract with dichloromethane three times, combine the organic phases, wash with saturated aqueous hydrochloric acid, dry over anhydrous sodium sulfate, filter, and spin dry the filtrate under reduced pressure to obtain a crude product.
- Example 14 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1 ,2-d]pyridin[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)prop-2-yl)amino)-4-(trifluoromethyl)pyridin Synthesis of oxazin-3(2H)-one (compound 14)
- the first step Synthesis of (3R)-4-5-(trifluoromethyl)pyridin-2-yl]-3-(hydroxymethyl)pyrazine-1-carboxylic acid tert-butyl ester (14-2)
- the first step Synthesis of (7aR)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6-oxo 5H-pyrazino[2,1-c]pyridine [2,3-e][1,4]thiazoline (15-1)
- reaction mixture was stirred at room temperature for 0.5 hours. After the reaction is completed, add water to quench, and extract with dichloromethane three times. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate is spin-dried under reduced pressure to obtain a solid crude product.
- the crude product was prepared by reverse-phase high-efficiency liquid phase (column: Xselect CSH OBD Column, 30*150mm 5um, mobile phase A: water (add 10 mol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 ml/min , elution gradient: mobile phase B increased from 5% to 42% in 8 minutes, detection wavelength: 220nm, retention time: 7.78min) after purification, white solid target product (0.01g, yield: 5%) was obtained.
- Example 16 (R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino )propoxy)propionyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-12H-pyrazino[2,1-c]pyrido[2, Synthesis of 3-f][1,4]oxazepin-12-one (Compound 16)
- the third step Synthesis of (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-12H-pyrazino[2,1-c]pyrido[2, 3-f][1,4]oxazepine-12-one (16-4)
- the fourth step synthesis (R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) Amino)propoxy)propionyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-12H-pyrazino[2,1-c]pyrido[2 , 3-f][1,4]oxazepine-12-one (Compound 16)
- Example 17 (S)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino )propoxy)propionyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-12H-pyrazino[2,1-c]pyrido[2, Synthesis of 3-f][1,4]oxazepin-12-one (Compound 17)
- the crude product was prepared by reverse-phase high-efficiency liquid phase (column: YMC-Actus Triart C18, 30mm ⁇ 150mm, 5um, mobile phase A: water (add 10 mol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 ml /min, elution gradient: mobile phase B increased from 10% to 52% in 8 minutes, detection wavelength: 220 nm, retention time: 7.02 min) and purified to obtain the white solid target product (0.03 g, yield: 29%).
- Example 18 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydro-12H-pyridine Azino[2,1-c]pyrido[2,3-f][1,4]oxazepin-8(6H)-yl)propoxy)propan-2-yl)amino)-4- Synthesis of (trifluoromethyl)pyridazin-3(2H)-one (Compound 18)
- the third step Synthesis of 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydro-12H- Pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepine-8(6H)-yl)propoxy)propan-2-yl)amino)-4 -(Trifluoromethyl)pyridazin-3(2H)-one (Compound 18)
- reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, it was quenched with water, extracted with dichloromethane three times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried under low pressure.
- the crude product was purified by preparative liquid phase, and the purification conditions were (column: YMC-Acms Triart C18, 30mm ⁇ 150mm, 5um, mobile phase A: water (add 10 mol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 ml/min, elution gradient: mobile phase B increased from 20% to 75% in 8 minutes, detection wavelength: 220nm, retention time: 7.58min) after purification, white solid target product 5-(((S)-1- (3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2, 3-f][1,4]oxazepine-8(6H)-yl)propoxy)prop-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)- Ketone (0.03 g, yield
- the crude product was subjected to preparative reverse-phase high performance liquid chromatography (column: YMC-Actus Triart C18, 30mm ⁇ 150mm, 5um, mobile phase A: water (add 10 mol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 ml/min, elution gradient: mobile phase B increased from 20% to 75% in 8 minutes, detection wavelength: 220nm, retention time: 7.58min) after purification, white solid target product (0.02g, yield: 18%) was obtained. .
- Step 2 Synthesis of (R)-3-fluoro-7a,8,10,11-tetrahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][1,4] Oxazoline-9(7H)-tert-butylcarboxylate (20-3)
- the third step Synthesis of (R)-3-fluoro-7,7a,8,9,10,11-hexahydro-5H-pyrazino[2,1-c]pyridine[2,3-e][ 1,4]oxazepine-5-one (20-4)
- reaction solution was poured into ice water (20 mL), the aqueous phase was extracted three times with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, anhydrous sodium sulfate was irritated, and anhydrous sulfuric acid was removed by filtration Sodium, the filtrate was spin-dried to obtain the crude product.
- the crude product was prepared by reverse-phase high-efficiency liquid phase (column: XBridge Prep OBD C18, 30 ⁇ 150mm 5um, mobile phase A: water (add 10 mol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 ml/min , elution gradient: mobile phase B increased from 20% to 52% in 8 minutes, detection wavelength: 220nm, retention time: 6.21min) after purification, white solid target product (52mg, 0.090mmol, yield: 25.01%) was obtained.
- the synthetic method is the same as that of Example 20.
- the crude product was prepared by reversed-phase high-efficiency liquid phase (column: XBridge Prep OBD C18, 30 ⁇ 150mm5um, mobile phase A: water (add 10 mol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 ml/min, Elution gradient: mobile phase B increased from 20% to 52% in 8 minutes, detection wavelength: 220nm, retention time: 6.10min) after purification, white solid target product (R)-9-(3-((S)- 2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-chloro-7,7a, 8,9,10,11-Hexahydro-5H-pyrazin[2,1-c]pyridine[2,3-e][1,4]oxazin-5-one (Compound 21) (52 mg,
- Example 22 5-(((S)-1-(3-((R)-6,6-dioxa-3-(trifluoromethyl)-7a,8,10,11-tetrahydro- 5H-pyrazino[2,1-c]pyrido[2,3-e][1,4]thiazin-9(7H)-yl)-3-oxopropoxy)propan-2-yl) Synthesis of Amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 22)
- the reaction was stirred at 0°C for 1 hour. After the reaction was completed, methanol was removed by rotary evaporation under reduced pressure.
- the crude product was prepared by reversed-phase high-efficiency liquid phase (column: Xselect CSH OBD Column 30*150mm5um, mobile phase A: mobile phase A: water (add 10 mol/L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 60 ml/ minutes, elution gradient: mobile phase B increased from 10% to 55% in 8 minutes, detection wavelength: 220 nm, retention time: 7.27 min) and purified to obtain the target product as a white solid (1.22 mg, yield: 1%).
- the first step Synthesis of (S)-6-methyl-3-(trifluoromethyl)-6,7,7a,8,9,10,11-octahydropyrazino[1,2-a]pyridine [3,2-f][1,4]diazepine-9(5H)-carboxylate tert-butyl ester (23-1)
- the third step Synthesis of 5-(((S)-1-(3-((S)-6-methyl-3-(trifluoromethyl)-6,7,7a,8,10,11-octa Hydropyrazino[1,2-a]pyridine[3,2-f][1,4]diazepin-9(5H)-yl)-3-propoxy)propan-2-yl)amino )-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 23)
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Abstract
Description
Claims (16)
- 一种如式IA所示的三并杂环类化合物或其药学上可接受的盐,其中,W为NH或O;R 1、R 1’、R 3、R 3’、R 5、R 5’独立地为H、C 1-6烷基或被一个或多个R 1a取代的C 1-6烷基;或,R 1和R 1’、R 3和R 3’、R 5和R 5’独立地为O=;当取代基为多个时,相同或不同;R 1a独立地为卤素、CN、OH;R 2、R 4独立地为卤素、CN、SF 5、C 1-6烷基、被一个或多个R 2a取代的C 1-6烷基、被一个或多个R 2b取代的C 1-6烷基-S-;当取代基为多个时,相同或不同;R 2a、R 2b独立地为卤素;X独立地为C(R 3a)、C或N;Q独立地为C(R 3a)或N;当Q为C(R 3a),C(R 3a)中的碳为手性碳原子时,为R构型、S构型或其混合物;T独立地为C(R 3b)或N;Y独立地为C(R 3c)或N;Z独立地为C(R 3d)或N;R 3a、R 3b、R 3c、R 3d独立地为H、卤素、CN、OH、NH 2、C 1-6烷基、被一个或多个R a4取代的C 1- 6烷基或C 1-6烷氧基;A 1独立地为C(R 4a)、C(R 4bR 4c)或C(=O);R 4a、R 4b、R 4c独立地为H、C 1-6烷基或被一个或多个R a1取代的C 1-6烷基;当取代基为多个时,相同或不同;当B独立地为C(R 6a)、C(R 6bR 6c)时,A 2独立地为C(R 5a)、C(R 5bR 5c)、O、S、N(R 5d)、N或连接键;当B独立地为O、S、S(=O)、S(=O) 2、N、N(R 6d)时,A 2独立地为C(R 5a)、C(R 5bR 5c)、连接键;R 5a、R 5b、R 5c、R 5d独立地为H、C 1-6烷基、被一个或多个R a2取代的C 1-6烷基,或R 5b和R 5c为=O;R 6a、R 6b、R 6c独立地为H、卤素、C 1-6烷基、被一个或多个R a3取代的C 1-6烷基、C 3-6环烷基、OH,或R 6b和R 6c为=O;R 6d独立地为H、C 1-6烷基、被一个或多个R a3取代的C 1-6烷基、C 3-6环烷基或-CN;当取代基为 多个时,相同或不同;R a1、R a2、R a3、R a4独立地为氘、卤素或OH;R 7和R 8独立地为H、C1-6烷基或被OR 7a取代的C 1-6烷基;R 7a选自H、C 1-6烷基和C 1-6卤代烷基;
- 如权利要求1所述的如式IA所示的三并杂环类化合物或其药学上可接受的盐,其特征在于,所述的如式IA所示的三并杂环类化合物如式I’所示,R 1、R 1’、R 3、R 3’、R 5、R 5’独立地为H、C 1-6烷基或被一个或多个R 1a取代的C 1-6烷基;或,R 1和R 1’、R 3和R 3’、R 5和R 5’独立地为O=;当取代基为多个时,相同或不同;R 1a独立地为卤素、CN、OH;R 2、R 4独立地为卤素、CN、C 1-6烷基、被一个或多个R 2a取代的C 1-6烷基、被一个或多个R 2b取代的C 1-6烷基-S-;当取代基为多个时,相同或不同;R 2a、R 2b独立地为卤素;X独立地为C(R 3a)、C或N;Q独立地为C(R 3a)或N;当Q为C(R 3a),C(R 3a)中的碳为手性碳原子时,为R构型、S构型或其混合物;T独立地为C(R 3b)或N;Y独立地为C(R 3c)或N;Z独立地为C(R 3d)或N;R 3a、R 3b、R 3c、R 3d独立地为H、卤素、CN、NH 2、C 1-6烷基、被一个或多个R a4取代的C 1-6烷基或C 1-6烷氧基;A 1独立地为C(R 4a)、C(R 4bR 4c)或C(=O);R 4a、R 4b、R 4c独立地为H、C 1-6烷基或被一个或多个R a1取代的C 1-6烷基;当取代基为多个时,相同或不同;当B独立地为C(R 6a)、C(R 6bR 6c)时,A 2独立地为C(R 5a)、C(R 5bR 5c)、O、S、N(R 5d)、N或连接键;当B独立地为O、S、S(=O)、S(=O) 2、N、N(R 6d)时,A 2独立地为C(R 5a)、C(R 5bR 5c)、连接键;R 5a、R 5b、R 5c、R 5d独立地为H、C 1-6烷基、被一个或多个R a2取代的C 1-6烷基,或R 5b和R 5c为=O;R 6a、R 6b、R 6c独立地为H、卤素、C 1-6烷基、被一个或多个R a3取代的C 1-6烷基、C 3-6环烷基、OH,或R 6b和R 6c为=O;R 6d独立地为H、C 1-6烷基、被一个或多个R a3取代的C 1-6烷基、C 3-6环烷基或-CN;当取代基为多个时,相同或不同;R a1、R a2、R a3、R a4独立地为氘、卤素或OH;
- 如权利要求1或2所述的如式IA所示的三并杂环类化合物或其药学上可接受的盐,其特征在于,如式IA所示的三并杂环类化合物为如式I所示的三并杂环类化合物;其中,R 1、R 1’、R 3、R 3’、R 5、R 5’独立地为H、C 1-6烷基或被一个或多个R 1a取代的C 1-6烷基;或,R 1和R 1’、R 3和R 3’、R 5和R 5’独立地为O=;当取代基为多个时,相同或不同;R 1a独立地为卤素、CN、OH;R 2、R 4独立地为卤素、CN、C 1-6烷基、被一个或多个R 2a取代的C 1-6烷基、被一个或多个R 2b取代的C 1-6烷基-S-;当取代基为多个时,相同或不同;R 2a、R 2b独立地为卤素;X独立地为C(R 3a)、C或N;T独立地为C(R 3b)或N;Y独立地为C(R 3c)或N;Z独立地为C(R 3d)或N;R 3a、R 3b、R 3c、R 3d独立地为H、卤素、CN、NH 2或C 1-6烷基;A 1独立地为C(R 4a)、C(R 4bR 4c)或C(=O);R 4a、R 4b、R 4c独立地为H、C 1-6烷基或被一个或多个R a1取代的C 1-6烷基;当取代基为多个时,相同或不同;当B独立地为C(R 6a)、C(R 6bR 6c)时,A 2独立地为C(R 5a)、C(R 5bR 5c)、O、S、N(R 5d)、N或连接键;当B独立地为O、S、N或N(R 6d)时,A 2独立地为C(R 5a)、C(R 5bR 5c)或连接键;R 5a、R 5b、R 5c、R 5d独立地为H、C 1-6烷基或被一个或多个R a2取代的C 1-6烷基;R 6a、R 6b、R 6c独立地为H、卤素、C 1-6烷基、被一个或多个R a3取代的C 1-6烷基、C 3-6环烷基;R 6d独立地为H、C 1-6烷基、被一个或多个R a3取代的C 1-6烷基、C 3-6环烷基;当取代基为多个时,相同或不同;R a1、R a2、R a3独立地为氘、卤素;
- 如权利要求1或2所述的如式IA所示的三并杂环类化合物或其药学上可接受的盐,其特征在于,R 1、R 1’中的一个为H,另一个为H、C 1-6烷基或被一个或多个R 1a取代的C 1-6烷基;或,R 1和R 1’一起形成O=;例如R 1、R 1’中的一个为H,另一个为H或C 1-6烷基;和/或,R 3、R 3’中的一个为H,另一个为H、C 1-6烷基或被一个或多个R 1a取代的C 1-6烷基;或,R 3和R 3’一起形成O=;例如R 3、R 3’中的一个为H,另一个为H或C 1-6烷基;和/或,R 5、R 5’中的一个为H,另一个为H、C 1-6烷基或被一个或多个R 1a取代的C 1-6烷基;或,R 5和R 5’一起形成O=;例如R 5、R 5’中的一个为H,另一个为H或C 1-6烷基;和/或,当R 1、R 1’所连接的碳为手性碳时,其为S构型或R构型;例如R构型;和/或,当R 3、R 3’所连接的碳为手性碳时,其为S构型或R构型;和/或,当R 5、R 5’所连接的碳为手性碳时,其为S构型或R构型;和/或,R 2独立地为卤素、CN、被一个或多个R 2a取代的C 1-6烷基、被一个或多个R 2b取代的C 1- 6烷基-S-;例如卤素、被一个或多个R 2a取代的C 1-6烷基;和/或,R 4独立地为卤素、CN、被一个或多个R 2a取代的C 1-6烷基;例如卤素、被一个或多个R 2a取代的C 1-6烷基;和/或,X独立地为N;和/或,T独立地为N;和/或,R 3c为H、CN、NH 2或C 1-6烷基;例如H;和/或,Y独立地为C(R 3c)或N;和/或,R 3d为H、卤素、CN或C 1-6烷基;例如H;和/或,Z独立地为C(R 3d)或N;和/或,R 4a、R 4b、R 4c独立地为H或C 1-6烷基;例如R 4b和R 4c中的一个为H、另一个为H或C 1- 6烷基;和/或,当A 1为C(R 4bR 4c)、所述的碳为手性碳时,其构型为S构型、R构型或其混合物;和/或,A 1独立地为C(R 4bR 4c)或C(=O);例如C(R 4bR 4c);和/或,R 5a、R 5b、R 5c、R 5d独立地为H或C 1-6烷基;例如R 5b和R 5c中的一个为H、另一个为H或C 1-6烷基;和/或,当A 2为C(R 5bR 5c)、所述的碳为手性碳时,其构型为S构型、R构型或其混合物;和/或,A 2独立地为C(R 5bR 5c)或连接键;和/或,R 6a、R 6b、R 6c独立地为H或卤素;例如R 6b、R 6c独立地为H;和/或,R 6d独立地为H、C 1-6烷基、被一个或多个R a3取代的C 1-6烷基、C 3-6环烷基;例如H或C 1- 6烷基和/或,B独立地为C(R 6bR 6c)、O、S或N(R 6d);例如-O-、-S-或N(R 6d);和/或, 独立地为-C(R 4bR 4c)-O-、-C(R 4bR 4c)-S-、-C(R 4bR 4c)-N(R 6d)-、-C(R 4bR 4c)-C(R 6bR 6c)-、 -C(=O)-O-、-C(=O)-N(R 6d)-;例如-C(R 4bR 4c)-O-、-C(R 4bR 4c)-S-、-C(R 4bR 4c)-N(R 6d)-、-C(=O)-N(R 6d)-;和/或, 独立地为-O-、-S-、-C(R 6bR 6c)-、-N(R 6d)-、-O-C(R 5bR 5c)-、-S-C(R 5bR 5c)-、-N(R 6d)-C(R 5bR 5c)-、-C(R 6bR 6c)-O-、-C(R 6bR 6c)-S-、-C(R 6bR 6c)-N(R 5d)-;例如-O-、-O-C(R 5bR 5c)-、-S-C(R 5bR 5c)-、-N(R 6d)-、-N(R 6d)-C(R 5bR 5c)-;
- 如权利要求1或2所述的如式IA所示的三并杂环类化合物或其药学上可接受的盐,其特征在于,和/或,当B独立地为O、S、N(R 6d)时,A 2独立地为C(R 5bR 5c)或连接键;和/或,当B独立地为C(R 6bR 6c)时,A 2独立地为O、N(R 5d)或连接键;和/或,当B独立地为N(R 6d),R 6d独立地为C 1-6烷基、被一个或多个R a3取代的C 1-6烷基时,A 1独立地为C(=O);和/或,当T和Z同时为N时,A 2独立地为O、N(R 5d)或C(R 5bR 5c);和/或, 独立地为-C(R 4bR 4c)-O-、-C(R 4bR 4c)-S-、-C(R 4bR 4c)-N(R 6d)-、-C(R 4bR 4c)-C(R 6bR 6c)-、-C(=O)-O-、-C(=O)-N(R 6d)-、-C(R 4bR 4c)-S(=O)-、-C(R 4bR 4c)-S(=O) 2、-C(R 4a)=C(R 6a)-;和/或, 独立地为-O-、-S-、-C(R 6bR 6c)-、-N(R 6d)-、-O-C(R 5bR 5c)-、-S-C(R 5bR 5c)-、-N(R 6d)-C(R 5bR 5c)-、-C(R 6bR 6c)-O-、-C(R 6bR 6c)-S-、-C(R 6bR 6c)-N(R 5d)-、-S(=O)-C(R 5bR 5c)-、-S(=O) 2-C(R 5bR 5c)-、-O-C(R 6bR 6c)-、=C(R 6a)-;和/或,当R 3a、R 3b、R 3c、R 3d独立地为C 1-6烷基或被一个或多个R a4取代的C 1-6烷基时,所述的C 1-6烷基和被一个或多个R a4取代的C 1-6烷基中的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;例如甲基;和/或,当R 3a、R 3b、R 3c、R 3d独立地为C 1-6烷氧基时,所述的C 1-6烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基;例如甲氧基;和/或,R 7和R 8独立地为C 1-6烷基和C 1-6卤代烷基里的C 1-6烷基中,所述的C 1-6烷基独立地为甲基、乙基、正丙基或异丙基;例如甲基;和/或,R 7a选自C 1-6烷基和C 1-6卤代烷基里的C 1-6烷基中,所述的C 1-6烷基独立地为甲基、乙基、正丙基或异丙基;和/或,R 7a选自C 1-6卤代烷基里的卤独立地为F、Cl、Br或I,例如F;和/或,当R 8所连接的碳为手性碳时,其为S构型或R构型;例如R构型;和/或,R 7和R 8独立地为H或C 1-3烷基;例如R 7和R 8中的一个为H,另一个为甲基。
- 如权利要求1或2所述的如式IA所示的三并杂环类化合物或其药学上可接受的盐,其特征在于,R 1、R 1’、R 3、R 3’、R 5、R 5’中的一个为H、C 1-6烷基或被一个或多个R 1a取代的C 1-6烷基,其余为H;例如R 1、R 1’、R 3、R 3’、R 5、R 5’为H;和/或,当R 1、R 1’、R 3、R 3’、R 5、R 5’独立地为C 1-6烷基或被一个或多个R 1a取代的C 1-6烷基时,所述的C 1-6烷基或被一个或多个R 1a取代的C 1-6烷基里的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;例如甲基;和/或,当R 1a为卤素时,所述的卤素为F、Cl、Br、I;例如F;和/或,当R 2、R 4独立地为卤素时,所述的卤素为F、Cl、Br、I;例如F;和/或,当R 2、R 4独立地为C 1-6烷基、被一个或多个R 2a取代的C 1-6烷基、被一个或多个R 2b取代的C 1-6烷基-S-时,所述的C 1-6烷基、被一个或多个R 2a取代的C 1-6烷基和被一个或多个R 2b取代的C 1- 6烷基-S-里的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;例如甲基;和/或,当R 2、R 4独立地为被一个或多个R 2a取代的C 1-6烷基、被一个或多个R 2b取代的C 1-6烷基-S-时,所述的取代基的个数为1、2、3;和/或,当R 2a、R 2b独立地为卤素时,所述的卤素为F、Cl、Br、I;例如F;和/或,当R 3a、R 3b、R 3c、R 3d独立地为卤素时,所述的卤素为F、Cl、Br、I;例如F;和/或,当R 3a、R 3b、R 3c、R 3d独立地为C 1-6烷基时,所述的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;例如甲基;和/或,当R 4a、R 4b、R 4c独立地为C 1-6烷基或被一个或多个R a1取代的C 1-6烷基时,所述的C 1-6烷基和被一个或多个R a1取代的C 1-6烷基里的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;例如甲基;和/或,当R 5a、R 5b、R 5c、R 5d独立地为C 1-6烷基或被一个或多个R a2取代的C 1-6烷基时,所述的C 1-6烷基和被一个或多个R a2取代的C 1-6烷基里的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;例如甲基;和/或,当R 6a、R 6b、R 6c独立地为卤素时,所述的卤素为F、Cl、Br、I;例如F;和/或,当R 6a、R 6b、R 6c、R 6d独立地为C 1-6烷基、被一个或多个R a3取代的C 1-6烷基时,所述的C 1-6烷基和被一个或多个R a3取代的C 1-6烷基里的C 1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;例如甲基或乙基;和/或,当R 6a、R 6b、R 6c、R 6d独立地为C 3-6环烷基时,所述的C 3-6环烷基为环丙基、环丁基、环戊基、环己基;例如环丙基;和/或,当R a1、R a2、R a3独立地为卤素时,所述的卤素为F、Cl、Br、I;例如F。
- 如权利要求1或2所述的如式IA所示的三并杂环类化合物或其药学上可接受的盐,其特征在于,T独立地为N、CH;Q独立地为N或CH;和/或,Y独立地为CH、N、C(CN)、C(NH 2)、C(CHF 2)、C(OMe);和/或,Z独立地为CH、N、C(CN)、C(NH 2)、C(CHF 2)、C(CH 3);和/或,A 1独立地为CH 2、C(CH 3)、C(=O)、CH;和/或,B独立地为CH 2、CF 2、O、S、NH、N(CH 3)、N(CD 3)、N(环丙基)、N(CH 2CF 3)、C(CH 3)、C(=O)、N(CN)、S(=O)、S(=O) 2、CH(OH)、N(CH 2CH 3)、N(CH 2CH 2OH)、CH;和/或,A 2独立地为CH 2、O、S、NH、N(CH 3)、N(环丙基)、CH(CH 3)、连接键、C(=O);
- 如权利要求1或2所述的如式IA所示的三并杂环类化合物或其药学上可接受的盐,其特征在于,R 1、R 1’、R 3、R 3’、R 5、R 5’独立地为H、甲基、HO-甲基、NC-甲基、CHF 2、CF 3;或者,R 1和R 1’、R 3和R 3’、R 5和R 5’独立地为O=;和/或,R 2、R 4独立地为氟、溴、氯、CN、CF 3、CF 3-S-;和/或,Y独立地为CH、N、C(CN)、C(NH 2);和/或,Z独立地为CH、N、C(CN)、C(NH 2);和/或,A 1独立地为CH 2、C(CH 3)或C(=O);和/或,B独立地为CH 2、CF 2、O、S、NH、N(CH 3)、N(CD 3)、N(环丙基)、N(CH 2CF 3)、C(CH 3)或C(=O);和/或,A 2独立地为CH 2、O、S、NH、N(CH 3)、N(环丙基)、CH(CH 3)或连接键;
- 如权利要求1或2所述的如式IA所示的三并杂环类化合物或其药学上可接受的盐,其特征在于,所述的如式IA所示的三并杂环类化合物为如下任一方案:方案1、R 1、R 1’独立地为H或C 1-6烷基;R 3、R 3’、R 5、R 5’独立地为H;R 2、R 4独立地为被一个或多个卤素取代的C 1-6烷基;X、T独立地为N;Y独立地为C(R 3c);Z独立地为C(R 3d)或N;A 1独立地为C(R 4bR 4c)或C(=O);B独立地为O、S、N或N(R 6d),A 2独立地为C(R 5bR 5c)或连接键;方案2、R 1、R 1’独立地为H或甲基;R 3、R 3’、R 5、R 5’独立地为H;R 2、R 4独立地为CF 3;X、T独立地为N;Y独立地为CH;Z独立地为CH或N;A 1独立地为CH 2或C(=O);B独立地为O、S、N或NH,A 2独立地为CH 2或连接键;方案3、R 1、R 1’、R 3、R 3’、R 5、R 5’独立地为H;R 2、R 4独立地为被一个或多个卤素取代的C 1-6烷基;X、T独立地为N;Y独立地为C(R 3c);Z独立地为C(R 3d);A 1独立地为C(R 4bR 4c);B独立地为O或S;A 2独立地为C(R 5bR 5c)或连接键;方案4、R 1、R 1’、R 3、R 3’、R 5、R 5’独立地为H;R 2、R 4独立地为CF 3;X、T独立地为N;Y、Z独立地为CH;A 1独立地为CH 2;B独立地为O或S;A 2独立地为CH 2或连接键;方案5、R 1、R 1’独立地为H,或R 1和R 1’为O=;R 3、R 3’独立地为H、C 1-6烷基,或R 3和R 3’为O=;R 5、R 5’独立地为H;R 2、R 4独立地为卤素、CN、被一个或多个卤素取代的C 1-6烷基;X为N;T为C(R 3b)或N;R 3b为H;Y为C(R 3c);R 3c为H、被一个或多个R a4取代的C 1-6烷基或C 1-6烷氧基;Z为C(R 3d);R 3d为H、C 1-6烷基或被一个或多个R a4取代的C 1-6烷基;A 1独立地为C(R 4a)、C(R 4bR 4c)或C(=O);R 4a、R 4b、R 4c独立地为H或C 1-6烷基;当B独立地为O、S(=O)、S(=O) 2、N(R 6d)时,A 2独立地为C(R 5a)、C(R 5bR 5c)、连接键;当B独立地为C(R 6a)、C(R 6bR 6c)时,A 2独立地为N(R 5d)、连接键;R 5b、R 5c独立地为H,或R 5b和R 5c为=O;R 5d为C 1-6烷基;R 6d为C 1-6烷基、被一个或多个R a3取代的C 1-6烷基、C 3-6环烷基、CN;R 6a为H;R 6b、R 6c独立地为H、-OH,或R 6b和R 6c为=O;R a3为卤素或-OH;方案6、R 1、R 1’独立地为H或C 1-6烷基;R 3、R 3’、R 5、R 5’独立地为H;R 2为CN、被一个或多个卤素取代的C 1-6烷基;R 4为被一个或多个卤素取代的C 1-6烷基;X为N;T为C(R 3b)或N;R 3b为H;Y独立地为C(R 3c);R 3c为H或C 1-6烷基;Z独立地为C(R 3d)或N;R 3d为H、CN或C 1-6烷基;A 1独立地为C(R 4bR 4c)或C(=O);R 4b、R 4c独立地为H;当B独立地为O、S、S(=O)、S(=O) 2、N(R 6d)时,A 2独立地为C(R 5bR 5c)或连接键;当B独立地为C(R 6bR 6c)时,A 2独立地为O、N(R 5d)或连接键;R 5b、R 5c独立地为H、C 1-6烷基、或R 5b和R 5c为=O;R 6d为H、C 1-6烷基、被一个或多个R a3取代的C 1-6烷基、C 3-6环烷基、CN;R 5d为H、C 1-6烷基;R 6b、R 6c独立地为H、-OH,或R 6b和R 6c为=O;R a3为氘或-OH;方案7、R 1、R 1’独立地为H或C 1-6烷基;R 3、R 3’、R 5、R 5’独立地为H;R 2为CN、被一个或多个卤素取代的C 1-6烷基;R 4为被一个或多个卤素取代的C 1-6烷基;X、T独立地为N;Y独立地为C(R 3c);R 3c为H;Z独立地为C(R 3d)或N;R 3d为H;A 1独立地为C(R 4bR 4c)或C(=O);R 4b、R 4c独立地为H;当B独立地为O、S、N(R 6d)时,A 2独立地为C(R 5bR 5c)或连接键;当B独立地为C(R 6bR 6c)时,A 2独立地为O、N(R 5d)或连接键;当A 1为C(=O),B为N(R 6d)时,A 2为连接键;R 5b、R 5c独立地为H;R 6d为H、C 1-6烷基、被一个或多个R a3取代的C 1-6烷基、C 3-6环烷基;R 6b、R 6c独立地为H、-OH,或R 6b和R 6c为=O;R 5d为H、C 1-6烷基;R a3为氘;方案8、R 1、R 1’、R 3、R 3’、R 5、R 5’独立地为H;R 2、R 4独立地为被一个或多个卤素取代的C 1-6烷基;X、T独立地为N;Y独立地为C(R 3c);R 3c为H;Z独立地为C(R 3d)或N;R 3d为H;A 1独立地为C(R 4bR 4c)或C(=O);R 4b、R 4c独立地为H;当B独立地为O、S、N(R 6d)时,A 2独立地为C(R 5bR 5c)或连接键;当B独立地为C(R 6bR 6c)时,A 2独立地为O、N(R 5d)或连接键;当B独立地为N(R 6d)时,A 1独立地为C(=O);当A 1为C(=O),B为N(R 6d)时,A 2为连接键;当T和Z同时为N时,A 2独立地为O、N(R 5d)或C(R 5bR 5c);R 5b、R 5c独立地为H;R 6d独立地为C 1-6烷基、被一个或多个R a3取代的C 1-6烷基;R 6b、R 6c独立地为H;R 5d为H;R a3为氘;
- 一种如权利要求1-11中任一项所述的如式IA所示的三并杂环类化合物的制备方法,其特征在于,其包括如下步骤:在溶剂中,在碱和缩合剂存在下,将如式IIA所示的化合物与如式IIIA所示的化合物进行如下所示的酰胺化反应,得到如式IA所示的三并杂环类化合物即可;其中,较佳地,所述的溶剂为DMF、二氯甲烷;和/或,所述的碱为二异丙基乙胺或K 2CO 3;和/或,所述的碱与所述的如式II所示的化合物的摩尔比为1∶1;和/或,所述的缩合剂为丙基磷酸酐;和/或,所述的缩合剂以50%的乙酸乙酯溶液使用;和/或,所述的缩合剂与所述的如式II所示的化合物的摩尔比为1∶1;和/或,所述的如式II所示的化合物与所述的如式III所示的化合物的摩尔比为1∶1;和/或,所述的酰胺化反应在氮气保护下进行;和/或,所述的酰胺化反应的温度为0℃至60℃。
- 一种药物组合物,其包含如权利要求1-11中任一项所述的式IA所示的三并杂环类化合物或其药学上可接受的盐,和,药用辅料。
- 一种如权利要求1-11中任一项所述的如式IA所示的三并杂环类化合物或其药学上可接受的盐在制备PARP抑制剂中的应用;所述的PARP可为PARP7。
- 一种如权利要求1-11中任一项所述的如式IA所示的三并杂环类化合物或其药学上可接受的盐在制备药物中的应用;所述的药物用于预防和/或治疗与PARP有关的或PARP介导的疾病;所述的PARP可为PARP7;和/或,所述的与PARP有关的或PARP介导的疾病可包括异常增殖性疾病;所述的异常增殖性疾病包括但不限于癌症,所述的癌症例如肺癌、结肠癌、大肠癌、胰腺癌、肾癌、胃癌、食道癌,卵巢癌,乳房癌、宫颈癌、头颈癌、膀胱癌、黑色素瘤、纤维肉瘤、胶质母细胞瘤。
- 一种如权利要求1-11中任一项所述的如式IA所示的三并杂环类化合物或其药学上可接受的盐在制备药物中的应用;所述的药物用于预防和/或治疗异常增殖性疾病;所述的异常增殖性疾病包括但不限于癌症,所述的癌症例如肺癌、结肠癌、大肠癌、胰腺癌、肾癌、胃癌、食道癌,卵巢癌,乳房癌、宫颈癌、头颈癌、膀胱癌、黑色素瘤、纤维肉瘤、胶质母细胞瘤。
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