CN110013483B - Antibacterial use of thiazolo[3,2-a]pyrimidine-6-carbonitrile derivatives - Google Patents
Antibacterial use of thiazolo[3,2-a]pyrimidine-6-carbonitrile derivatives Download PDFInfo
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- CN110013483B CN110013483B CN201910392457.4A CN201910392457A CN110013483B CN 110013483 B CN110013483 B CN 110013483B CN 201910392457 A CN201910392457 A CN 201910392457A CN 110013483 B CN110013483 B CN 110013483B
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- Prior art keywords
- thiazolo
- pyrimidine
- amino
- carbonitrile
- nmr
- Prior art date
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- 230000000844 anti-bacterial effect Effects 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- -1 hydroxy, amino Chemical group 0.000 claims description 100
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 241000191967 Staphylococcus aureus Species 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 229960003085 meticillin Drugs 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- 230000003385 bacteriostatic effect Effects 0.000 abstract description 3
- 230000003115 biocidal effect Effects 0.000 abstract 1
- ZIEWSZYVEDTXGH-UHFFFAOYSA-N pyrimidine-4-carbonitrile Chemical class N#CC1=CC=NC=N1 ZIEWSZYVEDTXGH-UHFFFAOYSA-N 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 69
- 238000005481 NMR spectroscopy Methods 0.000 description 40
- 238000002844 melting Methods 0.000 description 23
- 230000008018 melting Effects 0.000 description 23
- 239000007787 solid Substances 0.000 description 23
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 9
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 230000001580 bacterial effect Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 3
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 3
- WZWIQYMTQZCSKI-UHFFFAOYSA-N 4-cyanobenzaldehyde Chemical compound O=CC1=CC=C(C#N)C=C1 WZWIQYMTQZCSKI-UHFFFAOYSA-N 0.000 description 3
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000002547 new drug Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 2
- SRWILAKSARHZPR-UHFFFAOYSA-N 3-chlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1 SRWILAKSARHZPR-UHFFFAOYSA-N 0.000 description 2
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000002608 ionic liquid Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- SUISZCALMBHJQX-UHFFFAOYSA-N 3-bromobenzaldehyde Chemical compound BrC1=CC=CC(C=O)=C1 SUISZCALMBHJQX-UHFFFAOYSA-N 0.000 description 1
- FMKMKBLHMONXJM-UHFFFAOYSA-N 5-methyl-2-phenylpyrazol-3-amine Chemical compound N1=C(C)C=C(N)N1C1=CC=CC=C1 FMKMKBLHMONXJM-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
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- 239000013641 positive control Substances 0.000 description 1
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- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
Description
技术领域technical field
本发明属于医疗领域，具体涉及噻唑并[3,2-a]嘧啶-6-甲腈衍生物用于抗菌的用途。The invention belongs to the medical field, in particular to the use of thiazolo[3,2-a]pyrimidine-6-carbonitrile derivatives for antibacterial use.
背景技术Background technique
革兰氏阳性细菌感染为常见病和多发病，危害人类健康，近年来革兰氏阳性菌感染日见增多，耐甲氧西林金黄色葡萄球菌(MRSA)检出率上升，耐青霉素肺炎链球菌(PRSP)在许多国家与地区传播，耐糖肽和其他多种抗生素的耐万古霉素肠球菌(VRE)出现，也标志着抗菌药物的最后一道防线被攻破，因此，研究开发治疗革兰氏阳性菌感染的新型药物已成为当务之急。Gram-positive bacterial infection is a common and frequently-occurring disease, endangering human health. In recent years, the number of gram-positive bacterial infections has increased, the detection rate of methicillin-resistant Staphylococcus aureus (MRSA) has increased, and penicillin-resistant Streptococcus pneumoniae (PRSP) has spread in many countries and regions, and the emergence of vancomycin-resistant enterococci (VRE) resistant to glycopeptides and other antibiotics also marks the last line of defense against antibiotics has been broken. Therefore, research and development of treatment for Gram-positive New drugs for bacterial infections have become a top priority.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于提供一种噻唑并[3,2-a]嘧啶-6-甲腈衍生物用于抗菌的用途。The purpose of the present invention is to provide an antibacterial use of a thiazolo[3,2-a]pyrimidine-6-carbonitrile derivative.
本发明提供式I所示的化合物及其药学上可接受的盐在制备治疗抗菌剂的药物中的应用：The present invention provides the application of the compound shown in formula I and its pharmaceutically acceptable salt in the preparation of the medicine for the treatment of antibacterial agent:
其中，R1为卤素，硝基，氰基，被一个或多个卤素、羟基、氨基取代或未被取代的C1-5的烷基，被一个或多个卤素、羟基、氨基取代或未被取代的C1-5的烷氧基；wherein, R 1 is halogen, nitro, cyano, C 1-5 alkyl substituted or unsubstituted by one or more halogen, hydroxy, amino, substituted or unsubstituted by one or more halogen, hydroxy, amino substituted C 1-5 alkoxy;
R2为卤素，氰基，被一个或多个卤素、羟基、氨基取代或未被取代的C1-5的烷基，被一个或多个卤素、羟基、氨基取代或未被取代的C1-5的烷氧基。R 2 is halogen, cyano, C 1-5 alkyl substituted or unsubstituted by one or more halogen, hydroxy, amino, C 1 substituted or unsubstituted by one or more halogen, hydroxy, amino -5 alkoxy.
在上述式I所示化合物中，其中，所述C1-5的烷基选自甲基、乙基、丙基、丁基或戊基；所述C1-5的烷氧基选自甲氧基、乙氧基、丙氧基、丁氧基或戊氧基。In the compound represented by the above formula I, wherein, the C 1-5 alkyl group is selected from methyl, ethyl, propyl, butyl or pentyl; the C 1-5 alkoxy group is selected from methyl oxy, ethoxy, propoxy, butoxy or pentoxy.
在上述式I所示化合物中，其中，所述卤素选自氟、氯、溴或碘。In the compound represented by the above formula I, wherein, the halogen is selected from fluorine, chlorine, bromine or iodine.
在上述式I所示化合物中，其中，所述的R1为甲基，氯，氰基，溴，硝基，甲氧基；R1为甲基，氯，氰基，溴，甲氧基。In the compound represented by the above formula I, wherein, the R 1 is methyl, chlorine, cyano, bromine, nitro, methoxy; R 1 is methyl, chlorine, cyano, bromine, methoxy .
本发明进一步优选的实施例方案中，所述C1-5的烷基选自正丙基(n-Pr、 -CH2CH2CH3)或异丙基((i-Pr、-CH(CH3)2)；所述丁基选自正丁基(n-Bu、 -CH2CH2CH2CH3)，异丁基(i-Bu、-CH2CH(CH3)2)，仲丁基(s-Bu、-CH(CH3)CH2CH3) 或叔丁基(t-Bu、-C(CH3)3)；所述戊基选自正戊基(-CH2CH2CH2CH2CH3)，2-戊基 (-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)， 3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)或2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)。In a further preferred embodiment of the present invention, the C 1-5 alkyl group is selected from n-propyl (n-Pr, -CH 2 CH 2 CH 3 ) or isopropyl ((i-Pr, -CH ( CH 3 ) 2 ); the butyl group is selected from n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH( CH3 ) CH2CH3 ) or tert-butyl (t-Bu, -C( CH3 )3 ) ; the pentyl group is selected from n-pentyl ( -CH2) CH2CH2CH2CH3 ), 2 -pentyl (-CH( CH3 ) CH2CH2CH3 ) , 3 -pentyl (-CH( CH2CH3 ) 2 ) , 2 -methyl- 2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butane group ( -CH2CH2CH ( CH3 ) 2 ) or 2 -methyl-1-butyl (-CH2CH( CH3 ) CH2CH3 ) .
本发明进一步优选的实施例方案中，所述C1-5的烷氧基选自甲氧基(MeO、-OCH3)、乙氧基(EtO、-OCH2CH3)、1-丙氧基(n-PrO、n-丙氧基、-OCH2CH2CH3)、2-丙氧基 (i-PrO、i-丙氧基、-OCH(CH3)2)、1-丁氧基(n-BuO、n-丁氧基、-OCH2CH2CH2CH3)、 2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH2CH(CH3)2)、2-丁氧基(s-BuO、s-丁氧基、-OCH(CH3)CH2CH3)、2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH3)3)、1-戊氧基(n-戊氧基、-OCH2CH2CH2CH2CH3)、2-戊氧基(-OCH(CH3)CH2CH2CH3)、3-戊氧基 (-OCH(CH2CH3)2)、2-甲基-2-丁氧基(-OC(CH3)2CH2CH3)、3-甲基-2-丁氧基 (-OCH(CH3)CH(CH3)2)、3-甲基-l-丁氧基(-OCH2CH2CH(CH3)2)、2-甲基-l-丁氧基 (-OCH2CH(CH3)CH2CH3)。In a further preferred embodiment of the present invention, the C 1-5 alkoxy group is selected from methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy group (n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH (CH 3 ) 2 ), 2-butoxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t- Butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyloxy (-OCH(CH 3 ) CH 2 CH 2 CH 3 ), 3-pentyloxy (-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy (-OC(CH 3 ) 2 CH 2 CH 3 ), 3 -Methyl-2-butoxy (-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2- Methyl-l-butoxy ( -OCH2CH ( CH3 ) CH2CH3 ) .
本发明更优选的实施例方案中，所述C1-5的烷基优选自C1-3的烷基，所述C1-3的烷基选自甲基、乙基、正丙基(n-Pr、-CH2CH2CH3)或异丙基((i-Pr、-CH(CH3)2)。In a more preferred embodiment of the present invention, the C 1-5 alkyl group is preferably a C 1-3 alkyl group, and the C 1-3 alkyl group is selected from methyl, ethyl, n-propyl ( n-Pr, -CH2CH2CH3 ) or isopropyl ((i-Pr, -CH( CH3 ) 2 ) .
本发明更优选的实施例方案中，所述C1-5的烷氧基优选自C1-3的烷氧基，所述 C1-3的烷氧基选自甲氧基(MeO、-OCH3)、乙氧基(EtO、-OCH2CH3)、1-丙氧基(n-PrO、 n-丙氧基、-OCH2CH2CH3)或2-丙氧基(i-PrO、i-丙氧基、-OCH(CH3)2)。In a more preferred embodiment of the present invention, the C 1-5 alkoxy group is preferably a C 1-3 alkoxy group, and the C 1-3 alkoxy group is selected from a methoxy group (MeO, - OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ) or 2-propoxy (i- PrO, i-propoxy, -OCH( CH3 ) 2 ).
本发明优选的其他实施例方案中，所述式I所示的化合物的示例化合物如下所示：In other preferred embodiments of the present invention, exemplary compounds of the compound represented by the formula I are as follows:
本发明进一步提供式I所示的化合物、对映异构体的可药用的盐，所述可药用的盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐、酒石酸盐、马来酸盐、富马酸盐、甲磺酸盐、葡糖酸盐、糖二酸盐、苯甲酸盐、乙磺酸盐、苯磺酸盐或对甲苯磺酸盐。The present invention further provides pharmaceutically acceptable salts of compounds represented by formula I and enantiomers, the pharmaceutically acceptable salts are selected from hydrochloride, hydrobromide, hydroiodide, nitrate, sulfuric acid Salt, Bisulfate, Phosphate, Acid Phosphate, Acetate, Lactate, Citrate, Tartrate, Maleate, Fumarate, Mesylate, Gluconate, Sugar Diacid salts, benzoates, ethanesulfonates, benzenesulfonates or p-toluenesulfonates.
另外，本发明提供一种药物组合物包含治疗有效量的，如权利要求1-中任一项所述的式I所示的化合物、对映异构体或其可药用的盐和医学上可接受的载体。In addition, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula I as claimed in any one of claims 1-, an enantiomer or a pharmaceutically acceptable salt thereof and a medicinal acceptable carrier.
本发明优选的实施例方案中，药物组合物可以利用一种或多种可药用的载体按照常规的方式加以配制。因此，本发明的活性化合物可以被配制成口服、口腔含化给药、鼻内、肠胃外(例如静脉内、肌内或皮下)或直肠给药的剂型，或者适用于通过吸入或吹入给药的剂型。本发明的化合物也可以被配制成持续释放的剂型。In a preferred embodiment of the present invention, the pharmaceutical composition may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present invention may be formulated for oral, buccal, intranasal, parenteral (eg intravenous, intramuscular or subcutaneous) or rectal administration, or suitable for administration by inhalation or insufflation The dosage form of the medicine. The compounds of the present invention may also be formulated in sustained release dosage forms.
本发明优选的实施例方案中，有效剂量的本发明化合物可与如惰性稀释剂或某种载体一起口服。根据本发明的一些实施例，可将本发明的化合物包裹于明胶胶囊中或压制成片。为口服治疗的目的，本发明化合物可与赋形剂一起使用并以片剂、锭剂、胶囊、混悬剂、糖浆剂等形式使用。根据本发明的实施例，上述制剂应含有至少0.5％(w/w)的本发明的活性化合物，但可根据特定的剂型变化，其中占单位重量的4％至约70％是便利的。在这样的药物组合物中活性化合物的量应达到适当的剂量。In a preferred embodiment of the present invention, an effective dose of a compound of the present invention may be administered orally together with, for example, an inert diluent or some kind of carrier. According to some embodiments of the present invention, the compounds of the present invention may be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapy, the compounds of the present invention can be used with excipients and in the form of tablets, troches, capsules, suspensions, syrups and the like. According to embodiments of the invention, the above formulations should contain at least 0.5% (w/w) of the active compound of the invention, but may vary depending on the particular dosage form, where from 4% to about 70% by weight per unit is convenient. The amount of active compound in such pharmaceutical compositions should result in an appropriate dosage.
本发明提供的式I所示的化合物、对映异构体或其可药用的盐或所述的药物组合物在制备治疗抗菌药物中的用途。The compounds, enantiomers or pharmaceutically acceptable salts thereof or the pharmaceutical compositions provided by the present invention represented by formula I are used in the preparation of therapeutic antibacterial drugs.
另一方面，本发明提供一种制备式I所示的化合物、对映异构体或其可药用的盐的制备方法，该方法包括：将α-溴代苯乙酮与硫脲、丙二腈、芳香醛、催化剂2a和乙醇加入反应容器中，在80℃下充分反应至完全，制备式I化合物；反应式如下：On the other hand, the present invention provides a preparation method for preparing the compound shown in formula I, an enantiomer or a pharmaceutically acceptable salt thereof, the method comprising: combining α-bromoacetophenone with thiourea, propylene Dinitrile, aromatic aldehyde, catalyst 2a and ethanol are added to the reaction vessel, and fully reacted to completeness at 80 ° C to prepare the compound of formula I; the reaction formula is as follows:
本发明有益的技术效果Beneficial technical effects of the present invention
本发明提供的化合物对耐甲氧西林金黄色葡萄球菌有抑菌作用，且该化合物对五种细胞株均有抑制作用，其中22对耐甲氧西林金黄色葡萄球菌有很好的抑制作用，尤其是对18H6、18I1具有非常好的抑制效果，其MIC均在5μg/mL，若继续研究其抑菌机制，有望将其发展为耐甲氧西林金黄色葡萄球菌的新药物。The compound provided by the invention has bacteriostatic effect on methicillin-resistant Staphylococcus aureus, and the compound has inhibitory effect on five cell strains, among which 22 has a good inhibitory effect on methicillin-resistant Staphylococcus aureus, In particular, it has a very good inhibitory effect on 18H6 and 18I1, and its MIC is 5μg/mL. If we continue to study its antibacterial mechanism, it is expected to be developed into a new drug for methicillin-resistant Staphylococcus aureus.
实施例Example
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。除非另外指明，本文所指的比例、百分比等均以重量计。Embodiments of the present invention are described in detail below. The embodiments described below are exemplary, only for explaining the present invention, and should not be construed as limiting the present invention. Unless otherwise indicated, ratios, percentages, etc. referred to herein are by weight.
实施例1：5,12-二甲基-3,10-二苯基-二甲基-1H-吡唑并[b，f]的[4,5]-1,5-二氮杂二环[3.3.1]-2,6-辛二烯(1)Example 1: [4,5]-1,5-diazabicyclo of 5,12-dimethyl-3,10-diphenyl-dimethyl-1H-pyrazolo[b,f] [3.3.1]-2,6-Octadiene (1)
干燥的250mL三颈烧瓶中加入吡啶(0.5mol，39.5g)、正丁基溴(0.55mol， 68g)和60mL二氯甲烷，先加热至60℃，沸腾提起，防止爆沸，溶液不沸以后将温度升高至80℃，加热回流5～6小时直至反应完全。然后在该体系中加入四氟硼酸钠(0.5mol，55g)，交换阴离子，80℃温度下加热回流12小时，过滤，用二氯甲烷洗涤，将滤液减压蒸馏，除去溶剂二氯甲烷，即可得到金黄色离子液体[Bpy]BF4。Add pyridine (0.5mol, 39.5g), n-butyl bromide (0.55mol, 68g) and 60mL of dichloromethane to a dry 250mL three-necked flask, first heat to 60°C, and lift up to prevent bumping. After the solution does not boil The temperature was raised to 80 °C and heated to reflux for 5-6 hours until the reaction was complete. Then, sodium tetrafluoroborate (0.5mol, 55g) was added to the system to exchange anions, heated to reflux at 80°C for 12 hours, filtered, washed with dichloromethane, the filtrate was distilled under reduced pressure, and the solvent dichloromethane was removed, that is, Golden yellow ionic liquid [Bpy]BF 4 can be obtained.
25mL圆底烧瓶中加入1mL离子液体[Bpy]BF4、1mmol3-甲基-1-苯基-1H-吡唑 -5-胺、0.5mL甲醛水溶液(30％)和1mL三氟乙酸，室温下搅拌5～7小时，反应结束(TLC跟踪)后加入10mL蒸馏水，将混合物过滤，洗涤，干燥，得到粗产物，称量计算产率后，用无水乙醇重结晶得到纯净的产物2a:白色固体，熔点：266-267℃.1H NMR(400MHz,CDCl3)δ7.95-7.97(d,J＝8.4Hz,4H). 7.49-7.53(m,4H),7.30-7.32(t,J＝8.0Hz,2H),4.24-4.32(t,J＝7.2Hz,4H),3.59(d, J＝15.6Hz,2H),1.97(s,6H).13C NMR(100MHz,CDCl3)δ145.4,145.1,139.4,129.2,125.9,120.8,104.3,68.5,48.1,12.5.HRMS(ESI)m/z[M+H]+计算值 C23H22N6:383.1984；实验值:383.1969.A 25mL round-bottomed flask was charged with 1mL of ionic liquid [Bpy]BF 4 , 1mmol of 3-methyl-1-phenyl-1H-pyrazol-5-amine, 0.5mL of aqueous formaldehyde solution (30%) and 1mL of trifluoroacetic acid, at room temperature Stir for 5 to 7 hours, add 10 mL of distilled water after the completion of the reaction (TLC tracking), filter the mixture, wash, and dry to obtain a crude product, after weighing and calculating the yield, recrystallize with absolute ethanol to obtain pure product 2a: white solid , melting point: 266-267°C. 1 H NMR (400MHz, CDCl 3 )δ7.95-7.97(d, J=8.4Hz, 4H). 7.49-7.53(m, 4H), 7.30-7.32(t, J= 8.0Hz, 2H), 4.24-4.32(t, J=7.2Hz, 4H), 3.59(d, J=15.6Hz, 2H), 1.97(s, 6H). 13 C NMR (100MHz, CDCl 3 )δ145. 4, 145.1, 139.4, 129.2, 125.9, 120.8, 104.3, 68.5, 48.1, 12.5. HRMS(ESI) m/z [M+H] + calculated for C 23 H 22 N 6 : 383.1984; found: 383.1969.
实施例2、5-氨基-3-(4-甲氧基苯基)-7-(对-甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(2)Example 2, 5-amino-3-(4-methoxyphenyl)-7-(p-tolyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (2)
反应式(1)Reaction (1)
将4-甲氧基-溴代苯乙酮(1mmol)、硫脲(1.5mmol)、丙二腈(2mmol)、对甲基苯甲醛(1mmol)、催化剂2a(20mmol％)和乙醇(5mL)依次加入50mL圆底烧瓶中，80℃下充分反应至完全(TLC跟踪监测)。冷却至室温，用二氯甲烷萃取，收取有机相，经无水Na2SO4干燥，减压蒸馏，柱层析纯化的产物(V二氯甲烷：V甲醇＝80:1)。得到目标产物5-氨基-3-(4-甲氧基苯基)-7-(对-甲苯基)-7H-噻唑并[3,2-a]嘧啶 -6-甲腈：白色固体,熔点.108.6-109.4℃,1H NMR(400MHz,DMSO)δ7.43–7.30 (m,4H),7.25(d,J＝8.1Hz,4H),6.97(t,J＝12.3Hz,2H),5.64(d,J＝8.0Hz,1H),5.06 (d,J＝8.0Hz,1H),3.74(s,J＝35.8Hz,3H),2.31(s,3H).13C NMR(101MHz,)δ167.39, 159.45,150.22,138.09,135.60,130.30,130.14,127.96,127.58,115.09,114.35, 55.66,44.25,30.74,21.16.HRMS(ESI)m/z:计算值C21H19N4OS[M+H]+:375.1280；实验值:375.7574Combine 4-methoxy-bromoacetophenone (1 mmol), thiourea (1.5 mmol), malononitrile (2 mmol), p-tolualdehyde (1 mmol), catalyst 2a (20 mmol%) and ethanol (5 mL) Sequentially added to a 50 mL round-bottomed flask, and fully reacted to completion at 80° C. (TLC tracking monitoring). Cooled to room temperature, extracted with dichloromethane, collected the organic phase, dried over anhydrous Na 2 SO 4 , distilled under reduced pressure, and purified the product by column chromatography (V dichloromethane :V methanol =80:1). The target product 5-amino-3-(4-methoxyphenyl)-7-(p-tolyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile was obtained: white solid, melting point .108.6-109.4℃, 1H NMR(400MHz,DMSO)δ7.43-7.30(m,4H),7.25(d,J=8.1Hz,4H),6.97(t,J=12.3Hz,2H),5.64 (d, J=8.0Hz, 1H), 5.06 (d, J=8.0Hz, 1H), 3.74 (s, J=35.8Hz, 3H), 2.31 (s, 3H). 13 C NMR (101MHz,)δ167 .39, 159.45, 150.22, 138.09, 135.60, 130.30, 130.14, 127.96, 127.58, 115.09, 114.35, 55.66, 44.25, 30.74, 21.16.HRMS(ESI) m/z: Calculated C 21 H 19 N 4 OS[M +H] + : 375.1280; experimental value: 375.7574
实施例3、5-氨基-7-(4-氯苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(3)Example 3, 5-amino-7-(4-chlorophenyl)-3-(4-methoxyphenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (3)
用4-氯苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-氯苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(3)。Substitute 4-chlorobenzaldehyde for p-methylbenzaldehyde, prepare the target compound 5-amino-7-(4-chlorophenyl)-3-(4-methoxyphenyl)-7H- according to the method of Example 1 Thiazolo[3,2-a]pyrimidine-6-carbonitrile (3).
灰色固体,熔点:103.2-104.5℃,1H NMR(400MHz,DMSO)δ7.51(dd,J＝26.8,8.0Hz,4H),7.33(d,J＝6.2Hz,4H),6.99(d,J＝8.2Hz,2H),5.68(d,J＝7.9Hz,1H),5.17 (d,J＝16.1Hz,1H),3.78(s,3H).13C NMR(101MHz,)δ167.52,159.51,150.71, 137.60,133.48,130.31,130.06,129.62,127.45,114.38,114.18,113.75,113.59, 55.66,43.81,30.69.HRMS(ESI)m/z:计算值C20H15ClN4OS[M+H]+:395.0733；实验值:395.0728.Gray solid, melting point: 103.2-104.5℃, 1 H NMR (400MHz, DMSO) δ7.51(dd, J=26.8, 8.0Hz, 4H), 7.33(d, J=6.2Hz, 4H), 6.99(d, J=8.2Hz, 2H), 5.68 (d, J=7.9Hz, 1H), 5.17 (d, J=16.1Hz, 1H), 3.78 (s, 3H). 13 C NMR(101MHz,)δ167.52,159.51, [ M + H ] + : 395.0733; experimental value: 395.0728.
实施例4、5-氨基-7-(4-氰基苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6- 甲腈(4)Example 4, 5-amino-7-(4-cyanophenyl)-3-(4-methoxyphenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (4 )
用对氰基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-氰基苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(4)Substitute p-cyanobenzaldehyde for p-methylbenzaldehyde, and prepare the target compound 5-amino-7-(4-cyanophenyl)-3-(4-methoxyphenyl)-7H according to the method of Example 1 - Thiazolo[3,2-a]pyrimidine-6-carbonitrile (4)
黄色固体,熔点：112.4-113.2℃,1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.9Hz,2H),7.47(d,J＝7.8Hz,2H),7.23(d,J＝8.2Hz,2H),6.90(d,J＝7.8Hz,2H),5.28(s,2H), 4.89(d,J＝8.2Hz,1H),4.13(d,J＝7.6Hz,1H),3.79(s,3H).13C NMR(101MHz, DMSO)δ167.64,159.52,143.73,133.51,130.30,129.14,127.02,118.82,114.34, 113.76,113.54,113.34,111.58,55.61,55.35,44.08,30.27.HRMS(ESI)m/z:计算值 C21H15N5OS[M+H]+:386.1076；实验值:386.1072Yellow solid, melting point: 112.4-113.2°C, 1 H NMR (400 MHz, CDCl 3 ) δ 7.69 (d, J=7.9 Hz, 2H), 7.47 (d, J=7.8 Hz, 2H), 7.23 (d, J ＝8.2Hz, 2H), 6.90(d, J＝7.8Hz, 2H), 5.28(s, 2H), 4.89(d, J＝8.2Hz, 1H), 4.13(d, J＝7.6Hz, 1H), 3.79(s,3H). 13 C NMR(101MHz, DMSO)δ167.64,159.52,143.73,133.51,130.30,129.14,127.02,118.82,114.34,113.76,113.54,113.54,111.5,8,4.70.4.30,55 (ESI) m/z: calcd for C21H15N5OS [M+H] + : 386.1076 ; found: 386.1072
实施例5、5-氨基-3,7-双(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(5) 用对甲氧基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-3,7-双(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(5)Example 5, 5-amino-3,7-bis(4-methoxyphenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (5) with p-methoxybenzaldehyde Instead of p-methylbenzaldehyde, the target compound 5-amino-3,7-bis(4-methoxyphenyl)-7H-thiazolo[3,2-a]pyrimidine-6- Formonitrile (5)
黄色固体,熔点：99.6-100.5℃,1H NMR(400MHz,CDCl3)δ7.36–7.23(m,4H),6.90(m,J＝6.3Hz,4H),5.48(s,2H),4.80(d,J＝8.0Hz,1H),4.08(d,J＝7.8Hz,1H),3.78(d, J＝10.8Hz,6H).13C NMR(101MHz,DMSO)δ167.23,159.35,149.95,130.37,130.20, 129.27,127.51,115.17,114.83,114.27,113.86,113.71,55.63,55.59,43.80, 30.85.HRMS(ESI)m/z:计算值C21H18N4O2S[M-NH2]-:375.1041；实验值:375.1208Yellow solid, melting point: 99.6-100.5℃, 1 H NMR(400MHz, CDCl3)δ7.36-7.23(m, 4H), 6.90(m, J=6.3Hz, 4H), 5.48(s, 2H), 4.80( d, J=8.0Hz, 1H), 4.08 (d, J=7.8Hz, 1H), 3.78 (d, J=10.8Hz, 6H). 13 C NMR (101MHz, DMSO) δ 167.23, 159.35, 149.95, 130.37, 130.20, 129.27, 127.51, 115.17, 114.83, 114.27, 113.86, 113.71, 55.63, 55.59, 43.80, 30.85.HRMS(ESI)m/z: Calculated C 21 H 18 N 4 O 2 S[M-NH 2 ] - : 375.1041; experimental value: 375.1208
实施例6、5-氨基-7-(4-溴苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(6)Example 6, 5-amino-7-(4-bromophenyl)-3-(4-methoxyphenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (6)
用4-溴苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-溴苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(6)Substitute 4-bromobenzaldehyde for p-methylbenzaldehyde, prepare the target compound 5-amino-7-(4-bromophenyl)-3-(4-methoxyphenyl)-7H- according to the method of Example 1 Thiazolo[3,2-a]pyrimidine-6-carbonitrile (6)
灰色固体,熔点:132.5-133.6℃,1H NMR(400MHz,CDCl3)δ7.50(d,J＝7.9Hz,2H),7.24(d,J＝7.6Hz,2H),7.20(d,J＝7.7Hz,2H),6.89(d,J＝8.0Hz,2H),5.32(s,J＝73.8Hz,2H),4.79(d,J＝7.8Hz,1H),4.08(d,J＝7.8Hz,1H),3.78(s,3H).13C NMR(101MHz,)δ166.41,160.11,151.46,135.77,132.85,130.19,129.30,126.21,115.68,114.37,111.38,111.27,55.47,45.22,30.66.HRMS(ESI)m/z:计算值C20H15BrN4OS [M+H]+:439.0228；实验值:439.0217Gray solid, melting point: 132.5-133.6 ℃, 1 H NMR (400 MHz, CDCl 3 ) δ 7.50 (d, J=7.9 Hz, 2H), 7.24 (d, J=7.6 Hz, 2H), 7.20 (d, J ＝7.7Hz, 2H), 6.89(d, J＝8.0Hz, 2H), 5.32(s, J＝73.8Hz, 2H), 4.79(d, J＝7.8Hz, 1H), 4.08(d, J＝7.8 Hz,1H),3.78(s,3H). 13 C NMR(101MHz,)δ166.41,160.11,151.46,135.77,132.85,130.19,129.30,126.21,115.68,114.37,111.38,111.27,55.4H7,45.622,3RMS (ESI) m/z: calculated for C 20 H 15 BrN 4 OS [M+H] + : 439.0228; found: 439.0217
实施例7、5-氨基-7-(4-氯苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(7)Example 7, 5-amino-7-(4-chlorophenyl)-3-(p-tolyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (7)
用4-甲基-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-氯苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-氯苯基)-3-(对甲苯基)-7H- 噻唑并[3,2-a]嘧啶-6-甲腈(7)Use 4-methyl-bromoacetophenone to replace 4-methoxy-bromoacetophenone, use 4-chlorobenzaldehyde to replace p-methylbenzaldehyde, prepare the target compound 5-amino- 7-(4-Chlorophenyl)-3-(p-tolyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (7)
灰色固体,熔点：114.8-115.6℃,1H NMR(400MHz,CDCl3)δ7.42(d,J＝7.5Hz,2H),7.34(d,J＝7.5Hz,2H),7.26(dd,J＝12.6,8.2Hz,4H),5.49(s,2H),4.89(d,J＝7.5Hz,1H),4.14(d,J＝7.2Hz,1H),2.39(d,J＝15.5Hz,3H).13C NMR(101MHz,)δ166.49, 139.03,135.23,135.20,129.88,129.65,129.03,128.77,116.21,111.36,111.26, 45.08,30.73,21.43.HRMS(ESI)m/z:计算值C20H15ClN4S[M+H]+:379.0784；实验值： 379.0784Gray solid, melting point: 114.8-115.6°C, 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 (d, J=7.5 Hz, 2H), 7.34 (d, J=7.5 Hz, 2H), 7.26 (dd, J ＝12.6, 8.2Hz, 4H), 5.49(s, 2H), 4.89(d, J＝7.5Hz, 1H), 4.14(d, J＝7.2Hz, 1H), 2.39(d, J＝15.5Hz, 3H) ). 13 C NMR(101MHz,)δ166.49, 139.03, 135.23, 135.20, 129.88, 129.65, 129.03, 128.77, 116.21, 111.36, 111.26, 45.08, 30.73, 21.43.HRMS(ESI) m/z: Calculated C 20H15ClN4S [ M + H] + : 379.0784; found: 379.0784
实施例8、5-氨基-7-(4-氰基苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(8)Example 8, 5-amino-7-(4-cyanophenyl)-3-(p-tolyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (8)
用4-甲基-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-氰基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-氰基苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(8)Use 4-methyl-bromoacetophenone to replace 4-methoxy-bromoacetophenone, use 4-cyanobenzaldehyde to replace p-methylbenzaldehyde, prepare the target compound 5-amino according to the method of Example 1 -7-(4-Cyanophenyl)-3-(p-tolyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (8)
黄色固体,熔点：182.3-183.4℃,1H NMR(400MHz,CDCl3)δ7.68(d,J＝7.7Hz,2H),7.46(d,J＝7.4Hz,2H),7.19(s,4H),5.40(s,2H),4.90(d,J＝7.5Hz,1H),4.17(d,J＝7.1Hz,1H),2.34(s,3H).13C NMR(101MHz,)δ167.81,143.84,137.97,133.59, 129.58,129.20,128.98,118.90,113.99,113.62,113.41,111.64,44.10,30.37,21.36. HRMS(ESI)m/z:计算值C21H15N5S[M+H]+:370.1125；实验值：370.1132Yellow solid, melting point: 182.3-183.4°C, 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J=7.7 Hz, 2H), 7.46 (d, J=7.4 Hz, 2H), 7.19 (s, 4H) ), 5.40(s, 2H), 4.90(d, J=7.5Hz, 1H), 4.17(d, J=7.1Hz, 1H), 2.34(s, 3H). 13 C NMR(101MHz,)δ167.81,143.84 ,137.97,133.59, 129.58,129.20,128.98,118.90,113.99,113.62,113.41,111.64,44.10,30.37,21.36. HRMS(ESI)m/z: Calculated C 21 H 15 N 5 S[M+H] + :370.1125; experimental value: 370.1132
实施例9、5-氨基-7-(4-溴苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(9)Example 9, 5-amino-7-(4-bromophenyl)-3-(p-tolyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (9)
用4-甲基-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-溴苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-溴苯基)-3-(对甲苯基)-7H- 噻唑并[3,2-a]嘧啶-6-甲腈(9)Use 4-methyl-bromoacetophenone to replace 4-methoxy-bromoacetophenone, use 4-bromobenzaldehyde to replace p-methylbenzaldehyde, prepare the target compound 5-amino- 7-(4-Bromophenyl)-3-(p-tolyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (9)
灰色固体,熔点：102.5-102.9℃,1H NMR(400MHz,CDCl3)δ7.51(d,J＝7.9Hz,2H),7.20(dd,J＝14.1,9.1Hz,6H),5.21(s,2H),4.81(d,J＝7.6Hz,1H),4.06(d,J＝7.7Hz,1H),2.34(s,3H).13C NMR(101MHz,)δ166.52,151.75,139.02,135.75,132.83, 130.94,129.65,129.30,128.76,123.34,116.08,111.35,111.25,45.15,30.64,21.44. HRMS(ESI)m/z:计算值C20H15BrN4S[M+H]+:423.0279；实验值:423.0257Gray solid, melting point: 102.5-102.9°C, 1 H NMR (400MHz, CDCl 3 )δ7.51(d, J=7.9Hz, 2H), 7.20(dd, J=14.1, 9.1Hz, 6H), 5.21(s , 2H), 4.81(d, J=7.6Hz, 1H), 4.06(d, J=7.7Hz, 1H), 2.34(s, 3H). 13 C NMR(101MHz,)δ166.52,151.75,139.02,135.75, 132.83, 130.94, 129.65, 129.30, 128.76, 123.34, 116.08, 111.35, 111.25, 45.15, 30.64, 21.44. HRMS(ESI) m/z: Calculated C 20 H 15 BrN 4 S[M+H] + :423.0279; Experimental value: 423.0257
实施例10、5-氨基-7-(3-氯苯基)-3-(4-氯苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(10)Example 10, 5-amino-7-(3-chlorophenyl)-3-(4-chlorophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (10)
用4-氯-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用3-氯苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(3-氯苯基)-3-(4-氯苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(10)Use 4-chloro-bromoacetophenone to replace 4-methoxy-bromoacetophenone, use 3-chlorobenzaldehyde to replace p-methylbenzaldehyde, prepare the target compound 5-amino-7 according to the method of embodiment 1 -(3-Chlorophenyl)-3-(4-chlorophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (10)
灰色固体,熔点：113.5-114.1℃,1HNMR(400MHz,CDCl3)δ7.40–7.31(m,6H),7.28(d,J＝8.5Hz,2H),5.34(s,1H),4.75(d,J＝7.7Hz,1H),4.12(d,J＝7.8Hz,1H).HRMS (ESI)m/z:计算值C31H31N6[M+H]+:383.0051；实验值:384.3076.Gray solid, melting point: 113.5-114.1℃, 1 HNMR(400MHz, CDCl 3 )δ7.40-7.31(m, 6H), 7.28(d, J=8.5Hz, 2H), 5.34(s, 1H), 4.75( d, J=7.7Hz, 1H), 4.12 (d, J=7.8Hz, 1H). HRMS (ESI) m/z: calculated value C 31 H 31 N 6 [M+H] + : 383.0051; experimental value: 384.3076.
实施例11、5-氨基-3,7-双(4-氯苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(11)Example 11, 5-amino-3,7-bis(4-chlorophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (11)
用4-氯-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-氯苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-3,7-双(4-氯苯基)-7H-噻唑并[3,2-a] 嘧啶-6-甲腈(11)Use 4-chloro-bromoacetophenone to replace 4-methoxy-bromoacetophenone, use 4-chlorobenzaldehyde to replace p-methylbenzaldehyde, prepare the target compound 5-amino-3 according to the method of embodiment 1 ,7-Bis(4-chlorophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (11)
黄色固体,熔点：92.7-94.2℃,1H NMR(400MHz,CDCl3)δ7.52(d,J＝7.7Hz,2H),7.35 (d,J＝7.4Hz,2H),7.26(d,J＝7.0Hz,2H),7.09(d,J＝8.7Hz,2H),5.20(s,2H),4.75(d, J＝8.2Hz,1H),4.08(d,J＝7.3Hz,1H).13C NMR(101MHz,)δ166.39,135.44,135.14,134.88,132.23,130.24,130.02,129.21,128.94,117.13,111.21,111.05,45.15,30.87,27.00.HRMS(ESI)m/z:计算值C16H11N6O2S[M+H]+:384.3081；实验值:374.3076Yellow solid, melting point: 92.7-94.2℃, 1 H NMR (400MHz, CDCl 3 )δ7.52(d,J=7.7Hz,2H),7.35(d,J=7.4Hz,2H),7.26(d,J ＝7.0Hz, 2H), 7.09(d, J＝8.7Hz, 2H), 5.20(s, 2H), 4.75(d, J＝8.2Hz, 1H), 4.08(d, J＝7.3Hz, 1H). 13 C NMR (101MHz,) δ166.39, 135.44, 135.14, 134.88, 132.23, 130.24, 130.02, 129.21, 128.94, 117.13, 111.21, 111.05, 45.15, 30.87, 27.00.HRMS HRMS (ESI) m/z: Calculated 11 N 6 O 2 S[M+H] + : 384.3081; found: 374.3076
实施例12、5-氨基-7-(4-溴苯基)-3-(4-氯苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(12)Example 12, 5-amino-7-(4-bromophenyl)-3-(4-chlorophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (12)
用4-氯-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-溴苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-溴苯基)-3-(4-氯苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(12)Use 4-chloro-bromoacetophenone to replace 4-methoxy-bromoacetophenone, use 4-bromobenzaldehyde to replace p-methylbenzaldehyde, prepare the target compound 5-amino-7 according to the method of embodiment 1 -(4-Bromophenyl)-3-(4-chlorophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (12)
灰色固体,熔点：121.7-122.1℃,1H NMR(400MHz,CDCl3)δ7.70(d,J＝7.7Hz,2H),7.45(d,J＝7.8Hz,2H),7.37(d,J＝7.6Hz,2H),7.25(d,J＝7.8Hz,2H),5.22(s,2H), 4.84(d,J＝7.7Hz,1H),4.13(d,J＝7.7Hz,1H).13C NMR(101MHz,)δ167.88,149.60, 137.78,133.84,133.19,132.57,130.85,130.36,129.06,127.75,122.17,115.94, 43.58,30.55.HRMS(ESI)m/z:计算值C17H13N6O2S[M+H]+:442.9733；实验值： 442.9725Gray solid, melting point: 121.7-122.1°C, 1 H NMR (400 MHz, CDCl 3 ) δ 7.70 (d, J=7.7 Hz, 2H), 7.45 (d, J=7.8 Hz, 2H), 7.37 (d, J =7.6Hz, 2H), 7.25(d, J=7.8Hz, 2H), 5.22(s, 2H), 4.84(d, J=7.7Hz, 1H), 4.13(d, J=7.7Hz, 1H). 13 C NMR (101MHz,) δ 167.88, 149.60, 137.78, 133.84, 133.19, 132.57, 130.85, 130.36, 129.06, 127.75, 122.17, 115.94, 43.58, 30.55. HRMS H 13 N/z: Calculated C 17 6 O 2 S[M+H] + : 442.9733; found: 442.9725
实施例13、5-氨基-3-(4-氯苯基)-7-(4-氰基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(13)Example 13, 5-amino-3-(4-chlorophenyl)-7-(4-cyanophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (13)
用4-氯-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-氰基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-3-(4-氯苯基)-7-(4-氰基苯基) -7H-噻唑并[3,2-a]嘧啶-6-甲腈(13)Use 4-chloro-bromoacetophenone to replace 4-methoxy-bromoacetophenone, use 4-cyanobenzaldehyde to replace p-methylbenzaldehyde, prepare the target compound 5-amino- 3-(4-Chlorophenyl)-7-(4-cyanophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (13)
黄色固体,熔点：196.8-198.0℃,1H NMR(400MHz,CDCl3)δ7.70(d,J＝7.5Hz,2H),7.45(d,J＝7.7Hz,2H),7.36(d,J＝7.5Hz,2H),7.29–7.21(m,2H),5.20(s,2H),4.84 (d,J＝7.1Hz,1H),4.13(d,J＝7.6Hz,1H).13C NMR(101MHz,DMSO)δ167.95, 149.99,143.56,133.65,133.54,133.16,130.82,129.14,129.00,118.81,115.13, 113.52,113.29,111.62,43.80,30.22.HRMS(ESI)m/z:计算值C20H12ClN5S [M-H]-:388.0424；实验值:388.0499Yellow solid, melting point: 196.8-198.0℃, 1 H NMR(400MHz, CDCl 3 )δ7.70(d,J=7.5Hz,2H),7.45(d,J=7.7Hz,2H),7.36(d,J = 7.5Hz, 2H), 7.29–7.21 (m, 2H), 5.20 (s, 2H), 4.84 (d, J=7.1Hz, 1H), 4.13 (d, J=7.6Hz, 1H). 13 C NMR (101MHz, DMSO) δ167.95, 149.99, 143.56, 133.65, 133.54, 133.16, 130.82, 129.14, 129.00, 118.81, 115.13, 113.52, 113.29, 111.62, 43.80, 30.22.HRMS (calculated ESI C value) 20 H 12 ClN 5 S [MH] - : 388.0424; found: 388.0499
实施例14、5-氨基-7-(4-氯苯基)-3-(4-氰基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(14)Example 14, 5-amino-7-(4-chlorophenyl)-3-(4-cyanophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (14)
用4-氰基-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-氯苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-氯苯基)-3-(4-氰基苯基) -7H-噻唑并[3,2-a]嘧啶-6-甲腈(14)Use 4-cyano-bromoacetophenone to replace 4-methoxy-bromoacetophenone, use 4-chlorobenzaldehyde to replace p-methylbenzaldehyde, prepare the target compound 5-amino- 7-(4-Chlorophenyl)-3-(4-cyanophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (14)
黄色固体,熔点：158.7-159.5℃,1H NMR(400MHz,CDCl3)δ7.67(d,J＝7.4Hz,2H),7.46(d,J＝7.6Hz,2H),7.39(d,J＝7.5Hz,2H),7.27(d,J＝7.7Hz,2H),5.17(s,2H), 4.76(d,J＝7.5Hz,1H),4.10(d,J＝8.0Hz,1H).HRMS(ESI)m/z:计算值C20H12ClN5S [M-H]-:388.0424；实验值:388.0492Yellow solid, melting point: 158.7-159.5℃, 1 H NMR(400MHz, CDCl 3 )δ7.67(d,J=7.4Hz,2H),7.46(d,J=7.6Hz,2H),7.39(d,J =7.5Hz, 2H), 7.27(d, J=7.7Hz, 2H), 5.17(s, 2H), 4.76(d, J=7.5Hz, 1H), 4.10(d, J=8.0Hz, 1H). HRMS (ESI) m/z: calculated for C 20 H 12 ClN 5 S [MH] − : 388.0424; found: 388.0492
实施例15、5-氨基-7-(3-氯苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(15)Example 15, 5-amino-7-(3-chlorophenyl)-3-(4-methoxyphenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (15)
用3-氯苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(3-氯苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(15)Substitute 3-chlorobenzaldehyde for p-methylbenzaldehyde, prepare the target compound 5-amino-7-(3-chlorophenyl)-3-(4-methoxyphenyl)-7H- according to the method of Example 1 Thiazolo[3,2-a]pyrimidine-6-carbonitrile (15)
黄色固体,熔点：126.1-126.5℃,1H NMR(400MHz,DMSO)δ7.66(s,1H),7.58(s,1H), 7.43(s,2H),7.32(d,J＝9.0Hz,4H),6.99(d,J＝7.8Hz,2H),5.71(d,J＝8.0Hz,1H),5.20(d,J＝7.9Hz,1H),3.79(s,3H).13C NMR(101MHz,DMSO)δ167.07,158.91, 150.35,140.41,133.57,130.85,129.75,128.22,127.33,126.52,113.56,113.27, 55.06,48.65,43.27,30.02.HRMS(ESI)m/z:计算值C20H15ClN4OS[M+H]+:395.0720；实验值:395.0733。Yellow solid, melting point: 126.1-126.5℃, 1 H NMR(400MHz, DMSO)δ7.66(s,1H),7.58(s,1H), 7.43(s,2H),7.32(d,J=9.0Hz, 4H), 6.99(d, J=7.8Hz, 2H), 5.71(d, J=8.0Hz, 1H), 5.20(d, J=7.9Hz, 1H), 3.79(s, 3H). 13 C NMR( 101MHz, DMSO) δ167.07, 158.91, 150.35, 140.41, 133.57, 130.85, 129.75, 128.22, 127.33 , 126.52, 113.56 , 113.27, 55.06, 48.65, 43.27, 30.02. HRMS ClN4OS [M+H] + : 395.0720; found: 395.0733.
实施例16、5-氨基-7-(3-溴苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(16)Example 16, 5-amino-7-(3-bromophenyl)-3-(4-methoxyphenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (16)
用3-溴苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(3-溴苯基)-3-(4-甲氧基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(16)Substitute 3-bromobenzaldehyde for p-methylbenzaldehyde, prepare the target compound 5-amino-7-(3-bromophenyl)-3-(4-methoxyphenyl)-7H- according to the method of Example 1 Thiazolo[3,2-a]pyrimidine-6-carbonitrile (16)
灰色固体,熔点：163.4-164.8℃,1H NMR(400MHz,DMSO)δ7.66(s,1H),7.58(s,1H), 7.43(s,2H),7.32(d,J＝9.0Hz,4H),6.99(d,J＝7.8Hz,2H),5.71(d,J＝8.0Hz,1H),5.20(d,J＝7.9Hz,1H),3.79(s,3H).13C NMR(101MHz,DMSO)δ167.49,160.29, 159.45,150.75,141.08,131.72,131.65,130.62,130.25,127.37,127.27,122.66, 114.32,113.84,55.61,43.78,30.50.HRMS(ESI)m/z:计算值C20H15BrN4OS [M+H]+:439.0228；实验值：439.0217。Gray solid, melting point: 163.4-164.8℃, 1 H NMR(400MHz, DMSO)δ7.66(s,1H),7.58(s,1H), 7.43(s,2H),7.32(d,J=9.0Hz, 4H), 6.99(d, J=7.8Hz, 2H), 5.71(d, J=8.0Hz, 1H), 5.20(d, J=7.9Hz, 1H), 3.79(s, 3H). 13 C NMR( 101MHz, DMSO) δ167.49, 160.29, 159.45, 150.75, 141.08, 131.72, 131.65, 130.62, 130.25, 127.37, 127.27, 122.66, 114.32, 113.84 , 55.61, 43.78 H15BrN4OS [M + H] + : 439.0228; found: 439.0217.
实施例17、5-氨基-7-(3-硝基苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(17)Example 17, 5-amino-7-(3-nitrophenyl)-3-(p-tolyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (17)
用4-甲基-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用3-硝基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(3-硝基苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(17)Use 4-methyl-bromoacetophenone to replace 4-methoxy-bromoacetophenone, use 3-nitrobenzaldehyde to replace p-methylbenzaldehyde, prepare the target compound 5-amino according to the method of Example 1 -7-(3-Nitrophenyl)-3-(p-tolyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (17)
黄色固体,熔点:199.6-200.3℃,1H NMR(400MHz,DMSO)δ8.35(s,1H),8.25(d,J＝7.8Hz,1H),7.90(d,J＝7.4Hz,1H),7.77(t,J＝7.8Hz,1H),7.37(s,2H),7.25(dd,J＝14.3,7.4Hz,4H),5.79(d,J＝7.8Hz,1H),5.40(d,J＝7.7Hz,1H),2.34(s,3H).13C NMR(101MHz,DMSO)δ168.05,158.47,149.62,127.79,126.78,113.76,99.29,55.02. HRMS(ESI)m/z:计算值C20H15N5O2S[M-H]-:388.0868；实验值:388.0753。Yellow solid, melting point: 199.6-200.3℃, 1 H NMR (400MHz, DMSO) δ8.35(s, 1H), 8.25(d, J=7.8Hz, 1H), 7.90(d, J=7.4Hz, 1H) ,7.77(t,J＝7.8Hz,1H),7.37(s,2H),7.25(dd,J＝14.3,7.4Hz,4H),5.79(d,J＝7.8Hz,1H),5.40(d, J=7.7Hz, 1H), 2.34 (s, 3H). 13 C NMR (101MHz, DMSO) δ 168.05, 158.47, 149.62, 127.79, 126.78, 113.76, 99.29, 55.02. HRMS (ESI) m/z: calculated value C 20H15N5O2S [MH] - : 388.0868 ; found: 388.0753 .
实施例18、5-氨基-3-(4-甲氧基苯基)-7-(3-硝基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(18)Example 18, 5-amino-3-(4-methoxyphenyl)-7-(3-nitrophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (18 )
用3-硝基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-3-(4-甲氧基苯基)-7-(3-硝基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(18)Substitute 3-nitrobenzaldehyde for p-methylbenzaldehyde, and prepare the target compound 5-amino-3-(4-methoxyphenyl)-7-(3-nitrophenyl)- 7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (18)
黄色固体,熔点：132.9-133.2℃,1H NMR(400MHz,DMSO)δ8.36(s,1H),8.25(d,J＝7.8Hz,1H),7.90(d,J＝7.1Hz,1H),7.78(t,J＝7.9Hz,1H),7.35(s,2H),7.31(d,J＝7.4Hz,2H),6.98(d,J＝7.5Hz,2H),5.80(d,J＝7.7Hz,1H),5.41(d,J＝7.7Hz,1H),3.78(s,3H).13C NMR(101MHz,DMSO)δ172.70,167.61,159.52,148.53,147.39,140.53, 135.01,131.64,131.25,130.29,123.77,122.82,114.34,113.56,113.17,55.62,43.63,30.60.HRMS(ESI)m/z:计算值C20H15N5O3S[M+H]+:406.0974；实验值:406.0972。Yellow solid, melting point: 132.9-133.2℃, 1 H NMR (400MHz, DMSO)δ8.36(s,1H),8.25(d,J=7.8Hz,1H),7.90(d,J=7.1Hz,1H) ,7.78(t,J＝7.9Hz,1H),7.35(s,2H),7.31(d,J＝7.4Hz,2H),6.98(d,J＝7.5Hz,2H),5.80(d,J＝ 7.7Hz, 1H), 5.41(d, J=7.7Hz, 1H), 3.78(s, 3H). 13 C NMR (101MHz, DMSO) δ172.70, 167.61, 159.52, 148.53, 147.39, 140.53, 135.01, 131.64, 131.25 , 130.29, 123.77, 122.82, 114.34, 113.56, 113.17, 55.62, 43.63, 30.60. HRMS(ESI) m/z: Calculated C 20 H 15 N 5 O 3 S[M+H] + : 406.0974; Experiment: 406.0972.
实施例19、5-氨基-3-(4-氯苯基)-7-(3-硝基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(19)Example 19, 5-amino-3-(4-chlorophenyl)-7-(3-nitrophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (19)
用4-氯-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用3-硝基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-3-(4-氯苯基)-7-(3-硝基苯基) -7H-噻唑并[3,2-a]嘧啶-6-甲腈(19)Use 4-chloro-bromoacetophenone to replace 4-methoxy-bromoacetophenone, use 3-nitrobenzaldehyde to replace p-methylbenzaldehyde, prepare the target compound 5-amino- 3-(4-Chlorophenyl)-7-(3-nitrophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (19)
黄色固体,熔点：189.3-190.5℃,1H NMR(400MHz,DMSO)δ8.42–7.99(m,6H), 7.80(dd,J＝20.0,12.2Hz,2H),7.70(d,J＝7.0Hz,2H),5.72(d,J＝11.1Hz,1H),4.53 (d,J＝11.4Hz,1H).13C NMR(101MHz,DMSO)δ167.98,150.09,148.53,140.29, 135.02,133.59,133.23,131.26,130.82,130.00,129.00,128.65,123.82,122.82, 114.97,113.50,113.25,43.44,30.54,14.33,11.23.HRMS(ESI)m/z:计算值 C20H16ClN5O2S[M+H]+:410.0478；实验值：410.0472。Yellow solid, melting point: 189.3-190.5℃, 1 H NMR (400MHz, DMSO) δ8.42-7.99 (m, 6H), 7.80 (dd, J=20.0, 12.2Hz, 2H), 7.70 (d, J=7.0 Hz, 2H), 5.72 (d, J=11.1Hz, 1H), 4.53 (d, J=11.4Hz, 1H). 13 C NMR (101MHz, DMSO) δ167.98, 150.09, 148.53, 140.29, 135.02, 133.59, 133.23 ,131.26,130.82,130.00,129.00,128.65,123.82,122.82, 114.97,113.50,113.25,43.44,30.54,14.33,11.23.HRMS(ESI)m/z: Calculated C 20 H 16 ClN 5 O 2 S[M +H] + : 410.0478; Experiment: 410.0472.
实施例20、5-氨基-7-(4-硝基苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(20)Example 20, 5-amino-7-(4-nitrophenyl)-3-(p-tolyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (20)
用4-甲基-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-硝基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-硝基苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(20)Use 4-methyl-bromoacetophenone to replace 4-methoxy-bromoacetophenone, use 4-nitrobenzaldehyde to replace p-methylbenzaldehyde, prepare the target compound 5-amino according to the method of Example 1 -7-(4-Nitrophenyl)-3-(p-tolyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (20)
黄色固体,熔点：203.4-204.2℃,1H NMR(400MHz,DMSO)δ8.32(d,J＝7.5Hz,2H),7.71(d,J＝7.9Hz,2H),7.36(s,2H),7.25(d,J＝8.4Hz,4H),5.77(d,J＝7.1Hz,1H), 5.37(d,J＝7.9Hz,1H),2.34(s,3H).13C NMR(101MHz,DMSO)δ167.77,151.51, 147.67,145.63,137.92,132.01,129.56,129.51,128.90,124.71,113.80,113.52, 113.31,43.85,30.39,21.29.HRMS(ESI)m/z:计算值C20H15N5O2S[M+H]+:390.1025；Yellow solid, melting point: 203.4-204.2℃, 1 H NMR (400MHz, DMSO)δ8.32(d,J=7.5Hz,2H),7.71(d,J=7.9Hz,2H),7.36(s,2H) , 7.25(d, J=8.4Hz, 4H), 5.77(d, J=7.1Hz, 1H), 5.37(d, J=7.9Hz, 1H), 2.34(s, 3H). 13 C NMR(101MHz, DMSO) δ167.77, 151.51, 147.67, 145.63, 137.92, 132.01, 129.56, 129.51, 128.90, 124.71, 113.80, 113.52, 113.31, 43.85, 30.39, 21.29.HRMS ( ESI5 C 20 H 1 m/z: Calculated value O 2 S[M+H] + : 390.1025;
实验值390.1018。Experimental value 390.1018.
实施例21、5-氨基-3-(4-甲氧基苯基)-7-(4-硝基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(21)Example 21, 5-amino-3-(4-methoxyphenyl)-7-(4-nitrophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (21 )
用4-硝基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-3-(4-甲氧基苯基)-7-(4-硝基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(21)Substitute 4-nitrobenzaldehyde for p-methylbenzaldehyde, and prepare the target compound 5-amino-3-(4-methoxyphenyl)-7-(4-nitrophenyl)- 7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (21)
黄色固体,熔点：205.7-206.3℃,1H NMR(400MHz,DMSO)δ8.39(d,J＝7.8Hz,2H),7.78(d,J＝8.5Hz,2H),7.44(s,2H),7.38(d,J＝7.4Hz,2H),7.05(d,J＝7.7Hz,2H), 5.84(d,J＝7.6Hz,1H),5.44(d,J＝7.6Hz,1H),3.85(s,3H).13C NMR(101MHz, DMSO)δ167.64,159.48,151.23,147.66,145.70,130.26,129.58,127.24,124.71, 114.32,113.55,113.35,113.18,55.61,43.88,30.40.HRMS(ESI)m/z:计算值 C20H15N5O3S[M+H]+:406.0974；实验值：406.0972。Yellow solid, melting point: 205.7-206.3℃, 1 H NMR (400MHz, DMSO)δ8.39(d,J=7.8Hz,2H),7.78(d,J=8.5Hz,2H),7.44(s,2H) ,7.38(d,J＝7.4Hz,2H),7.05(d,J＝7.7Hz,2H),5.84(d,J＝7.6Hz,1H),5.44(d,J＝7.6Hz,1H),3.85 (s,3H). 13 C NMR(101MHz, DMSO)δ167.64,159.48,151.23,147.66,145.70,130.26,129.58,127.24,124.71, 114.32,113.55,113.35,113.18,55.61,4.4H RMS(3.88) m/z: calculated for C20H15N5O3S [ M +H] + : 406.0974 ; found: 406.0972.
实施例22、5-氨基-3-(4-氯苯基)-7-(4-硝基苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(22)Example 22, 5-amino-3-(4-chlorophenyl)-7-(4-nitrophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (22)
用4-氯-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-硝基苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物-氨基-3-(4-氯苯基)-7-(4-硝基苯基)-7H -噻唑并[3,2-a]嘧啶-6-甲腈(22)Use 4-chloro-bromoacetophenone to replace 4-methoxy-bromoacetophenone, use 4-nitrobenzaldehyde to replace p-methylbenzaldehyde, prepare target compound-amino-3 according to the method of embodiment 1 -(4-Chlorophenyl)-7-(4-nitrophenyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (22)
黄色固体,熔点：206.3-207.5℃,1H NMR(400MHz,DMSO)δ8.39(d,J＝7.5Hz,2H),7.77(d,J＝7.8Hz,2H),7.56(d,J＝7.1Hz,4H),7.46(d,J＝7.3Hz,2H),5.87(d,J＝8.1 Hz,1H),5.49(d,J＝7.4Hz,1H).13C NMR(101MHz,DMSO)δ167.47,149.50,147.26, 133.08,132.60,130.37,129.11,128.46,124.16,43.47,29.53.HRMS(ESI)m/z:计算值C20H16ClN5O2S[M+H]+:410.0478；实验值410.0472。Yellow solid, melting point: 206.3-207.5℃, 1 H NMR (400MHz, DMSO)δ8.39(d,J=7.5Hz,2H),7.77(d,J=7.8Hz,2H),7.56(d,J= 7.1Hz, 4H), 7.46 (d, J=7.3Hz, 2H), 5.87 (d, J=8.1 Hz, 1H), 5.49 (d, J=7.4Hz, 1H). 13 C NMR (101MHz, DMSO) δ167.47, 149.50, 147.26, 133.08, 132.60, 130.37, 129.11, 128.46, 124.16, 43.47, 29.53. HRMS(ESI) m/z: Calculated C 20 H 16 ClN 5 O 2 S[M+H] + : 410.0478; Experimental value 410.0472.
实施例23 5-氨基-7-(4-氯苯基)-3-(对甲苯基)-7H-噻唑并[3,2-a]嘧啶-6-甲腈(23)Example 23 5-Amino-7-(4-chlorophenyl)-3-(p-tolyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (23)
用4-甲基-溴代苯乙酮代替4-甲氧基-溴代苯乙酮，用4-氯苯甲醛代替对甲基苯甲醛，按实施例1的方法制备目标化合物5-氨基-7-(4-氯苯基)-3-(对甲苯基)-7H- 噻唑并[3,2-a]嘧啶-6-甲腈(23)Use 4-methyl-bromoacetophenone to replace 4-methoxy-bromoacetophenone, use 4-chlorobenzaldehyde to replace p-methylbenzaldehyde, prepare the target compound 5-amino- 7-(4-Chlorophenyl)-3-(p-tolyl)-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile (23)
白色固体，熔点：92.7-94.2oC.1H NMR(400MHz,DMSO)δ7.50(d,J＝8.1Hz,2H),7.41(d,J＝8.3Hz,2H),7.37–7.28(m,4H),7.25(d,J＝7.6Hz,2H),5.65(d,J＝8.3Hz, 1H),5.11(d,J＝8.1Hz,1H),2.31(s,3H).13C NMR(101MHz,)δ167.71,149.09, 138.15,135.40,134.00,133.06,130.82,130.16,129.03,127.94,116.92,113.88, 113.69,43.90,30.69,21.17.HRMS(ESI)m/z:计算值C20H15BrN4S[M+H]+: 379.0784；实验值:379.0713。White solid, melting point: 92.7-94.2oC.1H NMR(400MHz, DMSO) δ7.50(d,J=8.1Hz,2H),7.41(d,J=8.3Hz,2H),7.37-7.28(m,4H) ), 7.25(d, J=7.6Hz, 2H), 5.65(d, J=8.3Hz, 1H), 5.11(d, J=8.1Hz, 1H), 2.31(s, 3H).13C NMR(101MHz, )δ167.71,149.09, 138.15,135.40,134.00,133.06,130.82,130.16,129.03,127.94,116.92,113.88, 113.69,43.90,30.69,21.17.HRMS(ESIBr)m/z: Calculated value : 379.0784; experimental value: 379.0713.
实施例23、新型含多取代的5-氨基-3,7-二苯基-7H-噻唑并[3,2-a]嘧啶-6-甲腈衍生物抗菌活性试验：Example 23. Antibacterial activity test of novel polysubstituted 5-amino-3,7-diphenyl-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile derivatives:
通过临床分离的耐甲氧西林金黄色葡萄球菌对产物的抗菌活性进行筛选，具体实验步骤如下：The antibacterial activity of the product was screened by clinically isolated methicillin-resistant Staphylococcus aureus. The specific experimental steps are as follows:
用甲醇将产物配置成10mg/Ml溶液,吸出6μL到新的离心管，待甲醇挥干留下定量的固体产物加入6μL DMSO及294μLLuria-Bertani(LB)溶液(保证最终 96孔板中的DMSO溶液少于2％)，由此将产物配成200μg/mL的样品再用LB 溶液按比例稀释成20μg/mL、2μg/mL，在96孔板的第一排各孔中加入50μL浓度为200μg/mL的药物溶液，第二排各孔加入50μL溶度为20μg/mL的药物溶液，第三排各孔加入50μL溶度为2μg/mL的药物溶液。吸取50μL单一菌液到各孔中并使药液和菌液混匀。在新的一块96孔板中只加菌液，作为负对照BO；加入美罗培南和菌液混合液作为正对照。把装有药物溶液和菌液的96孔板放在酶标仪下测其吸光度值为B1，之后将其放入37℃培养箱培养18-20h,后在测其吸光度值B2，并计算其抑制率。The product was prepared into a 10 mg/Ml solution with methanol, 6 μL was aspirated into a new centrifuge tube, and 6 μL of DMSO and 294 μL of Luria-Bertani (LB) solution were added to the final 96-well plate after the methanol evaporated to leave a quantitative solid product. less than 2%), thus the product was prepared into a 200 μg/mL sample and then diluted with LB solution to 20 μg/mL and 2 μg/mL in proportion, and 50 μL was added to each well of the first row of the 96-well plate at a concentration of 200 μg/mL. mL of drug solution, 50 μL of drug solution with a solubility of 20 μg/mL was added to each well in the second row, and 50 μL of a drug solution with a solubility of 2 μg/mL was added to each well of the third row. Pipette 50 μL of a single bacterial solution into each well and mix the drug solution and bacterial solution. In a new 96-well plate, only the bacterial solution was added as a negative control BO ; a mixture of meropenem and bacterial solution was added as a positive control. Put the 96-well plate containing the drug solution and bacterial solution under the microplate reader to measure its absorbance value B 1 , then put it into a 37°C incubator for 18-20 hours, and then measure its absorbance value B 2 . Calculate its inhibition rate.
抑制率(％)＝[1-(样品OD600增加量(B2-B1)/负对照OD600增加量 (B2-B1))]×100％Inhibition rate (%)=[1-(sample OD 600 increase (B 2 -B 1 )/negative control OD 600 increase (B 2 -B 1 ))]×100%
表1化合物对五种菌株的最低抑菌浓度
a最低抑菌浓度大于百分之50％的标记为“-”。 aMinimum inhibitory concentration greater than 50% is marked with "-".
按照最低抑菌浓度大于50％为无效原则，七个化合物(4、6、9、10、12、 16、22)对耐甲氧西林金黄色葡萄球菌有抑菌作用，且该七个化合物对五种细胞株均有抑制作用，其中22对耐甲氧西林金黄色葡萄球菌有很好的抑制作用，尤其是对18H6、18I1具有非常好的抑制效果，其MIC均在5μg/mL，若继续研究其抑菌机制，有望将其发展为耐甲氧西林金黄色葡萄球菌的新药物。According to the principle that the minimum inhibitory concentration greater than 50% is invalid, seven compounds (4, 6, 9, 10, 12, 16, 22) have bacteriostatic effect on methicillin-resistant Staphylococcus aureus, and the seven compounds have antibacterial effect on methicillin-resistant Staphylococcus aureus Five cell lines have inhibitory effects, of which 22 have a very good inhibitory effect on methicillin-resistant Staphylococcus aureus, especially 18H6 and 18I1, and their MICs are all 5μg/mL. Studying its antibacterial mechanism is expected to develop it into a new drug for methicillin-resistant Staphylococcus aureus.
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