WO2019062872A1 - Deuterium-substituted carbazole compound - Google Patents

Deuterium-substituted carbazole compound Download PDF

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WO2019062872A1
WO2019062872A1 PCT/CN2018/108428 CN2018108428W WO2019062872A1 WO 2019062872 A1 WO2019062872 A1 WO 2019062872A1 CN 2018108428 W CN2018108428 W CN 2018108428W WO 2019062872 A1 WO2019062872 A1 WO 2019062872A1
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hydrogen
alkyl
cycloalkyl
deuterium
cancer
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PCT/CN2018/108428
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French (fr)
Chinese (zh)
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杨成
苏丹
钟治晖
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成都中创蜀洋生物科技有限公司
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • C07D209/56—Ring systems containing three or more rings
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Definitions

  • This invention relates to deuterated carbazole compounds.
  • the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof:
  • R 1 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 and SR e (or alternatively, either R 1 and R 4 or NR e and R 4 together with the atom to which they are attached form a 5- or 6-membered ring; or alternatively, Or R 1 and R 6 or NR e and R 6 together with the atom to which they are attached form a 5- or 6-membered ring;
  • R 2 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 and SR e Or alternatively, either R 2 and R 3 or NR e and R 3 together with the atom to which they are attached form a 5- or 6-membered ring; alternatively, alternatively, or R 2 And R 5 or NR e and R 5 together with the atoms to which they are attached form a 5- or 6-membered ring;
  • R a , R b , R c and R d are independently selected from the group consisting of hydrogen, hydrazine, hydrazine, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, OR e , N(R e ) 2 and SR e ;
  • R e is independently selected from hydrogen, deuterium, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R e groups are bonded to the nitrogen to which they are attached to form 5 Yuan or 6 yuan aliphatic ring;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R a , R b , R c , R d , R e , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is deuterium.
  • m is 1, R c is hydrogen or deuterium; or, m is 1, and R d is hydrogen or deuterium.
  • R 1 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 And SR e ; alternatively, alternatively, or R 1 and R 4 or NR e and R 4 together with the atoms to which they are attached form a 5- or 6-membered ring;
  • R 2 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 And SR e ; alternatively, alternatively, or R 2 and R 3 or NR e and R 3 together with the atom to which they are attached form a 5- or 6-membered ring;
  • R e is independently hydrogen, deuterium or C 1-6 alkyl.
  • the compound has the structural formula Ia:
  • R 1 is fluorene, C 1-3 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, N(R e ) 2 or OR e , or R 1 and R 4 and the carbon to which they are attached The atoms together form a 5- or 6-membered aliphatic carbocyclic ring;
  • R 2 is fluorene, C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, N(R e ) 2 or OR e , or R 2 and R 3 with the carbon atom to which they are attached Forming a 5- or 6-membered aliphatic carbocyclic ring or a 5- or 6-membered aliphatic ring containing a nitrogen atom;
  • R 3 is hydrogen, deuterium, C 1-3 alkyl, C 1-3 alkoxy or halogen
  • R 4 is hydrogen, deuterium or C 1-3 alkyl
  • R 5 is hydrogen, deuterium, hydroxyl, C 1-3 alkoxy or halogen
  • R 6 is hydrogen, deuterium, hydroxy or C 1-3 alkoxy
  • R 7 and R 8 are independently hydrogen, deuterium or C 1-3 alkyl
  • R 9 is ⁇ , C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl
  • R 10 is hydrogen, deuterium, C 1-4 alkyl or C 3-5 cycloalkyl, or R 10 and R d together with the atom to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, Or R 9 and R 10 are taken together to form a 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
  • R a is hydrogen or helium
  • R b is hydrogen or helium
  • R c is hydrogen, deuterium or C 1-3 alkyl
  • R d is hydrogen or helium
  • R e is independently hydrogen, deuterium or C 1-3 alkyl
  • n 0, 1, 2, 3, 4 or 5.
  • the compound has the structural formula Ib:
  • R 1 is hydrazine, methyl, ethyl, n-propyl, cyclopropyl, NH(CH 3 ) or OCH 3 , or R 1 and R 4 together with the carbon atom to which they are attached form a 5-membered aliphatic carbon ring;
  • R 2 is hydrazine, methyl, ethyl, n-propyl, cyclopropyl, NH(CH 3 ) or OCH 3 , or R 2 and R 3 together with the carbon atom to which they are attached form a 5-membered aliphatic carbocyclic ring or a 5-membered aliphatic ring containing a nitrogen atom;
  • R 3 is hydrogen, deuterium, methyl, methoxy or fluorine
  • R 4 is hydrogen or helium
  • R 5 is hydrogen or deuterium, hydroxyl, methoxy or fluorine
  • R 6 is hydrogen or deuterium, hydroxyl or methoxy
  • R 7 and R 8 are independently hydrogen or deuterium
  • R 9 is hydrazine, methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl;
  • R 10 is hydrogen, deuterium, methyl, ethyl or cyclobutyl, or R 10 and R d together with the atom to which they are attached form a 5-membered aliphatic ring containing a nitrogen atom, or R 9 and R 10 are bonded to Forming a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or section, Partial or Part; R 101 is methyl or ethyl;
  • R a is hydrogen or helium
  • R b is hydrogen or helium
  • R c is hydrogen or helium
  • R d is hydrogen or helium
  • n 1 or 2.
  • the present invention also provides a compound of Formula II or a pharmaceutically acceptable salt thereof or a hydrate thereof:
  • R a , R b , R c and R d are independently selected from the group consisting of hydrogen, hydrazine, hydrazine, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, OR e , N(R e ) 2 and SR e ;
  • R e is independently selected from hydrogen, deuterium, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R e groups are bonded to the nitrogen to which they are attached to form 5 Yuan or 6 yuan aliphatic ring;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R a , R b , R c , R d , R e , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is ⁇ .
  • m is 1, R c is hydrogen or deuterium; or, m is 1, and R d is hydrogen or deuterium.
  • R e is independently hydrogen, deuterium or C 1-6 alkyl.
  • the compound has the structural formula IIa:
  • R 3 is hydrogen, deuterium, C 1-3 alkyl, C 1-3 alkoxy or halogen
  • R 4 is hydrogen, deuterium or C 1-3 alkyl
  • R 5 is hydrogen, deuterium, hydroxyl, C 1-3 alkoxy or halogen
  • R 6 is hydrogen, deuterium, hydroxy or C 1-3 alkoxy
  • R 7 and R 8 are independently hydrogen, deuterium or C 1-3 alkyl
  • R 9 is ⁇ , C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl
  • R 10 is hydrogen, deuterium, C 1-4 alkyl or C 3-5 cycloalkyl, or R 10 and R d together with the atom to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, Or R 9 and R 10 are taken together to form a 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
  • R a is hydrogen or helium
  • R b is hydrogen or helium
  • R c is hydrogen, deuterium or C 1-3 alkyl
  • R d is hydrogen or helium
  • n 0, 1, 2, 3, 4 or 5.
  • the compound has the structural formula IIb:
  • R 3 is hydrogen, deuterium, methyl, methoxy or fluorine
  • R 4 is hydrogen or helium
  • R 5 is hydrogen or deuterium, hydroxyl, methoxy or fluorine
  • R 6 is hydrogen or deuterium, hydroxyl or methoxy
  • R 7 and R 8 are independently hydrogen or deuterium
  • R 9 is hydrazine, methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl;
  • R 10 is hydrogen, deuterium, methyl, ethyl or cyclobutyl, or R 10 and R d together with the atom to which they are attached form a 5-membered aliphatic ring containing a nitrogen atom, or R 9 and R 10 are bonded to Forming a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or section, section, Part; R 102 is methyl or ethyl;
  • R a is hydrogen or helium
  • R b is hydrogen or helium
  • R c is hydrogen or helium
  • R d is hydrogen or helium
  • n 1 or 2.
  • the present invention also provides a compound of the formula III or a pharmaceutically acceptable salt thereof or a hydrate thereof:
  • R h is independently selected from hydrogen, hydrazine, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two Rh groups are bonded to the nitrogen to which they are attached to form a 5 dollar Or a 6-membered aliphatic ring;
  • R 8 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
  • R 15 is hydrogen or helium
  • R 16 is hydrogen or helium
  • R 17 is hydrogen or helium
  • p is 0, 1, 2, 3, 4 or 5, and when p is 2, one of R f and R g is not ethyl;
  • R f , R g , R h , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 is ⁇ .
  • the compound has the structural formula IIIb:
  • R g is hydrogen, deuterium or methyl, or R g and R 8 together with the atom to which they are attached form a 5-membered aliphatic ring containing a nitrogen atom;
  • R 8 is hydrogen or helium
  • R 15 is hydrogen or helium
  • R 16 is hydrogen or helium
  • R 17 is hydrogen or helium
  • R g , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 is ⁇ .
  • the present invention also provides a compound of the formula IV or a pharmaceutically acceptable salt thereof or a hydrate thereof:
  • q 0, 1, 2, 3, 4 or 5;
  • R i is independently selected from hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R i groups are bonded to the nitrogen to which they are attached to form 5 or 6 yuan aliphatic ring.
  • R i is independently hydrogen or C 1-6 alkyl.
  • R 18 is C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl
  • R 19 is hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl, or R 18 and R 19 together with the atom to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, optionally containing an oxygen atom;
  • R 18 is methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl
  • R 19 is hydrogen, methyl, ethyl or cyclobutyl, or R 18 and R 19 combine to form a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or section, Partial or Part
  • R 103 is methyl or ethyl.
  • the present invention also provides a compound of the formula V or a pharmaceutically acceptable salt thereof or a hydrate thereof:
  • r 0, 1, 2, 3, 4 or 5;
  • R j is independently selected from hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R j groups are bonded to the nitrogen to which they are attached to form 5 ⁇ or 6 yuan aliphatic ring.
  • R j is independently hydrogen or C 1-6 alkyl.
  • R 20 is C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl;
  • R 21 is hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl, or R 20 and R 21 together with the atom to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, optionally Containing oxygen atoms;
  • R 20 is methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl
  • R 21 is hydrogen, methyl, ethyl or cyclobutyl, or R 20 and R 21 is combined to form a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or section, section, Part
  • R 104 is methyl or ethyl.
  • R 20 is a methyl group
  • R 21 is a methyl group, an ethyl group or a cyclobutyl group, or R 20 and R 21 are combined to form Part
  • R 104 is a methyl group.
  • the present invention also provides a compound of the formula VI or a pharmaceutically acceptable salt thereof or a hydrate thereof:
  • s 0, 1, 2, 3, 4 or 5;
  • R k is independently selected from hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R k groups are bonded to the nitrogen to which they are attached to form 5 ⁇ or 6 yuan aliphatic ring.
  • R k is independently hydrogen or C 1-6 alkyl.
  • R 22 is C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl;
  • R 23 is hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl, or R 22 and R 23 together with the atoms to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, optionally containing an oxygen atom.
  • R 22 is methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl
  • R 23 is hydrogen, methyl, ethyl or cyclobutyl, or R 22 and R 23 combine to form a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or section, section, Part
  • R 105 is methyl or ethyl.
  • R 22 is a methyl group
  • R 23 is a methyl group, an ethyl group or a cyclobutyl group, or R 22 and R 23 are combined to form Part
  • R 105 is a methyl group
  • the structural formula of the compound is as follows:
  • the present invention also provides a compound of the formula VII or a pharmaceutically acceptable salt thereof or a hydrate thereof:
  • t 0, 1, 2, 3, 4 or 5;
  • R m is independently selected from hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R m groups are bonded to the nitrogen to which they are attached to form 5 or 6 yuan aliphatic ring.
  • R m is independently hydrogen or C 1-6 alkyl.
  • R 24 is C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl;
  • R 25 is hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl, or R 24 and R 25 together with the atom to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, optionally Contains oxygen atoms.
  • R 24 is methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl
  • R 25 is hydrogen, methyl, ethyl or cyclobutyl, or R 22 and R 23 combine to form a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or section, section, Part
  • R 106 is methyl or ethyl.
  • t is 0, 1, 2, 3, 4 or 5; R 24 is methyl; R 25 is methyl.
  • the present invention also provides a deuterated carbazole compound or a pharmaceutically acceptable salt thereof or a hydrate thereof, which has the following structure:
  • the present invention also provides the use of the compound, a pharmaceutically acceptable salt thereof, or a hydrate thereof, for the preparation of a medicament for treating cancer.
  • the cancer is selected from the group consisting of: lung adenocarcinoma, lymphoid hematopoietic tumor, myeloid hematopoietic tumor, central and peripheral nervous system tumor, mesenchymal cell-derived tumor, xeroderma pigmentosum, keratinized echinoderma Tumor, seminoma, thyroid follicular carcinoma, teratocarcinoma, colorectal cancer, head and neck cancer, breast cancer, stomach cancer, vulvar cancer, melanoma, ovarian cancer, lung cancer, Ewing sarcoma, squamous cell carcinoma, Oral cancer, blood cell malignancy, thymoma lymphoma, small cell carcinoma, adrenal cortical cancer, ACTH-producing tumor, non-small cell carcinoma, ductal carcinoma, polyps associated with colorectal neoplasia, pancreatic cancer, liver cancer, urinary Systemic cancer, prostate cancer, primary peritoneal epithelial n
  • the cancer is selected from the group consisting of a deteriorated bladder cancer, metastatic bladder cancer, leukemia, B cell lymphoma, T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, tissue Cellular lymphoma, Burkitt's lymphoma, diffuse lymphoma, cutaneous T-cell lymphoma, glioma, exocrine pancreatic cancer, non-small cell lung cancer, esophageal squamous cell carcinoma, multiple myeloma, colon cancer, cervical cancer , endometrial cancer, endogenous brain tumors and astrocytic brain tumors.
  • a deteriorated bladder cancer metastatic bladder cancer
  • leukemia B cell lymphoma
  • T cell lymphoma Hodgkin's lymphoma
  • non-Hodgkin's lymphoma hairy cell lymphoma
  • tissue Cellular lymphoma
  • the cancer is selected from the group consisting of acute lymphoblastic leukemia, myeloid lymphoblastic leukemia, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, bone marrow Leukemia, promyelocytic leukemia, myeloma, astrocytoma, neuroblastoma, schwannomas, glioblastoma, fibrosarcoma, rhabdomyosarcoma, osteoma, small cell lung cancer and bladder cancer.
  • the cancer is selected from the group consisting of: a primary superficial bladder tumor, an invasive transitional cell carcinoma of the bladder, a bladder cancer that invades the muscle, and an osteosarcoma.
  • cancer is selected from the group consisting of acute lymphoblastic leukemia, and acute and chronic myelogenous leukemia.
  • the compound is administered in combination with a chemotherapeutic agent, radiation therapy, a drug affecting microtubules, a cytostatic agent, a TNF polypeptide, and a mixture thereof.
  • the invention also provides the use of a pharmaceutically acceptable salt of the compound, or a hydrate thereof, for the manufacture of a medicament for the treatment of an inflammatory disease in an individual in need thereof.
  • the inflammatory disease is selected from the group consisting of rheumatoid arthritis, psoriasis, leukoplakia, Wegener's granulomatosis, and systemic lupus erythematosus.
  • the aforementioned compound is administered in combination with an immunosuppressive drug.
  • the invention also provides the use of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, for the manufacture of a medicament for the treatment of a microbial infection, a protozoal infection or a viral infection.
  • the protozoan infection is malaria.
  • the invention also provides the use of a compound, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, for the manufacture of a medicament for the treatment of a disease or condition selected from the group consisting of atherosclerosis, restenosis, Vasculitis, retinopathy, nephropathy, proliferative skin disease, psoriasis, keloid scar formation, actinic keratosis, Stevens-Johnson syndrome, rheumatoid arthritis, systemic onset Chronic arthritis, osteoporosis, systemic lupus erythematosus, hyperproliferative diseases of the eye, vascular proliferative diseases, ichthyosis and papilloma.
  • a disease or condition selected from the group consisting of atherosclerosis, restenosis, Vasculitis, retinopathy, nephropathy, proliferative skin disease, psoriasis, keloid scar formation, actinic keratosis, Stevens-
  • the present invention also provides the use of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, for the preparation of a medicament for treating a disease or condition selected from the group consisting of nephritis, proliferative vitreoretinopathy, Diabetic retinopathy and hyperproliferative diseases of the eye involving epithelial ingrowth.
  • the compounds of the invention can be synthesized by the following routes:
  • the experimental results show that the compound 8 of the present invention can effectively inhibit the proliferation of ovarian cancer cells, and prove that it can effectively treat cancer, especially ovarian cancer.
  • the pharmacokinetic experiments show that the compound 8 has better pharmacokinetic stability in the animal, and the duration of the body It is 15% higher than the non-deuterated compound. Helps reduce the dose and duration of drug use. .
  • Figure 7 is an anti-tumor effect diagram of the compound of the present invention.
  • SKOV3 Human ovarian adenocarcinoma cells
  • MTT was used to detect the viability of Compound 8 after treatment of various tumor cells.
  • concentrations 100 nM, 500 nM, 5 ⁇ M, 10 ⁇ M
  • C21 non-deuterated derivative
  • 5 ⁇ M X treated cells for 24h the cell viability began to decrease significantly, and the higher the concentration, the longer the treatment time, the more obvious the cell viability decreased.
  • Derivative C21 treatment of A2780 is also a similar effect.
  • the 5 ⁇ M concentration of C21 and X treated other tumor cells SKOV3, Hela, HepG2
  • the cell viability decreased significantly at 24h, and the longer the treatment time, the more obvious.
  • the experimental results show that the compound 8 of the present invention can effectively inhibit the proliferation of ovarian cancer cells, and proves that it can effectively treat cancer, especially ovarian cancer, and provides a new choice for clinical treatment of cancer, and has a good application prospect.
  • pharmacokinetic experiments showed that Compound 8 has better pharmacokinetic stability in animals, and its duration in vivo is 15% higher than that of non-deuterated compounds. Helps reduce the dose and duration of drug use.

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Abstract

Disclosed is a deuterium-substituted carbazole compound, in particular a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof. The compound of the present invention can be used to treat cancers, inflammation, microbial infectious diseases, viral infections and protozoal infections, and has a good application prospect.

Description

氘代咔唑类化合物Deuterated carbazole compound 技术领域Technical field
本发明涉及氘代咔唑类化合物。This invention relates to deuterated carbazole compounds.
背景技术Background technique
在发达国家的世界中，随着人口的老龄化，人类癌症的频率不断增加。对于某些类型的癌症和在诊断上疾病的分期，近年来尽管进行了广泛深入的研究，但是发病率和死亡率一直没有显著地改善。细胞死亡的诱导是最引人注目的癌症治疗策略之一。存在鉴定能够诱导肿瘤细胞中的细胞死亡和/或增强化疗和放疗的药物的巨大需求。In the world of developed countries, as the population ages, the frequency of human cancer continues to increase. For some types of cancer and the stage of diagnosis of the disease, despite extensive and intensive research in recent years, morbidity and mortality have not been significantly improved. Induction of cell death is one of the most compelling cancer treatment strategies. There is a great need to identify drugs that are capable of inducing cell death in tumor cells and/or enhancing chemotherapy and radiation therapy.
发明内容Summary of the invention
本发明提供了式Ⅰ所示的化合物或其药学上可接受的盐或其水合物：The present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof:
Figure PCTCN2018108428-appb-000001
Figure PCTCN2018108428-appb-000001
其中，R 1选自氢、氘、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、N(R e) 2和SR e(；或者，两者中择一地，或者R 1和R 4或者NR e和R 4与它们所连接的原子一起形成5元环或者6元环；或者，两者中择一地，或者R 1和R 6或者NR e和R 6与它们所连接的原子一起形成5元环或者6元环； Wherein R 1 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 and SR e (or alternatively, either R 1 and R 4 or NR e and R 4 together with the atom to which they are attached form a 5- or 6-membered ring; or alternatively, Or R 1 and R 6 or NR e and R 6 together with the atom to which they are attached form a 5- or 6-membered ring;
R 2选自氢、氘、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、N(R e) 2和SR e；或者，两者中择一地，或者R 2和R 3或者NR e和R 3与它们所连接的原子一起形成5元环或者6元环；或者，两者中择一地，或者R 2和R 5或者NR e和R 5与它们所连接的原子一起形成5元环或者6元环； R 2 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 and SR e Or alternatively, either R 2 and R 3 or NR e and R 3 together with the atom to which they are attached form a 5- or 6-membered ring; alternatively, alternatively, or R 2 And R 5 or NR e and R 5 together with the atoms to which they are attached form a 5- or 6-membered ring;
R 3、R 4、R 5、R 6、R 7和R 8独立选自氢、氘、卤素、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、C(＝O)R e、C(＝O)OR e、OC(＝O)R e、C(＝O)N(R e) 2、C(＝O)NR e SO 2R e、N(R e) 2、NR e C(＝O)R e、NR eC(＝O)N(Re) 2、CN、NO 2、CF 3、OCF 3、SR e、SOR e、SO 2R e、SO 2N(R e) 2和OSO 2CF 3； R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl Base, heteroaryl, OR e , C(=O)R e , C(=O)OR e , OC(=O)R e , C(=O)N(R e ) 2 , C(=O) NR e SO 2 R e , N(R e ) 2 , NR e C(=O)R e , NR e C(=O)N(Re) 2 , CN, NO 2 , CF 3 , OCF 3 , SR e , SOR e , SO 2 R e , SO 2 N(R e ) 2 and OSO 2 CF 3 ;
R 9选自氢、氘、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R e，或者R 9和R 10结合在一起形成5元、6元或7元脂肪族环，任选含有氧原子； R 9 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C (=O) R e , or R 9 and R 10 are taken together to form a 5-, 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
R 10选自氢、氘、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R e，或者R 10和一个R d与它们所连接的原子一起形成5元或6元脂肪族环； R 10 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(=O)R e , or R 10 and a R d together with the atoms to which they are attached form a 5- or 6-membered aliphatic ring;
R a、R b、R c和R d独立地选自氢、氘、氚、卤素、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、N(R e) 2和SR e； R a , R b , R c and R d are independently selected from the group consisting of hydrogen, hydrazine, hydrazine, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, OR e , N(R e ) 2 and SR e ;
R e独立选自氢、氘、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基，或者两个R e基团与它们所连接的氮结合在一起形成5元或6元脂肪族环； R e is independently selected from hydrogen, deuterium, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R e groups are bonded to the nitrogen to which they are attached to form 5 Yuan or 6 yuan aliphatic ring;
n为0、1、2、3、4、5或6；n is 0, 1, 2, 3, 4, 5 or 6;
m为0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
且，R a、R b、R c、R d、R e、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10中至少一个为氘。 Further, at least one of R a , R b , R c , R d , R e , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is deuterium.
优选地，m为1，R c为氢或氘；或者，m为1，R d为氢或氘。 Preferably, m is 1, R c is hydrogen or deuterium; or, m is 1, and R d is hydrogen or deuterium.
优选地，R 1选自氢、氘、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、N(R e) 2和SR e；或者，两者中择一地，或者R 1和R 4或者NR e和R 4与它们所连接的原子一起形成5元环或者6元环； Preferably, R 1 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 And SR e ; alternatively, alternatively, or R 1 and R 4 or NR e and R 4 together with the atoms to which they are attached form a 5- or 6-membered ring;
优选地，R 2选自氢、氘、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、N(R e) 2和SR e；或者，两者中择一地，或者R 2和R 3或者NR e和R 3与它们所连接的原子一起形成5元环或者6元环； Preferably, R 2 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 And SR e ; alternatively, alternatively, or R 2 and R 3 or NR e and R 3 together with the atom to which they are attached form a 5- or 6-membered ring;
优选地，R e独立地为氢、氘或C 1-6烷基。 Preferably, R e is independently hydrogen, deuterium or C 1-6 alkyl.
优选地，所述化合物具有结构式Ⅰa：Preferably, the compound has the structural formula Ia:
Figure PCTCN2018108428-appb-000002
Figure PCTCN2018108428-appb-000002
其中，R 1为氘、C 1-3烷基、C 1-4卤代烷基、C 3-5环烷基、N(R e) 2或OR e，或者R 1和R4与它们所连接的碳原子一起形成5元或6元脂肪族碳环； Wherein R 1 is fluorene, C 1-3 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, N(R e ) 2 or OR e , or R 1 and R 4 and the carbon to which they are attached The atoms together form a 5- or 6-membered aliphatic carbocyclic ring;
R 2为氘、C 1-4烷基、C 1-4卤代烷基、C 3-5环烷基、N(R e) 2或OR e，或者R 2和R 3与它们所连接的碳原子一起形成5元或6元脂肪族碳环或者含有一个氮原子的5元或6元脂肪族环； R 2 is fluorene, C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, N(R e ) 2 or OR e , or R 2 and R 3 with the carbon atom to which they are attached Forming a 5- or 6-membered aliphatic carbocyclic ring or a 5- or 6-membered aliphatic ring containing a nitrogen atom;
R 3为氢、氘、C 1-3烷基、C 1-3烷氧基或卤素； R 3 is hydrogen, deuterium, C 1-3 alkyl, C 1-3 alkoxy or halogen;
R 4为氢、氘或C 1-3烷基； R 4 is hydrogen, deuterium or C 1-3 alkyl;
R 5为氢、氘、羟基、C 1-3烷氧基或卤素； R 5 is hydrogen, deuterium, hydroxyl, C 1-3 alkoxy or halogen;
R 6为氢、氘、羟基或C 1-3烷氧基； R 6 is hydrogen, deuterium, hydroxy or C 1-3 alkoxy;
R 7和R 8独立地为氢、氘或C 1-3烷基； R 7 and R 8 are independently hydrogen, deuterium or C 1-3 alkyl;
R 9为氘、C 1-6烷基、C 3-5环烷基或C 1-3羟基烷基； R 9 is 氘, C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl;
R 10为氢、氘、C 1-4烷基或C 3-5环烷基，或者R 10和R d与它们所连接的原子一起形成含有一个氮原子的5元或6元脂肪族环，或者R 9和R 10结合在一起形成6元或7元脂肪族环，任选含有氧原子； R 10 is hydrogen, deuterium, C 1-4 alkyl or C 3-5 cycloalkyl, or R 10 and R d together with the atom to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, Or R 9 and R 10 are taken together to form a 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
R a为氢或氘； R a is hydrogen or helium;
R b为氢或氘； R b is hydrogen or helium;
R c为氢、氘或C 1-3烷基； R c is hydrogen, deuterium or C 1-3 alkyl;
R d为氢或氘； R d is hydrogen or helium;
R e独立地为氢、氘或C 1-3烷基； R e is independently hydrogen, deuterium or C 1-3 alkyl;
且n为0、1、2、3、4或5。And n is 0, 1, 2, 3, 4 or 5.
优选地，所述化合物具有结构式Ⅰb：Preferably, the compound has the structural formula Ib:
Figure PCTCN2018108428-appb-000003
Figure PCTCN2018108428-appb-000003
其中，R 1为氘、甲基、乙基、正丙基、环丙基、NH(CH 3)或OCH 3，或者R 1和R 4与它们所连接的碳原子一起形成5元脂肪族碳环； Wherein R 1 is hydrazine, methyl, ethyl, n-propyl, cyclopropyl, NH(CH 3 ) or OCH 3 , or R 1 and R 4 together with the carbon atom to which they are attached form a 5-membered aliphatic carbon ring;
R 2为氘、甲基、乙基、正丙基、环丙基、NH(CH 3)或OCH 3，或者R 2和R 3与它们所连接的碳原子一起形成5元脂肪族碳环或含有一个氮原子的5元脂肪族环； R 2 is hydrazine, methyl, ethyl, n-propyl, cyclopropyl, NH(CH 3 ) or OCH 3 , or R 2 and R 3 together with the carbon atom to which they are attached form a 5-membered aliphatic carbocyclic ring or a 5-membered aliphatic ring containing a nitrogen atom;
R 3为氢、氘、甲基、甲氧基或氟； R 3 is hydrogen, deuterium, methyl, methoxy or fluorine;
R 4为氢或氘； R 4 is hydrogen or helium;
R 5为氢或氘、羟基、甲氧基或氟； R 5 is hydrogen or deuterium, hydroxyl, methoxy or fluorine;
R 6为氢或氘、羟基或甲氧基； R 6 is hydrogen or deuterium, hydroxyl or methoxy;
R 7和R 8独立地为氢或氘； R 7 and R 8 are independently hydrogen or deuterium;
R 9为氘、甲基、乙基、正丙基、异丙基、环丁基或2-羟基乙基； R 9 is hydrazine, methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl;
R 10为氢、氘、甲基、乙基或环丁基，或者R 10和R d与它们所连接的原子一起形成含有一个氮原子的5元脂肪族环，或者R 9和R 10结合在一起形成吗啉代部分、四氢呋喃基部分、哌啶基部分或
Figure PCTCN2018108428-appb-000004
部分、
Figure PCTCN2018108428-appb-000005
部分或
Figure PCTCN2018108428-appb-000006
部分；R 101为甲基或乙基； R 10 is hydrogen, deuterium, methyl, ethyl or cyclobutyl, or R 10 and R d together with the atom to which they are attached form a 5-membered aliphatic ring containing a nitrogen atom, or R 9 and R 10 are bonded to Forming a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or
Figure PCTCN2018108428-appb-000004
section,
Figure PCTCN2018108428-appb-000005
Partial or
Figure PCTCN2018108428-appb-000006
Part; R 101 is methyl or ethyl;
R a为氢或氘； R a is hydrogen or helium;
R b为氢或氘； R b is hydrogen or helium;
R c为氢或氘； R c is hydrogen or helium;
R d为氢或氘； R d is hydrogen or helium;
且n为1或2。And n is 1 or 2.
本发明还提供了式Ⅱ所示的化合物或其药学上可接受的盐或其水合物：The present invention also provides a compound of Formula II or a pharmaceutically acceptable salt thereof or a hydrate thereof:
Figure PCTCN2018108428-appb-000007
Figure PCTCN2018108428-appb-000007
R 3、R 4、R 5、R 6、R 7和R 8独立选自氢、氘、卤素、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、C(＝O)R e、C(＝O)OR e、OC(＝O)R e、C(＝O)N(R e) 2、C(＝O)NR e SO 2R e、N(R e) 2、NR e C(＝O)R e、NR eC(＝O)N(Re) 2、CN、NO 2、CF 3、OCF 3、SR e、SOR e、SO 2R e、SO 2N(R e) 2和OSO 2CF 3； R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl Base, heteroaryl, OR e , C(=O)R e , C(=O)OR e , OC(=O)R e , C(=O)N(R e ) 2 , C(=O) NR e SO 2 R e , N(R e ) 2 , NR e C(=O)R e , NR e C(=O)N(Re) 2 , CN, NO 2 , CF 3 , OCF 3 , SR e , SOR e , SO 2 R e , SO 2 N(R e ) 2 and OSO 2 CF 3 ;
R 9选自氢、氘、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R e，或者R 9和R 10结合在一起形成5元、6元或7元脂肪族环，任选含 有氧原子； R 9 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C (=O) R e , or R 9 and R 10 are taken together to form a 5-, 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
R 10选自氢、氘、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R e，或者R 10和一个R d与它们所连接的原子一起形成5元或6元脂肪族环； R 10 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(=O)R e , or R 10 and a R d together with the atoms to which they are attached form a 5- or 6-membered aliphatic ring;
R a、R b、R c和R d独立地选自氢、氘、氚、卤素、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、N(R e) 2和SR e； R a , R b , R c and R d are independently selected from the group consisting of hydrogen, hydrazine, hydrazine, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, OR e , N(R e ) 2 and SR e ;
R e独立选自氢、氘、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基，或者两个R e基团与它们所连接的氮结合在一起形成5元或6元脂肪族环； R e is independently selected from hydrogen, deuterium, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R e groups are bonded to the nitrogen to which they are attached to form 5 Yuan or 6 yuan aliphatic ring;
n为0、1、2、3、4、5或6；n is 0, 1, 2, 3, 4, 5 or 6;
m为0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
且，R a、R b、R c、R d、R e、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10中至少一个为氘。 Further, at least one of R a , R b , R c , R d , R e , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is 氘.
优选地，m为1，R c为氢或氘；或者，m为1，R d为氢或氘。 Preferably, m is 1, R c is hydrogen or deuterium; or, m is 1, and R d is hydrogen or deuterium.
优选地，R e独立地为氢、氘或C 1-6烷基。 Preferably, R e is independently hydrogen, deuterium or C 1-6 alkyl.
优选地，所述化合物具有结构式Ⅱa：Preferably, the compound has the structural formula IIa:
Figure PCTCN2018108428-appb-000008
Figure PCTCN2018108428-appb-000008
其中，R 3为氢、氘、C 1-3烷基、C 1-3烷氧基或卤素； Wherein R 3 is hydrogen, deuterium, C 1-3 alkyl, C 1-3 alkoxy or halogen;
R 4为氢、氘或C 1-3烷基； R 4 is hydrogen, deuterium or C 1-3 alkyl;
R 5为氢、氘、羟基、C 1-3烷氧基或卤素； R 5 is hydrogen, deuterium, hydroxyl, C 1-3 alkoxy or halogen;
R 6为氢、氘、羟基或C 1-3烷氧基； R 6 is hydrogen, deuterium, hydroxy or C 1-3 alkoxy;
R 7和R 8独立地为氢、氘或C 1-3烷基； R 7 and R 8 are independently hydrogen, deuterium or C 1-3 alkyl;
R 9为氘、C 1-6烷基、C 3-5环烷基或C 1-3羟基烷基； R 9 is 氘, C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl;
R 10为氢、氘、C 1-4烷基或C 3-5环烷基，或者R 10和R d与它们所连接的原子一起形成含有一个氮原子的5元或6元脂肪族环，或者R 9和R 10结合在一起形成6元或7元脂肪族环，任选含有氧原子； R 10 is hydrogen, deuterium, C 1-4 alkyl or C 3-5 cycloalkyl, or R 10 and R d together with the atom to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, Or R 9 and R 10 are taken together to form a 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
R a为氢或氘； R a is hydrogen or helium;
R b为氢或氘； R b is hydrogen or helium;
R c为氢、氘或C 1-3烷基； R c is hydrogen, deuterium or C 1-3 alkyl;
R d为氢或氘； R d is hydrogen or helium;
且n为0、1、2、3、4或5。And n is 0, 1, 2, 3, 4 or 5.
优选地，所述化合物具有结构式Ⅱb：Preferably, the compound has the structural formula IIb:
Figure PCTCN2018108428-appb-000009
Figure PCTCN2018108428-appb-000009
R 3为氢、氘、甲基、甲氧基或氟； R 3 is hydrogen, deuterium, methyl, methoxy or fluorine;
R 4为氢或氘； R 4 is hydrogen or helium;
R 5为氢或氘、羟基、甲氧基或氟； R 5 is hydrogen or deuterium, hydroxyl, methoxy or fluorine;
R 6为氢或氘、羟基或甲氧基； R 6 is hydrogen or deuterium, hydroxyl or methoxy;
R 7和R 8独立地为氢或氘； R 7 and R 8 are independently hydrogen or deuterium;
R 9为氘、甲基、乙基、正丙基、异丙基、环丁基或2-羟基乙基； R 9 is hydrazine, methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl;
R 10为氢、氘、甲基、乙基或环丁基，或者R 10和R d与它们所连接的原子一起形成含有一个氮原子的5元脂肪族环，或者R 9和R 10结合在一起形成吗啉代部分、四氢呋喃基部分、哌啶基部分或
Figure PCTCN2018108428-appb-000010
部分、
Figure PCTCN2018108428-appb-000011
部分、
Figure PCTCN2018108428-appb-000012
部分；R 102为甲基或乙基； R 10 is hydrogen, deuterium, methyl, ethyl or cyclobutyl, or R 10 and R d together with the atom to which they are attached form a 5-membered aliphatic ring containing a nitrogen atom, or R 9 and R 10 are bonded to Forming a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or
Figure PCTCN2018108428-appb-000010
section,
Figure PCTCN2018108428-appb-000011
section,
Figure PCTCN2018108428-appb-000012
Part; R 102 is methyl or ethyl;
R a为氢或氘； R a is hydrogen or helium;
R b为氢或氘； R b is hydrogen or helium;
R c为氢或氘； R c is hydrogen or helium;
R d为氢或氘； R d is hydrogen or helium;
且n为1或2。And n is 1 or 2.
本发明还提供了式Ⅲ所示的化合物或其药学上可接受的盐或其水合物：The present invention also provides a compound of the formula III or a pharmaceutically acceptable salt thereof or a hydrate thereof:
Figure PCTCN2018108428-appb-000013
Figure PCTCN2018108428-appb-000013
其中R f选自氢、氘、C 1-6烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R h，或者R f和R g结合在一起形成任选含有氧原子的5元、6元或7元脂肪族环； Wherein R f is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R h , or R f and R g are combined to form a 5-, 6-, or 7-membered aliphatic ring optionally containing an oxygen atom;
R g选自氢、氘、C 1-6烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R h，或者R g和R8与它们所连接的原子一起形成5元或6元脂肪族环； R g is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R h , or R g and R8 with the atom to which they are attached Forming a 5- or 6-membered aliphatic ring together;
R h独立选自氢、氘、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基，或者两个Rh基团与它们所连接的氮结合在一起形成5元或6元脂肪族环； R h is independently selected from hydrogen, hydrazine, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two Rh groups are bonded to the nitrogen to which they are attached to form a 5 dollar Or a 6-membered aliphatic ring;
R 8选自氢、氘、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基； R 8 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
R 9、R 10、R 11、R 12、R 13和R 14独立选自氢、氘、C 1-6烷基、环烷基、杂环烷基、芳基、杂芳基、卤素、OR h、C(＝O)R h、C(＝O)OR h、OC(＝O)R h、C(＝O)N(R h) 2、C(＝O)NR hSO 2R h、N(R h) 2、NR eC(＝O)R h、NR hC(＝O)N(R h) 2、CN、NO 2、CF 3、OCF 3、SR h、SOR h、SO 2R h、SO 2N(R h) 2和OSO 2CF 3； R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently selected from hydrogen, hydrazine, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halogen, OR h , C(=O)R h , C(=O)OR h , OC(=O)R h , C(=O)N(R h ) 2 , C(=O)NR h SO 2 R h , N(R h ) 2 , NR e C(=O)R h , NR h C(=O)N(R h ) 2 , CN, NO 2 , CF 3 , OCF 3 , SR h , SOR h , SO 2 R h , SO 2 N(R h ) 2 and OSO 2 CF 3 ;
R 15为氢或氘； R 15 is hydrogen or helium;
R 16为氢或氘； R 16 is hydrogen or helium;
R 17为氢或氘； R 17 is hydrogen or helium;
p为0、1、2、3、4或5，且，当p为2时，R f和R g中的一个不为乙基； p is 0, 1, 2, 3, 4 or 5, and when p is 2, one of R f and R g is not ethyl;
且R f、R g、R h、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16和R 17中至少一个为氘。 And at least one of R f , R g , R h , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 is 氘.
优选地，所述化合物具有结构式Ⅲb：Preferably, the compound has the structural formula IIIb:
Figure PCTCN2018108428-appb-000014
Figure PCTCN2018108428-appb-000014
R g为氢、氘或甲基，或者R g和R 8与它们所连接的原子一起形成含有一个氮原子的5元脂肪族环； R g is hydrogen, deuterium or methyl, or R g and R 8 together with the atom to which they are attached form a 5-membered aliphatic ring containing a nitrogen atom;
R 8为氢或氘； R 8 is hydrogen or helium;
R 15为氢或氘； R 15 is hydrogen or helium;
R 16为氢或氘； R 16 is hydrogen or helium;
R 17为氢或氘； R 17 is hydrogen or helium;
且p为1或2；And p is 1 or 2;
且R g、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16和R 17中至少一个为氘。 And at least one of R g , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 is 氘.
本发明还提供了式Ⅳ所示的化合物或其药学上可接受的盐或其水合物：The present invention also provides a compound of the formula IV or a pharmaceutically acceptable salt thereof or a hydrate thereof:
Figure PCTCN2018108428-appb-000015
Figure PCTCN2018108428-appb-000015
q为0、1、2、3、4或5；q is 0, 1, 2, 3, 4 or 5;
R 18选自氢、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R i，或者R 18和R 19结合在一起形成5元、6元或7元脂肪族环，任选含有氧原子； R 18 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R i , or R 18 and R 19 are taken together to form a 5-, 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
R 19选自氢、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R i； R 19 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R i ;
R i独立选自氢、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基，或者两个R i基团与它们所连接的氮结合在一起形成5元或6元脂肪族环。 R i is independently selected from hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R i groups are bonded to the nitrogen to which they are attached to form 5 or 6 yuan aliphatic ring.
优选地，R i独立地为氢或C 1-6烷基。 Preferably, R i is independently hydrogen or C 1-6 alkyl.
优选地，R 18为C 1-6烷基、C 3-5环烷基或C 1-3羟基烷基；R 19为氢、C 1-4烷基或C 3-5环烷基，或者R 18和R 19与它们所连接的原子一起形成含有一个氮原子的5元或6元脂肪族环，任选含有氧原子； Preferably, R 18 is C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl; R 19 is hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl, or R 18 and R 19 together with the atom to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, optionally containing an oxygen atom;
优选地，R 18为甲基、乙基、正丙基、异丙基、环丁基或2-羟基乙基；R 19为氢、甲基、乙基或环丁基，或者R 18和R 19结合在一起形成吗啉代部分、四氢呋喃基部分、哌啶基部分或
Figure PCTCN2018108428-appb-000016
部分、
Figure PCTCN2018108428-appb-000017
部分或
Figure PCTCN2018108428-appb-000018
部分；R 103为甲基或乙基。 Preferably, R 18 is methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl; R 19 is hydrogen, methyl, ethyl or cyclobutyl, or R 18 and R 19 combine to form a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or
Figure PCTCN2018108428-appb-000016
section,
Figure PCTCN2018108428-appb-000017
Partial or
Figure PCTCN2018108428-appb-000018
Part; R 103 is methyl or ethyl.
本发明还提供了式Ⅴ所示的化合物或其药学上可接受的盐或其水合物：The present invention also provides a compound of the formula V or a pharmaceutically acceptable salt thereof or a hydrate thereof:
Figure PCTCN2018108428-appb-000019
Figure PCTCN2018108428-appb-000019
r为0、1、2、3、4或5；r is 0, 1, 2, 3, 4 or 5;
R 20选自氢、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R j，或者R 20和R 21结合在一起形成5元、6元或7元脂肪族环，任选含有氧原子； R 20 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R j , or R 20 and R 21 are taken together to form a 5-, 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
R 21选自氢、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R j； R 21 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R j ;
R j独立选自氢、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基，或者两个R j基团与它们所连接的氮结合在一起形成5元或6元脂肪族环。 R j is independently selected from hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R j groups are bonded to the nitrogen to which they are attached to form 5 Å or 6 yuan aliphatic ring.
优选地，R j独立地为氢或C 1-6烷基。 Preferably, R j is independently hydrogen or C 1-6 alkyl.
优选地，R 20为C 1-6烷基、C 3-5环烷基或C 1-3羟基烷基； Preferably, R 20 is C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl;
R 21为氢、C 1-4烷基或C 3-5环烷基，或者R 20和R 21与它们所连接的原子一起形成含有一个氮原子的5元或6元脂肪族环，任选含有氧原子； R 21 is hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl, or R 20 and R 21 together with the atom to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, optionally Containing oxygen atoms;
优选地，R 20为甲基、乙基、正丙基、异丙基、环丁基或2-羟基乙基；R 21为氢、甲基、乙基或环丁基，或者R 20和R 21结合在一起形成吗啉代部分、四氢呋喃基部分、哌啶基部分或
Figure PCTCN2018108428-appb-000020
部分、
Figure PCTCN2018108428-appb-000021
部分、
Figure PCTCN2018108428-appb-000022
部分；R 104为甲基或乙基。 Preferably, R 20 is methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl; R 21 is hydrogen, methyl, ethyl or cyclobutyl, or R 20 and R 21 is combined to form a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or
Figure PCTCN2018108428-appb-000020
section,
Figure PCTCN2018108428-appb-000021
section,
Figure PCTCN2018108428-appb-000022
Part; R 104 is methyl or ethyl.
优选地，R 20为甲基；R 21为甲基、乙基或环丁基，或者R 20和R 21结合在一起形成
Figure PCTCN2018108428-appb-000023
部分；R 104为甲基。 Preferably, R 20 is a methyl group; R 21 is a methyl group, an ethyl group or a cyclobutyl group, or R 20 and R 21 are combined to form
Figure PCTCN2018108428-appb-000023
Part; R 104 is a methyl group.
本发明还提供了式Ⅵ所示的化合物或其药学上可接受的盐或其水合物：The present invention also provides a compound of the formula VI or a pharmaceutically acceptable salt thereof or a hydrate thereof:
Figure PCTCN2018108428-appb-000024
Figure PCTCN2018108428-appb-000024
s为0、1、2、3、4或5；s is 0, 1, 2, 3, 4 or 5;
R 22选自氢、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R j，或者R 22和R 23结合在一起形成5元、6元或7元脂肪族环，任选含有氧原子； R 22 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R j , or R 22 and R 23 are taken together to form a 5-, 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
R 23选自氢、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R k； R 23 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R k ;
R k独立选自氢、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基，或者两个R k基团与它们所连接的氮结合在一起形成5元或6元脂肪族环。 R k is independently selected from hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R k groups are bonded to the nitrogen to which they are attached to form 5 Å or 6 yuan aliphatic ring.
优选地，R k独立地为氢或C 1-6烷基。 Preferably, R k is independently hydrogen or C 1-6 alkyl.
优选地，R 22为C 1-6烷基、C 3-5环烷基或C 1-3羟基烷基；R 23为氢、C 1-4烷基或C 3-5环烷基，或者R 22和R 23与它们所连接的原子一起形成含有一个氮原子的5元或6元脂肪族环，任选含有氧原子。 Preferably, R 22 is C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl; R 23 is hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl, or R 22 and R 23 together with the atoms to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, optionally containing an oxygen atom.
优选地，R 22为甲基、乙基、正丙基、异丙基、环丁基或2-羟基乙基；R 23为氢、甲基、乙基或环丁基，或者R 22和R 23结合在一起形成吗啉代部分、四氢呋喃基部分、哌啶基部分或
Figure PCTCN2018108428-appb-000025
部分、
Figure PCTCN2018108428-appb-000026
部分、
Figure PCTCN2018108428-appb-000027
部分；R 105为甲基或乙基。 Preferably, R 22 is methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl; R 23 is hydrogen, methyl, ethyl or cyclobutyl, or R 22 and R 23 combine to form a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or
Figure PCTCN2018108428-appb-000025
section,
Figure PCTCN2018108428-appb-000026
section,
Figure PCTCN2018108428-appb-000027
Part; R 105 is methyl or ethyl.
优选地，R 22为甲基；R 23为甲基、乙基或环丁基，或者R 22和R 23结合在一起形成
Figure PCTCN2018108428-appb-000028
部分；R 105为甲基； Preferably, R 22 is a methyl group; R 23 is a methyl group, an ethyl group or a cyclobutyl group, or R 22 and R 23 are combined to form
Figure PCTCN2018108428-appb-000028
Part; R 105 is a methyl group;
优选地，所述化合物的结构式如下：Preferably, the structural formula of the compound is as follows:
Figure PCTCN2018108428-appb-000029
Figure PCTCN2018108428-appb-000029
本发明还提供了式Ⅶ所示的化合物或其药学上可接受的盐或其水合物：The present invention also provides a compound of the formula VII or a pharmaceutically acceptable salt thereof or a hydrate thereof:
Figure PCTCN2018108428-appb-000030
Figure PCTCN2018108428-appb-000030
t为0、1、2、3、4或5；t is 0, 1, 2, 3, 4 or 5;
R 24选自氢、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R j，或者R 24和R 25结合在一起形成5元、6元或7元脂肪族环，任选含有氧原子； R 24 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R j , or R 24 and R 25 are taken together to form a 5-, 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
R 25选自氢、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R m； R 25 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R m ;
R m独立选自氢、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基，或者两个R m基团与它们所连接的氮结合在一起形成5元或6元脂肪族环。 R m is independently selected from hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R m groups are bonded to the nitrogen to which they are attached to form 5 or 6 yuan aliphatic ring.
优选地，R m独立地为氢或C 1-6烷基。 Preferably, R m is independently hydrogen or C 1-6 alkyl.
优选地，R 24为C 1-6烷基、C 3-5环烷基或C 1-3羟基烷基； Preferably, R 24 is C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl;
R 25为氢、C 1-4烷基或C 3-5环烷基，或者R 24和R 25与它们所连接的原子一起形成含有一个氮原子的5元或6元脂肪族环，任选含有氧原子。 R 25 is hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl, or R 24 and R 25 together with the atom to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, optionally Contains oxygen atoms.
优选地，R 24为甲基、乙基、正丙基、异丙基、环丁基或2-羟基乙基；R 25为氢、甲基、乙基或环丁基，或者R 22和R 23结合在一起形成吗啉代部分、四氢呋喃基部分、哌啶 基部分或
Figure PCTCN2018108428-appb-000031
部分、
Figure PCTCN2018108428-appb-000032
部分、
Figure PCTCN2018108428-appb-000033
部分；R 106为甲基或乙基。 Preferably, R 24 is methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl; R 25 is hydrogen, methyl, ethyl or cyclobutyl, or R 22 and R 23 combine to form a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or
Figure PCTCN2018108428-appb-000031
section,
Figure PCTCN2018108428-appb-000032
section,
Figure PCTCN2018108428-appb-000033
Part; R 106 is methyl or ethyl.
优选地，其中t为0、1、2、3、4或5；R 24为甲基；R 25为甲基。 Preferably, wherein t is 0, 1, 2, 3, 4 or 5; R 24 is methyl; R 25 is methyl.
本发明还提供了一种氘代咔唑类化合物或其药学上可接受的盐或其水合物，所述化合物具有下述结构：The present invention also provides a deuterated carbazole compound or a pharmaceutically acceptable salt thereof or a hydrate thereof, which has the following structure:
Figure PCTCN2018108428-appb-000034
或者
Figure PCTCN2018108428-appb-000034
or
Figure PCTCN2018108428-appb-000035
Figure PCTCN2018108428-appb-000035
本发明还提供了所述的化合物其药学上可接受的盐或其水合物在制备用于治疗癌症的药物中的用途。The present invention also provides the use of the compound, a pharmaceutically acceptable salt thereof, or a hydrate thereof, for the preparation of a medicament for treating cancer.
优选地，其中所述癌症选自：肺腺癌、淋巴系造血系统肿瘤、髓系造血系统肿瘤、中枢和周围神经系统肿瘤、间充质细胞起源的肿瘤、着色性干皮病、角化棘皮瘤、精原细胞瘤、甲状腺滤泡癌、畸胎癌、结肠直肠癌、头颈部癌症、乳癌、胃癌、外阴癌、黑素瘤、卵巢癌、肺癌、尤因肉瘤、鳞状细胞癌、口腔癌、血细胞恶性肿瘤、胸腺淋巴瘤性肺癌、小细胞癌、肾上腺皮质的癌症、产生ACTH的肿瘤、非小细胞癌、导管癌、与结肠直肠瘤形成相关的息肉、胰腺癌、肝癌、泌尿系统癌症、前列腺癌、原发性腹膜上皮赘生物、阴道癌、外阴癌、子宫癌、卵泡内的实体瘤、睾丸癌、阴茎癌、脑癌、中枢神经系统内的转移性肿瘤细胞侵袭、骨癌、甲状腺癌、成视网膜细胞瘤、弥散性腹膜癌、恶性弥散性胸膜癌、间皮瘤、维尔姆斯瘤、胆囊癌、绒毛膜上皮肿瘤、血管外皮细胞瘤和卡波西肉瘤。Preferably, the cancer is selected from the group consisting of: lung adenocarcinoma, lymphoid hematopoietic tumor, myeloid hematopoietic tumor, central and peripheral nervous system tumor, mesenchymal cell-derived tumor, xeroderma pigmentosum, keratinized echinoderma Tumor, seminoma, thyroid follicular carcinoma, teratocarcinoma, colorectal cancer, head and neck cancer, breast cancer, stomach cancer, vulvar cancer, melanoma, ovarian cancer, lung cancer, Ewing sarcoma, squamous cell carcinoma, Oral cancer, blood cell malignancy, thymoma lymphoma, small cell carcinoma, adrenal cortical cancer, ACTH-producing tumor, non-small cell carcinoma, ductal carcinoma, polyps associated with colorectal neoplasia, pancreatic cancer, liver cancer, urinary Systemic cancer, prostate cancer, primary peritoneal epithelial neoplasm, vaginal cancer, vulvar cancer, uterine cancer, solid tumor in follicle, testicular cancer, penile cancer, brain cancer, metastatic tumor cell invasion in the central nervous system, bone Cancer, thyroid cancer, retinoblastoma, diffuse peritoneal cancer, malignant diffuse pleural cancer, mesothelioma, Wilms' tumor, gallbladder cancer, chorionic epithelial tumor, blood Tube epithelioma and Kaposi's sarcoma.
优选地，其中所述癌症选自恶化的膀胱癌、转移的膀胱癌、白血病、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤、组织细胞淋巴瘤、伯基特淋巴瘤、弥散性淋巴瘤、皮肤T细胞淋巴瘤、胶质瘤、外分泌胰腺癌、非小细胞肺癌、食管鳞状细胞癌、多发性骨髓瘤、结肠癌、宫颈癌、子宫内膜癌症、内源性脑肿瘤和星形细胞性脑肿瘤。Preferably, wherein the cancer is selected from the group consisting of a deteriorated bladder cancer, metastatic bladder cancer, leukemia, B cell lymphoma, T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, tissue Cellular lymphoma, Burkitt's lymphoma, diffuse lymphoma, cutaneous T-cell lymphoma, glioma, exocrine pancreatic cancer, non-small cell lung cancer, esophageal squamous cell carcinoma, multiple myeloma, colon cancer, cervical cancer , endometrial cancer, endogenous brain tumors and astrocytic brain tumors.
优选地，其中所述癌症选自：急性淋巴细胞白血病、骨髓性淋巴母细胞性白血病、急性非淋巴细胞白血病、慢性淋巴细胞白血病、慢性骨髓细胞白血病、毛细胞白血病、骨髓异常增生综合征、骨髓性白血病、早幼粒细胞白血病、骨髓瘤、星形细胞瘤、成神经细胞瘤、神经鞘瘤、成胶质细胞瘤、纤维肉瘤、横纹肌肉瘤、骨瘤、小细胞肺癌和膀胱癌。Preferably, the cancer is selected from the group consisting of acute lymphoblastic leukemia, myeloid lymphoblastic leukemia, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, bone marrow Leukemia, promyelocytic leukemia, myeloma, astrocytoma, neuroblastoma, schwannomas, glioblastoma, fibrosarcoma, rhabdomyosarcoma, osteoma, small cell lung cancer and bladder cancer.
优选地，其中所述癌症选自：原发性浅层膀胱肿瘤、膀胱的侵袭性过渡性细胞癌、侵袭肌肉的膀胱癌和骨肉瘤。Preferably, the cancer is selected from the group consisting of: a primary superficial bladder tumor, an invasive transitional cell carcinoma of the bladder, a bladder cancer that invades the muscle, and an osteosarcoma.
优选地，其中所述癌症选自：急性淋巴母细胞白血病、和急性和慢性骨髓性白血病。Preferably, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia, and acute and chronic myelogenous leukemia.
优选地，其中，所述的化合物与化疗药、放疗、影响微管的药物、细胞生长抑制药、TNF多肽及其混合物联合给予。Preferably, the compound is administered in combination with a chemotherapeutic agent, radiation therapy, a drug affecting microtubules, a cytostatic agent, a TNF polypeptide, and a mixture thereof.
本发明还提供了所述的化合物其药学上可接受的盐或其水合物在制备用于治疗有需要的个体中炎性疾病的药物中的用途。The invention also provides the use of a pharmaceutically acceptable salt of the compound, or a hydrate thereof, for the manufacture of a medicament for the treatment of an inflammatory disease in an individual in need thereof.
优选地，其中所述炎性疾病选自：类风湿性关节炎、银屑病、白斑、韦格纳肉芽肿病和系统性红斑狼疮。Preferably, wherein the inflammatory disease is selected from the group consisting of rheumatoid arthritis, psoriasis, leukoplakia, Wegener's granulomatosis, and systemic lupus erythematosus.
优选地，其中，前述化合物与免疫抑制药联合给予。Preferably, wherein the aforementioned compound is administered in combination with an immunosuppressive drug.
本发明还提供了所述的化合物或其药学上可接受的盐或其水合物在制备用于治疗微生物感染、原生动物感染或病毒感染的药物中的用途。The invention also provides the use of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, for the manufacture of a medicament for the treatment of a microbial infection, a protozoal infection or a viral infection.
优选地，其中所述原生动物感染是疟疾。Preferably, wherein the protozoan infection is malaria.
本发明还提供了所述的化合物或其药学上可接受的盐或其水合物在制备用于治疗疾病或病症的药物中的用途，所述疾病或病症选自动脉粥样硬化、再狭窄、血管炎、视网膜病、肾病、增生性皮肤病、银屑病、瘢痕瘤性疤痕形成、光化性角化病、斯蒂文斯-约翰逊综合征、类风湿性关节炎、系统性起病型青少年慢性关节炎、骨质疏松症、系统性红斑狼疮、眼的过度增殖性疾病、血管性增殖性疾病、鱼鳞病和乳头瘤。The invention also provides the use of a compound, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, for the manufacture of a medicament for the treatment of a disease or condition selected from the group consisting of atherosclerosis, restenosis, Vasculitis, retinopathy, nephropathy, proliferative skin disease, psoriasis, keloid scar formation, actinic keratosis, Stevens-Johnson syndrome, rheumatoid arthritis, systemic onset Chronic arthritis, osteoporosis, systemic lupus erythematosus, hyperproliferative diseases of the eye, vascular proliferative diseases, ichthyosis and papilloma.
本发明还提供了所述的化合物或其药学上可接受的盐或其水合物在制备用于治疗疾病或病症的药物中的用途，所述疾病或病症选自肾炎、增殖性玻璃体视网膜病、糖尿病性视网膜病和涉及上皮向内生长的眼的过度增殖性疾病。The present invention also provides the use of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, for the preparation of a medicament for treating a disease or condition selected from the group consisting of nephritis, proliferative vitreoretinopathy, Diabetic retinopathy and hyperproliferative diseases of the eye involving epithelial ingrowth.
本发明的化合物可以通过下述路线合成：The compounds of the invention can be synthesized by the following routes:
合成路线一Synthetic route one
Figure PCTCN2018108428-appb-000036
Figure PCTCN2018108428-appb-000036
合成路线二Synthetic route two
Figure PCTCN2018108428-appb-000037
Figure PCTCN2018108428-appb-000037
合成路线三Synthetic route three
Figure PCTCN2018108428-appb-000038
Figure PCTCN2018108428-appb-000038
实验结果证明，本发明化合物8可以有效抑制卵巢癌细胞的增殖，证明其可以有效治疗癌症，尤其是卵巢癌，药代实验表明化合物8在动物体内有更好的药代稳定性，体内持续期比未氘代化合物高出15％。有助于降低药物使用剂量和使用周期。。The experimental results show that the compound 8 of the present invention can effectively inhibit the proliferation of ovarian cancer cells, and prove that it can effectively treat cancer, especially ovarian cancer. The pharmacokinetic experiments show that the compound 8 has better pharmacokinetic stability in the animal, and the duration of the body It is 15% higher than the non-deuterated compound. Helps reduce the dose and duration of drug use. .
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。It is apparent that various other modifications, substitutions and changes can be made in the form of the above-described embodiments of the present invention.
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention.
附图说明DRAWINGS
图1-6为实施例3化合物的核磁谱图。1-6 are NMR spectra of the compound of Example 3.
图1实施例3化合物1的核磁谱图： 1H NMR(400MHz,CDCl 3)δ8.78(d,J＝1.2Hz,2H),8.19(dd,J＝8.6,1.6Hz,2H),7.50(d,J＝8.7Hz,2H),4.78(t,J＝7.0Hz,2H),3.75(t,J＝7.0Hz,2H),2.75(s,6H)。 Figure 1 NMR spectrum of Compound 1 of Example 3: 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (d, J = 1.2 Hz, 2H), 8.19 (dd, J = 8.6, 1.6 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 4.78 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 7.0 Hz, 2H), 2.75 (s, 6H).
图2实施例3化合物2的核磁谱图： 1H NMR(400MHz,CDCl 3)δ8.78(d,J＝1.3Hz,2H),8.19(dd,J＝8.6,1.5Hz,2H),7.50(d,J＝8.7Hz,2H),4.78(t,J＝7.0Hz,2H),3.75(t,J＝7.0Hz,2H),2.75(s,6H). Figure 2 NMR spectrum of Compound 2 of Example 3: 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (d, J = 1.3 Hz, 2H), 8.19 (dd, J = 8.6, 1.5 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 4.78 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 7.0 Hz, 2H), 2.75 (s, 6H).
图3实施例3化合物3的核磁谱图： 1H NMR(400MHz,CDCl 3)δ8.79(d,J＝1.3Hz,2H),8.19(dd,J＝8.7,1.7Hz,2H),7.50(d,J＝8.6Hz,2H),4.51(s,2H),2.78(s,2H),2.75(s,6H),2.38(s,6H). Figure 3 NMR spectrum of Compound 3 of Example 3: 1 H NMR (400 MHz, CDCl 3 ) δ 8.79 (d, J = 1.3 Hz, 2H), 8.19 (dd, J = 8.7, 1.7 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 4.51 (s, 2H), 2.78 (s, 2H), 2.75 (s, 6H), 2.38 (s, 6H).
图4实施例3化合物4的核磁谱图： 1H NMR(400MHz,CDCl 3)δ8.79(d,J＝1.3Hz,2H),8.19(dd,J＝8.7,1.7Hz,2H),7.50(d,J＝8.6Hz,2H),4.51(s,2H),2.78(s,2H),2.75(s,6H),2.38(s,6H). Figure 4 NMR spectrum of Compound 4 of Example 3: 1 H NMR (400 MHz, CDCl 3 ) δ 8.79 (d, J = 1.3 Hz, 2H), 8.19 (dd, J = 8.7, 1.7 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 4.51 (s, 2H), 2.78 (s, 2H), 2.75 (s, 6H), 2.38 (s, 6H).
图5实施例3化合物6的核磁谱图： 1H NMR(400MHz,CDCl 3)δ8.77(s,2H),8.18(dd,J＝8.6,0.9Hz,2H),7.50(d,J＝8.7Hz,2H),4.89–4.71(m,2H),3.72(dt,J＝7.3,6.0Hz,2H). Figure 5 NMR spectrum of Compound 6 of Example 3: 1 H NMR (400 MHz, CDCl 3 ) δ 8.77 (s, 2H), 8.18 (dd, J = 8.6, 0.9 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 4.89 - 4.71 (m, 2H), 3.72 (dt, J = 7.3, 6.0 Hz, 2H).
图6本实施例3化合物7的核磁谱图： 1H NMR(400MHz,CDCl 3)δ8.78–8.71(m,1H),8.20–8.09(m,2H),7.59–7.49(m,1H),7.46(dd,J＝13.3,6.1Hz,2H),7.34(t,J＝7.5Hz,1H),4.81–4.67(m,2H),3.71(t,J＝7.3Hz,2H). Figure 6 Nuclear magnetic resonance spectrum of the compound 7 of the present Example 3: 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 - 8.71 (m, 1H), 8.20 - 8.09 (m, 2H), 7.59 - 7.49 (m, 1H) , 7.46 (dd, J = 13.3, 6.1 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 4.81 - 4.67 (m, 2H), 3.71 (t, J = 7.3 Hz, 2H).
图7本发明化合物的抗肿瘤作用图Figure 7 is an anti-tumor effect diagram of the compound of the present invention
具体实施方式Detailed ways
化合物1的核磁谱图如图1所示： 1H NMR(400MHz,CDCl 3)δ8.78(d,J＝1.2Hz,2H),8.19(dd,J＝8.6,1.6Hz,2H),7.50(d,J＝8.7Hz,2H),4.78(t,J＝7.0Hz,2H),3.75(t,J＝7.0Hz,2H),2.75(s,6H)。 The NMR spectrum of Compound 1 is shown in Figure 1: 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (d, J = 1.2 Hz, 2H), 8.19 (dd, J = 8.6, 1.6 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 4.78 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 7.0 Hz, 2H), 2.75 (s, 6H).
化合物2的核磁谱图如图2所示： 1H NMR(400MHz,CDCl 3)δ8.78(d,J＝1.3Hz,2H),8.19(dd,J＝8.6,1.5Hz,2H),7.50(d,J＝8.7Hz,2H),4.78(t,J＝7.0Hz,2H),3.75(t,J＝7.0Hz,2H),2.75(s,6H). The NMR spectrum of Compound 2 is shown in Figure 2: 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (d, J = 1.3 Hz, 2H), 8.19 (dd, J = 8.6, 1.5 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 4.78 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 7.0 Hz, 2H), 2.75 (s, 6H).
实施例1 本发明化合物的合成Example 1 Synthesis of a Compound of the Invention
Figure PCTCN2018108428-appb-000039
Figure PCTCN2018108428-appb-000039
A将咔唑(1.7g，0.01mol)溶于硝基苯(30mL)中。在搅拌下并用冰浴冷却的同时加入无水AlCl 3(2.5g，0.02mol)。然后，慢慢地滴加AcCl(2.9g，0.04mol)。使反应混合物在搅拌下升温至室温并保持13h的时间。在用冰浴冷却下分小批量加入水(50mL)。去除冷浴，并将混合物在2h的时间内回流并用CHCl 3(3×150mL)萃取。合并的萃取液依次用饱和NaHCO 3溶液和饱和NaCl溶液洗涤，用无水Na 2SO 4干燥，和蒸发。残余物通过柱色谱法纯化(硅胶，CHCl 3/MeOH)，得到1.3g 3-乙酰基咔唑(4)。 A carbazole (1.7 g, 0.01 mol) was dissolved in nitrobenzene (30 mL). Anhydrous AlCl 3 (2.5 g, 0.02 mol) was added while stirring and cooling with an ice bath. Then, AcCl (2.9 g, 0.04 mol) was slowly added dropwise. The reaction mixture was allowed to warm to room temperature with stirring and maintained for a period of 13 h. Water (50 mL) was added in small portions under cooling with an ice bath. Cooling bath was removed, and the mixture was refluxed and extracted with CHCl 3 (3 × 150mL) over time 2h. The combined extracts were washed with saturated NaHCO 3 solution and saturated NaCl solution, dried over anhydrous Na 2 SO 4 dried, and evaporated. The residue was purified by column chromatography (silica gel, CHCl 3 / MeOH) to afford 1.3g 3- acetyl-carbazole (4).
B将咔唑1(16.9g，0.1mol)溶于硝基苯(300mL)中。在搅拌下并用冰浴冷却的同时加入无水AlCl 3(54.0g，0.4mol)。然后，慢慢地滴加CD 3COCl(55.5g，0.7mol)。使反应混合物在搅拌下升温至室温并保持13h的时间。在用冰浴冷却下分小批量加入水(500mL)。去除冷浴，并将混合物在2h的时间内回流并用CHCl 3(3×150mL)萃取。合并的萃取液依次用饱和NaHCO 3溶液和饱和NaCl溶液洗涤，用无水Na 2SO 4干燥，和蒸发。残余物通过柱色谱法纯化(硅胶，CHCl 3/MeOH)，得到12.5g(50％)3，6-二氘代乙酰基咔唑。 B. Indazole 1 (16.9 g, 0.1 mol) was dissolved in nitrobenzene (300 mL). Anhydrous AlCl 3 (54.0 g, 0.4 mol) was added while stirring and cooling with an ice bath. Then, CD 3 COCl (55.5 g, 0.7 mol) was slowly added dropwise. The reaction mixture was allowed to warm to room temperature with stirring and maintained for a period of 13 h. Water (500 mL) was added in small portions while cooling with an ice bath. Cooling bath was removed, and the mixture was refluxed and extracted with CHCl 3 (3 × 150mL) over time 2h. The combined extracts were washed with saturated NaHCO 3 solution and saturated NaCl solution, dried over anhydrous Na 2 SO 4 dried, and evaporated. The residue was purified by column chromatography (silica gel, CHCl 3 / MeOH) to afford 12.5g (50%) 3,6- dideutero acetyl carbazole.
实施例2 本发明化合物的合成Example 2 Synthesis of a Compound of the Invention
Figure PCTCN2018108428-appb-000040
Figure PCTCN2018108428-appb-000040
将1-N，N-二乙基氨基乙基咔唑(0.23g，0.86mmol)与2mL硝基苯的溶液在冰浴中冷却。加入AlCl 3(0.57g，4.3mmol)和3-氯丙酰基氯(0.2mL，2mmol)。将反应混合物搅拌过夜并用HCl水溶液稀释。产物用CHCl 3萃取，蒸发滤液。残余物色谱法在短硅胶柱中通 过色谱法快速纯化(CHCl 3/MeOH)，得到0.16g(50％)氯丙酰基-9-N，N-二乙基氨基乙基咔唑，为其盐酸盐。 A solution of 1-N,N-diethylaminoethylcarbazole (0.23 g, 0.86 mmol) and 2 mL of nitrobenzene was cooled in an ice bath. AlCl 3 (0.57 g, 4.3 mmol) and 3-chloropropanoyl chloride (0.2 mL, 2 mmol) were added. The reaction mixture was stirred overnight and diluted with aqueous HCl. The product was extracted with CHCl 3, and the filtrate was evaporated. The residue was purified by flash chromatography (CHCl 3 /MeOH) eluting Acid salt.
将化合物2(0.38g，0.79mmol)溶于98％H 2SO 4(3mL)中。将反应混合物加热到95C，在2.5h的时间内保持在该温度下(TLC监测，CHCl 3/MeOH，4∶1)，再倒入冰中。所得混合物用无水Na 2CO 3中和并用CHCl 3萃取。将萃取液蒸发，残余物通过柱色谱法纯化(CHCl 3/MeOH)。将所获得的粗产物(0.08g)溶于MeOH中。加入4M HCl的二噁烷溶液，并蒸发混合物。将残余物悬浮于MeOH中，并将悬浮液回流。(在此过程中固体不溶解)。将悬浮液冷却后滤出固体，得到0.07g(20％)化合物，为其盐酸盐。 Compound 2 (0.38g, 0.79mmol) was dissolved in 98% H 2 SO 4 (3mL ) in. The reaction mixture was heated to 95C, kept at this temperature for 2.5h in time (TLC monitoring, CHCl 3 / MeOH, 4:1) , then poured into ice. The resulting mixture was 2 CO 3 and extracted with CHCl 3 and dried over anhydrous Na. The extract was evaporated and the residue was purified by column chromatography (CHCl 3 / MeOH) through. The obtained crude product (0.08 g) was dissolved in MeOH. A solution of 4M HCl in dioxane was added and the mixture was evaporated. The residue was suspended in MeOH and the suspension was reflux. (The solid does not dissolve during this process). The suspension was cooled and the solid was filtered to give <RTI ID=0.0>>
实施例3 本发明化合物的合成Example 3 Synthesis of a Compound of the Invention
Figure PCTCN2018108428-appb-000041
Figure PCTCN2018108428-appb-000041
1g咔唑溶于5ml DMF中，在冰水浴冷却下逐渐加入1g NaH，此为混合液A，将混合液A滴加至10ml DMF与5ml 1,2-二溴乙烷的混合液B中。加料结束后，撤去冰浴，搅拌数小时后，产物不再增加，缓慢加水淬灭反应。减压蒸馏除去溶剂，加入DCM和水分液，得到有机相，干法上样过柱子。洗脱剂为，PE：DCM＝5:1。分离得产物120mg。1 g of carbazole was dissolved in 5 ml of DMF, and 1 g of NaH was gradually added under cooling in an ice water bath, which was a mixture A, and the mixture A was added dropwise to a mixture B of 10 ml of DMF and 5 ml of 1,2-dibromoethane. After the end of the addition, the ice bath was removed, and after stirring for several hours, the product was no longer increased, and the reaction was quenched by slowly adding water. The solvent was distilled off under reduced pressure, and DCM and aqueous solution were added to give an organic phase, which was applied to the column. The eluent was, PE: DCM = 5:1. The product was isolated in 120 mg.
Figure PCTCN2018108428-appb-000042
Figure PCTCN2018108428-appb-000042
870mg(3.2mmol)化合物1，溶于40ml DCM中，加入1.28g(3eq)AlCl 3，搅拌数分钟，加入2.5ml乙酰氯，再搅拌数分钟后，大部分原料已经反应。数十分钟后，加水淬灭反应，萃取分液。洗脱剂为，DCM：EA＝12.5:1。分离得产物920mg，产率81％。 870 mg (3.2 mmol) of compound 1 was dissolved in 40 ml of DCM, 1.28 g (3 eq) of AlCl 3 was added, stirred for a few minutes, 2.5 ml of acetyl chloride was added, and after stirring for a few more minutes, most of the starting materials had reacted. After tens of minutes, the reaction was quenched with water and the mixture was separated. The eluent was, DCM: EA = 12.5:1. The product was isolated in 920 mg, yield 81%.
Figure PCTCN2018108428-appb-000043
Figure PCTCN2018108428-appb-000043
207mg化合物2，22ml正丁醇：H 2O＝10:1的混合溶剂，800uL 33％的二甲胺水溶液，高压反应釜中升温至150℃，反应24h。TLC条件：DCM：MeOH＝10:1。 207 mg of compound 2, 22 ml of n-butanol: a mixed solvent of H 2 O = 10:1, 800 uL of a 33% aqueous solution of dimethylamine, and the temperature was raised to 150 ° C in an autoclave for 24 h. TLC conditions: DCM: MeOH = 10:1.
Figure PCTCN2018108428-appb-000044
Figure PCTCN2018108428-appb-000044
反应过程同二甲胺反应过程类似，205mg化合物2，22ml正丁醇：H 2O＝10:1的混合溶剂，200uL异丙胺，高压反应釜中升温至150℃，反应24h。TLC条件：MeOH＝10:1。 The reaction process was similar to the dimethylamine reaction process, 205 mg of compound 2 , 22 ml of n-butanol: H 2 O = 10:1 mixed solvent, 200 uL of isopropylamine, and the temperature was raised to 150 ° C in an autoclave for 24 h. TLC conditions: MeOH = 10:1.
Figure PCTCN2018108428-appb-000045
Figure PCTCN2018108428-appb-000045
55mg(0.2mmol)化合物1溶于20ml二氯甲烷，加入27mg(0.2mmol)无水AlCl 3，搅拌几分钟，加入15uL(0.2mmol)乙酰氯，转化率低，补加3eq无水AlCl 3和3eq乙酰氯，基本都转化为单取代产物，缓慢加水淬灭，水洗多次。干法上样，纯的DCM过柱子。TLC条件：DCM。 55 mg (0.2 mmol) of Compound 1 was dissolved in 20 ml of dichloromethane, 27 mg (0.2 mmol) of anhydrous AlCl 3 was added, stirred for a few minutes, 15 uL (0.2 mmol) of acetyl chloride was added, the conversion was low, and 3 eq of anhydrous AlCl 3 was added. 3 eq of acetyl chloride was basically converted into a monosubstituted product, slowly quenched with water and washed several times with water. Dry loading, pure DCM over the column. TLC conditions: DCM.
Figure PCTCN2018108428-appb-000046
Figure PCTCN2018108428-appb-000046
1g化合物1溶于200ml二氯甲烷，加入2g无水AlCl 3，搅拌几分钟，加入300uL氘代乙酰氯时，主要生成化合物，再加100uL时，化合物的量明显增多，停止反应。缓慢加水淬灭，水洗多次。干法上样，石油醚：二氯甲烷＝5:1分出化合物6，用纯的二氯甲烷分出化合物，用二氯甲烷：乙酸乙酯＝12.5:1分出化合物7。 1 g of Compound 1 was dissolved in 200 ml of dichloromethane, 2 g of anhydrous AlCl 3 was added, and stirred for several minutes. When 300 uL of deuterated acetyl chloride was added, a compound was mainly produced, and when 100 uL was added, the amount of the compound was significantly increased, and the reaction was stopped. Slowly add water to quench and wash several times. Dry-loading, petroleum ether: methylene chloride = 5:1, Compound 6 was isolated, and the compound was isolated from methylene chloride.
化合物8的反应过程同化合物4过程类似，205mg化合物7，22ml正丁醇：H 2O＝10:1的混合溶剂，200uL异丙胺，高压反应釜中升温至150℃，反应24h。TLC条件：MeOH＝10:1。 The reaction procedure of Compound 8 was similar to that of Compound 4, 205 mg of Compound 7, 22 ml of n-butanol: H 2 O = 10:1 mixed solvent, 200 uL of isopropylamine, and the temperature was raised to 150 ° C in an autoclave for 24 h. TLC conditions: MeOH = 10:1.
Figure PCTCN2018108428-appb-000047
Figure PCTCN2018108428-appb-000047
反应过程同化合物8过程类似。TLC条件：MeOH＝10:1。The reaction process is similar to the compound 8 process. TLC conditions: MeOH = 10:1.
本实施例化合物1的核磁谱图如图1所示： 1H NMR(400MHz,CDCl 3)δ8.78(d,J＝1.2Hz,2H),8.19(dd,J＝8.6,1.6Hz,2H),7.50(d,J＝8.7Hz,2H),4.78(t,J＝7.0Hz,2H),3.75(t,J＝7.0Hz,2H),2.75(s,6H). The NMR spectrum of Compound 1 of this example is shown in Figure 1: 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (d, J = 1.2 Hz, 2H), 8.19 (dd, J = 8.6, 1.6 Hz, 2H) ), 7.50 (d, J = 8.7 Hz, 2H), 4.78 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 7.0 Hz, 2H), 2.75 (s, 6H).
本实施例化合物2的核磁谱图如图2所示： 1H NMR(400MHz,CDCl 3)δ8.78(d,J＝1.3Hz,2H),8.19(dd,J＝8.6,1.5Hz,2H),7.50(d,J＝8.7Hz,2H),4.78(t,J＝7.0Hz,2H),3.75(t,J＝7.0Hz,2H),2.75(s,6H). The NMR spectrum of Compound 2 of this example is shown in Figure 2: 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (d, J = 1.3 Hz, 2H), 8.19 (dd, J = 8.6, 1.5 Hz, 2H) ), 7.50 (d, J = 8.7 Hz, 2H), 4.78 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 7.0 Hz, 2H), 2.75 (s, 6H).
本实施例化合物3的核磁谱图如图3所示： 1H NMR(400MHz,CDCl 3)δ8.79(d,J＝1.3Hz,2H),8.19(dd,J＝8.7,1.7Hz,2H),7.50(d,J＝8.6Hz,2H),4.51(s,2H),2.78(s,2H),2.75(s,6H),2.38(s,6H). The NMR spectrum of Compound 3 of this example is shown in Figure 3: 1 H NMR (400 MHz, CDCl 3 ) δ 8.79 (d, J = 1.3 Hz, 2H), 8.19 (dd, J = 8.7, 1.7 Hz, 2H) ), 7.50 (d, J = 8.6 Hz, 2H), 4.51 (s, 2H), 2.78 (s, 2H), 2.75 (s, 6H), 2.38 (s, 6H).
本实施例化合物4的核磁谱图如图4所示： 1H NMR(400MHz,CDCl 3)δ8.79(d,J＝1.3Hz,2H),8.19(dd,J＝8.7,1.7Hz,2H),7.50(d,J＝8.6Hz,2H),4.51(s,2H),2.78(s,2H),2.75(s,6H),2.38(s,6H). The NMR spectrum of Compound 4 of this example is shown in Figure 4: 1 H NMR (400 MHz, CDCl 3 ) δ 8.79 (d, J = 1.3 Hz, 2H), 8.19 (dd, J = 8.7, 1.7 Hz, 2H) ), 7.50 (d, J = 8.6 Hz, 2H), 4.51 (s, 2H), 2.78 (s, 2H), 2.75 (s, 6H), 2.38 (s, 6H).
本实施例化合物6的核磁谱图如图5所示： 1H NMR(400MHz,CDCl 3)δ8.77(s,2H),8.18(dd,J＝8.6,0.9Hz,2H),7.50(d,J＝8.7Hz,2H),4.89–4.71(m,2H),3.72(dt,J＝7.3,6.0Hz,2H). The NMR spectrum of Compound 6 of this example is shown in Figure 5: 1 H NMR (400 MHz, CDCl 3 ) δ 8.77 (s, 2H), 8.18 (dd, J = 8.6, 0.9 Hz, 2H), 7.50 (d) , J = 8.7 Hz, 2H), 4.89 - 4.71 (m, 2H), 3.72 (dt, J = 7.3, 6.0 Hz, 2H).
本实施例化合物7的核磁谱图如图6所示： 1H NMR(400MHz,CDCl 3)δ8.78–8.71(m,1H),8.20–8.09(m,2H),7.59–7.49(m,1H),7.46(dd,J＝13.3,6.1Hz,2H),7.34(t,J＝7.5Hz,1H),4.81–4.67(m,2H),3.71(t,J＝7.3Hz,2H). The NMR spectrum of Compound 7 of this example is shown in Figure 6: 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 - 8.71 (m, 1H), 8.20 - 8.09 (m, 2H), 7.59 - 7.49 (m, 1H), 7.46 (dd, J = 13.3, 6.1 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 4.81 - 4.67 (m, 2H), 3.71 (t, J = 7.3 Hz, 2H).
本实施例化合物8的核磁数据： 1H NMR(400MHz,CDCl 3)：δ8.79(d,J＝1.3Hz,2H),8.19(dd,J＝8.7,1.7Hz,2H),7.50(d,J＝8.6Hz,2H),4.51(s,2H),2.78(s,2H),2.38(s,6H). Nuclear magnetic data of Compound 8 of this example: 1 H NMR (400 MHz, CDCl 3 ): δ 8.79 (d, J = 1.3 Hz, 2H), 8.19 (dd, J = 8.7, 1.7 Hz, 2H), 7.50 (d , J = 8.6 Hz, 2H), 4.51 (s, 2H), 2.78 (s, 2H), 2.38 (s, 6H).
本实施例化合物9的核磁数据： 1H NMR(400MHz,CDCl 3)δ8.79(d,J＝1.3Hz,2H),8.19(dd,J＝8.7,1.7Hz,2H),7.50(d,J＝8.6Hz,2H),4.51(s,2H),2.78(s,2H),2.75(s,3H),2.38(s,6H). The nuclear magnetic data of the compound 9 of this example: 1 H NMR (400 MHz, CDCl 3 ) δ 8.79 (d, J = 1.3 Hz, 2H), 8.19 (dd, J = 8.7, 1.7 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 4.51 (s, 2H), 2.78 (s, 2H), 2.75 (s, 3H), 2.38 (s, 6H).
以下通过实验例的方式来证明本发明的有益效果：The beneficial effects of the present invention are demonstrated by way of experimental examples below:
实验例1化合物8及其衍生物对肿瘤细胞增殖抑制作用检测(MTT实验)Experimental Example 1 Inhibition of Tumor Cell Proliferation by Compound 8 and Its Derivatives (MTT Experiment)
SKOV3：人卵巢腺癌细胞SKOV3: Human ovarian adenocarcinoma cells
Figure PCTCN2018108428-appb-000048
Figure PCTCN2018108428-appb-000048
MTT检测化合物8处理多种肿瘤细胞后的细胞活力。首先在A2870细胞中加入不同浓度(100nM，500nM，5μM，10μM)的化合物8(X)及其未氘代衍生物(C21)处理不同时间(24h，48h，72h)后，细胞活力如图所示：5μM的X处理细胞24h，开始出现细胞活力明显下降，而浓度越高，处理时间越长，细胞活力下降越明显。衍生物C21处理A2780也是类似效果。而5μM浓度的C21和X处理其他肿瘤细胞(SKOV3,Hela,HepG2),均在24h时出现细胞活力明显下降，处理时间越长下降越明显。MTT was used to detect the viability of Compound 8 after treatment of various tumor cells. First, different concentrations (100 nM, 500 nM, 5 μM, 10 μM) of compound 8 (X) and its non-deuterated derivative (C21) were added to A2870 cells for different time (24h, 48h, 72h). It is shown that: 5μM X treated cells for 24h, the cell viability began to decrease significantly, and the higher the concentration, the longer the treatment time, the more obvious the cell viability decreased. Derivative C21 treatment of A2780 is also a similar effect. The 5μM concentration of C21 and X treated other tumor cells (SKOV3, Hela, HepG2), the cell viability decreased significantly at 24h, and the longer the treatment time, the more obvious.
如图7所示，Curaxin药物及其化合物8在浓度5μM及更高时，处理细胞时间达到24h，便能明显抑制肿瘤细胞的增殖活力。As shown in Fig. 7, when the Curaxin drug and its compound 8 were treated at a concentration of 5 μM and higher for 24 hours, the proliferation activity of the tumor cells was significantly inhibited.
实验结果证明，本发明化合物8可以有效抑制卵巢癌细胞的增殖，证明其可以有效治疗癌症，尤其是卵巢癌，为临床治疗癌症提供了一种新的选择，应用前景优良。另外，药代实验表明化合物8在动物体内有更好的药代稳定性，体内持续期比未氘代化合物高出15％。有助于降低药物使用剂量和使用周期。The experimental results show that the compound 8 of the present invention can effectively inhibit the proliferation of ovarian cancer cells, and proves that it can effectively treat cancer, especially ovarian cancer, and provides a new choice for clinical treatment of cancer, and has a good application prospect. In addition, pharmacokinetic experiments showed that Compound 8 has better pharmacokinetic stability in animals, and its duration in vivo is 15% higher than that of non-deuterated compounds. Helps reduce the dose and duration of drug use.

Claims (10)

  1. 式Ⅰ所示的化合物或其药学上可接受的盐或其水合物：a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof:
    Figure PCTCN2018108428-appb-100001
    Figure PCTCN2018108428-appb-100001
    其中，R 1选自氢、氘、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、N(R e) 2和SR e(；或者，两者中择一地，或者R 1和R 4或者NR e和R 4与它们所连接的原子一起形成5元环或者6元环；或者，两者中择一地，或者R 1和R 6或者NR e和R 6与它们所连接的原子一起形成5元环或者6元环； Wherein R 1 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 and SR e (or alternatively, either R 1 and R 4 or NR e and R 4 together with the atom to which they are attached form a 5- or 6-membered ring; or alternatively, Or R 1 and R 6 or NR e and R 6 together with the atom to which they are attached form a 5- or 6-membered ring;
    R 2选自氢、氘、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、N(R e) 2和SR e；或者，两者中择一地，或者R 2和R 3或者NR e和R 3与它们所连接的原子一起形成5元环或者6元环；或者，两者中择一地，或者R 2和R 5或者NR e和R 5与它们所连接的原子一起形成5元环或者6元环； R 2 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 and SR e Or alternatively, either R 2 and R 3 or NR e and R 3 together with the atom to which they are attached form a 5- or 6-membered ring; alternatively, alternatively, or R 2 And R 5 or NR e and R 5 together with the atoms to which they are attached form a 5- or 6-membered ring;
    R 3、R 4、R 5、R 6、R 7和R 8独立选自氢、氘、卤素、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、C(＝O)R e、C(＝O)OR e、OC(＝O)R e、C(＝O)N(R e) 2、C(＝O)NR eSO 2R e、N(R e) 2、NR eC(＝O)R e、NR eC(＝O)N(Re) 2、CN、NO 2、CF 3、OCF 3、SR e、SOR e、SO 2R e、SO 2N(R e) 2和OSO 2CF 3； R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl Base, heteroaryl, OR e , C(=O)R e , C(=O)OR e , OC(=O)R e , C(=O)N(R e ) 2 , C(=O) NR e SO 2 R e , N(R e ) 2 , NR e C(=O)R e , NR e C(=O)N(Re) 2 , CN, NO 2 , CF 3 , OCF 3 , SR e , SOR e , SO 2 R e , SO 2 N(R e ) 2 and OSO 2 CF 3 ;
    R 9选自氢、氘、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R e，或者R 9和R 10结合在一起形成5元、6元或7元脂肪族环，任选含有氧原子； R 9 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C (=O) R e , or R 9 and R 10 are taken together to form a 5-, 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
    R 10选自氢、氘、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R e，或者R 10和一个R d与它们所连接的原子一起形成5元或6元脂肪族环； R 10 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(=O)R e , or R 10 and a R d together with the atoms to which they are attached form a 5- or 6-membered aliphatic ring;
    R a、R b、R c和R d独立地选自氢、氘、氚、卤素、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、N(R e) 2和SR e； R a , R b , R c and R d are independently selected from the group consisting of hydrogen, hydrazine, hydrazine, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, OR e , N(R e ) 2 and SR e ;
    R e独立选自氢、氘、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基，或者两个R e基团与它们所连接的氮结合在一起形成5元或6元脂肪族环； R e is independently selected from hydrogen, deuterium, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R e groups are bonded to the nitrogen to which they are attached to form 5 Yuan or 6 yuan aliphatic ring;
    n为0、1、2、3、4、5或6；n is 0, 1, 2, 3, 4, 5 or 6;
    m为0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
    且，R a、R b、R c、R d、R e、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10中至少一个为氘； Further, at least one of R a , R b , R c , R d , R e , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is deuterium;
    优选地，m为1，R c为氢或氘；或者，m为1，R d为氢或氘； Preferably, m is 1, R c is hydrogen or deuterium; or, m is 1, R d is hydrogen or deuterium;
    和/或，R 1选自氢、氘、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、N(R e) 2和SR e；或者，两者中择一地，或者R 1和R 4或者NR e和R 4与它们所连接的原子一起形成5元环或者6元环； And/or R 1 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 and SR e ; alternatively, alternatively, or R 1 and R 4 or NR e and R 4 together with the atom to which they are attached form a 5- or 6-membered ring;
    和/或，and / or,
    R 2选自氢、氘、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、N(R e) 2和SR e；或者，两者中择一地，或者R 2和R 3或者NR e和R 3与它们所连接的原子一起形成5元环或者6元环； R 2 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e , N(R e ) 2 and SR e Or alternatively, either R 2 and R 3 or NR e and R 3 together with the atom to which they are attached form a 5- or 6-membered ring;
    和/或，R e独立地为氢、氘或C 1-6烷基。 And/or R e is independently hydrogen, deuterium or C 1-6 alkyl.
  2. 权利要求1或2所述的化合物或其药学上可接受的盐或其水合物，所述化合物具有结构式Ⅰa：The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which has the structural formula Ia:
    Figure PCTCN2018108428-appb-100002
    Figure PCTCN2018108428-appb-100002
    其中，R 1为氘、C 1-3烷基、C 1-4卤代烷基、C 3-5环烷基、N(R e) 2或OR e，或者R 1和R4与它们所连接的碳原子一起形成5元或6元脂肪族碳环； Wherein R 1 is fluorene, C 1-3 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, N(R e ) 2 or OR e , or R 1 and R 4 and the carbon to which they are attached The atoms together form a 5- or 6-membered aliphatic carbocyclic ring;
    R 2为氘、C 1-4烷基、C 1-4卤代烷基、C 3-5环烷基、N(R e) 2或OR e，或者R 2和R 3与它们所连接的碳原子一起形成5元或6元脂肪族碳环或者含有一个氮原子的5元或6元脂肪族环； R 2 is fluorene, C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, N(R e ) 2 or OR e , or R 2 and R 3 with the carbon atom to which they are attached Forming a 5- or 6-membered aliphatic carbocyclic ring or a 5- or 6-membered aliphatic ring containing a nitrogen atom;
    R 3为氢、氘、C 1-3烷基、C 1-3烷氧基或卤素； R 3 is hydrogen, deuterium, C 1-3 alkyl, C 1-3 alkoxy or halogen;
    R 4为氢、氘或C 1-3烷基； R 4 is hydrogen, deuterium or C 1-3 alkyl;
    R 5为氢、氘、羟基、C 1-3烷氧基或卤素； R 5 is hydrogen, deuterium, hydroxyl, C 1-3 alkoxy or halogen;
    R 6为氢、氘、羟基或C 1-3烷氧基； R 6 is hydrogen, deuterium, hydroxy or C 1-3 alkoxy;
    R 7和R 8独立地为氢、氘或C 1-3烷基； R 7 and R 8 are independently hydrogen, deuterium or C 1-3 alkyl;
    R 9为氘、C 1-6烷基、C 3-5环烷基或C 1-3羟基烷基； R 9 is 氘, C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl;
    R 10为氢、氘、C 1-4烷基或C 3-5环烷基，或者R 10和R d与它们所连接的原子一起形成含有一个氮原子的5元或6元脂肪族环，或者R 9和R 10结合在一起形成6元或7元脂肪族环，任选含有氧原子； R 10 is hydrogen, deuterium, C 1-4 alkyl or C 3-5 cycloalkyl, or R 10 and R d together with the atom to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, Or R 9 and R 10 are taken together to form a 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
    R a为氢或氘； R a is hydrogen or helium;
    R b为氢或氘； R b is hydrogen or helium;
    R c为氢、氘或C 1-3烷基； R c is hydrogen, deuterium or C 1-3 alkyl;
    R d为氢或氘； R d is hydrogen or helium;
    R e独立地为氢、氘或C 1-3烷基； R e is independently hydrogen, deuterium or C 1-3 alkyl;
    且n为0、1、2、3、4或5；And n is 0, 1, 2, 3, 4 or 5;
    或，所述化合物具有结构式Ⅰb：Or, the compound has the structural formula Ib:
    Figure PCTCN2018108428-appb-100003
    Figure PCTCN2018108428-appb-100003
    其中，R 1为氘、甲基、乙基、正丙基、环丙基、NH(CH 3)或OCH 3，或者R 1和R 4与它们所连接的碳原子一起形成5元脂肪族碳环； Wherein R 1 is hydrazine, methyl, ethyl, n-propyl, cyclopropyl, NH(CH 3 ) or OCH 3 , or R 1 and R 4 together with the carbon atom to which they are attached form a 5-membered aliphatic carbon ring;
    R 2为氘、甲基、乙基、正丙基、环丙基、NH(CH 3)或OCH 3，或者R 2和R 3与它们所连接的碳原子一起形成5元脂肪族碳环或含有一个氮原子的5元脂肪族环； R 2 is hydrazine, methyl, ethyl, n-propyl, cyclopropyl, NH(CH 3 ) or OCH 3 , or R 2 and R 3 together with the carbon atom to which they are attached form a 5-membered aliphatic carbocyclic ring or a 5-membered aliphatic ring containing a nitrogen atom;
    R 3为氢、氘、甲基、甲氧基或氟； R 3 is hydrogen, deuterium, methyl, methoxy or fluorine;
    R 4为氢或氘； R 4 is hydrogen or helium;
    R 5为氢或氘、羟基、甲氧基或氟； R 5 is hydrogen or deuterium, hydroxyl, methoxy or fluorine;
    R 6为氢或氘、羟基或甲氧基； R 6 is hydrogen or deuterium, hydroxyl or methoxy;
    R 7和R 8独立地为氢或氘； R 7 and R 8 are independently hydrogen or deuterium;
    R 9为氘、甲基、乙基、正丙基、异丙基、环丁基或2-羟基乙基； R 9 is hydrazine, methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl;
    R 10为氢、氘、甲基、乙基或环丁基，或者R 10和R d与它们所连接的原子一起形成含有一个氮原子的5元脂肪族环，或者R 9和R 10结合在一起形成吗啉代部分、四氢呋喃基部分、哌啶基部分或
    Figure PCTCN2018108428-appb-100004
    部分、
    Figure PCTCN2018108428-appb-100005
    部分或
    Figure PCTCN2018108428-appb-100006
    部分；R 101为甲基或乙基；     R 10 is hydrogen, deuterium, methyl, ethyl or cyclobutyl, or R 10 and R d together with the atom to which they are attached form a 5-membered aliphatic ring containing a nitrogen atom, or R 9 and R 10 are bonded to Forming a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or
    Figure PCTCN2018108428-appb-100004
    section,
    Figure PCTCN2018108428-appb-100005
    Partial or
    Figure PCTCN2018108428-appb-100006
    Part; R 101 is methyl or ethyl;
    R a为氢或氘； R a is hydrogen or helium;
    R b为氢或氘； R b is hydrogen or helium;
    R c为氢或氘； R c is hydrogen or helium;
    R d为氢或氘； R d is hydrogen or helium;
    且n为1或2。And n is 1 or 2.
  3. 式Ⅱ所示的化合物或其药学上可接受的盐或其水合物：a compound of the formula II or a pharmaceutically acceptable salt thereof or a hydrate thereof:
    Figure PCTCN2018108428-appb-100007
    Figure PCTCN2018108428-appb-100007
    R 3、R 4、R 5、R 6、R 7和R 8独立选自氢、氘、卤素、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、C(＝O)R e、C(＝O)OR e、OC(＝O)R e、C(＝O)N(R e) 2、C(＝O)NR eSO 2R e、N(R e) 2、NR eC(＝O)R e、NR eC(＝O)N(Re) 2、CN、NO 2、CF 3、OCF 3、SR e、SOR e、SO 2R e、SO 2N(R e) 2和OSO 2CF 3； R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl Base, heteroaryl, OR e , C(=O)R e , C(=O)OR e , OC(=O)R e , C(=O)N(R e ) 2 , C(=O) NR e SO 2 R e , N(R e ) 2 , NR e C(=O)R e , NR e C(=O)N(Re) 2 , CN, NO 2 , CF 3 , OCF 3 , SR e , SOR e , SO 2 R e , SO 2 N(R e ) 2 and OSO 2 CF 3 ;
    R 9选自氢、氘、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R e，或者R 9和R 10结合在一起形成5元、6元或7元脂肪族环，任选含有氧原子； R 9 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C (=O) R e , or R 9 and R 10 are taken together to form a 5-, 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
    R 10选自氢、氘、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R e，或者R 10和一个R d与它们所连接的原子一起形成5元或6元脂肪族环； R 10 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(=O)R e , or R 10 and a R d together with the atoms to which they are attached form a 5- or 6-membered aliphatic ring;
    R a、R b、R c和R d独立地选自氢、氘、氚、卤素、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基、OR e、N(R e) 2和SR e； R a , R b , R c and R d are independently selected from the group consisting of hydrogen, hydrazine, hydrazine, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, OR e , N(R e ) 2 and SR e ;
    R e独立选自氢、氘、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基，或者两个R e基团与它们所连接的氮结合在一起形成5元或6元脂肪族环； R e is independently selected from hydrogen, deuterium, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R e groups are bonded to the nitrogen to which they are attached to form 5 Yuan or 6 yuan aliphatic ring;
    n为0、1、2、3、4、5或6；n is 0, 1, 2, 3, 4, 5 or 6;
    m为0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
    且，R a、R b、R c、R d、R e、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10中至少一个为氘； Further, at least one of R a , R b , R c , R d , R e , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is 氘;
    优选地，m为1，R c为氢或氘；或者，m为1，R d为氢或氘； Preferably, m is 1, R c is hydrogen or deuterium; or, m is 1, R d is hydrogen or deuterium;
    优选地，R e独立地为氢、氘或C 1-6烷基； Preferably, R e is independently hydrogen, deuterium or C 1-6 alkyl;
    进一步优选地，所述化合物具有结构式Ⅱa：Further preferably, the compound has the structural formula IIa:
    Figure PCTCN2018108428-appb-100008
    Figure PCTCN2018108428-appb-100008
    其中，R 3为氢、氘、C 1-3烷基、C 1-3烷氧基或卤素； Wherein R 3 is hydrogen, deuterium, C 1-3 alkyl, C 1-3 alkoxy or halogen;
    R 4为氢、氘或C 1-3烷基； R 4 is hydrogen, deuterium or C 1-3 alkyl;
    R 5为氢、氘、羟基、C 1-3烷氧基或卤素； R 5 is hydrogen, deuterium, hydroxyl, C 1-3 alkoxy or halogen;
    R 6为氢、氘、羟基或C 1-3烷氧基； R 6 is hydrogen, deuterium, hydroxy or C 1-3 alkoxy;
    R 7和R 8独立地为氢、氘或C 1-3烷基； R 7 and R 8 are independently hydrogen, deuterium or C 1-3 alkyl;
    R 9为氘、C 1-6烷基、C 3-5环烷基或C 1-3羟基烷基； R 9 is 氘, C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl;
    R 10为氢、氘、C 1-4烷基或C 3-5环烷基，或者R 10和R d与它们所连接的原子一起形成含有一个氮原子的5元或6元脂肪族环，或者R 9和R 10结合在一起形成6元或7元脂肪族环，任选含有氧原子； R 10 is hydrogen, deuterium, C 1-4 alkyl or C 3-5 cycloalkyl, or R 10 and R d together with the atom to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, Or R 9 and R 10 are taken together to form a 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
    R a为氢或氘； R a is hydrogen or helium;
    R b为氢或氘； R b is hydrogen or helium;
    R c为氢、氘或C 1-3烷基； R c is hydrogen, deuterium or C 1-3 alkyl;
    R d为氢或氘； R d is hydrogen or helium;
    且n为0、1、2、3、4或5；And n is 0, 1, 2, 3, 4 or 5;
    进一步优选地，所述化合物具有结构式Ⅱb：Further preferably, the compound has the structural formula IIb:
    Figure PCTCN2018108428-appb-100009
    Figure PCTCN2018108428-appb-100009
    R 3为氢、氘、甲基、甲氧基或氟； R 3 is hydrogen, deuterium, methyl, methoxy or fluorine;
    R 4为氢或氘； R 4 is hydrogen or helium;
    R 5为氢或氘、羟基、甲氧基或氟； R 5 is hydrogen or deuterium, hydroxyl, methoxy or fluorine;
    R 6为氢或氘、羟基或甲氧基； R 6 is hydrogen or deuterium, hydroxyl or methoxy;
    R 7和R 8独立地为氢或氘； R 7 and R 8 are independently hydrogen or deuterium;
    R 9为氘、甲基、乙基、正丙基、异丙基、环丁基或2-羟基乙基； R 9 is hydrazine, methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl;
    R 10为氢、氘、甲基、乙基或环丁基，或者R 10和R d与它们所连接的原子一起形成含有一个氮原子的5元脂肪族环，或者R 9和R 10结合在一起形成吗啉代部分、四氢呋喃基部分、哌啶基部分或
    Figure PCTCN2018108428-appb-100010
    部分、
    Figure PCTCN2018108428-appb-100011
    部分、
    Figure PCTCN2018108428-appb-100012
    部分；R 102为甲基或乙基；     R 10 is hydrogen, deuterium, methyl, ethyl or cyclobutyl, or R 10 and R d together with the atom to which they are attached form a 5-membered aliphatic ring containing a nitrogen atom, or R 9 and R 10 are bonded to Forming a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or
    Figure PCTCN2018108428-appb-100010
    section,
    Figure PCTCN2018108428-appb-100011
    section,
    Figure PCTCN2018108428-appb-100012
    Part; R 102 is methyl or ethyl;
    R a为氢或氘； R a is hydrogen or helium;
    R b为氢或氘； R b is hydrogen or helium;
    R c为氢或氘； R c is hydrogen or helium;
    R d为氢或氘； R d is hydrogen or helium;
    且n为1或2。And n is 1 or 2.
  4. 式Ⅲ所示的化合物或其药学上可接受的盐或其水合物：a compound of the formula III or a pharmaceutically acceptable salt thereof or a hydrate thereof:
    Figure PCTCN2018108428-appb-100013
    Figure PCTCN2018108428-appb-100013
    其中R f选自氢、氘、C 1-6烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R h，或者R f和R g结合在一起形成任选含有氧原子的5元、6元或7元脂肪族环； Wherein R f is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R h , or R f and R g are combined to form a 5-, 6-, or 7-membered aliphatic ring optionally containing an oxygen atom;
    R g选自氢、氘、C 1-6烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R h，或者 R g is selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(=O)R h , or
    R g和R8与它们所连接的原子一起形成5元或6元脂肪族环； R g and R 8 together with the atom to which they are attached form a 5- or 6-membered aliphatic ring;
    R h独立选自氢、氘、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基，或者两个Rh基团与它们所连接的氮结合在一起形成5元或6元脂肪族环； R h is independently selected from hydrogen, hydrazine, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two Rh groups are bonded to the nitrogen to which they are attached to form a 5 dollar Or a 6-membered aliphatic ring;
    R 8选自氢、氘、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基； R 8 is selected from the group consisting of hydrogen, hydrazine, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
    R 9、R 10、R 11、R 12、R 13和R 14独立选自氢、氘、C 1-6烷基、环烷基、杂环烷基、芳基、杂芳基、卤素、OR h、C(＝O)R h、C(＝O)OR h、OC(＝O)R h、C(＝O)N(R h) 2、C(＝O)NR hSO 2R h、N(R h) 2、NR eC(＝O)R h、NR hC(＝O)N(R h) 2、CN、NO 2、CF 3、OCF 3、SR h、SOR h、SO 2R h、SO 2N(R h) 2和OSO 2CF 3； R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently selected from hydrogen, hydrazine, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halogen, OR h , C(=O)R h , C(=O)OR h , OC(=O)R h , C(=O)N(R h ) 2 , C(=O)NR h SO 2 R h , N(R h ) 2 , NR e C(=O)R h , NR h C(=O)N(R h ) 2 , CN, NO 2 , CF 3 , OCF 3 , SR h , SOR h , SO 2 R h , SO 2 N(R h ) 2 and OSO 2 CF 3 ;
    R 15为氢或氘； R 15 is hydrogen or helium;
    R 16为氢或氘； R 16 is hydrogen or helium;
    R 17为氢或氘； R 17 is hydrogen or helium;
    p为0、1、2、3、4或5，且，当p为2时，R f和R g中的一个不为乙基； p is 0, 1, 2, 3, 4 or 5, and when p is 2, one of R f and R g is not ethyl;
    且R f、R g、R h、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16和R 17中至少一个为氘； And at least one of R f , R g , R h , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 is 氘;
    优选地，所述化合物具有结构式Ⅲb：Preferably, the compound has the structural formula IIIb:
    Figure PCTCN2018108428-appb-100014
    Figure PCTCN2018108428-appb-100014
    R g为氢、氘或甲基，或者R g和R 8与它们所连接的原子一起形成含有一个氮原子的5元脂肪族环； R g is hydrogen, deuterium or methyl, or R g and R 8 together with the atom to which they are attached form a 5-membered aliphatic ring containing a nitrogen atom;
    R 8为氢或氘； R 8 is hydrogen or helium;
    R 15为氢或氘； R 15 is hydrogen or helium;
    R 16为氢或氘； R 16 is hydrogen or helium;
    R 17为氢或氘； R 17 is hydrogen or helium;
    且p为1或2；And p is 1 or 2;
    且R g、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16和R 17中至少一个为氘。 And at least one of R g , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 is 氘.
  5. 式Ⅳ所示的化合物或其药学上可接受的盐或其水合物：a compound of the formula IV or a pharmaceutically acceptable salt thereof or a hydrate thereof:
    Figure PCTCN2018108428-appb-100015
    Figure PCTCN2018108428-appb-100015
    q为0、1、2、3、4或5；q is 0, 1, 2, 3, 4 or 5;
    R 18选自氢、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R i，或者R 18和R 19结合在一起形成5元、6元或7元脂肪族环，任选含有氧原子； R 18 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R i , or R 18 and R 19 are taken together to form a 5-, 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
    R 19选自氢、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R i； R 19 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R i ;
    R i独立选自氢、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基，或者两个R i基团与它们所连接的氮结合在一起形成5元或6元脂肪族环； R i is independently selected from hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R i groups are bonded to the nitrogen to which they are attached to form 5 or 6 yuan aliphatic ring;
    优选地，R i独立地为氢或C 1-6烷基； Preferably, R i is independently hydrogen or C 1-6 alkyl;
    优选地，R 18为C 1-6烷基、C 3-5环烷基或C 1-3羟基烷基； Preferably, R 18 is C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl;
    R 19为氢、C 1-4烷基或C 3-5环烷基，或者R 18和R 19与它们所连接的原子一起形成含有一个氮原子的5或6元脂肪族环，任选含有氧原子； R 19 is hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl, or R 18 and R 19 together with the atom to which they are attached form a 5 or 6 membered aliphatic ring containing a nitrogen atom, optionally containing Oxygen atom;
    优选地，R 18为甲基、乙基、正丙基、异丙基、环丁基或2-羟基乙基； Preferably, R 18 is methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl;
    R 19为氢、甲基、乙基或环丁基，或者R 18和R 19结合在一起形成吗啉代部分、四氢呋喃基部分、哌啶基部分或
    Figure PCTCN2018108428-appb-100016
    部分、
    Figure PCTCN2018108428-appb-100017
    部分或
    Figure PCTCN2018108428-appb-100018
    部分；R 103为甲基或乙基。     R 19 is hydrogen, methyl, ethyl or cyclobutyl, or R 18 and R 19 are taken together to form a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or
    Figure PCTCN2018108428-appb-100016
    section,
    Figure PCTCN2018108428-appb-100017
    Partial or
    Figure PCTCN2018108428-appb-100018
    Part; R 103 is methyl or ethyl.
  6. 式Ⅴ所示的化合物或其药学上可接受的盐或其水合物：A compound of the formula V or a pharmaceutically acceptable salt thereof or a hydrate thereof:
    Figure PCTCN2018108428-appb-100019
    Figure PCTCN2018108428-appb-100019
    r为0、1、2、3、4或5；r is 0, 1, 2, 3, 4 or 5;
    R 20选自氢、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R j，或者R 20和R 21结合在一起形成5元、6元或7元脂肪族环，任选含有氧原子； R 20 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R j , or R 20 and R 21 are taken together to form a 5-, 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
    R 21选自氢、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R j； R 21 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R j ;
    R j独立选自氢、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基，或者两个R j基团与它们所连接的氮结合在一起形成5元或6元脂肪族环； R j is independently selected from hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R j groups are bonded to the nitrogen to which they are attached to form 5 Å or 6 yuan aliphatic ring;
    优选地，R j独立地为氢或C 1-6烷基； Preferably, R j is independently hydrogen or C 1-6 alkyl;
    优选地，R 20为C 1-6烷基、C 3-5环烷基或C 1-3羟基烷基； Preferably, R 20 is C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl;
    R 21为氢、C 1-4烷基或C 3-5环烷基，或者R 20和R 21与它们所连接的原子一起形成含有一个氮原子的5元或6元脂肪族环，任选含有氧原子； R 21 is hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl, or R 20 and R 21 together with the atom to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, optionally Containing oxygen atoms;
    优选地，R 20为甲基、乙基、正丙基、异丙基、环丁基或2-羟基乙基； Preferably, R 20 is methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl;
    R 21为氢、甲基、乙基或环丁基，或者R 20和R 21结合在一起形成吗啉代部分、四氢呋喃基部分、哌啶基部分或
    Figure PCTCN2018108428-appb-100020
    部分、
    Figure PCTCN2018108428-appb-100021
    部分、
    Figure PCTCN2018108428-appb-100022
    部分；R 104为甲基或乙基；     R 21 is hydrogen, methyl, ethyl or cyclobutyl, or R 20 and R 21 are taken together to form a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or
    Figure PCTCN2018108428-appb-100020
    section,
    Figure PCTCN2018108428-appb-100021
    section,
    Figure PCTCN2018108428-appb-100022
    Part; R 104 is methyl or ethyl;
    优选地，R 20为甲基； Preferably, R 20 is a methyl group;
    R 21为甲基、乙基或环丁基，或者R 20和R 21结合在一起形成
    Figure PCTCN2018108428-appb-100023
    部分；R 104为甲基。     R 21 is a methyl group, an ethyl group or a cyclobutyl group, or R 20 and R 21 are combined to form
    Figure PCTCN2018108428-appb-100023
    Part; R 104 is a methyl group.
  7. 式Ⅵ所示的化合物或其药学上可接受的盐或其水合物：a compound of the formula VI or a pharmaceutically acceptable salt thereof or a hydrate thereof:
    Figure PCTCN2018108428-appb-100024
    Figure PCTCN2018108428-appb-100024
    s为0、1、2、3、4或5；s is 0, 1, 2, 3, 4 or 5;
    R 22选自氢、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R j，或者R 22和R 23结合在一起形成5元、6元或7元脂肪族环，任选含有氧原子； R 22 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R j , or R 22 and R 23 are taken together to form a 5-, 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
    R 23选自氢、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R k； R 23 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R k ;
    R k独立选自氢、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基，或者两个R k基团与它们所连接的氮结合在一起形成5元或6元脂肪族环； R k is independently selected from hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R k groups are bonded to the nitrogen to which they are attached to form 5 Å or 6 yuan aliphatic ring;
    优选地，R k独立地为氢或C 1-6烷； Preferably, R k is independently hydrogen or C 1-6 alkane;
    优选地，R 22为C 1-6烷基、C 3-5环烷基或C 1-3羟基烷基； Preferably, R 22 is C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl;
    R 23为氢、C 1-4烷基或C 3-5环烷基，或者R 22和R 23与它们所连接的原子一起形成含有一个氮原子的5元或6元脂肪族环，任选含有氧原子； R 23 is hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl, or R 22 and R 23 together with the atom to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, optionally Containing oxygen atoms;
    优选地，R 22为甲基、乙基、正丙基、异丙基、环丁基或2-羟基乙基； Preferably, R 22 is methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl;
    R 23为氢、甲基、乙基或环丁基，或者R 22和R 23结合在一起形成吗啉代部分、四氢呋喃基部分、哌啶基部分或
    Figure PCTCN2018108428-appb-100025
    部分、
    Figure PCTCN2018108428-appb-100026
    部分、
    Figure PCTCN2018108428-appb-100027
    部分；R 105为甲基或乙基；     R 23 is hydrogen, methyl, ethyl or cyclobutyl, or R 22 and R 23 are taken together to form a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or
    Figure PCTCN2018108428-appb-100025
    section,
    Figure PCTCN2018108428-appb-100026
    section,
    Figure PCTCN2018108428-appb-100027
    Part; R 105 is methyl or ethyl;
    优选地，R 22为甲基； Preferably, R 22 is a methyl group;
    R 23为甲基、乙基或环丁基，或者R 22和R 23结合在一起形成
    Figure PCTCN2018108428-appb-100028
    部分；R 105为甲基；     R 23 is a methyl group, an ethyl group or a cyclobutyl group, or R 22 and R 23 are combined to form
    Figure PCTCN2018108428-appb-100028
    Part; R 105 is a methyl group;
    优选地，所述化合物的结构式如下：Preferably, the structural formula of the compound is as follows:
    Figure PCTCN2018108428-appb-100029
    Figure PCTCN2018108428-appb-100029
  8. 式Ⅶ所示的化合物或其药学上可接受的盐或其水合物：A compound of the formula VII or a pharmaceutically acceptable salt thereof or a hydrate thereof:
    Figure PCTCN2018108428-appb-100030
    Figure PCTCN2018108428-appb-100030
    t为0、1、2、3、4或5；t is 0, 1, 2, 3, 4 or 5;
    R 24选自氢、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R j，或者R 24和R 25结合在一起形成5元、6元或7元脂肪族环，任选含有氧原子； R 24 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R j , or R 24 and R 25 are taken together to form a 5-, 6- or 7-membered aliphatic ring, optionally containing an oxygen atom;
    R 25选自氢、C 1-6烷基、C 1-6卤代烷基、环烷基、杂环烷基、芳基、杂芳基和C(＝O)R m； R 25 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and C(=O)R m ;
    R m独立选自氢、C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基，或者两个R m基团与它们所连接的氮结合在一起形成5元或6元脂肪族环； R m is independently selected from hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, or two R m groups are bonded to the nitrogen to which they are attached to form 5 or 6 yuan aliphatic ring;
    优选地，R m独立地为氢或C 1-6烷基； Preferably, R m is independently hydrogen or C 1-6 alkyl;
    优选地，R 24为C 1-6烷基、C 3-5环烷基或C 1-3羟基烷基； Preferably, R 24 is C 1-6 alkyl, C 3-5 cycloalkyl or C 1-3 hydroxyalkyl;
    R 25为氢、C 1-4烷基或C 3-5环烷基，或者R 24和R 25与它们所连接的原子一起形成含有一个氮原子的5元或6元脂肪族环，任选含有氧原子； R 25 is hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl, or R 24 and R 25 together with the atom to which they are attached form a 5- or 6-membered aliphatic ring containing a nitrogen atom, optionally Containing oxygen atoms;
    优选地，R 24为甲基、乙基、正丙基、异丙基、环丁基或2-羟基乙基； Preferably, R 24 is methyl, ethyl, n-propyl, isopropyl, cyclobutyl or 2-hydroxyethyl;
    R 25为氢、甲基、乙基或环丁基，或者R 22和R 23结合在一起形成吗啉代部分、四氢呋喃基部分、哌啶基部分或
    Figure PCTCN2018108428-appb-100031
    部分、
    Figure PCTCN2018108428-appb-100032
    部分、
    Figure PCTCN2018108428-appb-100033
    部分；R 106为甲基或乙基；     R 25 is hydrogen, methyl, ethyl or cyclobutyl, or R 22 and R 23 are taken together to form a morpholino moiety, a tetrahydrofuranyl moiety, a piperidinyl moiety or
    Figure PCTCN2018108428-appb-100031
    section,
    Figure PCTCN2018108428-appb-100032
    section,
    Figure PCTCN2018108428-appb-100033
    Part; R 106 is methyl or ethyl;
    优选地，其中t为0、1、2、3、4或5；R 24为甲基；R 25为甲基。 Preferably, wherein t is 0, 1, 2, 3, 4 or 5; R 24 is methyl; R 25 is methyl.
  9. 一种氘代咔唑类化合物或其药学上可接受的盐或其水合物，所述化合物具有下述结构：A deuterated carbazole compound or a pharmaceutically acceptable salt thereof or a hydrate thereof, which has the following structure:
    Figure PCTCN2018108428-appb-100034
    或者
    Figure PCTCN2018108428-appb-100034
    or
    Figure PCTCN2018108428-appb-100035
    Figure PCTCN2018108428-appb-100035
  10. 权利要求1-9任一项所述的化合物其药学上可接受的盐或其水合物在制备用于治疗癌症的药物、制备用于治疗有需要的个体中炎性疾病的药物、制备治疗微生物感染、原生动物感染或病毒感染的药物和/或制备用于治疗疾病或病症的药物中的用途；The pharmaceutically acceptable salt of the compound according to any one of claims 1 to 9, or a hydrate thereof, for the preparation of a medicament for treating cancer, for the preparation of a medicament for treating an inflammatory disease in an individual in need thereof, and for the preparation of a therapeutic microorganism Use of a medicament for infection, protozoal infection or viral infection and/or for the preparation of a medicament for the treatment of a disease or condition;
    优选地，所述癌症选自：肺腺癌、淋巴系造血系统肿瘤、髓系造血系统肿瘤、中枢和周围神经系统肿瘤、间充质细胞起源的肿瘤、着色性干皮病、角化棘皮瘤、精原细胞瘤、甲状腺滤泡癌、畸胎癌、结肠直肠癌、头颈部癌症、乳癌、胃癌、外阴癌、黑素瘤、卵巢癌、肺癌、尤因肉瘤、鳞状细胞癌、口腔癌、血细胞恶性肿瘤、胸腺淋巴瘤性肺癌、小细胞癌、肾上腺皮质的癌症、产生ACTH的肿瘤、非小细胞癌、导管癌、与结肠直肠瘤形成相关的息肉、胰腺癌、肝癌、泌尿系统癌症、前列腺癌、原发性腹膜上皮赘生物、阴道癌、外阴癌、子宫癌、卵泡内的实体瘤、睾丸癌、阴茎癌、脑癌、中枢神经系统内的转移性肿瘤细胞侵袭、骨癌、甲状腺癌、成视网膜细胞瘤、弥散性腹膜癌、恶性弥散性胸膜癌、间皮瘤、维尔姆斯瘤、胆囊癌、绒毛膜上皮肿瘤、血管外皮细胞瘤和卡波西肉瘤；Preferably, the cancer is selected from the group consisting of: lung adenocarcinoma, lymphoid hematopoietic tumor, myeloid hematopoietic tumor, central and peripheral nervous system tumor, mesenchymal cell-derived tumor, xeroderma pigmentosum, keratoacanthoma , seminoma, thyroid follicular carcinoma, teratocarcinoma, colorectal cancer, head and neck cancer, breast cancer, stomach cancer, vulvar cancer, melanoma, ovarian cancer, lung cancer, Ewing sarcoma, squamous cell carcinoma, oral cavity Cancer, blood cell malignancy, thymoma lymphoma, small cell carcinoma, adrenal cortical cancer, ACTH-producing tumor, non-small cell carcinoma, ductal carcinoma, polyps associated with colorectal neoplasia, pancreatic cancer, liver cancer, urinary system Cancer, prostate cancer, primary peritoneal epithelial neoplasm, vaginal cancer, vulvar cancer, uterine cancer, solid tumor in follicle, testicular cancer, penile cancer, brain cancer, metastatic tumor cell invasion in the central nervous system, bone cancer , thyroid cancer, retinoblastoma, diffuse peritoneal cancer, malignant diffuse pleural cancer, mesothelioma, Wilms' tumor, gallbladder cancer, chorionic epithelial tumor, extravascular Dermatoma and Kaposi's sarcoma;
    优选地，所述癌症选自恶化的膀胱癌、转移的膀胱癌、白血病、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤、组织细胞淋巴瘤、伯基特淋巴瘤、弥散性淋巴瘤、皮肤T细胞淋巴瘤、胶质瘤、外分泌胰腺癌、非小细胞肺癌、食管鳞状细胞癌、多发性骨髓瘤、结肠癌、宫颈癌、子宫内膜癌症、内源性脑肿瘤和星形细胞性脑肿瘤；Preferably, the cancer is selected from the group consisting of deteriorated bladder cancer, metastatic bladder cancer, leukemia, B cell lymphoma, T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, histiocytic cells Lymphoma, Burkitt's lymphoma, diffuse lymphoma, cutaneous T-cell lymphoma, glioma, exocrine pancreatic cancer, non-small cell lung cancer, esophageal squamous cell carcinoma, multiple myeloma, colon cancer, cervical cancer, Endometrial cancer, endogenous brain tumors, and astrocytic brain tumors;
    优选地，急性淋巴细胞白血病、骨髓性淋巴母细胞性白血病、急性非淋巴细胞白血病、慢性淋巴细胞白血病、慢性骨髓细胞白血病、毛细胞白血病、骨髓异常增生综合征、骨髓性白血病、早幼粒细胞白血病、骨髓瘤、星形细胞瘤、成神经细胞瘤、神经鞘瘤、成胶质细胞瘤、纤维肉瘤、横纹肌肉瘤、骨瘤、小细胞肺癌和膀胱癌；Preferably, acute lymphoblastic leukemia, myeloid lymphoblastic leukemia, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloid leukemia, promyelocytic cells Leukemia, myeloma, astrocytoma, neuroblastoma, schwannomas, glioblastoma, fibrosarcoma, rhabdomyosarcoma, osteoma, small cell lung cancer and bladder cancer;
    优选地，所述癌症选自：原发性浅层膀胱肿瘤、膀胱的侵袭性过渡性细胞癌、侵袭肌肉的膀胱癌和骨肉瘤；Preferably, the cancer is selected from the group consisting of: a primary superficial bladder tumor, an invasive transitional cell carcinoma of the bladder, a bladder cancer that invades the muscle, and an osteosarcoma;
    优选地，其中所述癌症选自：急性淋巴母细胞白血病、和急性和慢性骨髓性白血病；Preferably, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia, and acute and chronic myelogenous leukemia;
    优选地，权利要求1-9任一项所述的化合物与化疗药、放疗、影响微管的药物、细胞 生长抑制药、TNF多肽及其混合物联合给予；Preferably, the compound according to any one of claims 1 to 9 is administered in combination with a chemotherapeutic agent, a radiation therapy, a drug affecting microtubules, a cell growth inhibitory drug, a TNF polypeptide, and a mixture thereof;
    优选地，所述炎性疾病选自：类风湿性关节炎、银屑病、白斑、韦格纳肉芽肿病和系统性红斑狼疮；Preferably, the inflammatory disease is selected from the group consisting of rheumatoid arthritis, psoriasis, leukoplakia, Wegener's granulomatosis and systemic lupus erythematosus;
    优选地，权利要求1-9任一项所述的化合物与免疫抑制药联合给予；Preferably, the compound of any one of claims 1-9 is administered in combination with an immunosuppressive drug;
    优选地，其中所述原生动物感染是疟疾；Preferably wherein said protozoal infection is malaria;
    优选地，所述疾病或病症选自动脉粥样硬化、再狭窄、血管炎、视网膜病、肾病、增生性皮肤病、银屑病、瘢痕瘤性疤痕形成、光化性角化病、斯蒂文斯-约翰逊综合征、类风湿性关节炎、系统性起病型青少年慢性关节炎、骨质疏松症、系统性红斑狼疮、眼的过度增殖性疾病、血管性增殖性疾病、鱼鳞病和乳头瘤；Preferably, the disease or condition is selected from the group consisting of atherosclerosis, restenosis, vasculitis, retinopathy, nephropathy, proliferative skin disease, psoriasis, keloid scar formation, actinic keratosis, sti Vince-Johnson syndrome, rheumatoid arthritis, systemic onset adolescent chronic arthritis, osteoporosis, systemic lupus erythematosus, ocular hyperproliferative disease, vascular proliferative disease, ichthyosis and nipple tumor;
    优选地，所述疾病或病症选自肾炎、增殖性玻璃体视网膜病、糖尿病性视网膜病和涉及上皮向内生长的眼的过度增殖性疾病。Preferably, the disease or condition is selected from the group consisting of nephritis, proliferative vitreoretinopathy, diabetic retinopathy, and hyperproliferative diseases of the eye involving epithelial ingrowth.
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