WO2022111517A1 - 氘修饰的噻吩并吡啶酮化合物 - Google Patents
氘修饰的噻吩并吡啶酮化合物 Download PDFInfo
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- WO2022111517A1 WO2022111517A1 PCT/CN2021/132748 CN2021132748W WO2022111517A1 WO 2022111517 A1 WO2022111517 A1 WO 2022111517A1 CN 2021132748 W CN2021132748 W CN 2021132748W WO 2022111517 A1 WO2022111517 A1 WO 2022111517A1
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- deuterium
- compound
- pharmaceutically acceptable
- acceptable salt
- hydrogen
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- 239000011734 sodium Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000009258 tissue cross reactivity Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- INQOMBQAUSQDDS-FIBGUPNXSA-N trideuterio(iodo)methane Chemical compound [2H]C([2H])([2H])I INQOMBQAUSQDDS-FIBGUPNXSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present application belongs to the field of medicinal chemistry, and relates to deuterium-modified thienopyridone compounds, in particular to a compound represented by formula I or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition thereof, and a medicinal use thereof.
- the deuterium-modified thienopyridone compounds of the present application show inhibition of HPK1 kinase activity and can achieve anti-tumor effects.
- Hematopoietic progenitor kinase 1 also known as mitogen-activated protein kinase 1 (MAP4K1)
- MAP4K1 mitogen-activated protein kinase 1
- the family also includes five subtypes, GCK/MAP4K2, GLK/MAP4K3, HGK/MAP4K4, KHS1/MAP4K5 and MINK1/MAP4K6.
- HPK1 is only expressed in hematopoietic tissue cells, which can mediate various cell signaling pathways (including MAPK signaling, antigen receptor signaling, and cytokine signaling, etc.) , involved in the regulation of signaling in the hematopoietic system including lymphocytes.
- various cell signaling pathways including MAPK signaling, antigen receptor signaling, and cytokine signaling, etc.
- HPK1 mainly acts through the c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinases (ERK) signaling pathways to inhibit immune cell responses.
- JNK c-Jun N-terminal kinase
- ERK extracellular regulated protein kinases
- HPK1 interacts with a large number of TCRs and is phosphorylated by tyrosine kinases Lck and Zap70, and activated HPK1 further phosphorylates T cell receptors
- the adaptor protein SLP-76 which establishes a docking site for the negative regulator 14-3-3, ultimately destabilizes the TCR signaling complex (lato-gads-SLP76) and impedes downstream mitogen-activated protein (MAP) kinase signaling , which negatively regulates TCR signaling, which in turn inhibits T cell proliferation.
- MAP mitogen-activated protein
- B cell receptor B cell receptor
- BCR B cell receptor
- HPK1 B cell linker protein
- HPK1 inhibitors Due to its important role in immunity, HPK1 inhibitors have been implicated in malignant solid tumors or blood cancers (such as acute myeloid leukemia, breast cancer, lung cancer, etc.), autoimmune diseases (such as systemic lupus erythematosus, psoriatic arthritis) and play an important role in the inflammatory response.
- malignant solid tumors or blood cancers such as acute myeloid leukemia, breast cancer, lung cancer, etc.
- autoimmune diseases such as systemic lupus erythematosus, psoriatic arthritis
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently is selected from hydrogen (H) or deuterium (D);
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 At least one of is selected from deuterium.
- said R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, Fifteen or sixteen are selected from deuterium.
- said R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 any one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, ten Four, fifteen or sixteen are selected from deuterium.
- R 1 , R 2 and R 3 are selected from deuterium
- R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen or deuterium.
- R 4 , R 5 , R 10 and R 11 are selected from deuterium
- R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen or deuterium.
- R 6 , R 7 , R 8 and R 9 are selected from deuterium
- R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen or deuterium.
- R 1 , R 2 , R 3 , R 4 , R 5 , R 10 and R 11 are selected from deuterium
- R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen or deuterium.
- R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 are selected from deuterium
- R 4 , R 5 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen or deuterium.
- R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are selected from deuterium
- R 1 , R 2 , R 3 , R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen or deuterium.
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are selected from deuterium
- R 12 , R 13 , R 14 , R 15 and R 16 are each independently selected from hydrogen or deuterium.
- R 12 and R 14 are selected from deuterium
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 13 , R 15 and R 16 are each independently selected from hydrogen or deuterium.
- the R 13 is selected from deuterium
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 , R 15 and R 16 are each independently selected from hydrogen or deuterium.
- the R 12 , R 13 and R 14 are selected from deuterium
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 15 and R 16 are each independently selected from hydrogen or deuterium.
- said R 1 , R 2 , R 3 , R 12 , R 13 and R 14 are selected from deuterium
- R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 15 and R 16 are each independently selected from hydrogen or deuterium.
- the R 15 is selected from deuterium
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 16 are each independently selected from hydrogen or deuterium.
- the R 16 is selected from deuterium
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each independently selected from hydrogen or deuterium.
- R 15 and R 16 are selected from deuterium
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen or deuterium.
- R 1 , R 2 , R 3 , R 15 and R 16 are selected from deuterium
- R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen or deuterium.
- the compound represented by formula I or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
- the compound represented by formula I or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
- compositions comprising a compound of the present application or a pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable excipient.
- the pharmaceutical composition further comprises a second active agent, which is another anticancer agent (eg, a small molecule anticancer agent or an antibody anticancer agent).
- the medicament further comprises a second active agent for treating the disease, the second active agent being another anticancer agent (eg, a small molecule anticancer agent or an antibody anticancer agent).
- a second active agent for treating the disease the second active agent being another anticancer agent (eg, a small molecule anticancer agent or an antibody anticancer agent).
- Another aspect of the present application provides the use of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the treatment of a disease that would benefit from inhibition of HPK1 kinase activity.
- Another aspect of the present application provides a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, for use in the treatment of diseases that benefit from inhibition of HPK1 kinase activity.
- Another aspect of the present application provides a method of treating a disease that would benefit from inhibition of HPK1 kinase activity, comprising administering to an individual in need of such treatment, the individual being selected from a mammal, preferably a human, a therapeutically effective amount of a compound of the present application or its A pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition.
- the disease that benefits from inhibition of HPKl kinase activity is selected from a tumor or cancer, eg, a blood cancer or a solid tumor, eg, acute myeloid leukemia, breast cancer, or lung cancer.
- a tumor or cancer eg, a blood cancer or a solid tumor, eg, acute myeloid leukemia, breast cancer, or lung cancer.
- the compound of the present application or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition is combined with other anti-cancer agents (eg, small molecule anti-cancer agents or antibody anti-cancer agents) or other Anticancer therapy (eg, radiotherapy and/or chemotherapy) is administered in combination.
- other anti-cancer agents eg, small molecule anti-cancer agents or antibody anti-cancer agents
- other Anticancer therapy eg, radiotherapy and/or chemotherapy
- the compounds of the present application have good HPK1 kinase inhibitory activity in vitro, cellular p-SLP76 phosphorylation inhibitory activity, and good stability of liver microsomes in vitro.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned .
- composition refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients.
- the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
- pharmaceutically acceptable excipients refers to those excipients which are not significantly irritating to the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
- the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
- Typical routes of administration of the compounds of the present application or pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
- treating generally refers to obtaining a desired pharmacological and/or physiological effect.
- the effect partially or completely stabilizes or cures the disease and/or side effects due to the disease, and may be therapeutic.
- Treatment encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie, preventing its progression; or (b) alleviating the symptoms of the disease, ie, causing regression of the disease or symptoms.
- the term "effective amount” means (i) treating a given disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying the described herein
- the amount of a compound of the present application for the onset of one or more symptoms of a particular disease, condition or disorder.
- the amount of an active substance eg, an antibody or compound of the present application
- the amount of an active substance that constitutes a "therapeutically effective amount” may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the elicitation of the therapeutic agent or combination of therapeutic agents in the individual. ability to respond. Effective amounts can also be routinely determined by those skilled in the art based on their own knowledge and this disclosure.
- the term "individual” includes humans and animals, eg, mammals (eg, primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, and birds, etc.).
- the subject or patient is a mouse.
- the subject or patient is a human.
- Therapeutic dosages of the compounds of the present application may depend, for example, on the particular use of the treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
- the ratio or concentration of a compound of the present application in a pharmaceutical composition may not be fixed and depends on a variety of factors including dosage, chemical properties (eg, hydrophobicity) and route of administration.
- the compounds of the present application can be provided for parenteral administration in physiologically buffered aqueous solutions containing about 0.1-10% w/v of the compounds. Some typical doses range from about 1 ⁇ g/kg to about 1 g/kg body weight/day.
- the dose ranges from about 0.01 mg/kg to about 100 mg/kg body weight/day.
- the dosage is likely to depend on such variables as the type and extent of the disease or disorder, the general state of health of the particular patient, the relative biological potency of the compound selected, the excipient formulation and its route of administration. Effective doses can be obtained by extrapolation from dose-response curves derived from in vitro or animal model test systems.
- the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include but are not limited to the examples of the present application.
- Step 5 Preparation of ethyl 2-(5-(4-(methyl-d 3 )piperazin-1-yl)-1H-benzo[d]imidazol-2-yl)acetate (compound 1E)
- Step four 4-amino-5-(5-(4-methylpiperazin-1-yl-2,2,3,3,5,5,6,6-d 8 )-1H-benzo[d Preparation of ]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one (Compound I-2)
- compound 3A (20g), sodium methoxide (23.23g), deuterated ethanol (150mL), heavy water (225mL) and nickel-aluminum alloy (60g) were added in sequence, and the reaction was stirred at 30°C. The reaction was complete and filtered. , the filtrate was concentrated under reduced pressure, the residue was extracted with dichloromethane (100 mL*3), the organic phases were combined, dried, filtered, and concentrated under reduced pressure to obtain compound 3B (13 g).
- Step 7 ethyl 2-(5-(4-methylpiperazin-1-yl-3,3,5,5-d 4 )-1H benzo[d]imidazol-2-yl)acetate (Compound 3G ) preparation
- Step 8 4-Amino-5-(5-(4-methylpiperazin-1-yl-3,3,5,5-d 4 )-1H-benzo[d]imidazol-2-yl)thiophene Preparation of [2,3-b]pyridin-6(7H)-one (Compound I-3)
- Step 7 4-Amino-5-(5-(4-methylpiperazin-1-yl-2,2,6,6-d 4 )-1H-benzo[d]imidazol-2-yl)thiophene Preparation of [2,3-b]pyridin-6(7H)-one (Compound I-4)
- Step 1 4-Amino-5-(5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl-4,6-d 2 )thieno[2, Preparation of 3-b]pyridin-6(7H)-one-2-d (Compound I-11)
- Kinase buffer Enzymatic buffer 5X was diluted to 1X and 10 mM MgCl2 , 1 mM DTT and 0.005% Tween 20 were added.
- the 100 ng/ ⁇ L HPK1 (Life technology) stock solution was prepared into a 1.67 ⁇ 1.67 ng/ ⁇ L working solution (final concentration of 1 ng/ ⁇ L) with kinase buffer, and 6 ⁇ L per well was used for seeding (384-well plate).
- Different compounds dissolved in DMSO were added to the wells with a nanoliter sampler, so that the final concentration of the compounds was 1000nM-0.244nM, with a 4-fold gradient, with a total of 7 concentrations.
- a blank control (without enzyme) and negative control wells were set. (containing enzyme, adding solvent DMSO), set 2 duplicate wells. After the enzyme and compound were incubated for 1 h at room temperature, 5 ⁇ of 0.5 mM ATP (final concentration of 0.1 mM) and 5 ⁇ of 2.5 ⁇ M substrate (Cisbio, STK Substrate 1-biotin, final concentration of 0.1 mM) were diluted with kinase buffer. 500nM) and mixed in equal volume, adding 4 ⁇ L to each well, sealing the plate with a sealing film, and incubating at room temperature for 2h.
- Antibody STK Antibody-cryptate (Cisbio, 5 ⁇ l/test) and 4 ⁇ 500nM Streptavidin-XL665 (Cisbio, final concentration of 125nM) were mixed in equal volume to prepare detection antibody, 10 ⁇ L was added to each well, and incubated at room temperature for 1h.
- PE Envision multi-function plate reader was used to detect signal values (excitation 665nm, emission 620nm), and four-parameter fitting was used to calculate IC50. The results are shown in Table 1:
- Test Example 2 Jurkat cell p-SLP76 phosphorylation inhibitory activity detection
- liver microsome incubation samples Mix PBS buffer (pH 7.4), liver microsome solution (0.5 mg/mL, HLM and MLM, respectively), test compound and NADPH+MgCl 2 solution at 37°C, 300rpm Incubate for 1 hour. 0 hour samples were prepared: PBS buffer (pH 7.4), liver microsome solution (0.5 mg/mL, HLM and MLM, respectively), and test compound were mixed. The supernatant was prepared by protein precipitation by adding acetonitrile solution containing internal standard to the sample, and then diluted for LC/MS/MS determination. The results are shown in Table 3.
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Abstract
涉及氘修饰的噻吩并吡啶酮化合物，其制备方法、其药物组合物及其医药用途。该氘修饰的噻吩并吡啶酮化合物如式I所示，其显示抑制HPK1激酶活性，可实现抗肿瘤的作用。
Description
本申请属于药物化学领域，涉及氘修饰的噻吩并吡啶酮化合物，具体涉及式I所示化合物或其药学上可接受的盐、其制备方法、其药物组合物及其医药用途。本申请的氘修饰的噻吩并吡啶酮化合物显示抑制HPK1激酶活性，可实现抗肿瘤的作用。
造血祖细胞激酶1(Hematopoietic progenitor kinase 1,HPK1)，又称有丝分裂原激活蛋白激酶1(Mitogen-activated protein kinase 1,MAP4K1)，是一种哺乳动物Ste20相关的丝氨酸/苏氨酸蛋白激酶，属于微管相关蛋白，也是有丝分裂原激活蛋白激酶(Mitogen-activated protein kinase,MAP4K)家族成员之一。该家族中还包括GCK/MAP4K2、GLK/MAP4K3、HGK/MAP4K4、KHS1/MAP4K5以及MINK1/MAP4K6五种亚型。不同于其他五种MAP4K亚型在组织细胞中的广泛表达，HPK1仅表达于造血组织细胞中，其可以通过介导多种细胞信号通路(包括MAPK信号、抗原受体信号和细胞因子信号等)，参与调节包括淋巴细胞在内的造血系统的信号传导。
研究发现，HPK1主要通过c-Jun氨基末端激酶(c-Jun N-terminal kinase,JNK)和细胞外信号调节激酶(Extracellular regulated protein kinases,ERK)信号通路发挥作用，抑制免疫细胞反应。在T细胞中，T细胞受体(T cell receptor,TCR)蛋白活化后，HPK1与大量TCR相互作用，并被酪氨酸激酶Lck和Zap70磷酸化，活化后的HPK1进一步磷酸化T细胞受体适配器蛋白SLP-76，为负调节因子14-3-3建立一个对接位点，最终破坏TCR信号复合物(lato-gads-SLP76)的稳定，并阻碍下游丝裂原活化蛋白(MAP)激酶信号的传递，负向调节TCR信号传导，继而抑制T细胞增殖。在B细胞中，同样存在着类似的负反馈机制，B细胞受体(B cell receptor,BCR)信号通过HPK1介导的磷酸化和活化的B细胞连接蛋白(B-cell linker protein,BLNK)，进而阻碍下游信号传递，抑制B细胞增殖。除此以外，HPK1对NK细胞(Natural killer)和树突状细胞(Dendritic cells,DC)同样存在着负反馈调节作用。
由于在免疫方面的重要作用，HPK1抑制剂在恶性实体肿瘤或者血液癌(如急性髓性白血病、乳腺癌、肺癌等)、自身免疫性疾病(如系统性红斑狼疮、银屑病关节炎) 和炎症反应中均扮演重要的角色。
目前针对HPK1靶点尚未有药物上市，本领域仍需开发具有选择性抑制活性、或更好的药效学、或更好的药代动力学的化合物。
发明内容
本申请提供一种式I所示的化合物或其药学上可接受的盐，
其中，
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14、R
15和R
16各自独立地选自氢或者氘。
在部分方案中，所述R
1、R
2、R
3、R
4、R
5、R
10和R
11选自氘，R
6、R
7、R
8、R
9、 R
12、R
13、R
14、R
15和R
16各自独立地选自氢或者氘。
在部分方案中，所述R
1、R
2、R
3、R
6、R
7、R
8和R
9选自氘，R
4、R
5、R
10、R
11、R
12、R
13、R
14、R
15和R
16各自独立地选自氢或者氘。
在部分方案中，所述R
4、R
5、R
6、R
7、R
8、R
9、R
10和R
11选自氘，R
1、R
2、R
3、R
12、R
13、R
14、R
15和R
16各自独立地选自氢或者氘。
在部分方案中，所述R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、R
9、R
10和R
11选自氘，R
12、R
13、R
14、R
15和R
16各自独立地选自氢或者氘。
在部分方案中，所述R
12和R
14选自氘，R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、R
13、R
15和R
16各自独立地选自氢或者氘。
在部分方案中，所述R
13选自氘，R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、R
12、R
14、R
15和R
16各自独立地选自氢或者氘。
在部分方案中，所述R
12、R
13和R
14选自氘，R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、R
15和R
16各自独立地选自氢或者氘。
在部分方案中，所述R
1、R
2、R
3、R
12、R
13和R
14选自氘，R
4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、R
15和R
16各自独立地选自氢或者氘。
在部分方案中，所述R
15选自氘，R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、R
12、R
13、R
14和R
16各自独立地选自氢或者氘。
在部分方案中，所述R
16选自氘，R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、R
12、R
13、R
14和R
15各自独立地选自氢或者氘。
在部分方案中，所述R
15和R
16选自氘，R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、R
12、R
13和R
14各自独立地选自氢或者氘。
在部分方案中，所述R
1、R
2、R
3、R
15和R
16选自氘，R
4、R
5、R
6、R
7、R
8、R
9、R
10、R
11、R
12、R
13和R
14各自独立地选自氢或者氘。
在部分方案中，式I所示的化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐：
| 化合物 | R 1 | R 2 | R 3 | R 4 | R 5 | R 6 | R 7 | R 8 | R 9 | R 10 | R 11 | R 12 | R 13 | R 14 | R 15 | R 16 |
| I-1 | D | D | D | H | H | H | H | H | H | H | H | H | H | H | H | H |
| I-2 | H | H | H | D | D | D | D | D | D | D | D | H | H | H | H | H |
| I-3 | H | H | H | D | D | H | H | H | H | D | D | H | H | H | H | H |
| I-4 | H | H | H | H | H | D | D | D | D | H | H | H | H | H | H | H |
| I-5 | D | D | D | D | D | D | D | D | D | D | D | H | H | H | H | H |
| I-6 | D | D | D | D | D | H | H | H | H | D | D | H | H | H | H | H |
| I-7 | H | H | H | H | H | H | H | H | H | H | H | D | D | D | H | H |
| I-8 | H | H | H | H | H | H | H | H | H | H | H | H | H | H | D | D |
| I-9 | D | D | D | H | H | H | H | H | H | H | H | D | D | D | H | H |
| I-10 | D | D | D | H | H | H | H | H | H | H | H | H | H | H | D | D |
| I-11 | H | H | H | H | H | H | H | H | H | H | H | D | H | D | H | D |
在部分方案中，式I所示的化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐：
本申请另一方面提供药物组合物，其包括本申请的化合物或其药学上可接受的盐，任选地进一步包括药学上可接受的辅料。在一个实施方案中，所述药物组合物还包含第二活性剂，第二活性剂为其他抗癌剂(例如小分子抗癌剂或抗体抗癌剂)。
本申请另一方面提供本申请的化合物或其药学上可接受的盐、或上述药物组合物在制备治疗得益于抑制HPK1激酶活性的疾病的药物中的用途。在一个实施方案中，所述药物还包含用于治疗所述疾病的第二活性剂，第二活性剂为其他抗癌剂(例如小分子抗癌剂或抗体抗癌剂)。
本申请另一方面提供本申请的化合物或其药学上可接受的盐、或上述药物组合物在治疗得益于抑制HPK1激酶活性的疾病中的用途。
本申请另一方面提供用于治疗得益于抑制HPK1激酶活性的疾病的本申请的化合物或其药学上可接受的盐、或上述药物组合物。
本申请另一方面提供治疗得益于抑制HPK1激酶活性的疾病的方法，包括对需要该治疗的个体(所述个体选自哺乳动物，优选人类)，给予治疗有效量的本申请的化合物或其药学上可接受的盐、或上述药物组合物。
在部分方案中，所述得益于抑制HPK1激酶活性的疾病选自肿瘤或癌症，例如血液癌或实体瘤，例如急性髓性白血病、乳腺癌或肺癌。
在一个实施方案中，在上述疾病治疗方法中，本申请的化合物或其药学上可接受的盐或上述药物组合物与其他抗癌剂(例如小分子抗癌剂或抗体抗癌剂)或其他抗癌疗法(例如放疗和/或化疗)联合施用。
本申请化合物具备良好的HPK1体外激酶抑制活性、细胞p-SLP76磷酸化抑制活 性，并且体外肝微粒体稳定性良好。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
术语“独立地”当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。例如，如果一个基团被2个R所取代，则每个R都有独立的选项。或者例如，多个基团被某个R所取代，则其中每个基团被R取代的情况相互之间是独立的。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不 限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
术语“治疗”一般是指获得需要的药理和/或生理效应。该效应部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
术语“有效量”意指(i)治疗定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的活性物质(例如本申请的抗体或化合物)的量可根据一些因素而变化，诸如个体的疾病状态、年龄、性别和重量，以及治疗剂或治疗剂组合在个体中引发所需应答的能力。有效量也可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
本申请中，术语“个体”包括人和动物，例如，哺乳动物(如灵长类动物，牛，马，猪，狗，猫，小鼠，大鼠，兔，山羊，绵羊以及禽类等)。在部分实施方案中，所述受试者或患者是小鼠。在部分实施方案中，所述受试者或患者是人。
本申请化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本申请化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1～10％w/v该化合物的生理缓冲水溶液提供本申请化合物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推，得到有效剂量。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领 域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
实施例
为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
除下述实施例外，本申请公开的其他化合物可以参考实施例的制备方法或本领域已知的制备方法制备得到。本领域技术人员可以通过本申请的方法或本领域已知的制备方法检测化合物的质谱(MS)或核磁(NMR)。
实施例1：4-氨基-5-(5-(4-(甲基-d
3)哌嗪-1-基)-1H-苯并[d]咪唑-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮(化合物I-1)的制备
步骤一：4-(甲基-d
3)哌嗪-1-羧酸叔丁酯(化合物1A)的制备
向250mL的反应瓶中，哌嗪-1-羧酸叔丁酯(5g)，碳酸钾(7.42g)溶于四氢呋喃(100mL)，在氮气保护条件下，于25℃搅拌反应，然后于-30℃下滴加碘甲烷-d
3(4.28g)，继续在氮气保护条件下，于25℃搅拌反应，反应完全，过滤，减压浓缩。得到化合物1A(5.5g)。
MS:m/z＝204.2[M+H]
+.
步骤二：1-(甲基-d
3)哌嗪(化合物1B)的制备
向100mL的反应瓶中，依次加入化合物1A(5.5g)，三氟乙酸(12g)，二氯甲烷(30mL)，于25℃搅拌反应，反应完全，将反应液调至碱性，二氯甲烷萃取(50mL*3)，合并有机相，干燥，过滤，减压浓缩。得到化合物1B(2.8g)。
MS:m/z＝104.2[M+H]
+.
步骤三：5-(4-(甲基-d
3)哌嗪-1-基)-2-硝基苯胺(化合物1C)的制备
向100mL的反应瓶中，依次加入化合物1B(2.8g)，5-氯-2-硝基苯胺(2.7g)，碳酸钾(8.6g)，N-甲基吡咯烷酮(20mL)，于160℃搅拌反应，反应完全，减压浓缩。残余物经柱层析(二氯甲烷/甲醇＝9/1)分离得到化合物1C(1.12g)。
MS:m/z＝240.2[M+H]
+.
步骤四：4-(4-(甲基-d
3)哌嗪-1-基)苯-1,2-二胺(化合物1D)的制备
向100mL的反应瓶中，依次加入1C(1.12g)，乙醇(20mL)，水(10mL)，锌粉(1.6g)，氯化铵(0.131g)。于80℃搅拌反应，反应完全，抽滤，滤液减压浓缩，得到化合物1D(1g)。
MS:m/z＝210.3[M+H]
+.
步骤五：2-(5-(4-(甲基-d
3)哌嗪-1-基)-1H-苯并[d]咪唑-2-基)乙酸乙酯(化合物1E)的制备
向100mL的反应瓶中，依次加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(1.4g)，化合物1D(1g)，二甲基甲酰胺(20mL)，在氮气保护条件下，于80℃搅拌反应，反应完全，减压浓缩。残余物经柱层析(二氯甲烷/甲醇＝4/1)分离得到化合物1E(1.416g)。
MS:m/z＝306.1[M+H]
+.
步骤六：4-氨基-5-(5-(4-(甲基-d
3)哌嗪-1-基)-1H-苯并[d]咪唑-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮(化合物I-1)的制备
向100mL的反应瓶中，依次加入化合物1E(1.416g)，2-氨基噻吩-3-甲腈(0.576g)，四氢呋喃(20mL)，二异丙基氨基锂(4.9g)，在氮气保护条件下，于60℃搅拌反应，反应完全，饱和氯化铵淬灭反应，乙酸乙酯萃取(30mL*3)，合并有机相，干燥，过滤，减压浓缩。残余物经柱层析(二氯甲烷/甲醇＝9/1)分离得到化合物I-1(0.1g)。
MS:m/z＝384.6[M+H]
+.
1H NMR(500MHz,DMSO-d
6)δ12.62(s,1H),12.10(s,1H),10.67(d,1H),8.00(s,1H),7.45-7.60(m,2H),7.19(s,2H),6.89(s,1H),3.13(s,4H),2.60(s,4H)。
实施例2：4-氨基-5-(5-(4-甲基哌嗪-1-基-2,2,3,3,5,5,6,6-d
8)-1H-苯并[d]咪唑-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮(化合物I-2)的制备
步骤一：5-(4-甲基哌嗪-1-基-2,2,3,3,5,5,6,6-d
8)-2-硝基苯胺(化合物2A)的制备
向100mL的反应瓶中，依次加入化合物1-甲基哌嗪-2,2,3,3,5,5,6,6-d
8(0.847g)，5-氯-2-硝基苯胺(1.356g)，碳酸钾(4.330g)，N-甲基吡咯烷酮(20mL)，于160℃搅拌反应，反应完全，减压浓缩。残余物经柱层析(二氯甲烷/甲醇＝9/1)分离得到化合物2A(0.619g)。
MS:m/z＝245.1[M+H]
+.
步骤二：4-(4-甲基哌嗪-1-基-2,2,3,3,5,5,6,6-d
8)苯-1,2-二胺(化合物2B)的制备
向100mL的反应瓶中，依次加入化合物2A(0.618g)，乙醇(30mL)，水(5mL)，锌粉(0.828g)和氯化铵(1.354g)。于80℃搅拌反应，反应完全，抽滤，滤液减压浓缩，得到化合物2B(0.543g)。
MS:m/z＝215.2[M+H]
+.
步骤三：2-(5-(4-甲基哌嗪-1-基-2,2,3,3,5,5,6,6-d
8)-1H-苯并[d]咪唑-2-基)乙酸乙酯(化合物2C)的制备
向100mL的反应瓶中，依次加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(0.826g)，化合物2B(0.543g)和二甲基甲酰胺(10mL)，在氮气保护条件下，于80℃搅拌反应，反应完全，减压浓缩。残余物经柱层析(二氯甲烷/甲醇＝4/1)分离得到化合物2C(0.314g)。
MS:m/z＝311.5[M+H]
+.
步骤四：4-氨基-5-(5-(4-甲基哌嗪-1-基-2,2,3,3,5,5,6,6-d
8)-1H-苯并[d]咪唑-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮(化合物I-2)的制备
向100mL的反应瓶中，依次加入化合物2C(0.310g)，2-氨基噻吩-3-甲腈(0.200g)，四氢呋喃(30mL)，二异丙基氨基锂2M四氢呋喃溶液(5mL)，在氮气保护条件下，于60℃搅拌反应，反应完全，饱和氯化铵淬灭反应，乙酸乙酯萃取，合并有机相，干燥，过滤，减压浓缩。残余物经柱层析(二氯甲烷/甲醇＝9/1)分离得到化合物I-2(46mg)。
MS:m/z＝389.5[M+H]
+.
1H NMR(500MHz,DMSO-d
6)δ12.61(s,1H),12.10(s,1H),10.67(d,J＝51.5Hz,1H),7.99(s,1H),7.60(d,J＝5.5Hz,1H),7.47(dd,J＝8.5,32.0Hz,1H),7.19-7.10(m,2H),6.90-6.87(m,1H),2.29(s,3H).
实施例3：4-氨基-5-(5-(4-甲基哌嗪-1-基-3,3,5,5-d
4)-1H-苯并[d]咪唑-2-基)噻吩 [2,3-b]吡啶-6(7H)-酮(化合物I-3)的制备
步骤一：1-苄基-4-亚硝基哌嗪-3,3,5,5-d4(化合物3A)的制备
向500mL的反应瓶中，依次加入重水(200mL)，1-苄基-4-亚硝基哌嗪(30g)和甲醇钠(23.69g)，在氮气保护条件下，80℃搅拌反应，然后加入氘代乙醇(150mL)，继续在氮气保护条件下，于80℃搅拌反应，反应完全，反应液降至0℃，抽滤，将滤饼洗涤，干燥，得到化合物3A(25g)。
MS:m/z＝210.5[M+H]
+.
步骤二：1-苄基哌嗪-3,3,5,5-d
4(化合物3B)的制备
在1L反应瓶中，依次加入化合物3A(20g)，甲醇钠(23.23g)，氘代乙醇(150mL)，重水(225mL)和镍铝合金(60g)，于30℃搅拌反应，反应完全，过滤，滤液减压浓缩，残余物经二氯甲烷萃取(100mL*3)，合并有机相，干燥，过滤，减压浓缩，得到化合物3B(13g)。
MS:m/z＝181.5[M+H]+.
1H NMR(500MHz,CDCl
3)δ7.35-7.20(m,5H),3.49(d,J＝7.0Hz,2H),2.40(s,4H).
步骤三：1-苄基-4-甲基哌嗪-3,3,5,5-d
4(化合物3C)的制备
于0℃条件下，向100mL的反应瓶中，依次加入化合物3B(13g)，四氢呋喃(50mL)，氢化钠(2.88g)，缓慢升至25℃搅拌0.5h，然后，于0℃条件下，向反应液中加入4-甲基苯磺酸甲酯(6.71g)，于25℃搅拌反应，反应完全，淬灭反应，减压浓缩。残余物经柱层析(二氯甲烷/甲醇＝30/1)分离得到化合物3C(4.5g)。
MS:m/z＝195.5[M+H]
+.
步骤四：1-甲基哌嗪-2,2,6,6-d
4(化合物3D)的制备
于100mL反应瓶中，依次加入化合物3C(4.5g)，10％钯碳(4g)和无水甲醇(50mL)，于氢气条件下，于25℃搅拌反应，反应完全，过滤，滤液减压浓缩，得到化合物3D(1.3g)。
MS:m/z＝105.4[M+H]
+.
步骤五：5-(4-甲基哌嗪-1-基-3,3,5,5-d
4)-2-硝基苯胺(化合物3E)的制备
于100mL反应瓶中，依次加入化合物3D(1.3g)，5-氯-2-硝基苯胺(2.15g)，碳酸钾(6.9g)，N-甲基吡咯烷酮(40mL)。于160℃搅拌反应，反应完全，减压浓缩。残余物经柱层析(二氯甲烷/甲醇＝9/1)分离得到化合物3E(1.4g)。
MS:m/z＝241.2[M+H]
+.
步骤六：4-(4-甲基哌嗪-1-基-3,3,5,5-d
4)苯-1,2-二胺(化合物3F)的制备
于100mL反应瓶中，依次加入化合物3E(1.4g)，锌粉(1.9g)，氯化铵(0.31g)，乙醇(30mL)和水(5mL)。于80℃搅拌反应，反应完全，抽滤，滤液减压浓缩，得到化合物3F(1.2g)。
MS:m/z＝211.3[M+H]
+.
步骤七：2-(5-(4-甲基哌嗪-1-基-3,3,5,5-d
4)-1H苯并[d]咪唑-2-基)乙酸乙酯(化合物3G)的制备
于100mL反应瓶中，依次加入化合物3F(1.2g)，3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(2.23g)和乙醇(30mL)。于80℃搅拌反应，反应完全，减压浓缩。残余物经柱层析(二氯甲烷/甲醇＝30/1)分离得到化合物3G(0.5g)。
MS:m/z＝306.9[M+H]
+.
步骤八：4-氨基-5-(5-(4-甲基哌嗪-1-基-3,3,5,5-d
4)-1H-苯并[d]咪唑-2-基)噻吩[2,3-b]吡啶-6(7H)-酮(化合物I-3)的制备
向100mL的反应瓶中，依次加入化合物3G(0.5g)，2-氨基噻吩-3-甲腈(0.32g)，四氢呋喃(20ml)，二异丙基氨基锂(1.75g)，在氮气保护条件下，于60℃搅拌反应，反应完全，饱和氯化铵淬灭反应，乙酸乙酯萃取(30mL*3)，合并有机相，干燥，过滤，减压浓缩。残余物经柱层析(二氯甲烷/甲醇＝9/1)分离得到化合物I-3(0.1g)。
MS:m/z＝385.5[M+H]
+.
1H NMR(500MHz,DMSO-d
6)δ12.62(s,1H),12.10(s,1H),10.67(d,J＝47.3Hz, 1H),8.01(s,1H),7.60(d,J＝5.6Hz,1H),7.48(dd,J＝32.3,8.4Hz,1H),7.17(dd,J＝24.0,18.4Hz,2H),6.90(s,1H),3.13(s,4H),2.33(s,3H).
实施例4：4-氨基-5-(5-(4-甲基哌嗪-1-基-2,2,6,6-d
4)-1H-苯并[d]咪唑-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮(化合物I-4)的制备
步骤一：1-甲基-4-亚硝基哌嗪(化合物4A)的制备
在100mL反应瓶中，依次加入1-甲基哌嗪(10g)，水(20mL)和浓盐酸(25mL)，于0℃条件下，向反应液中加入溶解在水(20mL)中的亚硝酸钠(8.27g)溶液，于25℃搅拌反应，反应完全，调节反应液至碱性，反应液经二氯甲烷萃取(100mL*3)，合并有机相，干燥，过滤，减压浓缩，得到化合物4A(10.8g)。
MS:m/z＝130.2[M+H]
+.
步骤二：1-甲基-4-亚硝基哌嗪-3,3,5,5-d
4(化合物4B)的制备
向100mL的反应瓶中，依次加入重水(30mL)，化合物4A(5g)和氘代氢氧化钠(5.29g)，在氮气保护条件下，于100℃搅拌反应，反应完全，反应液经二氯甲烷萃取(50mL*3)，合并有机相，干燥，过滤，减压浓缩，得到化合物4B(5.3g)。
1H NMR(500MHz,CDCl
3)δ2.57(s,2H),2.33(s,2H),2.31(s,3H).
步骤三：1-甲基哌嗪-3,3,5,5-d
4(化合物4C)的制备
在100mL反应瓶中，依次加入化合物4B(5g)，甲醇钠(15.2g)，氘代乙醇(23mL)，重水(23mL)和镍铝合金(15g)，于30℃搅拌反应，反应完全，过滤，滤液减压浓缩，残余物经二氯甲烷萃取(100mL*3)，合并有机相，干燥，过滤，减压浓缩，得到化合物4C(4g)。
MS:m/z＝105.5[M+H]
+.
步骤四：5-(4-甲基哌嗪-1-基-2,2,6,6-d
4)-2-硝基苯胺(化合物4D)的制备
向100mL的反应瓶中，依次加入化合物4C(3.677g)，5-氯-2-硝基苯胺(5.413g)，碳酸钾(10.847g)，N-甲基吡咯烷酮(50mL)，于160℃搅拌反应，反应完全，减压浓缩。残余物经柱层析(二氯甲烷/甲醇＝9/1)分离得到化合物4D(1.410g)。
MS:m/z＝241.2[M+H]
+.
步骤五：4-(4-甲基哌嗪-1-基-2,2,6,6-d
4)苯-1,2-二胺(化合物4E)的制备
向100mL的反应瓶中，依次加入4D(1.400g)，乙醇(30mL)，水(5mL)，锌粉(2.245g)和氯化铵(0.400g)。于80℃搅拌反应，反应完全，抽滤，滤液减压浓缩，得到化合物4E(1.403g)。
MS:m/z＝211.3[M+H]
+.
步骤六：2-(5-(4-甲基哌嗪-1-基-2,2,6,6-d
4)-1H-苯并[d]咪唑-2-基)乙酸乙酯(化合物4F)的制备
向100mL的反应瓶中，依次加入3-乙氧基-3-亚氨基丙酸乙酯盐酸盐(2.230g)，化合物4E(1.400g)，乙醇(50mL)，在氮气保护条件下，于80℃搅拌反应，反应完全，减压浓缩。残余物经柱层析(二氯甲烷/甲醇＝4/1)分离得到化合物4F(1.241g)。
MS:m/z＝307.3[M+H]
+.
步骤七：4-氨基-5-(5-(4-甲基哌嗪-1-基-2,2,6,6-d
4)-1H-苯并[d]咪唑-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮(化合物I-4)的制备
向100mL的反应瓶中，依次加入化合物4F(1.241g)，2-氨基噻吩-3-甲腈(0.600g)，四氢呋喃(40mL)，二异丙基氨基锂2M四氢呋喃溶液(20mL)，在氮气保护条件下，于60℃搅拌反应，反应完全，饱和氯化铵淬灭反应，乙酸乙酯萃取，合并有机相，干燥，过滤，减压浓缩。残余物经柱层析(二氯甲烷/甲醇＝9/1)分离得到化合物I-4(70mg)。
MS:m/z＝385.5[M+H]
+.
1H NMR(500MHz,DMSO-d
6)δ12.61(s,1H),12.10(s,1H),10.69(d,J＝51.0Hz,1H),7.99(s,1H),7.60(d,J＝5.5Hz,1H),7.47(dd,J＝9.0,32.5Hz,1H),7.19-7.10(m,2H),6.90-6.87(m,1H),2.51-2.48(m,4H),2.24(s,3H)。
实施例5：4-氨基-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基-4,6-d
2)噻吩并[2,3-b]吡啶-6(7H)-酮-2-d(化合物I-11)的制备
步骤一：4-氨基-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基-4,6-d
2)噻吩并[2,3-b]吡啶-6(7H)-酮-2-d(化合物I-11)的制备
于25mL的微波管中，依次加入化合物4-氨基-5-(5-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基-4,6)噻吩并[2,3-b]吡啶-6(7H)-酮(0.3g)，重水(8mL)和三氟乙酸酐(0.11mL)。加毕将反应液微波加热至140℃搅拌反应。反应完全，将反应液调节至碱性，乙酸乙酯萃取(30mL*3)，合并有机相，干燥，过滤，减压浓缩。残余物经柱层析(二氯甲烷/甲醇＝9/1)分离得到化合物I-11(0.197g)。
MS:m/z＝384.5[M+H]
+.
1H NMR(500MHz,DMSO-d
6)δ12.64(s,1H),12.12(s,1H),10.68(d,J＝48.1Hz,1H),8.04(s,1H),7.62(s,1H),7.49(d,J＝32.3Hz,1H),3.21–3.12(m,4H),2.69(d,J＝12.0Hz,4H),2.37(d,J＝8.3Hz,3H).
试验例1：HPK1体外激酶抑制活性检测
将激酶缓冲液Enzymatic buffer 5×稀释为1×，并添加10mM MgCl
2、1mM DTT和0.005％Tween 20。将100ng/μL的HPK1(Life technology)母液用激酶缓冲液配制成1.67×的1.67ng/μL的工作液(终浓度为1ng/μL)，每孔6μL进行种板(384孔板)。用纳升加样仪将DMSO溶解的不同化合物加入到孔中，使化合物终浓度为1000nM-0.244nM，4倍梯度，共7个浓度，同时设空白对照空(不含酶)与阴性对照孔(含酶，加溶媒DMSO)，设2个复孔。酶与化合物在室温孵育1h后，将用激酶缓冲液稀释好的5×的0.5mM ATP(终浓度为0.1mM)和5×的2.5μM底物(Cisbio，STK Substrate 1-biotin，终浓度为500nM)等体积混合，每孔加入4μL，封板膜封板，在室温孵育2h。将抗体STK Antibody-cryptate(Cisbio，5μl/test)和4×的500nM的Streptavidin-XL665(Cisbio，终浓度为125nM)等体积混合配制检测抗体，每孔加入10μL，在室温孵育1h。PE Envision多功能读板仪进行检测信号值(激发665nm，发射620nm)，四参数拟合计算IC50。结果见表1所示：
表1
| 实施例 | 体外酶抑制活性HPK1 IC50(nM) |
| 2 | 9.7 |
| 3 | 7.5 |
| 4 | 9.2 |
| 5 | 8.8 |
试验例2 Jurkat细胞p-SLP76磷酸化抑制活性检测
取处于生长状态良好的Jurkat细胞，收集至离心管，离心后重悬，调整细胞密度至6.25×10
6个/mL，接种于384孔小体积白板(8μL/孔)；使用纳升加样仪进行化合物加样，使化合物终浓度为2500nM-10.29nM，2个复孔，同时设置对照，细胞培养1小时后，加入刺激剂CD3CD28(厂家：stemcell，4μL)，37℃孵育30分钟；每孔加入3μL裂解液(厂家：BioAuxilium)，并在室温下摇动裂解30分钟，裂解混匀后，加入5μL检测缓冲液配制的预先混合的抗体(厂家：BioAuxilium)，室温孵育过夜，PerkinElmer Envision多功能酶标仪进行检测(激发320nm，发射615nm/665nm)，采用四参数拟合，计算IC50。试验结果见表2。
表2
试验例3体外肝微粒体稳定性
制备肝微粒体温孵样本：将PBS缓冲液(pH 7.4)、肝微粒体溶液(0.5mg/mL，分别为HLM和MLM)、受试化合物及NADPH+MgCl
2溶液混合，于37℃下，300rpm孵育1小时。制备0小时样本：将PBS缓冲液(pH 7.4)、肝微粒体溶液(0.5mg/mL，分别为HLM和MLM)以及受试化合物混合。在样本加入含内标的乙腈溶液经蛋白沉淀制备上清液，稀释后用于LC/MS/MS测定。结果见表3。
表3
Claims (23)
- 一种式I所示的化合物或其药学上可接受的盐，
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15和R 16各自独立地选自氢或者氘；条件是R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15和R 16中的至少一个选自氘。 - 如权利要求1所述的化合物或其药学上可接受的盐，其中，所述R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15和R 16中的至少两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个、十二个、十三个、十四个、十五个或十六个选自氘。
- 如权利要求1所述的化合物或其药学上可接受的盐，其中，所述R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15和R 16中的任选一个、两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个、十二个、十三个、十四个、十五个或十六个选自氘。
- 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，R 1、R 2和R 3选自氘，R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15和R 16各自独立地选自氢或者氘。
- 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，R 4、R 5、R 10和R 11选自氘，R 1、R 2、R 3、R 6、R 7、R 8、R 9、R 12、R 13、R 14、R 15和R 16各自独立地选自氢或者氘。
- 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，R 6、R 7、R 8和R 9选自氘，R 1、R 2、R 3、R 4、R 5、R 10、R 11、R 12、R 13、R 14、R 15和R 16各自独立地选自氢或者氘。
- 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，R 1、R 2、R 3、R 4、R 5、R 10和R 11选自氘，R 6、R 7、R 8、R 9、R 12、R 13、R 14、R 15和R 16各自独立地选自氢或者氘。
- 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，R 1、R 2、R 3、R 6、R 7、R 8和R 9选自氘，R 4、R 5、R 10、R 11、R 12、R 13、R 14、R 15和R 16各自独立地选自氢或者氘。
- 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，所述R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11选自氘，R 1、R 2、R 3、R 12、R 13、R 14、R 15和R 16各自独立地选自氢或者氘。
- 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11选自氘，R 12、R 13、R 14、R 15和R 16各自独立地选自氢或者氘。
- 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，R 12和R 14选自氘，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 13、R 15和R 16各自独立地选自氢或者氘。
- 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，所述R 13选自氘，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 14、R 15和R 16各自独立地选自氢或者氘。
- 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，所述R 12、R 13和R 14选自氘，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 15和R 16各自独立地选自氢或者氘。
- 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，所述R 1、R 2、R 3、R 12、R 13和R 14选自氘，R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 15和R 16各自独立地选自氢或者氘。
- 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，所述R 15选自氘，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 16各自独立地选自氢或者氘。
- 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，所述R 16选自氘，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15各 自独立地选自氢或者氘。
- 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，所述R 15和R 16选自氘，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、和R 14各自独立地选自氢或者氘。
- 如权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，所述R 1、R 2、R 3、R 15和R 16选自氘，R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、和R 14各自独立地选自氢或者氘。
- 如权利要求1-18任一项所述的化合物或其药学上可接受的盐，选自以下化合物或其药学上可接受的盐：
- 药物组合物，其包括权利要求1-19任一项所述化合物或其药学上可接受的盐，任选地进一步包括药学上可接受的辅料。
- 如权利要求20所述的药物组合物，其还包括第二活性剂，所述第二活性剂选自抗癌剂。
- 权利要求1-19任一项所述的化合物或其药学上可接受的盐、或权利要求20所述的药物组合物在制备治疗得益于抑制HPK1激酶活性的疾病的药物中的用途，所述药物可选地还包含治疗所述疾病的第二活性剂，所述第二活性剂选自抗癌剂。
- 如权利要求22所述的用途，其中，所述得益于抑制HPK1激酶活性的疾病选自肿瘤或癌症。
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
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| CN202180078165.9A CN116472041A (zh) | 2020-11-24 | 2021-11-24 | 氘修饰的噻吩并吡啶酮化合物 |
| EP21897018.4A EP4253386A1 (en) | 2020-11-24 | 2021-11-24 | Deuterium-modified thienopyridone compound |
| US18/037,523 US20240002394A1 (en) | 2020-11-24 | 2021-11-24 | Deuterium-modified thienopyridone compound |
| JP2023529951A JP2023550380A (ja) | 2020-11-24 | 2021-11-24 | 重水素修飾チエノピリドン化合物 |
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| CN202011334883.1 | 2020-11-24 | ||
| CN202011334883 | 2020-11-24 |
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| WO2022111517A1 true WO2022111517A1 (zh) | 2022-06-02 |
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| PCT/CN2021/132748 WO2022111517A1 (zh) | 2020-11-24 | 2021-11-24 | 氘修饰的噻吩并吡啶酮化合物 |
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| US (1) | US20240002394A1 (zh) |
| EP (1) | EP4253386A1 (zh) |
| JP (1) | JP2023550380A (zh) |
| CN (1) | CN116472041A (zh) |
| WO (1) | WO2022111517A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11897878B2 (en) | 2018-10-31 | 2024-02-13 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds |
| US11925631B2 (en) | 2018-10-31 | 2024-03-12 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107922431A (zh) * | 2015-06-25 | 2018-04-17 | 大学健康网络 | Hpk1抑制剂及其使用方法 |
| CN109721620A (zh) * | 2017-10-27 | 2019-05-07 | 南京药捷安康生物科技有限公司 | Hpk1抑制剂及其用途 |
| WO2021226707A1 (en) * | 2020-05-11 | 2021-11-18 | University Health Network | Salt and crystal forms of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1h-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7h)-one |
-
2021
- 2021-11-24 WO PCT/CN2021/132748 patent/WO2022111517A1/zh active Application Filing
- 2021-11-24 CN CN202180078165.9A patent/CN116472041A/zh active Pending
- 2021-11-24 EP EP21897018.4A patent/EP4253386A1/en active Pending
- 2021-11-24 US US18/037,523 patent/US20240002394A1/en active Pending
- 2021-11-24 JP JP2023529951A patent/JP2023550380A/ja active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107922431A (zh) * | 2015-06-25 | 2018-04-17 | 大学健康网络 | Hpk1抑制剂及其使用方法 |
| CN109721620A (zh) * | 2017-10-27 | 2019-05-07 | 南京药捷安康生物科技有限公司 | Hpk1抑制剂及其用途 |
| WO2021226707A1 (en) * | 2020-05-11 | 2021-11-18 | University Health Network | Salt and crystal forms of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1h-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7h)-one |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11897878B2 (en) | 2018-10-31 | 2024-02-13 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds |
| US11925631B2 (en) | 2018-10-31 | 2024-03-12 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| EP4253386A1 (en) | 2023-10-04 |
| US20240002394A1 (en) | 2024-01-04 |
| CN116472041A (zh) | 2023-07-21 |
| JP2023550380A (ja) | 2023-12-01 |
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