WO2019120297A1 - Immunomodulator and preparation method and medical use thereof - Google Patents

Immunomodulator and preparation method and medical use thereof Download PDF

Info

Publication number
WO2019120297A1
WO2019120297A1 PCT/CN2018/122818 CN2018122818W WO2019120297A1 WO 2019120297 A1 WO2019120297 A1 WO 2019120297A1 CN 2018122818 W CN2018122818 W CN 2018122818W WO 2019120297 A1 WO2019120297 A1 WO 2019120297A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cancer
compound
mmol
group
Prior art date
Application number
PCT/CN2018/122818
Other languages
French (fr)
Chinese (zh)
Inventor
彭建彪
龚超骏
茅佳荣
彭冠
林崇懒
刘力锋
张青
席宝信
关慧平
陈曦
周福生
王玮玮
Original Assignee
上海海雁医药科技有限公司
扬子江药业集团有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海海雁医药科技有限公司, 扬子江药业集团有限公司 filed Critical 上海海雁医药科技有限公司
Publication of WO2019120297A1 publication Critical patent/WO2019120297A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Hematology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The present invention relates to an immunomodulator, a preparation method thereof, and an application of the same as a PD-1/PD-L1 inhibitor. In particular, disclosed are a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof and a preparation method and application thereof. The definition of each substituent in the formula is described in detail in the specification and claims.

Description

免疫调节剂及其制法与医药上的用途Immunomodulator, its preparation method and medical use 技术领域Technical field
本发明属于医药技术领域。具体地，本发明特别涉及一种免疫调节剂及其制法和作为PD-1/PD-L1抑制剂的应用，以及由其制备的药物组合物。The invention belongs to the field of medical technology. In particular, the present invention relates in particular to an immunomodulator, a process for its preparation and use as a PD-1/PD-L1 inhibitor, and a pharmaceutical composition prepared therefrom.
背景技术Background technique
程序性细胞死亡-1(PD-1)是CD28超家族的成员，其与它的两种配体，PD-L1或PD-L2相互作用时递送负性信号。PD-1和其配体广泛表达并且与其他CD28成员相比，在T细胞活化和耐受方面发挥更宽范围的免疫调节作用。PD-1和其配体参与减弱感染性免疫和肿瘤免疫，并且促进慢性感染和肿瘤进展。PD-1和其配体的生物学重要性提示了PD-1通路的操作对各种人类疾病的治疗可能性(Ariel Pedoeem等人，Curr Top Microbiol Immunol.(2011)；350：17-37)。Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers a negative signal when interacting with its two ligands, PD-L1 or PD-L2. PD-1 and its ligands are widely expressed and exert a broader range of immunomodulatory effects in T cell activation and tolerance compared to other CD28 members. PD-1 and its ligands are involved in attenuating infectious and tumor immunity and promoting chronic infection and tumor progression. The biological importance of PD-1 and its ligands suggests the possibility of treatment of the PD-1 pathway for a variety of human diseases (Ariel Pedoeem et al, Curr Top Microbiol Immunol. (2011); 350: 17-37). .
T细胞活化和功能失调依赖于直接和调节的受体。基于它们的功能结果，共信号转导分子可以分为共刺激剂和共抑制剂，其正面和负面控制T细胞应答的启动、生长、分化和功能成熟(Li Shi，等人，Journal of Hematology&Oncology 2013，6：74)。T cell activation and dysfunction are dependent on direct and regulated receptors. Based on their functional results, co-signaling molecules can be divided into co-stimulants and co-inhibitors that positively and negatively control the initiation, growth, differentiation, and functional maturation of T cell responses (Li Shi, et al, Journal of Hematology & Oncology 2013) , 6:74).
阻断程序性细胞死亡蛋白-1(PD-1)免疫检查点通路的治疗性抗体阻止T细胞下调并且促进针对癌症的免疫应答。多种PD-1通路抑制剂在临床实验的各个阶段显示出强烈的活性(RD Harvey，Clinical Pharmacology&Therapeutics(2014)；96 2，214-223)。Therapeutic antibodies that block the programmed cell death protein-1 (PD-1) immunological checkpoint pathway prevent T cell down-regulation and promote an immune response against cancer. A variety of PD-1 pathway inhibitors show strong activity at various stages of clinical trials (RD Harvey, Clinical Pharmacology & Therapeutics (2014); 96 2, 214-223).
程序性死亡-1(PD-1)是T细胞主要表达的共受体。PD-1与其配体，PD-L1或PD-L2的结合，对于免疫系统的生理调节至关重要。PD-1信号传导通路的主要功能作用是抑制自反应性T细胞，其用于保护免于自身免疫性疾病。因此PD-1通路的消除可以导致免疫耐受的破坏，其可以最终导致发展出病理性自身免疫。相反，肿瘤细胞有时可以指定PD-1通路逃脱免疫监督机制。因此，阻断PD-1通路已经变为癌症治疗的有吸引力的靶点。目前的方法包括六种药剂，其是靶向PD-1和PD-L1的中和抗体或融合蛋白。多于四十个临床试验在进行中，以更好地定义PD-1阻断在多种肿瘤类型中的作用(Hyun-Tak Jin等人，Clinical Immunology(Amsterdam，Netherlands)(2014)，153(1)，145-152)。Programmed death-1 (PD-1) is a co-receptor that is primarily expressed by T cells. The binding of PD-1 to its ligand, PD-L1 or PD-L2, is critical for the physiological regulation of the immune system. The primary functional role of the PD-1 signaling pathway is to inhibit autoreactive T cells, which are used to protect against autoimmune diseases. Thus elimination of the PD-1 pathway can lead to disruption of immune tolerance, which can ultimately lead to the development of pathological autoimmunity. In contrast, tumor cells can sometimes specify the PD-1 pathway to escape immune surveillance mechanisms. Therefore, blocking the PD-1 pathway has become an attractive target for cancer therapy. Current methods include six agents that are neutralizing antibodies or fusion proteins that target PD-1 and PD-L1. More than forty clinical trials are underway to better define the role of PD-1 blockade in a variety of tumor types (Hyun-Tak Jin et al, Clinical Immunology (Amsterdam, Netherlands) (2014), 153 ( 1), 145-152).
国际申请报道了PD-1或PD-L1抑制性抗体或融合蛋白。International applications report PD-1 or PD-L1 inhibitory antibodies or fusion proteins.
此外，国际申请还报道过能够压制和/或抑制程序性细胞死亡1(PD1)信号传导通路的肽或肽类化合物。In addition, international applications have reported peptide or peptide compounds that are capable of suppressing and/or inhibiting the programmed cell death 1 (PD1) signaling pathway.
然而，对PD-1通路的更有效、更好和/或选择性的免疫调节剂，仍然存在需要。本发明提供1，3，4-二唑和1，3，4-噻二唑化合物，这些化合物能够压制和/或抑制程序性细胞死亡1(PD1)信号传导通路。However, there is still a need for more effective, better and/or selective immunomodulators for the PD-1 pathway. The present invention provides 1,3,4-diazole and 1,3,4-thiadiazole compounds which are capable of suppressing and/or inhibiting the programmed cell death 1 (PD1) signaling pathway.
发明内容Summary of the invention
本发明的目的是提供一种结构新颖的可作为PD-1/PD-L1抑制剂的化合物。It is an object of the present invention to provide a novel structure which is useful as a PD-1/PD-L1 inhibitor.
本发明第一方面提供了一种式(I)所示的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药：A first aspect of the invention provides a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:
Figure PCTCN2018122818-appb-000001
Figure PCTCN2018122818-appb-000001
式中，In the formula,
Z 1为N或CR 1；Z 2为N或CR 2；Z 3为N或CR 3；Z 4为N或CR 4； Z 1 is N or CR 1 ; Z 2 is N or CR 2 ; Z 3 is N or CR 3 ; Z 4 is N or CR 4 ;
A 1为N或CR 5；A 2为N或CR 6；A 3为N或CR 7；A 4为N或CR 8； A 1 is N or CR 5 ; A 2 is N or CR 6 ; A 3 is N or CR 7 ; A 4 is N or CR 8 ;
X为一个键、NH、O、S、S(O)或S(O) 2； X is a bond, NH, O, S, S(O) or S(O) 2 ;
W为C 6-10芳基(如苯环)、具有1到3个独立选自氮、氧或硫的杂原子的5至6元单环杂芳基环W 1、具有1到5个独立选自氮、氧或硫的杂原子的8至10元双环杂芳基环W 2、具有1到3个独立选自氮、氧或硫的杂原子的3至7元饱和或部分不饱和单杂环W 3、3至7元饱和或部分不饱和单环W 4、具有1到5个独立选自氮、氧或硫的杂原子的8至10元饱和或部分不饱和双杂环W 5、或8至10元饱和或部分不饱和双环W 6； W is a C 6-10 aryl group (such as a benzene ring), a 5- to 6-membered monocyclic heteroaryl ring W 1 having 1 to 3 hetero atoms independently selected from nitrogen, oxygen or sulfur, having 1 to 5 independent An 8- to 10-membered bicyclic heteroaryl ring W 2 of a hetero atom selected from nitrogen, oxygen or sulfur, a 3 to 7-membered saturated or partially unsaturated single having 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Heterocyclic W 3 , 3 to 7 membered saturated or partially unsaturated monocyclic W 4 , 8 to 10 membered saturated or partially unsaturated heterocyclic W 5 having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur. , or 8 to 10 yuan saturated or partially unsaturated bicyclic W 6 ;
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8各自独立地为氢、羟基、CN、NO 2、卤素(优选为F或Cl)、-NR a0R b0、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、C 3-8环烷氧基(优选为C 3-6环烷氧基)、C 2-10烯基(优选为C 2-6烯基，更优选为C 2-4烯基)、C 2-10炔基(优选为C 2-6炔基，更优选为C 2-4炔基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、-CHO、-C(O)C 1-10烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)C 6-10芳基(优选为-C(O)C 6芳基，如-C(O)-苯基)、C 6-10芳基(优选为C 6芳基，如苯基)、-CONR a0R b0、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)或叔丁氧羰基；其中R a0、R b0各自独立地为氢或C 1-8烷基； R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen, hydroxy, CN, NO 2 , halogen (preferably F or Cl), -NR a0 R b0 , C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 3- 8- cycloalkoxy (preferably C 3-6 cycloalkoxy), C 2-10 alkenyl (preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl), C 2-10 alkyne a group (preferably a C 2-6 alkynyl group, more preferably a C 2-4 alkynyl group), a C 1-10 alkoxy group (preferably a C 1-6 alkoxy group, more preferably a C 1-3 alkoxy group) ), -CHO, -C(O)C 1-10 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C( O) C 6-10 aryl (preferably -C(O)C 6 aryl, such as -C(O)-phenyl), C 6-10 aryl (preferably C 6 aryl, such as phenyl) , -CONR a0 R b0 , -C(O)OC 1-10 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), - OC(O)C 1-10 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 C 6-10 aryl (preferably -SO 2 C 6 aryl such as -SO 2 -phenyl) or tert-butoxycarbonyl; wherein R a0 , R b0 are each independently hydrogen or C 1-8 alkyl;
R 9、R 10各自独立地为氢、羟基、卤素(优选为F或Cl)、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)； R 9 and R 10 are each independently hydrogen, hydroxy, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);
R a为
Figure PCTCN2018122818-appb-000002
或C 3-8环烷基，R b为氢或C 1-8烷基；或者R a、R b与相邻氮原子连接形成5至6元饱和单杂环B； R a is
Figure PCTCN2018122818-appb-000002
Or a C 3-8 cycloalkyl group, R b is hydrogen or a C 1-8 alkyl group; or R a , R b are bonded to an adjacent nitrogen atom to form a 5- to 6-membered saturated monoheterocyclic ring B;
其中R a1、R b1各自独立地为氢、羟基、羧基或C 1-8烷基； Wherein R a1 and R b1 are each independently hydrogen, hydroxy, carboxy or C 1-8 alkyl;
R 0为C 1-8烷基、羟基、羧基、乙酰胺基、吡咯酮基、-(O-(CH 2) 2) m-NH 2； R 0 is C 1-8 alkyl, hydroxy, carboxyl, acetamido, pyrrolidone, -(O-(CH 2 ) 2 ) m -NH 2 ;
n为2或3；m为1、2或3；n is 2 or 3; m is 1, 2 or 3;
所述烷基、烷氧基、环烷基、环烷氧基、烯基、炔基、芳基、W 1、W 2、W 3、W 4、W 5、 W 6为未取代的或被1、2或3个选自下组的取代基所取代：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤素(优选为F或Cl)、硝基、C 6-10芳基(优选苯基)、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、C 3-8环烷氧基(优选为C 3-6环烷氧基)、C 2-10烯基(优选为C 2-6烯基，更优选为C 2-4烯基)、C 2-10炔基(优选为C 2-6炔基，更优选为C 2-4炔基)、-CONR a0R b0、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-CHO、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)。 The alkyl, alkoxy, cycloalkyl, cycloalkoxy, alkenyl, alkynyl, aryl, W 1 , W 2 , W 3 , W 4 , W 5 , W 6 are unsubstituted or 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, halogenated C 1-8 alkyl (preferably halogenated C 1- 6 alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably F or Cl), nitro, C 6-10 aryl (preferably phenyl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 3 -8 cycloalkyl (preferably C 3-6 cycloalkyl), C 3-8 cycloalkoxy (preferably C 3-6 cycloalkoxy), C 2-10 alkenyl (preferably C 2- 6 alkenyl, more preferably C 2-4 alkenyl), C 2-10 alkynyl (preferably C 2-6 alkynyl, more preferably C 2-4 alkynyl), -CONR a0 R b0 , -C (O) OC 1-10 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -CHO, -OC(O)C 1 -10 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl group, more preferably -SO 2 C 1-3 alkyl), -SO 2 C 6-10 aryl (preferably -SO 2 C 6 aryl, such as -SO 2 -phenyl), -COC 6-10 aryl (preferably -COC 6 aryl) Base, such as -CO-phenyl).
在另一优选例中，X为一个键。In another preferred embodiment, X is a bond.
在另一优选例中，所述单杂环B为未取代的或被1、2或3个选自下组的取代基所取代：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤素(优选为F或Cl)、硝基、C 6-10芳基(优选苯基)、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、C 3-8环烷氧基(优选为C 3-6环烷氧基)、C 2-10烯基(优选为C 2-6烯基，更优选为C 2-4烯基)、C 2-10炔基(优选为C 2-6炔基，更优选为C 2-4炔基)、-CONR a0R b0、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-CHO、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)。 In another preferred embodiment, the monoheterocyclic ring B is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl Carboxyl, halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably F or Cl), nitro, C 6 -10 aryl (preferably phenyl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1- 6 alkoxy, more preferably C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 3-8 cycloalkoxy (preferably C 3- 6 cycloalkoxy), C 2-10 alkenyl (preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl), C 2-10 alkynyl (preferably C 2-6 alkynyl, More preferably, it is C 2-4 alkynyl), -CONR a0 R b0 , -C(O)OC 1-10 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O) OC 1-3 alkyl), -CHO, -OC(O)C 1-10 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 Alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 C 6-10 aryl ( Preferred is -SO 2 C 6 aryl, such as -SO 2 -phenyl), -COC 6-10 aryl (preferably -COC 6 aryl, such as -CO-phenyl).
在另一优选例中，所述单杂环B为未取代的或被1、2或3个选自下组的取代基所取代：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、C 1-8烷基、C 1-8烷氧基或卤代C 1-8烷基。 In another preferred embodiment, the monoheterocyclic ring B is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl Carboxy, C 1-8 alkyl, C 1-8 alkoxy or halogenated C 1-8 alkyl.
在另一优选例中，Z 1为CR 1；Z 2为CR 2；Z 3为CR 3；Z 4为N。 In another preferred embodiment, Z 1 is CR 1 ; Z 2 is CR 2 ; Z 3 is CR 3 ; Z 4 is N.
在另一优选例中，A 1为CR 5；A 2为CR 6；A 3为CR 7；A 4为CR 8。 In another preferred embodiment, A 1 is CR 5 ; A 2 is CR 6 ; A 3 is CR 7 ; A 4 is CR 8 .
在另一优选例中，W为苯环，所述苯环为未取代的或被1、2或3个选自下组的取代基所取代：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤素(优选为F或Cl)、硝基、C 6-10芳基(优选苯基)、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、C 3-8环烷氧基(优选为C 3-6环烷氧基)、C 2-10烯基(优选为C 2-6烯基，更优选为C 2-4烯基)、C 2-10炔基(优选为C 2-6炔基，更优选为C 2-4炔基)、-CONR a0R b0、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-CHO、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)。 In another preferred embodiment, W is a benzene ring which is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, hydroxy, hydroxymethyl, Hydroxyethyl, carboxy, halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably F or Cl), nitro , C 6-10 aryl (preferably phenyl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 3-8 cycloalkoxy (preferably C 3-6 cycloalkoxy), C 2-10 alkenyl (preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl), C 2-10 alkynyl (preferably C 2-6) Alkynyl, more preferably C 2-4 alkynyl), -CONR a0 R b0 , -C(O)OC 1-10 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably - C(O)OC 1-3 alkyl), -CHO, -OC(O)C 1-10 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 C 6-10 an aryl group (preferably a -SO 2 C 6 aryl group such as -SO 2 - Yl), - COC 6-10 aryl group (preferably an aryl group -COC 6, such as a phenyl group -CO-).
在另一优选例中，R 1、R 2、R 3各自独立地为氢、CN、卤素(优选为F或Cl)、C 1-10烷基(优 选为C 1-6烷基，更优选为C 1-3烷基)或C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)；所述烷基、烷氧基为未取代的或被1、2或3个选自下组的取代基所取代：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤素(优选为F或Cl)、硝基、C 6-10芳基(优选苯基)、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、C 3-8环烷氧基(优选为C 3-6环烷氧基)、C 2-10烯基(优选为C 2-6烯基，更优选为C 2-4烯基)、C 2-10炔基(优选为C 2-6炔基，更优选为C 2-4炔基)、-CONR a0R b0、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-CHO、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)。 In another preferred embodiment, R 1 , R 2 , and R 3 are each independently hydrogen, CN, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably Is C 1-3 alkyl) or C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); the alkyl, alkoxy is unsubstituted Or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, halo C 1-8 alkyl (preferably halogenated) C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably F or Cl), nitro, C 6-10 aryl (preferably phenyl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) , C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 3-8 cycloalkoxy (preferably C 3-6 cycloalkoxy), C 2-10 alkenyl (preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl), C 2-10 alkynyl (preferably C 2-6 alkynyl, more preferably C 2-4 alkynyl), -CONR a0 R b0 -C(O)OC 1-10 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -CHO, -OC(O ) C 1-10 Group (preferably a -OC (O) C 1-6 alkyl, more preferably -OC (O) C 1-3 alkyl), - SO 2 C 1-10 alkyl group (preferably -SO 2 C 1- 6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 C 6-10 aryl (preferably -SO 2 C 6 aryl, such as -SO 2 -phenyl), -COC 6 -10 aryl (preferably -COC 6 aryl, such as -CO-phenyl).
在另一优选例中，R 1、R 2、R 3各自独立地为氢、CN、卤素(优选为F或Cl)、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)或C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)；所述烷基、烷氧基为未取代的或被1、2或3个选自下组的取代基所取代：氰基、羟基、F、Cl、Br、环丙基、环丁基、环戊基、环己基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基。 In another preferred embodiment, R 1 , R 2 , and R 3 are each independently hydrogen, CN, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably Is C 1-3 alkyl) or C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); the alkyl, alkoxy is unsubstituted Or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, B Oxyl, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl.
在另一优选例中，R 1为氢、CN、卤素(优选为F或Cl)、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)或C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)；R 2、R 3为氢；所述烷基、烷氧基为未取代的或被1、2或3个选自下组的取代基所取代：氰基、羟基、卤代C 1-3烷基、卤素(优选为F或Cl)、C 1-3烷氧基、C 3-6环烷基。 In another preferred embodiment, R 1 is hydrogen, CN, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); R 2 , R 3 are hydrogen; the alkyl, alkoxy is unsubstituted Or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, halo C 1-3 alkyl, halogen (preferably F or Cl), C 1-3 alkoxy, C 3-6 cycloalkyl.
在另一优选例中，R 5、R 6、R 7、R 8各自独立地为氢、CN、卤素(优选为F或Cl)、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)或C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)；所述烷基、烷氧基为未取代的或被1、2或3个选自下组的取代基所取代：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤素(优选为F或Cl)、硝基、C 6-10芳基(优选苯基)、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、C 3-8环烷氧基(优选为C 3-6环烷氧基)、C 2-10烯基(优选为C 2-6烯基，更优选为C 2-4烯基)、C 2-10炔基(优选为C 2-6炔基，更优选为C 2-4炔基)、-CONR a0R b0、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-CHO、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)。 In another preferred embodiment, R 5 , R 6 , R 7 , R 8 are each independently hydrogen, CN, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl) More preferably, it is a C 1-3 alkyl group or a C 1-10 alkoxy group (preferably a C 1-6 alkoxy group, more preferably a C 1-3 alkoxy group); the alkyl group, alkoxy group Substituted as unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, halo C 1-8 alkyl (preferred Is a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group), a halogen (preferably F or Cl), a nitro group, a C 6-10 aryl group (preferably a phenyl group), C 1- 10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkane Oxy), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 3-8 cycloalkoxy (preferably C 3-6 cycloalkoxy), C 2-10 alkenyl (preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl), C 2-10 alkynyl (preferably C 2-6 alkynyl, more preferably C 2-4 alkynyl), -CONR A0 R b0 , -C(O)OC 1-10 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -CHO, - OC(O) C 1-10 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably - SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 C 6-10 aryl (preferably -SO 2 C 6 aryl, such as -SO 2 -phenyl ), -COC 6-10 aryl (preferably -COC 6 aryl, such as -CO-phenyl).
在另一优选例中，所述取代基中的C 6-10芳基(优选苯基)为未取代的或被1、2或3个选自下组的取代基所取代：氰基、羟基、C 1-3烷基、卤代C 1-3烷基、卤素(优选为F或Cl)、C 1-3烷氧基、C 3-6环烷基。 In another preferred embodiment, the C 6-10 aryl group (preferably phenyl group) in the substituent is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano and hydroxy groups. C 1-3 alkyl, halo C 1-3 alkyl, halogen (preferably F or Cl), C 1-3 alkoxy, C 3-6 cycloalkyl.
在另一优选例中，R 5、R 7各自独立地为氢、CN、卤素(优选为F或Cl)、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)或C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)；R 6、R 8为氢；所述烷基、烷氧基为未取代的或被1、2或3个选自下组的取代基所取代：氰基、羟基、苯基、卤代C 1-3烷基、卤素(优选为F或Cl)、C 1-3烷氧基、C 3-6环烷基；其中所述苯基为未取代的或被1、2或3个选自下组的取代基所取代：氰基、羟基、C 1-3烷基、卤代C 1-3烷基、卤素(优选为F或Cl)、C 1-3烷氧基、C 3-6环烷基。 In another preferred embodiment, R 5 and R 7 are each independently hydrogen, CN, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1 -3 alkyl) or C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); R 6 , R 8 are hydrogen; the alkyl, alkane The oxy group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, phenyl, halo C 1-3 alkyl, halogen (preferably F or Cl), C 1-3 alkoxy, C 3-6 cycloalkyl; wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, C 1 a -3 alkyl group, a halogenated C 1-3 alkyl group, a halogen (preferably F or Cl), a C 1-3 alkoxy group, a C 3-6 cycloalkyl group.
在另一优选例中，R 5、R 7各自独立地为氢、CN、卤素(优选为F或Cl)、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)或C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)；R 6、R 8为氢；所述烷基、烷氧基为未取代的或被1、2或3个选自下组的取代基所取代：氰基、羟基、苯基、F、Cl、Br、环丙基、环丁基、环戊基、环己基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基；其中所述苯基为未取代的或被1、2或3个选自下组的取代基所取代：氰基、羟基、甲基、乙基、丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、F、Cl、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基。 In another preferred embodiment, R 5 and R 7 are each independently hydrogen, CN, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1 -3 alkyl) or C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); R 6 , R 8 are hydrogen; the alkyl, alkane The oxy group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, phenyl, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl; Wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, methyl, ethyl, propyl, isopropyl, monofluoromethyl, Difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, F, Cl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl.
在另一优选例中，R 5为氢、CN、F、Cl或C 1-3烷基；R 7为氢、C 1-3烷基或C 1-3烷氧基；R 6、R 8为氢；所述烷基、烷氧基为未取代的或被1、2或3个选自下组的取代基所取代：氰基、羟基、卤代C 1-3烷基、卤素(优选为F或Cl)、C 1-3烷氧基、苯基、C 3-6环烷基；其中所述苯基为未取代的或被1、2或3个选自下组的取代基所取代：氰基、羟基、C 1-3烷基、卤代C 1-3烷基、卤素(优选为F或Cl)、C 1-3烷氧基、C 3-6环烷基。 In another preferred embodiment, R 5 is hydrogen, CN, F, Cl or C 1-3 alkyl; R 7 is hydrogen, C 1-3 alkyl or C 1-3 alkoxy; R 6 , R 8 Is hydrogen; the alkyl group, alkoxy group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, hydroxy, halo C 1-3 alkyl, halogen (preferably Is F or Cl), C 1-3 alkoxy, phenyl, C 3-6 cycloalkyl; wherein the phenyl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of Substituted: cyano, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, halogen (preferably F or Cl), C 1-3 alkoxy, C 3-6 cycloalkyl.
在另一优选例中，R 9、R 10为氢。 In another preferred embodiment, R 9 and R 10 are hydrogen.
在另一优选例中，R a、R b与相邻氮原子连接形成的5至6元饱和单杂环B选自：四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉或硫代吗啉-1,1-二氧化物；所述单杂环B为未取代的或被1、2或3个选自下组的取代基所取代：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、C 1-8烷基、C 1-8烷氧基或卤代C 1-8烷基。 In another preferred embodiment, the 5- to 6-membered saturated monoheterocyclic ring B formed by linking R a and R b to an adjacent nitrogen atom is selected from the group consisting of: tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine or Thiomorpholine-1,1-dioxide; said monoheterocyclic ring B is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, hydroxy, hydroxy Methyl, hydroxyethyl, carboxyl, C 1-8 alkyl, C 1-8 alkoxy or halogenated C 1-8 alkyl.
在另一优选例中，R a、R b与相邻氮原子连接形成的5至6元饱和单杂环B选自以下结构： In another preferred embodiment, the 5- to 6-membered saturated monoheterocyclic ring B formed by linking R a and R b to an adjacent nitrogen atom is selected from the following structures:
Figure PCTCN2018122818-appb-000003
Figure PCTCN2018122818-appb-000003
在另一优选例中，
Figure PCTCN2018122818-appb-000004
选自： In another preferred example,
Figure PCTCN2018122818-appb-000004
From:
Figure PCTCN2018122818-appb-000005
Figure PCTCN2018122818-appb-000005
Figure PCTCN2018122818-appb-000006
Figure PCTCN2018122818-appb-000006
在另一优选例中，W 1选自：噻吩环、N-烷环吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环或吡嗪环。 In another preferred embodiment, W 1 is selected from the group consisting of: a thiophene ring, an N-alkylcyclopyrrole ring, a furan ring, a thiazole ring, an imidazole ring, an oxazole ring, a pyrrole ring, a pyrazole ring, a triazole ring, 1, 2, 3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine Ring, pyridazine ring, pyrimidine ring or pyrazine ring.
在另一优选例中，W 1选自： In another preferred embodiment, W 1 is selected from the group consisting of
Figure PCTCN2018122818-appb-000007
Figure PCTCN2018122818-appb-000008
上述5至6元单环杂芳基环任选地被1、2或3个选自AI组的取代基所取代。
Figure PCTCN2018122818-appb-000007
Figure PCTCN2018122818-appb-000008
The above 5- to 6-membered monocyclic heteroaryl ring is optionally substituted with 1, 2 or 3 substituents selected from the AI group.
在另一优选例中，AI组的取代基为：卤素、-O(CH 2) pOC 1-8烷基、-O(CH 2) pOH、-(CH 2) pOC 1-8烷基、4至6元饱和单杂环、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 3-8环烷基(优选为卤代C 3-6环烷基)、羟基取代的C 1-8烷基(优选为羟基取代的C 1-6烷基，更优选为羟基取代的C 1-3烷基)、羟甲基、羟乙基、羟基、羧基、NR a0R b0、-C(O)OC 1-6烷基、乙酰基、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 1-8烷氧基取代的C 1-8烷基(优选为C 1-6烷氧基取代的C 1-6烷基，更优选为C 1-3烷氧基取代的C 1-3烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、C 6-10芳基(优选苯基)、5至6元单环杂芳基或-Y-L；其中Y为(CH 2) q或C(O)；L为4至6元饱和单杂环；p、q各自独立地为1、2或3；R a0、R b0各自独立地为氢、乙酰基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-8烷氧基取代的C 1-8烷基(优选为C 1-6烷氧基取代的C 1-6烷基，更优选为C 1-3烷氧基取代的C 1-3烷基)。 In another preferred embodiment, the substituent of the AI group is: halogen, -O(CH 2 ) p OC 1-8 alkyl, -O(CH 2 ) p OH, -(CH 2 ) p OC 1-8 alkane a 4- to 6-membered saturated monoheterocyclic ring, a C 1-8 alkyl group (preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group), a C 3-8 cycloalkyl group (preferably C 3 ) -6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 3-8 cycloalkyl ( Preferred is a halogenated C 3-6 cycloalkyl group, a hydroxy-substituted C 1-8 alkyl group (preferably a hydroxy-substituted C 1-6 alkyl group, more preferably a hydroxy-substituted C 1-3 alkyl group), and a hydroxy group. Methyl, hydroxyethyl, hydroxy, carboxy, NR a0 R b0 , -C(O)OC 1-6 alkyl, acetyl, C 1-8 alkoxy (preferably C 1-6 alkoxy, more Preferred is a C 1-3 alkoxy group, a C 1-8 alkoxy-substituted C 1-8 alkyl group (preferably a C 1-6 alkoxy-substituted C 1-6 alkyl group, more preferably C 1 ) a -3 alkoxy-substituted C 1-3 alkyl), halogenated C 1-8 alkoxy group (preferably a halogenated C 1-6 alkoxy group, more preferably a halogenated C 1-3 alkoxy group) , -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), C 6-10 aryl (preferably phenyl), 5 To 6 yuan single ring An aryl group or YL; wherein Y is (CH 2) q or C (O); L is 4 to 6-membered saturated heteromonocyclic; p, q are each independently 1, 2 or 3; R a0, R b0 each Independently hydrogen, acetyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy substituted C 1-8 alkyl (preferably a C 1-6 alkoxy-substituted C 1-6 alkyl group, more preferably a C 1-3 alkoxy-substituted C 1-3 alkyl group).
在另一优选例中，AI组取代基中的4至6元饱和单杂环选自氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃。In another preferred embodiment, the 4- to 6-membered saturated monocyclic ring in the AI group substituent is selected from the group consisting of azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazole Alkane, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
在另一优选例中，AI组取代基中的4至6元饱和单杂环为未取代的或被1、2或3个选自下组的取代基所取代：卤素、羟基、C 1-3烷基、O＝、NR a0R b0、羟甲基、羟乙基、羟丙基、 羧基、-C(O)OC 1-3烷基、乙酰基、卤代C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、噻吩环、N-烷基吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、四唑环、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环；其中R a0、R b0各自独立地为氢或C 1-3烷基。 In another preferred embodiment, the 4- to 6-membered saturated monoheterocyclic ring in the AI group substituent is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy, C 1- 3 alkyl, O=, NR a0 R b0 , hydroxymethyl, hydroxyethyl, hydroxypropyl, carboxyl, -C(O)OC 1-3 alkyl, acetyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxane Pento ring, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, thiophene ring, N-alkylpyrrole ring, furan ring, thiazole ring, Imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring Wherein R a0 and R b0 are each independently hydrogen or C 1-3 alkyl.
在另一优选例中，AI组的取代基为氟、氯、溴、羟甲基、羟乙基、羟基、羧基、-O(CH 2) pOC 1-3烷基、-O(CH 2) pOH、-(CH 2) pOC 1-3烷基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、甲基、乙基、正丙基、异丙基、环丙基、一氯乙基、二氯甲基、1,2-二氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、一氯环丙基、二氯环丙基、三氯环丙基、一氟环丙基、二氟环丙基、三氟环丙基、NR a0R b0、-C(O)OC 1-3烷基、乙酰基、甲氧基、乙氧基、丙氧基、异丙氧基、三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基、苯基、吡啶基或-Y-L；其中Y为(CH 2) q或C(O)；L为氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃；p为1、2或3；q为1；R a0、R b0各自独立地为氢、乙酰基、甲基、乙基、正丙基、异丙基、甲氧基取代的C 1-3烷基。 In another preferred embodiment, the substituent of the AI group is fluorine, chlorine, bromine, hydroxymethyl, hydroxyethyl, hydroxy, carboxy, -O(CH 2 ) p OC 1-3 alkyl, -O(CH 2 p OH, -(CH 2 ) p OC 1-3 alkyl, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, two Oxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, methyl, ethyl, n-propyl, isopropyl, ring Propyl, monochloroethyl, dichloromethyl, 1,2-dichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl , trifluoroethyl, monochlorocyclopropyl, dichlorocyclopropyl, trichlorocyclopropyl, monofluorocyclopropyl, difluorocyclopropyl, trifluorocyclopropyl, NR a0 R b0 , -C (O)OC 1-3 alkyl, acetyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoro Ethoxy, difluoromethoxy, difluoroethoxy, phenyl, pyridyl or -YL; wherein Y is (CH 2 ) q or C(O); L is azetidine, oxygen heterocycle Butane , tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide , tetrahydropyran; p is 1, 2 or 3; q is 1; R a0 , R b0 are each independently hydrogen, acetyl, methyl, ethyl, n-propyl, isopropyl, methoxy Substituted C 1-3 alkyl.
在另一优选例中，W 2选自：苯并呋喃环、苯并噻吩环、吲哚环、异吲哚环、喹啉环、异喹啉环、吲唑环、苯并噻唑环、苯并咪唑环、喹唑啉环、喹喔啉环、噌啉环、酞嗪环。 In another preferred embodiment, W 2 is selected from the group consisting of a benzofuran ring, a benzothiophene ring, an anthracene ring, an isoindole ring, a quinoline ring, an isoquinoline ring, an indazole ring, a benzothiazole ring, and a benzene. And an imidazole ring, a quinazoline ring, a quinoxaline ring, a porphyrin ring, a pyridazine ring.
在另一优选例中，W 3选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃。 In another preferred embodiment, W 3 is selected from the group consisting of azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, and Oxycyclohexyl, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
在另一优选例中，W 4选自：环丙基环、环丁基环、环戊基环、环己烷、环己二烯环、环庚烷、环庚三稀环。 In another preferred embodiment, W 4 is selected from the group consisting of a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, a cyclohexane, a cyclohexadiene ring, a cycloheptane, and a cycloheptatriene ring.
在另一优选例中，W 5选自：四氢喹啉环、四氢异喹啉环、十氢喹啉环。 In another preferred embodiment, W 5 is selected from the group consisting of: a tetrahydroquinoline ring, a tetrahydroisoquinoline ring, and a decahydroquinoline ring.
在另一优选例中，式(I)化合物为式(II)所示化合物：In another preferred embodiment, the compound of formula (I) is a compound of formula (II):
Figure PCTCN2018122818-appb-000009
Figure PCTCN2018122818-appb-000009
式中，In the formula,
Z 4为N或CR 4； Z 4 is N or CR 4 ;
R 1、R 2、R 3、R 5、R 6、R 7、R 8各自独立地为氢、卤素、羟基、氰基、C 1-8烷基、卤代 C 1-8烷基、C 3-8环烷基、C 1-8烷氧基、卤代C 1-8烷氧基、C 3-8环烷氧基、C 6-10芳基、-C(O)C 1-8烷基、-C(O)OC 1-8烷基、-CONR a0R b0或NR a0R b0；R a0、R b0各自独立地为氢或C 1-8烷基； R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen, halogen, hydroxy, cyano, C 1-8 alkyl, halo C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, C 3-8 cycloalkoxy, C 6-10 aryl, -C(O)C 1-8 Alkyl, -C(O)OC 1-8 alkyl, -CONR a0 R b0 or NR a0 R b0 ; R a0 , R b0 are each independently hydrogen or C 1-8 alkyl;
R w1、R w2、R w3、R w4、R w5各自独立地为氢、卤素、羟基、氰基、C 1-8烷基、卤代C 1-8烷基；或者R w1、R w2与相邻苯环上的碳原子连接形成5至6元饱和单杂环A； R w1 , R w2 , R w3 , R w4 , R w5 are each independently hydrogen, halogen, hydroxy, cyano, C 1-8 alkyl, halo C 1-8 alkyl; or R w1 , R w2 and The carbon atoms on adjacent benzene rings are bonded to form a 5- to 6-membered saturated monoheterocyclic ring A;
R a为
Figure PCTCN2018122818-appb-000010
或C 3-8环烷基，R b为氢或C 1-8烷基；或者R a、R b与相邻氮原子连接形成5至6元饱和单杂环B； R a is
Figure PCTCN2018122818-appb-000010
Or a C 3-8 cycloalkyl group, R b is hydrogen or a C 1-8 alkyl group; or R a , R b are bonded to an adjacent nitrogen atom to form a 5- to 6-membered saturated monoheterocyclic ring B;
其中R a1、R b1各自独立地为氢、羟基、羧基或C 1-8烷基； Wherein R a1 and R b1 are each independently hydrogen, hydroxy, carboxy or C 1-8 alkyl;
R 0为C 1-8烷基、羟基、羧基、乙酰胺基、吡咯酮基、-(O-(CH 2) 2) m-NH 2； R 0 is C 1-8 alkyl, hydroxy, carboxyl, acetamido, pyrrolidone, -(O-(CH 2 ) 2 ) m -NH 2 ;
n为2或3；m为1、2或3；n is 2 or 3; m is 1, 2 or 3;
所述烷基、烷氧基、环烷基、单杂环A、单杂环B为未取代的或被1、2或3个选自下组的取代基所取代：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、C 1-8烷基、C 1-8烷氧基或卤代C 1-8烷基。 The alkyl, alkoxy, cycloalkyl, monoheterocyclic A, monoheterocyclic B is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, Hydroxy, hydroxymethyl, hydroxyethyl, carboxy, C 1-8 alkyl, C 1-8 alkoxy or halogenated C 1-8 alkyl.
在另一优选例中，Z 4为N。 In another preferred embodiment, Z 4 is N.
在另一优选例中，单杂环A选自：四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃或为结构
Figure PCTCN2018122818-appb-000011
其中p为1、2或3。 In another preferred embodiment, the monoheterocyclic ring A is selected from the group consisting of: tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide , tetrahydropyran or structure
Figure PCTCN2018122818-appb-000011
Where p is 1, 2 or 3.
在另一优选例中，单杂环B选自：四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉或硫代吗啉-1,1-二氧化物。In another preferred embodiment, the monoheterocyclic ring B is selected from the group consisting of: tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine or thiomorpholine-1,1-dioxide.
在另一优选例中，R w1、R w2、R w3、R w4、R w5各自独立地为氢、卤素、C 1-8烷基。 In another preferred embodiment, R w1 , R w2 , R w3 , R w4 , R w5 are each independently hydrogen, halogen, C 1-8 alkyl.
在另一优选例中，R 1为氰基。 In another preferred embodiment, R 1 is a cyano group.
在另一优选例中，R 6、R 8各自独立地为氢。 In another preferred embodiment, R 6 and R 8 are each independently hydrogen.
在另一优选例中，R 6、R 7、R 8各自独立地为氢。 In another preferred embodiment, R 6 , R 7 and R 8 are each independently hydrogen.
在另一优选例中，R 5为氢、卤素、C 1-3烷基、卤代C 1-3烷基或C 1-3烷氧基。 In another preferred embodiment, R 5 is hydrogen, halogen, C 1-3 alkyl, halo C 1-3 alkyl or C 1-3 alkoxy.
在另一优选例中，R 5为氢、氟、氯、三氟甲基或甲氧基。 In another preferred embodiment, R 5 is hydrogen, fluorine, chlorine, trifluoromethyl or methoxy.
在另一优选例中，R 2、R 3为氢。 In another preferred embodiment, R 2 and R 3 are hydrogen.
在另一优选例中，
Figure PCTCN2018122818-appb-000012
选自： In another preferred example,
Figure PCTCN2018122818-appb-000012
From:
Figure PCTCN2018122818-appb-000013
Figure PCTCN2018122818-appb-000013
Figure PCTCN2018122818-appb-000014
Figure PCTCN2018122818-appb-000014
在另一优选例中，
Figure PCTCN2018122818-appb-000015
选自：
Figure PCTCN2018122818-appb-000016
Figure PCTCN2018122818-appb-000017
In another preferred example,
Figure PCTCN2018122818-appb-000015
From:
Figure PCTCN2018122818-appb-000016
Figure PCTCN2018122818-appb-000017
在另一优选例中，所述化合物选自表A。In another preferred embodiment, the compound is selected from Table A.
在另一优选例中，表A的化合物包括：In another preferred embodiment, the compounds of Table A include:
Figure PCTCN2018122818-appb-000018
Figure PCTCN2018122818-appb-000018
Figure PCTCN2018122818-appb-000019
Figure PCTCN2018122818-appb-000019
在另一优选例中，所述化合物选自表B。在另一优选例中，表B的化合物包括：In another preferred embodiment, the compound is selected from Table B. In another preferred embodiment, the compounds of Table B include:
Figure PCTCN2018122818-appb-000020
Figure PCTCN2018122818-appb-000020
Figure PCTCN2018122818-appb-000021
Figure PCTCN2018122818-appb-000021
本发明第二方面提供了一种药物组合物，所述药物组合物包括本发明第一方面所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药；以及药学可接受的载体。A second aspect of the invention provides a pharmaceutical composition comprising the compound of the first aspect of the invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; And a pharmaceutically acceptable carrier.
本发明第三方面提供了一种药物组合物，所述药物组合物包括本发明第一方面所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药；以及至少一种其他药剂，其中所述其他药剂是抗癌剂、化疗剂或抗增殖化合物。A third aspect of the invention provides a pharmaceutical composition comprising the compound of the first aspect of the invention or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; And at least one other agent, wherein the other agent is an anticancer agent, a chemotherapeutic agent, or an antiproliferative compound.
本发明第四方面提供了如本发明第一方面所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药、或如本发明第二、三方面所述药物组合物在制备药物中的用途，所述药物为治疗癌症或感染性疾病的药物。A fourth aspect of the invention provides a compound according to the first aspect of the invention, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or as described in the second and third aspects of the invention The use of a pharmaceutical composition for the preparation of a medicament for the treatment of cancer or an infectious disease.
在另一优选例中，所述癌症选自：骨癌、头或颈癌、胰腺癌、皮肤癌、皮肤或眼内恶性黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌系统癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病、包括急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、儿童实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤、环境诱发的癌症、包括石棉诱发的癌症、和所述癌症的组合。In another preferred embodiment, the cancer is selected from the group consisting of bone cancer, head or neck cancer, pancreatic cancer, skin cancer, skin or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer , testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, thyroid Paracancerous adenocarcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, solid tumor of children, lymphocytic lymph Tumor, bladder cancer, renal or ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumor, primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma , epidermoid carcinoma, squamous cell carcinoma, T cell lymphoma, environmentally induced cancer, including asbestos-induced cancer, and combinations of said cancers.
在另一优选例中，所述感染性疾病是细菌感染性疾病、病毒感染性疾病或真菌感染性疾病。In another preferred embodiment, the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease.
本发明第五方面提供了一种调节受治疗者中由PD-1信号传导通路介导的免疫应答的方法，所述方法包括向受治疗者施用治疗有效量的本发明第一方面所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药、或如本发明第二、三方面所述药物组合物。A fifth aspect of the invention provides a method of modulating an immune response mediated by a PD-1 signaling pathway in a subject, the method comprising administering to the subject a therapeutically effective amount of the first aspect of the invention a compound or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second and third aspects of the invention.
本发明第六方面提供了一种抑制受治疗者中肿瘤细胞生长和/或迁移的方法，所述方法包括向受治疗者施用治疗有效量的本发明第一方面所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药、或如本发明第二、三方面所述药物组合物。A sixth aspect of the invention provides a method of inhibiting growth and/or migration of tumor cells in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the first aspect of the invention or a stereoisod thereof A construct, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second and third aspects of the invention.
在另一优选例中，所述肿瘤细胞是选自于以下的癌症：乳腺癌、结肠癌、肺癌、黑素瘤、前列腺癌和肾癌。In another preferred embodiment, the tumor cell is a cancer selected from the group consisting of breast cancer, colon cancer, lung cancer, melanoma, prostate cancer, and kidney cancer.
在另一优选例中，所述肿瘤细胞是选自由以下各项组成的列表中的癌症：骨癌、头或颈癌、胰腺癌、皮肤癌、皮肤或眼内恶性黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、非 霍奇金淋巴瘤、食道癌、小肠癌、内分泌系统癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病、包括急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、儿童实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤、环境诱发的癌症、包括石棉诱发的癌症、和所述癌症的组合。In another preferred embodiment, the tumor cell is a cancer selected from the list consisting of bone cancer, head or neck cancer, pancreatic cancer, skin cancer, skin or intraocular malignant melanoma, uterine cancer, Ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, Small bowel cancer, endocrine cancer, thyroid cancer, parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymph Cell leukemia, solid tumor of children, lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumor, primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glia Tumor, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancer, including asbestos-induced cancer And a combination of the cancer.
本发明第七方面提供了一种治疗受治疗者感染性疾病的方法，所述方法包括向受治疗者施用治疗有效量的本发明第一方面所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药、或如本发明第二、三方面所述药物组合物。A seventh aspect of the invention provides a method of treating an infectious disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the first aspect of the invention or a stereoisomer thereof, or A pharmaceutically acceptable salt, solvate or prodrug, or a pharmaceutical composition according to the second and third aspects of the invention.
本发明第八方面提供了一种治疗受治疗者中细菌、病毒和真菌感染方法，所述方法包括向受治疗者施用治疗有效量的本发明第一方面所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药、或如本发明第二、三方面所述药物组合物。An eighth aspect of the invention provides a method of treating bacterial, viral and fungal infections in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the first aspect of the invention or a stereoisomer thereof Or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second and third aspects of the invention.
在另一优选例中，感染性疾病包括但不限于HIV、流感、疱疹、贾第虫、疟疾、利什曼原虫、由肝炎病毒(A、B、&C)导致的致病感染、疱疹病毒(例如、VZV、HSV-I、HAV-6、HSV-II、和CMV、EB(Epstein Barr)病毒)、腺病毒、流感病毒、虫媒病毒、埃可病毒、鼻病毒、柯萨奇病毒、冠状病毒、呼吸道合胞体病毒、腮腺炎病毒、轮状病毒、麻疹病毒、风疹病毒、细小病毒、牛痘病毒、HTLV病毒、登革热病毒、乳头瘤病毒、软疣病毒、脊髓灰质炎病毒、狂犬病毒、JC病毒和虫媒病毒脑炎病毒、细菌衣原体导致的致病感染、立克次体细菌、分枝杆菌、葡萄球菌、链球菌、肺炎球菌(pneumonococci)、脑膜炎球菌和conococci、克雷白氏杆菌、变形杆菌、沙雷氏菌、假单胞菌、大肠杆菌、军团杆菌、白喉、沙门氏菌、杆菌、霍乱、破伤风、肉毒中毒、炭疽、鼠疫、细螺旋体病、和莱姆病细菌，以下真菌引起的致病感染：假丝酵母(白色假丝酵母、克鲁斯假丝酵母(krusei)、光滑假丝酵母(glabrata)、热带假丝酵母(tropicalis)等)、新型隐球菌、曲霉属(烟曲霉(fumigatus)、黑曲霉(niger)等)、毛霉属(毛霉菌、腐化米霉菌、根霉(rhizophus))、申克孢子丝菌、皮炎芽生菌(Blastomyces dermatitidis)、巴西副球孢子菌(Paracoccidioides brasiliensis)、粗球孢子菌(Coccidioides immitis)和荚膜组织胞浆菌(Histoplasma capsulatum)，和由以下寄生虫导致的致病感染：痢疾内变形虫(Entamoeba histolytica)、结肠小袋虫(Balantidium coli)、福纳氏虫(Naegleriafowleri)、棘变形虫(Acanthamoeba sp.)、吸吮贾第虫(Girdia lambia)、隐孢子虫(Cryptosporidium sp.)、卡氏肺囊虫(Pneumocystis carinii)、间日疟原虫(Plasmodium vivax)、果氏巴贝虫(Babesia microti)、布鲁斯锥虫(Trypanosoma brucei)、克鲁斯锥虫(Trypanosoma cruzi)、多氏利什曼原虫(Leishmania donovani)、鼠弓浆虫(Toxoplasma gondi)、巴西日圆线虫(Nippostrongylus brasiliensis)。In another preferred embodiment, the infectious diseases include, but are not limited to, HIV, influenza, herpes, Giardia, malaria, Leishmania, pathogenic infections caused by hepatitis viruses (A, B, & C), herpes viruses ( For example, VZV, HSV-I, HAV-6, HSV-II, and CMV, EB (Epstein Barr) virus, adenovirus, influenza virus, arbovirus, echovirus, rhinovirus, coxsackie virus, coronal Virus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papilloma virus, soft prion virus, poliovirus, rabies virus, JC Viral and arboviruses encephalitis virus, pathogenic infections caused by bacterial chlamydia, rickettsial bacteria, mycobacteria, staphylococcus, streptococcus, pneumonococci, meningococcus and conococci, Klebsiella , Proteus, Serratia, Pseudomonas, Escherichia coli, Legionella, diphtheria, Salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme disease Pathogenic infections caused by the following fungi: Candida (Candida albicans, Krusei, glabrata, tropical tropicalis, etc.), Cryptococcus neoformans , Aspergillus (Fumigatus, Aspergillus niger, etc.), Mucor (Maucus, Rotating Mildew, Rhizophus), S. sphaeroides, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum, and pathogenic infections caused by parasites: Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba sp., Girdia lambia, Cryptosporidium sp., Pneumocystis Carinii), Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishman (Leishmania donovani), murine toxoplasmosis (Toxoplasma gondi), Brazil NIPPOSTRONGYLUS (Nippostrongylus brasiliensis).
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
具体实施方式Detailed ways
本发明人经过广泛而深入的研究，意外地发现了这类免疫调节剂，特别是对PPI-HTRF等酶具有较高的抑制活性。因此该系列化合物有望开发成为用于治疗肿瘤的药物。在此基础上，发明人完成了本发明。The inventors have unexpectedly discovered such immunomodulators, particularly those having high inhibitory activity against enzymes such as PPI-HTRF, through extensive and intensive research. Therefore, this series of compounds is expected to be developed as a drug for treating tumors. On this basis, the inventors completed the present invention.
术语定义Definition of Terms
如本文所用，“烷基”指直链和支链的饱和的脂族烃基，C 1-10烷基为包含1至10个碳原子的烷基，优选为C 1-8烷基，更优选为C 1-6烷基，更优选为C 1-3烷基，定义类似；烷基的非限制性的例子包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。 As used herein, "alkyl" refers to both straight-chain and branched saturated aliphatic hydrocarbon groups, and C1-10- alkyl is alkyl having from 1 to 10 carbon atoms, preferably C1-8 alkyl, more preferably C 1-6 alkyl, more preferably C 1-3 alkyl, is similarly defined; non-limiting examples of alkyl include: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropane Base, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethyl Butyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methyl Pentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethyl Pentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2- Methylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl Base, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, N-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof.
如本文所用，“环烷基”指饱和或部分不饱和单环环状烃基，“C 3-8环烷基”是指包含3至8个碳原子的环烃基，优选为C 3-6环烷基，定义类似；。环烷基的非限制性实施例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环戊基、环己烯基。 As used herein, "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group, and "C 3-8 cycloalkyl" refers to a cyclic hydrocarbon group containing from 3 to 8 carbon atoms, preferably a C 3-6 ring. Alkyl, defined similarly; Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl A cyclooctyl group or the like is preferably a cyclopropyl group, a cyclopentyl group or a cyclohexenyl group.
如本文所用，“C 2-10烯基”指具有2-10个(较佳地2-6个)碳原子的直链或支链的具有碳碳双键(C＝C)的不饱和脂族烃基。例如乙烯基、丙烯基、异丙烯基、正丁烯基、异丁烯基、戊烯基、己烯基等。 As used herein, "C 2-10 alkenyl" refers to a straight or branched, unsaturated carbon having a carbon-carbon double bond (C=C) having from 2 to 10, preferably 2 to 6 carbon atoms. A hydrocarbon group. For example, vinyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl, hexenyl, and the like.
如本文所用，“C 2-10炔基”指具有2-10个(较佳地2-6个)碳原子的直链和支链的具有碳碳三键的不饱和脂族烃基。例如乙炔基、丙炔基、正丁炔基、异丁炔基、戊炔基、己炔基等。 As used herein, "C 2-10 alkynyl" refers to a straight-chain and branched unsaturated aliphatic hydrocarbon group having a carbon-carbon triple bond having 2 to 10 (preferably 2 to 6) carbon atoms. For example, ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl, and the like.
如本文所用，“螺环”是指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环的数目将螺环分为双螺环或多螺环，优选为双螺环。更优选为优选为4元/5元、5元/5元或5元/6元双螺环。例如：As used herein, "spirocyclic" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the individual rings, which may contain one or more double bonds, but none of the rings have fully conjugated π electrons. system. The spiro ring is divided into a double spiro ring or a multi-spiral ring depending on the number of rings, preferably a double spiro ring. More preferably, it is preferably a 4 member/5 member, a 5 member/5 member or a 5 member/6 member double screw ring. E.g:
Figure PCTCN2018122818-appb-000022
Figure PCTCN2018122818-appb-000022
如本文所用，“螺杂环”指单环之间共用一个原子(称螺原子)的多环烃，其中一个或两个 环原子选自氮、氧或S(O) n(其中n是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环的数目将螺杂环分为双螺杂环或多螺杂环，优选双螺杂环。更优选为4元/5元、5元/5元或5元/6元双螺杂环。例如： As used herein, "spiroheterocycle" refers to a polycyclic hydrocarbon in which one atom (called a spiro atom) is shared between monocyclic rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(O) n (where n is an integer) From 0 to 2), the remaining atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. The spiroheterocycle is classified into a bispiral heterocyclic ring or a polyspirocyclic ring according to the number of rings, preferably a double spiro heterocyclic ring. More preferably, it is 4 yuan/5 yuan, 5 yuan/5 yuan or 5 yuan / 6 yuan double spiro heterocycle. E.g:
Figure PCTCN2018122818-appb-000023
Figure PCTCN2018122818-appb-000023
如本文所用，“桥环”是指共用两个或两个以上碳原子的多环基团，共用的碳原子称为桥头碳，两个桥头碳之间可以是碳链，也可以是一个键，称为桥。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为双环或三环桥环。例如：As used herein, "bridged ring" refers to a polycyclic group that shares two or more carbon atoms. The shared carbon atom is called the bridgehead carbon. The two bridgehead carbons may be carbon chains or a bond. , called the bridge. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably a bicyclic or tricyclic bridged ring. E.g:
Figure PCTCN2018122818-appb-000024
Figure PCTCN2018122818-appb-000024
如本文所用，“桥杂环”指共用两个或两个以上原子的多环基团，其中一个或多个环原子选自氮、氧或S(O) n(其中n是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为双环或三环桥杂环。例如： As used herein, "bridge heterocycle" refers to a polycyclic group that shares two or more atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) n (where n is an integer from 0 to 2) a hetero atom, the remaining ring atoms being carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably a bicyclic or tricyclic bridge heterocycle. E.g:
Figure PCTCN2018122818-appb-000025
Figure PCTCN2018122818-appb-000025
如本文所用，“8至10元双环”是指含8至10个环原子的含两个环的桥环，双环可为饱和全碳双环或部分不饱和的全碳双环，双环的实例包括(但不限于)：As used herein, "8- to 10-membered bicyclic" refers to a bridged ring containing two rings of 8 to 10 ring atoms, which may be a saturated all-carbon bicyclic or partially unsaturated all-carbon bicyclic ring, examples of which include ( But not limited to):
Figure PCTCN2018122818-appb-000026
Figure PCTCN2018122818-appb-000026
如本文所用，“8至10元双杂环”是指含8至10个环原子的含两个环的桥杂环，其中1、2、3、4或5个环碳原子被选自氮、氧或硫的杂原子所取代。双杂环的实例包括(但不限于)四氢喹啉环、四氢异喹啉环、十氢喹啉环等。As used herein, "8- to 10-membered bicyclic heterocycle" refers to a two-ring-containing bridged heterocyclic ring containing from 8 to 10 ring atoms, wherein 1, 2, 3, 4 or 5 ring carbon atoms are selected from nitrogen Substituted by a hetero atom of oxygen or sulfur. Examples of bicyclic heterocycles include, but are not limited to, tetrahydroquinoline rings, tetrahydroisoquinoline rings, decahydroquinoline rings, and the like.
如本文所用，“C 1-10烷氧基”指-O-(C 1-10烷基)，其中烷基的定义如上所述。优选C 1-8烷氧基，更优选C 1-6烷氧基，更优选C 1-3烷氧基。非限制性实施例包含甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、戊氧基等。 As used herein, "C 1-10 alkoxy" refers to -O-(C 1-10 alkyl), wherein alkyl is as defined above. A C 1-8 alkoxy group is preferred, a C 1-6 alkoxy group is more preferred, and a C 1-3 alkoxy group is more preferred. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentyloxy and the like.
如本文所用，“C 3-8环烷氧基”指-O-(C 3-8环烷基)，其中环烷基的定义如上所述。优选C 3-6环烷氧基。非限制性实施例包含环丙氧基、环丁氧基、环戊氧基、环己氧基等。 As used herein, "C 3-8 cycloalkoxy" refers to -O-(C 3-8 cycloalkyl), wherein cycloalkyl is as defined above. Preference is given to C 3-6 cycloalkoxy. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
如本文所用，“C 6-10芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，指含有6至10个碳原子的芳基；优选苯基和萘基，更优选苯基。除非特别指出，所述芳基(优选苯基和萘基，更优选苯基)包括取代或未取代的芳基，所述芳基为取代的芳基时，芳基上1-3个氢独立地被取代基取代，所述的取代基包括：CN、卤素、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、C 1-8烷基取代的胺基、胺基、卤代C 1-8烷基取代的胺基；较佳地，所述的取代基选自下组：CN、卤素、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)。 As used herein, "C 6-10 aryl" refers to an all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, meaning 6 to 10 An aryl group of a carbon atom; preferably a phenyl group and a naphthyl group, more preferably a phenyl group. Unless otherwise specified, the aryl group (preferably phenyl and naphthyl, more preferably phenyl) includes a substituted or unsubstituted aryl group which, when substituted aryl, has 1-3 hydrogen independent on the aryl group. The substituent is substituted by a substituent including: CN, halogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy a group (preferably a C 1-6 alkoxy group, more preferably a C 1-3 alkoxy group), a halogenated C 1-8 alkyl group (preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C) 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably a halogenated C 1-3 alkoxy group, a C 1-8 alkyl substituted amine group, an amine group, a halogenated C 1-8 alkyl group substituted amine group; preferably, the substituent is selected from the group consisting of The lower group: CN, halogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl).
如本文所用，“一个键”指由其连接的两个基团通过一个共价键连接。As used herein, "a bond" refers to the attachment of two groups attached thereto through a covalent bond.
如本文所用，“卤素”指氟、氯、溴或碘。As used herein, "halogen" refers to fluoro, chloro, bromo or iodo.
如本文所用，“卤代”指基团中一个或多个(如1、2、3、4或5个)氢被卤素所取代。As used herein, "halo" means that one or more (eg 1, 2, 3, 4 or 5) hydrogens in the group are replaced by a halogen.
例如，“卤代C 1-8烷基”指烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷基的定义如上所述。选为卤代C 1-6烷基，更优选为卤代C 1-3烷基。卤代C 1-8烷基的例子包括(但不限于)一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基等。 For example, "halo C 1-8 alkyl" refers to an alkyl group substituted with one or more (eg 1, 2, 3, 4 or 5) halo, wherein alkyl is as defined above. It is selected as a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group. Examples of halogenated C 1-8 alkyl groups include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, Monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.
又例如，“卤代C 1-8烷氧基”指烷氧基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷氧基的定义如上所述。优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基。包括(但不限于)三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基等。 As another example, "halo C 1-8 alkoxy" means that the alkoxy group is substituted by one or more (eg 1, 2, 3, 4 or 5) halogens, wherein the alkoxy group is as defined above. It is preferably a halogenated C 1-6 alkoxy group, more preferably a halogenated C 1-3 alkoxy group. These include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
又例如，“卤代C 3-8环烷基”指环烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中环烷基的定义如上所述。优选为卤代C 3-6环烷基。包括(但不限于)三氟环丙基、一氟环丙 基、一氟环己基、二氟环丙基、二氟环己基等。 As another example, "halo C 3-8 cycloalkyl" refers to a cycloalkyl group substituted with one or more (eg, 1, 2, 3, 4, or 5) halo, wherein cycloalkyl is as defined above. Preferred is a halogenated C 3-6 cycloalkyl group. These include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.
如本文所用，“氘代C 1-8烷基”指烷基被一个或多个(如1、2、3、4或5个)氘原子取代，其中烷基的定义如上所述。优选为氘代C 1-6烷基，更优选为氘代C 1-3烷基。氘代C 1-20烷基的例子包括(但不限于)单氘代甲基、单氘代乙基、二氘代甲基、二氘代乙基、三氘代甲基、三氘代乙基等。 As used herein, "deuterated C 1-8 alkyl" refers to an alkyl group substituted with one or more (eg 1, 2, 3, 4 or 5) deuterium atoms, wherein alkyl is as defined above. It is preferably a deuterated C 1-6 alkyl group, more preferably a deuterated C 1-3 alkyl group. Examples of deuterated C 1-20 alkyl groups include, but are not limited to, monodeuterated methyl, monodeuterated ethyl, dideuterated methyl, didecanoethyl, triterpene methyl, triterpenoid Base.
如本文所用，“氨基”指NH 2，“氰基”指CN，“硝基”指NO 2，“苄基”指-CH 2-苯基，“氧代基”指＝O，“羧基”指-C(O)OH、-COOH或-CO 2H，“乙酰基”指-C(O)CH 3，“羟甲基”指-CH 2OH，“羟乙基”指-CH 2CH 2OH或-CH(OH)CH 3，“羟基”指-OH，“硫醇”指SH，“亚环丙基”结构为：
Figure PCTCN2018122818-appb-000027
“乙酰胺基”指-NH-C(O)CH 3，“吡咯酮基”指
Figure PCTCN2018122818-appb-000028
As used herein, "amino" refers to NH 2, "cyano" refers to the CN, "Nitro" refers to NO 2, "benzyl" refers to -CH 2 - phenyl, "oxo" refers to = O, "carboxy" Refers to -C(O)OH, -COOH or -CO 2 H, "acetyl" refers to -C(O)CH 3 , "hydroxymethyl" refers to -CH 2 OH, and "hydroxyethyl" refers to -CH 2 CH 2 OH or -CH(OH)CH 3 , "hydroxy" means -OH, "thiol" means SH, "cyclopropylene" structure is:
Figure PCTCN2018122818-appb-000027
"Acetylamino" means -NH-C(O)CH 3 and "pyrrolidone" means
Figure PCTCN2018122818-appb-000028
如本文所用，“杂芳基环”与“杂芳基”可互换使用，是指具有5到10个环原子，优选5或6元单环杂芳基或8至10元双环杂芳基；环阵列中共享6、10或14个π电子；且除碳原子外还具有1到5个杂原子的基团。“杂原子”是指氮、氧或硫。As used herein, "heteroaryl ring" and "heteroaryl" are used interchangeably and mean having 5 to 10 ring atoms, preferably 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl. The ring array shares 6, 10 or 14 π electrons; and has a group of 1 to 5 hetero atoms in addition to carbon atoms. "Hetero atom" means nitrogen, oxygen or sulfur.
如本文所用，“3至7元饱和或部分不饱和单环”是指含3至7个环原子的饱和或部分不饱和的全碳单环。单环的实例包括(但不限于)：环丙基环、环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环、环庚基环、环庚三烯基环、环辛基环等。As used herein, "3- to 7-membered saturated or partially unsaturated monocyclic" refers to a saturated or partially unsaturated, all-carbon monocyclic ring containing from 3 to 7 ring atoms. Examples of monocyclic rings include, but are not limited to, cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, cycloheptyl groups. Ring, cycloheptatrienyl ring, cyclooctyl ring, and the like.
如本文所用，“3至7元饱和单杂环”是指3至7元单环中的1、2或3个碳原子被选自氮、氧或S(O) t(其中t是整数0至2)的杂原子所取代，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳；优选4至6元，更优选5至6元。饱和单杂环的实例包括(但不限于)环氧丙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、吡咯啉、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃等。 As used herein, "3 to 7 membered saturated monoheterocycle" means that 1, 2 or 3 carbon atoms in a 3 to 7 membered monocyclic ring are selected from nitrogen, oxygen or S(O) t (where t is an integer 0) The heteroatoms to 2) are substituted, but do not include the ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon; preferably 4 to 6 members, more preferably 5 to 6 members. Examples of saturated monoheterocycles include, but are not limited to, propylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine, piperazine , dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, and the like.
如本文所用，“5至6元单环杂芳基环”是指含5至6个环原子的单杂芳基环，例如包括(但不限于)：噻吩环、N-烷基吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环等。As used herein, a "5- to 6-membered monocyclic heteroaryl ring" refers to a monoheteroaryl ring containing from 5 to 6 ring atoms, including, for example, but not limited to, a thiophene ring, an N-alkylpyrrole ring, Furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5- a triazole ring, a 1,3,4-triazole ring, a tetrazole ring, an isoxazole ring, an oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, and the like.
如本文所用，“8至10元双环杂芳基环”是指含8至10个环原子的双杂芳基环，例如包括(但不限于)：苯并呋喃、苯并噻吩、吲哚、异吲哚、喹啉、异喹啉、吲唑、苯并噻唑、苯并咪唑、喹唑啉、喹喔啉、噌啉、酞嗪。As used herein, "8- to 10-membered bicyclic heteroaryl ring" refers to a bi-heteroaryl ring containing from 8 to 10 ring atoms, including, for example, but not limited to, benzofuran, benzothiophene, anthracene, Isoindole, quinoline, isoquinoline, carbazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, porphyrin, pyridazine.
如本文所用，“8至10元饱和或部分不饱和双环”是指含8至10个环原子的饱和的全碳双环或部分不饱和的全碳双环。“3至7元饱和或部分不饱和单杂环”是指含3至7个环原子且1到3个碳原子被选自氮、氧或硫的杂原子所取代的饱和单环或部分不饱和单环。单杂环的实例包括(但不限于)四氢呋喃环、四氢噻吩环、吡咯烷基环、哌啶环、吡咯啉环、噁唑烷环、哌嗪环、二氧戊环、吗啉环。As used herein, "8- to 10-membered saturated or partially unsaturated bicyclic" refers to a saturated all-carbon bicyclic or partially unsaturated, all-carbon bicyclic ring containing from 8 to 10 ring atoms. "3 to 7 membered saturated or partially unsaturated monoheterocyclic ring" means a saturated monocyclic or partially unsubstituted ring containing from 3 to 7 ring atoms and one to three carbon atoms substituted with a hetero atom selected from nitrogen, oxygen or sulfur. Saturated single ring. Examples of monoheterocycles include, but are not limited to, tetrahydrofuran ring, tetrahydrothiophene ring, pyrrolidinyl ring, piperidine ring, pyrroline ring, oxazolidine ring, piperazine ring, dioxolane, morpholine ring.
如本文所用，“8至10元饱和或部分不饱和双杂环”是指具有8至10个环原子且1到5个碳原子被选自氮、氧或硫的杂原子所取代的饱和双环或部分不饱和双环。双杂环的实例包 括(但不限于)四氢喹啉环、四氢异喹啉环、十氢喹啉环。As used herein, "8 to 10 membered saturated or partially unsaturated bicyclic heterocycle" means a saturated bicyclic ring having 8 to 10 ring atoms and 1 to 5 carbon atoms substituted with a hetero atom selected from nitrogen, oxygen or sulfur. Or partially unsaturated double rings. Examples of the bicyclic heterocycle include, but are not limited to, a tetrahydroquinoline ring, a tetrahydroisoquinoline ring, and a decahydroquinoline ring.
如本文所用，“取代的”指基团中的一个或多个氢原子，优选为1～5个氢原子彼此独立地被相应数目的取代基取代，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。As used herein, "substituted" refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently substituted with each other by a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independent of each other. The ground is replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
如本文所用，本文任一基团可以是取代的或未取代的。上述基团为取代时，取代基优选为1至5个以下基团，独立地选自CN、卤素、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、C 1-8烷基取代的胺基、胺基、卤代C 1-8烷基取代的胺基、4至6元饱和单杂环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环。 As used herein, any of the groups herein may be substituted or unsubstituted. When the above group is substituted, the substituent is preferably a group of 1 to 5 or less, independently selected from the group consisting of CN, halogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3) Alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferably halogen C 1- 6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkoxy (preferably halogenated) C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 alkyl substituted amine, amine, halogenated C 1-8 alkyl substituted amine, 4 Up to 6-membered saturated monoheterocyclic ring, 5- to 6-membered monocyclic heteroaryl ring, 8- to 10-membered bicyclic heteroaryl ring, spiro ring, spiro heterocyclic ring, bridged ring or bridged heterocyclic ring.
本文以上所述的各类取代基团其自身也是可以被本文所描述的基团取代。The various substituent groups described herein above are themselves themselves replaceable by the groups described herein.
本文所述的3至7元(或5至6元)饱和单杂环被取代时，取代基的位置可处在它们可能的化学位置，示例性的单杂环的代表性的取代情况如下所示：When a 3 to 7 membered (or 5 to 6 membered) saturated monoheterocyclic ring as described herein is substituted, the positions of the substituents may be at their possible chemical positions, and representative substitutions of the exemplary monoheterocyclic ring are as follows. Show:
Figure PCTCN2018122818-appb-000029
Figure PCTCN2018122818-appb-000030
其中“Sub”表示本文所述的各类取代基；
Figure PCTCN2018122818-appb-000031
表示与其他原子的连接。
Figure PCTCN2018122818-appb-000029
Figure PCTCN2018122818-appb-000030
Wherein "Sub" means each of the substituents described herein;
Figure PCTCN2018122818-appb-000031
Represents a connection to another atom.
除非另有定义，本发明所述的4至6元或5至6元饱和单杂环，或者当本发明所述的4至6元或5至6元饱和单杂环为取代基时，其自身也可以为未取代或被1、2或3个选自下组的取代基所取代：卤素、羟基、C 1-3烷基、O＝、NR a0R b0、羟甲基、羟乙基、羧基、-C(O)OC 1-3烷基、乙酰基、卤代C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、噻吩环、N-烷基吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、四唑环、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环；其中R a0、R b0各自独立地为氢或C 1-3烷基。 Unless otherwise defined, the 4 to 6 membered or 5 to 6 membered saturated monoheterocyclic ring of the present invention, or when the 4 to 6 membered or 5 to 6 membered saturated monoheterocyclic ring of the present invention is a substituent, It may itself be unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, O=, NR a0 R b0 , hydroxymethyl, hydroxyethyl , carboxyl group, -C(O)OC 1-3 alkyl group, acetyl group, halogenated C 1-3 alkyl group, C 1-3 alkoxy group, C 3-6 cycloalkyl group, azetidine, oxygen Heterocyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1, 1-dioxide, tetrahydropyran, thiophene ring, N-alkylpyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, tetrazole ring, different An oxazole ring, an oxadiazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring; wherein R a0 and R b0 are each independently hydrogen or C 1-3 alkyl.
所述“药学上可接受的盐”包括药学可接受的酸加成盐和药学可接受的碱加成盐。The "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其他副作用的，与无机酸或有机酸所形成的盐。"Pharmaceutically acceptable acid addition salt" means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without any other side effects.
“药学可接受的碱加成盐”，包括但不限于无机碱的盐如钠盐，钾盐，钙盐和镁盐等。包括但不限于有机碱的盐，比如铵盐，三乙胺盐，赖氨酸盐，精氨酸盐等。"Pharmaceutically acceptable base addition salts", including but not limited to salts of inorganic bases such as sodium, potassium, calcium and magnesium salts, and the like. These include, but are not limited to, salts of organic bases such as ammonium salts, triethylamine salts, lysine salts, arginine salts and the like.
本发明中提及的“溶剂化物”是指本发明的化合物与溶剂形成的配合物。它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。例如，一个与水形成的配合物称为“水合物”。式(I)化合物的溶剂化物属于本发明范围之内。As used herein, "solvate" refers to a complex of a compound of the invention with a solvent. They either react in a solvent or precipitate out of the solvent or crystallize out. For example, a complex formed with water is referred to as a "hydrate." Solvates of the compounds of formula (I) are within the scope of the invention.
本发明式(I)或式(Ⅱ)所示的化合物可以含有一个或多个手性中心，并以不同的光学活性形式存在。当化合物含有一个手性中心时，化合物包含对映异构体。本发明包括这两种异构体和异构体的混合物，如外消旋混合物。对映异构体可以通过本专业已知的方法拆分，例如结晶以及手性色谱等方法。当式(I)或式(Ⅱ)化合物含有多于一个手性中心时，可以存在非对映异构体。本发明包括拆分过的光学纯的特定异构体以及非对映异构体的混合物。非对映异构体可由本专业已知方法拆分，比如结晶以及制备色谱。The compounds of formula (I) or formula (II) of the present invention may contain one or more chiral centers and exist in different optically active forms. When the compound contains a chiral center, the compound contains the enantiomer. The invention includes mixtures of the two isomers and isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When a compound of formula (I) or formula (II) contains more than one chiral center, diastereomers may be present. The present invention includes resolved optically pure specific isomers as well as mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
本发明包括上述化合物的前药。前药包括已知的氨基保护基和羧基保护基，在生理条件下被水解或经由酶反应释放得到母体化合物。具体的前药制备方法可参照(Saulnier，M.G.；Frennesson，D.B.；Deshpande，M.S.；Hansel，S.B and Vysa，D.M.Bioorg.Med.Chem Lett.1994，4，1985-1990；和Greenwald，R.B.；Choe，Y.H.；Conover，C.D.；Shum，K.；Wu，D.；Royzen，M.J.Med.Chem.2000，43，475.)。The invention includes prodrugs of the above compounds. Prodrugs include known amino protecting groups and carboxy protecting groups which are hydrolyzed under physiological conditions or released via an enzymatic reaction to give the parent compound. Specific prodrug preparation methods can be referred to (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
通常，本发明化合物或其药学可接受的盐、或其溶剂化物、或其立体异构体、或前药可以与一种或多种药用载体形成适合的剂型施用。这些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括水、生理盐水、葡萄糖水溶 液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。In general, a compound of the invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer, or prodrug thereof, can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers. These dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like. The compound of the present invention contained in these preparations may be a solid powder or granule; a solution or suspension in an aqueous or non-aqueous liquid; a water-in-oil or oil-in-water emulsion or the like. The above dosage forms can be prepared from the active compound with one or more carriers or excipients via conventional pharmaceutical methods. The above carriers need to be compatible with the active compound or other excipients. For solid formulations, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Carriers for liquid preparations include water, physiological saline, aqueous glucose solution, ethylene glycol, polyethylene glycol, and the like. The active compound can form a solution or suspension with the above carriers.
本发明的组合物以符合医学实践规范的方式配制，定量和给药。给予化合物的“治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。The compositions of the present invention are formulated, quantified, and administered in a manner consistent with medical practice. The "therapeutically effective amount" of a given compound will be determined by the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
如本文所用，“治疗有效量”是指将引起个体的生物学或医学响应，例如降低或抑制酶或蛋白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等的本发明化合物的量。As used herein, "therapeutically effective amount" refers to a compound of the invention that will elicit a biological or medical response to an individual, such as reducing or inhibiting the activity of an enzyme or protein or ameliorating a condition, alleviating a condition, slowing or delaying the progression of a disease, or preventing a disease, and the like. the amount.
本发明的药物组合物中含有的本发明化合物或其药学上可接受的盐、或其溶剂化物、或其立体异构体的治疗有效量优选为0.1mg-5g/kg(体重)。The therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, contained in the pharmaceutical composition of the present invention is preferably 0.1 mg to 5 g/kg (body weight).
如本文所用，“药学可接受的载体”是指无毒、惰性、固态、半固态的物质或液体灌装机、稀释剂、封装材料或辅助制剂或任何类型辅料，其与患者相兼容，最好为哺乳动物，更优选为人，其适合将活性试剂输送到目标靶点而不终止试剂的活性。As used herein, "pharmaceutically acceptable carrier" means a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating or auxiliary formulation or any type of excipient that is compatible with the patient, most Preferably, it is a mammal, more preferably a human, which is suitable for delivering the active agent to a target of interest without terminating the activity of the agent.
如本文所用，“患者”是指一种动物，最好为哺乳动物，更好的为人。术语“哺乳动物”是指温血脊椎类哺乳动物，包括如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪和人类。As used herein, "patient" refers to an animal, preferably a mammal, and more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.
如本文所用，“治疗”是指减轻、延缓进展、衰减、预防，或维持现有疾病或病症(例如癌症)。治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。As used herein, "treating" refers to alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing, or alleviating one or more symptoms of the disease or condition to some extent.
制备方法Preparation
本发明提供了式(I-1)化合物的制备方法，本发明中的化合物可以通过多种合成操作制备，这些化合物的示例性制备方法可以包括(但不限于)下文所述的流程。The present invention provides a process for the preparation of a compound of formula (I-1). The compounds of the present invention can be prepared by a variety of synthetic procedures, and exemplary methods of preparing such compounds can include, but are not limited to, the schemes described below.
较佳地，本发明式(I-1)化合物可以通过以下方案及实施例中所述的示例性方法以及本领域技术人员所用的相关公开文献操作完成。Preferably, the compound of the formula (I-1) of the present invention can be carried out by the following schemes and the exemplary methods described in the examples and related publications used by those skilled in the art.
在具体操作过程中，可以根据需要对方法中的步骤进行扩展或合并。The steps in the method can be extended or merged as needed during the specific operation.
方案1:plan 1:
Figure PCTCN2018122818-appb-000032
Figure PCTCN2018122818-appb-000032
步骤:将化合物I-1-1与化合物I-1-2在合适的还原剂和有机溶剂存在下进行还原胺化反应。包括催化氢化法(如金属催化氢化、金属络合物催化还原胺化)、硼烷还原法、有机小分子催化的还原胺化、Lenckart反应等。所选用的还原剂包括(但不限于)NaBH 4、NaBH 3CN、NaB(OAc) 3H、NaBH(OEh) 3(Eh为2-乙基己酰氧基)、HCOONH 4与Pd/C等。 Step: Reductive amination of compound I-1-1 with compound I-1-2 in the presence of a suitable reducing agent and an organic solvent. Including catalytic hydrogenation methods (such as metal-catalyzed hydrogenation, metal complex catalytic reductive amination), borane reduction, reductive amination of small organic molecules, Lenckart reaction, and the like. The reducing agents selected include, but are not limited to, NaBH 4 , NaBH 3 CN, NaB(OAc) 3 H, NaBH(OEh) 3 (Eh is 2-ethylhexanoyloxy), HCOONH 4 and Pd/C, etc. .
方案2:Scenario 2:
Figure PCTCN2018122818-appb-000033
Figure PCTCN2018122818-appb-000033
步骤1:将化合物I-1-1-1与三氟乙烯基硼酸钾在合适的碱、溶剂和钯催化剂存在下反应，得到化合物I-1-1-2。合适的碱包括(但不限于)氢氧化钾、氢氧化钠、碳酸钠、碳酸氢钠、碳酸钾、碳酸铯等。合适的钯催化剂可以是但不限于醋酸钯、Pd(dppf) 2Cl 2、Pd2(dba) 3。 Step 1: Compound I-1-1-1 is reacted with potassium trifluorovinylborate in the presence of a suitable base, solvent and palladium catalyst to give compound I-1-1-2. Suitable bases include, but are not limited to, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, cesium carbonate, and the like. Suitable palladium catalysts can be, but are not limited to, palladium acetate, Pd(dppf) 2 Cl 2 , Pd2(dba) 3 .
步骤2:将化合物I-1-1-2与化合物I-1-1-3在一定温度下，在合适的溶剂和钯催化和配体存在下反应得化合物I-1-1。合适的钯催化剂可以是但不限于醋酸钯、Pd(dppf) 2Cl 2、Pd2(dba) 3。所用的配体可以是但不限于XantPhos(4,5-双(二苯基膦)-9,9-二甲基氧杂蒽)、三(邻甲基苯基)磷。 Step 2: Compound I-1-1-2 is reacted with compound I-1-1-3 at a temperature in the presence of a suitable solvent and palladium catalyst and ligand to give compound 1-1-1. Suitable palladium catalysts can be, but are not limited to, palladium acetate, Pd(dppf) 2 Cl 2 , Pd2(dba) 3 . The ligand used may be, but not limited to, XantPhos (4,5-bis(diphenylphosphino)-9,9-dimethyloxaxan), tris(o-methylphenyl)phosphorus.
以上各步骤中的反应均是本领域技术人员已知的常规反应。如无特殊说明，合成路线中所使用的试剂和原料化合物均可市购得到，或本领域技术人员根据所设计的不同化合物结构参考已知方法制备得到。The reactions in the above various steps are conventional reactions known to those skilled in the art. Unless otherwise stated, the reagents and starting materials used in the synthetic route are either commercially available or can be prepared by those skilled in the art according to known methods of designing different compound structures.
与现有技术相比，本发明的主要优点在于：The main advantages of the present invention over the prior art are:
提供了一系列结构新颖的免疫调节剂，其对PD-1/PD-L1具有高抑制活性，可用作治疗肿瘤的药物。A series of novel immunomodulators are provided which have high inhibitory activity against PD-1/PD-L1 and are useful as drugs for treating tumors.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated. Unless otherwise defined, the terms used herein have the same meaning as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the present invention.
如本文所用，DMB为2,4-二甲氧基苄基，THF为四氢呋喃，EA为乙酸乙酯，PE为石油醚，Ac 2O为乙酸酐，NBS为N-溴代琥珀酰亚胺，DCM为二氯甲烷，AIBN为偶氮二异丁腈，Pd(dppf)Cl 2为1,1'-双(二苯基磷)二茂铁]二氯化钯，TFA为三氟乙酸，TBSCl为叔丁基二甲基氯硅烷，NCS为N-氯代丁二酰亚胺，DHP为二氢吡喃，LiAlH 4为氢化铝锂，PMB为对甲氧基苄基，LiHMDS为二(三甲基硅基)氨基锂，Pd 2(dba) 3为三(二亚苄基丙酮)二钯，RuPhos为2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯,DMAP为4-二甲氨基吡啶，THP为四氢吡喃，n-BuLi为正丁基锂，TMsOTf为三氟甲磺酸三甲基硅酯，TEBAC为三乙基苄基氯化铵，HATU为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，DMF为二甲基甲酰胺，DMSO为二甲基亚砜，DIEA为N,N-二异丙基乙胺，BINAP为(2R,3S)-2,2'-双二苯膦基-1,1'-联萘。 As used herein, DMB is 2,4-dimethoxybenzyl, THF is tetrahydrofuran, EA is ethyl acetate, PE is petroleum ether, Ac 2 O is acetic anhydride, and NBS is N-bromosuccinimide. DCM is dichloromethane, AIBN is azobisisobutyronitrile, Pd(dppf)Cl 2 is 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, TFA is trifluoroacetic acid, TBSCl Is tert-butyldimethylchlorosilane, NCS is N-chlorosuccinimide, DHP is dihydropyran, LiAlH 4 is lithium aluminum hydride, PMB is p-methoxybenzyl, and LiHMDS is two (three Methylsilyl) lithium amide, Pd 2 (dba) 3 is tris(dibenzylideneacetone)dipalladium, RuPhos is 2-dicyclohexylphosphorin-2',6'-diisopropoxy-1,1 '-Biphenyl, DMAP is 4-dimethylaminopyridine, THP is tetrahydropyran, n-BuLi is n-butyllithium, TMsOTf is trimethylsilyl trifluoromethanesulfonate, TEBAC is triethylbenzyl Ammonium chloride, HATU is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, DMF is dimethylformamide, DMSO is two Methyl sulfoxide, DIEA is N,N-diisopropylethylamine, BINAP is (2R,3S)-2,2'-bisdiphenylphosphino-1,1'-binaphthyl.
如本文所用，室温是指约为20-25℃。As used herein, room temperature means about 20-25 °C.
中间体1a的制备Preparation of intermediate 1a
Figure PCTCN2018122818-appb-000034
Figure PCTCN2018122818-appb-000034
步骤1：在4-溴-2-氯-3-甲基吡啶(2g,10mmol)的二氧六环(20ml)/水(6ml)溶液中加入苯 硼酸(1.35g,11mmol)，Pd(dppf) 2Cl 2(366mg,0.5mmol)和碳酸钠(2.12g,20mmol)，混合物在氮气保护下80℃搅拌过夜，LC-MS跟踪至反应结束。反应液冷却至室温后用乙酸乙酯萃取，有机相减压浓缩，经柱层析纯化得白色固体化合物1a-1(1.82g，产率92％)。MS m/z(ESI):204.1[M+H] +。 Step 1: To a solution of 4-bromo-2-chloro-3-methylpyridine (2g, 10mmol) in dioxane (20ml) / water (6ml), phenylboronic acid (1.35g, 11mmol), Pd (dppf) 2 Cl 2 (366 mg, 0.5 mmol) and sodium carbonate (2.12 g, 20 mmol), and the mixture was stirred at 80 ° C overnight under nitrogen atmosphere, and LC-MS was followed until the end of the reaction. After the reaction mixture was cooled to room temperature, ethyl acetate was evaporated. MS m/z (ESI): 204.1 [M+H] + .
步骤2：在1a-1(1.82g,9mmol)的二氧六环(20ml)/水(6ml)溶液中加入三氟乙烯基硼酸钾(3g,22.5mmol)，碳酸钠(2.879g,27mmol)和Pd(dppf) 2Cl 2(329mg,0.45mmol)，混合物在氮气保护下85℃搅拌4h，LC-MS跟踪至反应结束。反应液冷却至室温后用乙酸乙酯萃取，有机相减压浓缩，经柱层析纯化得无色油状化合物1a-2(1.42g，产率81％)，MS m/z(ESI):196.1[M+H] +。 Step 2: To a solution of 1a-1 (1.82 g, 9 mmol) in dioxane (20 ml) / water (6 ml) And Pd(dppf) 2 Cl 2 (329 mg, 0.45 mmol), the mixture was stirred at 85 ° C for 4 h under nitrogen atmosphere, and LC-MS was followed until the end of the reaction. The reaction mixture was cooled to room temperature, EtOAc EtOAc (EtOAc m. [M+H] + .
步骤3：在化合物1a-2(500mg,2.56mmol)的三乙胺(5ml)溶液中加入4-溴-3-氯苯甲醛(674mg,3.07mmol)，醋酸钯(57mg,0.26mmol)和三(邻甲基苯基)磷(156mg,0.51mmol)，混合物在氮气保护下130℃微波反应1h，LC-MS跟踪至反应结束。反应冷却至室温后用乙酸乙酯萃取，有机相减压浓缩，经柱层析纯化后得黄色固体化合物1a(187mg,产率18％)，MS m/z(ESI):334.1[M+H] +。 Step 3: To a solution of compound 1a-2 (500 mg, 2.56 mmol) in triethylamine (5 ml) was added 4-bromo-3-chlorobenzaldehyde (674 mg, 3.07 mmol), palladium acetate (57 mg, 0.26 mmol) and (o-methylphenyl)phosphorus (156 mg, 0.51 mmol), the mixture was subjected to microwave reaction at 130 ° C for 1 h under nitrogen atmosphere, and LC-MS was followed until the end of the reaction. After the reaction was cooled to room temperature, the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjj ] + .
中间体2a的制备Preparation of intermediate 2a
Figure PCTCN2018122818-appb-000035
Figure PCTCN2018122818-appb-000035
步骤1：在肉桂醛(2.64g,20mmol)和氰基乙酰胺(1.85g,22mmol)的DMSO溶液(40ml)中加入叔丁醇钾(8.96g,80mmol)，混合物在室温下搅拌16h，LC-MS跟踪至反应结束。反应液用水(400ml)稀释，加入盐酸溶液(4N,30ml)，过滤，滤饼用水洗涤，干燥，得棕色固体化合物2a-1(1.65g，产率63％)，MS m/z(ESI):197.0[M+H] +。 Step 1: To a solution of cinnamaldehyde (2.64 g, 20 mmol) and cyanoacetamide (1.85 g, 22 mmol) in EtOAc (40 mL) - MS tracks until the end of the reaction. The reaction mixture was diluted with water (400 ml), EtOAc (EtOAc, m. :197.0[M+H] + .
步骤2：化合物2a-1(1.65g,8.42mmol)的三氯氧磷(20ml)溶液回流3h。反应液冷却至室温后，减压浓缩。剩余物中加入饱和碳酸氢钠溶液(100ml)，混合物用乙酸乙酯萃取，有机相减压浓缩，经柱层析纯化得浅棕色固体化合物2a-2(750mg,产率42％)，MS m/z(ESI):215.0[M+H] +。 Step 2: A solution of compound 2a-1 (1.65 g, 8.42 mmol). The reaction solution was cooled to room temperature and concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate (100 ml) was added, and the mixture was evaporated. EtOAcjjjjjjjjjjjjj /z (ESI): 215.0 [M + H] + .
步骤3：化合物2a-3的制备方法同化合物1a-2的制备方法。Step 3: The preparation method of Compound 2a-3 is the same as the preparation method of Compound 1a-2.
步骤4：化合物2a的制备方法同化合物1a的制备方法。Step 4: The preparation method of Compound 2a is the same as the preparation method of Compound 1a.
中间体3a-36a的制备Preparation of intermediates 3a-36a
中间体化合物如式(II-a)所示，取代基Ar 1、R 1、R 5与R 7如下表所示： The intermediate compound is represented by the formula (II-a), and the substituents Ar 1 , R 1 , R 5 and R 7 are as shown in the following table:
Figure PCTCN2018122818-appb-000036
Figure PCTCN2018122818-appb-000036
制备方法参照中间体1a或2a的制备方法。The preparation method is referred to the preparation method of the intermediate 1a or 2a.
Figure PCTCN2018122818-appb-000037
Figure PCTCN2018122818-appb-000037
Figure PCTCN2018122818-appb-000038
Figure PCTCN2018122818-appb-000038
Figure PCTCN2018122818-appb-000039
Figure PCTCN2018122818-appb-000039
中间体1b的制备Preparation of intermediate 1b
Figure PCTCN2018122818-appb-000040
Figure PCTCN2018122818-appb-000040
以化合物1a-2与1b.1为原料，制备方法参考化合物1a。MS m/z(ESI):315.1[M+H] +。 Starting from the compounds 1a-2 and 1b.1, the preparation method is referred to the compound 1a. MS m/z (ESI): 315.1 [M+H] + .
中间体3b的制备Preparation of intermediate 3b
Figure PCTCN2018122818-appb-000041
Figure PCTCN2018122818-appb-000041
步骤1：参考中间体1a制备方法的步骤1，得化合物3b-2。MS m/z(ESI):267[M+H] +。 Step 1: Referring to Step 1 of the preparation method of Intermediate 1a, Compound 3b-2 was obtained. MS m/z (ESI): 266 [M+H] + .
步骤2：化合物3b-2(100mg,0.375mmol)，碘化钠(281mg,1.873mmol)，TMSCl(81mg,0.75mmol)的1,4-二氧六环(2mL)溶液在80℃搅拌20h。LC-MS跟踪至反应结束。反应液减压浓缩后经柱层析得化合物3b(63mg,产率47％)，MS m/z(ESI):360[M+H] +。 Step 2: Compound 3b-2 (100 mg, 0.375 mmol), EtOAc (EtOAc, EtOAc (EtOAc) LC-MS was followed until the end of the reaction. After the reaction mixture was concentrated under reduced pressure and purified by column chromatography to give compound 3b (63mg, yield 47%), MS m / z (ESI): 360 [M + H] +.
中间体4b的制备Preparation of intermediate 4b
Figure PCTCN2018122818-appb-000042
Figure PCTCN2018122818-appb-000042
化合物4b-1(900mg,3.54mmol)和1,1-二氯甲醚(1.21g,10.63mmol)的DCM(20mL)溶液在氩气保护下于0℃逐滴加入TiCl 4(2g,10.63mmol)，混合物室温搅拌2h。反应液倒入冰水中，二氯甲烷萃取，有机层减压蒸干，残留物经combiflash纯化得白色固体化合物4b(240mg,产率24％)。 Compound 4b-1 (900mg, 3.54mmol) and 1,1-dichloro methyl ether (1.21g, 10.63mmol) in DCM (20mL) was added dropwise TiCl 4 (2g, 10.63mmol at 0 ℃ under argon protection The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into EtOAc (EtOAc m.)
中间体5b的制备Preparation of intermediate 5b
Figure PCTCN2018122818-appb-000043
Figure PCTCN2018122818-appb-000043
制备方法参考化合物4b。The preparation method is referred to the compound 4b.
中间体6b的制备Preparation of intermediate 6b
Figure PCTCN2018122818-appb-000044
Figure PCTCN2018122818-appb-000044
步骤1：化合物6b-1(1.33g,5.1mmol)的CCl 4(20ml)溶液在氮气氛围下加入NBS(910mg,5.1mmol)和AIBN(84mg,0.51mmol)，混合物在110℃搅拌24h，LC-MS跟踪至反应结束。反应液冷却后加水淬灭，乙酸乙酯萃取后减压浓缩得粗产品6b-2，不纯化直接用于下一步反应。MS m/z(ESI):341.4[M+H] +。 Step 1: CCl compound 6b-1 (1.33g, 5.1mmol) of 4 (20ml) was added NBS (910mg, 5.1mmol) and AIBN (84mg, 0.51mmol) under a nitrogen atmosphere, the mixture was stirred at 110 ℃ 24h, LC - MS tracks until the end of the reaction. After the reaction mixture was cooled, it was quenched with water, and ethyl acetate was evaporated. MS m/z (ESI): 341.4 [M+H] + .
步骤2：化合物6b-2(1.94g,5.7mmol)的DMF(20ml)溶液在氮气氛围下加入化合物 6b.1(814mg,6.84mmol)和碳酸钾(1.6g,11.4mmol)。混合物在60℃搅拌4h，LC-MS跟踪至反应结束。反应液冷却后加水淬灭，乙酸乙酯萃取后减压浓缩得粗产品6b-3，不纯化直接用于下一步反应。MS m/z(ESI):380.9[M+H] +。 A solution of compound 6b-2 (1.94 g, 5.7 mmol The mixture was stirred at 60 ° C for 4 h and LC-MS was followed until the end of the reaction. After the reaction mixture was cooled, it was quenched with water, and ethyl acetate was evaporated. MS m/z (ESI): 380.9 [M+H] + .
步骤3：参考化合物1a制备方法的步骤3。MS m/z(ESI):496.1[M+H]+。Step 3: Refer to step 3 of the preparation method of Compound 1a. MS m/z (ESI): 496.1 [M+H]+.
中间体7b的制备Preparation of intermediate 7b
Figure PCTCN2018122818-appb-000045
Figure PCTCN2018122818-appb-000045
步骤1：化合物6b-2(500mg,1.5mmol)的甲醇(20ml)溶液在氮气氛围下于0℃缓慢加入甲醇钠(180mg,4.5mmol)，混合物在40℃搅拌过夜，LC-MS跟踪至反应结束。反应液冷却后加饱和氯化铵溶液淬灭，乙酸乙酯萃取后减压浓缩，乙醚纯化后得化合物7b-1。MS m/z(ESI):292.9[M+H] +。 Step 1: A solution of compound 6b-2 (500 mg, 1.5 mmol) in MeOH (20 mL) EtOAc (EtOAc) End. After the reaction mixture was cooled, it was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. MS m/z (ESI): 29.29 [M+H] + .
步骤2：化合物7b-1(115mg,0.4mmol)的THF(5ml)溶液冷却至0℃，在氩气保护下加入LiAlH 4(30mg,0.8mmol),混合物在0℃搅拌2h，LC-MS跟踪至反应结束。反应液过滤，乙酸乙酯萃取后减压浓缩得粗产品7b-2直接用于下一步反应。 Step 2: A solution of compound 7b-1 (115 mg, 0.4 mmol) in THF (5 ml) was cooled to 0 ° C, and then argon was added LiAlH 4 (30 mg, 0.8 mmol), and the mixture was stirred at 0 ° C for 2 h, LC-MS tracking Until the end of the reaction. The reaction solution was filtered, extracted with ethyl acetate and concentrated under reduced pressure to afford crude product 7b-2.
步骤3：化合物7b-2(106mg,0.4mmol)的DCM(8ml)溶液冷却至0℃，在氮气保护下缓慢加入Dess-martin(340mg,0.8mmol),混合物室温搅拌2h，TLC跟踪至反应结束。反应液过滤，乙酸乙酯萃取后减压浓缩，柱层析得白色固体化合物7b。Step 3: A solution of compound 7b-2 (106 mg, 0.4 mmol) in EtOAc (EtOAc)EtOAc. . The reaction mixture was filtered, and ethyl acetate was evaporated.
中间体8b的制备Preparation of intermediate 8b
Figure PCTCN2018122818-appb-000046
Figure PCTCN2018122818-appb-000046
步骤1：化合物5b(200mg,0.81mmol)的DCM(15ml)溶液冷却至0℃，在氮气保护下加入AlCl 3(540mg,4.05mmol),混合物室温搅拌4h。反应液倒入冰水中，二氯甲烷萃取，无水硫酸钠干燥，减压浓缩得粗产品8b-1。 Step 1: Compound 5b (200mg, 0.81mmol) (15ml ) in DCM was cooled to 0 ℃, AlCl 3 were added under nitrogen (540mg, 4.05mmol), the mixture was stirred at rt for 4h. The reaction mixture was poured into ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate
中间体9b的制备Preparation of intermediate 9b
Figure PCTCN2018122818-appb-000047
Figure PCTCN2018122818-appb-000047
以化合物8b和碘乙烷为原料，制备方法参考化合物6b-3的步骤2。Starting from compound 8b and ethyl iodide, the preparation method is referred to step 2 of compound 6b-3.
中间体10b的制备Preparation of intermediate 10b
Figure PCTCN2018122818-appb-000048
Figure PCTCN2018122818-appb-000048
以化合物8b和碘乙烷为原料，制备方法参考化合物6b-3的步骤2。Starting from compound 8b and ethyl iodide, the preparation method is referred to step 2 of compound 6b-3.
中间体11b的制备Preparation of intermediate 11b
Figure PCTCN2018122818-appb-000049
Figure PCTCN2018122818-appb-000049
以化合物8b和碘乙腈为原料，制备方法参考化合物6b-3的步骤2。Starting from compound 8b and iodoacetonitrile, the preparation method is referred to step 2 of compound 6b-3.
实施例1：(E)-N-(3-氯-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄基)环戊胺(P-1)的制备Example 1: (E)-N-(3-Chloro-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzyl)cyclopentylamine (P-1) Preparation
Figure PCTCN2018122818-appb-000050
Figure PCTCN2018122818-appb-000050
在化合物1a(50mg,0.145mmol)的甲醇溶液(4ml)中加入环戊胺(37mg,0.435mmol)和氰基硼氢化钠(27mg,0.435mmol)，混合物85℃搅拌5h，LC-MS跟踪至反应结束。反应液浓缩后，经Pre-HPLC纯化后得白色固体P-1(12.3mg,产率14％)，MS m/z(ESI):403.1[M+H] +。 1H NMR(400MHz,DMSO d6)δ8.49(d,J＝4.8Hz,1H),8.12(d,J＝15.5Hz,1H),7.96(d,J＝8.1Hz,1H),7.59(d,J＝15.5Hz,1H),7.41-7.53(m,4H),7.29-7.38(m,2H),7.33(d,J＝8.0Hz,1H),7.14(d,J＝4.8Hz,1H),3.68(s,2H),2.93-3.03(m,1H),2.33(s,3H),1.57-1.71(m,4H),1.41-1.50(m,2H),1.27-1.39(m,2H). Add cyclopentylamine (37 mg, 0.435 mmol) and sodium cyanoborohydride (27 mg, 0.435 mmol) in MeOH (4 mL). The reaction is over. The reaction mixture was concentrated and purified by Pre-HPLC to give a white solid P-1 (12.3mg, yield 14%), MS m / z (ESI): 403.1 [M + H] +. 1 H NMR (400 MHz, DMSO d6) δ 8.49 (d, J = 4.8 Hz, 1H), 8.12 (d, J = 15.5 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.59 (d) , J = 15.5 Hz, 1H), 7.41 - 7.53 (m, 4H), 7.29-7.38 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 4.8 Hz, 1H) , 3.68 (s, 2H), 2.93-3.03 (m, 1H), 2.33 (s, 3H), 1.57-1.71 (m, 4H), 1.41-1.50 (m, 2H), 1.27-1.39 (m, 2H) .
实施例2：(E)-N-(2-(3-氯-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄基氨基)乙基)乙酰胺(P-2)的制备Example 2: (E)-N-(2-(3-chloro-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzylamino)ethyl)ethyl Preparation of amide (P-2)
Figure PCTCN2018122818-appb-000051
Figure PCTCN2018122818-appb-000051
化合物1a(50mg,0.145mmol)、化合物2.1(23mg,0.22mmol)的二氯甲烷(2ml)和醋酸溶液(1ml)室温搅拌1h后加入三乙酰氧基硼氢化钠(47mg,0.22mmol)，混合物混合物室温搅拌过夜，LC-MS跟踪至反应结束。反应液浓缩后，经Pre-HPLC纯化后得白色固体P-2(15.27mg,产率24.3％)，MS m/z(ESI):421[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝4.8Hz,1H),8.12(d,J＝15.6Hz,1H),7.99(d,J＝8.0Hz,1H),7.82(t,J＝5.2Hz,1H),7.61(d,J＝15.6Hz,1H),7.44(d,J＝7.3Hz,1H),7.43-7.53(m,4H),7.35-7.39(m,3H),7.15(d,J＝4.8Hz,1H),3.73(s,2H),3.11-3.16(m,2H),2.54(t,J＝6.4Hz,2H),2.34(s,3H),1.79(s,3H). Compound 1a (50 mg, 0.145 mmol), Compound 2.1 (23 mg, 0.22 mmol), methylene chloride (2 ml) and acetic acid (1 ml) was stirred at room temperature for 1 h then sodium triacetoxyborohydride (47 mg, 0.22 mmol) The mixture was stirred at room temperature overnight and LC-MS was followed until the end of the reaction. The reaction mixture was concentrated and purified by Pre-HPLC to give a white solid P-2 (15.27mg, yield 24.3%), MS m / z (ESI): 421 [M + H] +. 1 H NMR (400MHz, DMSO- d6) δ8.49 (d, J = 4.8Hz, 1H), 8.12 (d, J = 15.6Hz, 1H), 7.99 (d, J = 8.0Hz, 1H), 7.82 ( t, J = 5.2 Hz, 1H), 7.61 (d, J = 15.6 Hz, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.43 - 7.53 (m, 4H), 7.35 - 7.39 (m, 3H) ), 7.15 (d, J = 4.8 Hz, 1H), 3.73 (s, 2H), 3.11-3.16 (m, 2H), 2.54 (t, J = 6.4 Hz, 2H), 2.34 (s, 3H), 1.79 (s, 3H).
实施例3：(S，E)-4-(3-氯-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄氨基)-3-羟基丁酸(P-3)的制备Example 3: (S,E)-4-(3-chloro-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzylamino)-3-hydroxybutyric acid Preparation of (P-3)
Figure PCTCN2018122818-appb-000052
Figure PCTCN2018122818-appb-000052
以化合物1a为原料，制备方法参考化合物P-1，得化合物P-3。MS m/z(ESI):438[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝4.8Hz,1H),8.36(br,2H),8.12(d,J＝15.6Hz,1H),7.99(d,J＝8.0Hz,1H),7.61(d,J＝15.6Hz,1H),7.43-7.53(m,4H),7.34-7.39(m,3H),7.14(d,J＝4.8Hz,1H),3.86-3.94(m,1H),3.76(s,2H),2.47-2.52(m,2H),2.31-2.41(m,4H),2.18-2.23(m,1H). Starting from the compound 1a, the preparation method is referred to the compound P-1 to obtain the compound P-3. MS m/z (ESI): 438 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ8.49 (d, J = 4.8Hz, 1H), 8.36 (br, 2H), 8.12 (d, J = 15.6Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 15.6 Hz, 1H), 7.43 - 7.53 (m, 4H), 7.34 - 7.39 (m, 3H), 7.14 (d, J = 4.8 Hz, 1H), 3.86-3.94 (m, 1H), 3.76 (s, 2H), 2.47-2.52 (m, 2H), 2.31-2.41 (m, 4H), 2.18-2.23 (m, 1H).
实施例4：(E)-2-(3-氯-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄基氨基)乙醇(P-4)的制备Example 4: (E)-2-(3-Chloro-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzylamino)ethanol (P-4) preparation
Figure PCTCN2018122818-appb-000053
Figure PCTCN2018122818-appb-000053
以化合物1a和乙醇胺为原料，制备方法参考化合物P-2，得化合物P-4。MS m/z(ESI):379.9[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝4.8Hz,1H),8.12(d,J＝15.6Hz,1H),8.00(d,J＝8.0Hz,1H),7.62(d,J＝15.6Hz,1H),7.43-7.53(m,4H),7.35-7.39(m,3H),7.15(d,J＝4.8Hz,1H),3.79(s,2H),3.49(t,J＝5.6Hz,2H),2.61(t,J＝5.6Hz,2H),2.34(s,3H). Starting from the compound 1a and ethanolamine, the preparation method is referred to the compound P-2 to obtain the compound P-4. MS m/z (ESI): 379.9 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ8.49 (d, J = 4.8Hz, 1H), 8.12 (d, J = 15.6Hz, 1H), 8.00 (d, J = 8.0Hz, 1H), 7.62 ( d, J = 15.6 Hz, 1H), 7.43 - 7.53 (m, 4H), 7.35-7.39 (m, 3H), 7.15 (d, J = 4.8 Hz, 1H), 3.79 (s, 2H), 3.49 (t , J = 5.6 Hz, 2H), 2.61 (t, J = 5.6 Hz, 2H), 2.34 (s, 3H).
实施例5：(E)-1-(3-(3-氯-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄基氨基)丙基)吡咯烷-2-酮(P-5)的制备Example 5: (E)-1-(3-(3-chloro-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzylamino)propyl)pyrrole Preparation of alkan-2-one (P-5)
Figure PCTCN2018122818-appb-000054
Figure PCTCN2018122818-appb-000054
以化合物1a为原料，制备方法参考化合物P-1，得化合物P-5。MS m/z(ESI):460.1[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.46(d,J＝4.8Hz,1H),8.08(d,J＝15.4Hz,1H),7.99(d,J＝8.1Hz,1H),7.60(d,J＝15.5Hz,1H),7.39–7.52(m,4H),7.32–7.38(m,3H),7.12(d,J＝4.8Hz,1H),4.02(d,J＝13.4Hz,2H),3.71(d,J＝13.4Hz,2H),2.99–3.07(m,2H),2.50–2.60(m,2H),2.31(s,3H),2.06–2.16(m,2H),1.65–1.89(m,4H). Starting from the compound 1a, the preparation method is referred to the compound P-1 to obtain the compound P-5. MS m/z (ESI): 460.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ8.46 (d, J = 4.8Hz, 1H), 8.08 (d, J = 15.4Hz, 1H), 7.99 (d, J = 8.1Hz, 1H), 7.60 ( d, J = 15.5 Hz, 1H), 7.39 - 7.52 (m, 4H), 7.32 - 7.38 (m, 3H), 7.12 (d, J = 4.8 Hz, 1H), 4.02 (d, J = 13.4 Hz, 2H ), 3.71 (d, J = 13.4 Hz, 2H), 2.99 - 3.07 (m, 2H), 2.50 - 2.60 (m, 2H), 2.31 (s, 3H), 2.06 - 2.16 (m, 2H), 1.65 - 1.89 (m, 4H).
实施例6：(S，E)-1-(3-氯-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄基)吡咯烷-2-羧酸(P-6)的制备Example 6: (S,E)-1-(3-chloro-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzyl)pyrrolidine-2-carboxylate Preparation of acid (P-6)
Figure PCTCN2018122818-appb-000055
Figure PCTCN2018122818-appb-000055
以化合物1a为原料，制备方法参考化合物P-1，得化合物P-6。MS m/z(ESI):433.1[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.46(d,J＝4.8Hz,1H),8.09(d,J＝15.5Hz,1H),7.96(d,J＝8.1Hz,1H),7.58(d,J＝15.5Hz,1H),7.40–7.51(m,4H),7.29–7.37(m,3H),7.11(d,J＝4.8Hz,1H),3.30–3.15(m,2H),2.43(d,J＝6.7Hz,1H),2.31(s,3H),2.16(t,J＝8.0Hz,2H),1.86(dt,J＝15.2,7.5Hz,2H),1.64–1.55(m,2H). Starting from the compound 1a, the preparation method is referred to the compound P-1 to obtain the compound P-6. MS m/z (ESI): 433.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ8.46 (d, J = 4.8Hz, 1H), 8.09 (d, J = 15.5Hz, 1H), 7.96 (d, J = 8.1Hz, 1H), 7.58 ( d, J = 15.5 Hz, 1H), 7.40 - 7.51 (m, 4H), 7.29 - 7.37 (m, 3H), 7.11 (d, J = 4.8 Hz, 1H), 3.30 - 3.15 (m, 2H), 2.43 (d, J = 6.7 Hz, 1H), 2.31 (s, 3H), 2.16 (t, J = 8.0 Hz, 2H), 1.86 (dt, J = 15.2, 7.5 Hz, 2H), 1.64 - 1.55 (m, 2H).
实施例7：(E)-2-(2-(2-氨基乙氧基)乙氧基)-N-(3-氯-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄基)乙胺(P-7)的制备Example 7: (E)-2-(2-(2-Aminoethoxy)ethoxy)-N-(3-chloro-4-(2-(3-methyl-4-phenylpyridine)- Preparation of 2-yl)vinyl)benzyl)ethylamine (P-7)
Figure PCTCN2018122818-appb-000056
Figure PCTCN2018122818-appb-000056
以化合物1a为原料，制备方法参考化合物P-1，得化合物P-7。MS m/z(ESI):466.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝4.8Hz,1H),8.36(s,2H),8.12(d,J＝15.5Hz,1H), 7.99(d,J＝8.1Hz,1H),7.61(d,J＝15.5Hz,1H),7.41–7.54(m,4H),7.31–7.41(m,3H),7.15(d,J＝4.8Hz,1H),3.75(s,2H),3.46–3.59(m,8H),2.89(t,J＝5.1Hz,2H),2.65(t,J＝5.7Hz,2H),2.34(s,3H). Starting from the compound 1a, the preparation method is referred to the compound P-1 to obtain the compound P-7. MS m/z (ESI): 466.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ8.49 (d, J = 4.8Hz, 1H), 8.36 (s, 2H), 8.12 (d, J = 15.5Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 15.5 Hz, 1H), 7.41 - 7.54 (m, 4H), 7.31 - 7.41 (m, 3H), 7.15 (d, J = 4.8 Hz, 1H), 3.75 (s) , 2H), 3.46–3.59 (m, 8H), 2.89 (t, J = 5.1 Hz, 2H), 2.65 (t, J = 5.7 Hz, 2H), 2.34 (s, 3H).
实施例8：(2R，3R)-2-(3-氯-4-((E)-2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄基氨基)丁烷-1,3-二醇(P-8)的制备Example 8: (2R,3R)-2-(3-Chloro-4-((E)-2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzylamino)butyl Preparation of alkane-1,3-diol (P-8)
Figure PCTCN2018122818-appb-000057
Figure PCTCN2018122818-appb-000057
以化合物1a为原料，制备方法参考化合物P-1，得化合物P-8。MS m/z(ESI):426[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.46(d,J＝4.7Hz,1H),8.08(d,J＝9.1Hz,1H),7.95(d,J＝8.1Hz,1H),7.57(m,1H),7.39–7.50(m,4H),7.30–7.37(m,3H),7.11(d,J＝4.8Hz,1H),4.25–4.50(m,2H),3.88–3.69(m,2H),3.59–3.69(m,1H),3.49(dd,J＝10.9,5.0Hz,1H),3.35–3.37(m,1H),2.31(s,4H),2.05(s,1H),1.04(d,J＝6.4Hz,3H). Using Compound 1a as a raw material, the preparation method is referred to as Compound P-1 to give Compound P-8. MS m/z (ESI): 426 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ8.46 (d, J = 4.7Hz, 1H), 8.08 (d, J = 9.1Hz, 1H), 7.95 (d, J = 8.1Hz, 1H), 7.57 ( m,1H), 7.39–7.50 (m, 4H), 7.30–7.37 (m, 3H), 7.11 (d, J=4.8 Hz, 1H), 4.25–4.50 (m, 2H), 3.88–3.69 (m, 2H), 3.59–3.69 (m, 1H), 3.49 (dd, J = 10.9, 5.0 Hz, 1H), 3.35–3.37 (m, 1H), 2.31 (s, 4H), 2.05 (s, 1H), 1.04 (d, J = 6.4 Hz, 3H).
实施例9：(2S，3S)-2-(3-氯-4-((E)-2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄氨基)-3-羟基丁酸(P-9)的制备Example 9: (2S,3S)-2-(3-Chloro-4-((E)-2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzylamino)-3 -Preparation of hydroxybutyric acid (P-9)
Figure PCTCN2018122818-appb-000058
Figure PCTCN2018122818-appb-000058
以化合物1a为原料，制备方法参考化合物P-1，得化合物P-9。MS m/z(ESI):437[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.46(d,J＝4.8Hz,1H),8.11(d,J＝5.7Hz,1H),8.07(s,1H),7.99(d,J＝8.1Hz,1H),7.60(d,J＝15.5Hz,1H),7.52(s,1H),7.39–7.45(m,3H),7.32–7.38(m,3H),7.12(d,J＝4.8Hz,1H),3.93(d,J＝14.0Hz,1H),3.89–3.79(m,1H),3.70(d,J＝14.3Hz,1H),2.92(d,J＝4.7Hz,3H),1.11(d,J＝6.3Hz,3H). Starting from the compound 1a, the preparation method is referred to the compound P-1 to obtain the compound P-9. MS m/z (ESI): 437 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ8.46 (d, J = 4.8Hz, 1H), 8.11 (d, J = 5.7Hz, 1H), 8.07 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.60 (d, J = 15.5 Hz, 1H), 7.52 (s, 1H), 7.39 - 7.45 (m, 3H), 7.32 - 7.38 (m, 3H), 7.12 (d, J = 4.8 Hz) , 1H), 3.93 (d, J = 14.0 Hz, 1H), 3.89 - 3.79 (m, 1H), 3.70 (d, J = 14.3 Hz, 1H), 2.92 (d, J = 4.7 Hz, 3H), 1.11 (d, J = 6.3 Hz, 3H).
实施例10(E)-1-(3-氯-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄基)哌啶-4-醇(P-10)的制备Example 10(E)-1-(3-chloro-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzyl)piperidin-4-ol (P- Preparation of 10)
Figure PCTCN2018122818-appb-000059
Figure PCTCN2018122818-appb-000059
以化合物1a为原料，制备方法参考化合物P-1，得化合物P-10。MS m/z(ESI):419.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝4.8Hz,1H),8.19(s,1H),8.12(d,J＝15.5Hz,1H),7.99(d,J＝8.1Hz,1H),7.61(d,J＝15.5Hz,1H),7.35–7.45(m,6H),7.31(d,J＝8.1Hz,1H),7.14(d,J＝4.8Hz,1H),3.48(s,3H),2.67(dd,J＝6.6,4.7Hz,2H),2.34(s,3H),2.08(dd,J＝11.9,7.9Hz,2H),1.71(d,J＝9.4Hz,2H),1.40(td,J＝12.7,3.6Hz,2H). The compound 1a is used as a raw material, and the preparation method is referred to the compound P-1 to obtain the compound P-10. MS m/z (ESI): 419.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ8.49 (d, J = 4.8Hz, 1H), 8.19 (s, 1H), 8.12 (d, J = 15.5Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 15.5 Hz, 1H), 7.35 - 7.45 (m, 6H), 7.31 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 4.8 Hz, 1H), 3.48(s,3H), 2.67(dd,J=6.6,4.7Hz,2H), 2.34(s,3H),2.08(dd,J=11.9,7.9Hz,2H),1.71(d,J=9.4Hz , 2H), 1.40 (td, J = 12.7, 3.6 Hz, 2H).
实施例11(S,E)-1-(3-氯-4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)苄基)哌啶-2-羧酸(P-11)的制备Example 11 (S,E)-1-(3-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)benzyl)piperidine-2-carboxylic acid Preparation of (P-11)
Figure PCTCN2018122818-appb-000060
Figure PCTCN2018122818-appb-000060
步骤1：将肉桂醛(2.64g，20.0mol)和2-氰基乙酰胺(1.85g，22.0mmol)溶解于40mL二甲亚砜中，一次性加入叔丁醇钾(8.96g，80.0mmol)，室温搅拌反应16小时。向反应液中加入400mL水，4M盐酸(30mL)。析出的固体过滤，滤饼水洗(10mL×3)，真空干燥得到2-氧代-4-苯基-1,2-二氢吡啶-3-腈(1.65g，淡棕色固体)，产率：42.1％。MS m/z(ESI):197.0[M+H] +。 Step 1: Dissolve cinnamaldehyde (2.64 g, 20.0 mol) and 2-cyanoacetamide (1.85 g, 22.0 mmol) in 40 mL of dimethyl sulfoxide and add potassium tert-butoxide (8.96 g, 80.0 mmol) in one portion. The reaction was stirred at room temperature for 16 hours. 400 mL of water and 4 M hydrochloric acid (30 mL) were added to the reaction mixture. The precipitated solid was filtered, and the filter cake was washed with water (10mL×3) and dried in vacuo to give 2-oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile (1.65 g, light brown solid). 42.1%. MS m/z (ESI): 197.0 [M+H] + .
步骤2：2-氧代-4-苯基-1,2-二氢吡啶-3-腈(1.65g，8.42mmol)溶解于20mL三氯氧磷中，回流搅拌反应3小时。反应液减压浓缩，加入100mL饱和碳酸氢钠溶液，用乙酸乙酯萃取(100mL×2)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以0～20％乙酸乙酯在石油醚中纯化所得残余物，得到2-氯-4-苯基烟腈(750mg，淡棕色固体)，产率：41.6％。MS m/z(ESI):215.0[M+H] +。 Step 2: 2-Oxo-4-phenyl-1,2-dihydropyridine-3-carbonitrile (1.65 g, 8.42 mmol) was dissolved in 20 mL of EtOAc. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The obtained residue was purified by ethyl acetate (EtOAc) elute MS m/z (ESI): 215.0 [M+H] + .
步骤3：将2-氯-4-苯基烟腈(700mg，3.27mmol)溶解于25mL1,4-二氧六环和4mL水中，加入乙烯基氟硼酸钾(1.31g，9.81mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(131mg，0.16mmol)，碳酸钠(1.04g，9.81mmol)，在氩气保护下85℃搅拌反应16小时。反应液减压浓缩，加入100mL乙酸乙酯，过滤，滤液减压浓缩，用硅胶柱色谱法硅胶柱色谱法以0～15％乙酸乙酯在石油醚中纯化所得残余物，得到4-苯基-2-乙烯基烟腈(650mg，灰白色固体)，产率：96.5％。MS m/z(ESI):207.0[M+H] +。 Step 3: 2-Chloro-4-phenylnicotinonitrile (700 mg, 3.27 mmol) was dissolved in 25 mL of 1,4-dioxane and 4 mL water, and potassium fluoroborate (1.31 g, 9.81 mmol) was added, [1 , 1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (131 mg, 0.16 mmol), sodium carbonate (1.04 g, 9.81 mmol), stirred at 85 ° C under argon atmosphere. The reaction was continued for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated, evaporated, evaporated, evaporated. -2-vinyl nicotinonitrile (650 mg, off-white solid), yield: 96.5%. MS m/z (ESI): 207.0 [M+H] + .
步骤4：往20mL微波管里加入：4-苯基-2-乙烯基烟腈(150mg，0.73mmol)，4-溴-3-氯苯甲醛(241mg，1.10mmol)，醋酸钯(16mg，0.07mmol)，三(邻甲基苯)磷(44mg，0.15mmol)，2mL三乙胺和6mL二甲基乙酰胺。氩气吹2分钟，盖上微波盖，在150℃微波反应30分钟。加入30mL乙酸乙酯，过滤，滤液减压浓缩，用硅胶柱色谱法硅胶柱色谱法以50％～90％二氯甲烷在石油醚中纯化所得残余物，得到(E)-2-(2-氯-4-甲酰苯乙烯基)-4-苯基烟腈(125mg，黄色固体)，产率：49.9％。MS m/z(ESI):345.0[M+H] +。 Step 4: Add to the 20 mL microwave tube: 4-phenyl-2-vinyl nicotinonitrile (150 mg, 0.73 mmol), 4-bromo-3-chlorobenzaldehyde (241 mg, 1.10 mmol), palladium acetate (16 mg, 0.07) Methyl), tris(o-methylphenyl)phosphorus (44 mg, 0.15 mmol), 2 mL of triethylamine and 6 mL of dimethylacetamide. The mixture was blown with argon for 2 minutes, covered with a microwave cover, and microwave-reacted at 150 ° C for 30 minutes. 30 mL of ethyl acetate was added, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography eluting with 50% to 90% dichloromethane in petroleum ether to afford (E)-2-(2- Chloro-4-formylstyryl-4-phenylnicotinonitrile (125 mg, yellow solid), yield: 49.9%. MS m/z (ESI): 345.0 [M+H] + .
步骤5：将(E)-2-(2-氯-4-甲酰苯乙烯基)-4-苯基烟腈(50mg，0.14mmol)和(S)-哌啶-2-羧酸(36mg，0.28mol)溶解于8mL甲醇中，加入氰基硼氢化钠(18mg，0.28mmol)，回流搅拌反应4小时。减压浓缩，用制备HPLC色谱法得到标题产物(S,E)-1-(3-氯-4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)苄基)哌啶-2-羧酸(化合物P-11)(26mg，白色固体)，产率：39.1％。MS m/z(ESI):458.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.91(d,1H),8.35(d,1H),7.92(d,1H),7.72-7.66(m,2H),7.62-7.58(m,5H),7.53(s,1H),7.41(d,1H),3.84(d,1H),3.50(d,1H),3.16-3.13(m,1H),2.86-2.83(m,1H),2.22-2.19(m,1H),1.86-1.71(m,2H),1.55-1.37(m,4H). Step 5: (E)-2-(2-Chloro-4-formylstyryl)-4-phenylnicotinonitrile (50 mg, 0.14 mmol) and (S)-piperidine-2-carboxylic acid (36 mg 0.28 mol) was dissolved in 8 mL of methanol, sodium cyanoborohydride (18 mg, 0.28 mmol) was added, and the reaction was stirred under reflux for 4 hours. The title product (S, E)-1-(3-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)benzylidene Base piperidine-2-carboxylic acid (Compound P-11) (26 mg, white solid), yield: 39.1%. MS m/z (ESI): 458.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ8.91 (d, 1H), 8.35 (d, 1H), 7.92 (d, 1H), 7.72-7.66 (m, 2H), 7.62-7.58 (m, 5H) , 7.53 (s, 1H), 7.41 (d, 1H), 3.84 (d, 1H), 3.50 (d, 1H), 3.16-3.13 (m, 1H), 2.86-2.83 (m, 1H), 2.22-2.19 (m, 1H), 1.86-1.71 (m, 2H), 1.55-1.37 (m, 4H).
实施例12(S，E)-1-(4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄基)哌啶-2-羧酸 (P-12)的制备Example 12 (S,E)-1-(4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzyl)piperidine-2-carboxylic acid (P-12 Preparation
Figure PCTCN2018122818-appb-000061
Figure PCTCN2018122818-appb-000061
以化合物3a为原料，制备方法参考化合物P-1，得化合物P-12。MS m/z(ESI):413.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.46(d,J＝4.8Hz,1H),7.79(d,J＝15.6Hz,1H),7.72(d,J＝8.0Hz,2H),7.58(d,J＝15.6Hz,1H),7.36-7.54(m,7H),7.11(d,J＝4.8Hz,1H),4.03(d,J＝13.2Hz,1H),3.69(d,J＝13.2Hz,1H),3.23-3.26(m,1H),2.96-2.99(m,1H),2.38-2.44(m,1H),2.33(s,3H),1.85-1.92(m,1H),1.68-1.76(m,1H),1.48-1.60(m,3H),1.35-1.43(m,1H). Using the compound 3a as a raw material, the preparation method is referred to the compound P-1 to obtain the compound P-12. MS m/z (ESI): 413.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ8.46 (d, J = 4.8Hz, 1H), 7.79 (d, J = 15.6Hz, 1H), 7.72 (d, J = 8.0Hz, 2H), 7.58 ( d, J = 15.6 Hz, 1H), 7.36-7.54 (m, 7H), 7.11 (d, J = 4.8 Hz, 1H), 4.03 (d, J = 13.2 Hz, 1H), 3.69 (d, J = 13.2) Hz,1H),3.23-3.26(m,1H),2.96-2.99(m,1H), 2.38-2.44(m,1H),2.33(s,3H),1.85-1.92(m,1H),1.68- 1.76 (m, 1H), 1.48-1.60 (m, 3H), 1.35-1.43 (m, 1H).
实施例13(S,E)-1-(3-氯-4-(2-(4-(2,3-二氢苯并[b][1,4]二氧六环-6-基)-3-甲基吡啶-2-基)乙烯基)苄基)哌啶-2-羧酸(P-13)的制备Example 13(S,E)-1-(3-chloro-4-(2-(4-(2,3-dihydrobenzo[b][1,4]dioxol-6-yl)) Preparation of -3-methylpyridin-2-yl)vinyl)benzyl)piperidine-2-carboxylic acid (P-13)
Figure PCTCN2018122818-appb-000062
Figure PCTCN2018122818-appb-000062
步骤1：将4-溴-2-氯-3-甲基吡啶(300mg,1.46mmol)溶解于15mL1,4-二氧六环和3mL水中，加入苯并-1,4-二氧六环-6-硼酸(290mg,1.61mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(131mg,0.16mmol)，碳酸钠(387mg,3.65mmol)，在氩气保护下85℃搅拌反应4小时。反应液过滤，滤液减压浓缩，用硅胶柱色谱法硅胶柱色谱法以10～30％乙酸乙酯在石油醚中纯化所得残余物，得到2-氯-4-(2，3-二氢苯并[b][1,4]二氧六环-6-基)-3-甲基吡啶(350mg，白色固体)，产率：92.1％。MS m/z(ESI):262.1[M+H] +。 Step 1: 4-Bromo-2-chloro-3-methylpyridine (300 mg, 1.46 mmol) was dissolved in 15 mL of 1,4-dioxane and 3 mL of water, and benzo-1,4-dioxane was added. 6-boric acid (290 mg, 1.61 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (131 mg, 0.16 mmol), sodium carbonate (387 mg, 3.65) Methyl), the reaction was stirred at 85 ° C for 4 hours under argon gas protection. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjj And [b][1,4]dioxol-6-yl)-3-methylpyridine (350 mg, white solid), yield: 92.1%. MS m/z (ESI): 2621. [M+H] + .
步骤2：将2-氯-4-(2，3-二氢苯并[b][1,4]二氧六环-6-基)-3-甲基吡啶(200mg,0.77mmol)溶解于15mL1,4-二氧六环和3mL水中，加入乙烯基氟硼酸钾(310mg,2.31mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(32mg，0.04mmol)，碳酸钠(245mg,2.31mmol)，在氩气保护下85℃搅拌反应16小时。反应液过滤，滤液减压浓缩，用硅胶柱色谱法硅胶柱色谱法以0～20％乙酸乙酯在石油醚中纯化所得残余物，得到4-(2，3-二氢苯并[b][1,4]二氧六环-6-基)-3-甲基-2-乙烯基吡啶(142mg，无色液体)，产率：73.2％。MS m/z(ESI):254.2[M+H] +。 Step 2: Dissolve 2-chloro-4-(2,3-dihydrobenzo[b][1,4]dioxol-6-yl)-3-methylpyridine (200 mg, 0.77 mmol) in 15 mL of 1,4-dioxane and 3 mL of water, potassium vinyl fluoroborate (310 mg, 2.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane The compound (32 mg, 0.04 mmol), sodium carbonate (245 mg, 2.31 mmol) was stirred under argon atmosphere for 15 hours. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjj [1,4] Dioxocyclo-6-yl)-3-methyl-2-vinylpyridine (142 mg, colorless liquid), yield: 73.2%. MS m/z (ESI): 254.2 [M+H] + .
步骤3：往20mL微波管里加入：4-(2，3-二氢苯并[b][1,4]二氧六环-6-基)-3-甲基-2-乙烯基吡啶(115mg，0.45mmol)，4-溴-3-氯苯甲醛(148mg，0.68mmol)，醋酸钯(10mg，0.05mmol)，三(邻甲基苯)磷(27mg，0.09mmol)，1mL三乙胺和5mL二甲基乙酰胺。氩气吹1分钟，盖上微波盖，在140℃微波反应30分钟。加入25mL乙酸乙酯，过滤，滤液减压浓 缩，用硅胶柱色谱法硅胶柱色谱法以0％～30％乙酸乙酯在石油醚中纯化所得残余物，得到(E)-3-氯-4-(2-(4-(2,3-二氢苯并[b][1,4]二氧六环-6-基)-3-甲基吡啶-2-基)乙烯基)苯甲醛(140mg，黄色固体)，产率：78.8％。MS m/z(ESI):392.1[M+H] +。 Step 3: Add to the 20 mL microwave tube: 4-(2,3-dihydrobenzo[b][1,4]dioxol-6-yl)-3-methyl-2-vinylpyridine ( 115 mg, 0.45 mmol), 4-bromo-3-chlorobenzaldehyde (148 mg, 0.68 mmol), palladium acetate (10 mg, 0.05 mmol), tris(o-methylphenyl)phosphine (27 mg, 0.09 mmol), 1 mL triethylamine And 5 mL of dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwave-reacted at 140 ° C for 30 minutes. 25 mL of ethyl acetate was added, and the filtrate was concentrated under reduced pressure. The residue obtained was purified from silica gel column chromatography eluting -(2-(4-(2,3-dihydrobenzo[b][1,4]dioxol-6-yl)-3-methylpyridin-2-yl)vinyl)benzaldehyde ( 140 mg, yellow solid), Yield: 78.8%. MS m/z (ESI): 3921. [M+H] + .
步骤4：(E)-3-氯-4-(2-(4-(2,3-二氢苯并[b][1,4]二氧六环-6-基)-3-甲基吡啶-2-基)乙烯基)苯甲醛(50mg，0.13mmol)和(S)-哌啶-2-羧酸(34mg，0.26mol)溶解于8mL甲醇中，加入氰基硼氢化钠(16mg，0.26mmol)，回流搅拌反应4小时。减压浓缩，用制备HPLC色谱法得到标题产物(S,E)-1-(3-氯-4-(2-(4-(2,3-二氢苯并[b][1,4]二氧六环-6-基)-3-甲基吡啶-2-基)乙烯基)苄基)哌啶-2-羧酸(化合物P-13)(18mg，白色固体)，产率：27.9％。MS m/z(ESI):505.1[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.45(d,1H),8.09(d,1H),7.99(d,1H),7.60(d,1H),7.48(s,1H),7.35(d,1H),7.11(d,1H),6.96(d,1H),6.87(d,1H),6.82(dd,1H),4.29(s,4H),3.88(d,1H),3.54(d,1H),3.19-3.15(m,1H),2.90-2.84(m,1H),2.35(s,3H),2.30-2.22(m,1H),1.87-1.68(m,2H),1.57-1.33(m,4H). Step 4: (E)-3-Chloro-4-(2-(4-(2,3-dihydrobenzo[b][1,4]dioxol-6-yl)-3-methyl Pyridin-2-yl)vinyl)benzaldehyde (50 mg, 0.13 mmol) and (S)-piperidine-2-carboxylic acid (34 mg, 0.26 mol) were dissolved in 8 mL of methanol and sodium cyanoborohydride (16 mg, 0.26 mmol), and the reaction was stirred under reflux for 4 hours. The title product (S, E)-1-(3-chloro-4-(2-(4-(2,3-dihydrobenzo[b][1,4]]] Dioxol-6-yl)-3-methylpyridin-2-yl)vinyl)benzyl)piperidine-2-carboxylic acid (Compound P-13) (18 mg, white solid), yield: 27.9 %. MS m/z (ESI): 505.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.45 (d, 1H), 8.09 (d, 1H), 7.99 (d, 1H), 7.60 (d, 1H), 7.48 (s, 1H), 7.35 (d, 1H), 7.11 (d, 1H), 6.96 (d, 1H), 6.87 (d, 1H), 6.82 (dd, 1H), 4.29 (s, 4H), 3.88 (d, 1H), 3.54 (d, 1H) ), 3.19-3.15 (m, 1H), 2.90-2.84 (m, 1H), 2.35 (s, 3H), 2.30-2.22 (m, 1H), 1.87-1.68 (m, 2H), 1.57-1.33 (m , 4H).
实施例14(S,E)-1-(4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)-3-(三氟甲基)苄基)哌啶-2-羧酸(P-14)的制备Example 14 (S,E)-1-(4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)-3-(trifluoromethyl)benzyl)piperidine Preparation of 2-carboxylic acid (P-14)
Figure PCTCN2018122818-appb-000063
Figure PCTCN2018122818-appb-000063
步骤1：往20mL微波管里加入：3-甲基-4-苯基-2-乙烯基吡啶(100mg，0.51mmol)，4-溴-3-三氟甲基苯甲醛(192mg，0.76mmol)，醋酸钯(11mg，0.05mmol)，三(邻甲基苯)磷(30mg，0.10mmol)，1mL三乙胺和5mL二甲基乙酰胺。氩气吹1分钟，盖上微波盖，在150℃微波反应30分钟。加入25mL乙酸乙酯，过滤，滤液减压浓缩，用硅胶柱色谱法硅胶柱色谱法以0％～20％乙酸乙酯在石油醚中纯化所得残余物，得到(E)-4-2-(3-甲基-4-苯基吡啶-2-基)乙烯基)-3-(三氟甲基)苯甲醛(78mg，黄色固体)，产率：41.4％。MS m/z(ESI):368.1[M+H] +。 Step 1: To a 20 mL microwave tube was added: 3-methyl-4-phenyl-2-vinylpyridine (100 mg, 0.51 mmol), 4-bromo-3-trifluoromethylbenzaldehyde (192 mg, 0.76 mmol) Palladium acetate (11 mg, 0.05 mmol), tris(o-methylphenyl)phosphorus (30 mg, 0.10 mmol), 1 mL of triethylamine and 5 mL of dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwave-reacted at 150 ° C for 30 minutes. 25 mL of ethyl acetate was added, and the filtrate was concentrated under reduced pressure. The obtained residue was purified from silica gel column chromatography eluting 3-Methyl-4-phenylpyridin-2-yl)vinyl)-3-(trifluoromethyl)benzaldehyde (78 mg, yellow solid), yield: 41.4%. MS m/z (ESI): 368.1 [M+H] + .
步骤2：(E)-4-2-(3-甲基-4-苯基吡啶-2-基)乙烯基)-3-(三氟甲基)苯甲醛(37mg，0.10mmol)和(S)-哌啶-2-羧酸(26mg，0.20mol)溶解于6mL甲醇中，加入氰基硼氢化钠(13mg，0.20mmol)，回流搅拌反应4小时。减压浓缩，用制备HPLC色谱法得到标题产物(S,E)-1-(4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)-3-(三氟甲基)苄基)哌啶-2-羧酸(化合物P-14)(18mg，白色固体)，产率：37.1％。MS m/z(ESI):481.2[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.51(d,1H),8.15-8.06(m,2H),7.74(s,1H),7.68-7.62(m,2H),7.53-7.43(m,3H),7.39-7.36(m,2H),7.16(d,1H),3.95(d,1H),3.62(d,1H),3.25-3.18(m,1H),2.91-2.84(m,1H),2.35(s,3H),2.31-2.23(m,1H),1.88-1.68(m,2H),1.56-1.34(m,4H). Step 2: (E)-4-2-(3-Methyl-4-phenylpyridin-2-yl)vinyl)-3-(trifluoromethyl)benzaldehyde (37 mg, 0.10 mmol) and (S) The piperidine-2-carboxylic acid (26 mg, 0.20 mol) was dissolved in 6 mL of methanol, sodium cyanoborohydride (13 mg, 0.20 mmol) was added, and the reaction was stirred under reflux for 4 hours. The title product (S, E)-1-(4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)-3-(3) was obtained. Fluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound P-14) (18 mg, white solid). MS m/z (ESI): 481.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.51 (d, 1H), 8.15-8.06 (m, 2H), 7.74 (s, 1H), 7.68-7.62 (m, 2H), 7.53-7.43 (m, 3H) ), 7.39-7.36 (m, 2H), 7.16 (d, 1H), 3.95 (d, 1H), 3.62 (d, 1H), 3.25-3.18 (m, 1H), 2.91-2.84 (m, 1H), 2.35 (s, 3H), 2.31-2.23 (m, 1H), 1.88-1.68 (m, 2H), 1.56-1.34 (m, 4H).
实施例15(S，E)-1-(3-甲氧基-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄基)哌啶-2-羧酸(P-15)的制备Example 15 (S,E)-1-(3-methoxy-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzyl)piperidin-2- Preparation of carboxylic acid (P-15)
Figure PCTCN2018122818-appb-000064
Figure PCTCN2018122818-appb-000064
以化合物6a为原料，制备方法参考化合物P-1，得化合物P-15。MS m/z(ESI):443.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝4.8Hz,1H),8.07(d,J＝16.0Hz,1H),7.75(d,J＝8.0Hz,1H),7.40-7.58(m,4H),7.34-7.38(m,2H),7.08(d,J＝4.8Hz,1H),7.05(s,1H),6.98(d,J＝8.0Hz,1H),3.93(d,J＝14.4Hz,1H),3.87(s,3H),3.61(d,J＝14.4Hz,1H),3.12(dd,J＝7.6,4.0Hz,1H),2.89-3.96(m,1H),2.25-2.34(m,4H),1.69-1.87(m,2H),1.32-1.56(m,4H). The compound 6a is used as a raw material, and the preparation method is referred to the compound P-1 to obtain the compound P-15. MS m/z (ESI): 443.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ8.44 (d, J = 4.8Hz, 1H), 8.07 (d, J = 16.0Hz, 1H), 7.75 (d, J = 8.0Hz, 1H), 7.40- 7.58(m,4H),7.34-7.38(m,2H),7.08(d,J=4.8Hz,1H),7.05(s,1H),6.98(d,J=8.0Hz,1H),3.93(d , J = 14.4 Hz, 1H), 3.87 (s, 3H), 3.61 (d, J = 14.4 Hz, 1H), 3.12 (dd, J = 7.6, 4.0 Hz, 1H), 2.89-3.96 (m, 1H) , 2.25-2.34 (m, 4H), 1.69-1.87 (m, 2H), 1.32-1.56 (m, 4H).
实施例16(S,E)-1-(5-氯-2-甲氧基-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄基)哌啶-2-羧酸(P-16)的制备Example 16(S,E)-1-(5-Chloro-2-methoxy-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzyl)piperidin Preparation of pyridine-2-carboxylic acid (P-16)
Figure PCTCN2018122818-appb-000065
Figure PCTCN2018122818-appb-000065
步骤1：往20mL微波管里加入：3-甲基-4-苯基-2-乙烯基吡啶(100mg，0.51mmol)，4-溴-5-氯-2-甲氧基苯甲醛(165mg，0.66mmol)，醋酸钯(11mg，0.05mmol)，三(邻甲基苯)磷(30mg，0.10mmol)，1mL三乙胺和5mL二甲基乙酰胺。氩气吹1分钟，盖上微波盖，在150℃微波反应45分钟。加入25mL乙酸乙酯，过滤，滤液减压浓缩，用硅胶柱色谱法硅胶柱色谱法以0％～25％乙酸乙酯在石油醚中纯化所得残余物，得到(E)-5-氯-2-甲氧基-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苯甲醛(9mg，黄色固体)，产率：48.3％。MS m/z(ESI):364.1[M+H] +。 Step 1: To a 20 mL microwave tube was added: 3-methyl-4-phenyl-2-vinylpyridine (100 mg, 0.51 mmol), 4-bromo-5-chloro-2-methoxybenzaldehyde (165 mg, 0.66 mmol), palladium acetate (11 mg, 0.05 mmol), tris(o-methylphenyl)phosphorus (30 mg, 0.10 mmol), 1 mL triethylamine and 5 mL dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwave-reacted at 150 ° C for 45 minutes. 25 mL of ethyl acetate was added, and the filtrate was concentrated under reduced pressure. The obtained residue was purified from silica gel column chromatography eluting Methoxy-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzaldehyde (9 mg, yellow solid), yield: 48.3%. MS m/z (ESI): 364.1 [M+H] + .
步骤2：(E)-5-氯-2-甲氧基-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苯甲醛(50mg，0.14mmol)和(S)-哌啶-2-羧酸(36mg，0.28mol)溶解于6mL甲醇中，加入氰基硼氢化钠(18mg，0.28mmol)，回流搅拌反应4小时。减压浓缩，用制备HPLC色谱法得到标题产物(S,E)-1-(5-氯-2-甲氧基-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄基)哌啶-2-羧酸(化合物P-16)(32mg，白色固体)，产率：48.8％。MS m/z(ESI):477.1[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.50(d,1H),8.10(d,1H),7.66(d,1H),7.56-7.42(m,5H),7.41-7.34(m,2H),7.15(d,1H),3.89(s,3H),3.73(d,1H),3.63(d,1H),3.19(dd,1H),2.93-2.86(m,1H),2.36(s,3H),2.30-2.24(m,1H),1.85-1.71(m,2H),1.54-1.34(m,4H). Step 2: (E)-5-Chloro-2-methoxy-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzaldehyde (50 mg, 0.14 mmol) (S)-Piperidine-2-carboxylic acid (36 mg, 0.28 mol) was dissolved in 6 mL of methanol, sodium cyanoborohydride (18 mg, 0.28 mmol) was added, and the reaction was stirred under reflux for 4 hours. The title product (S, E)-1-(5-chloro-2-methoxy-4-(2-(3-methyl-4-phenylpyridine-2-) Vinyl)benzyl)piperidine-2-carboxylic acid (Compound P-16) (32 mg, white solid), yield: 48.8%. MS m/z (ESI): 477.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.50 (d, 1H), 8.10 (d, 1H), 7.66 (d, 1H), 7.56-7.42 (m, 5H), 7.41-7.34 (m, 2H), 7.15(d,1H), 3.89(s,3H), 3.73(d,1H), 3.63(d,1H), 3.19(dd,1H),2.93-2.86(m,1H), 2.36(s,3H) , 2.30-2.24 (m, 1H), 1.85-1.71 (m, 2H), 1.54-1.34 (m, 4H).
实施例17(S，E)-1-(3-氟-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄基)哌啶-2-羧酸(P-17)的制备Example 17 (S,E)-1-(3-Fluoro-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzyl)piperidine-2-carboxylic acid Preparation of (P-17)
Figure PCTCN2018122818-appb-000066
Figure PCTCN2018122818-appb-000066
以化合物8a为原料，制备方法参考化合物P-1，得化合物P-17。MS m/z(ESI): 431.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝4.8Hz,1H),7.83-7.96(m,2H),7.63(d,J＝15.6Hz,1H),7.39-7.49(m,3H),7.33-7.37(m,2H),7.21-7.25(m,2H),7.11(d,J＝4.8Hz,1H),3.98(d,J＝13.6Hz,1H),3.67(d,J＝14.0Hz,1H),3.29-3.35(m,1H),2.92-2.99(m,1H),2.33-2.43(m,1H),2.29(s,3H),1.66-1.91(m,2H),1.32-1.56(m,4H). Starting from the compound 8a, the preparation method is referred to the compound P-1 to obtain the compound P-17. MS m/z (ESI): 4321. [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ8.44 (d, J = 4.8Hz, 1H), 7.83-7.96 (m, 2H), 7.63 (d, J = 15.6Hz, 1H), 7.39-7.49 (m , 3H), 7.33 - 7.37 (m, 2H), 7.21 - 7.25 (m, 2H), 7.11 (d, J = 4.8 Hz, 1H), 3.98 (d, J = 13.6 Hz, 1H), 3.67 (d, J=14.0 Hz, 1H), 3.29-3.35 (m, 1H), 2.92-2.99 (m, 1H), 2.33-2.43 (m, 1H), 2.29 (s, 3H), 1.66-1.91 (m, 2H) , 1.32-1.56 (m, 4H).
实施例18：(S，E)-1-(3-氯-4-(2-(2-甲基-[1,1'-联苯]-3-基)乙烯基)苄基)哌啶-2-羧酸(P-18)的制备Example 18: (S,E)-1-(3-chloro-4-(2-(2-methyl-[1,1'-biphenyl]-3-yl)vinyl)benzyl)piperidine Preparation of 2-carboxylic acid (P-18)
Figure PCTCN2018122818-appb-000067
Figure PCTCN2018122818-appb-000067
步骤1：将化合物18-1(1.7g,4.45mmol)溶于二氯甲烷(50ml)中，缓慢加入m-CPBA(3.84g,22.25mmol)，反应液在室温下搅拌，LC-MS跟踪至反应结束。用饱和硫代硫酸钠溶液淬灭反应，分液，水相用二氯甲烷萃取，合并有机相，减压浓缩，经柱层析纯化得白色固体化合物18-2(1.4g)，MS m/z(ESI):413.0[M+H] +。 Step 1: Compound 18-1 (1.7 g, 4.45 mmol) was dissolved in dichloromethane <RTI ID=0.0>(50</RTI><RTIgt; The reaction is over. The reaction was quenched with saturated aqueous sodium thiosulfate. EtOAc (EtOAc m. z (ESI): 413.0 [M+H] + .
步骤2：将化合物18-2(1.4g,3.34mmol)溶于四氢呋喃(20ml)中，用干冰-丙酮浴冷却至-78℃，慢慢滴加20ml化合物18.1(553mg,2.82mmol)的四氢呋喃溶液，反应体系自然升至室温后，在室温下搅拌过夜，LC-MS跟踪至反应结束。加入饱和氯化铵水溶液淬灭反应，加入100ml水，用乙酸乙酯萃取，有机相减压浓缩，经柱层析纯化得化合物18-3(400mg)，MS m/z(ESI):385.0[M+H] +。 Step 2: Compound 18-2 (1.4 g, 3.34 mmol) was dissolved in tetrahydrofuran (20 ml), cooled to -78 ° C with dry ice-acetone bath, and 20 ml of compound 18.1 (553 mg, 2.82 mmol) in tetrahydrofuran was slowly added dropwise. After the reaction system was naturally warmed to room temperature, it was stirred at room temperature overnight, and LC-MS was followed until the end of the reaction. The reaction was quenched with aq. EtOAc EtOAc (EtOAc) M+H] + .
步骤3：化合物18-3(350mg,0.92mmol)，氰化亚铜(245mg,2.75mmol)，四三苯基磷钯(35mg)，碳酸铯(891mg,2.75mmol)的二氧六环(80ml)溶液，100℃反应过夜，LC-MS跟踪至反应结束。反应液减压浓缩，经柱层析纯化得化合物18-4(110mg)，MS m/z(ESI):330.0[M+H] +。 Step 3: Compound 18-3 (350 mg, 0.92 mmol), cuprous cyanide (245 mg, 2.75 mmol), tetratriphenylphosphine palladium (35 mg), cesium carbonate (891 mg, 2.75 mmol) of dioxane (80 ml) The solution was reacted at 100 ° C overnight, and LC-MS was followed until the end of the reaction. The reaction solution was concentrated under reduced pressure, purified by column chromatography to give compound 18-4 (110mg), MS m / z (ESI): 330.0 [M + H] +.
步骤4：化合物18-4(105mg,0.32mmol)溶于甲苯(20ml)中，将体系置于干冰-丙酮浴中冷却至-78℃，慢慢滴加DIBAL，反应液自然升至室温后，室温反应过夜，LC-MS跟踪至反应结束。反应液用1N盐酸溶液调节PH至中性，用乙酸乙酯萃取，有机相减压浓缩，经柱层析纯化得油状化合物18-5(60mg)，MS m/z(ESI):333.0[M+H] +。 Step 4: Compound 18-4 (105 mg, 0.32 mmol) was dissolved in toluene (20 ml). The system was placed in a dry ice-acetone bath and cooled to -78 ° C. DIBAL was slowly added dropwise, and the reaction was allowed to rise to room temperature. The reaction was allowed to proceed overnight at room temperature and LC-MS was followed until the end of the reaction. The reaction mixture was adjusted to pH with EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHH +H] + .
步骤5：化合物18-5(60mg,0.18mmol)，18.2(47mg,0.36mmol)溶于甲醇(20ml)中，加入两滴冰醋酸，室温搅拌2h，加入氰基硼氢化钠(23mg,0.36mmol)，反应液室温搅拌过夜，LC-MS跟踪至反应结束。反应液减压浓缩，经TLC纯化，得白色固体化合物P-18(10mg)，MS m/z(ESI):446.0[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.88(d,J＝8.0Hz,1H),7.64(d,J＝7.2,1H),7.54(d,J＝16.0Hz,1H),7.44-7.48(m,3H),7.36-7.39(m,1H),7.27-7.35(m,5H),7.17(d,J＝6.8Hz,1H),3.83(d,J＝13.8,1H),3.47d,J＝13.8,1H),3.08-3.11(m,1H),2.83-2.87(m,1H),2.27(s,3H),2.16-2.23(m,1H),1.67-1.83(m,2H),1.33-1.54(m,4H). Step 5: Compound 18-5 (60 mg, 0.18 mmol), 18.2 (47 mg, <RTI ID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; The reaction solution was stirred at room temperature overnight, and LC-MS was followed until the end of the reaction. The reaction mixture was concentrated under reduced pressure and purified by TLC, to give a white solid compound P-18 (10mg), MS m / z (ESI): 446.0 [M + H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.88 (d, J = 8.0Hz, 1H), 7.64 (d, J = 7.2,1H), 7.54 (d, J = 16.0Hz, 1H), 7.44-7.48 ( m, 3H), 7.36-7.39 (m, 1H), 7.27-7.35 (m, 5H), 7.17 (d, J = 6.8 Hz, 1H), 3.83 (d, J = 13.8, 1H), 3.47d, J =13.8,1H),3.08-3.11(m,1H),2.83-2.87(m,1H), 2.27(s,3H),2.16-2.23(m,1H),1.67-1.83(m,2H),1.33 -1.54 (m, 4H).
实施例19(S,E)-1-1-(4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-3-(三氟甲基)苄基)哌啶-2-羧 酸(P-19)的制备Example 19(S,E)-1-1-(4-(2-(3-Cyano-4-phenylpyridin-2-yl)vinyl)-3-(trifluoromethyl)benzyl) Preparation of piperidine-2-carboxylic acid (P-19)
Figure PCTCN2018122818-appb-000068
Figure PCTCN2018122818-appb-000068
步骤1：将2-氯-4-苯基烟腈(3.3g,15.4mmol)溶解于100mL四氢呋喃中，加入乙烯基三氟硼酸钾(2.27g,17mmol)、碳酸钠(4.9g,46.2mmol)、[1,1'‐双(二苯基膦基)二茂铁]二氯化钯(902mg,1.23mmol)和水30mL，在80℃氮气保护下反应20小时。向反应液中加入水100mL，用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和食盐水50mL洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化所得残余物(洗脱剂：乙酸乙酯：石油醚＝1：1)，得到4-苯基-2-乙烯基烟腈(2.8g，黄色固体)，产率：88.3％。MS m/z(ESI):207.1[M+H] +。 Step 1: 2-Chloro-4-phenylnicotinonitrile (3.3 g, 15.4 mmol) was dissolved in 100 mL of tetrahydrofuran, and added potassium trifluoroborate (2.27 g, 17 mmol), sodium carbonate (4.9 g, 46.2 mmol) [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (902 mg, 1.23 mmol) and water 30 mL were reacted under nitrogen at 80 ° C for 20 hours. 100 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (50 mL×3). The residue (eluent: ethyl acetate: petroleum ether = 1:1) gave 4-phenyl-2-vinylnicotinonitrile (2.8 g, yellow solid). MS m/z (ESI): 207.1 [M+H] + .
步骤2：将4-苯基-2-乙烯基烟腈(85mg,0.41mmol)和4-溴-3-(三氟甲基)苯甲醛(115mg,0.45mmol)溶解于N,N-二甲基乙酰胺3mL和三乙胺1mL中,加入醋酸钯(9mg,0.041mmol)和三(邻甲基苯基)膦(25mg，0.082mmol)，反应在氮气保护下160℃微波反应30分钟。减压浓缩，用硅胶柱色谱法以展开剂体系(洗脱剂：乙酸乙酯：石油醚＝1：1)纯化所得残余物，得到(E)-2-(4-甲酰基-2-(三氟甲基)苯乙烯基)-4-苯基烟腈(25mg，黄色固体)，产率：16.1％。MS m/z(ESI):379.1[M+H] +。 Step 2: Dissolve 4-phenyl-2-vinylnicotinonitrile (85 mg, 0.41 mmol) and 4-bromo-3-(trifluoromethyl)benzaldehyde (115 mg, 0.45 mmol) in N,N-dimethyl To 3 mL of acetamide and 1 mL of triethylamine, palladium acetate (9 mg, 0.041 mmol) and tris(o-methylphenyl)phosphine (25 mg, 0.082 mmol) were added, and the reaction was subjected to microwave reaction at 160 ° C for 30 minutes under nitrogen atmosphere. The organic layer was concentrated under reduced pressure. EtOAcjjjjjjj Trifluoromethyl)styryl)-4-phenylnicotinonitrile (25 mg, yellow solid), yield: 16.1%. MS m/z (ESI): 379.1 [M+H] + .
步骤3：将(E)-2-(4-甲酰基-2-(三氟甲基)苯乙烯基)-4-苯基烟腈(20mg，0.053mmol)和(S)-哌啶-2-羧酸(14mg，0.11mmol)溶解于甲醇5mL中，加入氰基硼氢化钠(7mg,0.11mmol)，搅拌反应20小时。减压浓缩，用制备色谱法得到标题产物(S,E)-1-1-(4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-3-(三氟甲基)苄基)哌啶-2-羧酸(化合物P-19)(11mg，白色固体)，产率：42.3％。MS m/z(ESI):492.2[M+H] +。 Step 3: (E)-2-(4-Formyl-2-(trifluoromethyl)styryl)-4-phenylnicotinonitrile (20 mg, 0.053 mmol) and (S)-piperidine-2 The carboxylic acid (14 mg, 0.11 mmol) was dissolved in 5 mL of methanol, sodium cyanoborohydride (7 mg, 0.11 mmol) was added, and the reaction was stirred for 20 hours. The title product (S, E)-1-1-(4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)-3-( Trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound P-19) (11 mg, white solid). MS m / z (ESI): 492.2 [M + H] +.
实施例20(S,E)-1-(4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-甲氧基-5-(三氟甲基)苄基)哌啶-2-羧酸(P-20)的制备Example 20(S,E)-1-(4-(2-(3-Cyano-4-phenylpyridin-2-yl)vinyl)-2-methoxy-5-(trifluoromethyl) Preparation of benzyl)piperidine-2-carboxylic acid (P-20)
Figure PCTCN2018122818-appb-000069
Figure PCTCN2018122818-appb-000069
步骤1：将2-溴-4-甲氧基-1-(三氟甲基)苯(900mg，3.54mmol)和二氯甲基甲醚(1.21g，10.63mmol)溶解于二氯甲烷20mL中，在0℃下加入四氯化钛(2g，10.63mmol)，室温搅拌2小时。将反应液倒入冰水中(100mL),用二氯甲烷萃取(50mL×2)，合并有机相，用饱和食盐水洗涤(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化所得残余物(洗脱剂：乙酸乙酯：石油醚＝2：1)纯化所得残余物，得到4-溴-2-甲氧基-5-(三氟甲基)苯甲醛(240mg，黄色固体)，产率：24％。MS m/z(ESI):282.9[M+H] +。 Step 1: 2-Bromo-4-methoxy-1-(trifluoromethyl)benzene (900 mg, 3.54 mmol) and dichloromethyl methyl ether (1.21 g, 10.63 mmol) were dissolved in dichloromethane (20 mL) Titanium tetrachloride (2 g, 10.63 mmol) was added at 0 ° C and stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (100 mL), EtOAc (EtOAc) The obtained residue was purified by column chromatography (yield: ethyl acetate: petroleum ether = 2:1) to afford 4-bromo-2-methoxy-5-(trifluoromethyl)benzaldehyde ( 240 mg, yellow solid), Yield: 24%. MS m/z (ESI): 282.9 [M+H] + .
步骤2：将4-溴-2-甲氧基-5-(三氟甲基)苯甲醛(141mg,0.5mmol)和4-苯基-2-乙烯基烟腈(103mg,0.5mmol)溶解于3mL N,N-二甲基乙酰胺和1mL三乙胺中,加入醋酸钯(11mg,0.05mmol)和三(邻甲基苯基)膦(30mg，0.1mmol)，反应在氮气保护下160℃微波反应30分钟。减压浓缩，用硅胶柱色谱法以展开剂体系(洗脱剂：乙酸乙酯：石油醚＝1：1)纯化所得残余物， 得到(E)-2-(4-甲酰基-5-甲氧基-2-(三氟甲基)苯乙烯基)-4-苯基烟腈(55mg，黄色固体)，产率：27％。MS m/z(ESI):409.1[M+H] +。 Step 2: Dissolve 4-bromo-2-methoxy-5-(trifluoromethyl)benzaldehyde (141 mg, 0.5 mmol) and 4-phenyl-2-vinylnicotinonitrile (103 mg, 0.5 mmol) To 3 mL of N,N-dimethylacetamide and 1 mL of triethylamine, palladium acetate (11 mg, 0.05 mmol) and tris(o-methylphenyl)phosphine (30 mg, 0.1 mmol) were added, and the reaction was carried out under nitrogen atmosphere at 160 ° C. The microwave was reacted for 30 minutes. The residue was purified by silica gel column chromatography eluting elut elut eluting eluting Oxy-2-(trifluoromethyl)styryl)-4-phenylnicotinonitrile (55 mg, yellow solid), yield: 27%. MS m/z (ESI): 409.1 [M+H] + .
步骤3：将(E)-2-(4-甲酰基-5-甲氧基-2-(三氟甲基)苯乙烯基)-4-苯基烟腈(55mg，0.13mmol)和(S)-哌啶-2-羧酸(35mg，0.26mmol)溶解于10mL甲醇中，加入氰基硼氢化钠(17mg,0.26mmol)，搅拌反应20小时。减压浓缩，用制备色谱法得到标题产物(S,E)-1-(4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-甲氧基-5-(三氟甲基)苄基)哌啶-2-羧酸(化合物P-20)(8mg，白色固体)，产率：11.8％。MS m/z(ESI):522.2[M+H] +。 Step 3: (E)-2-(4-Formyl-5-methoxy-2-(trifluoromethyl)styryl)-4-phenylnicotinonitrile (55 mg, 0.13 mmol) and (S) The piperidine-2-carboxylic acid (35 mg, 0.26 mmol) was dissolved in 10 mL of methanol, and sodium cyanoborohydride (17 mg, 0.26 mmol) was added, and the reaction was stirred for 20 hours. The title product (S, E)-1-(4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)-2-methoxy was obtained by preparative chromatography. 5-5-(Trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound P-20) (8 mg, white solid). MS m/z (ESI): 522.2 [M+H] + .
实施例21(R,E)-2-(5-氯-4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-甲氧基苄氨基)-3-羟基丙酸(P-21)的制备Example 21 (R,E)-2-(5-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)-2-methoxybenzylamino)- Preparation of 3-hydroxypropionic acid (P-21)
Figure PCTCN2018122818-appb-000070
Figure PCTCN2018122818-appb-000070
步骤1：将4-溴-5-氯-2-甲氧基苯甲醛(190mg,0.76mmol)和4-苯基-2-乙烯基烟腈(150mg,0.73mmol)溶解于4.5mL N,N-二甲基乙酰胺和1.5mL三乙胺中,加入醋酸钯(16mg,0.073mmol)和三(邻甲基苯基)膦(44mg，0.15mmol)，反应在氮气保护下160℃微波反应30分钟。减压浓缩，用硅胶柱色谱法以展开剂体系(洗脱剂：乙酸乙酯：石油醚＝1：1)纯化所得残余物，得到(E)-2-(2-氯-4-甲酰基-5-甲氧基苯乙烯基)-4-苯基烟腈(115mg，黄色固体)，产率：42.1％。MS m/z(ESI):375.1[M+H] +。 Step 1: Dissolve 4-bromo-5-chloro-2-methoxybenzaldehyde (190 mg, 0.76 mmol) and 4-phenyl-2-vinylnicotinonitrile (150 mg, 0.73 mmol) in 4.5 mL N, N -Dimethylacetamide and 1.5 mL of triethylamine, palladium acetate (16 mg, 0.073 mmol) and tris(o-methylphenyl)phosphine (44 mg, 0.15 mmol) were added, and the reaction was carried out under microwave protection at 160 ° C for microwave reaction 30 minute. The residue was purified by silica gel column chromatography eluting elut elut elut elut eluting -5-Methoxystyryl)-4-phenylnicotinonitrile (115 mg, yellow solid), yield: 42.1%. MS m/z (ESI): 375.1 [M+H] + .
步骤2：将(E)-2-(2-氯-4-甲酰基-5-甲氧基苯乙烯基)-4-苯基烟腈(70mg，0.19mmol)和(R)-2-氨基-3-羟基丙酸(40mg，0.38mmol)溶解于10mL甲醇中，加入氰基硼氢化钠(19mg,0.3mmol)，搅拌反应20小时。减压浓缩，用制备色谱法得到标题产物(R,E)-2-(5-氯-4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-甲氧基苄氨基)-3-羟基丙酸(化合物P-21)(3mg，白色固体)，产率：3.4％。MS m/z(ESI):464.1[M+H] +。 Step 2: (E)-2-(2-Chloro-4-formyl-5-methoxystyryl)-4-phenylnicotinonitrile (70 mg, 0.19 mmol) and (R)-2-amino 3-Hydroxypropionic acid (40 mg, 0.38 mmol) was dissolved in 10 mL of methanol, sodium cyanoborohydride (19 mg, 0.3 mmol) was added, and the reaction was stirred for 20 hours. The title product (R, E)-2-(5-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)-2 was obtained by preparative chromatography. -Methoxybenzylamino)-3-hydroxypropionic acid (Compound P-21) (3 mg, white solid). MS m/z (ESI): 464.1 [M+H] + .
实施例22至26Examples 22 to 26
化合物P-22、P-23、P-25以化合物11a为原料，采用实施例21中步骤2的类似方法制备。Compounds P-22, P-23, and P-25 were prepared in a similar manner to that of Step 2 in Example 21 using Compound 11a as a starting material.
化合物P-24以化合物13a为原料，采用实施例20中步骤3的类似方法制备。Compound P-24 was prepared in the same manner as in Step 3 of Example 20 using Compound 13a as a material.
化合物P-26以化合物14a为原料，采用实施例20中步骤3的类似方法制备。Compound P-26 was prepared from compound 14a using a similar procedure as in Step 3 of Example 20.
Figure PCTCN2018122818-appb-000071
Figure PCTCN2018122818-appb-000071
Figure PCTCN2018122818-appb-000072
Figure PCTCN2018122818-appb-000072
实施例27(S,E)-1-(5-氯-4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-(氰甲氧基)苄基)哌啶-2-羧酸(P-27)的制备Example 27(S,E)-1-(5-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)-2-(cyanomethoxy)benzyl Preparation of piperidine-2-carboxylic acid (P-27)
Figure PCTCN2018122818-appb-000073
Figure PCTCN2018122818-appb-000073
步骤1：将4-溴-5-氯-2-甲氧基苯甲醛(500mg，2mmol)溶解于35mL二氯甲烷中，在0℃下加入三氯化铝(1.32g，10mmol)，室温搅拌20小时。将反应液倒入冰水中(70mL)，用二氯甲烷萃取(30mL×2)，合并有机相，用饱和氯化钠洗涤(30mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化所得残余物(洗脱剂：乙酸乙酯：石油醚＝1：1)纯化所得残余物，得到4-溴-5-氯-2-羟基苯甲醛(320mg，白色固体)，产率：62％。Step 1: 4 -Bromo-5-chloro-2-methoxybenzaldehyde (500 mg, 2 mmol) was dissolved in 35 mL of dichloromethane, and then added aluminum trichloride (1.32 g, 10 mmol) at 0 ° C, stirring at room temperature 20 hours. The reaction mixture was poured into EtOAc (3 mL). The obtained residue was purified to silicagel elut elut elut elut elut elut Yield: 62%.
步骤2：将4-溴-5-氯-2-羟基苯甲醛(515mg，2.2mmol)和溴乙腈(314mg，2.64mmol)溶解于8mL N,N-二甲基甲酰胺中，加入碳酸钾(455mg，3.3mmol)，室温搅拌3小时。向反应液中加水(100mL)，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠洗涤(30mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化所得残余物(洗脱剂：乙酸乙酯：石油醚＝1：1)纯化所得残余物，得到2-(5-溴-4-氯-2-甲酰基苯氧基)乙腈(532mg，黄色固体)，产率：88.7％。MS m/z(ESI):273.9[M+H] +。 Step 2: Dissolve 4-bromo-5-chloro-2-hydroxybenzaldehyde (515 mg, 2.2 mmol) and bromoacetonitrile (314 mg, 2.64 mmol) in 8 mL of N,N-dimethylformamide and add potassium carbonate ( 455 mg, 3.3 mmol), stirred at room temperature for 3 hours. Water (100 mL) was added to the mixture, and the mixture was evaporated. The residue obtained was purified by silica gel column chromatography (lululululu (532 mg, yellow solid), Yield: 88.7%. MS m/z (ESI): 273.9 [M+H] + .
步骤3：2-(5-溴-4-氯-2-甲酰基苯氧基)乙腈(125mg,0.46mmol)和4-苯基-2-乙烯基烟腈(90mg,0.44mmol)溶解于1.5mL N,N-二甲基乙酰胺和0.5mL三乙胺中,加入醋酸钯(10mg,0.044 mmol)和三(邻甲基苯基)膦(27mg，0.088mmol)，反应在氮气保护下160℃微波反应30分钟。减压浓缩，用硅胶柱色谱法以展开剂体系(洗脱剂：乙酸乙酯：石油醚＝1：1)纯化所得残余物，得到(E)-2-(2-氯-5-(氰甲氧基)-4-甲酰基苯乙烯基)-4-苯基烟腈(60mg，黄色固体)，产率：34.3％。MS m/z(ESI):400.0[M+H] +。 Step 3: 2-(5-Bromo-4-chloro-2-formylphenoxy)acetonitrile (125 mg, 0.46 mmol) and 4-phenyl-2-vinylnicotinonitrile (90 mg, 0.44 mmol) dissolved in 1.5 To a solution of 0.5 N, N-dimethylacetamide and 0.5 mL of triethylamine, palladium acetate (10 mg, 0.044 mmol) and tris(o-methylphenyl)phosphine (27 mg, 0.088 mmol) were added. The microwave reaction was carried out for 30 minutes at °C. The residue was purified by silica gel column chromatography eluting eluting eluting Methoxy)-4-formylstyryl)-4-phenylnicotinonitrile (60 mg, yellow solid), yield: 34.3%. MS m/z (ESI): 400.0 [M+H] + .
步骤4：将(E)-2-(2-氯-5-(氰甲氧基)-4-甲酰基苯乙烯基)-4-苯基烟腈(60mg，0.15mmol)和(S)-哌啶-2-羧酸(39mg，0.3mmol)溶解于10mL甲醇中，加入氰基硼氢化钠(19mg,0.3mmol)，搅拌反应20小时。减压浓缩，用制备色谱法得到标题产物(S,E)-1-(5-氯-4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-(氰甲氧基)苄基)哌啶-2-羧酸(化合物P-27)(20mg，白色固体)，产率：26％。MS m/z(ESI):513.2[M+H] +。 Step 4: (E)-2-(2-Chloro-5-(cyanomethoxy)-4-formylstyryl)-4-phenylnicotinonitrile (60 mg, 0.15 mmol) and (S)- Piperidine-2-carboxylic acid (39 mg, 0.3 mmol) was dissolved in 10 mL of methanol, sodium cyanoborohydride (19 mg, 0.3 mmol) was added, and the reaction was stirred for 20 hours. The title product (S, E)-1-(5-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)-2 was obtained by preparative chromatography. -(Cyanomethoxy)benzyl)piperidine-2-carboxylic acid (Compound P-27) (20 mg, white solid). MS m/z (ESI): 513.2 [M+H] + .
实施例28(S,E)-1-(5-氯-4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-(环丙甲氧基)苄基)哌啶-2-羧酸(P-28)的制备Example 28(S,E)-1-(5-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)-2-(cyclopropylmethoxy) Preparation of benzyl)piperidine-2-carboxylic acid (P-28)
Figure PCTCN2018122818-appb-000074
Figure PCTCN2018122818-appb-000074
步骤1：将4-溴-5-氯-2-甲氧基苯甲醛(300mg，1.21mmol)溶解于10mL二氯甲烷中，冰水浴下分批加入三氯化铝(479mg，3.63mmol)，加毕，升温至室温，继续搅拌反应15小时。加入十水合硫酸钠(500mg)淬灭，混合物室温下搅拌反应0.5小时后，过滤，减压浓缩得化合物4-溴-5-氯-2-羟基苯甲醛(230mg，类白色固体)，产率：82％。MS m/z(ESI):233.1[M+H] +。 Step 1: 4-Bromo-5-chloro-2-methoxybenzaldehyde (300 mg, 1.21 mmol) was dissolved in 10 mL of dichloromethane. After the addition was completed, the temperature was raised to room temperature, and the reaction was further stirred for 15 hours. After adding sodium sulfate decahydrate (500 mg), the mixture was stirred and the mixture was stirred at room temperature for 0.5 hr. : 82%. MS m/z (ESI): 233.1 [M+H] + .
步骤2：将4-溴-5-氯-2-羟基苯甲醛(50mg，0.21mmol)溶解于10mL乙腈中，依次加入碳酸钾(89mg，0.64mmol)，环丙甲基溴(57mg，0.43mmol)反应液室温下搅拌反应16小时，过滤，减压浓缩，剩余物用硅胶柱色谱法(洗脱剂：石油醚：乙酸乙酯＝90:10)纯化后得化合物4-溴-5-氯-2-(环丙甲氧基)苯甲醛(67mg，白色固体)，产率：100％。MS m/z(ESI):289.1[M+H] +。 Step 2: Dissolve 4-bromo-5-chloro-2-hydroxybenzaldehyde (50 mg, 0.21 mmol) in 10 mL of acetonitrile, and then add potassium carbonate (89 mg, 0.64 mmol), cyclopropylmethyl bromide (57 mg, 0.43 mmol) The reaction mixture was stirred at room temperature for 16 hours, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=90:10) to give compound 4-bromo-5-chloro 2-(cyclopropylmethoxy)benzaldehyde (67 mg, white solid), yield: 100%. MS m/z (ESI): 289.1 [M+H] + .
步骤3：将4-溴-5-氯-2-(环丙甲氧基)苯甲醛(45mg，0.16mmol)，4-苯基-2-乙烯基烟腈(32mg，0.16mmol)溶解于2mL N,N-二甲基甲酰胺中，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(5mg，0.016mmol)和1mL三乙胺，氮气置换三次，加热到140℃，在微波反应器中搅拌反应50分钟后冷却至室温，反应液通过硅藻土过滤，滤液减压浓缩，剩余物用硅胶柱色谱法(洗脱剂：石油醚：乙酸乙酯＝80:20)纯化后得化合物(E)-2-(2-氯-5-(环丙甲氧基)-4-甲酰基苯乙烯基)-4-苯基烟腈(10mg，白色固体)，产率：15％。MS m/z(ESI):415.2[M+H] +。 Step 3: Dissolve 4-bromo-5-chloro-2-(cyclopropylmethoxy)benzaldehyde (45 mg, 0.16 mmol), 4-phenyl-2-vinylnicotinonitrile (32 mg, 0.16 mmol) in 2 mL [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (5 mg, 0.016 mmol) and 1 mL of triethylamine were added to N,N-dimethylformamide. The mixture was replaced with nitrogen three times, heated to 140 ° C, stirred in a microwave reactor for 50 minutes, and then cooled to room temperature. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. Ether: ethyl acetate = 80:20) purified compound (E)-2-(2-chloro-5-(cyclopropylmethoxy)-4-formylstyryl)-4-phenylnicotinonitrile (10 mg, white solid), Yield: 15%. MS m/z (ESI): 415.2 [M+H] + .
步骤4：将(E)-2-(2-氯-5-(环丙甲氧基)-4-甲酰基苯乙烯基)-4-苯基烟腈(10mg，0.024mmol)溶解于5mL甲醇中，依次加入L-哌啶-2-甲酸(6mg，0.048mmol)，氰基硼氢化钠(3mg，0.048mmol)，氮气置换三次，加热到80℃，搅拌反应6小时，冷却到室温，反应液减压浓缩，剩余物用制备色谱法纯化后得目标化合物(S,E)-1-(5-氯-4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-(环丙甲氧基)苄基)哌啶-2-羧酸(化合物P-28)(1.2mg，类白色固体)，产率：10％。MS m/z(ESI):528.3[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.26(d,2H),7.65-7.53(m,7H),7.43(s,1H),3.96-3.77(m，4H),1.78-1.71(m,2H),1.53(br,5H),1.20(br,3H),0.56(d,2H),0.34(d,2H)。 Step 4: Dissolve (E)-2-(2-chloro-5-(cyclopropylmethoxy)-4-formylstyryl)-4-phenylnicotinonitrile (10 mg, 0.024 mmol) in 5 mL of methanol L-piperidine-2-carboxylic acid (6 mg, 0.048 mmol), sodium cyanoborohydride (3 mg, 0.048 mmol), three times with nitrogen, heated to 80 ° C, stirred for 6 hours, cooled to room temperature, reaction The liquid was concentrated under reduced pressure and the residue was purified by preparative chromatography to give the title compound (S, E)-1-(5-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl) Vinyl)-2-(cyclopropylmethoxy)benzyl)piperidine-2-carboxylic acid (Compound P-28) (1.2 mg, off-white solid), yield: 10%. MS m/z (ESI): 528.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.88 (s, 1H), 8.26 (d, 2H), 7.65-7.53 (m, 7H), 7.43 (s, 1H), 3.96-3.77 (m, 4H), 1.78-1.71 (m, 2H), 1.53 (br, 5H), 1.20 (br, 3H), 0.56 (d, 2H), 0.34 (d, 2H).
实施例29(S,E)-1-(5-氯-4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-(3-氰基苄氧基)苄基)哌啶-2-羧酸(P-29)的制备Example 29(S,E)-1-(5-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)-2-(3-cyanobenzyloxy) Of benzyl)benzyl)piperidine-2-carboxylic acid (P-29)
Figure PCTCN2018122818-appb-000075
Figure PCTCN2018122818-appb-000075
步骤1：将4-溴-5-氯-2-羟基苯甲醛(250mg，1.06mmol)，3-(溴甲基)苯甲腈(208mg，1.06mmol)，碳酸钾(293mg，2.12mmol)溶解于20mL乙腈中，回流，过夜。将反应液过滤，旋干，硅胶柱分离纯化(0-100％EA/PE)，得到产物3((5-溴-4-氯-2-甲酰基苯氧基)甲基)苯甲腈(200mg，白色固体)，产率：57％。MS m/z(ESI):349.9[M+H] +。 Step 1: Dissolve 4-bromo-5-chloro-2-hydroxybenzaldehyde (250 mg, 1.06 mmol), 3-(bromomethyl)benzonitrile (208 mg, 1.06 mmol), potassium carbonate (293 mg, 2.12 mmol) In 20 mL of acetonitrile, reflux and overnight. The reaction solution was filtered, dried, and purified by silica gel column (0-100% EA/PE) to give product 3 ((5-bromo-4-chloro-2-formylphenoxy)methyl)benzonitrile ( 200 mg, white solid), yield: 57%. MS m/z (ESI): 349.9 [M+H] + .
步骤2：将3((5-溴-4-氯-2-甲酰基苯氧基)甲基)苯甲腈(100mg，0.29mmol)，4-苯基-2-乙烯基烟酰胺(59mg，0.29mmol)，三乙胺(0.5mL)，Pd(dppf)Cl 2(22mg，0.03mmol)溶解于4mL N，N二甲基乙酰胺中。在氩气保护下微波140℃，搅拌1小时。将反应液旋干，用乙酸乙酯(20mL)溶解，有机相用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，硅胶柱分离纯化(0-100％EA/PE)，得到产物(E)-2(2-氯-5-(3-氰基苄基氧基)-4-甲酰基苯乙烯基)-4-苯基烟酰胺(50mg，棕色固体)，产率：36％。MS m/z(ESI):476.1[M+H] +。 Step 2: 3((5-Bromo-4-chloro-2-formylphenoxy)methyl)benzonitrile (100 mg, 0.29 mmol), 4-phenyl-2-vinylnicotinamide (59 mg, 0.29 mmol), triethylamine (0.5 mL), Pd(dppf)Cl 2 (22 mg, 0.03 mmol) was dissolved in 4 mL of N,N dimethylacetamide. The microwave was stirred at 140 ° C under argon for 1 hour. The reaction mixture was dried with EtOAc (EtOAc) (EtOAc)EtOAc. 100% EA/PE) gave the product (E)-2 (2-chloro-5-(3-cyanobenzyloxy)-4-formylstyryl)-4-phenylnicotinamide (50 mg, Brown solid), Yield: 36%. MS m/z (ESI): 476.1 [M+H] + .
步骤3：将(E)-2(2-氯-5-(3-氰基苄基氧基)-4-甲酰基苯乙烯基)-4-苯基烟酰胺(50mg，0.1mmol)，(S)-哌啶-2-羧酸(40mg，0.31mmol)溶解于10mL甲醇中，60℃，搅拌1小时，加入氰基硼氢化钠(20mg，0.31mmol)。在60℃，搅拌2小时，旋干，制备分离得白色固体(S,E)-1-(5-氯-4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-(3-氰基苄氧基)苄基)哌啶-2-羧酸(化合物P-29)(5mg，0.0008mmol)，产率：8.5％。MS m/z(ESI):589.2[M+H] +。1H NMR(400MHz,dmso)δ8.88(d,J＝5.0Hz,1H),8.25(d,J＝15.4Hz,1H),7.92(s,1H),7.86(d,J＝7.7Hz,1H),7.78(d,J＝8.0Hz,1H),7.69–7.64(m,2H),7.62–7.46(m,8H),5.33(s,2H),3.74(d,J＝15.3Hz,1H),3.62(d,J＝15.4Hz,1H),2.86(s,1H),2.64(s,1H),2.29(s,2H),1.76(s, 2H),1.47(s,4H). Step 3: (E)-2(2-Chloro-5-(3-cyanobenzyloxy)-4-formylstyryl)-4-phenylnicotinamide (50 mg, 0.1 mmol), ( S)-Piperidine-2-carboxylic acid (40 mg, 0.31 mmol) was dissolved in 10 mL of methanol, and stirred at 60 ° C for 1 hour, and sodium cyanoborohydride (20 mg, 0.31 mmol) was added. Stir at 60 ° C for 2 hours, spin dry, to obtain a white solid (S, E)-1-(5-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl)) Vinyl)-2-(3-cyanobenzyloxy)benzyl)piperidine-2-carboxylic acid (Compound P-29) (5 mg, 0.0008 mmol), yield: 8.5%. MS m/z (ESI): 589.2 [M+H] + . 1H NMR (400MHz, dmso) δ 8.88 (d, J = 5.0 Hz, 1H), 8.25 (d, J = 15.4 Hz, 1H), 7.92 (s, 1H), 7.86 (d, J = 7.7 Hz, 1H) ), 7.78 (d, J = 8.0 Hz, 1H), 7.69 - 7.64 (m, 2H), 7.62 - 7.46 (m, 8H), 5.33 (s, 2H), 3.74 (d, J = 15.3 Hz, 1H) , 3.62 (d, J = 15.4 Hz, 1H), 2.86 (s, 1H), 2.64 (s, 1H), 2.29 (s, 2H), 1.76 (s, 2H), 1.47 (s, 4H).
实施例30(S,E)-1-(4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-苯乙基-5-(三氟甲基)苄基)哌啶-2-羧酸(P-30)的制备Example 30(S,E)-1-(4-(2-(3-Cyano-4-phenylpyridin-2-yl)vinyl)-2-phenylethyl-5-(trifluoromethyl) Preparation of benzyl)piperidine-2-carboxylic acid (P-30)
Figure PCTCN2018122818-appb-000076
Figure PCTCN2018122818-appb-000076
步骤1：将5-溴-2-(三氟甲基)苯胺(1g，4.18mmol)溶解于20mL 1,4-二氧六环中，依次加入苯乙基硼酸(628mg，4.18mmol)，碳酸钾(1.15g，8.36mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(170mg，0.21mmol)和2mL水，氮气置换三次，加热到100℃，搅拌反应20小时后冷却至室温，反应液通过硅藻土过滤，滤液减压浓缩，剩余物用硅胶柱色谱法(洗脱剂：石油醚：乙酸乙酯＝95:5)纯化后得化合物5-苯乙基-2-(三氟甲基)苯胺(700mg，黄色油状物)，产率：64％。MS m/z(ESI):266.1[M+H] +。 Step 1: Dissolve 5-bromo-2-(trifluoromethyl)aniline (1 g, 4.18 mmol) in 20 mL of 1,4-dioxane, followed by the addition of phenylethylboronic acid (628 mg, 4.18 mmol). Potassium (1.15 g, 8.36 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (170 mg, 0.21 mmol) and 2 mL of water, three times with nitrogen, The mixture was heated to 100 ° C, stirred for 20 hours, and then cooled to room temperature. The reaction mixture was filtered over EtOAc EtOAc. After purification, the compound 5-phenylethyl-2-(trifluoromethyl)aniline (700 mg, m. MS m/z (ESI): 266.1 [M+H] + .
步骤2：将5-苯乙基-2-(三氟甲基)苯胺(600mg，2.26mmol)溶解于10mL N,N-二甲基甲酰胺中，加入N-溴代丁二酰亚胺(403mg，2.26mmol)，氮气置换三次，室温下搅拌反应16小时，减压浓缩，剩余物用硅胶柱色谱法(洗脱剂：石油醚：乙酸乙酯＝95:5)纯化后得化合物4-溴-5-苯乙基-2-(三氟甲基)苯胺(480mg，黄色油状物)，产率：62％。MS m/z(ESI):344.2[M+H] +,346.2[M+3]。 Step 2: Dissolve 5-phenylethyl-2-(trifluoromethyl)aniline (600 mg, 2.26 mmol) in 10 mL of N,N-dimethylformamide and add N-bromosuccinimide ( 403 mg, 2.26 mmol), three times with nitrogen, and the mixture was stirred at room temperature for 16 hours, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 95:5) Bromo-5-phenethyl-2-(trifluoromethyl)aniline (480 mg, yellow oil), yield: 62%. MS m/z (ESI): 344.2 [M+H] + , 346.2 [M+3].
步骤3：将4-溴-5-苯乙基-2-(三氟甲基)苯胺(480mg，1.40mmol)溶解于4mL N-甲基吡咯烷酮中，加入氰化亚铜(622mg，6.99mmol)，氮气置换三次，加热至220℃，微波反应器中搅拌反应40分钟后冷却到室温。将反应液倒入40mL乙酸乙酯中，用17％氨水(40mL)，食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得化合物4-胺基-2-苯乙基-5-(三氟甲基)苯基腈(400mg，黄色油状物)，产率：97％。MS m/z(ESI):291.1[M+H] +。 Step 3: Dissolve 4-bromo-5-phenethyl-2-(trifluoromethyl)aniline (480 mg, 1.40 mmol) in 4 mL of N-methylpyrrolidone and add cuprous cyanide (622 mg, 6.99 mmol) The mixture was replaced with nitrogen three times, heated to 220 ° C, stirred in a microwave reactor for 40 minutes and then cooled to room temperature. The reaction mixture was poured into ethyl acetate (40 mL), EtOAc (EtOAc) 5-5-(Trifluoromethyl)phenylcarbonitrile (400 mg, yellow oil), yield: 97%. MS m/z (ESI): 29.21. [M+H] + .
步骤4：将4-胺基-2-苯乙基-5-(三氟甲基)苯基腈(400mg，1.38mmol)溶解于20mL乙腈中，加入溴化铜(457mg，2.07mmol)，冰水浴冷却到0℃，缓慢滴加亚硝酸异戊酯(242mg，2.07mmol)，加毕，升温至室温，继续搅拌反应16小时。反应液减压浓缩，剩余物倒入40mL乙酸乙酯中，用17％氨水(40mL)，食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得化合物4-溴-2-苯乙基-5-(三氟甲基)苯基腈(300mg，黄色油状物)，产率：62％。MS m/z(ESI):354.1[M+H] +，356.1[M+3]。 Step 4: Dissolve 4-amino-2-phenethyl-5-(trifluoromethyl)phenylcarbonitrile (400 mg, 1.38 mmol) in 20 mL of acetonitrile and add copper bromide (457 mg, 2.07 mmol), ice The mixture was cooled to 0 ° C in a water bath, and isoamyl nitrite (242 mg, 2.07 mmol) was slowly added dropwise, and the mixture was warmed to room temperature, and the reaction was further stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc m. Phenylethyl-5-(trifluoromethyl)benzonitrile (300 mg, yellow oil), yield: 62%. MS m/z (ESI): 354.1 [M+H] + , 356.1 [M+3].
步骤5：将4-溴-2-苯乙烯基-5-(三氟甲基)苯基腈(150mg，0.43mmol)溶解于10mL二氯甲烷中，冰水浴冷却到0℃，缓慢滴加二异丁基氢化铝(1.0M，0.64mL，0.64mmol)，加毕，在此温度下继续搅拌反应2小时。依次加入甲醇(5mL)和36％盐酸(5mL)。反应液升温到室温，继续搅拌反应0.5小时，乙酸乙酯(20mL)萃取两次，合并的有机相经食盐水(30mL)洗涤后无水硫酸钠干燥，过滤，减压浓缩得化合物4-溴-2-苯乙烯基-5-(三氟甲基)苯甲醛(130mg，黄色油状物)，产率：86％。MS m/z(ESI):357.1[M+H] +。 Step 5: Dissolve 4-bromo-2-styryl-5-(trifluoromethyl)phenyl nitrile (150 mg, 0.43 mmol) in 10 mL of dichloromethane, cool to 0 ° C in ice water, slowly add two Isobutylaluminum hydride (1.0 M, 0.64 mL, 0.64 mmol) was added, and stirring was continued at this temperature for 2 hours. Methanol (5 mL) and 36% hydrochloric acid (5 mL) were added in that order. The reaction mixture was warmed to room temperature, and the mixture was stirred for 0.5 hr. EtOAc (EtOAc) 2-Styryl-5-(trifluoromethyl)benzaldehyde (130 mg, yellow oil), yield: 86%. MS m/z (ESI): 357.1 [M+H] + .
步骤6：将4-溴-2-苯乙烯基-5-(三氟甲基)苯甲醛(110mg，0.31mmol)溶解于2mL N,N-二甲基乙酰胺中，依次加入4-苯基-2-乙烯基烟腈1g(64mg，0.31mmol)，醋酸钯(7mg，0.031mmol)，三(邻甲基苯基)磷(18mg，0.062mmol)和1mL三乙胺，氮气置换三次，加热到150℃，在微波反应器中搅拌反应45分钟后冷却至室温，反应液通过硅藻土过滤，滤液减压浓缩，剩余物用硅胶柱色谱法(洗脱剂：石油醚：乙酸乙酯＝70:30)纯化后得目标化合物2-(4-甲酰基-5-苯乙基-2-(三氟甲基)苯乙烯基)-4-苯基烟腈(100mg，黄色油状物)，产率：67％。MS m/z(ESI):483.2[M+H] +。 Step 6: Dissolve 4-bromo-2-styryl-5-(trifluoromethyl)benzaldehyde (110 mg, 0.31 mmol) in 2 mL of N,N-dimethylacetamide, and then add 4-phenyl -2-vinyl nicotinonitrile 1 g (64 mg, 0.31 mmol), palladium acetate (7 mg, 0.031 mmol), tris(o-methylphenyl)phosphine (18 mg, 0.062 mmol) and 1 mL of triethylamine. The reaction was stirred at 150 ° C for 45 minutes in a microwave reactor, and then cooled to room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. 70:30) The title compound 2-(4-formyl-5-phenethyl-2-(trifluoromethyl)styryl)-4-phenylnicotinonitrile (100 mg, yellow oil) Yield: 67%. MS m/z (ESI): 483.2 [M+H] + .
步骤7：将2-(4-甲酰基-5-苯乙基-2-(三氟甲基)苯乙烯基)-4-苯基烟腈(100mg，0.21mmol)溶解于15mL甲醇中，依次加入L-哌啶-2-甲酸(53.5mg，0.42mmol)，氰基硼氢化钠(26mg，0.42mmol)，氮气置换三次，加热到80℃，搅拌反应16小时，冷却到室温，反应液减压浓缩，剩余物用制备色谱法纯化后得目标化合物(S,E)-1-(4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-苯乙基-5-(三氟甲基)苄基)哌啶-2-羧酸(化合物P-30)(37mg，白色固体)，产率：30％。MS m/z(ESI):596.3[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.88(d,1H),8.25(dd,1H),7.78(s,1H),7.73(s,1H),7.68-7.66(m，4H),7.48(d,1H),7.25(d,4H),7.16-7.13(m,1H),3.89(d,1H),3.52-3.49(m,2H),3.10-3.09(m,2H),2.17-2.15(m,1H),1.74(d,2H),1.45-1.41(m,4H)。 Step 7: Dissolve 2-(4-formyl-5-phenethyl-2-(trifluoromethyl)styryl)-4-phenylnicotinonitrile (100 mg, 0.21 mmol) in 15 mL of methanol. Add L-piperidine-2-carboxylic acid (53.5 mg, 0.42 mmol), sodium cyanoborohydride (26 mg, 0.42 mmol), replace three times with nitrogen, heat to 80 ° C, stir the reaction for 16 hours, cool to room temperature, reduce the reaction Concentration by pressure, the residue was purified by preparative chromatography to give the title compound (S, E)-1-(4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)-2- Phenylethyl-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound P-30) (37 mg, white solid). MS m/z (ESI): 596.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.88 (d, 1H), 8.25 (dd, 1H), 7.78 (s, 1H), 7.73 (s, 1H), 7.68-7.66 (m, 4H), 7.48 ( d, 1H), 7.25 (d, 4H), 7.16-7.13 (m, 1H), 3.89 (d, 1H), 3.52-3.49 (m, 2H), 3.10-3.09 (m, 2H), 2.17-2.15 ( m, 1H), 1.74 (d, 2H), 1.45-1.41 (m, 4H).
实施例32(S，E)-1-(4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-甲基-5-(三氟甲基)苄基)哌啶-2-羧酸(P-32)的制备Example 32 (S,E)-1-(4-(2-(3-Cyano-4-phenylpyridin-2-yl)vinyl)-2-methyl-5-(trifluoromethyl) Preparation of benzyl)piperidine-2-carboxylic acid (P-32)
Figure PCTCN2018122818-appb-000077
Figure PCTCN2018122818-appb-000077
以化合物20a为原料，制备方法参考化合物P-1，得化合物P-32。MS m/z(ESI):506.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.92(d,1H),8.31(d,1H),7.87(s,1H),7.75(s,1H),7.71-7.69(m,2H),7.62-7.60(m,5H),3.84(d,1H),3.57(d,1H),3.20-3.18(m,1H),2.88-2.80(m,1H),2.45(m,3H),2.25-2.20(m,1H),1.79-1.77(m,2H),1.52-1.42(m,4H). Starting from the compound 20a, the preparation method is referred to the compound P-1 to obtain the compound P-32. MS m/z (ESI): 506.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ8.92 (d, 1H), 8.31 (d, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 7.71-7.69 (m, 2H), 7.62 -7.60 (m, 5H), 3.84 (d, 1H), 3.57 (d, 1H), 3.20-3.18 (m, 1H), 2.88-2.80 (m, 1H), 2.45 (m, 3H), 2.25-2.20 (m, 1H), 1.79-1.77 (m, 2H), 1.52-1.42 (m, 4H).
实施例33(S,E)-1-(5-氯-2-(2-羟基乙氧基)-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苄基)哌啶-2-羧基(P-33)的制备Example 33(S,E)-1-(5-chloro-2-(2-hydroxyethoxy)-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl Preparation of benzyl)piperidine-2-carboxyl (P-33)
Figure PCTCN2018122818-appb-000078
Figure PCTCN2018122818-appb-000078
步骤1：将4-溴-5-氯-2-羟基苯甲醛(2g,8.48mmol)，叔丁基二甲基羟乙氧基硅烷(1.5g,8.48mmol)，三苯基膦(4g,15.28mmol)溶解于20mL无水四氢呋喃中，在氩气保护下室温搅拌20分钟。加入偶氮二甲酸二异丙酯(3g,12.76mmol),室温搅拌过夜。将反应液旋 干，用乙酸乙酯(50mL)溶解，有机相用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，硅胶柱分离纯化(0-50％EA/PE)，得到产物4-溴-2-(2-(叔丁基二甲基硅氧基)乙氧基)-5-氯苯甲醛(650mg，白色固体)，产率：20％。Step 1: 4-Bromo-5-chloro-2-hydroxybenzaldehyde (2 g, 8.48 mmol), tert-butyldimethylhydroxyethoxysilane (1.5 g, 8.48 mmol), triphenylphosphine (4 g, 15.28 mmol) was dissolved in 20 mL of dry tetrahydrofuran and stirred at room temperature for 20 min under argon. Diisopropyl azodicarboxylate (3 g, 12.76 mmol) was added and stirred at room temperature overnight. The reaction mixture was dried with EtOAc (EtOAc) (EtOAc)EtOAc. 50% EA/PE) gave the product 4-bromo-2-(2-(tert-butyldimethylsilyloxy)ethoxy)-5-chlorobenzaldehyde (650 mg, white solid). %.
步骤2：将4-溴-2-(2-(叔丁基二甲基硅氧基)乙氧基)-5-氯苯甲醛(500mg，1.27mmol)，3-甲基-4-苯基-2-乙烯基吡啶(248mg，1.27mmol)，三乙胺(0.5mL)，三(邻甲基苯基)磷(78mg，0.25mmol)，醋酸钯(29mg，0.13mmol)溶解于4mLN，N二甲基乙酰胺中。在氩气保护下微波150℃，搅拌1小时。将反应液旋干，用乙酸乙酯(20mL)溶解，有机相用饱和氯化钠溶液洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，硅胶柱分离纯化(0-100％EA/PE)，得到产物(E)-2-(2-(叔丁基二甲基硅氧基)乙氧基)-5-氯-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苯甲醛(200mg，黄色固体)，产率：9％。MS m/z(ESI):508.2[M+H] +。 Step 2: 4-Bromo-2-(2-(tert-butyldimethylsilyloxy)ethoxy)-5-chlorobenzaldehyde (500 mg, 1.27 mmol), 3-methyl-4-phenyl 2-vinylpyridine (248 mg, 1.27 mmol), triethylamine (0.5 mL), tris(o-methylphenyl)phosphine (78 mg, 0.25 mmol), palladium acetate (29 mg, 0.13 mmol) dissolved in 4 mL N, N In dimethylacetamide. The microwave was stirred at 150 ° C under argon for 1 hour. The reaction mixture was dried with EtOAc (EtOAc) (EtOAc)EtOAc. 100% EA/PE) gave the product (E)-2-(2-(tert-butyldimethylsilyloxy)ethoxy)-5-chloro-4-(2-(3-methyl-4) -Phenylpyridin-2-yl)vinyl)benzaldehyde (200 mg, yellow solid), yield: 9%. MS m/z (ESI): 508.2 [M+H] + .
步骤3：将(E)-2-(2-(叔丁基二甲基硅氧基)乙氧基)-5-氯-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苯甲醛(200mg，0.51mmol)溶解在10mL四氢呋喃和10mL，1M HCl溶液中，室温搅拌1小时。用乙酸乙酯(20mL×3)溶解，有机相用饱和氯化钠溶液洗涤(50mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得粗产品(E)-5-氯-2-(2-羟基乙氧基)-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苯甲醛(60mg，0.12mmol)，产率：42％。MS m/z(ESI):394.1[M+H] +。 Step 3: (E)-2-(2-(tert-Butyldimethylsilyloxy)ethoxy)-5-chloro-4-(2-(3-methyl-4-phenylpyridine)- 2-Based)Vinyl)benzaldehyde (200 mg, 0.51 mmol) was dissolved in 10 mL of tetrahydrofuran and 10 mL of 1M HCl solution and stirred at room temperature for 1 hour. The organic phase was washed with a saturated sodium chloride solution (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product (E)-5-chloro- 2-(2-Hydroxyethoxy)-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzaldehyde (60 mg, 0.12 mmol), yield: 42%. MS m/z (ESI): 394.1 [M+H] + .
步骤4：将(E)-5-氯-2-(2-羟基乙氧基)-4-(2-(3-甲基-4-苯基吡啶-2-基)乙烯基)苯甲醛(60mg，0.12mmol)，(S)-哌啶-2-羧酸(48mg，0.36mmol)溶解于10mL甲醇中，60℃，搅拌1小时，加入氰基硼氢化钠(22mg，0.36mmol)。在60℃，搅拌2小时，旋干，制备分离得白色固体(化合物P-33)(3mg，0.0006mmol)，产率：5％。MS m/z(ESI):507.2[M+H] +。 1H NMR(400MHz,dmso)δ8.47(d,J＝4.8Hz,1H),8.06(d,J＝15.4Hz,1H),7.63(d,J＝15.4Hz,1H),7.53–7.39(m,5H),7.35(d,J＝6.7Hz,2H),7.12(d,J＝4.9Hz,1H),4.13(s,2H),3.94–3.63(m,5H),3.14(s,2H),2.91(s,2H),2.64(s,1H),2.33(s,3H),2.29(s,1H),1.81(s,1H),1.70(s,1H),1.50(s,3H),1.36(s,1H). Step 4: (E)-5-Chloro-2-(2-hydroxyethoxy)-4-(2-(3-methyl-4-phenylpyridin-2-yl)vinyl)benzaldehyde ( 60 mg, 0.12 mmol), (S)-piperidine-2-carboxylic acid (48 mg, 0.36 mmol) was dissolved in 10 mL of methanol, and stirred at 60 ° C for 1 hour, and sodium cyanoborohydride (22 mg, 0.36 mmol) was added. After stirring at 60 ° C for 2 hours, it was dried to give a white solid (Compound P-33) (3 mg, 0.0006 mmol). MS m/z (ESI): 507.2 [M+H] + . 1 H NMR (400MHz, dmso) δ8.47 (d, J = 4.8Hz, 1H), 8.06 (d, J = 15.4Hz, 1H), 7.63 (d, J = 15.4Hz, 1H), 7.53-7.39 ( m, 5H), 7.35 (d, J = 6.7 Hz, 2H), 7.12 (d, J = 4.9 Hz, 1H), 4.13 (s, 2H), 3.94 - 3.63 (m, 5H), 3.14 (s, 2H) ), 2.91 (s, 2H), 2.64 (s, 1H), 2.33 (s, 3H), 2.29 (s, 1H), 1.81 (s, 1H), 1.70 (s, 1H), 1.50 (s, 3H) , 1.36 (s, 1H).
实施例36(S)-1-(4-((E)-2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-苯乙烯基-5-(三氟甲基)苄基)哌啶-2-羧酸(P-36)的制备Example 36(S)-1-(4-((E)-2-(3-Cyano-4-phenylpyridin-2-yl)vinyl)-2-styryl-5-(trifluoro) Preparation of methyl)benzyl)piperidine-2-carboxylic acid (P-36)
Figure PCTCN2018122818-appb-000079
Figure PCTCN2018122818-appb-000079
步骤1：将5-溴-2-(三氟甲基)苯胺(10g，41.84mmol)溶解于200mL 1,4-二氧六环中，依次加入乙烯三氟硼酸钾(6.17g，46.03mmol)，碳酸钾(11.55g，83.68mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(683mg，0.84mmol)和5mL水，氮气置换三次，加热到100℃，搅拌反应20小时后冷却至室温，反应液通过硅藻土过滤，滤液减压浓缩， 剩余物用硅胶柱色谱法(洗脱剂：石油醚：乙酸乙酯＝80:20)纯化后得2-(三氟甲基)-5-乙烯基苯胺(4.9g，黄色油状物)，产率：63％。MS m/z(ESI):188.1[M+H] +。 Step 1: Dissolve 5-bromo-2-(trifluoromethyl)aniline (10 g, 41.84 mmol) in 200 mL of 1,4-dioxane, and then add potassium trifluoroborate (6.17 g, 46.03 mmol). , potassium carbonate (11.55 g, 83.68 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (683 mg, 0.84 mmol) and 5 mL of water, nitrogen replacement After three times, the mixture was heated to 100 ° C, the reaction was stirred for 20 hours, and then cooled to room temperature. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. 20) After purification, 2-(trifluoromethyl)-5-vinylaniline (4.9 g, yellow oil). MS m/z (ESI): 188.1 [M+H] + .
步骤2：将2-(三氟甲基)-5-乙烯基苯胺(1g，5.35mmol)溶解于2mL N,N-二甲基乙酰胺中，依次加入溴苯(1.25g，8.03mmol)，醋酸钯(60mg，0.27mmol)，三(邻甲基苯基)磷(164mg，0.54mmol)和1mL三乙胺，氮气置换三次，加热到150℃，在微波反应器中搅拌反应50分钟后冷却至室温，反应液通过硅藻土过滤，滤液减压浓缩，剩余物用硅胶柱色谱法(洗脱剂：石油醚：乙酸乙酯＝90:10)纯化后得(E)-5-苯乙烯基-2-(三氟甲基)苯胺(1.4g，黄色油状物)，产率：99％。MS m/z(ESI):264.2[M+H] +。 Step 2: 2-(Trifluoromethyl)-5-vinylaniline (1 g, 5.35 mmol) was dissolved in 2 mL of N,N-dimethylacetamide, followed by bromobenzene (1.25 g, 8.03 mmol). Palladium acetate (60 mg, 0.27 mmol), tris(o-methylphenyl)phosphine (164 mg, 0.54 mmol) and 1 mL of triethylamine, three times with nitrogen, heated to 150 ° C, stirred in a microwave reactor for 50 minutes and then cooled The reaction solution was filtered through celite, and the filtrate was evaporated to dryness. The residue was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate=90:10) to give (E)-5-styrene. Base-2-(trifluoromethyl)aniline (1.4 g, yellow oil), yield: 99%. MS m/z (ESI): 264.2 [M+H] + .
步骤3：将(E)-5-苯乙烯基-2-(三氟甲基)苯胺(1.2g，4.56mmol)溶解于20mL N,N-二甲基甲酰胺中，加入N-溴代丁二酰亚胺(0.90g，5.02mmol)，氮气置换三次，室温下搅拌反应16小时，减压浓缩，剩余物用硅胶柱色谱法(洗脱剂：石油醚：乙酸乙酯＝90:10)纯化后得(E)-4-溴-5-苯乙烯基-2-(三氟甲基)苯胺(1.6g，黄色油状物)，产率：99％。MS m/z(ESI):342.2[M+H] +,344.2[M+3]。 Step 3: Dissolve (E)-5-styryl-2-(trifluoromethyl)aniline (1.2 g, 4.56 mmol) in 20 mL of N,N-dimethylformamide and add N-bromobutane The diimide (0.90 g, 5.02 mmol) was replaced with nitrogen three times. The reaction was stirred at room temperature for 16 hr, and concentrated under reduced pressure. The residue was applied to silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 90:10) After purification, (E)-4-bromo-5-styryl-2-(trifluoromethyl)aniline (1.6 g, yellow oil). MS m/z (ESI): 342.2 [M+H] + , 344.2 [M+3].
步骤4：将(E)-4-溴-5-苯乙烯基-2-(三氟甲基)苯胺(300mg，0.88mmol)溶解于2mL N-甲基吡咯烷酮中，加入氰化亚铜(157mg，1.76mmol)，氮气置换三次，加热至220℃，微波反应器中搅拌反应40分钟后冷却到室温。将反应液倒入20mL乙酸乙酯中，用17％氨水(20mL)，食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物用硅胶柱色谱法(洗脱剂：石油醚：乙酸乙酯＝80:20)纯化后得(E)-4-胺基-2-苯乙烯基-5-(三氟甲基)苯基腈(160mg，黄色油状物)，产率：63％。MS m/z(ESI):289.1[M+H] +。 Step 4: Dissolve (E)-4-bromo-5-styryl-2-(trifluoromethyl)aniline (300 mg, 0.88 mmol) in 2 mL of N-methylpyrrolidone and add cuprous cyanide (157 mg) , 1.76 mmol), three times with nitrogen, heated to 220 ° C, stirred in a microwave reactor for 40 minutes and then cooled to room temperature. The reaction solution was poured into 20 mL of ethyl acetate, washed with EtOAc (EtOAc) (EtOAc) : Petroleum ether: ethyl acetate = 80:20) (O)-4-Amino-2-styryl-5-(trifluoromethyl)phenylcarbonitrile (160 mg, yellow oil) Rate: 63%. MS m/z (ESI): 289.1 [M+H] + .
步骤5：将(E)-4-胺基-2-苯乙烯基-5-(三氟甲基)苯基腈(160mg，0.56mmol)溶解于15mL乙腈中，加入溴化铜(183mg，0.83mmol)，冰水浴冷却到0℃，缓慢滴加亚硝酸异戊酯(0.11mL，0.83mmol)，加毕，升温至室温，继续搅拌反应16小时。反应液减压浓缩，剩余物倒入20mL乙酸乙酯中，用17％氨水(20mL)，食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得化合物(E)-4-溴-2-苯乙烯基-5-(三氟甲基)苯基腈(200mg，黄色固体)，产率：99％。MS m/z(ESI):352.1[M+H] +，354.1[M+3]。 Step 5: Dissolve (E)-4-amino-2-styryl-5-(trifluoromethyl)phenylcarbonitrile (160 mg, 0.56 mmol) in 15 mL of acetonitrile and add copper bromide (183 mg, 0.83) (mmol), the ice water bath was cooled to 0 ° C, and isoamyl nitrite (0.11 mL, 0.83 mmol) was slowly added dropwise, and the mixture was warmed to room temperature and stirring was continued for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc m. Bromo-2-styryl-5-(trifluoromethyl)phenylcarbonitrile (200 mg, yellow solid), yield: 99%. MS m/z (ESI): 3521. [M+H] + , 354.1 [M+3].
步骤6：将(E)-4-溴-2-苯乙烯基-5-(三氟甲基)苯基腈(170mg，0.48mmol)溶解于20mL二氯甲烷中，干冰丙酮浴冷却到-78℃，缓慢滴加二异丁基氢化铝(1.1M，0.48mL，0.53mmol)，加毕，在此温度下继续搅拌反应0.5小时。依次加入甲醇(5mL)和36％盐酸(5mL)。反应液升温到室温，继续搅拌反应0.5小时，减压浓缩，剩余物用硅胶柱色谱法(洗脱剂：石油醚：乙酸乙酯＝90:10)纯化后得化合物(E)-4-溴-2-苯乙烯基-5-(三氟甲基)苯甲醛(180mg，黄色固体)，产率：99％。MS m/z(ESI):355.1[M+H] +。 Step 6: Dissolve (E)-4-bromo-2-styryl-5-(trifluoromethyl)phenylcarbonitrile (170 mg, 0.48 mmol) in 20 mL of dichloromethane and dry ice-br. °C, diisobutylaluminum hydride (1.1 M, 0.48 mL, 0.53 mmol) was slowly added dropwise, and the reaction was continued at this temperature for 0.5 hour. Methanol (5 mL) and 36% hydrochloric acid (5 mL) were added in that order. The reaction mixture was warmed to room temperature, and the reaction was further stirred for 0.5 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=90:10) 2-Styryl-5-(trifluoromethyl)benzaldehyde (180 mg, yellow solid), yield: 99%. MS m/z (ESI): 355.1 [M+H] + .
步骤7：将(E)-4-溴-2-苯乙烯基-5-(三氟甲基)苯甲醛(85mg，0.24mmol)溶解于2mL N,N-二甲基乙酰胺中，依次加入4-苯基-2-乙烯基烟腈(49mg，0.24mmol)，醋酸钯(3mg，0.012mmol)，三(邻甲基苯基)磷(7mg，0.024mmol)和1mL三乙胺，氮气置换三次，加热到150℃，在微波反应器中搅拌反应50分钟后冷却至室温，反应液通过硅藻土过滤，滤液减压浓缩，剩余物用硅胶柱色谱法(洗脱剂：石油醚：乙酸乙酯＝40:60)纯化后得化合物2-(4-甲酰基-5-苯乙烯基-2-(三氟甲基)苯乙烯基)-4-苯基烟腈(40mg，黄色固体)，产 率：35％。MS m/z(ESI):481.2[M+H] +。 Step 7: Dissolve (E)-4-bromo-2-styryl-5-(trifluoromethyl)benzaldehyde (85 mg, 0.24 mmol) in 2 mL of N,N-dimethylacetamide and add sequentially 4-Phenyl-2-vinylnicotinonitrile (49 mg, 0.24 mmol), palladium acetate (3 mg, 0.012 mmol), tris(o-methylphenyl)phosphonate (7 mg, 0.024 mmol) and 1 mL of triethylamine After three times, the mixture was heated to 150 ° C, stirred in a microwave reactor for 50 minutes, and then cooled to room temperature. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography (eluent: petroleum ether: acetic acid Ethyl ester = 40: 60) Compound 2-(4-formyl-5-styryl-2-(trifluoromethyl)styryl)-4-phenylnicotinonitrile (40 mg, yellow solid) , yield: 35%. MS m/z (ESI): 481.2 [M+H] + .
步骤8：将2-(4-甲酰基-5-苯乙烯基-2-(三氟甲基)苯乙烯基)-4-苯基烟腈(40mg，0.08mmol)溶解于10mL甲醇中，依次加入L-哌啶-2-甲酸(32mg，0.25mmol)，氰基硼氢化钠(26mg，0.42mmol)，氮气置换三次，加热到80℃，搅拌反应16小时，冷却到室温，反应液减压浓缩，剩余物用制备色谱法纯化后得目标化合物(S)-1-(4-((E)-2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-苯乙烯基-5-(三氟甲基)苄基)哌啶-2-羧酸(化合物P-36)(2.36mg，白色固体)，产率：4.8％。MS m/z(ESI):594.3[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.94(d,1H),8.33-8.28(m,2H),7.88(d,1H),7.77-7.69(m,6H),7.63-7.57(m，4H),7.43-7.39(m,3H),7.34-7.30(m,1H),4.14(d,1H),3.69(br,1H),2.80(br,1H),2.32(br,2H),1.84(s,1H),1.75(br,1H),1.55-1.21(m,4H)。 Step 8: Dissolve 2-(4-formyl-5-styryl-2-(trifluoromethyl)styryl)-4-phenylnicotinonitrile (40 mg, 0.08 mmol) in 10 mL of methanol. Add L-piperidine-2-carboxylic acid (32 mg, 0.25 mmol), sodium cyanoborohydride (26 mg, 0.42 mmol), replace three times with nitrogen, heat to 80 ° C, stir the reaction for 16 hours, cool to room temperature, decompress the reaction solution Concentration, the residue was purified by preparative chromatography to give the title compound (S)-1-(4-((E)-2-(3-cyano-4-phenylpyridin-2-yl)vinyl)-2 - Styryl-5-(trifluoromethyl)benzyl)piperidine-2-carboxylic acid (Compound P-36) (2.36 mg, white solid). MS m/z (ESI): 594.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.94 (d, 1H), 8.33-8.28 (m, 2H), 7.88 (d, 1H), 7.77-7.69 (m, 6H), 7.63-7.57 (m, 4H) ), 7.43-7.39 (m, 3H), 7.34-7.30 (m, 1H), 4.14 (d, 1H), 3.69 (br, 1H), 2.80 (br, 1H), 2.32 (br, 2H), 1.84 ( s, 1H), 1.75 (br, 1H), 1.55-1.21 (m, 4H).
实施例38(S,E)-1-(3-氯-4-(2-(4-(2-氯苯基)-3-甲基吡啶-2-基)乙烯基)苄基)哌啶-2-羧酸(P-38)的制备Example 38(S,E)-1-(3-Chloro-4-(2-(4-(2-chlorophenyl)-3-methylpyridin-2-yl)vinyl)benzyl)piperidine Preparation of 2-carboxylic acid (P-38)
Figure PCTCN2018122818-appb-000080
Figure PCTCN2018122818-appb-000080
步骤1：将4-溴-2-氯-3-甲基吡啶(820mg,4mmol)溶解于25mL1,4-二氧六环中，加入2-氯苯基硼酸(637mg，4.08mmol)、碳酸钠(848mg，8mmol)、[1,1'‐双(二苯基膦基)二茂铁]二氯化钯(205mg，0.28mmol)和4mL水，在110℃氮气保护下反应5小时。向反应液中加入30mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和食盐水洗涤(30mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化所得残余物(洗脱剂：乙酸乙酯：石油醚＝1：1)，得到2-氯-4-(2-氯苯基)-3-甲基吡啶(890mg，无水液体)，产率：94％。MS m/z(ESI):238.0[M+H] +。 Step 1: Dissolve 4-bromo-2-chloro-3-methylpyridine (820 mg, 4 mmol) in 25 mL of 1,4-dioxane, add 2-chlorophenylboronic acid (637 mg, 4.08 mmol), sodium carbonate (848 mg, 8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (205 mg, 0.28 mmol) and 4 mL of water were reacted under nitrogen at 110 ° C for 5 hours. 30 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (30 mL × 3). The obtained residue was purified (eluent: ethyl acetate: petroleum ether = 1:1) to give 2-chloro-4-(2-chlorophenyl)-3-methylpyridine (890 mg, anhydrous liquid). Rate: 94%. MS m/z (ESI): 238.0 [M+H] + .
步骤2：将2-氯-4-(2-氯苯基)-3-甲基吡啶(120mg，0.51mmol)溶解于20mL 1,4-二氧六环中，加入乙烯基三氟硼酸钾(74mg，0.56mmol)、碳酸钠(162mg,1.53mmol)、[1,1'‐双(二苯基膦基)二茂铁]二氯化钯(29mg，0.04mmol)和4mL水，在80℃氮气保护下反应20小时。向反应液中加入30mL水，用乙酸乙酯萃取(30mL×2)，合并有机相，用饱和食盐水洗涤(30mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化所得残余物(洗脱剂：乙酸乙酯：石油醚＝1：1)，得到4-(2-氯苯基)-3-甲基-2-乙烯基吡啶(100mg，黄色固体)，产率：87％。MS m/z(ESI):230.1[M+H] +。 Step 2: Dissolve 2-chloro-4-(2-chlorophenyl)-3-methylpyridine (120 mg, 0.51 mmol) in 20 mL of 1,4-dioxane and add potassium trifluoroborate ( 74 mg, 0.56 mmol), sodium carbonate (162 mg, 1.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (29 mg, 0.04 mmol) and 4 mL of water at 80 ° C The reaction was carried out under nitrogen for 20 hours. 30 mL of water was added to the reaction mixture, and the mixture was combined with ethyl acetate (30 mL × 2). The obtained residue was purified (EtOAc: EtOAc:EtOAc:EtOAc) Rate: 87%. MS m/z (ESI): 230.1 [M+H] + .
步骤3：将4-溴-3-氯苯甲醛(105mg,0.48mmol)和4-(2-氯苯基)-3-甲基-2-乙烯基吡啶(100mg,0.44mmol)溶解于3mL N,N-二甲基乙酰胺和1mL三乙胺中,加入醋酸钯(10mg,0.044mmol)和三(邻甲基苯基)膦(27mg，0.088mmol)，反应在氮气保护下160℃微波反应30分钟。减压浓缩，用硅胶柱色谱法以展开剂体系(洗脱剂：乙酸乙酯：石油醚＝1：1)纯化所得残余物，得到(E)-3-氯-4-(2-(4-(2-氯苯基)-3-甲基吡啶-2-基)乙烯基)苯甲醛(100mg，黄色固体)，产率：62％。MS m/z(ESI):368.0[M+H] +。 Step 3: Dissolve 4-bromo-3-chlorobenzaldehyde (105 mg, 0.48 mmol) and 4-(2-chlorophenyl)-3-methyl-2-vinylpyridine (100 mg, 0.44 mmol) in 3 mL of N , N-dimethylacetamide and 1 mL of triethylamine, palladium acetate (10 mg, 0.044 mmol) and tris(o-methylphenyl)phosphine (27 mg, 0.088 mmol) were added, and the reaction was carried out under microwave protection at 160 ° C for microwave reaction. 30 minutes. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut -(2-Chlorophenyl)-3-methylpyridin-2-yl)vinyl)benzaldehyde (100 mg, yellow solid), yield: 62%. MS m/z (ESI): 368.0 [M+H] + .
步骤4：将(E)-3-氯-4-(2-(4-(2-氯苯基)-3-甲基吡啶-2-基)乙烯基)苯甲醛(100mg，0.27mmol)和(S)-哌啶-2-羧酸(70mg，0.54mmol)溶解于10mL甲醇中，加入氰基硼氢化钠(34mg, 0.54mmol)，搅拌反应20小时。减压浓缩，用制备色谱法得到标题产物(S,E)-1-(3-氯-4-(2-(4-(2-氯苯基)-3-甲基吡啶-2-基)乙烯基)苄基)哌啶-2-羧酸(化合物P-38)(28mg，白色固体)，产率：21.7％。MS m/z(ESI):481.1[M+H] +。 Step 4: (E)-3-Chloro-4-(2-(4-(2-chlorophenyl)-3-methylpyridin-2-yl)vinyl)benzaldehyde (100 mg, 0.27 mmol) (S)-Piperidine-2-carboxylic acid (70 mg, 0.54 mmol) was dissolved in 10 mL of methanol, and sodium cyanoborohydride (34 mg, 0.54 mmol) was added, and the reaction was stirred for 20 hours. The title product (S, E)-1-(3-chloro-4-(2-(4-(2-chlorophenyl)-3-methylpyridin-2-yl) was obtained by preparative chromatography. Vinyl)benzyl)piperidine-2-carboxylic acid (Compound P-38) (28 mg, white solid). MS m/z (ESI): 481.1 [M+H] + .
实施例39至46Examples 39 to 46
化合物P-39以化合物27a为原料，采用实施例38中步骤4的类似方法制备。Compound P-39 was prepared from compound 27a using a similar procedure as in Step 4 of Example 38.
化合物P-40以化合物28a为原料，采用实施例38中步骤4的类似方法制备。Compound P-40 was prepared from compound 28a using a similar procedure as in step 4 of Example 38.
化合物P-41以化合物29a为原料，采用实施例38中步骤4的类似方法制备。Compound P-41 was prepared from compound 29a using a similar procedure as in step 4 of Example 38.
化合物P-42以化合物30a为原料，采用实施例38中步骤4的类似方法制备。Compound P-42 was prepared from compound 30a using a similar procedure as in Step 4 of Example 38.
化合物P-43以化合物31a为原料，采用实施例38中步骤4的类似方法制备。Compound P-43 was prepared from compound 31a using a similar method to that of step 4 in Example 38.
化合物P-44以化合物11a为原料，采用实施例38中步骤4的类似方法制备。Compound P-44 was prepared from compound 11a using a similar procedure as in step 4 of Example 38.
化合物P-45以化合物32a为原料，采用实施例38中步骤4的类似方法制备。Compound P-45 was prepared from compound 32a using a similar procedure as in step 4 of Example 38.
化合物P-46以化合物33a为原料，采用实施例38中步骤4的类似方法制备。Compound P-46 was prepared from compound 33a using a similar procedure as in step 4 of Example 38.
Figure PCTCN2018122818-appb-000081
Figure PCTCN2018122818-appb-000081
Figure PCTCN2018122818-appb-000082
Figure PCTCN2018122818-appb-000082
实施例48(S,E)-1-(3-氯-4-(2-(3-氰基-2-苯基吡啶-4-基)乙烯基)苄基)哌啶-2-羧酸(P-48)的制备Example 48(S,E)-1-(3-Chloro-4-(2-(3-cyano-2-phenylpyridin-4-yl)vinyl)benzyl)piperidine-2-carboxylic acid Preparation of (P-48)
Figure PCTCN2018122818-appb-000083
Figure PCTCN2018122818-appb-000083
步骤1：将4-甲氧基-2-氧代-1,2-二氢吡啶-3-腈(3.0g，20.0mol)溶解于80mL乙腈中，加入三溴氧磷(11.40g，40.0mmol)，在氩气保护下70℃搅拌反应16小时。向反应液中加入50mL水和50mL饱和食盐水，用乙酸乙酯萃取(100mL×2)，合并有机相，饱和食盐水洗涤(100mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用异丙基醚打浆，过滤，真空干燥得到2,4-二溴吡啶-3-甲腈(4.0g,淡棕色固体)，产率：42.1％。1H NMR(400MHz,DMSO-d6)δ8.51(d,1H),8.05(d,1H).Step 1: 4-Methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (3.0 g, 20.0 mol) was dissolved in 80 mL of acetonitrile, and phosphorus tribromide (11.40 g, 40.0 mmol) was added. The reaction was stirred at 70 ° C for 16 hours under argon gas protection. 50 mL of water and 50 mL of saturated brine were added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL×2). It was pulverized with isopropyl ether, filtered and dried in vacuo to give 2,4-dibromopyridine-3-carbonitrile (4.0 g, pale brown solid). 1H NMR (400MHz, DMSO-d6) δ 8.51 (d, 1H), 8.05 (d, 1H).
步骤2：将2,4-二溴吡啶-3-甲腈(1.05g,4.0mmol)溶解于30mL四氢呋喃和7.5mL水中，加入乙烯基氟硼酸钾(590mg,4.40mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(164mg，0.20mmol)，碳酸钠(1.27g,12.0mmol)，在氩气保护下60℃搅拌反应16小时。加入50mL饱和氯化铵溶液，用乙酸乙酯萃取(50mL×2)，合并有机相，饱和食盐水洗涤(30mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法硅胶柱色谱法以0～20％乙酸乙酯在石油醚中纯化所得残余物，得到2-溴-4-乙烯基烟腈(460mg，白色固体)，产率：54.9％。MS m/z(ESI):209.0,211.0[M+H] +。 Step 2: Dissolve 2,4-dibromopyridine-3-carbonitrile (1.05 g, 4.0 mmol) in 30 mL of tetrahydrofuran and 7.5 mL of water and add potassium fluoroborate (590 mg, 4.40 mmol), [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (164 mg, 0.20 mmol), sodium carbonate (1.27 g, 12.0 mmol), stirred under argon at 60 ° C for 16 hours. . Add 50 mL of a saturated ammonium chloride solution, and extract with ethyl acetate (50 mL × 2), EtOAc (EtOAc) Column chromatography The residue was purified with EtOAc EtOAc (EtOAc) MS m/z (ESI): 209.0, 211.0 [M+H] + .
步骤3：将2-溴-4-乙烯基烟腈(460mg,2.20mmol)溶解于20mL四氢呋喃和5mL水中，加入苯硼酸(402mg,3.30mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(90mg，0.11mmol)，碳酸钠(700mg,6.60mmol)，在氩气保护下回流搅拌反应16小时。加入50mL饱和氯化铵溶液，用乙酸乙酯萃取(40mL×2)，合并有机相，饱和食盐水洗涤(30mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法硅胶柱色谱法以0～20％乙酸乙酯在石油醚中纯化所得残余物，得到2-苯基-4-乙烯基烟腈(350mg，白色固体)，产率：77.2％。MS m/z(ESI):207.1[M+H] +。 Step 3: Dissolve 2-bromo-4-vinylnicotinonitrile (460 mg, 2.20 mmol) in 20 mL of tetrahydrofuran and 5 mL of water, add phenylboronic acid (402 mg, 3.30 mmol), [1,1'-bis(diphenylphosphine) The ferrocene]palladium dichloride dichloromethane complex (90 mg, 0.11 mmol), sodium carbonate (700 mg, 6.60 mmol) was stirred under reflux with argon for 16 hours. After adding 50 mL of a saturated ammonium chloride solution, and extracting with ethyl acetate (40 mL × 2), the organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate Column chromatography The residue was purified with EtOAc EtOAc (EtOAc) MS m/z (ESI): 207.1 [M+H] + .
步骤4：往20mL微波管里加入：2-苯基-4-乙烯基烟腈(100mg，0.48mmol)，4-溴-3-氯-苯甲醛(158mg，0.72mmol)，醋酸钯(11mg，0.05mmol)，三(邻甲基苯)磷(29mg，0.10mmol)，1mL 三乙胺和5mL二甲基乙酰胺。氩气吹1分钟，盖上微波盖，在150℃微波反应30分钟。加入25mL乙酸乙酯，过滤，滤液减压浓缩，用硅胶柱色谱法硅胶柱色谱法以0％～100％二氯甲烷在石油醚中纯化所得残余物，得到(E)-4-(2-氯-4-甲酰基苯乙烯基)-2-苯基烟腈(62mg，灰白色固体)，产率：37.1％。MS m/z(ESI):345.1[M+H] +。 Step 4: To a 20 mL microwave tube was added: 2-phenyl-4-vinylnicotinonitrile (100 mg, 0.48 mmol), 4-bromo-3-chloro-benzaldehyde (158 mg, 0.72 mmol), palladium acetate (11 mg, 0.05 mmol), tris(o-methylphenyl)phosphorus (29 mg, 0.10 mmol), 1 mL of triethylamine and 5 mL of dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwave-reacted at 150 ° C for 30 minutes. 25 mL of ethyl acetate was added, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography eluting with EtOAc Chloro-4-formylstyryl)-2-phenylnicotinonitrile (62 mg, off-white solid), yield: 37.1%. MS m/z (ESI): 345.1 [M+H] + .
步骤5：(E)-4-(2-氯-4-甲酰基苯乙烯基)-2-苯基烟腈(35mg，0.10mmol)和(S)-哌啶-2-羧酸(26mg，0.20mol)溶解于6mL甲醇中，加入氰基硼氢化钠(13mg，0.20mmol)，回流搅拌反应4小时。减压浓缩，用制备HPLC色谱法得到标题产物(S,E)-1-(3-氯-4-(2-(3-氰基-2-苯基吡啶-4-基)乙烯基)苄基)哌啶-2-羧酸(化合物P-48)(11mg，白色固体)，产率：48.8％。MS m/z(ESI):458.1[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.88(d,1H),8.03(d,1H),7.96(d,1H),7.90–7.79(m,3H),7.58-7.56(m,4H),7.47-7.40(m,2H),3.84(d,1H),3.50(d,1H),3.15-3.12(m,1H),2.87-2.80(m,1H),2.24-2.17(m,1H),1.86-1.67(m,2H),1.56-1.32(m,4H). Step 5: (E)-4-(2-Chloro-4-formylstyryl)-2-phenylnicotinonitrile (35 mg, 0.10 mmol) and (S)-piperidine-2-carboxylic acid (26 mg, 0.20 mol) was dissolved in 6 mL of methanol, sodium cyanoborohydride (13 mg, 0.20 mmol) was added, and the reaction was stirred under reflux for 4 hours. The title product (S, E)-1-(3-chloro-4-(2-(3-cyano-2-phenylpyridin-4-yl)vinyl)benzylidene was obtained by preparative HPLC chromatography. Base piperidine-2-carboxylic acid (Compound P-48) (11 mg, white solid), yield: 48.8%. MS m/z (ESI): 458.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.88 (d, 1H), 8.03 (d, 1H), 7.96 (d, 1H), 7.90 - 7.79 (m, 3H), 7.58-7.56 (m, 4H), 7.47-7.40(m,2H), 3.84(d,1H), 3.50(d,1H), 3.15-3.12(m,1H),2.87-2.80(m,1H),2.24-2.17(m,1H), 1.86-1.67 (m, 2H), 1.56-1.32 (m, 4H).
实施例49(S，E)-1-(4-(2-(3-溴-4-苯基吡啶-2-基)乙烯基)-5-氯-2-甲氧基苄基)哌啶-2-羧酸(P-49)的制备Example 49 (S,E)-1-(4-(2-(3-Bromo-4-phenylpyridin-2-yl)vinyl)-5-chloro-2-methoxybenzyl)piperidine Preparation of 2-carboxylic acid (P-49)
Figure PCTCN2018122818-appb-000084
Figure PCTCN2018122818-appb-000084
化合物P-49以化合物34a为原料，采用实施例48中步骤5的类似方法制备。MS m/z(ESI):541.1[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.61(d,1H),8.10(d,1H),7.80(d,1H),7.51-7.41(m,7H),7.31(d,1H),3.86(s,3H),2.96(br,2H),1.71(br,2H),1.53-1.40(m,5H),1.20(s,2H). Compound P-49 was prepared from compound 34a using a similar procedure as in Step 5 in Example 48. MS m/z (ESI): 541.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.61 (d, 1H), 8.10 (d, 1H), 7.80 (d, 1H), 7.51-7.41 (m, 7H), 7.31 (d, 1H), 3.86 ( s, 3H), 2.96 (br, 2H), 1.71 (br, 2H), 1.53-1.40 (m, 5H), 1.20 (s, 2H).
实施例50(S,E)-1-(4-(2-(4-(苯并[d]噁唑-6-基)-3-氰基吡啶-2-基)乙烯基)-5-氯-2-甲氧基苄基)哌啶-2-羧酸(P-50)的制备Example 50 (S,E)-1-(4-(2-(4-(benzo[d]oxazol-6-yl)-3-cyanopyridin-2-yl)vinyl)-5- Preparation of chloro-2-methoxybenzyl)piperidine-2-carboxylic acid (P-50)
Figure PCTCN2018122818-appb-000085
Figure PCTCN2018122818-appb-000085
步骤1：将6-溴苯并[d]噁唑(500mg，2.53mmol)溶解于20mL 1,4-二氧六环中，依次加入联硼酸频那醇酯(962mg，3.79mmol)，醋酸钾(743mg，7.58mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(207mg，0.25mmol)，氮气置换三次，加热到100℃，搅拌反应20小时后冷却至室温，反应液通过硅藻土过滤，滤液减压浓缩，剩余物用硅胶柱色谱法(洗脱剂：石油醚：乙酸乙酯＝80:20)纯化后得化合物6-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯并[d]噁唑(520mg，白色固体)，产率：85％。MS m/z(ESI):246.1[M+H] +。 Step 1: 6-Bromobenzo[d]oxazole (500 mg, 2.53 mmol) was dissolved in 20 mL of 1,4-dioxane, followed by the addition of pinacol borate (962 mg, 3.79 mmol), potassium acetate. (743 mg, 7.58 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (207 mg, 0.25 mmol), three times with nitrogen, heated to 100 ° C, After the reaction was stirred for 20 hours, the mixture was cooled to room temperature. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc. -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (520 mg, white solid), yield: 85%. MS m/z (ESI): 242.[M+H] + .
步骤2：将6-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯并[d]噁唑(520mg，2.12mmol)溶解于20mL1,4-二氧六环中，依次加入2,4-二溴烟腈(552mg，2.12mmol)，碳酸钾(585mg，4.24mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(173mg，0.21mmol)和2mL水，氮气置换三次，加热到100℃，搅拌反应20小时后冷却至室温，反应液通过硅藻土过滤，滤液减压浓缩，剩余物用硅胶柱色谱法(洗脱剂：石油醚：乙酸乙酯＝70:30)纯化后得化合物4-(苯并[d]噁唑-6-基)-2-溴烟腈(442mg，白色固体)，产率：70％。MS m/z(ESI):300.2[M+H] +。 Step 2: Dissolve 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (520 mg, 2.12 mmol) in 20 mL 1 In the 4-dioxane, 2,4-dibromonicotinonitrile (552 mg, 2.12 mmol), potassium carbonate (585 mg, 4.24 mmol), [1,1'-bis(diphenylphosphine) dioxin were sequentially added. Iron] palladium dichloride dichloromethane complex (173 mg, 0.21 mmol) and 2 mL of water, three times with nitrogen, heated to 100 ° C, stirred for 20 hours, cooled to room temperature, filtered through celite, filtrate reduced The mixture was concentrated under pressure and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 70:30) to give compound 4-(benzo[d]oxazol-6-yl)-2-bromo Nitrile (442 mg, white solid), yield: 70%. MS m/z (ESI): 300.2 [M+H] + .
步骤3：将4-(苯并[d]噁唑-6-基)-2-溴烟腈(442mg，1.47mmol)溶解于20mL 1,4-二氧六环中，依次加入乙烯三氟硼酸钾(592mg，4.42mmol)，碳酸钾(611mg，4.42mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(120mg，0.15mmol)和2mL水，氮气置换三次，加热到100℃，搅拌反应16小时后冷却至室温，反应液通过硅藻土过滤，滤液减压浓缩，剩余物用硅胶柱色谱法(洗脱剂：石油醚：乙酸乙酯＝80:20)纯化后得化合物4-(苯并[d]噁唑-6-基)-2-乙烯基烟腈(114mg，白色固体)，产率：31％。MS m/z(ESI):248.1[M+H] +。 Step 3: Dissolve 4-(benzo[d]oxazol-6-yl)-2-bromonicotinonitrile (442 mg, 1.47 mmol) in 20 mL of 1,4-dioxane, followed by ethylene trifluoroborate Potassium (592 mg, 4.42 mmol), potassium carbonate (611 mg, 4.42 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (120 mg, 0.15 mmol) And 2 mL of water, nitrogen was replaced three times, heated to 100 ° C, stirred for 16 hours, cooled to room temperature, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure, and the residue was applied to silica gel column chromatography (eluent: petroleum ether: Ethyl acetate = 80: 20) purified to give the compound 4-(benzo[d]oxazole-6-yl)-2-vinylnicotinonitrile (114 mg, white solid). MS m / z (ESI): 248.1 [M + H] +.
步骤4：将4-(苯并[d]噁唑-6-基)-2-乙烯基烟腈(114mg，0.46mmol)溶解于3mL N,N-二甲基乙酰胺中，依次加入4-溴-5-氯-2-甲氧基苯甲醛(172mg，0.69mmol)，醋酸钯(10mg，0.046mmol)，三(邻甲基苯基)磷(28mg，0.092mmol)和1mL三乙胺，氮气置换三次，加热到150℃，在微波反应器中搅拌反应60分钟后冷却至室温，反应液通过硅藻土过滤，滤液减压浓缩，剩余物用硅胶柱色谱法(洗脱剂：石油醚：乙酸乙酯＝60:40)纯化后得目标化合物(E)-4-(苯并[d]噁唑-6-基)-2-(2-氯-4-甲酰基-5-甲氧基苯乙烯基)烟腈(140mg，黄色固体)，产率：73％。MS m/z(ESI):416.2[M+H] +。 Step 4: Dissolve 4-(benzo[d]oxazol-6-yl)-2-vinylnicotinonitrile (114 mg, 0.46 mmol) in 3 mL of N,N-dimethylacetamide and add 4- Bromo-5-chloro-2-methoxybenzaldehyde (172 mg, 0.69 mmol), palladium acetate (10 mg, 0.046 mmol), tris(o-methylphenyl)phosphonate (28 mg, 0.092 mmol) and 1 mL triethylamine. The mixture was replaced with nitrogen three times, heated to 150 ° C, stirred in a microwave reactor for 60 minutes, and then cooled to room temperature. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. :ethyl acetate = 60:40) The title compound (E)-4-(benzo[d]oxazole-6-yl)-2-(2-chloro-4-formyl-5-methoxy) was obtained after purification. Nitrostyrene) Nicotinonitrile (140 mg, yellow solid), Yield: 73%. MS m/z (ESI): 416.2 [M+H] + .
步骤5：将(E)-4-(苯并[d]噁唑-6-基)-2-(2-氯-4-甲酰基-5-甲氧基苯乙烯基)烟腈(140mg，0.34mmol)溶解于20mL甲醇中，依次加入L-哌啶-2-甲酸(129mg，1.01mmol)，氰基硼氢化钠(64mg，1.01mmol)，氮气置换三次，加热到85℃，搅拌反应16小时，冷却到室温，反应液减压浓缩，剩余物用制备色谱法纯化后得目标化合物(S,E)-1-(4-(2-(4-(苯并[d]噁唑-6-基)-3-氰基吡啶-2-基)乙烯基)-5-氯-2-甲氧基苄基)哌啶-2-羧酸(化合物P-50)(11mg，黄色固体)，产率：6％。MS m/z(ESI):529.3[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.91-8.88(m,2H),8.30(d,1H),8.15(s,1H),7.99(d,1H),7.70-7.62(m，3H),7.51(s,1H),7.39(s,1H),3.86(s,3H),3.72-3.58(m,2H),3.16(br,1H),2.85(br,1H),2.23(br,1H),1.77(br,2H),1.48-1.37(m,4H). Step 5: (E)-4-(Benzo[d]oxazol-6-yl)-2-(2-chloro-4-formyl-5-methoxystyryl)nicotinonitrile (140 mg, 0.34 mmol) was dissolved in 20 mL of methanol, and then added L-piperidine-2-carboxylic acid (129 mg, 1.01 mmol), sodium cyanoborohydride (64 mg, 1.01 mmol), three times with nitrogen, heated to 85 ° C, stirring reaction 16 After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative chromatography to give the title compound (S, E)-1-(4-(4-(4-(benzo[d]oxazole-6) -yl)cyanopyridin-2-yl)vinyl)-5-chloro-2-methoxybenzyl)piperidine-2-carboxylic acid (Compound P-50) (11 mg, yellow solid) Yield: 6%. MS m/z (ESI): 529.3 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ8.91-8.88 (m, 2H), 8.30 (d, 1H), 8.15 (s, 1H), 7.99 (d, 1H), 7.70-7.62 (m, 3H) , 7.51 (s, 1H), 7.39 (s, 1H), 3.86 (s, 3H), 3.72-3.58 (m, 2H), 3.16 (br, 1H), 2.85 (br, 1H), 2.23 (br, 1H) ), 1.77 (br, 2H), 1.48-1.37 (m, 4H).
实施例51(2S，E)-1-(4-(2-(4-(苯并[d]噻唑-5-基)-3-氰基吡啶-2-基)乙烯基)-5-氯-2-甲氧基苄基)哌啶2-羧酸(P-51)的制备Example 51 (2S,E)-1-(4-(2-(4-(benzo[d]thiazol-5-yl)-3-cyanopyridin-2-yl)vinyl)-5-chloro Preparation of 2-methoxybenzyl)piperidine 2-carboxylic acid (P-51)
Figure PCTCN2018122818-appb-000086
Figure PCTCN2018122818-appb-000086
化合物P-51采用实施例50类似的方法制备。MS m/z(ESI):545.1[M+H] +。1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.92(d,1H),8.40-8.29(d,3H),7.76(d,1H),7.68-7.63(m,2H),7.51(s,1H),7.40(s,1H),3.86(s,3H),3.72-3.58(m,2H),3.17(br,1H),2.85(br,1H),2.23(br,1H),1.76(br,2H),1.48-1.38(m,4H). Compound P-51 was prepared in a similar manner to that in Example 50. MS m/z (ESI): 545.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 9.51 (s, 1H), 8.92 (d, 1H), 8.40-8.29 (d, 3H), 7.76 (d, 1H), 7.68-7.63 (m, 2H), 7.51 (s, 1H), 7.40 (s, 1H), 3.86 (s, 3H), 3.72-3.58 (m, 2H), 3.17 (br, 1H), 2.85 (br, 1H), 2.23 (br, 1H) , 1.76 (br, 2H), 1.48-1.38 (m, 4H).
实施例52(2S)-1-[[5-氯-4-[(E)-2-[3-氰基-4-(2,6-二氟苯基)-2-吡啶基]乙烯基]-2-甲氧基-苯基]甲基]哌啶-2-羧酸(P-52)的制备Example 52(2S)-1-[[5-chloro-4-[(E)-2-[3-cyano-4-(2,6-difluorophenyl)-2-pyridyl]vinyl Preparation of 2-methoxy-phenyl]methyl]piperidine-2-carboxylic acid (P-52)
Figure PCTCN2018122818-appb-000087
Figure PCTCN2018122818-appb-000087
步骤1：将2，4-二溴烟腈(1.31g,5.0mmol)溶解于20mL1,4-二氧六环和6mL水中，加入2，6-二氟苯基硼酸频哪醇酯(1.2g,5.0mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(370mg,0.50mmol)，碳酸钠(530mg,5.0mmol)，在氩气保护下100℃搅拌反应过夜。反应液过滤，滤液减压浓缩，用硅胶柱色谱法以10～30％乙酸乙酯在石油醚中纯化，得到产物2-溴-4-(2，6-二氟苯基)烟腈(400mg，淡棕色固体)，产率：30.3％。MS m/z(ESI):295.1[M+H] +。 Step 1: 2,4-dibromonicotinonitrile (1.31 g, 5.0 mmol) was dissolved in 20 mL of 1,4-dioxane and 6 mL of water, and 2,6-difluorophenylboronic acid pinacol ester (1.2 g) was added. , 5.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (370 mg, 0.50 mmol), sodium carbonate (530 mg, 5.0 mmol) in argon The reaction was stirred at 100 ° C under a gas atmosphere overnight. The reaction solution was filtered, and the filtrate was evaporated, evaporated, mjjjjjjjjjjj , light brown solid), yield: 30.3%. MS m/z (ESI): 295.1 [M+H] + .
步骤2：将2-溴-4-(2，6-二氟苯基)烟腈(410mg,1.30mmol)溶解于15mL1,4-二氧六环和5mL水中，加入乙烯基氟硼酸钾(200mg,1.30mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(100mg，0.13mmol)，碳酸钠(140mg,1.30mmol)，在氩气保护下100℃搅拌反应16小时。反应液过滤，滤液减压浓缩，用硅胶柱色谱法以0～25％乙酸乙酯在石油醚中纯化，得到产物4-(2，6-二氟苯基)-2-乙烯基烟腈(103mg，无色液体)，产率：31.1％。MS m/z(ESI):243.2[M+H] +。 Step 2: Dissolve 2-bromo-4-(2,6-difluorophenyl)nicotinonitrile (410 mg, 1.30 mmol) in 15 mL of 1,4-dioxane and 5 mL of water, and add potassium fluoroborate (200 mg). , 1.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (100 mg, 0.13 mmol), sodium carbonate (140 mg, 1.30 mmol) in argon The reaction was stirred at 100 ° C for 16 hours under gas protection. The reaction solution was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjjjj 103 mg, colorless liquid), yield: 31.1%. MS m / z (ESI): 243.2 [M + H] +.
步骤3：往20mL微波管里加入：4-(2，6-二氟苯基)-2-乙烯基烟腈(50mg，0.20mmol)，4-溴-5-氯-2-甲氧基苯甲醛(50mg，0.20mmol)，醋酸钯(4.5mg，0.1mmol)，三(邻甲基苯)磷(6.0mg，0.1mmol)，0.2mL三乙胺和3mL二甲基乙酰胺。氩气吹1分钟，盖上微波盖，在160℃微波反应45分钟。减压浓缩，用硅胶柱色谱法以0％～40％乙酸乙酯在石油醚中纯化，得到标题产物(E)-2-((2-氯-4-甲酰基-5-甲氧基苯基)烯基)-4-(2,6-二氟苯基)烟腈(41mg，黄色固体)，产率：48.4％。MS m/z(ESI):411.1[M+H] +。 Step 3: Add to the 20 mL microwave tube: 4-(2,6-difluorophenyl)-2-vinylnicotinonitrile (50 mg, 0.20 mmol), 4-bromo-5-chloro-2-methoxybenzene Formaldehyde (50 mg, 0.20 mmol), palladium acetate (4.5 mg, 0.1 mmol), tris(o-methylphenyl)phosphine (6.0 mg, 0.1 mmol), 0.2 mL of triethylamine and 3 mL of dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwave-reacted at 160 ° C for 45 minutes. Concentration under reduced pressure, EtOAc (EtOAc:EtOAc) Alkenyl)-4-(2,6-difluorophenyl)nicotinonitrile (41 mg, yellow solid), yield: 48.4%. MS m/z (ESI): 4121. [M+H] + .
步骤4：(E)-2-((2-氯-4-甲酰基-5-甲氧基苯基)烯基)-4-(2,6-二氟苯基)烟腈(41mg，0.1mmol)和(S)-哌啶-2-羧酸(26mg，0.2mol)溶解于10mL甲醇中，加入氰基硼氢化钠(10mg，0.15mmol)，回流搅拌反应2小时。减压浓缩，用制备HPLC色谱法得到标题产物(2S)-1-[[5-氯-4-[(E)-2-[3-氰基-4-(2,6-二氟苯基)-2-吡啶基]乙烯基]-2-甲氧基-苯基]甲基]哌啶-2-羧酸(化合物P-52)(6mg，白色固体)，产率：17.9％。MS m/z(ESI):524.1[M+H] +。1H NMR(400MHz,DMSO-d6)δ9.02(d,1H),8.36(d,1H),7.70-7.76(m,3H),7.62-7.68(m,2H),7.40-7.49(m,2H),3.89(s,3H),3.61-3.72(m,2H),3.25(d,1H),2.89(d,1H),2.26(d,1H),1.78(d,2H),1.57-1.33(m,4H). Step 4: (E)-2-((2-Chloro-4-formyl-5-methoxyphenyl)alkenyl)-4-(2,6-difluorophenyl)nicotinonitrile (41 mg, 0.1 Methyl) and (S)-piperidine-2-carboxylic acid (26 mg, 0.2 mol) were dissolved in 10 mL of methanol, sodium cyanoborohydride (10 mg, 0.15 mmol) was added, and the mixture was stirred under reflux for 2 hours. The title product (2S)-1-[[5-chloro-4-[(E)-2-[3-cyano-4-(2,6-difluorophenyl) was obtained. -2-Pyridyl]vinyl]-2-methoxy-phenyl]methyl]piperidine-2-carboxylic acid (Compound P-52) (6 mg, white solid). MS m/z (ESI): 524.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 9.02 (d, 1H), 8.36 (d, 1H), 7.70-7.76 (m, 3H), 7.62-7.68 (m, 2H), 7.40-7.49 (m, 2H) ), 3.89 (s, 3H), 3.61-3.72 (m, 2H), 3.25 (d, 1H), 2.89 (d, 1H), 2.26 (d, 1H), 1.78 (d, 2H), 1.57-1.33 ( m, 4H).
实施例53(2S)-1-[[2-(3-羧基环丁氧基)-5-氯-4-[(E)-2-(3-氰基-4-苯基-2-吡啶基)乙烯基]苯基]甲基]哌啶-2-羧酸(P-53)的制备Example 53(2S)-1-[[2-(3-Carboxycyclobutoxy)-5-chloro-4-[(E)-2-(3-cyano-4-phenyl-2-pyridine) Of vinyl)phenyl]methyl]piperidine-2-carboxylic acid (P-53)
Figure PCTCN2018122818-appb-000088
Figure PCTCN2018122818-appb-000088
步骤1：将3-羟基环丁基甲酸甲酯(650mg，5.0mol)和三乙胺(1g，10.0mol)溶解于15mL二氯甲烷中，在氩气保护下，0℃缓慢加入三氟甲磺酐(1.86g，6.5mmol)，0℃搅拌反应0.5小时。向反应液中加入50mL水，用二氯甲烷萃取(100mL×2)，合并有机相，饱和食盐水洗涤(100mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物3-(三氟磺酰氧基)环丁基甲酸甲酯(780mg，无色液体)，产率：62.1％。Step 1: Methyl 3-hydroxycyclobutylcarboxylate (650 mg, 5.0 mol) and triethylamine (1 g, 10.0 mol) were dissolved in 15 mL of dichloromethane, and trifluoromethyl was slowly added at 0 ° C under argon atmosphere. The sulfonic anhydride (1.86 g, 6.5 mmol) was stirred at 0 ° C for 0.5 h. 50 mL of water was added to the reaction mixture, and the mixture was extracted with methylene chloride (100 mL × 2). The organic phase was combined, washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate Methyl (trifluorosulfonyloxy)cyclobutylcarboxylate (780 mg, colorless liquid), yield: 62.1%.
步骤2：将3-(三氟磺酰氧基)环丁基甲酸甲酯(650mg，2.4mmol)，4-溴-5-氯-2-羟基苯甲醛(470mg，2.0mmol)，碳酸钾(1.0g，6mmol)和碘化钾(700mg，4mmol)溶解于15mL二甲基甲酰胺中，130℃搅拌反应1小时。向反应液中加入50mL水，用二氯甲烷萃取(100mL×2)，合并有机相，水洗涤(100mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以0％～23％乙酸乙酯在石油醚中纯化，得到产物3-(5-溴-4-氯-2-甲酰基苯氧基)环丁烷甲酸甲酯(230mg，无色液体)，产率：32.1％。MS m/z(ESI):349.1[M+H] +。 Step 2: Methyl 3-(trifluorosulfonyloxy)cyclobutylcarboxylate (650 mg, 2.4 mmol), 4-bromo-5-chloro-2-hydroxybenzaldehyde (470 mg, 2.0 mmol), 1.0 g, 6 mmol) and potassium iodide (700 mg, 4 mmol) were dissolved in 15 mL of dimethylformamide, and stirred at 130 ° C for 1 hour. 50 ml of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL×2). The organic phase was combined, washed with water (100 mL×2), dried over anhydrous sodium sulfate 0% to 23% ethyl acetate was purified in petroleum ether to give the product methyl 3-(5-bromo-4-chloro-2-formylphenoxy)cyclobutanecarboxylate (230 mg, colorless liquid). Rate: 32.1%. MS m/z (ESI): 349.1 [M+H] + .
步骤3：往20mL微波管里加入：4-苯基-2-乙烯基烟腈(41mg，0.20mmol)，3-(5-溴-4-氯-2-甲酰基苯氧基)环丁烷甲酸甲酯(76mg，0.20mmol)，醋酸钯(4.5mg，0.1mmol)，三(邻甲基苯)磷(6.0mg，0.1mmol)，0.2mL三乙胺和3mL二甲基乙酰胺。氩气吹1分钟，盖上微波盖，160℃微波反应45分钟。减压浓缩，用硅胶柱色谱法以0％～40％乙酸乙酯在石油醚中纯化，得到标题产物(E)-3-(4-氯-5-(2-(3-腈-4-苯基吡啶-2-基)乙烯基)-2-甲酰基苯氧基)环丁烷甲酸甲酯(50mg，黄色固体)，产率：47.6％。MS m/z(ESI):473.1[M+H] +。 Step 3: Add to the 20 mL microwave tube: 4-phenyl-2-vinyl nicotinonitrile (41 mg, 0.20 mmol), 3-(5-bromo-4-chloro-2-formylphenoxy)cyclobutane Methyl formate (76 mg, 0.20 mmol), palladium acetate (4.5 mg, 0.1 mmol), tris(o-methylphenyl)phosphine (6.0 mg, 0.1 mmol), 0.2 mL of triethylamine and 3 mL of dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwaved at 160 ° C for 45 minutes. Concentration under reduced pressure and purification with EtOAc EtOAc EtOAc EtOAc Methyl phenylpyridin-2-yl)vinyl)-2-formylphenoxy)cyclobutanecarboxylate (50 mg, yellow solid), yield: 47.6%. MS m/z (ESI): 473.1 [M+H] + .
步骤4：(E)-3-(4-氯-5-(2-(3-腈-4-苯基吡啶-2-基)乙烯基)-2-甲酰基苯氧基)环丁烷甲酸甲酯(47mg，0.1mmol)和(S)-哌啶-2-羧酸(26mg，0.2mol)溶解于10mL甲醇中，加入氰基硼氢化钠(10mg，0.15mmol)，回流搅拌反应2小时。减压浓缩，得到产物(S,E)-1-(5-氯-4-(2-(3-腈-4-苯基吡啶-2-基)乙烯基)-2-(3-(甲氧羰基)环丁氧基)苯基)吡啶-2-羧酸(70mg，白色固体)，产率：100％。Step 4: (E)-3-(4-Chloro-5-(2-(3-carbonitrile-4-phenylpyridin-2-yl)vinyl)-2-formylphenoxy)cyclobutanecarboxylic acid The methyl ester (47 mg, 0.1 mmol) and (S)-piperidine-2-carboxylic acid (26 mg, 0.2 mol) were dissolved in 10 mL of methanol, sodium cyanoborohydride (10 mg, 0.15 mmol) was added, and the mixture was stirred and refluxed for 2 hours. . Concentration under reduced pressure gave the product (S, E)-1-(5-chloro-4-(2-(3-carbonitrile-4-phenylpyridin-2-yl)vinyl)-2-(3-(A) Oxycarbonyl)cyclobutoxy)phenyl)pyridine-2-carboxylic acid (70 mg, white solid), yield: 100%.
步骤5：(S,E)-1-(5-氯-4-(2-(3-腈-4-苯基吡啶-2-基)乙烯基)-2-(3-(甲氧羰基)环丁氧基)苯基)吡啶-2-羧酸(70mg，0.12mmol)和氢氧化钠(10mg，0.24mol)溶解于5mL甲醇和3mL水中，40℃搅拌反应10分钟。减压浓缩，用制备HPLC色谱法得到标题产物(2S)-1-[[2-(3-羧基环丁氧基)-5-氯-4-[(E)-2-(3-氰基-4-苯基-2-吡啶基)乙烯基]苯基]甲基]哌啶-2-羧酸(化合物P-53)(9mg，白色固体)，产率：13.6％。MS m/z(ESI):572.1[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.86(d,1H),8.24(d,1H),7.69(d,2H),7.57-7.54(m,6H),7.09(d,1H),4.76(m,1H),3.63(m,2H),3.12(d,2H),2.89(d,1H),2.63(m,3H),2.26(d,2H),1.74(d,2H),1.54-1.33(m,4H). Step 5: (S,E)-1-(5-chloro-4-(2-(3-carbonitrile-4-phenylpyridin-2-yl)vinyl)-2-(3-(methoxycarbonyl) Cyclobutoxy)phenyl)pyridine-2-carboxylic acid (70 mg, 0.12 mmol) and sodium hydroxide (10 mg, 0.24 mol) were dissolved in 5 mL of methanol and 3 mL of water, and the mixture was stirred at 40 ° C for 10 minutes. The title product (2S)-1-[[2-(3-carboxycyclobutoxy)-5-chloro-4-[(E)-2-(3-cyano) 4-Phenyl-2-pyridyl)vinyl]phenyl]methyl]piperidine-2-carboxylic acid (Compound P-53) (9 mg, white solid). MS m/z (ESI): 5721. [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.86 (d, 1H), 8.24 (d, 1H), 7.69 (d, 2H), 7.57-7.54 (m, 6H), 7.09 (d, 1H), 4.76 ( m,1H), 3.63 (m, 2H), 3.12 (d, 2H), 2.89 (d, 1H), 2.63 (m, 3H), 2.26 (d, 2H), 1.74 (d, 2H), 1.54-1.33 (m, 4H).
实施例54(2S)-1-[[5-氯-4-[(E)-2-(3-氰基-4-苯基-2-吡啶基)乙烯基]-2-(1-苯基乙氧基)苯基]甲基]哌啶-2-羧酸(P-54)的制备Example 54 (2S)-1-[[5-chloro-4-[(E)-2-(3-cyano-4-phenyl-2-pyridyl)vinyl]-2-(1-benzene Preparation of ethoxy)phenyl]methyl]piperidine-2-carboxylic acid (P-54)
Figure PCTCN2018122818-appb-000089
Figure PCTCN2018122818-appb-000089
步骤1：将1-(溴乙基)苯(280mg，1.5mmol)，4-溴-5-氯-2-羟基苯甲醛(117mg，0.5mmol)，碳酸钾(200mg，1.5mmol)和碘化钾(160mg，1.0mmol)溶解于15mL二甲基甲酰胺中，130℃搅拌反应1小时。向反应液中加入50mL水，用二氯甲烷萃取(100mL×2)，合并有机相，水洗涤(100mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物4-溴-5-氯-2-(1-苯乙氧基)苯甲醛(290mg，无色液体)，产率：98.1％。Step 1: 1-(Bromoethyl)benzene (280 mg, 1.5 mmol), 4-bromo-5-chloro-2-hydroxybenzaldehyde (117 mg, 0.5 mmol), potassium carbonate (200 mg, 1.5 mmol) and potassium iodide ( 160 mg, 1.0 mmol) was dissolved in 15 mL of dimethylformamide, and the reaction was stirred at 130 ° C for 1 hour. 50 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL×2). The organic phase was combined, washed with water (100 mL×2), dried over anhydrous sodium sulfate, filtered, 5-Chloro-2-(1-phenylethoxy)benzaldehyde (290 mg, colorless liquid), yield: 98.1%.
步骤2：往20mL微波管里加入：4-苯基-2-乙烯基烟腈(70mg，0.35mmol)，4-溴-5-氯-2-(1-苯乙氧基)苯甲醛(290mg，0.70mmol)，醋酸钯(8.0mg，0.07mmol)，三(邻甲基苯)磷(12.0mg，0.07mmol)，0.4mL三乙胺和4mL二甲基乙酰胺。氩气吹1分钟，盖上微波盖，160℃微波反应45分钟。减压浓缩，用硅胶柱色谱法以0％～50％乙酸乙酯在石油醚中纯化，得到产物(E)-2-(2-氯-4-甲酰基-5-(1-苯氧基)苯乙烯基-4-苯基烟酰胺(47mg，黄色固体)，产率：27.6％。MS m/z(ESI):465.1[M+H] +。 Step 2: Add to a 20 mL microwave tube: 4-phenyl-2-vinyl nicotinonitrile (70 mg, 0.35 mmol), 4-bromo-5-chloro-2-(1-phenylethoxy)benzaldehyde (290 mg) , 0.70 mmol), palladium acetate (8.0 mg, 0.07 mmol), tris(o-methylphenyl)phosphine (12.0 mg, 0.07 mmol), 0.4 mL of triethylamine and 4 mL of dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwaved at 160 ° C for 45 minutes. Concentration under reduced pressure, purification by silica gel column chromatography eluting with EtOAc EtOAc EtOAc EtOAc ) styrene-4-phenyl nicotinamide (47 mg, yellow solid), yield: 27.6% .MS m / z ( ESI): 465.1 [m + H] +.
步骤3：(E)-2-(2-氯-4-甲酰基-5-(1-苯氧基)苯乙烯基-4-苯基烟酰胺(47mg，0.1mmol)和(S)-哌啶-2-羧酸(26mg，0.2mol)溶解于10mL甲醇中，加入氰基硼氢化钠(10mg，0.15mmol)，回流搅拌反应2小时。减压浓缩，用制备HPLC色谱法得到产物(2S)-1-[[5-氯-4-[(E)-2-(3-氰基-4-苯基-2-吡啶基)乙基]-2-(1-苯基乙氧基)苯基]甲基]哌啶-2-羧酸(化合物P-54)(6.53mg，白色固体)，产率：13.2％。MS m/z(ESI):578.1[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.86(d,1H),8.14(d,1H),7.67-7.23(m,14H),5.69(s,1H),3.89(s,2H),3.12(d,2H),2.93(d,2H),1.89(d,1H),1.81(d,1H),1.59-1.33(m,6H). Step 3: (E)-2-(2-Chloro-4-formyl-5-(1-phenoxy)styryl-4-phenylnicotinamide (47 mg, 0.1 mmol) and (S)- The pyridine-2-carboxylic acid (26 mg, 0.2 mol) was dissolved in 10 mL of methanol, and sodium cyanoborohydride (10 mg, 0.15 mmol) was added, and the mixture was stirred under reflux for 2 hours, concentrated under reduced pressure and purified by preparative HPLC (2S) )-1-[[5-chloro-4-[(E)-2-(3-cyano-4-phenyl-2-pyridyl)ethyl]-2-(1-phenylethoxy) Phenyl]methyl]piperidine-2-carboxylic acid (Compound P-54) (6.53 mg, white solid), yield: 13.2%. MS m/z (ESI): 578.1 [M+H] + . NMR (400MHz, DMSO-d6) δ 8.86 (d, 1H), 8.14 (d, 1H), 7.67-7.23 (m, 14H), 5.69 (s, 1H), 3.89 (s, 2H), 3.12 (d) , 2H), 2.93 (d, 2H), 1.89 (d, 1H), 1.81 (d, 1H), 1.59-1.33 (m, 6H).
实施例55(S，E)-1-(5-氯-2-甲氧基-4-(2-(4-苯基-3-(三氟甲基)吡啶-2-基)乙烯基)苄基)哌啶-2-羧酸(P-55)的制备Example 55(S,E)-1-(5-Chloro-2-methoxy-4-(2-(4-phenyl-3-(trifluoromethyl)pyridin-2-yl)vinyl) Preparation of benzyl)piperidine-2-carboxylic acid (P-55)
Figure PCTCN2018122818-appb-000090
Figure PCTCN2018122818-appb-000090
步骤1：将2-甲氧基-4-苯基-3-(三氟甲基)吡啶(470mg，1.86mol)溶解于10mL乙腈中，一次性加入三溴氧磷(1.07g，3.72mmol)，加热到80摄氏度搅拌反应3小时。反应液冷却到室温后，在搅拌下慢慢倒入冰水中，用乙酸乙酯萃取(30mL×2)。合并有机相，用饱和食盐水洗(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品2-溴-4-苯基-3-(三氟甲基)吡啶(460mg，黄色油状物)，产率：81.9％，该粗产品无需纯化，直接用于下一步反应。MS m/z(ESI):304.0[M+H] +。 Step 1: 2 -Methoxy-4-phenyl-3-(trifluoromethyl)pyridine (470 mg, 1.86 mol) was dissolved in 10 mL of acetonitrile, and then added to the solution of phosphorus bromide (1.07 g, 3.72 mmol) The mixture was heated to 80 ° C and stirred for 3 hours. After the reaction mixture was cooled to room temperature, it was slowly poured into ice water with stirring, and extracted with ethyl acetate (30 mL × 2). The organic phase was combined, washed with EtOAc EtOAc EtOAc m. The yield was 81.9%. The crude product was used in the next step without purification. MS m/z (ESI): 304.0 [M+H] + .
步骤2：将2-溴-4-苯基-3-(三氟甲基)吡啶(460mg，1.52mmol)溶解于15mL1,4-二氧六环和1mL水中，加入乙烯基氟硼酸钾(408mg,3.04mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(124mg，0.15mmol)，碳酸钾(420mg，3.04mmol)，在氩气保护下80℃搅拌反应16小时。反应液减压浓缩，加入50mL乙酸乙酯，过滤，滤液减压浓缩，用硅胶柱色谱法硅胶柱色谱法以0～10％乙酸乙酯在石油醚中纯化所得残余物，得到产物4-苯基-3-(三氟甲基)-2-乙烯基吡啶(175mg，黄色油状物)，产率：46.3％。MS m/z(ESI):250.1[M+H] +。 Step 2: Dissolve 2-bromo-4-phenyl-3-(trifluoromethyl)pyridine (460 mg, 1.52 mmol) in 15 mL of 1,4-dioxane and 1 mL of water and add potassium fluoroborate (408 mg). , 3.04 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (124 mg, 0.15 mmol), potassium carbonate (420 mg, 3.04 mmol) in argon The reaction was stirred at 80 ° C for 16 hours under gas protection. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Base-3-(trifluoromethyl)-2-vinylpyridine (175 mg, yellow oil), yield: 46.3%. MS m/z (ESI): 250.1 [M+H] + .
步骤3：往20mL微波管里加入：4-苯基-3-(三氟甲基)-2-乙烯基吡啶(125mg，0.5mmol)，4-溴-5-氯-2-甲氧基苯甲醛(187mg，0.75mmol)，醋酸钯(11mg，0.05mmol)，三(邻甲基苯)磷(15mg，0.05mmol)，0.5mL三乙胺和4mL二甲基乙酰胺。氩气吹2分钟，盖上微波盖，在160℃微波反应45分钟。加入30mL乙酸乙酯，过滤，滤液减压浓缩，用硅胶柱色谱法硅胶柱色谱法以0～30％乙酸乙酯在石油醚中纯化所得残余物，得到产物(E)-5-氯-2-甲氧基-4-(2-(4-苯基-3-(三氟甲基)吡啶-2-基)乙烯基)苯甲醛(115mg，黄色固体)，产率：55.0％。MS m/z(ESI):418.1[M+H] +。 Step 3: Add to the 20 mL microwave tube: 4-phenyl-3-(trifluoromethyl)-2-vinylpyridine (125 mg, 0.5 mmol), 4-bromo-5-chloro-2-methoxybenzene Formaldehyde (187 mg, 0.75 mmol), palladium acetate (11 mg, 0.05 mmol), tris(o-methylphenyl)phosphine (15 mg, 0.05 mmol), 0.5 mL of triethylamine and 4 mL of dimethylacetamide. The mixture was blown with argon for 2 minutes, covered with a microwave cover, and microwave-reacted at 160 ° C for 45 minutes. 30 mL of ethyl acetate was added, and the filtrate was concentrated under reduced pressure. The residue obtained was purified from silica gel column chromatography eluting with Methoxy-4-(2-(4-phenyl-3-(trifluoromethyl)pyridin-2-yl)vinyl)benzaldehyde (115 mg, yellow solid), yield: 55.0%. MS m/z (ESI): 418.1 [M+H] + .
步骤4：将(E)-5-氯-2-甲氧基-4-(2-(4-苯基-3-(三氟甲基)吡啶-2-基)乙烯基)苯甲醛(42mg，0.1mol)和(S)-哌啶-2-羧酸(26mg，0.2mol)溶解于3mL甲醇中，加入氰基硼氢化钠(13mg，0.2mmol)，回流搅拌反应1小时。减压浓缩，用制备HPLC色谱法得到产物(S，E)-1-(5-氯-2-甲氧基-4-(2-(4-苯基-3-(三氟甲基)吡啶-2-基)乙烯基)苄基)哌啶-2-羧酸的甲酸盐(化合物P-55)(5mg，白色固体)，产率：8.6％。MS m/z(ESI):531.2[M+H] +。1H NMR(400MHz,dmso-d6)δ8.82(d,J＝5.0Hz,1H),8.28–8.14(m,2H),7.57–7.40(m,5H),7.38–7.25(m,4H),3.84(s,3H),3.70(d,J＝15.9Hz,1H),3.57(d,J＝15.2Hz,1H),3.12(brs,1H),2.85(brs,1H),2.20(brs,1H),1.76(brs,2H),1.47(brs,3H),1.36(brs,1H). Step 4: (E)-5-Chloro-2-methoxy-4-(2-(4-phenyl-3-(trifluoromethyl)pyridin-2-yl)vinyl)benzaldehyde (42 mg 0.1 mol) and (S)-piperidine-2-carboxylic acid (26 mg, 0.2 mol) were dissolved in 3 mL of methanol, sodium cyanoborohydride (13 mg, 0.2 mmol) was added, and the reaction was stirred under reflux for 1 hour. Concentration under reduced pressure gave product (S,E)-1-(5-chloro-2-methoxy-4-(2-(4-phenyl-3-(trifluoromethyl)) Formate of 2-yl)vinyl)benzyl)piperidine-2-carboxylic acid (Compound P-55) (5 mg, white solid). MS m/z (ESI): 5321. [M+H] + . 1H NMR (400MHz, dmso-d6) δ 8.82 (d, J = 5.0 Hz, 1H), 8.28 - 8.14 (m, 2H), 7.57 - 7.40 (m, 5H), 7.38 - 7.25 (m, 4H), 3.84 (s, 3H), 3.70 (d, J = 15.9 Hz, 1H), 3.57 (d, J = 15.2 Hz, 1H), 3.12 (brs, 1H), 2.85 (brs, 1H), 2.20 (brs, 1H) ), 1.76 (brs, 2H), 1.47 (brs, 3H), 1.36 (brs, 1H).
实施例56(S,E)-1-(3-氯-4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)苄基)哌啶-2-羧酸(P-56)的制备Example 56 (S,E)-1-(3-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)benzyl)piperidine-2-carboxylic acid Preparation of (P-56)
Figure PCTCN2018122818-appb-000091
Figure PCTCN2018122818-appb-000091
步骤1：(S,E)-1-(5-氯-4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-甲氧基苄基)哌啶-2-甲酸(化合物P-44)(50mg，0.10mmol)，甲胺盐酸盐(69mg,1.02mmol)，二异丙基乙胺(79mg,0.61mmol)和2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(77mg，0.20mol)溶解于2mL N,N-二甲基甲酰胺，室温搅拌反应10小时。减压浓缩，用制备HPLC色谱法得到标题产物(S,E)-1-(5-氯-4-(2-(3-氰基-4-苯基吡啶-2-基)乙烯基)-2-甲氧基苄基)-N-甲基哌啶-2-酰胺(化合物P-56)(1.53mg，白色固体)，产率：3.0％。MS m/z(ESI):501.1[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.91(d,1H),8.32(d,1H),7.74-7.68(m,3H),7.64-7.59(m,5H),7.43(s,1H),3.90(s,3H),3.53-3.49(m,2H),3.30-3.27(d,2H),2.67-2.61(m,2H),2.58(d,3H),2.33(m,1H),1.94-1.90(m,2H),1.57-1.50(m,3H),1.47-1.43(m,1H). Step 1: (S,E)-1-(5-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)-2-methoxybenzyl)piperidin Pyridine-2-carboxylic acid (Compound P-44) (50 mg, 0.10 mmol), methylamine hydrochloride (69 mg, 1.02 mmol), diisopropylethylamine (79 mg, 0.61 mmol) and 2-(7- benzene oxide And triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (77 mg, 0.20 mol) was dissolved in 2 mL of N,N-dimethylformamide, and the reaction was stirred at room temperature for 10 hours. The title product (S, E)-1-(5-chloro-4-(2-(3-cyano-4-phenylpyridin-2-yl)vinyl)- 2-Methoxybenzyl)-N-methylpiperidin-2-amide (Compound P-56) (1.53 mg, white solid). MS m/z (ESI): 5021. [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.91 (d, 1H), 8.32 (d, 1H), 7.74 - 7.68 (m, 3H), 7.64 - 7.59 (m, 5H), 7.43 (s, 1H), 3.90 (s, 3H), 3.53-3.49 (m, 2H), 3.30-3.27 (d, 2H), 2.67-2.61 (m, 2H), 2.58 (d, 3H), 2.33 (m, 1H), 1.94 1.90 (m, 2H), 1.57-1.50 (m, 3H), 1.47-1.43 (m, 1H).
实施例57(2S)-1-[[5-氯-4-(E)-2-(3-氰基-4-(4-吡啶基)-2-吡啶基)乙烯基)-2-甲氧基苯基)甲基]哌啶-2-羧酸(P-57)的制备Example 57(2S)-1-[[5-chloro-4-(E)-2-(3-cyano-4-(4-pyridyl)-2-pyridyl)vinyl)-2-yl Preparation of oxyphenyl)methyl]piperidine-2-carboxylic acid (P-57)
Figure PCTCN2018122818-appb-000092
Figure PCTCN2018122818-appb-000092
步骤1：将2，4-二溴烟腈(2.60g,10.0mmol)溶解于45mL1,4-二氧六环和15mL水中，加入吡啶-4-硼酸(1.2g,10.0mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(733mg,1.0mmol)，碳酸钠(1.0g,10.0mmol)，在氩气保护下100℃搅拌反应3小时。反应液过滤，滤液减压浓缩，用硅胶柱色谱法以10～75％乙酸乙酯在石油醚中纯化，得到产物2-溴-4,4’-二吡啶-3-腈(1.3g，淡棕色固体)，产率：70.3％。MS m/z(ESI):260.1[M+H] +。 Step 1: 2,4-Dibromonicotinonitrile (2.60 g, 10.0 mmol) was dissolved in 45 mL of 1,4-dioxane and 15 mL of water, and pyridine-4-boronic acid (1.2 g, 10.0 mmol) was added, [1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (733 mg, 1.0 mmol), sodium carbonate (1.0 g, 10.0 mmol), stirred at 100 ° C under argon atmosphere 3 hours. The reaction solution was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjj Brown solid), yield: 70.3%. MS m/z (ESI): 260.1 [M+H] + .
步骤2：将2-溴-4,4’-二吡啶-3-腈(1.3g,5.0mmol)溶解于30mL1,4-二氧六环和10mL水中，加入乙烯基氟硼酸钾(670mg,5.0mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(370mg，0.5mmol)，碳酸钠(530mg,5.0mmol)，在氩气保护下100℃搅拌反应16小时。反应液过滤，滤液减压浓缩，用硅胶柱色谱法以0～25％乙酸乙酯在石油醚中纯化，得到产物2-乙烯基-4,4’-二吡啶-3-腈(710mg，淡棕色固体)，产率：31.1％。MS m/z(ESI):208.2[M+H] +。 Step 2: Dissolve 2-bromo-4,4'-dipyridine-3-carbonitrile (1.3 g, 5.0 mmol) in 30 mL of 1,4-dioxane and 10 mL of water, and add potassium fluoroborate (670 mg, 5.0). Ment), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (370 mg, 0.5 mmol), sodium carbonate (530 mg, 5.0 mmol), protected with argon The reaction was stirred at 100 ° C for 16 hours. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjj Brown solid), Yield: 31.1%. MS m/z (ESI): 208.2 [M+H] + .
步骤3：往20mL微波管里加入：2-乙烯基-4,4’-二吡啶-3-腈(40mg，0.20mmol)，4-溴-5-氯-2-甲氧基苯甲醛(50mg，0.20mmol)，醋酸钯(4.5mg，0.1mmol)，三(邻甲基苯)磷(6.0mg，0.1mmol)，0.2mL三乙胺和3mL二甲基乙酰胺。氩气吹1分钟，盖上微波盖，在160℃微波反应45分钟。减压浓缩，用硅胶柱色谱法以0％～56％乙酸乙酯在石油醚中纯化，得到产物(E)-2-((2-氯-4-甲酰基-5-甲氧基苯基)烯基)-4,4’-二吡啶-3-腈(39mg，黄色固体)，产率：48.4％。MS m/z(ESI):376.1[M+H] +。 Step 3: Add to the 20 mL microwave tube: 2-vinyl-4,4'-dipyridine-3-carbonitrile (40 mg, 0.20 mmol), 4-bromo-5-chloro-2-methoxybenzaldehyde (50 mg , 0.20 mmol), palladium acetate (4.5 mg, 0.1 mmol), tris(o-methylphenyl)phosphorus (6.0 mg, 0.1 mmol), 0.2 mL of triethylamine and 3 mL of dimethylacetamide. The mixture was blown with argon for 1 minute, covered with a microwave cover, and microwave-reacted at 160 ° C for 45 minutes. Concentration under reduced pressure, purification by silica gel column chromatography eluting with EtOAc EtOAc EtOAc EtOAc Alkenyl)-4,4'-bipyridine-3-carbonitrile (39 mg, yellow solid), yield: 48.4%. MS m/z (ESI): 376.1 [M+H] + .
步骤4：(E)-2-((2-氯-4-甲酰基-5-甲氧基苯基)烯基)-4,4’-二吡啶-3-腈(38mg，0.1mmol)和(S)-哌啶-2-羧酸(26mg，0.2mol)溶解于20mL甲醇中，加入氰基硼氢化钠(10mg，0.15mmol)，回流搅拌反应2小时。减压浓缩，用制备HPLC色谱法得到标题产物(2S)-1-[[5-氯-4-(E)-2-(3-氰基-4-(4-吡啶基)-2-吡啶基)乙烯基)-2-甲氧基苯基)甲基]哌啶-2-羧酸(化合物P-57)(5mg，白色固体)，产率：16.9％。MS m/z(ESI):489.1[M+H] +。1H NMR(400MHz,DMSO-d6)δ9.00(d,1H),8.83(d,2H),8.36(d,1H),7.70-7.46(m,6H),3.89(s,3H),3.74(m,2H),2.89(d,2H),2.40(d,1H),1.78(d,2H),1.57-1.33(m,4H). Step 4: (E)-2-((2-Chloro-4-formyl-5-methoxyphenyl)alkenyl)-4,4'-dipyridine-3-carbonitrile (38 mg, 0.1 mmol) (S)-piperidine-2-carboxylic acid (26 mg, 0.2 mol) was dissolved in 20 mL of methanol, sodium cyanoborohydride (10 mg, 0.15 mmol) was added, and the reaction was stirred under reflux for 2 hours. The title product (2S)-1-[[5-chloro-4-(E)-2-(3-cyano-4-(4-pyridyl)-2-pyridine was obtained. Vinyl)-2-methoxyphenyl)methyl]piperidine-2-carboxylic acid (Compound P-57) (5 mg, white solid), yield: 16.9%. MS m/z (ESI): 489.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 9.00 (d, 1H), 8.83 (d, 2H), 8.36 (d, 1H), 7.70-7.46 (m, 6H), 3.89 (s, 3H), 3.74 ( m, 2H), 2.89 (d, 2H), 2.40 (d, 1H), 1.78 (d, 2H), 1.57-1.33 (m, 4H).
测试例1 PD-1/PD-L1结合试验Test Example 1 PD-1/PD-L1 binding test
实验材料：Experimental Materials:
DMSO来自Sigma，产品编号：D5879；384孔小体积板(白色)来自Greiner，产品编号：784075；抗PD1阻断抗体(IC50:10nM)来自Cisbio，产品编号：64CUS000C-1a；抗PDL1阻断抗体(IC50:0.3nM)来自Cisbio，产品编号：64CUS000C-1b；HTRF PD1/PD-L1结合测试试剂盒来自Cisbio，，产品编号：63ADK000CPDPEB。试剂准备DMSO from Sigma, product number: D5879; 384-well small volume plate (white) from Greiner, product number: 784075; anti-PD1 blocking antibody (IC50: 10 nM) from Cisbio, product number: 64CUS000C-1a; anti-PDL1 blocking antibody (IC50: 0.3 nM) from Cisbio, product number: 64CUS000C-1b; HTRF PD1/PD-L1 binding test kit from Cisbio, product number: 63ADK000CPDPEB. Reagent preparation
1、配置2X浓度的待测化合物于含有4％DMSO的1X的反应缓冲液中；1. Configure a 2X concentration of the test compound in a 1X reaction buffer containing 4% DMSO;
2、Tag1-PD-L1蛋白和Tag2-PD1蛋白分别以50nM和10nM浓度配制在1X的反应缓冲液中，实 验最终反应浓度为Tag1-PD-L1 10nM,Tag1-PD-L1 2nM；2, Tag1-PD-L1 protein and Tag2-PD1 protein were prepared in 1X reaction buffer at 50nM and 10nM respectively, and the final reaction concentration was Tag1-PD-L1 10nM, Tag1-PD-L1 2nM;
3、anti-Tag1-Eu3+抗体以1:100的比例配置在1X浓度检测缓冲液中；3. The anti-Tag1-Eu3+ antibody is disposed in the 1X concentration detection buffer at a ratio of 1:100;
4、anti-Tag2-XL665抗体以1:25的比例配置在1X浓度检测缓冲液中；4. The anti-Tag2-XL665 antibody is disposed in a 1X concentration detection buffer at a ratio of 1:25;
实验步骤Experimental procedure
1、加入5ul 2X待测化合物；1. Add 5 ul of 2X test compound;
2、分别加入2.5ul Tag1-PD-L1蛋白和Tag2-PD1蛋白，总反应体系为10ul，25℃反应15分钟；2. Add 2.5ul of Tag1-PD-L1 protein and Tag2-PD1 protein respectively, the total reaction system is 10ul, and react at 25 °C for 15 minutes;
3、分别加入anti-Tag1-Eu 3+抗体以及anti-Tag2-XL665抗体各5ul，25℃反应16小时； 3. Add 5 μl of anti-Tag1-Eu 3+ antibody and anti-Tag2-XL665 antibody, respectively, and react at 25 ° C for 16 hours;
4、利用荧光酶标仪HTRF读板程序读出波长为665nm和620nm两个读值，利用两个波长的比例来判断化合物的活性，用XLFIT5.0(IDBS)计算出待测化合物的IC50。测试结果如表1所示。4. The readings of the wavelengths of 665 nm and 620 nm were read by the HTRF plate reader program. The ratio of the two wavelengths was used to judge the activity of the compound, and the IC50 of the test compound was calculated by XLFIT 5.0 (IDBS). The test results are shown in Table 1.
表1 PPI-HTRF测试结果Table 1 PPI-HTRF test results
化合物编号Compound number PPI-HTRF(IC 50/μM) PPI-HTRF (IC 50 /μM) 化合物编号Compound number PPI-HTRF(IC 50/μM) PPI-HTRF (IC 50 /μM)
P-1P-1 0.7610.761 P-4P-4 0.3570.357
P-3P-3 0.2330.233 P-6P-6 0.2080.208
P-7P-7 0.8030.803 P-8P-8 0.4180.418
P-11P-11 0.0320.032 P-13P-13 0.2110.211
P-14P-14 0.0520.052 P-16P-16 0.0230.023
P-19P-19 0.0030.003 P-20P-20 0.0030.003
P-21P-21 0.0240.024 P-22P-22 0.0240.024
P-23P-23 0.0230.023 P-24P-24 0.0040.004
P-25P-25 0.0120.012 P-26P-26 0.0120.012
P-27P-27 0.0040.004 P-28P-28 0.0350.035
P-29P-29 0.0020.002 P-30P-30 0.0230.023
P-32P-32 0.0010.001 P-33P-33 0.0580.058
P-36P-36 0.3430.343 P-39P-39 0.0510.051
P-41P-41 0.0030.003 P-42P-42 0.7070.707
P-44P-44 0.0020.002 P-45P-45 0.0310.031
P-46P-46 0.0270.027 P-48P-48 0.3790.379
P-49P-49 0.0100.010 P-50P-50 0.1360.136
P-51P-51 0.4260.426 P-52P-52 0.0100.010
P-57P-57 ＞1>1    
从表1可以看出，本发明示例化合物对PPI-HTRF具有较好的抑制活性。尤其是，当本发明的化合物式I最右侧氮原子α位的碳上连接有羧基，W为与吡啶环直接相连的取代或未取代的苯环，Z 4为N，Z 2、Z 3为CH，Z 1为CR 1，与烯基相连的右侧为取代或未取代的苯环时，化合物的活性可达几十甚至几个nM。研究发现，与烯基相连的左侧为吡啶环时，N原子的位置对活性产生较大的影响，当Z 2为N原子时，其活性显著降低(如化合物P-48和P-11)。此外与烯基相连的右侧苯环上具有烯基取代的长链基团时，其活性相对于烷基长链基团时的活性显著降低(如化合物P-30和P-36)。 As can be seen from Table 1, the exemplified compounds of the present invention have a good inhibitory activity against PPI-HTRF. In particular, when the compound of the present invention has a carboxyl group attached to the carbon at the α position of the rightmost nitrogen atom, W is a substituted or unsubstituted benzene ring directly bonded to the pyridine ring, and Z 4 is N, Z 2 , Z 3 When CH, Z 1 is CR 1 , and the right side connected to the alkenyl group is a substituted or unsubstituted benzene ring, the activity of the compound can be several tens or even several nM. It has been found that when the left side of the alkenyl group is a pyridine ring, the position of the N atom has a large effect on the activity, and when Z 2 is an N atom, its activity is significantly reduced (such as compounds P-48 and P-11). . Further, when the alkenyl-substituted long-chain group is bonded to the alkenyl ring on the right side, the activity thereof is remarkably lowered relative to the activity of the alkyl long-chain group (e.g., compounds P-30 and P-36).
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims (22)

  1. 一种式(I)所示的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药：A compound of the formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof:
    Figure PCTCN2018122818-appb-100001
    Figure PCTCN2018122818-appb-100001
    式中，In the formula,
    Z 1为N或CR 1；Z 2为N或CR 2；Z 3为N或CR 3；Z 4为N或CR 4； Z 1 is N or CR 1 ; Z 2 is N or CR 2 ; Z 3 is N or CR 3 ; Z 4 is N or CR 4 ;
    A 1为N或CR 5；A 2为N或CR 6；A 3为N或CR 7；A 4为N或CR 8； A 1 is N or CR 5 ; A 2 is N or CR 6 ; A 3 is N or CR 7 ; A 4 is N or CR 8 ;
    X为一个键、NH、O、S、S(O)或S(O) 2； X is a bond, NH, O, S, S(O) or S(O) 2 ;
    W为C 6-10芳基(如苯环)、具有1到3个独立选自氮、氧或硫的杂原子的5至6元单环杂芳基环W 1、具有1到5个独立选自氮、氧或硫的杂原子的8至10元双环杂芳基环W 2、具有1到3个独立选自氮、氧或硫的杂原子的3至7元饱和或部分不饱和单杂环W 3、3至7元饱和或部分不饱和单环W 4、具有1到5个独立选自氮、氧或硫的杂原子的8至10元饱和或部分不饱和双杂环W 5、或8至10元饱和或部分不饱和双环W 6； W is a C 6-10 aryl group (such as a benzene ring), a 5- to 6-membered monocyclic heteroaryl ring W 1 having 1 to 3 hetero atoms independently selected from nitrogen, oxygen or sulfur, having 1 to 5 independent An 8- to 10-membered bicyclic heteroaryl ring W 2 of a hetero atom selected from nitrogen, oxygen or sulfur, a 3 to 7-membered saturated or partially unsaturated single having 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Heterocyclic W 3 , 3 to 7 membered saturated or partially unsaturated monocyclic W 4 , 8 to 10 membered saturated or partially unsaturated heterocyclic W 5 having 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur. , or 8 to 10 yuan saturated or partially unsaturated bicyclic W 6 ;
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8各自独立地为氢、羟基、CN、NO 2、卤素(优选为F或Cl)、-NR a0R b0、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、C 3-8环烷氧基(优选为C 3-6环烷氧基)、C 2-10烯基(优选为C 2-6烯基，更优选为C 2-4烯基)、C 2-10炔基(优选为C 2-6炔基，更优选为C 2-4炔基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、-CHO、-C(O)C 1-10烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)C 6-10芳基(优选为-C(O)C 6芳基，如-C(O)-苯基)、C 6-10芳基(优选为C 6芳基，如苯基)、-CONR a0R b0、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)或叔丁氧羰基；其中R a0、R b0各自独立地为氢或C 1-8烷基； R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen, hydroxy, CN, NO 2 , halogen (preferably F or Cl), -NR a0 R b0 , C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 3- 8- cycloalkoxy (preferably C 3-6 cycloalkoxy), C 2-10 alkenyl (preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl), C 2-10 alkyne a group (preferably a C 2-6 alkynyl group, more preferably a C 2-4 alkynyl group), a C 1-10 alkoxy group (preferably a C 1-6 alkoxy group, more preferably a C 1-3 alkoxy group) ), -CHO, -C(O)C 1-10 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C( O) C 6-10 aryl (preferably -C(O)C 6 aryl, such as -C(O)-phenyl), C 6-10 aryl (preferably C 6 aryl, such as phenyl) , -CONR a0 R b0 , -C(O)OC 1-10 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), - OC(O)C 1-10 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 C 6-10 aryl (preferably -SO 2 C 6 aryl such as -SO 2 -phenyl) or tert-butoxycarbonyl; wherein R a0 , R b0 are each independently hydrogen or C 1-8 alkyl;
    R 9、R 10各自独立地为氢、羟基、卤素(优选为F或Cl)、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)； R 9 and R 10 are each independently hydrogen, hydroxy, halogen (preferably F or Cl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);
    R a为
    Figure PCTCN2018122818-appb-100002
    或C 3-8环烷基，R b为氢或C 1-8烷基；或者R a、R b与相邻氮原子连接形成5至6元饱和单杂环B；     R a is
    Figure PCTCN2018122818-appb-100002
    Or a C 3-8 cycloalkyl group, R b is hydrogen or a C 1-8 alkyl group; or R a , R b are bonded to an adjacent nitrogen atom to form a 5- to 6-membered saturated monoheterocyclic ring B;
    其中R a1、R b1各自独立地为氢、羟基、羧基或C 1-8烷基； Wherein R a1 and R b1 are each independently hydrogen, hydroxy, carboxy or C 1-8 alkyl;
    R 0为C 1-8烷基、羟基、羧基、乙酰胺基、吡咯酮基、-(O-(CH 2) 2) m-NH 2； R 0 is C 1-8 alkyl, hydroxy, carboxyl, acetamido, pyrrolidone, -(O-(CH 2 ) 2 ) m -NH 2 ;
    n为2或3；m为1、2或3；n is 2 or 3; m is 1, 2 or 3;
    所述烷基、烷氧基、环烷基、环烷氧基、烯基、炔基、芳基、W 1、W 2、W 3、W 4、W 5、 W 6为未取代的或被1、2或3个选自下组的取代基所取代：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤素(优选为F或Cl)、硝基、C 6-10芳基(优选苯基)、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、C 3-8环烷氧基(优选为C 3-6环烷氧基)、C 2-10烯基(优选为C 2-6烯基，更优选为C 2-4烯基)、C 2-10炔基(优选为C 2-6炔基，更优选为C 2-4炔基)、-CONR a0R b0、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-CHO、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)。 The alkyl, alkoxy, cycloalkyl, cycloalkoxy, alkenyl, alkynyl, aryl, W 1 , W 2 , W 3 , W 4 , W 5 , W 6 are unsubstituted or 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, halogenated C 1-8 alkyl (preferably halogenated C 1- 6 alkyl, more preferably halogenated C 1-3 alkyl), halogen (preferably F or Cl), nitro, C 6-10 aryl (preferably phenyl), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 3 -8 cycloalkyl (preferably C 3-6 cycloalkyl), C 3-8 cycloalkoxy (preferably C 3-6 cycloalkoxy), C 2-10 alkenyl (preferably C 2- 6 alkenyl, more preferably C 2-4 alkenyl), C 2-10 alkynyl (preferably C 2-6 alkynyl, more preferably C 2-4 alkynyl), -CONR a0 R b0 , -C (O) OC 1-10 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -CHO, -OC(O)C 1 -10 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl group, more preferably -SO 2 C 1-3 alkyl), -SO 2 C 6-10 aryl (preferably -SO 2 C 6 aryl, such as -SO 2 -phenyl), -COC 6-10 aryl (preferably -COC 6 aryl) Base, such as -CO-phenyl).
  2. 如权利要求1所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药，其特征在于，式(I)化合物为式(II)所示化合物：The compound of claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the compound of formula (I) is a compound of formula (II):
    Figure PCTCN2018122818-appb-100003
    Figure PCTCN2018122818-appb-100003
    式中，In the formula,
    Z 4为N或CR 4； Z 4 is N or CR 4 ;
    R 1、R 2、R 3、R 5、R 6、R 7、R 8各自独立地为氢、卤素、羟基、氰基、C 1-8烷基、卤代C 1-8烷基、C 3-8环烷基、C 1-8烷氧基、卤代C 1-8烷氧基、C 3-8环烷氧基、C 6-10芳基、-C(O)C 1-8烷基、-C(O)OC 1-8烷基、-CONR a0R b0或NR a0R b0；R a0、R b0各自独立地为氢或C 1-8烷基； R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen, halogen, hydroxy, cyano, C 1-8 alkyl, halo C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy, C 3-8 cycloalkoxy, C 6-10 aryl, -C(O)C 1-8 Alkyl, -C(O)OC 1-8 alkyl, -CONR a0 R b0 or NR a0 R b0 ; R a0 , R b0 are each independently hydrogen or C 1-8 alkyl;
    R w1、R w2、R w3、R w4、R w5各自独立地为氢、卤素、羟基、氰基、C 1-8烷基、卤代C 1-8烷基；或者R w1、R w2与相邻苯环上的碳原子连接形成5至6元饱和单杂环A； R w1 , R w2 , R w3 , R w4 , R w5 are each independently hydrogen, halogen, hydroxy, cyano, C 1-8 alkyl, halo C 1-8 alkyl; or R w1 , R w2 and The carbon atoms on adjacent benzene rings are bonded to form a 5- to 6-membered saturated monoheterocyclic ring A;
    R a为
    Figure PCTCN2018122818-appb-100004
    或C 3-8环烷基，R b为氢或C 1-8烷基；或者R a、R b与相邻氮原子连接形成5至6元饱和单杂环B；     R a is
    Figure PCTCN2018122818-appb-100004
    Or a C 3-8 cycloalkyl group, R b is hydrogen or a C 1-8 alkyl group; or R a , R b are bonded to an adjacent nitrogen atom to form a 5- to 6-membered saturated monoheterocyclic ring B;
    其中R a1、R b1各自独立地为氢、羟基、羧基或C 1-8烷基； Wherein R a1 and R b1 are each independently hydrogen, hydroxy, carboxy or C 1-8 alkyl;
    R 0为C 1-8烷基、羟基、羧基、乙酰胺基、吡咯酮基、-(O-(CH 2) 2) m-NH 2； R 0 is C 1-8 alkyl, hydroxy, carboxyl, acetamido, pyrrolidone, -(O-(CH 2 ) 2 ) m -NH 2 ;
    n为2或3；m为1、2或3；n is 2 or 3; m is 1, 2 or 3;
    所述烷基、烷氧基、环烷基、单杂环A、单杂环B为未取代的或被1、2或3个选自下组的取代基所取代：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、C 1-8烷基、C 1-8烷氧基或卤代C 1-8烷基。 The alkyl, alkoxy, cycloalkyl, monoheterocyclic A, monoheterocyclic B is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of cyano, acetyl, Hydroxy, hydroxymethyl, hydroxyethyl, carboxy, C 1-8 alkyl, C 1-8 alkoxy or halogenated C 1-8 alkyl.
  3. 如权利要求2所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药，其特征在于，Z 4为N。 The compound according to claim 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein Z 4 is N.
  4. 如权利要求2所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药，其特征在于，单杂环A选自：四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃或为结构
    Figure PCTCN2018122818-appb-100005
    其中p为1、2或3。     The compound of claim 2 or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the monoheterocyclic ring A is selected from the group consisting of: tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole , piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran or as structure
    Figure PCTCN2018122818-appb-100005
    Where p is 1, 2 or 3.
  5. 如权利要求2所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药，其特征在于，单杂环B选自：四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉或硫代吗啉-1,1-二氧化物。The compound of claim 2 or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the monoheterocyclic ring B is selected from the group consisting of: tetrahydropyrrole, piperidine, piperazine , morpholine, thiomorpholine or thiomorpholine-1,1-dioxide.
  6. 如权利要求2所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药，其特征在于，R 6、R 8各自独立地为氢。 The compound or a stereoisomer thereof according to claim 2, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 6 and R 8 are each independently hydrogen.
  7. 如权利要求2所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药，其特征在于，R 6、R 7、R 8各自独立地为氢。 The compound according to claim 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 6 , R 7 and R 8 are each independently hydrogen.
  8. 如权利要求2所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药，其特征在于，R 5为氢、卤素、C 1-3烷基、卤代C 1-3烷基或C 1-3烷氧基。 The compound or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, according to claim 2, wherein R 5 is hydrogen, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl or C 1-3 alkoxy.
  9. 如权利要求2所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药，其特征在于，R 5为氢、氟、氯、三氟甲基或甲氧基。 The compound or a stereoisomer thereof according to claim 2, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 5 is hydrogen, fluorine, chlorine, trifluoromethyl or methoxy base.
  10. 如权利要求2所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药，其特征在于，R 2、R 3为氢。 The compound according to claim 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 2 and R 3 are hydrogen.
  11. 如权利要求2所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药，其特征在于，
    Figure PCTCN2018122818-appb-100006
    选自：     The compound of claim 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein
    Figure PCTCN2018122818-appb-100006
    From:
    Figure PCTCN2018122818-appb-100007
    Figure PCTCN2018122818-appb-100007
  12. 如权利要求2所述的化合物、或其药学上可接受的盐、或其溶剂化物、或其立体异构体、或其前药，其特征在于，所述化合物选自表A或表B。The compound according to claim 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof, wherein the compound is selected from Table A or Table B.
  13. 一种药物组合物，所述药物组合物包括权利要求1至12中任一项所述的化合物或 其立体异构体，或其药学上可接受的盐、溶剂化物或前药；以及药学可接受的载体。A pharmaceutical composition comprising the compound of any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; Accepted carrier.
  14. 一种药物组合物，所述药物组合物包括权利要求1至12中任一项所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药；以及至少一种其他药剂，其中所述其他药剂是抗癌剂、化疗剂或抗增殖化合物。A pharmaceutical composition comprising the compound of any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and at least one Other agents, wherein the other agent is an anticancer agent, a chemotherapeutic agent or an antiproliferative compound.
  15. 如权利要求1至12中任一项所述的化合物或其立体异构体，或其药学上可接受的盐、溶剂化物或前药、或如权利要求13所述药物组合物在制备药物中的用途，所述药物为治疗癌症或感染性疾病的药物。The compound according to any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or the pharmaceutical composition according to claim 13 in the preparation of a medicament The use of the drug as a medicament for the treatment of cancer or an infectious disease.
  16. 如权利要求15所述的用途，其特征在于，所述癌症选自：骨癌、头或颈癌、胰腺癌、皮肤癌、皮肤或眼内恶性黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌系统癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病、包括急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、儿童实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤、环境诱发的癌症、包括石棉诱发的癌症、和所述癌症的组合。The use according to claim 15, wherein the cancer is selected from the group consisting of bone cancer, head or neck cancer, pancreatic cancer, skin cancer, skin or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer. , anal regional cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system Cancer, thyroid cancer, parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, child entity Tumor, lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumor, primary CNS lymphoma, tumor angiogenesis, spinal tumor, brainstem glioma, pituitary adenoma , Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancer, including asbestos-induced cancer, and said cancer Combination.
  17. 如权利要求15所述的用途，其特征在于，所述感染性疾病是细菌感染性疾病、病毒感染性疾病或真菌感染性疾病。The use according to claim 15, wherein the infectious disease is a bacterial infectious disease, a viral infectious disease or a fungal infectious disease.
  18. 一种调节受治疗者中由PD-1信号传导通路介导的免疫应答的方法，所述方法包括向受治疗者施用治疗有效量的如权利要求1至12中任一项所述的化合物。A method of modulating an immune response mediated by a PD-1 signaling pathway in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 12.
  19. 一种抑制受治疗者中肿瘤细胞生长和/或迁移的方法，所述方法包括向受治疗者施用治疗有效量的如权利要求1至12中任一项所述的化合物。A method of inhibiting tumor cell growth and/or migration in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 12.
  20. 如权利要求19所述的方法，其特征在于，所述肿瘤细胞是选自于以下的癌症：乳腺癌、结肠癌、肺癌、黑素瘤、前列腺癌和肾癌。The method according to claim 19, wherein the tumor cell is a cancer selected from the group consisting of breast cancer, colon cancer, lung cancer, melanoma, prostate cancer, and kidney cancer.
  21. 一种治疗受治疗者感染性疾病的方法，所述方法包括向受治疗者施用治疗有效量的根据权利要求1至12中任一项所述的化合物。A method of treating an infectious disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 12.
  22. 一种治疗受治疗者中细菌、病毒和真菌感染方法，所述方法包括向受治疗者施用治疗有效量的根据权利要求1至12中任一项所述的化合物。A method of treating bacterial, viral and fungal infections in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 12.
PCT/CN2018/122818 2017-12-22 2018-12-21 Immunomodulator and preparation method and medical use thereof WO2019120297A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201711415523.2 2017-12-22
CN201711415523 2017-12-22

Publications (1)

Publication Number Publication Date
WO2019120297A1 true WO2019120297A1 (en) 2019-06-27

Family

ID=66992484

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/122818 WO2019120297A1 (en) 2017-12-22 2018-12-21 Immunomodulator and preparation method and medical use thereof

Country Status (2)

Country Link
CN (1) CN109956898B (en)
WO (1) WO2019120297A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11059834B2 (en) 2017-08-08 2021-07-13 Chemocentryx, Inc. Macrocyclic immunomodulators
US11135210B2 (en) 2018-02-22 2021-10-05 Chemocentryx, Inc. Indane-amines as PD-L1 antagonists
CN114057655A (en) * 2021-12-13 2022-02-18 郑州华赞医药科技有限公司 Synthetic method of dibromo compound
US11266643B2 (en) 2019-05-15 2022-03-08 Chemocentryx, Inc. Triaryl compounds for treatment of PD-L1 diseases
US11426364B2 (en) 2016-06-27 2022-08-30 Chemocentryx, Inc. Immunomodulator compounds
US11485708B2 (en) 2019-06-20 2022-11-01 Chemocentryx, Inc. Compounds for treatment of PD-L1 diseases
US11708326B2 (en) 2017-07-28 2023-07-25 Chemocentryx, Inc. Immunomodulator compounds
US11713307B2 (en) 2019-10-16 2023-08-01 Chemocentryx, Inc. Heteroaryl-biphenyl amides for the treatment of PD-L1 diseases
US11866429B2 (en) 2019-10-16 2024-01-09 Chemocentryx, Inc. Heteroaryl-biphenyl amines for the treatment of PD-L1 diseases
US11872217B2 (en) 2019-07-10 2024-01-16 Chemocentryx, Inc. Indanes as PD-L1 inhibitors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2023540612A (en) * 2020-09-09 2023-09-25 グアンジョウ マキシノベル ファーマシューティカルズ カンパニー リミテッド Aromatic ethylene compounds, their production methods, intermediates, pharmaceutical compositions and uses thereof
CN114230512A (en) * 2020-09-09 2022-03-25 广州再极医药科技有限公司 Aromatic vinyl compound, preparation method thereof, intermediate, pharmaceutical composition and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105705489A (en) * 2013-09-04 2016-06-22 百时美施贵宝公司 Compounds useful as immunomodulators
CN107573332A (en) * 2016-07-05 2018-01-12 广州再极医药科技有限公司 Aromatic vinylene or aromatic ethylene class compound, wherein mesosome, preparation method, pharmaceutical composition and application

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10745382B2 (en) * 2015-10-15 2020-08-18 Bristol-Myers Squibb Company Compounds useful as immunomodulators
CN107573322A (en) * 2017-09-06 2018-01-12 南京优科生物医药研究有限公司 Imatinib dinitrogen oxide, preparation method and use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105705489A (en) * 2013-09-04 2016-06-22 百时美施贵宝公司 Compounds useful as immunomodulators
CN107573332A (en) * 2016-07-05 2018-01-12 广州再极医药科技有限公司 Aromatic vinylene or aromatic ethylene class compound, wherein mesosome, preparation method, pharmaceutical composition and application

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11793771B2 (en) 2016-06-27 2023-10-24 Chemocentryx, Inc. Immunomodulator compounds
US11426364B2 (en) 2016-06-27 2022-08-30 Chemocentryx, Inc. Immunomodulator compounds
US11708326B2 (en) 2017-07-28 2023-07-25 Chemocentryx, Inc. Immunomodulator compounds
US11691985B2 (en) 2017-08-08 2023-07-04 Chemocentryx, Inc. Macrocyclic immunomodulators
US11059834B2 (en) 2017-08-08 2021-07-13 Chemocentryx, Inc. Macrocyclic immunomodulators
US11759458B2 (en) 2018-02-22 2023-09-19 Chemocentryx, Inc. Indane-amines as PD-L1 antagonists
US11135210B2 (en) 2018-02-22 2021-10-05 Chemocentryx, Inc. Indane-amines as PD-L1 antagonists
US11266643B2 (en) 2019-05-15 2022-03-08 Chemocentryx, Inc. Triaryl compounds for treatment of PD-L1 diseases
US11485708B2 (en) 2019-06-20 2022-11-01 Chemocentryx, Inc. Compounds for treatment of PD-L1 diseases
US11872217B2 (en) 2019-07-10 2024-01-16 Chemocentryx, Inc. Indanes as PD-L1 inhibitors
US11713307B2 (en) 2019-10-16 2023-08-01 Chemocentryx, Inc. Heteroaryl-biphenyl amides for the treatment of PD-L1 diseases
US11866429B2 (en) 2019-10-16 2024-01-09 Chemocentryx, Inc. Heteroaryl-biphenyl amines for the treatment of PD-L1 diseases
CN114057655A (en) * 2021-12-13 2022-02-18 郑州华赞医药科技有限公司 Synthetic method of dibromo compound
CN114057655B (en) * 2021-12-13 2023-10-27 郑州华赞医药科技有限公司 Synthesis method of dibromo compound

Also Published As

Publication number Publication date
CN109956898A (en) 2019-07-02
CN109956898B (en) 2021-03-26

Similar Documents

Publication Publication Date Title
CN109956898B (en) Immunomodulator, preparation method and medical application thereof
CN102026970B (en) Biaryl pde4 inhibitors for treating pulmonary and cardiovascular disorders
KR102057877B1 (en) Nitrogenous heterocyclic derivatives and their application in drugs
TWI697486B (en) 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as hdac inhibitors
TW202214605A (en) Immunomodulators, compositions and methods thereof
CN106458934B (en) Quinoxaline compounds and application thereof
TW201605775A (en) Aryl ethers and uses thereof
JP6592512B2 (en) Tricyclic atropisomeric compounds
TWI664166B (en) Kcnq 2~5 channel activating agent
WO2020228649A1 (en) Substituted phenylpropenylpyridine derivative, and preparation method therefor and medical use thereof
CN111566103B (en) Aminoimidazopyrazines as kinase inhibitors
JP7458987B2 (en) imidazopyridinone compounds
WO2020108661A1 (en) Heterocyclic compound as cdk-hdac double-channel inhibitor
WO2022166860A1 (en) Pim kinase inhibitor
WO2020108579A1 (en) Amino-substituted pyridone derivative, preparation method therefor, and pharmaceutical use thereof
CN111727186A (en) Biheterocyclic substituted pyridine-2 (1H) -ketone derivative, preparation method and medical application thereof
CN110582495B (en) Fused pentacyclic imidazole derivatives as modulators of TNF activity
CN111808086B (en) Heterocyclic substituted styryl-4-phenylpyridine derivative, preparation method and medical application thereof
CN107428682B (en) Amide derivatives, preparation method and medical application thereof
WO2022007966A1 (en) Pb2 inhibitor, and preparation method therefor and use thereof
TW202134213A (en) Compound having lysophosphatidic acid receptor agonistic activity and pharmaceutical use of said compound
CN112384502B (en) Cycloalkyl-substituted amide derivatives, preparation method and medical application thereof
CN110105275B (en) Amide derivatives, preparation method and medical application thereof
WO2023280254A1 (en) Tead inhibitor
TWI835770B (en) Cardiac sarcomere inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18892514

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18892514

Country of ref document: EP

Kind code of ref document: A1