CN116813560A - Triazole amide compound, and preparation method and application thereof - Google Patents

Triazole amide compound, and preparation method and application thereof Download PDF

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CN116813560A
CN116813560A CN202211494346.2A CN202211494346A CN116813560A CN 116813560 A CN116813560 A CN 116813560A CN 202211494346 A CN202211494346 A CN 202211494346A CN 116813560 A CN116813560 A CN 116813560A
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substituted
formula
compound
nmr
dmso
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程建军
谢成英
蒋华良
闫文仲
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Shanghai Institute of Materia Medica of CAS
ShanghaiTech University
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Shanghai Institute of Materia Medica of CAS
ShanghaiTech University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The invention discloses a triazole amide compound, a preparation method and application thereof, and in particular discloses a triazole amide compound shown as a formula I or pharmaceutically acceptable salt thereof, and application thereof in preparing medicines for treating and/or preventing diseases related to HDAC (high-definition television)For use, the disease may be cancer.

Description

Triazole amide compound, and preparation method and application thereof
Technical Field
The invention relates to a triazole amide compound, and a preparation method and application thereof.
Background
A number of studies have shown that Histone Deacetylases (HDACs) are overexpressed in a variety of tumor cells, playing an important role in the development and progression of tumors. HDACs are a class of epigenetic enzymes that function to regulate histone as well as many non-histone acetylation levels. HDACs associated with transcript levels are located primarily in the nucleus, and exert deacetylation by catalyzing the active center to hydrolyze epsilon-amino groups on lysine residue side chains in histones, causing histones to have positive charges and to bind tightly to DNA, ultimately leading to gene silencing; inhibiting this effect would relax the chromatin conformation and facilitate gene expression (Kazantsev, thompson, nat Rev Drug Discov 2008,7 (10): 854-868).
HDAC has 18 subtypes in total, and can be divided into four subgroups of Class I-IV (Ho et al, J Med Chem 2020,63 (21): 12460-12484) based on homology. Class I includes HDACl, 2, 3 and 8; class II includes HDACs 4, 5, 6, 7, 9 and 10; class III is often referred to as Sirtuins, including SIRTl-7; class IV has HDAC11 only. Class II can be further divided into Class IIa (HDAC 4, 5, 7 and 9) and Class IIb (HDAC 6 and 10). HDAC can be divided into two broad classes based on the mechanism of catalytic activity, where Sirtuis 1-7 is nicotinamide adenineDinucleotide (NAD) + ) Depended on, whereas HDAC1-11 is Zn 2+ Dependent on the type of the cell. HDAC refers to HDAC1-11.
HDAC inhibitors are small molecule compounds capable of inhibiting HDAC activity. Currently, there are five approved HDAC inhibitors on the market, including Vorinostat (SAHA), panobinostat (Panobinostat, LBH-589), belinostat (PXD-101), romidepsin (Romidepsin, FK-228), and cidamide (Chidamide), which are mainly used to treat cutaneous T cell lymphomas, recurrent or refractory peripheral T cell lymphomas, and the like. These inhibitors are pan HDAC inhibitors, except for sitagliptin and romidepsin, and are not subtype selective. In addition, there are many HDAC inhibitors in the research stage that have potential for the treatment of lymphomas, solid tumors, and hematological tumors. The current poor therapeutic efficacy of HDAC inhibitors against solid tumors may be associated with lower activity requiring high doses, lack of subtype specificity, in vivo pharmacokinetic and pharmacodynamic limitations, endogenous tumor resistance mechanisms, dose-dependent side effects (e.g., thrombocytopenia), and the like (Hogg et al Nat Rev Drug Discov 2020,19 (11): 776-800.).
Hydroxamic acid HDACs inhibitors are currently the most structurally related and most widely studied class of compounds. Hydroxamic acid and Zn 2+ The chelating ability is extremely strong, so hydroxamic acid HDAC inhibitors have a strong activity and are generally not selective (pan HDAC inhibitors). Benzamides are another common ZBG group, and are of great interest. Compared to hydroxamic acid HDAC inhibitors, benzanilide HDAC inhibitors have a certain selectivity for Class i HDAC. Representative compounds among the benzanilide class of HDAC inhibitors are cetadamine, MS275 and MGCD0103. Of these, MGCD0103 has good oral antitumor activity, its strongest effect on HDAC1, 2 to 10 times weaker activity on HDACs 2,3 and 11, and no inhibitory activity on HDACs 4,5,6,7 and 8 (Fournel et al, mol Cancer Ther 2008,7 (4): 759-768).
From the action mechanism, HDAC inhibitors can modulate multiple signaling pathways by changing gene expression and protein activity, resulting in antitumor activity, the mechanism mainly comprising: cell cycle arrest, induction of apoptosis, induction of autophagy, inhibition of angiogenesis, promotion of ROS production, etc. (Li et al, front Cell Dev Biol 2020,8,576946). In addition, it has been shown that subtype selective HDAC inhibitors such as MGCD0103 can alter tumor microenvironment to promote anti-tumor immunity (Briere et al, cancer Immunol Immunother 2018,67 (3): 381-392).
Tumor Microenvironment (TME) has immunosuppressive properties. Key drivers of immune escape in TMEs include tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), which mediate not only immunosuppression but also promote metastasis and resistance to immunotherapy. Studies have shown that some HDAC inhibitors can up-regulate the expression of co-stimulatory molecules such as MHC and CD80/86 (Deng et al, mol Cancer Ther 2019,18 (5): 900-908), while promoting the expression of non-classical MHC such as CD1d, and thus promote antigen presentation, thereby enhancing immune recognition and NK cell activation (Tiper et al, cancer Immunol Immunother 2016,65 (11): 1411-1421). Class I HDAC inhibitors have been shown to up-regulate PD-L1 and PD-L2 in tumor cells, thereby synergistically enhancing the activity of anti-PD-L1 drugs (Woods et al, cancer Immunol Res 2015,3 (12): 1375-1385), and can be used as potential tumor immunotherapeutic drugs. The combination of HDAC inhibitors with radiotherapy, chemotherapy, molecular targeted therapy, immunotherapeutic drugs, etc. also holds very broad promise, and clinical trials are underway with multiple HDAC inhibitors in combination with immunotherapeutic drugs.
However, the existing HDAC inhibitors have the disadvantages of low selectivity, obvious side effects, poor pharmacokinetic properties and the like, which severely limit the clinical application of the HDAC inhibitors. Therefore, the development of novel HDAC inhibitors is designed to have important application value for the treatment of tumors.
Disclosure of Invention
The invention aims to overcome the defect of single HDAC inhibitor in the prior art, and provides a triazole amide compound with a novel structure, and a preparation method and application thereof. The triazole amide compound provided by the invention has good HDAC (high-level HDAC) inhibitory activity and can inhibit proliferation of tumor cells. Part of the compounds have good pharmacokinetic properties, have an inhibiting effect on the growth of mouse MC38 colon cancer subcutaneous transplantation tumor, and have an obvious inhibiting effect on the growth of human HCT-116 colon cancer mouse subcutaneous transplantation tumor.
The invention provides a triazole amide compound shown as a formula I or pharmaceutically acceptable salt thereof,
wherein ring A is a 6-14 membered aryl group, substituted with one or more R 7a Substituted 6-14 membered aryl, 5-10 membered heteroaryl, substituted with one or more R 7b Substituted 5-10 membered heteroaryl, orSaid 5-10 membered heteroaryl and is substituted with one or more R 7b In the 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-4; when the substituents are plural, the same or different;
R 7a and R is 7b Independently halogen, -CN, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 6 Alkynyl, C substituted by one or more halogens 1 -C 6 Alkyl or- (CH) 2 ) n -N(R 8a R 8b )；
L is a bond or
R 5 Is hydrogen, halogen or C 1 -C 6 An alkyl group;
R 6 is hydroxy, 6-14 membered aryl or is substituted with one or more R 9 Substituted 6-14 membered aryl; when the substituents are plural, the same or different;
R 9 is-N (R) 9a R 9b ) Or halogen;
R 1 ，R 2 ，R 3 ，R 4 ，R 8a ，R 8b 、R 9a and R is 9b Independently hydrogen orC 1 -C 6 An alkyl group;
n is 0, 1, 2 or 3;
the carbon atoms with "×" represent, when chiral, S configuration, R configuration or mixtures thereof.
In the present invention, when ring A is a 6-14 membered aryl or is substituted with one or more R 7a In the case of substituted 6-14 membered aryl, said 6-14 membered aryl is optionally substituted with one or more R 7a The 6-14 membered aryl group in the substituted 6-14 membered aryl group is preferably a 6-10 membered aryl group, for example, phenyl,
In the present invention, when ring A is a 5-10 membered heteroaryl or is substituted with one or more R 7b In the case of substituted 5-10 membered heteroaryl, said 5-10 membered heteroaryl is optionally substituted with one or more R 7b The 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl is preferably pyridinyl or quinolinyl, e.g
In the present invention, when R 5 、R 7a 、R 7b And R is 9 When independently halogen, the halogen is preferably fluorine, chlorine, bromine or iodine, such as fluorine, chlorine or bromine.
In the present invention, when R 1 、R 2 、R 3 、R 4 、R 5 、R 7a 、R 7b 、R 8a 、R 8b 、R 9a And R is 9b Independently C 1 -C 6 In the case of alkyl, said C 1 -C 6 The alkyl group is preferably a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl group, for example a methyl, ethyl or isopropyl group.
In the present application, when R 7a And R is 7b Each independently is C 1 -C 6 In the case of alkoxy, said C 1 -C 6 Alkoxy is preferably C 1 ～C 3 Alkoxy, such as methoxy or ethoxy.
In the present application, when R 7a And R is 7b Independently C 2 -C 6 In the case of alkynyl, said C 2 -C 6 Alkynyl is preferably C 2 -C 4 Alkynyl groups such as ethynyl.
In the present application, when R 7a And R is 7b Independently C substituted by one or more halogens 1 -C 6 In the case of alkyl radicals, said C being substituted by one or more halogens 1 -C 6 Alkyl is preferably C substituted by one or more halogens 1 -C 3 Alkyl groups such as trifluoromethyl.
In the present application, when R 6 Is a 6-14 membered aryl or is substituted with one or more R 9 In the case of substituted 6-14 membered aryl, said 6-14 membered aryl is optionally substituted with one or more R 7a The 6-14 membered aryl group in the substituted 6-14 membered aryl group is preferably a 6-10 membered aryl group, for example, phenyl.
In certain preferred embodiments of the present application, certain groups of the triazole amide compounds of formula I are defined below (groups not mentioned are as described in any of the embodiments of the application),
ring A is a 6-14 membered aryl group, substituted with one or more R 7a Substituted 6-14 membered aryl, 5-10 membered heteroaryl or
In certain preferred embodiments of the present application, certain groups of the triazole amide compounds of formula I are defined below (groups not mentioned are as described in any of the embodiments of the application),
R 5 is hydrogen.
In certain preferred embodiments of the present application, certain groups of the triazole amide compounds of formula I are defined below (groups not mentioned are as described in any of the embodiments of the application),
R 6 is hydroxy, or is substituted with one or more R 9 Substituted 6-14 membered aryl.
In certain preferred embodiments of the present application, certain groups of the triazole amide compounds of formula I are defined below (groups not mentioned are as described in any of the embodiments of the application),
R 8a and R is 8b Independently C 1 -C 6 An alkyl group.
In certain preferred embodiments of the present application, certain groups of the triazole amide compounds of formula I are defined below (groups not mentioned are as described in any of the embodiments of the application),
R 9a and R is 9b Independently hydrogen.
In certain preferred embodiments of the present application, certain groups of the triazole amide compounds of formula I are defined below (groups not mentioned are as described in any of the embodiments of the application),
n is 0 or 1.
In certain preferred embodiments of the present application, certain groups of the triazole amide compounds of formula I are defined below (groups not mentioned are as described in any of the embodiments of the application),
Ring A is a 6-14 membered aryl group, substituted with one or more R 7a Substituted 6-14 membered aryl, 5-10 membered heteroaryl orWhen the substituents are plural, the same or different;
R 7a is halogen, -CN, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 6 Alkynyl, C substituted by one or more halogens 1 -C 6 Alkyl or- (CH) 2 ) n -N(R 8a R 8b )；
L is a bond or
R 1 、R 2 、R 3 And R is 4 Independently hydrogen or C 1 -C 6 An alkyl group;
R 5 is hydrogen;
R 6 is hydroxy, or is substituted with one or more R 9 Substituted 6-14 membered aryl;
R 8a and R is 8b Independently C 1 -C 6 An alkyl group;
R 9 is-N (R) 9a R 9b ) Or halogen;
R 9a and R is 9b Independently hydrogen;
n is 0 or 1.
In certain preferred embodiments of the present application, certain groups of the triazole amide compounds of formula I are defined below (groups not mentioned are as described in any of the embodiments of the application),
ring A is phenyl,
In certain preferred embodiments of the present application, certain groups of the triazole amide compounds of formula I are defined below (groups not mentioned are as described in any of the embodiments of the application),
R 1 and R is 2 Independently H or methyl.
In certain preferred embodiments of the present application, certain groups of the triazole amide compounds of formula I are defined below (groups not mentioned are as described in any of the embodiments of the application),
R 3 and R is 4 Independently H or ethyl.
In certain preferred embodiments of the present application, certain groups of the triazole amide compounds of formula I are defined below (groups not mentioned are as described in any of the embodiments of the application),
R 6 is hydroxy group,
In certain preferred embodiments of the present application, the triazole amide compound of formula I is selected from any one of the following structures, isomers thereof, or mixtures thereof:
the application also provides a pharmaceutical composition which comprises the triazole amide compound shown in the formula I or pharmaceutically acceptable salt thereof and at least one pharmaceutical excipient.
The choice of the pharmaceutical excipients is varied depending on the route of administration and the nature of the action, and may generally be fillers, diluents, binders, wetting agents, disintegrants, lubricants, emulsifiers, suspending agents, etc. which are conventional in the art.
The application also provides application of the triazole amide compound shown in the formula I and pharmaceutically acceptable salt thereof as an HDAC inhibitor.
The application also provides a pharmaceutical composition which comprises the triazole amide compound shown in the formula I or pharmaceutically acceptable salt thereof and the PD-1 or PD-L1 antibody.
The pharmaceutical composition is a pharmaceutical composition comprising the triazole amide compound shown as the formula I and the PD-1 or PD-L1 antibody, wherein each component is independently applied in a packaged form or other non-premixed forms, such as by sequential administration.
In certain preferred embodiments of the invention, the PD-1 antibody may be InVivomab anti-mouse PD-1 (Bio X Cell), na Wu Liyou mab (Nivolumab), palbociclizumab (Pembrolizumab), cimipro Li Shan antibody (Cemiplimab), terlipressin Li Shan antibody (Torilaimab), sindi Li Shan antibody (Cindilimab) and Carrilizumab (Camrelizumab); PD-L1 antibodies can be Ab Zhu Shankang (Atezolizumab), avelumab (Avelumab) and Durvalumab (Durvalumab). The pharmaceutical combination can be a combination of a compound I-38 and PD-1 antibody sodium Wu Liyou monoclonal antibody (Nivolumab), palbociclizumab (Pembrolizumab), cimipp Li Shan antibody (Cemiplimab), terlipp Li Shan antibody (Torilimiab), xindi Li Shan antibody (Cindilimab) or Carrilizumab (Camrelizumab); or in combination with the PD-L1 antibody alt Zhu Shankang (Atezolizumab), avistuzumab (Avelumab) or dimstuzumab (Durvalumab).
In certain preferred embodiments of the present invention, the triazolamide compound of formula I or a pharmaceutically acceptable salt thereof, and PD-1 or PD-L1 mab are administered separately.
The invention also provides application of the triazole amide compound shown in the formula I and pharmaceutically acceptable salt thereof in preparation of medicines for treating and/or preventing diseases related to HDAC by combining PD-1 or PD-L1 monoclonal antibody.
The invention also provides application of the triazole amide compound shown in the formula I and pharmaceutically acceptable salt thereof in preparing medicaments for treating and/or preventing diseases related to HDAC.
The triazole amide compound shown as the formula I, the pharmaceutically acceptable salt thereof or the pharmaceutical composition as described above can be in a therapeutically effective amount.
The disease may be cancer. The cancer may be a cancer of the head and neck (e.g., thyroid, nasopharyngeal, meninges, or intracranial metastases), a cancer of the respiratory system (e.g., small cell lung cancer or non-small cell lung cancer), a cancer of the digestive system (e.g., liver, stomach, oesophageal, rectal, colon or pancreas), a cancer of the urinary system (e.g., renal, bladder, prostate or testicular), bone, gynaecological (e.g., breast, cervical or ovarian), a cancer of the blood system (e.g., leukemia, lymphoma or myeloma), or other types of cancer (e.g., melanoma, glioma or skin cancer).
The triazolamide compound of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical combination as described above may be administered to a subject by any suitable route, preferably orally, by injection (intravenous, intramuscular, subcutaneous, and coronary), sublingually, nasally, by inhalation, or by topical route, more preferably orally.
In the present invention, the triazole amide compound shown in formula I or a pharmaceutically acceptable salt thereof may exist as a single stereoisomer or a mixture thereof (e.g., a racemate) if a stereoisomer exists. The term "stereoisomer" refers to a cis, trans or optical isomer. These stereoisomers may be isolated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and may be obtained by chiral resolution by bonding (chemical bonding, etc.) or salifying (physical bonding, etc.) other chiral compounds. The term "single stereoisomer" means that one stereoisomer of the compound of the present invention is present in an amount of not less than 95% by mass relative to all stereoisomers of the compound.
In the present invention, if a tautomer exists in the triazole amide compound shown in the formula I or a pharmaceutically acceptable salt thereof, the triazole amide compound can exist in the form of a single tautomer or a mixture of the single tautomer and the tautomer, and preferably exists in the form of a more stable tautomer.
The invention also provides a preparation method of the triazole amide compound shown in the formula I, which comprises the following scheme I or scheme II:
scheme one: when R is 6 In the case of hydroxyl, the compound shown in the formula II and hydroxylamine hydrochloride are reacted in the presence of alkali in an organic solvent to obtain the compoundTriazole amide compounds shown in the formula I,
scheme II: when R is 6 Is thatIn the presence of condensing agent and alkali, the compound shown in formula III and the compound shown in formula IV are subjected to condensation reaction in an organic solvent to obtain the triazole amide compound shown in formula I,
wherein the ring A, R 1 、R 2 、R 3 、R 4 、R 5 And L are as defined above.
The reaction operations and conditions in schemes one and two may be those conventional in this type of reaction in the art, and the invention is preferably as follows:
In the first embodiment, the organic solvent may be an alcohol solvent, such as methanol. The amount of the organic solvent is such that the reaction is not affected.
In the first embodiment, the base may be an alkali metal hydroxide, such as potassium hydroxide.
In the first embodiment, the molar ratio of the base to the hydroxylamine hydrochloride may be 1-3:1, for example 1.5:1.
In the first embodiment, the molar ratio of the hydroxylamine hydrochloride to the compound of formula II may be 1-100:1, for example 45:1.
In the first embodiment, the temperature of the reaction may be-40 ℃ to the boiling temperature of the organic solvent, for example, room temperature.
In scheme one, the progress of the reaction can be monitored by methods conventional in the art (e.g., TLC, HPLC or NMR), typically with the end point of the reaction when the compound of formula II is lost or no longer reacted. The reaction time may be from 5 minutes to 24 hours, for example 1 hour.
In the second embodiment, the organic solvent may be an amide solvent, such as N, N-dimethylformamide DMF. The amount of the organic solvent is such that the reaction is not affected.
In the second embodiment, the base may be an organic base such as N, N-Diisopropylethylamine (DIPEA).
In the second embodiment, the molar ratio of the base to the compound of formula III may be 1-3:1, for example 2:1.
In the second embodiment, the condensing agent may be a carbodiimide type condensing agent, a phosphorus positive ion type condensing agent, or a urea positive ion type condensing agent. The carbodiimide type condensing agent is preferably N, N '-Dicyclohexylcarbodiimide (DCC) or N, N' -Diisopropylcarbodiimide (DIC). The phosphorus positive ion condensing agent is preferably a Kate condensing agent BOP or a PyBOP. The urea positive ion condensing agent is preferably HATU, TBTU or TOTU.
In the second embodiment, the molar ratio of the condensing agent to the compound represented by formula III may be 1-3:1, for example, 2:1.
In the second embodiment, the molar ratio of the compound represented by formula IV to the compound represented by formula III may be 1-3:1, for example, 2:1.
In the second embodiment, the temperature of the condensation reaction may be-40 ℃ to the boiling temperature of the organic solvent, for example, room temperature.
In scheme II, the progress of the condensation reaction can be monitored by methods conventional in the art (e.g., TLC, HPLC or NMR), typically using the compound of formula III as the end point of the reaction when it is lost or no longer reacted. The condensation reaction time may be 1 to 48 hours, for example 12 to 24 hours.
The invention also provides a compound which has any one of the following structures:
wherein the ring A, R 1 、R 2 、R 3 、R 4 、R 5 And L are as defined above.
In certain preferred embodiments of the present invention, the compound of formula II is any one of the following structures:
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in certain preferred embodiments of the present invention, the compound of formula III is any one of the following structures:
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in the present invention, unless otherwise indicated, the terms are defined as follows:
the following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato:1999, and "March's Advanced Organic Chemistry" by Michael b.smith and Jerry March, john Wiley & Sons, new york:2007, the entire contents of which are incorporated herein by reference.
In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds. When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left.
Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C 1 -C 6 Alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.
In this context, a numerical range as defined in substituents, such as 0 to 4, 1-4, 1 to 3, etc., indicates an integer within the range, such as 1-6 is 1, 2, 3, 4, 5, 6.
As is conventional in the art, are used herein in the structural formulaFor depicting the bond at the point of attachment of the moiety or substituent to the core or backbone structure.
As is conventional in the art, "-" at the end of a group means that the group is attached to other fragments in the molecule through that site. For example, CH 3 -C (=o) -means acetyl.
The term "one(s)" or "one(s) or two or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.
The term "comprising" is an open-ended expression, i.e. including what is indicated by the invention, but not excluding other aspects.
The term "substituted" refers to any one or more hydrogen atoms on a particular atom being substituted with a substituent, including heavy hydrogen and variants of hydrogen, so long as the valence of the particular atom is normal and the substituted compound is stable.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Further, when the group is substituted with 1 or more of the substituents, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1 -C 6 Alkyl "or" C 1 -C 6 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 An alkyl group; "C 1-4 Alkyl "refers specifically to independently disclosed methyl, ethyl, C 3 Alkyl (i.e. propyl, including n-propyl and isopropyl), C 4 Alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "alkyl" as used herein refers to a straight or branched saturated hydrocarbon chain, such as a straight or branched saturated hydrocarbon chain containing from 1 to 20 carbon atoms. The term "C x -C y Alkyl "refers to a straight or branched chain saturated hydrocarbon containing from x to y carbon atoms. For example "C 1 -C 8 Alkyl "refers to straight or branched chain saturated hydrocarbons containing 1 to 8 carbon atoms. Representative examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2-dimethylpentyl, 2, 3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
The term "alkoxy" refers to the group-O-R X Wherein R is X Are alkyl groups as defined above.
The term "alkynyl" refers to a straight or branched hydrocarbon chain radical having at least one triple bond, consisting of only carbon and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms, and being attached to the remainder of the molecule by single bonds, including, for example, but not limited to, ethynyl, 1-propynyl, n-propargyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, or pent-1, 4-dialkynyl, and the like.
The term "aryl" refers to an aromatic group consisting of carbon atoms that satisfies the 4n+2 rule of conjugated hydrocarbon ring systems, each ring having aromaticity. In one embodiment, "aryl" refers to an aromatic group having from 6 to 18 (preferably from 6 to 10) carbon atoms. Examples of aryl groups include, but are not limited to, phenyl or naphthyl, and the like.
The term "heteroaryl" means a conjugated ring system group having a carbon atom and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur within the ring. Preferably a 5-10 membered heteroaryl group comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, more preferably a 5-6 membered heteroaryl group comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoxazolyl, thiadiazolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, cinnolinyl, quinazolinyl, indolizinyl, phenanthridinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, benzoxazolyl, or benzisoxazolyl.
As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: S.M. Berge et al describe pharmaceutically acceptable salts in detail in J.pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptableNon-toxic acid-forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods described in the literature such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonates, benzoic acid salts, bisulfate salts, borates, butyric acid salts, camphoric acid salts, cyclopentylpropionates, digluconate, dodecylsulfate, ethanesulfonate, formate salts, fumaric acid salts, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodic acid salts, 2-hydroxy-ethanesulfonate salts, lactobionic aldehyde salts, lactate salts, laurate salts, lauryl sulfate, malate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, palmitate salts, pamoate salts, pectate salts, persulfate salts, 3-phenylpropionate salts, picrate salts, pivalate salts, propionate salts, stearate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, and the like. Salts obtained by suitable bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl group 4 Is a salt of (a). The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations, such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C 1-8 Sulfonate and aromatic sulfonate.
The term "pharmaceutical excipients" refers to excipients and additives used in the manufacture of medicaments and formulation of prescriptions, and is all matter contained in the pharmaceutical formulation except for the active ingredient. See in particular the pharmacopoeia of the people's republic of China (2020 edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).
The term "pharmaceutical combination" is a pharmaceutical composition comprising an HDAC inhibitor and a PD-1 or PD-L1 antibody, and wherein the components are administered independently in a packaged form or other form that is not pre-mixed, e.g., by sequential administration.
The term "therapeutically effective amount" refers to an amount of a compound administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted as appropriate by one skilled in the art.
The term "treatment" refers to any of the following conditions: (1) alleviating one or more biological manifestations of a disease; (2) Interfere with one or more points in the biological cascade that trigger the disease; (3) Slowing the progression of one or more biological manifestations of the disease.
The term "preventing" refers to reducing the risk of developing a disease.
The term "subject" refers to any animal, preferably a mammal, most preferably a human, that has been or is about to be treated. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the triazole amide compounds with novel structures provided by the invention have good HDAC (high-level alternating current) inhibition activity and can inhibit proliferation of tumor cells. Part of the compounds have good pharmacokinetic properties, have an inhibiting effect on the growth of mouse MC38 colon cancer subcutaneous transplantation tumor, and have an obvious inhibiting effect on the growth of human HCT-116 colon cancer mouse subcutaneous transplantation tumor.
Drawings
FIG. 1 shows the change in tumor volume of compound I-38 administered by gavage in combination with PD-1 antibodies.
FIG. 2 shows the change in body weight of mice given compound I-38 by gavage in combination with PD-1 antibodies.
FIG. 3 shows the change in tumor volume of compound I-1 administered by gavage.
FIG. 4 shows the change in body weight of mice administered with Compound I-1 by gavage.
FIG. 5 shows the change in tumor volume of subcutaneous transplantable tumors in mice with human HCT-116 colon cancer, given compound I-38 by gavage.
FIG. 6 shows the change in body weight of mice with compound I-38 administered by gavage, human HCT-116 colon cancer.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Examples 1-2: preparation of Compounds I-1 and I-2
Step 1: cyanoacetic acid (1.89 g,22 mmol) was dissolved in dichloromethane (200 mL), HATU (10.13 g,27 mmol) was added dropwise triethylamine (6.2 mL,44 mmol) with ice, and after stirring for 15 min, methyl 4-aminomethylbenzoate hydrochloride (4.02 g,20 mmol) was added and reacted overnight at room temperature. Dichloromethane extraction, washing with saturated brine, drying the organic phase over anhydrous sodium sulfate, concentrating, and purifying with ethanol to give sn01006 as a white solid (4 g, 86% yield). 1 H NMR (800 MHz, deuterated chloroform) δ8.03 (d, j=8.2 hz, 2H), 7.36 (d, j=8.2 hz, 2H), 6.49 (s, 1H), 4.54 (d, j=5.9 hz, 2H), 3.92 (s, 3H), 3.44 (s, 2H) HRMS (ESI) C 12 H 13 N 2 O 3 + [M+H] + Calculated values: 233.0921, found: 233.0937.
step 2: aniline (481 mg,5.2 mmol) was dissolved in 3mL of concentrated hydrochloric acid and 1mL of water, and 2mL (660 mg,9.7 mmol) of sodium nitrite solution was added dropwise thereto under ice-bath conditions, keeping the ice-bath under stirringAfter 30min, it was slowly dropped into a mixed solution of sn01006 (1.00 g,4.3 mmol), sodium acetate trihydrate (10 g,73 mmol), ethanol, and water. After stirring for 1h, filtration and washing of the filter cake with ethanol gave sn01009 as a pale yellow solid (1.2 g, 83% yield). 1 H NMR(800MHz,DMSO-d 6 )δ13.84(s,1H),9.11(t,J＝6.0Hz,1H),7.94–7.92(m,2H),7.47(d,J＝8.3Hz,2H),7.40–7.37(m,4H),7.17–7.13(m,1H),4.47(d,J＝6.0Hz,2H),3.84(s,3H).HRMS(ESI)C 18 H 17 N 4 O 3 + [M+H] + Calculated values: 337.1295, found: 337.1312.
step 3: sn01009 (1.18 g,3.5 mmol), hydroxylamine hydrochloride (300 mg,4.3 mmol), anhydrous potassium acetate (425 mg,4.3 mmol) were dissolved in ethanol (100 mL) and refluxed at 100℃for 2h. After completion of the reaction, the mixture was filtered while it was still hot, and concentrated under reduced pressure to give sn01016 (0.6 g, yield 46%) as a yellow viscous solid. 1 H NMR(800MHz,DMSO-d 6 )δ13.50(s,1H),10.24(s,1H),8.90(t,J＝6.4Hz,1H),7.93(d,J＝8.3Hz,2H),7.45(d,J＝8.3Hz,2H),7.39(s,2H),7.35(t,J＝7.9Hz,2H),7.02(t,J＝7.3Hz,1H),6.71(s,2H),4.51(d,J＝6.3Hz,2H),3.84(s,3H).HRMS(ESI)C 18 H 20 N 5 O 4 + [M+H] + Calculated values: 370.1510, found: 370.1510.
step 4: sn01016 (600 mg,1.6 mmol) was dissolved in anhydrous DMF (10 mL), and triethylamine (0.25 mL,1.79 mmol) was added dropwise, followed by reflux at 180℃for 1h. Ethyl acetate, saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by flash column chromatography (ethyl acetate/petroleum ether=1:2) to give an oil which was purified by beating with ethanol to give sn01021 as a pale yellow solid (300 mg, yield 53%). 1 H NMR(800MHz,DMSO-d 6 )δ9.04(t,J＝6.2Hz,1H),7.93(d,J＝8.2Hz,4H),7.56–7.52(m,2H),7.48(d,J＝8.3Hz,2H),7.37(t,J＝7.4Hz,1H),5.95(s,2H),4.54(d,J＝6.2Hz,2H),3.84(s,3H). 13 C NMR (201 MHz, deuterated chloroform) delta 166.9,162.2,153.9,143.4,139.4,130.2 (2C), 129.5,129.4 (2C), 127.6 (2C), 127.5,126.8,118.5 (2C), 52.3,42.7.HRMS (ESI) C 18 H 18 N 5 O 3 + [M+H] + Calculated values: 352.1404, in factMeasuring: 352.1404.
step 5: hydroxylamine hydrochloride (1.07 g) was dissolved in absolute methanol (5.52 mL) to obtain solution a, potassium hydroxide (1.29 g) was dissolved in absolute methanol (3.22 mL) to obtain solution B, a was dropped into B, ice bath stirring was performed for 30min, filtration was performed to obtain a free hydroxylamine solution, and it was dropped into a bottle containing sn01021 (120 mg,0.34 mmol), ice bath was performed and then stirring was performed at room temperature for 1h. The reaction mixture was adjusted to be weakly alkaline in pH with 1, 4-dioxane solution (2 mol/L) of hydrogen chloride, concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was concentrated and purified by beating with ethanol to give I-1 (100 mg, yield 83%) as a pale yellow solid. 1 H NMR(800MHz,DMSO-d 6 )δ11.17(s,1H),9.02(t,J＝6.2Hz,1H),8.98(s,1H),7.93(d,J＝7.6Hz,2H),7.71(d,J＝8.3Hz,2H),7.56–7.52(m,2H),7.40(d,J＝8.2Hz,2H),7.37(t,J＝7.4Hz,1H),5.96(s,2H),4.49(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ164.2,161.6,154.4,142.9,139.0,131.4,129.6(2C),127.3(2C),127.2,127.0(2C),126.7,117.8(2C),41.7.HRMS(ESI)C 17 H 17 N 6 O 3 + [M+H] + Calculated values: 353.1357, found: 353.1353.hplc:98.5%.
Step 6: sn01021 (100 mg,0.3 mmol) was dissolved in ethanol (50 mL), and a potassium hydroxide solution (600 mg potassium hydroxide, 10mL water) was added and refluxed at 100℃for 2h. The reaction solution was acidified with dilute hydrochloric acid to precipitate brown solid sn01028, which was directly subjected to the next reaction without purification.
Step 7: raw material sn01028 was dissolved in anhydrous DMF (10 mL), HATU (228 mg,0.6 mmol), DIPEA (0.1 mL,0.6 mmol) and after stirring for 15 min o-phenylenediamine (65 mg,0.6 mmol) was added and reacted overnight at room temperature. Ethyl acetate, saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by flash column chromatography (ethyl acetate/petroleum ether=3:1) to give an oil which was purified by beating with ethanol to give I-2 as a white solid (60 mg, yield 47%). 1 H NMR(800MHz,DMSO-d 6 )δδ9.67(s,1H),9.08(t,J＝6.3Hz,1H),7.98–7.92(m,4H),7.58–7.52(m,2H),7.46(d,J＝8.1Hz,2H),7.37(t,J＝7.4Hz,1H),7.17(d,J＝7.6Hz,1H),6.98(t,J＝7.0Hz,1H),6.80(d,J＝7.8Hz,1H),6.63(t,J＝7.4Hz,1H),5.99(s,2H),4.53(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.2,161.6,154.4,143.2,142.5,139.0,133.2,129.6(2C),127.9(2C),127.2(2C),127.1,126.7,126.7,126.5,123.7,117.8(2C),116.7,116.4,41.7.HRMS(ESI)C 23 H 22 N 7 O 2 + [M+H] + Calculated values: 428.1829, found: 418.1823.HPLC:97.1%.
Example 3: compound I-3
Step 1: the o-phenylenediamine in step 7 of example 1-2 was replaced with "2-Boc-amino-4-fluoroaniline", and the remaining required raw materials and reagents were the same, to give intermediate YWZ-02-085-1 as a pale yellow oil (51 mg, yield 31%). 1 H NMR(800MHz,DMSO-d 6 )δ7.94–7.89(m,4H),7.53–7.49(m,1H),7.45–7.40(m,4H),7.31(t,J＝7.4Hz,1H),7.21–7.16(m,2H),7.14(s,1H),6.83(t,J＝8.2Hz,1H),5.29(s,1H),4.68(d,J＝6.2Hz,2H),1.49(s,9H).HRMS(ESI)C 28 H 29 FN 7 O 4 + [M+H] + Calculated values: 546.2260, found: 546.2271.
step 2: YWZ-02-085-1 (60 mg,0.1 mmol) was dissolved in ethyl acetate, concentrated hydrochloric acid (0.06 mL) was added, stirred overnight at room temperature, the pH was adjusted to neutrality, extracted with ethyl acetate, washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by flash column chromatography (ethyl acetate/petroleum ether=1:1) to give brown solid I-3 (20 mg, yield 41%). 1 H NMR(800MHz,DMSO-d 6 )δ9.57(s,1H),9.05(t,J＝6.1Hz,1H),7.94(t,J＝7.4Hz,4H),7.55(t,J＝7.9Hz,2H),7.46(d,J＝7.9Hz,2H),7.37(t,J＝7.4Hz,1H),7.14–7.10(m,1H),6.58–6.53(m,1H),6.38(t,J＝7.1Hz,1H),4.53(d,J＝6.1Hz,2H).HRMS(ESI)C 23 H 21 FN 7 O 2 + [M+H] + Calculated values: 446.1735, found: 446.1740.HPLC:95.6%.
Examples 4 to 5: preparation of Compounds I-4 and I-5
Step 1-3: following the procedure of step 2-4 described in example 1-2, the aniline in step 2 was replaced with p-methoxyaniline, and the remaining starting materials and reagents required were the same to give sn01040 as a pale yellow solid (400 mg, 66% yield). 1 H NMR (800 MHz, deuterated chloroform) δ8.03 (d, j=8.1 hz, 2H), 7.84 (d, j=9.0 hz, 2H), 7.44 (d, j=8.0 hz, 2H), 7.03 (t, j=5.7 hz, 1H), 6.95 (d, j=9.0 hz, 2H), 4.96 (s, 2H), 4.70 (d, j=6.2 hz, 2H), 3.91 (s, 3H), 3.84 (s, 3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.7,158.3,154.2,145.3,132.7,129.2(2C),128.1,127.5(2C),125.9,119.3(2C),114.6(2C),55.5,52.0,41.7.HRMS(ESI)C 19 H 20 N 5 O 4 [M+H] + Calculated values: 382.1510, found: 382.1513.
step 4: following the procedure of step 5 described in example 1-2, sn01021 was replaced with sn01040, and the remaining starting materials, reagents were identical to give I-4 as a tan solid (59 mg, 45% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.17(s,1H),8.95(t,J＝6.3Hz,1H),7.86–7.81(m,2H),7.71(d,J＝8.3Hz,2H),7.39(d,J＝8.3Hz,2H),7.11–7.07(m,2H),5.89(s,2H),4.48(d,J＝6.2Hz,2H),3.81(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ164.2,161.6,158.3,154.2,142.9,132.7,131.3,127.2(2C),126.9(2C),125.9,119.3(2C),114.7(2C),55.5,41.6.HRMS(ESI)C 18 H 19 N 6 O 4 + [M+H] + Calculated values: 383.1462, found: 383.1467.HPLC:99.2%.
Step 5: the procedure of step 6 described in example 1-2 was followed, substituting sn01021 with sn01040, and the remaining starting materials and reagents were identical to each other to give sn01042, which was directly subjected to the next reaction without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn01042, and the remaining starting materials, reagents were the same to give white solid I-5 (41 mg, 30% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.63(s,1H),8.98(t,J＝6.3Hz,1H),7.94(d,J＝7.9Hz,2H),7.85(d,J＝9.1Hz,2H),7.45(d,J＝8.1Hz,2H),7.17(d,J＝7.6Hz,1H),7.10(d,J＝9.1Hz,2H),6.97(t,J＝7.6Hz,1H),6.78(d,J＝8.0Hz,1H),6.60(t,J＝7.4Hz,1H),5.90(s,2H),4.94(s,2H),4.52(d,J＝6.2Hz,2H),3.81(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ165.2,161.7,158.3,154.2,143.2,143.0,133.2,132.7,127.8(2C),127.1(2C),126.7,126.5,125.9,123.4,119.3(2C),116.3,116.2,114.7(2C),55.5,41.7.HRMS(ESI)C 24 H 24 N 7 O 3 + [M+H] + Calculated values: 458.1935, found: 458.1938.HPLC:99.2%.
Examples 6 to 7: preparation of Compounds I-6 and I-7
Step 1-3: following the procedure of step 2-4 described in example 1-2, the aniline in step 2 was replaced with "p-chloroaniline" and the remaining starting materials and reagents required were the same to give sn01041 as a pale yellow solid (360 mg, 58% yield). 1 H NMR (800 MHz, deuterated chloroform) δ8.03 (d, j=8.2 hz, 2H), 7.87 (d, j=8.9 hz, 2H), 7.44 (d, j=8.2 hz, 2H), 7.40 (d, j=8.9 hz, 2H), 7.04 (t, j=5.7 hz, 1H), 5.02 (s, 2H), 4.70 (d, j=6.2 hz, 2H), 3.92 (s, 3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.4,154.5,145.2,137.7,131.2,129.6(2C),129.3(2C),128.2,127.5(2C),127.0,119.3(2C),52.0,41.7.HRMS(ESI)C 18 H 17 ClN 5 O 3 [M+H] + Calculated values: 386.1014, found: 386.1009.
step 4: following the procedure of step 5 described in example 1-2, sn01021 was replaced with sn01041, and the remaining starting materials, reagents were identical to afford brown solid I-6 (76 mg, 58% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.17(s,1H),9.06(t,J＝6.2Hz,1H),8.98(s,1H),7.92(d,J＝8.9Hz,2H),7.71(d,J＝7.9Hz,2H),7.62(d,J＝8.8Hz,2H),7.39(d,J＝8.1Hz,2H),6.01(s,2H),4.49(d,J＝6.1Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.4,154.5,142.8,137.7,131.4,131.2,129.6(2C),127.2(2C),127.1,126.9(2C),119.3(2C),41.7.HRMS(ESI)C 17 H 16 ClN 6 O 3 + [M+H] + Calculated 387.0967, found: 387.0969.HPLC:96.0%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn01041, and the remaining starting materials, reagents were identical to each other to give sn01043, which was directly subjected to the next reaction without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn01043, and the remaining starting materials, reagents were the same to give white solid I-7 (89 mg, 64% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.63(s,1H),9.09(t,J＝6.3Hz,1H),7.96–7.90(m,4H),7.62(d,J＝9.0Hz,2H),7.46(d,J＝8.1Hz,2H),7.17(d,J＝7.6Hz,1H),6.97(t,J＝8.3Hz,1H),6.79(d,J＝8.0Hz,1H),6.61(t,J＝7.4Hz,1H),6.02(s,2H),5.01(s,2H),4.53(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.1,161.4,154.5,143.0,137.7,133.2,131.2,130.4,129.6(2C),127.8(2C),127.13(2C),127.11,126.7,126.5,123.4,119.3(2C),116.3,116.2,41.7.HRMS(ESI)C 23 H 21 ClN 7 O 2 + [M+H] + Calculated values: 462.1440, found: 462.1441.HPLC:99.7%.
Examples 8 to 9: preparation of Compounds I-8 and I-9
Step 1-3: the aniline in step 2 was replaced with "para-fluoroaniline" following the procedure of step 2-4 described in example 1-2, and the remaining required starting materials, reagents were the same, giving sn01055 as a pale yellow solid. 1 H NMR(800MHz,DMSO-d 6 )δ9.07(t,J＝6.2Hz,1H),7.95–7.92(m,4H),7.47(d,J＝8.4Hz,2H),7.40(t,J＝8.8Hz,2H),5.98(s,2H),4.53(d,J＝6.2Hz,2H),3.84(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.5,160.8(d,J＝244.3Hz),154.4,145.2,135.5,129.3(2C),128.2,127.5(2C),126.7,119.8(d,J＝8.5Hz,2C),116.4(d,J＝23.4Hz,2C),52.0,41.7.HRMS(ESI)C 18 H 17 FN 5 O 3 [M+H] + Calculated values: 370.1310, found: 370.1317.
step 4 was performed in analogy to step 5 described in example 1-2, substituting sn01021 for sn01055 and the remaining starting materials, reagents were identical to give I-8 as a tan solid (34 mg, 27% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.17(s,1H),9.02(t,J＝6.2Hz,1H),7.95–7.91(m,2H),7.71(d,J＝8.2Hz,2H),7.42–7.38(m,4H),5.97(s,2H),4.49(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.5,160.8(d,J＝244.3Hz),154.4,142.8,135.6,131.4,127.2(2C),126.9,126.7(2C),119.8(d,J＝8.6Hz,2C),116.4(d,J＝23.3Hz,2C),41.7.HRMS(ESI)C 17 H 16 FN 6 O 3 + [M+H] + Calculated values: 371.1262, found: 371.1254.HPLC:98.4%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn01055, and the remaining starting materials, reagents were identical to each other to give sn01056, which was carried out directly in the next step without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn01056, and the remaining starting materials, reagents were the same to give pale yellow solid I-9 (75 mg, 56% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.63(s,1H),9.06(t,J＝6.3Hz,1H),7.96–7.93(m,4H),7.46(d,J＝8.1Hz,2H),7.41(t,J＝8.8Hz,2H),7.17(d,J＝7.7Hz,1H),6.97(t,J＝7.6Hz,1H),6.78(d,J＝8.0Hz,1H),6.61(t,J＝7.4Hz,1H),5.97(s,2H),4.91(s,2H),4.53(d,J＝6.2Hz,2H). 13 C NMR(800MHz,DMSO-d 6 )δ165.2,161.5,160.8(d,J＝244.3Hz),154.4,143.1,135.6(d,J＝2.6Hz),133.2,127.8(2C),127.1(2C),126.74,126.71,126.66,126.5,123.4,119.8(d,J＝8.6Hz,2C),116.4(d,J＝23.3Hz,2C),116.3,116.2,41.7.HRMS(ESI)C 23 H 21 FN 7 O 2 + [M+H] + Calculated values: 446.1735, found: 446.1736.HPLC:96.0%.
Examples 10 to 11: preparation of Compounds I-10 and I-11
Step 1-3: the aniline in step 2 was replaced with "4-amino-N, N-dimethylaniline" following the procedure of step 2-4 described in example 1-2, with the remaining starting materials, reagents, being identical, to give sn01073 as a pale yellow solid. 1 H NMR(800MHz,DMSO-d 6 )δ8.92(t,J＝6.2Hz,1H),7.93(d,J＝8.3Hz,2H),7.74(d,J＝9.1Hz,2H),7.46(d,J＝8.2Hz,2H),6.83(d,J＝9.1Hz,2H),4.51(d,J＝6.1Hz,2H),3.84(s,3H),2.95(s,6H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.8,154.0,149.5,145.4,129.2(2C),129.1,128.1,127.4(2C),125.0,119.0(2C),112.2(2C),52.0,41.6,40.0(2C).HRMS(ESI)C 20 H 23 N 6 O 3 [M+H] + Calculated values: 395.1826, found: 395.1822.
step 4: following the procedure of step 5 described in example 1-2, sn01021 was replaced by sn01073, and the remaining starting materials, reagents, were the same to give a pale grey solid I-10 (42 mg, 31% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.17(s,1H),8.99(s,1H),8.88(t,J＝6.2Hz,1H),7.74(d,J＝9.1Hz,2H),7.71(d,J＝8.2Hz,2H),7.39(d,J＝8.1Hz,2H),6.83(d,J＝9.1Hz,2H),5.82(s,2H),4.48(d,J＝6.2Hz,2H),2.95(s,6H). 13 C NMR(201MHz,DMSO-d 6 )δ162.9,161.8,154.0,149.5,143.0,131.3,129.1,127.2(2C),126.9(2C),125.1,119.1(2C),112.2(2C),41.6,40.1(2C).HRMS(ESI)C 19 H 22 N 7 O 3 + Calculated values: 396.1179, found: 396.1776.HPLC:97.2%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn01073, and the remaining starting materials and reagents required were the same to give sn01075, which was carried out directly in the next reaction without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn01075, and the remaining starting materials, reagents were the same to give I-11 as a pale yellow solid (33 mg, 23% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.68(s,1H),8.94(t,J＝6.3Hz,1H),7.94(d,J＝8.0Hz,2H),7.76–7.73(m,2H),7.45(d,J＝8.1Hz,2H),7.17(d,J＝7.6Hz,1H),6.99(t,J＝7.5Hz,1H),6.85–6.79(m,3H),6.66–6.62(m,1H),5.84(s,2H),4.51(d,J＝6.3Hz,2H),2.95(s,6H). 13 C NMR(201MHz,DMSO-d 6 )δ165.2,161.8,154.0,149.5,143.3,143.0,133.1,129.1,127.8(2C),127.1(2C),126.7,126.4,125.1,123.4,119.1(2C),116.3,116.2,112.2(2C),41.7,40.1(2C).HRMS(ESI)C 25 H 27 N 8 O 2 + [M+H] + Calculated values: 471.2251, found: 471.2261.Hplc:>99.9％。
examples 12 to 13: preparation of Compounds I-12 and I-13
Step 1-3: the aniline in step 2 was replaced by "3-amino-pyridine" following the procedure of step 2-4 described in example 1-2, the remaining starting materials and reagents were identical, giving sn01065 as a white solid. 1 H NMR(800MHz,DMSO-d 6 )δ9.16–9.12(m,2H),8.59–8.55(m,1H),8.25–8.22(m,1H),7.94(d,J＝8.3Hz,1H),7.61–7.59(m,1H),7.48(d,J＝8.3Hz,2H),6.08(s,2H),4.54(d,J＝6.1Hz,2H),3.84(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.3,154.6,147.9,145.1,139.1,135.4,129.3(2C),128.2,127.5(2C),127.5,125.0,124.3,52.0,41.7.HRMS(ESI)C 17 H 17 N 6 O 3 [M+H] + Calculated values: 353.1357, found: 353.1350.
step 4: following the procedure of step 5 described in example 1-2, sn01021 was replaced with sn01065, and the remaining starting materials, reagents were identical to afford I-12 as a pale yellow solid (95 mg, 79% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.17(s,1H),9.15(d,J＝2.5Hz,1H),9.10(t,J＝6.2Hz,1H),8.99(s,1H),8.57(d,J＝4.7Hz,1H),8.24(d,J＝8.4Hz,1H),7.71(d,J＝8.2Hz,2H),7.61–7.58(m,1H),7.40(d,J＝8.2Hz,2H),6.07(s,2H),4.50(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.3,154.6,147.9,142.7,139.1,135.4,131.4,127.5,127.3(2C),127.0(2C),125.1,124.4,41.7.HRMS(ESI)C 16 H 16 N 7 O 3 + [M+H] + Calculated values: 354.1309, found: 354.1316.Hplc:99.0%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn01065, and the remaining starting materials, reagents were identical to afford sn01087, which was carried on to the next reaction without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn01087, and the remaining starting materials, reagents were the same to give light brown solid I-13 (30 mg, 23% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.64(s,1H),9.16(d,J＝2.6Hz,1H),9.13(t,J＝6.3Hz,1H),8.59–8.55(m,1H),8.25–8.23(m,1H),7.95(d,J＝7.9Hz,2H),7.62–7.59(m,1H),7.47(d,J＝8.1Hz,2H),7.17(d,J＝7.6Hz,1H),6.97(t,J＝7.6Hz,1H),6.79(d,J＝7.9Hz,1H),6.61(t,J＝7.3Hz,1H),6.08(s,2H),4.54(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.2,161.3,154.6,147.9,143.1,143.0,139.1,135.4,133.2,127.9(2C),127.6,127.2(2C),126.7,126.5,125.0,124.4,123.4,116.3,116.2,41.8.HRMS(ESI)C 22 H 21 N 8 O 2 + [M+H] + Calculated values: 429.1782, found: 429.1772.HPLC:96.8%.
Examples 14 to 15: preparation of Compounds I-14 and I-15
Step 1-3: the aniline in step 2 was replaced by "4-bromoaniline" following the procedure of step 2-4 described in example 1-2, with the remaining starting materials and reagents required being identical, to give sn01094 as a yellow solid. 1 H NMR(800MHz,DMSO-d 6 )δ9.11(t,J＝6.2Hz,1H),7.93(d,J＝8.4Hz,2H),7.86(d,J＝9.0Hz,2H),7.75(d,J＝9.0Hz,2H),7.47(d,J＝8.4Hz,2H),6.02(s,2H),4.53(d,J＝6.2Hz,2H),3.84(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.4,154.5,145.2,138.1,132.5(2C),129.3(2C),128.2,127.5(2C),127.1,119.6(2C),119.5,52.0,41.7.HRMS(ESI)C 18 H 17 BrN 5 O 3 [M+H] + Calculated values: 430.0509, found: 430.0534.
step 4: following the procedure of step 5 described in example 1-2, sn01021 was replaced with sn01094, and the remaining starting materials, reagents were identical to afford brown solid I-14 (52 mg, 35% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.17(s,1H),9.07(t,J＝6.3Hz,1H),8.99(s,1H),7.86(d,J＝8.8Hz,2H),7.77–7.68(m,4H),7.39(d,J＝7.9Hz,2H),6.01(s,2H),4.48(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.3,154.4,142.7,138.1,132.5(2C),131.3,127.2(2C),127.1,126.9(2C),119.6(2C),119.5,41.7.HRMS(ESI)C 17 H 16 BrN 6 O 3 + [M+H] + Calculated values: 431.0462, found: 431.0459.HPLC:97.3%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn01094, and the remaining starting materials, reagents were identical to each other to give sn01097, which was carried out directly in the next step without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn01097, and the remaining starting materials, reagents were the same to give white solid I-15 (79 mg, 52% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.63(s,1H),9.10(t,J＝6.3Hz,1H),7.94(d,J＝8.0Hz,2H),7.88–7.83(m,2H),7.78–7.72(m,2H),7.46(d,J＝8.1Hz,2H),7.17(d,J＝7.6Hz,1H),6.97(t,J＝7.6Hz,1H),6.79(d,J＝7.9Hz,1H),6.61(t,J＝7.3Hz,1H),6.02(s,2H),4.93(s,2H),4.53(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.2,161.4,154.5,143.1,143.0,138.1,133.2,132.5(2C),127.8(2C),127.1(2C),126.7,126.5,123.4,122.1,119.6(2C),119.5,116.3,116.2,41.7.HRMS(ESI)C 23 H 21 BrN 7 O 2 + [M+H] + Calculated values: 506.0935, found: 506.0942.HPLC:98.8%.
Examples 16 to 17: preparation of Compounds I-16 and I-17
Step 1-3: the aniline in step 2 was replaced with "4-ethoxyaniline" following the procedure of step 2-4 described in example 1-2, and the remaining required starting materials, reagents were the same, giving sn01095 as a pale yellow solid. 1 H NMR(800MHz,DMSO-d 6 )δ8.99(t,J＝6.3Hz,1H),7.93(d,J＝8.4Hz,2H),7.83(d,J＝9.1Hz,2H),7.47(d,J＝8.4Hz,2H),7.08(d,J＝9.1Hz,2H),5.89(s,2H),4.52(d,J＝6.2Hz,2H),4.09–4.05(m,2H),3.84(s,3H),1.34(t,J＝7.0Hz,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.7,157.6,154.2,145.3,132.5,129.2(2C),128.1,127.5(2C),125.8,119.3(2C),115.1(2C),63.5,52.0,41.7,14.6.HRMS(ESI)C 20 H 22 N 5 O 4 [M+H] + Calculated values: 396.1666, found: 396.1665.
step 4: following the procedure of step 5 described in example 1-2, sn01021 was replaced with sn01095, and the remaining starting materials, reagents were identical to afford I-16 as a pale brown solid (112 mg, 83% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.17(s,1H),8.98(s,1H),8.95(t,J＝6.3Hz,1H),7.82(d,J＝9.0Hz,2H),7.71(d,J＝8.1Hz,2H),7.39(d,J＝8.1Hz,2H),7.07(d,J＝9.1Hz,2H),5.88(s,2H),4.48(d,J＝6.1Hz,2H),4.10–4.05(m,2H),1.34(t,J＝6.9Hz,3H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.6,157.6,154.2,142.9,132.5,131.3,127.2(2C),126.9(2C),125.9,119.3(2C),115.1(2C),63.5,41.6,14.6.HRMS(ESI)C 19 H 21 N 6 O 4 + [M+H] + Calculated values: 397.1619, found: 396.1617.HPLC:96.5%.
Step 5: the procedure of step 6 described in example 1-2 was followed, substituting sn01021 with sn01095 and the remaining starting materials and reagents were identical to each other to give sn01098, which was used in the next step without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn01098, and the remaining starting materials, reagents were the same to give white solid I-17 (19 mg, 13% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.63(s,1H),8.98(t,J＝6.3Hz,1H),7.94(d,J＝7.7Hz,2H),7.83(d,J＝9.1Hz,2H),7.45(d,J＝8.1Hz,2H),7.17(d,J＝7.5Hz,1H),7.08(d,J＝9.1Hz,2H),6.97(t,J＝7.6Hz,1H),6.79(d,J＝7.9Hz,1H),6.61(t,J＝7.3Hz,1H),5.89(s,2H),4.95(s,2H),4.52(d,J＝6.2Hz,2H),4.10–4.06(m,2H),1.34(t,J＝7.0Hz,3H). 13 C NMR(201MHz,DMSO-d 6 )δ165.2,161.7,157.6,154.2,143.2,143.1,133.2,132.6,127.8(2C),127.1(2C),126.7,126.5,125.9,123.4,119.3(2C),116.3,116.1,115.1(2C),63.5,41.7,14.6.HRMS(ESI)C 25 H 26 N 7 O 3 + [M+H] + Calculated values: 472.2092, found: 472.2086.HPLC:96.6%.
Examples 18 to 19: preparation of Compounds I-18 and I-19
Step 1-3: the aniline in step 2 was replaced with "4-isopropylaniline" in analogy to the procedure of step 2-4 described in example 1-2, and the remaining required starting materials, reagents were the same to give a white flocculent solid sn01109. 1 H NMR(800MHz,DMSO-d 6 )δ9.04(t,J＝6.3Hz,1H),7.94(d,J＝8.4Hz,2H),7.86(d,J＝8.6Hz,2H),7.48(d,J＝8.4Hz,2H),7.41(d,J＝8.6Hz,2H),5.95(s,2H),4.54(d,J＝6.2Hz,2H),3.85(s,3H),3.01–2.88(m,1H),1.23(d,J＝6.9Hz,6H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.6,154.3,147.5,145.3,137.0,129.2(2C),128.1,127.5(2C),127.3(2C),126.3,117.8(2C),52.0,41.7,33.0,23.7(2C).HRMS(ESI)C 21 H 24 N 5 O 3 [M+H] + Calculated values: 394.1874, found: 394.1882.
step 4: following the procedure of step 5 described in example 1-2, sn01021 was replaced with sn01109, and the remaining starting materials, reagents were the same to give I-18 as a white solid (85 mg, 63% yield). 1 H NMR(800MHz,DMSO-d 6 )δ8.99(s,1H),7.84(d,J＝8.3Hz,2H),7.72(d,J＝7.4Hz,2H),7.48–7.29(m,4H),5.93(s,2H),4.48(d,J＝5.5Hz,2H),2.97–2.90(m,1H),1.22(d,J＝6.9Hz,6H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.6,154.2,147.5,142.8,137.1,131.3,127.3(2C),127.2(2C),126.9(2C),126.3,117.8(2C),41.6,33.0,23.7(2C).HRMS(ESI)C 20 H 23 N 6 O 3 + [M+H] + Calculated values: 395.1826, found: 395.1831.HPLC:99.5%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn01109, and the remaining starting materials and reagents were identical to each other to give sn01114, which was then directly subjected to the next reaction without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn01114, and the remaining starting materials, reagents were the same to give white solid I-19 (65 mg, 46% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.63(s,1H),9.02(t,J＝6.3Hz,1H),7.95(d,J＝7.9Hz,2H),7.85(d,J＝8.6Hz,2H),7.46(d,J＝8.1Hz,2H),7.41(d,J＝8.6Hz,2H),7.17(d,J＝7.6Hz,1H),6.97(t,J＝7.6Hz,1H),6.79(d,J＝8.0Hz,1H),6.60(t,J＝7.4Hz,1H),5.94(s,2H),4.94(s,2H),4.53(d,J＝6.2Hz,2H),2.98–2.92(m,1H),1.23(d,J＝6.9Hz,6H). 13 C NMR(201MHz,DMSO-d 6 )δ165.2,161.6,154.2,147.5,143.2,143.0,137.1,133.2,127.8(2C),127.3(2C),127.1(2C),126.7,126.5,126.3,123.4,117.8(2C),116.4,116.2,41.7,33.0,23.8(2C).HRMS(ESI)C 26 H 28 N 7 O 2 + [M+H] + Calculated values: 470.2299, found: 470.2294.HPLC:99.7%.
Examples 20 to 21: preparation of Compounds I-20 and I-21
Step 1-3: the aniline in step 2 was replaced by "3-chloroaniline" in analogy to the procedure of step 2-4 described in example 1-2, the remaining required starting materials, reagents were the same, giving sn01123 as a brown solid. 1 H NMR(800MHz,DMSO-d 6 )δ9.14(t,J＝6.2Hz,1H),7.97(t,J＝2.0Hz,1H),7.93(d,J＝8.3Hz,2H),7.87–7.83(m,1H),7.56(t,J＝8.1Hz,1H),7.47(d,J＝8.4Hz,2H),7.43–7.41(m,1H),6.05(s,2H),4.54(d,J＝6.2Hz,2H),3.83(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.3,154.5,145.1,139.9,134.0,131.4,129.3(2C),128.2,127.5(2C),127.3,126.7,117.4,116.1,52.0,41.7.HRMS(ESI)C 18 H 17 ClN 5 O 3 [M+H] + Calculated values: 386.1014, found: 386.1012.
step 4: following the procedure of step 5 described in example 1-2, sn01021 was replaced with sn01123, and the remaining starting materials, reagents were the same to give I-20 as a white solid (96 mg, 73% yield). 1 H NMR(800MHz,DMSO-d 6 )δδ11.21(s,1H),9.25–8.88(m,2H),7.97(s,1H),7.85(d,J＝8.0Hz,1H),7.73(d,J＝8.0Hz,2H),7.56(t,J＝8.1Hz,1H),7.46–7.37(m,3H),6.05(s,2H),4.50(d,J＝6.0Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.3,154.5,142.7,139.9,134.0,131.4,131.4,127.3,127.2(2C),127.0(2C),126.7,117.4,116.2,41.7.HRMS(ESI)C 17 H 16 ClN 6 O 3 + [M+H] + Calculated values: 387.0967, found: 387.0987.HPLC:99.1%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn01123, and the remaining required starting materials, reagents were the same to give sn01124, which was carried out directly in the next reaction without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn01124, and the remaining starting materials, reagents were the same to give pale yellow solid I-21 (97 mg, 70% yield). 1 H NMR(800MHz,DMSO-d 6 )δ12.34(s,1H),11.85(t,J＝6.3Hz,1H),10.68(t,J＝2.1Hz,1H),10.66(d,J＝8.0Hz,2H),10.59–10.54(m,1H),10.27(t,J＝8.1Hz,1H),10.17(d,J＝8.1Hz,2H),10.14–10.11(m,1H),9.88(d,J＝7.6Hz,1H),9.70–9.64(m,1H),9.51–9.46(m,1H),9.30(t,J＝7.2Hz,1H),8.76(s,2H),7.61(s,2H),7.24(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.2,161.3,154.5,143.1,143.0,139.9,134.0,133.2,131.4,127.9(2C),127.4,127.2(2C),126.7,126.7,126.5,123.4,117.4,116.3,116.18,116.16,41.7.HRMS(ESI)C 23 H 21 ClN 7 O 2 + [M+H] + Calculated values: 462.1440, found: 462.1412.Hplc:>99.9％。
examples 22-23: preparation of Compounds I-22 and I-23
Step 1-3: the aniline in step 2 was replaced with "3-methoxyaniline" following the procedure of step 2-4 described in example 1-2, and the remaining required starting materials, reagents were the same to give sn01122 as a pale yellow solid. 1 H NMR(800MHz,DMSO-d 6 )δ9.07(t,J＝6.2Hz,1H),7.93(d,J＝8.3Hz,2H),7.53–7.51(m,1H),7.49–7.46(m,3H),7.44(t,J＝8.2Hz,1H),6.95–6.92(m,1H),5.97(s,2H),4.54(d,J＝6.2Hz,2H),3.83(d,J＝3.3Hz,6H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.5,160.0,154.3,145.2,140.0,130.5,129.3(2C),128.2,127.5(2C),126.7,112.9,109.9,103.3,55.4,52.1,41.7.HRMS(ESI)C 19 H 20 N 5 O 4 [M+H] + Calculated values: 382.1510, found: 382.1505.
step 4: following the procedure of step 5 described in example 1-2, sn01021 was replaced with sn01126, and the remaining starting materials, reagents were the same to give I-22 as a white solid (117 mg, 90% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.21(s,1H),9.05(t,J＝6.2Hz,1H),9.01(s,1H),7.73(d,J＝8.2Hz,2H),7.51(d,J＝8.0Hz,1H),7.48(t,J＝2.2Hz,1H),7.43(t,J＝8.2Hz,1H),7.40(d,J＝8.2Hz,2H),6.99–6.88(m,1H),5.98(s,2H),4.50(d,J＝6.2Hz,2H),3.83(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ164.2,161.5,160.1,154.3,142.9,140.1,131.4,130.5,127.2(2C),127.0(2C),126.7,112.9,110.0,103.3,55.5,41.7.HRMS(ESI)C 18 H 19 N 6 O 4 + [M+H] + Calculated values: 383.1462, found: 383.1477.HPLC:96.1%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn01122, and the remaining required starting materials, reagents were the same to give sn01126, which was carried out directly in the next reaction without purification.
Step 6: following the procedure of step 7 described in examples 1-2, sn01028 was replaced by sn01043, and the remaining starting materials, reagents were identical to each other to give white solid I-23 (64 mg, yield 46%). 1 H NMR(800MHz,DMSO-d 6 )δ9.64(s,1H),9.07(t,J＝6.3Hz,1H),7.96(d,J＝7.9Hz,2H),7.53(d,J＝8.1Hz,1H),7.50(t,J＝2.1Hz,1H),7.47(d,J＝8.1Hz,2H),7.44(t,J＝8.2Hz,1H),7.18(d,J＝7.6Hz,1H),6.97(t,J＝7.6Hz,1H),6.96–6.93(m,1H),6.79(d,J＝7.9Hz,1H),6.61(t,J＝7.4Hz,1H),5.99(s,2H),4.93(s,2H),4.55(d,J＝6.2Hz,2H),3.84(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ165.2,161.5,160.1,154.3,143.1,143.0,140.1,133.2,130.5,127.9(2C),127.2(2C),126.8,126.7,126.5,123.4,116.4,116.2,112.9,110.0,103.4,55.5,41.7.HRMS(ESI)C 24 H 24 N 7 O 3 + [M+H] + Calculated values: 458.1953, found: 458.1941.HPLC:96.0%.
Examples 24 to 25: preparation of Compounds I-24 and I-25
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Step 1-3: the aniline in step 2 was replaced by "4-ethynylaniline" in analogy to the procedure of step 2-4 described in example 1-2, the remaining required starting materials, reagents were the same, giving sn01133 as a pale brown solid. 1 H NMR(800MHz,DMSO-d 6 )δ9.11(t,J＝6.3Hz,1H),7.94–7.91(m,4H),7.64(d,J＝8.8Hz,2H),7.47(d,J＝8.3Hz,2H),6.05(s,2H),4.54(d,J＝6.2Hz,2H),4.29(s,1H),3.83(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.4,154.5,145.1,138.7,133.1(2C),129.3(2C),128.2,127.5(2C),127.3,120.1,117.8(2C),82.8,81.9,52.0,41.7.HRMS(ESI)C 20 H 18 N 5 O 3 [M+H] + Calculated values: 376.1404, found: 376.1395.
step 4: following the procedure of step 5 described in example 1-2, sn01021 was replaced with sn01133 and the remaining starting materials, reagents were identical to give light brown solid I-24 (76 mg, 83% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.22(s,1H),9.10(t,J＝5.8Hz,1H),9.01(s,1H),7.92(d,J＝8.5Hz,2H),7.73(d,J＝8.1Hz,2H),7.65(d,J＝8.5Hz,2H),7.40(d,J＝8.0Hz,2H),6.04(s,2H),4.50(d,J＝6.0Hz,2H),4.30(s,1H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.3,154.5,142.8,138.7,133.1(2C),131.4,127.3(2C),127.2(2C),127.0,120.1,117.8(2C),82.8,81.9,41.7.HRMS(ESI)C 19 H 17 N 6 O 3 + [M+H] + Calculated values: 377.1357, found: 377.1352.HPLC:96.3%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn01133, and the remaining required starting materials, reagents were the same to give sn01135, which was carried out directly in the next reaction without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn01135, and the remaining starting materials, reagents were the same to give I-25 as a white solid (82 mg, 60% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.64(s,1H),9.12(t,J＝6.2Hz,1H),7.99–7.89(m,4H),7.66(d,J＝8.6Hz,2H),7.47(d,J＝8.0Hz,2H),7.18(d,J＝7.6Hz,1H),6.97(t,J＝7.3Hz,1H),6.79(d,J＝7.8Hz,1H),6.60(t,J＝7.4Hz,1H),6.05(s,2H),4.93(s,2H),4.54(d,J＝6.2Hz,2H),4.30(s,1H). 13 C NMR(201MHz,DMSO-d 6 )δ165.2,161.4,154.5,143.1,143.0,138.8,133.2,133.1(2C),127.9(2C),127.3,127.2(2C),126.7,126.5,123.4,120.1,117.8(2C),116.3,116.2,82.8,81.9,41.8.HRMS(ESI)C 25 H 22 N 7 O 2 + [M+H] + Calculated values: 452.1829, found: 452.1820.HPLC:99.5%.
Examples 26 to 27: preparation of Compounds I-26 and I-27
Step 1-3: the aniline in step 2 was replaced with "4-trifluoromethylaniline" following the procedure of step 2-4 described in example 1-2, and the remaining starting materials and reagents were the same to give sn01113 as a white solid. 1 H NMR(800MHz,DMSO-d 6 )δ9.18(t,J＝6.2Hz,1H),8.10(d,J＝8.6Hz,2H),7.99–7.86(m,4H),7.48(d,J＝8.3Hz,2H),6.11(s,2H),4.54(d,J＝6.2Hz,2H),3.83(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.3,154.7,145.1,141.5,129.3(2C),128.2,127.9,127.5(2C),127.0(d,J＝3.6Hz,2C),124.7,123.4,118.0(2C),52.0,41.7.HRMS(ESI)C 19 H 17 F 3 N 5 O 3 [M+H] + Calculated values: 420.1278, found: 420.1270.
step 4: following the procedure of step 5 described in example 1-2, sn01021 was replaced with sn01113, and the remaining starting materials, reagents were the same to give I-26 as a white solid (76 mg, 53% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.19(s,1H),9.15(t,J＝6.2Hz,1H),9.00(s,1H),8.10(d,J＝8.4Hz,2H),7.92(d,J＝8.4Hz,2H),7.73(d,J＝7.9Hz,2H),7.41(d,J＝7.9Hz,2H),6.10(s,2H),4.50(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.2,154.6,142.7,141.5,131.4,128.0(2C),127.3(2C),127.0(2C),126.8,124.8,123.4,118.0(2C),41.7.HRMS(ESI)C 18 H 16 F 3 N 6 O 3 + [M+H] + Calculated values: 421.1230, found: 421.1233.HPLC:97.7%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn01113, and the remaining required starting materials, reagents were the same to give sn01142, which was carried out directly in the next reaction without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn01142, and the remaining starting materials, reagents were the same to give white solid I-27 (94 mg, 63% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.63(s,1H),9.19(t,J＝6.3Hz,1H),8.12(d,J＝8.4Hz,2H),8.00–7.87(m,4H),7.47(d,J＝7.9Hz,2H),7.18(d,J＝7.8Hz,1H),6.97(t,J＝7.6Hz,1H),6.79(d,J＝8.0Hz,1H),6.60(t,J＝7.6Hz,1H),6.12(s,2H),4.94(s,2H),4.55(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.1,161.2,154.6,143.1,143.0,141.5,133.2,128.0,127.9(2C),127.2(2C),127.0,126.7,126.5(2C),124.8,123.4,123.4,118.0(2C),116.3,116.2,41.8.HRMS(ESI)C 24 H 21 F 3 N 7 O 2 + [M+H] + Calculated values: 496.1703, found: 496.1718.HPLC:97.7%.
Examples 28 to 29: preparation of Compound I-28 and Compound I-29
Step 1-3: the aniline in step 2 was replaced by "4-amino-N, N-dimethylbenzylamine" following the procedure of step 2-4 described in example 1-2, the remaining starting materials, reagents were identical, giving a brown solid sn01148. 1 H NMR(800MHz,DMSO-d 6 )δ9.11(t,J＝5.5Hz,1H),8.04–7.88(m,4H),7.74(d,J＝7.9Hz,2H),7.47(d,J＝7.8Hz,2H),6.03(s,2H),4.54(d,J＝5.6Hz,2H),4.26(s,2H),3.83(s,3H),2.66(s,6H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.5,154.4,145.2,139.4,132.4,132.3(2C),129.3(2C),128.2,127.5(2C),127.1,117.7(2C),58.9,52.1,41.7,41.6(2C).HRMS(ESI)C 21 H 25 N 6 O 3 [M+H] + Calculated values: 409.1983, found: 409.1980.
step 4: following the procedure of step 5 described in example 1-2, sn01021 was replaced with sn01148, and the remaining starting materials, reagents were the same to give I-28 as a white solid (112 mg, 80% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.20(s,1H),9.04–8.98(m,2H),7.87(d,J＝8.5Hz,2H),7.72(d,J＝8.2Hz,2H),7.44(d,J＝8.4Hz,2H),7.39(d,J＝8.2Hz,2H),5.95(s,2H),4.49(d,J＝6.2Hz,2H),3.43(s,2H),2.16(s,6H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.5,154.3,142.9,137.9,132.6,131.3,129.8(2C),127.2(2C),127.0(2C),126.5,117.6(2C),62.6,44.9(2C),41.7.HRMS(ESI)C 20 H 24 N 7 O 3 + [M+H] + Calculated values: 410.1935, found: hplc 99.0% of 1938.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn01148, and the remaining required starting materials, reagents were the same to give sn01149, which was carried out directly in the next reaction without purification.
Step 6: following the procedure of step 7 described in examples 1-2, sn01028 was replaced by sn01142, and the remaining starting materials, reagents were identical to one another to give a white, foamy solid I-29(57 mg, yield 39%). 1 H NMR(800MHz,DMSO-d 6 )δ9.64(s,1H),9.06(t,J＝6.2Hz,1H),8.01(d,J＝8.5Hz,2H),7.95(d,J＝7.7Hz,2H),7.66(d,J＝8.5Hz,2H),7.46(d,J＝7.9Hz,2H),7.17(d,J＝7.4Hz,1H),6.98(t,J＝7.4Hz,1H),6.79(d,J＝7.8Hz,1H),6.61(t,J＝6.9Hz,1H),6.03(s,2H),4.54(d,J＝6.1Hz,2H),4.32(s,2H),2.75(s,6H). 13 C NMR(201MHz,DMSO-d 6 )δ165.1,161.4,154.4,143.0,142.7,139.6,133.2,132.4(2C),128.8,127.8(2C),127.3,127.1(2C),126.6,126.5,123.5,120.7,117.9(2C),116.3,59.1,41.8(2C),41.7.HRMS(ESI)C 26 H 29 N 8 O 2 + [M+H] + Calculated values: 485.2408, found: 485.2406.HPLC:95.2%.
Examples 30 to 31: preparation of Compounds I-30 and I-31
Step 1: methyl paraformylbenzoate (5.0 g,31 mmol) was dissolved in dichloromethane (120 mL), and (S) -tert-butylsulfonamide (4.4 g,37 mmol) and cesium carbonate (13 g,37 mmol) were added and heated under reflux for 18 hours. The solvent was removed under reduced pressure, the residue was extracted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by flash column chromatography (ethyl acetate/petroleum ether=1:10) to give sn01130S as a white solid (5.78 g, yield 71%). 1 H NMR (800 MHz, deuterated chloroform) delta 8.63 (s, 1H), 8.13 (d, j=8.2 hz, 2H), 7.91 (d, j=8.2 hz, 2H), 3.95 (s, 3H), 1.28 (s, 9H) HRMS (ESI) C 13 H 18 NO 3 S[M+H] + Calculated values: 268.1002, found: 268.1017.
step 2: diethyl zinc (1.7 mL,1.7 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) at room temperature, and ethyl magnesium bromide (1.5 mL,1.5 mmol) was added thereto. After stirring for 30 minutes, it was cooled to-78℃and sn01130S (267 mg,1.0 mmol) was dissolved in anhydrous tetrahydrofuran (1.5 mL) and added thereto, and after stirring at the maintained temperature for 4 hours, it was returned to room temperature. Diluting with saturated ammonium chloride solution, extracting with ethyl acetate, washing with saturated saline solution, and organic phaseThe phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by flash column chromatography (ethyl acetate/petroleum ether=1:2) to give sn01137S as a colorless oil. 1 H NMR (800 MHz, deuterated chloroform) δ8.01 (d, j=8.2 hz, 2H), 7.38 (d, j=8.2 hz, 2H), 4.36-4.31 (m, 1H), 3.91 (s, 3H), 3.41 (d, j=3.6 hz, 1H), 2.08-2.01 (m, 1H), 1.82-1.73 (m, 1H), 1.23 (s, 9H), 0.80 (t, j=7.4 hz, 3H) HRMS (ESI) C 15 H 24 NO 3 S[M+H] + Calculated values: 298.1471, found: 298.1486.
step 3: raw material sn01137S (1.2 g,4.2 mmol) was dissolved in dichloromethane (5 mL), 2N hydrochloric acid/methanol (10 mL) was added under ice bath condition, stirred at room temperature for 3 hours, concentrated under reduced pressure to give pale yellow oily sn01144S, which was directly carried out for the next reaction without purification.
Step 4: following the procedure of step 1 described in example 1-2, substituting sn01144S for methyl 4-aminomethylbenzoate hydrochloride, the remaining starting materials and reagents were the same to give sn01145S as a white solid (550 mg, 31% yield). 1 H NMR (800 MHz, deuterated chloroform) δ8.01 (d, j=8.2 hz, 2H), 7.34 (d, j=8.2 hz, 2H), 6.43 (d, j=7.5 hz, 1H), 4.89 (q, j=7.5 hz, 1H), 3.91 (s, 3H), 3.41-3.34 (m, 2H), 1.91-1.83 (m, 2H), 0.92 (t, j=7.4 hz, 3H) HRMS (ESI) C 14 H 17 N 2 O 3 [M+H] + Calculated values: 261.1234, found: 261.1240.
step 5-7: the procedure of step 2-4 of example 1-2 was followed, substituting sn01006 in step 2 with sn01145S, and the remaining starting materials and reagents were the same to give a pale yellow solid, sn01157S. 1 H NMR(800MHz,Methanol-d 4 )δ8.01(d,J＝7.4Hz,2H),7.98(d,J＝8.1Hz,2H),7.52(d,J＝8.1Hz,2H),7.47(t,J＝7.1Hz,2H),7.33(t,J＝7.2Hz,1H),5.04(t,J＝6.6Hz,1H),3.88(s,3H),2.01–1.90(m,2H),1.01(t,J＝7.3Hz,3H). 13 C NMR(201MHz,Methanol-d 4 )δ168.4,163.7,155.8,149.9,140.8,130.7(2C),130.3(2C),130.1,128.3,127.99,127.96(2C),119.4(2C),56.0,52.5,29.9,11.5.HRMS(ESI)C 20 H 22 N 5 O 3 [M+H] + Calculated 380.1717, found 380.1719.
Step 8: as described in examples 1-2The procedure of step 5 was followed, substituting sn01021 for sn01157S, and the remaining starting materials and reagents were the same, to give pale yellow foamy solid I-30 (91 mg, yield 70%). 1 H NMR(800MHz,Methanol-d 4 )δ8.0(d,J＝7.8Hz,2H),7.7(d,J＝8.3Hz,2H),7.5(d,J＝8.2Hz,2H),7.5(t,J＝7.9Hz,2H),7.3(t,J＝7.4Hz,1H),5.1–5.0(m,1H),2.0–1.9(m,2H),1.2(t,J＝7.1Hz,1H),1.0(t,J＝7.3Hz,3H). 13 C NMR(201MHz,Methanol-d 4 )δ168.0,163.7,155.8,148.3,140.8,132.3,130.3(2C),128.35,128.32(2C),128.05(2C),128.01,119.4(2C),56.0,30.0,11.5.HRMS(ESI)C 19 H 21 N 6 O 3 + [M+H] + Calculated values: 381.1670, found: 381.1670.HPLC:99.2%. Optical rotation:
step 9: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn01157S, and the remaining desired starting materials, reagents were the same to give sn01160S, which was carried on directly to the next reaction without purification.
Step 10: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn01160S, and the remaining starting materials, reagents were the same to give pale yellow foamy solid I-31 (73 mg, 53% yield). 1 H NMR(800MHz,Methanol-d 4 )δ8.03(d,J＝8.5Hz,2H),7.97(d,J＝8.2Hz,2H),7.57(d,J＝8.3Hz,2H),7.51–7.46(m,2H),7.34(t,J＝7.4Hz,1H),7.20(d,J＝7.8Hz,1H),7.08(t,J＝7.7Hz,1H),6.91(d,J＝8.0Hz,1H),6.77(t,J＝7.9Hz,1H),5.07-5.05(m,1H),2.04–1.94(m,2H),1.03(t,J＝7.3Hz,3H). 13 C NMR(201MHz,Methanol-d 4 )δ168.7,163.7,155.8,148.5,143.7,140.8,134.4,130.3(2C),129.0(2C),128.5,128.4,128.1,128.0(2C),127.6,125.3,119.7,119.4(2C),118.7,56.1,30.0,11.5.HRMS(ESI)C 25 H 26 N 7 O 2 + [M+H] + Calculated values: 456.2142, found: 456.2149.HPLC:96.2%. Optical rotation:
examples 32 to 33: preparation of Compounds I-32 and I-33
By following a procedure consistent with the preparation of I-30 and I-31 in examples 30-31, compounds I-32 and I-33 were prepared by substituting (R) -tert-butylsulfonamide for (S) -tert-butylsulfonamide in step 1.
sn01145R, white solid. 1 H NMR(800MHz,DMSO-d 6 )δ8.73(d,J＝8.0Hz,1H),7.92(d,J＝8.3Hz,2H),7.43(d,J＝8.2Hz,2H),4.74(q,J＝7.7Hz,1H),3.84(s,3H),3.75–3.65(m,2H),1.75–1.62(m,2H),0.84(t,J＝7.3Hz,3H).HRMS(ESI)C 14 H 17 N 2 O 3 [M+H] + Calculated values: 261.1234, found: 261.1254.
sn01157R, pale yellow oil. 1 H NMR(800MHz,Methanol-d 4 )δ8.04-8.03(m,2H),8.02–8.00(m,2H),7.55(d,J＝8.4Hz,2H),7.52–7.48(m,2H),7.36(t,J＝7.4Hz,1H),5.06-5.04(m,1H),3.90(s,3H),2.08–1.91(m,2H),1.03(t,J＝7.4Hz,3H). 13 C NMR(201MHz,Methanol-d 4 )δ168.4,163.8,155.8,150.0,140.9,130.8(2C),130.3(2C),130.2,128.4,128.01,127.98(2C),119.4(2C),56.1,52.6,30.0,11.6.
Compound I-32, white solid. 1 H NMR(800MHz,Methanol-d 4 )δ8.01(d,J＝7.9Hz,2H),7.74(d,J＝8.1Hz,2H),7.51(d,J＝8.0Hz,2H),7.47(t,J＝7.9Hz,2H),7.34(t,J＝7.4Hz,1H),5.05–4.99(m,1H),2.01–1.88(m,2H),1.00(t,J＝7.3Hz,3H). 13 C NMR(201MHz,Methanol-d 4 )δ168.0,163.7,155.8,148.3,140.8,132.3,130.3(2C),128.35,128.32(2C),128.05(2C),128.00,119.4(2C),56.0,30.0,11.5.HRMS(ESI)C 19 H 21 N 6 O 3 + [M+H] + Calculated values: 381.1670, found: 381.1666.HPLC:99.5%. Optical rotation:
compound I-33, pale yellow foamy solid. 1 H NMR(800MHz,Methanol-d 4 )δ8.02(d,J＝8.0Hz,2H),7.96(d,J＝8.0Hz,2H),7.55(d,J＝7.4Hz,2H),7.47(t,J＝7.2Hz,2H),7.33(t,J＝7.4Hz,1H),7.20(d,J＝7.8Hz,1H),7.08(t,J＝7.6Hz,1H),6.90(d,J＝7.9Hz,1H),6.77(t,J＝7.5Hz,1H),5.08–5.03(m,1H),2.01–1.92(m,2H),1.01(t,J＝7.2Hz,3H). 13 C NMR(201MHz,Methanol-d 4 )δ173.0,168.6,163.7,155.8,148.5,143.7,140.8,134.3,130.3(2C),129.0(2C),128.5,128.3,128.0(2C),127.6,125.3,119.6,119.4(2C),118.7,56.0,30.0,11.6.HRMS(ESI)C 25 H 26 N 7 O 2 + [M+H] + Calculated values: 456.2142, found: 456.2138.HPLC:96.5%. Optical rotation:
examples 34 to 35: preparation of Compound I-34 and Compound I-35
Step 1: sodium hydride (140 mg,5.8 mmol) was added to tetrahydrofuran (10 mL), methyl 4-bromomethylcinnamate (1.35 g,5.3 mmol) was added as a starting material, bis (t-butoxycarbonyl) amine (1.27g,5.8mmol,10mL THF) was added under ice-bath conditions, and after stirring in an ice bath for 20 minutes, the mixture was allowed to react at room temperature for 14 hours. Ethyl acetate extraction, washing with saturated brine, drying the organic phase over anhydrous sodium sulfate, concentrating, and separating and purifying the residue by flash column chromatography (ethyl acetate/petroleum ether=1:10) to give sn01152a as a white solid (1.46 g, yield 95%). 1 H NMR (800 MHz, deuterated chloroform) delta 7.67 (d, j=16.0 hz, 1H), 7.47 (d, j=8.1 hz, 2H), 7.30 (d, j=8.1 hz, 2H), 6.42 (d, j=16.0 hz, 1H), 4.78 (s, 2H), 3.80 (s, 3H), 1.45 (s, 9H) HRMS (ESI) C 16 H 21 NNaO 4 [M+Na] + Calculated values: 314.1363, found: 314.1368.
step 2:sn01152a (1.46 g,5.0 mmol) was dissolved in ethyl acetate, concentrated hydrochloric acid (3.3 mL) was added, stirred overnight at room temperature, and suction filtration gave sn01152 (797 mg, yield 83%) as a white solid which was used in the next reaction without purification. 1 H NMR(800MHz,DMSO-d 6 )δ8.37(s,2H),7.78(d,J＝8.2Hz,2H),7.67(d,J＝16.0Hz,1H),7.52(d,J＝8.2Hz,2H),6.70(d,J＝16.1Hz,1H),4.12–4.00(m,2H),3.73(s,3H).HRMS(ESI)C 11 H 14 NO 2 [M+H] + Calculated values: 192.1019, found: 192.1024.
step 3: following the procedure of step 1 described in example 1-2, substituting sn01152 for methyl 4-aminomethylbenzoate hydrochloride, the remaining starting materials and reagents were the same to give sn01153 as a white solid (1.59 g, 74% yield). 1 H NMR(800MHz,DMSO-d 6 )δ8.75(t,J＝5.7Hz,1H),7.69(d,J＝8.2Hz,2H),7.65(d,J＝16.0Hz,1H),7.31(d,J＝8.1Hz,2H),6.63(d,J＝16.0Hz,1H),4.31(d,J＝5.9Hz,2H),3.72(s,3H),3.71(s,2H).HRMS(ESI)C 14 H 14 N 2 NaO 3 [M+Na] + Calculated values: 281.0897, found: 281.0893.
step 4-6: following the procedure of steps 2-4 described in example 1-2, sn01006 was replaced by sn01153, the remaining starting materials, reagents were the same, giving a white solid, sn01159. 1 H NMR(800MHz,DMSO-d 6 )δ9.01(t,J＝6.2Hz,1H),7.95–7.90(m,2H),7.68(d,J＝8.3Hz,2H),7.64(d,J＝16.0Hz,1H),7.56–7.50(m,2H),7.39(d,J＝8.2Hz,2H),7.36(t,J＝7.4Hz,1H),6.60(d,J＝16.0Hz,1H),5.97(s,2H),4.49(d,J＝6.2Hz,2H),3.71(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.7,161.5,154.3,144.3,142.2,139.0,132.6,129.5(2C),128.4(2C),127.9(2C),127.1,126.7,117.7(2C),117.3,51.4,41.7.HRMS(ESI)C 20 H 20 N 5 O 3 [M+H] + Calculated values: 378.1561, found; 378.1568.
step 7: following the procedure of step 5 described in example 1-2, sn01021 was replaced by sn01159, and the remaining starting materials, reagents, were the same to give I-34 as a pale yellow oil (52 mg, 40% yield). 1 H NMR(800MHz,DMSO-d 6 )δ10.75(s,1H),9.06–8.97(m,2H),7.93(d,J＝8.0Hz,2H),7.57–7.50(m,4H),7.43(d,J＝15.8Hz,1H),7.39–7.35(m,3H),6.44(d,J＝15.8Hz,1H),5.97(s,2H),4.47(d,J＝6.1Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ162.8,161.5,154.3,141.1,138.9,138.1,133.4,129.5(2C),127.9(2C),127.5(2C),127.1,126.7,118.7,117.7(2C),41.7.HRMS(ESI)C 19 H 19 N 6 O 3 + [M+H] + Calculated values: 379.1513, found: 379.1522.HPLC:98.1%.
Step 8: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn01159, and the remaining starting materials and reagents required were the same to give sn01163, which was carried out directly in the next reaction without purification.
Step 9: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn01163, and the remaining starting materials, reagents were the same to give I-35 as a pale yellow solid (83 mg, 61% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.40(s,1H),9.02(t,J＝6.3Hz,1H),7.94(d,J＝8.0Hz,2H),7.59(d,J＝8.0Hz,2H),7.57–7.52(m,3H),7.41(d,J＝8.0Hz,2H),7.37(t,J＝7.4Hz,1H),7.34(d,J＝7.7Hz,1H),6.92(t,J＝7.5Hz,1H),6.88(d,J＝15.7Hz,1H),6.76(d,J＝7.9Hz,1H),6.58(t,J＝7.6Hz,1H),5.98(s,2H),5.00(s,2H),4.50(d,J＝6.1Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ163.5,161.5,154.3,141.5,141.3,139.4,139.0,133.5,129.6(2C),128.0(2C),127.7(2C),127.1,126.7,125.8,124.8,123.6,121.9,117.7(2C),116.4,116.1,41.7.HRMS(ESI)C 25 H 24 N 7 O 2 + [M+H] + Calculated values: 454.1986, found: 454.1987.HPLC:99.7%.
Example 36: preparation of Compound I-36
Step 1-3: the aniline in step 2 was replaced with "para-aminobenzonitrile" following the procedure of step 2-4 described in example 1-2, the remaining required starting materials, reagents were the same, giving sn01112 as a yellow solid. 1 H NMR(800MHz,DMSO-d 6 )δ9.19(t,J＝6.2Hz,1H),8.06–8.04(m,2H),8.03–8.00(m,2H),7.95–7.88(m,2H),7.47(d,J＝8.4Hz,2H),6.15(s,2H),4.54(d,J＝6.2Hz,2H),3.83(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.2,154.7,145.0,141.6,134.1(2C),129.3(2C),128.3,128.2,127.5(2C),118.4,118.0(2C),108.9,52.1,41.7.HRMS(ESI)C 19 H 17 N 6 O 3 [M+H] + Calculated values: 377.1357, found: 377.1355.
step 4: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn01112, and the remaining starting materials and reagents were identical to give sn01138, which was directly subjected to the next reaction without purification.
Step 5: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn01138, and the remaining starting materials, reagents were the same to give I-36 as a white solid (55 mg, 40% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.63(s,1H),9.19(t,J＝6.2Hz,1H),8.07–8.05(m,2H),8.04–8.02(m,2H),7.95(d,J＝7.9Hz,2H),7.47(d,J＝8.1Hz,2H),7.17(d,J＝7.6Hz,1H),6.97(t,J＝8.3Hz,1H),6.78(d,J＝9.1Hz,1H),6.60(t,J＝7.3Hz,1H),6.15(s,2H),4.88(s,2H),4.54(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.1,161.1,154.7,143.1,142.9,141.6,134.1(2C),133.2,128.4,127.8(2C),127.1(2C),126.7,126.5,123.3,118.4,118.0(2C),116.3,116.1,108.9,41.8.HRMS(ESI)C 24 H 21 N 8 O 2 + [M+H] + Calculated values: 453.1782, found: 457.1783.HPLC:95.7%.
Examples 37 to 38: preparation of Compounds I-37 and I-38
Step 1-3: the aniline in step 2 was replaced with "2-chloroaniline" following the procedure of step 2-4 described in example 1-2, and the remaining required starting materials, reagents were the same, giving sn02017 as a pale yellow solid. 1 H NMR(800MHz,DMSO-d 6 )δ9.04(t,J＝6.2Hz,1H),7.93(d,J＝8.2Hz,2H),7.72–7.70(m,2H),7.58–7.52(m,2H),7.46(d,J＝8.2Hz,2H),5.92(s,2H),4.50(d,J＝6.2Hz,2H),3.84(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.6,154.2,145.2,137.4,130.9,130.7,129.2(2C),128.4,128.1,128.0,127.5(2C),127.1,126.9,52.0,41.7.HRMS(ESI)C 18 H 17 ClN 5 O 3 [M+H] + Calculated values: 386.1014, found: 386.1012.
step 4: following the procedure of step 5 described in example 1-2 substituting sn01021 with sn02017, the remaining starting materials and reagents required were the same to give I-37 as a white solid (97 mg, yield 74%). 1 H NMR(800MHz,DMSO-d 6 )δ11.15(s,1H),9.02–8.95(m,2H),7.74–7.67(m,4H),7.59–7.51(m,2H),7.37(d,J＝8.0Hz,2H),5.89(s,2H),4.45(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.5,154.1,142.8,137.4,131.3(2C),130.9,130.7,128.4,128.2,128.1,127.2(2C),126.9,126.9,41.7.HRMS(ESI)C 17 H 16 ClN 6 O 3 + [M+H] + Calculated values: 387.0967, found: 387.0961.HPLC:96.4%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn02017 and the remaining starting materials and reagents required were the same to give sn02018 which was directly used in the next step without purification.
Step 6: following the procedure of step 7 described in example 1-2 substituting sn01028 with sn02018, the remaining starting materials, reagents were identical to give I-38 as pale yellow solid (72 mg, 52% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.60(s,1H),9.03(d,J＝6.3Hz,1H),7.93(d,J＝7.9Hz,2H),7.74–7.69(m,2H),7.59–7.52(m,2H),7.44(d,J＝8.1Hz,2H),7.17(d,J＝7.6Hz,1H),6.96(t,J＝6.9Hz,1H),6.78(d,J＝8.0Hz,1H),6.59(t,J＝7.5Hz,1H),5.90(s,2H),4.88(s,2H),4.49(d,J＝6.3Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.1,161.5,154.2,143.1,143.1,137.4,133.2,130.9,130.7,128.4,128.1,128.1,127.8(2C),127.1(2C),127.0,126.6,126.4,123.4,116.3,116.1,41.7.HRMS(ESI)C 23 H 21 ClN 7 O 2 + [M+H] + Calculated values: 462.1440, found: 462.1397.HPLC:98.2%.
Examples 39 to 40: preparation of Compound I-39 and Compound I-40
Step 1-3: the aniline in step 2 was replaced by "3, 4-dichloroaniline" following the procedure of step 2-4 described in example 1-2, the remaining required starting materials, reagents were the same, giving sn02023 as a white solid. 1 H NMR(800MHz,DMSO-d 6 )δ9.16(t,J＝6.2Hz,1H),8.10(d,J＝2.4Hz,1H),7.93(d,J＝8.3Hz,2H),7.86–7.84(m,1H),7.81(d,J＝8.8Hz,1H),7.47(d,J＝8.3Hz,2H),6.08(s,2H),4.53(d,J＝6.2Hz,2H),3.83(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.2,154.5,145.0,138.3,132.1,131.6,129.2(2C),129.0,128.2,127.6,127.5(2C),119.1,117.5,52.0,41.7.HRMS(ESI)C 18 H 16 Cl 2 N 5 O 3 [M+H] + Calculated values: 420.0625, found: 420.0628.
step 4: following the procedure of step 5 described in example 1-2 substituting sn01021 with sn02023, the remaining starting materials and reagents required were identical to give I-39 as a white solid (115 mg, 80% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.20(s,1H),9.13(t,J＝5.7Hz,1H),8.99(s,1H),8.10(d,J＝2.2Hz,1H),7.87–7.84(m,1H),7.81(d,J＝8.8Hz,1H),7.73(d,J＝8.1Hz,2H),7.40(d,J＝8.1Hz,2H),6.08(s,2H),4.49(d,J＝3.0Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.1,154.5,142.6,138.3,132.0,131.6,131.4,129.0,127.6,127.2(2C),126.9(2C),119.1,117.5,41.6.HRMS(ESI)C 17 H 15 Cl 2 N 6 O 3 + [M+H] + Calculated values: 421.0577, found: 421.0574.HPLC:99.3%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn02023 and the remaining starting materials and reagents required were the same to give sn02024 which was directly used in the next step without purification.
Step 6: following the procedure of step 7 described in examples 1-2, sn01028 was replaced by sn02024, the remainder of the starting material was desiredThe reagents were the same, giving I-40 as a pale yellow solid (36 mg, yield 24%). 1 H NMR(800MHz,DMSO-d 6 )δ9.62(s,1H),9.16(t,J＝6.2Hz,1H),8.12(d,J＝2.4Hz,1H),7.95(d,J＝7.8Hz,2H),7.88–7.84(m,1H),7.81(d,J＝8.8Hz,1H),7.46(d,J＝8.1Hz,2H),7.17(d,J＝7.6Hz,1H),6.97(t,J＝7.0Hz,1H),6.78(d,J＝7.1Hz,1H),6.60(t,J＝7.4Hz,1H),6.09(s,2H),4.88(s,2H),4.54(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.1,161.1,154.5,143.0,142.9,138.3,133.2,132.1,131.6,129.0,127.8(2C),127.7,127.1(2C),126.6,126.4,123.3,119.1,117.5,116.2,116.1,41.7.HRMS(ESI)C 23 H 20 Cl 2 N 7 O 2 + [M+H] + Calculated values: 496.1050, found: 496.1054.HPLC:98.4%.
Examples 41 to 42: preparation of Compound I-41 and Compound I-42
Step 1-3: the aniline in step 2 was replaced with "2-aminonaphthalene" following the procedure of step 2-4 described in example 1-2, and the remaining required starting materials, reagents were the same to give brown solid sn02034. 1 H NMR(800MHz,DMSO-d 6 )δ9.14(t,J＝6.2Hz,1H),8.40(d,J＝1.7Hz,1H),8.18–8.14(m,1H),8.10(d,J＝8.9Hz,1H),8.02(d,J＝8.2Hz,1H),7.98(d,J＝8.1Hz,1H),7.94(d,J＝8.3Hz,2H),7.59(t,J＝7.4Hz,1H),7.55(t,J＝7.4Hz,1H),7.50(d,J＝8.2Hz,2H),6.03(s,2H),4.56(d,J＝6.2Hz,2H),3.84(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.5,154.5,145.2,136.4,132.9,131.6,129.5,129.2(2C),128.1,128.0,127.8,127.5(2C),127.3,126.9,126.3,117.0,115.0,52.0,41.7.HRMS(ESI)C 22 H 20 N 5 O 3 [M+H] + Calculated values: 402.1561, found: 402.1583.
step 4: following the procedure of step 5 described in example 1-2, sn01021 was replaced with sn02034, and the remaining starting materials, reagents, were the same to give grey solid I-41 (135 mg, 70% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.17(s,1H),9.09(t,J＝6.3Hz,1H),8.98(s,1H),8.39(s,1H),8.16(d,J＝8.9Hz,1H),8.10(d,J＝8.9Hz,1H),8.03(d,J＝8.1Hz,1H),7.99(d,J＝8.1Hz,1H),7.72(d,J＝8.0Hz,2H),7.60(t,J＝7.4Hz,1H),7.55(t,J＝7.4Hz,1H),7.42(d,J＝8.0Hz,2H),6.02(s,2H),4.52(d,J＝6.1Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ164.6,162.0,154.9,143.3,136.9,133.4,132.1,131.9,130.0,128.5,128.3,127.8(2C),127.7(2C),127.4,126.8,126.0,117.5,115.5,42.2.HRMS(ESI)C 21 H 19 N 6 O 3 + [M+H] + Calculated values: 403.1513, found: hplc:98.7%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn02034, and the remaining starting materials and reagents required were the same to give sn02035, which was carried out directly in the next reaction without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn02035, and the remaining starting materials, reagents were the same to give I-42 as a white solid (96 mg, 62% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.64(s,1H),9.13(t,J＝6.2Hz,1H),8.45–8.36(m,1H),8.21–8.15(m,1H),8.11(d,J＝9.0Hz,1H),8.03(d,J＝8.2Hz,1H),7.99–7.95(m,3H),7.60(t,J＝7.5Hz,1H),7.55(t,J＝7.5Hz,1H),7.49(d,J＝8.1Hz,2H),7.18(d,J＝7.6Hz,1H),6.97(t,J＝8.1Hz,1H),6.79(d,J＝7.9Hz,1H),6.60(t,J＝7.4Hz,1H),6.04(s,2H),5.18(s,2H),4.57(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.1,162.3,161.5,154.5,143.1,143.0,133.2,132.9,131.6,129.5,128.0,127.8(2C),127.3,127.1(2C),127.0,126.6,126.4,126.3,123.4,117.0,116.2,116.3,116.1,115.0,41.7.HRMS(ESI)C 27 H 24 N 7 O 2 + [M+H] + Calculated values: 478.1986, found: 478.1988.HPLC:97.9%.
Examples 43 to 44: preparation of Compound I-43 and Compound I-44
Step 1-3: imitation implementationThe aniline in step 2 was replaced with "8-aminoquinoline" in the procedure of step 2-4 described in example 1-2, and the remaining required starting materials, reagents were the same to give sn02043 as a brown solid. 1 H NMR(800MHz,DMSO-d 6 )δ8.99(t,J＝6.2Hz,1H),8.96–8.95(m,1H),8.55–8.51(m,1H),8.22–8.18(m,1H),8.02–7.99(m,1H),7.92(d,J＝8.2Hz,2H),7.76(t,J＝7.8Hz,1H),7.68–7.64(m,1H),7.46(d,J＝8.2Hz,2H),5.83(s,2H),4.50(d,J＝6.3Hz,2H),3.84(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.9,154.0,151.6,145.4,142.4,137.1,136.4,130.1,129.2(2C),128.6,128.1,127.5(2C),127.4,126.5,125.9,122.4,52.0,41.7.HRMS(ESI)C 21 H 19 N 6 O 3 [M+H] + Calculated values: 403.1513, found: 403.1520.
step 4: following the procedure of step 5 described in example 1-2 substituting sn01021 with sn02043, the remaining starting materials and reagents required were the same to give white solid I-43 (135 mg, 98% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.16(s,1H),9.01–8.92(m,3H),8.54(d,J＝8.2Hz,1H),8.21(d,J＝8.1Hz,1H),8.00(d,J＝7.2Hz,1H),7.76(t,J＝7.8Hz,1H),7.70(d,J＝8.1Hz,2H),7.68–7.65(m,1H),7.38(d,J＝8.1Hz,2H),5.81(s,2H),4.45(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.9,154.0,151.6,143.0,142.4,137.1,136.4,131.3,130.1,128.6,127.5,127.2(2C),126.9(2C),126.6,126.0,122.5,41.6.HRMS(ESI)C 20 H 18 N 7 O 3 + [M+H] + Calculated values: 404.1466, found: 404.1461.HPLC:97.6%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn02043 and the remaining starting materials and reagents required were the same to give sn02044 which was directly used in the next step without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn02044, and the remaining starting materials, reagents were the same to give white solid I-44 (96 mg, 67% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.60(s,1H),8.99–8.95(m,2H),8.55–8.53(m,1H),8.21(d,J＝7.5Hz,1H),8.00(d,J＝8.3Hz,1H),7.93(d,J＝7.9Hz,2H),7.77(t,J＝7.8Hz,1H),7.69–7.64(m,1H),7.44(d,J＝8.0Hz,2H),7.17(d,J＝7.6Hz,1H),6.96(t,J＝7.6Hz,1H),6.78(d,J＝7.9Hz,1H),6.59(t,J＝7.4Hz,1H),5.82(s,2H),4.88(s,2H),4.49(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.2,161.9,154.0,151.6,143.3,143.0,142.4,137.1,136.4,133.2,130.1,128.6,127.8(2C),127.5,127.2(2C),126.6,126.6,126.4,125.9,123.4,122.5,116.3,116.1,41.7.HRMS(ESI)C 26 H 23 N 8 O 2 + [M+H] + Calculated values: 479.1938, found: 479.1939.HPLC:99.8%.
Examples 45 to 46: preparation of Compound I-45 and Compound I-46
Step 1-3: the aniline in step 2 was replaced by "3, 4-methylenedioxyaniline" following the procedure of step 2-4 described in example 1-2, with the remaining starting materials, reagents required being identical, to give sn02050 as a yellow solid. 1 H NMR(800MHz,DMSO-d 6 )δ8.99(t,J＝5.6Hz,1H),7.93(d,J＝8.3Hz,2H),7.48–7.45(m,3H),7.42–7.40(m,1H),7.05(d,J＝8.4Hz,1H),6.11(s,2H),5.91(s,2H),4.53(d,J＝6.2Hz,2H),3.84(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.5,154.1,148.0,146.4,145.2,133.8,129.2(2C),128.1,127.5(2C),126.0,111.2,108.4,101.9,99.5,52.0,41.6.HRMS(ESI)C 19 H 18 N 5 O 5 [M+H] + Calculated values: 396.1302, found: 396.1298.
step 4: following the procedure of step 5 described in example 1-2 substituting sn01021 with sn02050, the remaining starting materials and reagents required were the same to give yellow solid I-45 (123 mg, 92% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.17(s,1H),8.99(s,1H),8.96(t,J＝6.2Hz,1H),7.71(d,J＝8.2Hz,2H),7.46(d,J＝2.1Hz,1H),7.42–7.40(m,1H),7.39(d,J＝8.2Hz,2H),7.06(d,J＝8.4Hz,1H),6.12(s,2H),5.91(s,2H),4.48(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.5,154.1,148.0,146.4,142.8,133.8,131.3,127.2(2C),126.9(2C),126.0,111.2,108.5,102.0,99.5,41.6.HRMS(ESI)C 18 H 17 N 6 O 5 + [M+H] + Calculated values: 397.1255, found: 397.1253.HPLC:97.4%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn02050, and the remaining starting materials and reagents required were the same to give sn02051, which was directly used in the next step without purification.
Step 6: following the procedure of step 7 described in example 1-2 substituting sn01028 with sn02051, the remaining starting materials, reagents were identical to give I-46 as a white solid (36 mg, yield 25%). 1 H NMR(800MHz,DMSO-d 6 )δ9.62(s,1H),8.99(t,J＝6.2Hz,1H),7.94(d,J＝7.9Hz,2H),7.47–7.44(m,3H),7.43–7.40(m,1H),7.16(d,J＝7.6Hz,1H),7.06(d,J＝8.5Hz,1H),6.96(t,J＝7.6Hz,1H),6.78(d,J＝8.0Hz,1H),6.59(t,J＝7.4Hz,1H),6.12(s,2H),5.92(s,2H),4.88(s,2H),4.52(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.1,161.5,154.1,148.0,146.4,143.1,143.0,133.8,133.2,127.8(2C),127.1(2C),126.6,126.4,126.0,123.4,116.3,116.1,111.2,108.4,102.0,99.5,41.7.HRMS(ESI)C 24 H 22 N 7 O 4 + [M+H] + Calculated values: 472.1728, found: 472.1736.HPLC:99.0%.
Examples 47 to 48: preparation of Compounds I-47 and I-48
Step 1-3: the aniline in step 2 was replaced by "6-aminoquinoline" following the procedure of step 2-4 described in example 1-2, the remaining required starting materials, reagents were the same, giving sn02058 as a pale yellow solid. 1 H NMR(800MHz,DMSO-d 6 )δ9.17(t,J＝6.2Hz,1H),8.93–8.90(m,1H),8.48(d,J＝8.0Hz,1H),8.43(d,J＝2.4Hz,1H),8.40–8.37(m,1H),8.18(d,J＝9.1Hz,1H),7.94(d,J＝8.4Hz,2H),7.61–7.58(m,1H),7.50(d,J＝8.4Hz,2H),6.08(s,2H),4.56(d,J＝6.2Hz,2H),3.83(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.4,154.6,150.7,146.4,145.1,136.5,136.2,130.7,129.2(2C),128.2,128.0,127.5(2C),127.3,122.5,120.3,115.0,52.0,41.7.HRMS(ESI)C 21 H 19 N 6 O 3 [M+H] + Calculated values: 403.1513, found: 403.1511.
step 4: following the procedure of step 5 described in example 1-2 substituting sn01021 with sn02058, the remaining starting materials and reagents required were identical to give pale pink solid I-47 (56 mg, 42% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.19(s,1H),9.13(t,J＝6.2Hz,1H),8.99(s,1H),8.93–8.91(m,1H),8.49(d,J＝7.9Hz,1H),8.43(d,J＝2.4Hz,1H),8.40–8.38(m,1H),8.18(d,J＝9.1Hz,1H),7.73(d,J＝8.3Hz,2H),7.62–7.59(m,1H),7.42(d,J＝8.3Hz,2H),6.07(s,2H),4.52(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.4,154.6,150.7,146.4,142.7,136.5,136.3,131.4,130.7,128.0,127.4,127.2(2C),126.9(2C),122.6,120.4,115.0,41.7.HRMS(ESI)C 20 H 18 N 7 O 3 + [M+H] + Calculated values: 404.1466, found: hplc:98.9%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn02058, and the remaining starting materials and reagents required were the same to give sn02063, which was directly subjected to the next reaction without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn02063, and the remaining starting materials, reagents were identical to give light orange solid I-48 (124 mg, 86%). 1 H NMR(800MHz,DMSO-d 6 )δ9.62(s,1H),9.16(t,J＝6.2Hz,1H),8.94–8.91(m,1H),8.50(d,J＝8.2Hz,1H),8.44(d,J＝2.3Hz,1H),8.41–8.38(m,1H),8.19(d,J＝9.1Hz,1H),7.96(d,J＝7.9Hz,2H),7.62–7.60(m,1H),7.48(d,J＝8.1Hz,2H),7.17(d,J＝7.7Hz,1H),6.96(t,J＝7.6Hz,1H),6.78(d,J＝8.0Hz,1H),6.59(t,J＝7.5Hz,1H),6.07(s,2H),4.88(s,2H),4.56(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.2,161.4,154.6,150.7,146.4,143.1,143.0,136.5,136.2,133.2,130.7,128.0,127.8(2C),127.4,127.2(2C),126.6,126.4,123.4,122.5,120.4,116.3,116.1,115.0,41.8.HRMS(ESI)C 26 H 23 N 8 O 2 + [M+H] + Calculated values: 479.1938, found: 479.1928.HPLC:99.5%.
Examples 49 to 50: preparation of Compounds I-49 and I-50
Step 1-3: the aniline in step 2 was replaced by "3, 5-dichloroaniline" following the procedure of steps 2-4 described in example 1-2, the remaining required starting materials, reagents were the same, giving sn02062 as a pale brown solid. 1 H NMR(800MHz,DMSO-d 6 )δ9.19(t,J＝6.2Hz,1H),7.93(d,J＝8.3Hz,2H),7.87(d,J＝1.8Hz,2H),7.58(t,J＝1.8Hz,1H),7.47(d,J＝8.2Hz,2H),6.12(s,2H),4.54(d,J＝6.2Hz,2H),3.83(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.0,161.1,154.5,145.0,140.3,135.0(2C),129.2(2C),128.2,127.9,127.5(2C),126.0,116.0(2C),52.0,41.7.HRMS(ESI)C 18 H 16 Cl 2 N 5 O 3 [M+H] + Calculated values: 420.0625, found: 420.0616.
step 4: following the procedure of step 5 described in example 1-2 substituting sn01021 with sn02062, the remaining starting materials, reagents were identical to afford I-49 as a pale brown solid (103 mg, 72% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.16(s,1H),9.16(t,J＝6.2Hz,1H),8.99(s,1H),7.89(d,J＝1.8Hz,2H),7.72(d,J＝8.2Hz,2H),7.62(t,J＝1.8Hz,1H),7.39(d,J＝8.2Hz,2H),6.11(s,2H),4.49(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ164.0,161.0,154.5,142.5,140.4,135.1(2C),131.6,128.0,127.2(2C),126.9(2C),126.0,116.1(2C),41.7.HRMS(ESI)C 17 H 15 Cl 2 N 6 O 3 + [M+H] + Calculated values: 421.0577, found: 421.0576.HPLC:97.6%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn02062, and the remaining starting materials and reagents required were the same to give sn02066, which was directly subjected to the next reaction without purification.
Step (a)6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn02066, and the remaining starting materials, reagents were the same to give I-50 as a white solid (82 mg, yield 55%). 1 H NMR(800MHz,DMSO-d 6 )δ9.62(s,1H),9.19(t,J＝6.3Hz,1H),7.95(d,J＝7.9Hz,2H),7.90(d,J＝1.8Hz,2H),7.62(t,J＝1.9Hz,1H),7.46(d,J＝8.0Hz,2H),7.16(d,J＝7.8Hz,1H),6.96(t,J＝8.3Hz,1H),6.78(d,J＝9.0Hz,1H),6.59(t,J＝7.4Hz,1H),6.12(s,2H),4.88(s,2H),4.54(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.1,161.0,154.5,143.1,142.9,140.4,135.1(2C),133.2,128.0,127.8(2C),127.1(2C),126.6,126.4,126.0,123.3,116.3,116.1,116.1(2C),41.7.HRMS(ESI)C 23 H 20 Cl 2 N 7 O 2 + [M+H] + Calculated values: 496.1050, found: 496.1060 HPLC:99.3%.
Examples 51 to 52: preparation of Compounds I-51 and I-52
Step 1-3: the aniline in step 2 was replaced by "1-aminonaphthalene" following the procedure of step 2-4 described in example 1-2, and the remaining required starting materials, reagents were the same to give sn02033 as a pale yellow solid. 1 H NMR(800MHz,DMSO-d 6 )δ9.10(t,J＝6.2Hz,1H),8.29–8.25(m,1H),8.10–8.06(m,2H),7.93(d,J＝8.3Hz,2H),7.84(d,J＝8.0Hz,1H),7.67–7.62(m,3H),7.48(d,J＝8.3Hz,2H),5.98(s,2H),4.54(d,J＝6.2Hz,2H),3.84(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.7,154.3,145.3,136.0,133.9,129.24,129.20(2C),128.3,128.1,127.48(2C),127.46,126.8,126.8,126.5,125.3,123.3,122.5,52.0,41.7.HRMS(ESI)C 22 H 20 N 5 O 3 [M+H] + Calculated values: 402.1561, found: 420.1559.
step 4: following the procedure of step 5 described in example 1-2 substituting sn01021 with sn02033, the remaining starting materials and reagents required were identical to give light brown solid I-51 (119 mg, 87% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.00(t,J＝6.3Hz,1H),8.27–8.24(m,1H),8.11–8.05(m,2H),7.83(d,J＝7.3Hz,1H),7.68(d,J＝8.2Hz,2H),7.67–7.62(m,3H),7.29(d,J＝8.0Hz,2H),5.95(s,2H),4.45(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ163.7,161.6,154.3,140.4,136.0,134.5,133.9,129.2,128.3,127.5,127.0,126.8,126.7(2C),126.6,126.2(2C),125.3,123.4,122.5,41.8.HRMS(ESI)C 21 H 19 N 6 O 3 + [M+H] + Calculated values: 403.1513, found: hplc:98.0%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn02033, and the remaining starting materials and reagents required were the same to give sn02039, which was directly subjected to the next reaction without purification.
Step 6: following the procedure of step 7 described in example 1-2, substituting sn01028 for sn02039, the remaining starting materials, reagents were the same to give I-52 as a pale yellow solid (108 mg, 75% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.61(s,1H),9.09(t,J＝6.1Hz,1H),8.28–8.24(m,1H),8.12–8.07(m,2H),7.94(d,J＝7.9Hz,2H),7.84(d,J＝7.0Hz,1H),7.68–7.63(m,3H),7.47(d,J＝8.0Hz,2H),7.17(d,J＝7.6Hz,1H),6.96(t,J＝7.6Hz,1H),6.78(d,J＝8.8Hz,1H),6.59(t,J＝7.4Hz,1H),5.96(s,2H),4.88(s,2H),4.53(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.2,161.7,154.3,143.2,143.0,136.0,133.9,133.2,129.3,128.3,127.8(2C),127.5,127.1(2C),126.9,126.8,126.6,126.6,126.4,125.3,123.4,123.4,122.5,116.3,116.1,41.8.HRMS(ESI)C 27 H 24 N 7 O 2 + [M+H] + Calculated values: 478.1986, found: 478.1976.HPLC:97.7%.
Examples 53 to 54: preparation of Compound I-53 and Compound I-54
Step 1-3: the aniline in step 2 was replaced by "3-fluoroaniline" in analogy to the procedure of steps 2-4 described in examples 1-2, the remaining starting materials, reagents were the sameSn02096 was obtained as a white solid. 1 H NMR(800MHz,DMSO-d 6 )δ9.11(t,J＝6.2Hz,1H),7.93(d,J＝8.3Hz,2H),7.78–7.74(m,1H),7.72–7.67(m,1H),7.61–7.56(m,1H),7.47(d,J＝8.3Hz,2H),7.23–7.19(m,1H),6.04(s,2H),4.54(d,J＝6.2Hz,2H),3.84(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,162.4(d,J＝244.2Hz),161.3,154.4,145.1,140.2(d,J＝10.6Hz),131.6(d,J＝9.3Hz),129.3(2C),128.2,127.5(2C),127.2,113.7(d,J＝21.1Hz),113.6(d,J＝2.6Hz),105.0(d,J＝27.1Hz),52.0,41.7。HRMS(ESI)C 18 H 17 FN 5 O 3 [M+H] + Calculated values: 370.1310, found: 370.1315.
step 4: following the procedure of step 5 described in example 1-2 substituting sn01021 with sn02096, the remaining starting materials and reagents required were the same to give white solid I-53 (51 mg, 40% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.04(t,J＝5.6Hz,1H),7.75(d,J＝8.0Hz,1H),7.70(d,J＝8.0Hz,3H),7.61–7.55(m,1H),7.33(d,J＝7.7Hz,2H),7.21(t,J＝7.4Hz,1H),6.03(s,2H),4.47(d,J＝5.8Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ163.8,162.5(d,J＝244.6Hz),161.2,154.4,141.3,140.2(d,J＝10.8Hz),133.2,131.6(d,J＝9.4Hz),127.3,127.0(2C),126.5(2C),113.7,113.6,105.0(d,J＝26.8Hz),41.7.HRMS(ESI)C 17 H 16 FN 6 O 3 + [M+H] + Calculated values: 371.1262, found: 371.1280.HPLC:99.1%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn02096 and the remaining starting materials and reagents required were the same to give sn02097 which was directly used in the next step without purification.
Step 6: following the procedure of step 7 described in example 1-2 substituting sn01028 with sn02097, the remaining starting materials, reagents were identical to give I-54 as a white solid (127 mg, 95% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.62(s,1H),9.11(t,J＝6.3Hz,1H),7.95(d,J＝7.9Hz,2H),7.79–7.74(m,1H),7.73–7.69(m,1H),7.63–7.56(m,1H),7.46(d,J＝8.1Hz,2H),7.25–7.20(m,1H),7.17(d,J＝7.6Hz,1H),6.99–6.93(m,1H),6.80–6.76(m,1H),6.59(t,J＝7.2Hz,1H),6.04(s,2H),4.88(s,2H),4.54(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.1,162.5(d,J＝244.2Hz),161.3,154.4,143.1,143.0,140.2(d,J＝10.9Hz),133.2,131.6(d,J＝9.3Hz),127.8(2C),127.3,127.1(2C),126.7,126.5,123.4,116.3,116.1,113.7(d,J＝21.1Hz),113.6(d,J＝2.3Hz),105.0(d,J＝27.3Hz),41.7.HRMS(ESI)C 23 H 21 FN 7 O 2 + [M+H] + Calculated values: 446.1735, found: 446.1748.HPLC:95.9%.
Examples 55 to 56: preparation of Compounds I-55 and I-56
Step 1-3: the aniline in step 2 was replaced by "2, 3-dichloroaniline" following the procedure of step 2-4 described in example 1-2, the remaining required starting materials, reagents were the same, giving a brown solid sn02102. 1 H NMR(800MHz,DMSO-d 6 )9.07(t,J＝6.2Hz,1H),7.92(d,J＝8.3Hz,2H),7.87–7.82(m,1H),7.73–7.70(m,1H),7.56(t,J＝8.1Hz,1H),7.45(d,J＝8.3Hz,2H),5.96(s,2H),4.50(d,J＝6.2Hz,2H),3.84(s,3H). 13 C NMR(201MHz,DMSO-d 6 )166.1,161.4,154.3,145.2,139.0,133.0,131.4,129.2(2C),128.8,128.1,127.5(2C),127.4,127.2,126.9,52.0,41.7。HRMS(ESI)C 18 H 16 Cl 2 N 5 O 3 [M+H] + Calculated values: 420.0625, found: 420.0634.
step 4: following the procedure of step 5 described in example 1-2, sn01021 was replaced by sn02102 and the remaining starting materials, reagents, were identical to give light brown solid I-55 (113 mg, 79% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.17(s,1H),9.03(t,J＝6.2Hz,1H),8.99(s,1H),7.87–7.84(m,1H),7.72–7.69(m,3H),7.57(t,J＝8.1Hz,1H),7.37(d,J＝8.2Hz,2H),5.94(s,2H),4.45(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )164.1,161.4,154.3,142.8,139.0,133.0,131.4,131.3,128.8,127.4,127.3,127.2(2C),126.9(2C),126.9,41.7.HRMS(ESI)C 17 H 15 Cl 2 N 6 O 3 + [M+H] + Calculated values: 421.0577, found: 421.0579.HPLC:98.8%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn02102, and the remaining required starting materials, reagents were the same to give sn02103, which was directly subjected to the next reaction without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn02103, and the remaining starting materials, reagents were the same to give I-56 as a white solid (55 mg, 37% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.61(s,1H),9.07(t,J＝6.3Hz,1H),7.94(d,J＝7.8Hz,2H),7.88–7.83(m,1H),7.74–7.70(m,1H),7.57(t,J＝8.1Hz,1H),7.44(d,J＝8.1Hz,2H),7.17(d,J＝8.2Hz,1H),6.98–6.95(m,1H),6.82–6.75(m,1H),6.60(t,J＝7.2Hz,1H),5.96(s,2H),4.88(s,2H),4.50(d,J＝6.3Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.1,161.4,154.3,143.1,143.1,139.0,133.2,133.0,131.4,128.8,127.8(2C),127.4,127.3,127.2(2C),127.0,126.6,126.4,123.3,116.3,116.1,41.7.HRMS(ESI)C 23 H 20 Cl 2 N 7 O 2 + [M+H] + Calculated values: 496.1050, found: 496.1054.HPLC:99.5%.
Examples 57 to 58: preparation of Compounds I-57 and I-58
Step 1-3: the aniline in step 2 was replaced with "2-fluoroaniline" following the procedure of step 2-4 described in example 1-2, and the remaining required starting materials, reagents were the same, giving sn02095 as a tan solid. 1 H NMR(800MHz,DMSO-d 6 )δ9.03(t,J＝6.2Hz,1H),7.92(d,J＝8.3Hz,2H),7.81(t,J＝7.2Hz,1H),7.53–7.44(m,4H),7.40–7.35(m,1H),5.96(s,2H),4.51(d,J＝6.2Hz,2H),3.84(s,3H). 13 C NMR(201MHz,DMSO-d 6 )δ166.1,161.5,154.4,153.7(d,J＝253.1Hz),145.2,130.0(d,J＝7.8Hz),129.2(2C),128.1,127.5(2C),127.2,125.1(d,J＝3.6Hz),125.0,117.5,117.4,52.0,41.7。HRMS(ESI)C 18 H 17 FN 5 O 3 [M+H] + Calculated values: 370.1310, found: 370.1313.
step 4: following the procedure of step 5 described in example 1-2 substituting sn01021 with sn02095, the remaining starting materials and reagents required were identical to give light brown solid I-57 (88 mg, 70% yield). 1 H NMR(800MHz,DMSO-d 6 )δ11.16(s,1H),9.01–8.96(m,2H),7.81(t,J＝7.8Hz,1H),7.70(d,J＝8.2Hz,2H),7.53–7.47(m,2H),7.40–7.36(m,3H),5.95(s,2H),4.47(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ164.1,161.4,154.4,153.8(d,J＝253.5Hz),142.8,131.3,130.0(d,J＝7.4Hz),127.5(d,J＝9.2Hz),127.3,127.2(2C),126.9,125.1(d,J＝3.7Hz),125.1(2C),117.5(d,J＝19.6Hz),41.7.HRMS(ESI)C 17 H 16 FN 6 O 3 + [M+H] + Calculated values: 371.1262, found: 371.1280.HPLC:98.3%.
Step 5: following the procedure of step 6 described in examples 1-2, sn01021 was replaced with sn02095, and the remaining starting materials and reagents required were the same to give sn02111, which was directly subjected to the next reaction without purification.
Step 6: following the procedure of step 7 described in example 1-2, sn01028 was replaced by sn02111, and the remaining starting materials, reagents were the same to give I-58 as a white solid (86 mg, 64% yield). 1 H NMR(800MHz,DMSO-d 6 )δ9.62(s,1H),9.03(t,J＝6.3Hz,1H),7.95(d,J＝8.0Hz,2H),7.82(t,J＝7.3Hz,1H),7.53–7.47(m,2H),7.45(d,J＝8.1Hz,2H),7.40–7.37(m,1H),7.17(d,J＝7.6Hz,1H),6.97(t,J＝6.9Hz,1H),6.78(d,J＝6.8Hz,1H),6.60(t,J＝7.2Hz,1H),5.97(s,2H),4.89(s,2H),4.52(d,J＝6.2Hz,2H). 13 C NMR(201MHz,DMSO-d 6 )δ165.2,161.4,154.4,153.8(d,J＝253.3Hz),143.1,133.2,130.0(d,J＝7.8Hz),127.8(2C),127.5(d,J＝9.1Hz),127.3,127.1(2C),126.6,126.4,125.1(d,J＝3.8Hz),125.1,123.3,117.5,117.4,116.3,116.1,41.8.HRMS(ESI)C 23 H 21 FN 7 O 2 + [M+H] + Calculated values: 446.1735, found: 446.1743.HPLC:97.4%.
Biological test example 1: inhibitory Activity of the Compounds of the invention on HDAC
The specific operation method is as follows:
(1) Preparing a buffer solution (50mM Tris PH,0.01% Tween-20,50mM NaCl) for experiments;
(2) Preparing a compound to be tested into a corresponding DMSO solution with the concentration of 10mM, diluting the solution to 1mM by using DMSO, and carrying out gradient dilution by 3 times, wherein the concentration points are 10;
(3) Different concentrations of test compounds were transferred to 384 well plates (Perkin Elmer, cat.no. 6007279) with Echo, 250nL per well (final DMSO content of 1%);
(4) Preparing a solution of histone deacetylase with the buffer of step (1), HDAC1 (BPS bioscience, cat.no. 50051) at a final concentration of 4nM; HDAC2 (BPS, cat.No.50002); HDAC3 (BPS, cat.No.50003); HDAC4 (BPS, cat.No.50004); HDAC5 (BPS, cat.No.50005); HDAC6 (BPS bioscience, cat. No. 50056) was 5nM final concentration; HDAC7 (BPS, cat.No.50007); HDAC8 (BPS, cat.No.50008); HDAC9 (BPS, cat.No.50009); HDAC10 (BPS, cat.No.50010);
(5) Preparing a mixed solution of a substrate (LGK (Ac) -AMC, trypsin) with the buffer in step (1), for the determination of HDAC1 activity: LGK (Ac) -AMC (gil biochemistry) concentration was 8 μm and Trypsin concentration was 0.05 μm;
(6) Add 15. Mu.L of the enzyme solution prepared in step (4) to each well in the 384 well plate tested, add 15. Mu.L of the buffer solution in step (1) to the low control group, centrifuge at 1000rmp for 1 min, then incubate at room temperature for 15 min;
(7) 10. Mu.L of the enzyme solution prepared in step (5) was added to each well of the 384-well plate for testing, centrifuged at 1000rmp for 1 minute, and then incubated at room temperature for 60 minutes;
(8) Reading the values with Synergy MX (maximum excitation light: 355nm, maximum emission light: 460 nm);
(9) Data were processed with GraphPad Prism5 to calculate IC 50 Values.
Among them, SAHA (CAS: 149647-78-9), MGCD0103 (CAS: 726169-73-9) and Sidamide (CAS: 1616493-44-7) are commercially available.
TABLE 1 inhibitory Activity of the inventive Compounds on HDAC1 and HDAC6
Remarks: "-" indicates no test.
TABLE 2 selectivity of I-38 for HDAC subtypes
As can be seen from table 2, compound I-38 was selective for HDACs 1,2,3 and 10.
Biological test example 2: proliferation inhibitory Activity of the Compounds of the invention against tumor cells
1. Activity screening of Compounds for inhibition of proliferation of tumor cells
The determination is carried out by selecting mouse colon cancer MC38 and human colon cancer HCT-116 cells. Cells were incubated in DMEM medium with 10% foetal calf serum and 1% green streptomycin diabody at 37℃with 5% CO 2 Is grown in the environment of (a).
The assays for MC38 and HCT-116 cells were as follows:
(1) Cell plating
a. Preparing a complete culture medium, and fully and uniformly mixing.
b. Selecting a cell line with good growth state.
c. The cell culture flask was removed from the incubator, and the cell name, medium type and cell number marked on the flask were checked.
The medium is discarded from the MC38 and HCT-116 cells, the cells are digested by pancreatin, and after the digestion is completed, the cells are neutralized by the medium containing serum and blown off, so that the cells are shed. The cell suspension was pipetted into a centrifuge tube and centrifuged at 800-1000rmp for 3-5 minutes.
e. The cell supernatant in the centrifuge tube is sucked and removed, a proper volume of culture medium is added into the centrifuge tube, and the cells are gently beaten to be resuspended uniformly.
f. The Cell suspension was brought to the appropriate concentration using a Vi-Cell XR cytometer.
g. The cell suspension was added to a bottom wall white 384 well plate, 36 μL/well. Labeling detailed information such as cell name, plate density, date, etc., placing the culture plate in CO 2 The incubator was left overnight.
(2) Cell experiment
a. Test compounds were made 200× with DMSO, and compounds were diluted 3-fold with DMSO to give 10 concentration gradients of compounds.
b. After 24 hours of cell plating, 1. Mu.L of the compound was added to 19. Mu.L of the medium to prepare a 10X intermediate plate, and then 4. Mu.L of the 10X corresponding compound was added to each well, followed by incubation in an incubator at 37℃for 72 hours.
c. Cell morphology was observed under an inverted microscope.
d. The cell culture plates were left to equilibrate at room temperature for 30 minutes, 25 μl of CTG was added to each well, and then mixed on a plate shaker for 10 minutes to induce cell lysis.
e. The 384 well plate was left at room temperature for 10 minutes to stabilize the luminescence signal, and then a white bottom film was attached to the bottom of the plate using a Flexstation 3 plate (related settings: luminescence, integration time 500 ms).
The cell growth inhibition was calculated by the following formula: inhibition = (OD value control well-OD value dosing well)/OD value control well x 100%.
Calculation of IC from compound concentration and corresponding inhibition ratio using Graphpad prism 5.0 software 50 Values. The test results are shown in Table 3:
2. the compounds of the examples of the present invention have broad-spectrum anti-tumor cell proliferation activity
The candidate compounds I-1, I-38 and the control compounds SAHA, MGCD0103 and Sidamascine have broad-spectrum cytotoxicity, and 13 tumor cells from various tissue sources are selected together, wherein the tumor cells comprise: activity detection was performed on human lung cancer cells A549 and PC-9, human cervical cancer cells HeLa, human kidney cancer cells Caki-1, human pancreatic cancer cells MIAPaCa, human prostate cancer cells PC-3, human gastric cancer cells NCI-N87, human ovarian cancer cells ES-2, human breast cancer cells MDA-MB-231 and ZR-751, human chronic leukemia cells K562, human diffuse large B lymphoma cells DoHH2 and T leukemia cells Jurkat, and normal renal epithelial cells HEK 293. All cells were derived from the American Type Culture Collection (ATCC). Cells RPMI1640 medium in 10% foetal calf serum and 1% green streptomycin diabody at 37 ℃,5% co 2 Is grown in the environment of (a).
The measurement method is as follows:
(1) Cell plating
a. Preparing a complete culture medium, and fully and uniformly mixing.
b. Selecting a cell line with good growth state.
c. The cell culture dish was removed from the incubator, and the names of the cells marked on the dish, the type of medium and the number of cell passages were checked.
d. The medium was discarded, digested with pancreatin, and after digestion, neutralized with serum-containing medium, and the cells were blown off to shed the cells. The cell suspension was pipetted into a centrifuge tube and centrifuged at 500g for 5 minutes.
e. The cell supernatant in the centrifuge tube is sucked and removed, a proper volume of culture medium is added into the centrifuge tube, and the cells are gently beaten to be resuspended uniformly.
f. The cell suspension was brought to the appropriate concentration using a Countstar cytometer.
g. The cell suspension was added to a bottom-permeable 96-well plate at 180. Mu.L/well. Labeling detailed information such as cell name, plate density, date, etc., placing the culture plate in CO 2 The incubator was left overnight.
(2) Cell experiment
a. Test compounds were formulated at 10mM with DMSO, and 2. Mu.L of the compound was added to 198. Mu.L of 1% DMSO in culture medium to dilute to 100. Mu.M. The compound was then diluted 3-fold to give 9 concentration gradients of the compound.
b. After 12 hours of cell plating, 20. Mu.L of the compound was added to the cell culture plate and incubated in an incubator at 37℃for 72 hours.
c. Cell morphology was observed under an inverted microscope.
d. The supernatant from the cell culture plate was discarded, 10% TCA was added and the plate was fixed at 4℃for 1 hour, followed by rinsing and drying. The cells were stained with 4mg/ml SRB for 15 minutes, rinsed with 1% acetic acid, dried and mixed with 150. Mu.L Tris-HCl on a shaker for 40 minutes.
e. Detection was performed using a TECAN microplate reader (parameter settings: wavelength 510 nm).
The cell growth inhibition was calculated by the following formula: inhibition = 1- (OD dosing well-blank well)/(OD control well-blank well) ×100%. Calculation of IC from compound concentration and corresponding inhibition ratio using Graphpad prism 7.0 software 50 Values. The test results are shown in Table 4.
TABLE 3 Activity of the compounds of the invention to inhibit proliferation of tumor cells in vitro
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TABLE 4 in vitro inhibitory Activity of Compounds I-1 and I-38 against proliferation of different cell lines
Biological test example 3: animal Metabolic Properties of the Compounds of the invention
Pharmacokinetic property test of the Compounds of the invention administered to C57 Male mice, SD Male rats and Male beagle dogs by one time by gastric lavage and intravenous injection
(1) Purpose of experiment
After single dose administration of the compound of the invention in C57 male mice, SD male rats and male beagle dogs, blood samples were collected at different time points (3 animals per sampling point), and the concentration of the compound in the plasma of experimental animals was determined by LC-MS/MS and relevant pharmacokinetic parameters were calculated to examine the pharmacokinetic conditions of the compound in mice, rats and dogs.
(2) Design of experiment
Male C57 mice (Suzhou Zhaoyan), male SD rats (Suzhou Zhaoyan), male beagle dogs (Beijing Ma Siquan), experiments (3 animals per group or per sampling point) were performed as shown in Table 5 below.
(3) Sample collection
0.030mL of blood is taken by each mouse through the eye socket, 0.1mL of blood is taken by each rat through the eye socket, 1.0mL of blood is taken by each beagle dog through the jugular vein, EDTA-K2 is anticoagulated, and the collection time point is as follows: 0,5,15,30min,1,2,4,6,8,24h after administration of the test agent. Blood samples were collected and placed on ice and the plasma was centrifuged within 30 minutes (centrifugation conditions: 5000 rpm, 10 minutes, 4 ℃). Stored at-80 ℃ prior to analysis.
(4) Data processing
The data acquisition and control system software is Analyst1.5.1 software (Applied Biosystem). The peak integration mode of the map sample is automatic integration; regression was performed using the ratio of the peak area of the sample to the peak area of the internal standard as an index, and the concentration of the sample. Regression mode: linear regression, weight coefficient 1/X2. Pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin Professional v 6.3.6.3 (Pharsight, USA). Cmax is the measured maximum blood concentration, the area under the blood concentration-time curve AUC (0- > t) is calculated by a trapezoidal method, and Tmax is the peak time of the blood concentration after administration. Experimental data are expressed as "Mean ± standard deviation" (Mean ± ICR, n.
(5) Experimental results
The pharmacokinetic results of the compounds of the present invention are shown in tables 6 to 9. Thus, the compound has good pharmacokinetic properties in C57 male mice, SD male rats and male beagle dogs.
TABLE 5 dosing regimen of compounds
TABLE 6 oral drug substitution parameters of a fraction of the compounds (experimental animals: mice, dose: 20 mg.kg) -1 )
As can be seen from the data in table 6, some of the compounds of formula I have good oral exposure to mice.
TABLE 7 intravenous and oral pharmacokinetic parameters of Compounds I-21 and I-38 in mice
Remarks: "-" means not applicable.
As can be seen from the data in Table 7, the mice of compounds I-21 and I-38 have good metabolic properties and high bioavailability.
TABLE 8 intravenous and oral pharmacokinetic parameters of Compound I-38 in rats
Remarks: "-" means not applicable.
As can be seen from the data in Table 8, compound I-38 has good metabolic properties and an oral bioavailability of 61.0%.
TABLE 9 intravenous and oral pharmacokinetic parameters of Compound I-38 in beagle dogs
Remarks: "-" means not applicable.
As can be seen from the data in table 9, compound I-38 has good beagle metabolic properties with an oral bioavailability of 29.6%. Biological test example 4: experimental animals with inhibitory activity of the compound of the embodiment of the invention on growth of mouse MC38 colon cancer subcutaneous transplantation tumor
(1) C57BL/6 mice, 6-8 weeks, male, purchased from Fukang Biotech Co., ltd. The use and welfare of the experimental animals were carried out in compliance with the regulations of the international commission on assessment and approval of experimental animals (AAALAC). The health condition and death of animals are monitored every day, and routine examination includes observing the influence of test substances and medicines on the daily behavior of animals, such as behavior activity, weight change, appearance signs and the like.
(2) Experimental procedure
Mouse MC38 colon cancer cells were cultured at 5.0X10 5 Cells/mice were inoculated subcutaneously into the right armpit of the mice, respectively. Mice were monitored daily and vernier caliper measurements were started when tumors became visible. The width (W) and length (L) of each tumor were measured by calipers using the equation v= (l×w2)/2. When the tumor grows to 100mm 3 After that, mice were randomly grouped (n=5-6). I-38 (60 mg/kg, 120 mg/kg) and I-1 (60 mg/kg, 90 mg/kg) were administered by intragastric administration once daily, respectively. In the experiment of combining with anti-mPD-1, I-38 (60 mg/kg, 120 mg/kg), anti-mPD-1 (InVivoMab anti-mouse PD-1,Bio X Cell,10mg/kg), or I-38 (60 mg/kg, 120 mg/kg) +anti-mPD-1 (10 mg/kg) were respectively administered by intragastric administration once a day, and the control group was given an equivalent amount of solvent (5% DMSO+40% PEG400+55% thousandth penta-concentrated hydrochloric acid) by intragastric administration once a day. Tumor volumes and mouse body weights were recorded every two days. The evaluation index of tumor inhibition is relative tumor inhibition rate: TGI% = (1-T/C)% = (average tumor growth volume of 1-treated group/average tumor growth volume of control group) ×100%.
(3) Experimental results
The compound I-38 of the embodiment of the invention has obvious inhibition effect on the growth of mouse MC38 colon cancer subcutaneous transplantation tumor singly, and the anti-tumor activity is obviously enhanced when the compound is combined with anti-PD-1. As shown in FIG. 1, on day 15, TGI (%) of the I-38 60mg/kg group, 120mg/kg group and anti-PD-1 group were 77.3% (P < 0.01), 92.7% (P < 0.001) and 51.7% (P < 0.05), respectively; TGI (%) after anti-PD-1 and I-38 (60 mg/kg, 120 mg/kg) was 89.7% (P < 0.001) and 100.6% (P < 0.001), respectively, and 3 and 5 mice tumors completely regressed (CR, complete Regression), CR% was 50% and 84% on day 15 and 21, respectively, in the anti-PD-1 and I-38 120mg combination. Furthermore, there was no significant difference in weight gain among the groups of mice throughout the experiment (fig. 2).
As shown in FIGS. 3 and 4, TGI (%) of the present invention example compound I-1 60mg/kg, 90mg/kg group was 86.0% (P < 0.01) and 96.5% (P < 0.01), respectively; the mice had a weight loss of 13.0% and 17.9% compared to the control group, respectively.
In conclusion, in a C57BL/6 mouse model, the compounds I-1 and I-38 of the embodiment of the invention have obvious inhibition effect on the growth of the subcutaneous transplantation tumor of the MC38 colon cancer of the mouse by single use; the combination of the I-38 and the anti-mPD-1 has a synergistic effect, and the weight of mice in the combination is not obviously reduced.
Biological test example 5: inhibitory Activity of Compound I-38 against growth of HCT-116 nude mice transplantation tumor
Experimental animal
(1) BALB/c nude mice, 6-7 weeks, male, purchased from Beijing Fukang Biotech Co., ltd. The use and welfare of the experimental animals were carried out in compliance with the regulations of the international commission on assessment and approval of experimental animals (AAALAC). The health condition and death of animals are monitored every day, and routine examination includes observing the influence of test substances and medicines on the daily behavior of animals, such as behavior activity, weight change, appearance signs and the like.
(2) Experimental procedure
Human HCT-116 colon cancer cells were cultured at a rate of 7.0X10 6 Cells/mice were inoculated subcutaneously into the right armpit of the mice, respectively. Mice were monitored daily and vernier caliper measurements were started when tumors became visible. The width (W) and length (L) of each tumor were measured by calipers using the equation v= (l×w2)/2. When the tumor grows to 100mm 3 After that, mice were randomly grouped (n=5). I-38 (30 mg/kg;60mg/kg;120 mg/kg) or MGCD0103 (120 mg/kg) was administered by gavage once a day, respectively, and the control group was given an equivalent amount of solvent by gavage every day. Tumor volumes and mouse body weights were recorded every two days. The evaluation index of tumor inhibition is relative tumor inhibition rate: TGI% = (1-T/C)% = (average tumor growth volume of 1-treated group/average tumor growth volume of control group) ×100%.
(3) Experimental results
The compound I-38 of the embodiment of the invention has obvious inhibition effect on the growth of subcutaneous transplantation tumor of mice with human HCT-116 colon cancer. As shown in FIG. 5, on day 15, the TGI (%) of the groups I-38, 60 and 120mg/kg were 38.9 (P < 0.01), 65.9 (P < 0.001) and 85.8% (P < 0.0001), respectively, and the TGI (%) of the group MGCD0103 (120 mg/kg) was 61.5%. Furthermore, there was no significant difference in weight gain among the groups of mice throughout the experiment (fig. 6). In conclusion, the compound I-38 of the embodiment of the invention has obvious inhibition effect on the growth of subcutaneous transplantation tumor of naked mice of human HCT-116 colon cancer, and the activity is stronger than that of MGCD0103.

Claims (15)

1. A triazole amide compound shown in formula I or pharmaceutically acceptable salt thereof,
wherein ring A is a 6-14 membered aryl group, substituted with one or more R 7a Substituted 6-14 membered aryl, 5-10 membered heteroaryl, substituted with one or more R 7b Substituted 5-10 membered heteroaryl, orSaid 5-10 membered heteroaryl and is substituted with one or more R 7b In the 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, O and S, and the heteroatom number is 1-4; when the substituents are plural, the same or different;
R 7a and R is 7b Independently halogen, -CN, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 6 Alkynyl, C substituted by one or more halogens 1 -C 6 Alkyl or- (CH) 2 ) n -N(R 8a R 8b )；
L is a bond or
R 5 Is hydrogen, halogen or C 1 -C 6 An alkyl group;
R 6 is hydroxy, 6-14 membered aryl or is substituted with one or more R 9 Substituted 6-14 membered aryl; when the substituents are plural, the same or different;
R 9 is-N (R) 9a R 9b ) Or halogen;
R 1 ，R 2 ，R 3 ，R 4 ，R 8a ，R 8b 、R 9a and R is 9b Independently hydrogen or C 1 -C 6 An alkyl group;
n is 0, 1, 2 or 3;
the carbon atoms with "×" represent, when chiral, S configuration, R configuration or mixtures thereof.
2. The triazole amide compound of formula I of claim 1, or a pharmaceutically acceptable salt thereof, wherein the triazole amide compound of formula I meets one or more of the following conditions:
(1) When ring A is a 6-14 membered aryl or is substituted with one or more R 7a In the case of substituted 6-14 membered aryl, said 6-14 membered aryl is optionally substituted with one or more R 7a The 6-14 membered aryl group in the substituted 6-14 membered aryl group is a 6-10 membered aryl group, for example, phenyl,
(2) When ring A is a 5-10 membered heteroaryl or is substituted with one or more R 7b In the case of substituted 5-10 membered heteroaryl, said 5-10 membered heteroaryl is optionally substituted with one or more R 7b The 5-10 membered heteroaryl group in the substituted 5-10 membered heteroaryl group is pyridinyl or quinolinyl, e.g
(3) When R is 5 、R 7a 、R 7b And R is 9 When independently halogen, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine, chlorine or bromine;
(4) When R is 1 、R 2 、R 3 、R 4 、R 5 、R 7a 、R 7b 、R 8a 、R 8b 、R 9a And R is 9b Independently C 1 -C 6 In the case of alkyl, said C 1 -C 6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl or isopropyl;
(5) When R is 7a And R is 7b Each independently is C 1 -C 6 In the case of alkoxy, said C 1 -C 6 Alkoxy is C 1 ～C 3 Alkoxy groups such as methoxy or ethoxy;
(6) When R is 7a And R is 7b Independently C 2 -C 6 In the case of alkynyl, said C 2 -C 6 Alkynyl is C 2 -C 4 Alkynyl groups such as ethynyl;
(7) When R is 7a And R is 7b Independently C substituted by one or more halogens 1 -C 6 In the case of alkyl radicals, said C being substituted by one or more halogens 1 -C 6 Alkyl is C substituted by one or more halogens 1 -C 3 Alkyl groups such as trifluoromethyl;
(8) When R is 6 Is a 6-14 membered aryl or is substituted with one or more R 9 In the case of substituted 6-14 membered aryl, said 6-14 membered aryl is optionally substituted with one or more R 7a The 6-14 membered aryl group in the substituted 6-14 membered aryl group is a 6-10 membered aryl group, for example, phenyl.
3. The triazole amide compound of formula I of claim 1, or a pharmaceutically acceptable salt thereof, wherein the triazole amide compound of formula I meets one or more of the following conditions:
(1) Ring A is a 6-14 membered aryl group, substituted with one or more R 7a Substituted 6-14 membered aryl, 5-10 membered heteroaryl or
(2)R 5 Is hydrogen;
(3)R 6 is hydroxy, or is substituted with one or more R 9 Substituted 6-14 membered aryl;
(4)R 8a and R is 8b Independently C 1 -C 6 An alkyl group;
(5)R 9a and R is 9b Independently hydrogen;
(6) n is 0 or 1.
4. The triazole amide compound of formula I of claim 1, or a pharmaceutically acceptable salt thereof, wherein the triazole amide compound of formula I meets one or more of the following conditions:
(1) Ring A is phenyl,
(2)R 1 And R is 2 Independently H or methyl;
(3)R 3 and R is 4 Independently H or ethyl;
(4)R 6 is hydroxy group,
5. The triazolamide compound shown in formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the triazolamide compound shown in formula I is selected from any one of the following structures, isomers thereof, or a mixture thereof:
6. the use of a triazolamide compound of formula I according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, as an HDAC inhibitor.
7. A pharmaceutical composition comprising a triazolamide compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, and at least one pharmaceutical excipient.
8. Use of a triazolamide compound of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7 according to any one of claims 1-5 in the manufacture of a medicament for the treatment and/or prevention of diseases associated with HDAC.
9. A pharmaceutical combination comprising a triazolamide compound of formula I according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a PD-1 or PD-L1 antibody; the PD-1 antibody can be InVivoMab anti-mouse PD-1, nano Wu Liyou monoclonal antibody, palbociclizumab, cimiput Li Shan antibody, terlipp Li Shan antibody, xindi Li Shan antibody or Carrilizumab; the PD-L1 antibody can be Ab Zhu Shan antibody, ab-lurumab or Duvaluzumab.
10. Use of a triazolylamide compound of formula I according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of diseases associated with HDAC in combination with a PD-1 or PD-L1 antibody.
11. The use according to claim 8 or 10, wherein the HDAC-related disease is cancer; the cancer can be head and neck cancer, respiratory system cancer, digestive system cancer, urinary system cancer, bone cancer, gynecological cancer, blood system cancer, melanoma, glioma or skin cancer.
12. A process for the preparation of a triazole amide compound of formula I as defined in any one of claims 1 to 5, characterized in that the process comprises scheme one or scheme two;
scheme one: when R is 6 When the compound is hydroxyl, in an organic solvent, in the presence of alkali, the compound shown in the formula II and hydroxylamine hydrochloride react as shown below to obtain the triazole amide compound shown in the formula I,
scheme II: when R is 6 Is thatIn the presence of condensing agent and alkali, the compound shown in formula III and the compound shown in formula IV are subjected to condensation reaction in an organic solvent to obtain the triazole amide compound shown in formula I,
13. the method for preparing a triazole amide compound of formula I of claim 12, wherein the method satisfies one or more of the following conditions:
(1) In the first aspect, the organic solvent is an alcohol solvent, such as methanol;
(2) In the first embodiment, the base is an alkali metal hydroxide such as potassium hydroxide;
(3) In the first embodiment, the molar ratio of the base to the hydroxylamine hydrochloride is 1-3:1, for example 1.5:1;
(4) In the first scheme, the molar ratio of the hydroxylamine hydrochloride to the compound shown in the formula II is 1-100:1, such as 45:1;
(5) In the first embodiment, the temperature of the reaction is-40 ℃ to the boiling temperature of the organic solvent, for example, room temperature;
(6) In the second scheme, the organic solvent is an amide solvent, such as N, N-dimethylformamide DMF;
(7) In the second scheme, the base is an organic base such as N, N-diisopropylethylamine;
(8) In the second scheme, the molar ratio of the base to the compound of formula III is 1-3:1, e.g., 2:1;
(9) In the second scheme, the condensing agent is a carbodiimide condensing agent, a phosphorus positive ion condensing agent or a urea positive ion condensing agent; the carbodiimide type condensing agent is preferably N, N '-dicyclohexylcarbodiimide or N, N' -diisopropylcarbodiimide; the phosphorus positive ion condensing agent is preferably a Kate condensing agent or PyBOP; the urea positive ion condensing agent is preferably HATU, TBTU or TOTU;
(10) In the second scheme, the molar ratio of the condensing agent to the compound shown in the formula III is 1-3:1, for example, 2:1;
(11) In the second scheme, the molar ratio of the compound shown in the formula IV to the compound shown in the formula III is 1-3:1, for example, 2:1;
(12) In the second embodiment, the temperature of the condensation reaction is-40 ℃ to the boiling temperature of the organic solvent, for example, room temperature.
14. A compound which is any one of the following structures:
wherein the ring A, R 1 、R 2 、R 3 、R 4 、R 5 And L is as defined in claim 1.
15. The compound of claim 14, wherein the compound of formula II is
The compound shown in the formula III is
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CN202211494346.2A 2022-03-28 2022-11-25 Triazole amide compound, and preparation method and application thereof Pending CN116813560A (en)

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