CN115109048A - (hetero) aryl amide compound - Google Patents

(hetero) aryl amide compound Download PDF

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CN115109048A
CN115109048A CN202210953698.3A CN202210953698A CN115109048A CN 115109048 A CN115109048 A CN 115109048A CN 202210953698 A CN202210953698 A CN 202210953698A CN 115109048 A CN115109048 A CN 115109048A
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CN115109048B (en
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韩进松
崔文禹
赵若熙
韩路路
刘宇航
张文慧
缪顺童
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The invention belongs to the field of medicinal chemistry, and relates to (hetero) aryl amide compounds which can inhibit the tyrosine kinase enzyme activity of Abelson protein (Abl1), Abelson related protein (Abl2) and related chimeric protein, in particular Bcr-Abl1, or pharmaceutically acceptable stereoisomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, a preparation method of the compounds, a pharmaceutical composition containing the compounds, and application of the compounds or the composition in pharmaceutical preparation. The compound has better Bcr-Abl kinase inhibition activity and pharmacodynamic performance, and can be used for treating and/or preventing diseases caused by Bcr-Abl in a subject.

Description

(hetero) aryl amide compound
Technical Field
The invention relates to the technical field of medicines, in particular to (hetero) aryl amide compounds capable of inhibiting tyrosine kinase enzyme activities of Abelson protein (Abl1), Abelson related protein (Abl2) and related chimeric protein, especially Bcr-Abl1, pharmaceutical compositions containing the compounds, and a preparation method and application of the compounds.
Background
The known (hetero) aryl amide compounds are a Bcr-Abl kinase inhibitory active compound and are allosteric inhibitors of Bcr-Abl tyrosine kinase. The Bcr-Abl fusion gene results from the reciprocal translocation between chromosomes 9 and 22 in human hematopoietic stem cells, the fusion of the Bcr and Abl1 genes on philadelphia chromosome (Ph). The expressed tyrosine kinase enables a series of signal channels for regulating cell growth, differentiation and death to be abnormally activated, so that cell proliferation, adhesion and survival properties are changed, and then a plurality of tumors are generated, and therefore, the inhibition of the Bcr-Abl tyrosine kinase can effectively inhibit the tumor growth.
(hetero) aryl amide structural compounds such as ABL001 (also known as Asciminib, chemical name (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide), is an allosteric inhibitor of ABL1 kinase developed by nova pharmaceutical company, targets the allosteric site myristoyl pocket of ABL1 to inactivate, and can be used in combination with an ATP-competitive Bcr-ABL tyrosine kinase inhibitor to effectively prevent the development of resistance in ATP competitive inhibitors and/or allosteric inhibitor applications. The combination of ABL-001 and a second-generation Bcr-ABL inhibitor nilotinib has been proved to have the effect of radically treating CML in a mouse model. Norwalk is developing treatment regimens in which ABL001 is combined with multiple ATP competitive Bcr-ABL inhibitors, including imatinib, nilotinib, and dasatinib. This drug has been marketed in the United states at 2021.
TGRX-678 is the first Chinese Bcr-Abl1 allosteric inhibitor developed by Tajiri pharmaceutical company in China and the fourth generation Bcr-Abl1 allosteric inhibitor which is the fastest in development, and is the second Bcr-Abl1 allosteric inhibitor in the world, and clinical precursor in-vitro and in-vitro research results show that compared with ABL001, TGRX-678 has higher activity and selectivity on Bcr-ablT315I cells, oral bioavailability is better, and the in-vivo safety of animals is better than that of ABL 001.
However, there is still a need in the art to develop compounds with inhibitory activity, or better pharmacodynamic properties, on Bcr-Abl kinase.
Disclosure of Invention
The invention aims to provide a novel (hetero) aryl amide compound with Bcr-Abl kinase inhibition activity and better pharmacodynamic performance, or a pharmaceutically acceptable stereoisomer, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, and the (hetero) aryl amide compound can be used for treating and/or preventing diseases caused by Bcr-Abl in a subject.
The invention also provides a preparation method of the (hetero) aryl amide compound and an intermediate thereof.
The present invention also provides a pharmaceutical composition comprising at least one compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.
The invention also provides the use of a compound of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof or a pharmaceutical composition of the invention for the manufacture of a medicament.
In contrast, the technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided a compound according to formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof:
Figure BDA0003790398760000011
wherein Y is selected from CH or N;
R 1 independently selected from hydrogen, halogen, nitrile group and hydroxyl, and can be mono, bi or polysubstituted; r 2 Is selected from-CF 2 -Y 1 ；
Y 1 Selected from hydrogen, chloro, fluoro, methyl, difluoromethyl and trifluoromethyl;
z is selected from the group consisting of a bond, O and S (O) 0-2 (ii) a or-Z-R 2 Together represent-SF 5 ；
Het is pyrrolidinyl; wherein said pyrrolidinyl is substituted with 1 or more R a Substituted by groups;
R a selected from the group consisting of hydrogen, hydroxy, methyl, halogen, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, cyano and amino-carbonyl;
link is urea, thiourea,
Figure BDA0003790398760000021
Figure BDA0003790398760000022
R 3 Is composed of
Figure BDA0003790398760000023
Wherein X 1 -X 9 Independently selected from CR c Or N, and X 6 ，X 7 ，X 8 And X 9 Is a mother core connectionC atom of (2), X 10 Selected from O, S or NR b ，X 11 Selected from O, S, NR b Or C (R) c ) 2 ；
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3, 4, 5, 6 or 7;
R b independently selected from hydrogen, acetyl, C 1-6 Alkyl or C 1-6 A haloalkyl group;
r and R c Independently selected from hydrogen, halogen, nitrile group, nitro group, hydroxyl group, aldehyde group, carboxyl group, acetamido group, ethoxycarbonyl group, aminoacyl group and-NH 2 、-NHC 1-6 Alkyl, -N (C) 1-6 Alkyl radical) 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Haloalkoxy, C 3-7 Heterocycloalkyl radical, C 6-10 Aryl or C 5-10 A heteroaryl group;
or two R groups on the same atom or on adjacent atoms may together form C 3-7 Cycloalkyl radical, C 3-7 Heterocycloalkyl radical, C 6-10 Aryl or C 5-10 A heteroaryl group;
the halogen is F, Cl or Br.
In certain preferred embodiments, disclosed is a compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof:
Figure BDA0003790398760000024
wherein R is 1 Independently selected from hydrogen, halogen, nitrile group and hydroxyl, and can be mono, bi or polysubstituted;
R a independently selected from hydrogen, hydroxyl, halogen, nitrile group and carboxyl, and can be mono, bi or polysubstituted;
link is urea, thiourea,
Figure BDA0003790398760000025
Figure BDA0003790398760000026
R 3 Is composed of
Figure BDA0003790398760000027
Wherein X 1 -X 9 Independently selected from CR c Or N, and X 6 ,X 7 ,X 8 And X 9 One of them being a mother-nuclear-bound C atom, X 10 Selected from O, S or NR b ，X 11 Selected from O, S, NR b Or C (R) c ) 2 ；
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3, 4, 5, 6 or 7;
R b independently selected from hydrogen, acetyl, C 1-6 Alkyl or C 1-6 A haloalkyl group;
r and R c Independently selected from hydrogen, halogen, nitrile group, nitro group, hydroxyl group, aldehyde group, carboxyl group, acetamido group, ethoxycarbonyl group, aminoacyl group and-NH 2 、-NHC 1-6 Alkyl, -N (C) 1-6 Alkyl radical) 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Haloalkoxy, C 3-7 Heterocycloalkyl radical, C 6-10 Aryl or C 5-10 A heteroaryl group;
two R groups on either the same atom or on adjacent atoms may together form C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 A heteroaryl group;
the halogen is F, Cl or Br.
Further, said R 1 Independently selected from hydrogen and halogen; r a Independently selected from hydrogen and hydroxyl;
link is urea, thiourea,
Figure BDA0003790398760000031
R b Independently selected from hydrogen, acetyl, C 1-3 Alkyl or C 1-3 A haloalkyl group;
r and R c Independently selected from hydrogen, halogen, nitrile group, nitro group, hydroxyl group, aldehyde group, carboxyl group, acetamido group, ethoxycarbonyl group, aminoacyl group and-NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl radical) 2 、C 1-3 Alkyl radical, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy radical, C 1-3 Alkylthio radical, C 1-3 Haloalkoxy, C 3-7 Heterocycloalkyl radical, C 6-10 Aryl or C 5-10 A heteroaryl group;
or two R groups on the same atom or on adjacent atoms may together form C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl radical, C 6-10 Aryl or C 5-10 A heteroaryl group.
In certain preferred embodiments, disclosed is a compound of formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof:
Figure BDA0003790398760000032
wherein R is a Independently selected from hydrogen and hydroxyl;
link is urea, thiourea,
Figure BDA0003790398760000033
R 3 Selected from the following groups optionally substituted with one, two or three R:
Figure BDA0003790398760000034
R b independently selected from hydrogen, acetyl or C 1-3 An alkyl group;
r is independently selected from hydrogen, halogen, nitrile group, nitro group, hydroxyl group, aldehyde group, carboxyl group, acetamido group, ethoxycarbonyl group and amino groupAcyl, -NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl radical) 2 、C 1-3 Alkyl radical, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy radical, C 1-3 Alkylthio radical, C 1-3 Haloalkoxy, C 3-7 Heterocycloalkyl radical, C 6-10 Aryl or C 5-10 A heteroaryl group.
Further, said R a Is a hydroxyl group;
link is thiourea,
Figure BDA0003790398760000041
R is independently selected from hydrogen, halogen, nitrile group, nitro group, hydroxyl group, aldehyde group, carboxyl group, acetamido group, ethoxycarbonyl group, aminoacyl group and-NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl radical) 2 、C 1-3 Alkyl radical, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy radical, C 1-3 Alkylthio radical, C 1-3 A haloalkoxy group.
In certain more preferred embodiments, the (hetero) arylamide compounds of the present invention are any of the compounds of table 1 below, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof:
table 1 shows some of the compounds of the present invention
Figure BDA0003790398760000042
Figure BDA0003790398760000051
Figure BDA0003790398760000061
Figure BDA0003790398760000071
In a further aspect the present invention provides a process for the preparation of a compound according to formula (XI) and intermediates thereof, comprising the steps of:
Figure BDA0003790398760000072
(1) preparation of intermediate (V): dissolving 2-amino-5-methylpyridine (IV) in concentrated sulfuric acid, and adding a mixture of the two in a volume ratio of 1:1, heating the mixed acid solution of concentrated sulfuric acid and concentrated nitric acid to 55 ℃, pouring the reaction solution into crushed ice, adding sodium nitrite, and stirring in an ice bath to obtain an intermediate (V);
(2) preparation of intermediate (VI): adding 2-hydroxy-5-methyl-3-nitropyridine (V) into a reaction bottle, adding phosphorus oxychloride, and heating and refluxing for 8 hours to obtain an intermediate (VI);
(3) preparation of intermediate (VII): dissolving 2-chloro-5-methyl-3-nitropyridine (VI) in concentrated sulfuric acid, adding potassium dichromate in batches under an ice bath condition, and stirring at room temperature for 16h to obtain an intermediate (VII);
(4) preparation of intermediate (VIII): 6-chloro-5-nitronicotinic acid (VII) was dissolved in anhydrous DCM, and thionyl chloride (SOCl) was added 2 ) Heating and stirring for reaction for 4 hours, drying in vacuum, adding anhydrous DCM for dissolution, adding corresponding substituted aniline, and stirring for reaction at room temperature to obtain an intermediate (VIII);
(5) preparation of Intermediate (IX): dissolving the intermediate (VIII) in anhydrous DMSO, adding N, N-Diisopropylethylamine (DIEA) and corresponding substituted pyrrolidine, and heating to react to obtain an Intermediate (IX);
(6) preparation of intermediate (X): intermediate (IX) was dissolved in anhydrous MeOH and palladium on carbon (Pd/C) was added, followed by addition of hydrogen 2 Heating and reacting under the condition to obtain an intermediate (X);
(7) preparation of the target product (XI):
a condensation reaction, which comprises the specific steps of dissolving the intermediate (X) in anhydrous acetonitrile, adding various substituted acyl chlorides and Triethylamine (TEA), and stirring at room temperature for 1 hour to obtain a target product (XI);
or an addition reaction, which comprises the specific steps of dissolving the intermediate (X) in anhydrous methanol, adding various substituted cycloalkyl ketones, and heating and stirring for reaction to obtain a target product (XI);
or reductive amination reaction, specifically comprising dissolving intermediate (X) in anhydrous methanol, adding various substituted cycloalkyl ketones, heating and stirring for 2 hr, and adding sodium cyanoborohydride (NaBH) 3 CN), heating to react to obtain a target product (XI);
or addition reaction, specifically comprising the steps of dissolving the intermediate (X) in absolute ethyl alcohol, adding various substituted isothiocyanates and TEA, and stirring at 80 ℃ for 4h to obtain a target product (XI);
or condensation reaction, specifically comprising the steps of dissolving the intermediate (X) in N, N-dimethylformamide, adding various substituted carboxylic acids, adding 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) and DIEA, and stirring at room temperature for 18 hours to obtain the target product (XI).
In yet another aspect, the present invention provides a pharmaceutical composition comprising a compound of any one of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient. The compound can be added with pharmaceutically acceptable carriers to prepare common pharmaceutical preparations, such as tablets, capsules, syrup, suspending agents and injections, and common pharmaceutical excipients such as spices, sweeteners, liquid or solid fillers or diluents and the like can be added. In a specific embodiment, the compounds of the present invention are provided in an effective amount in the pharmaceutical composition. In particular embodiments, the compounds of the present invention are provided in a therapeutically effective amount. In particular embodiments, the compounds of the present invention are provided in a prophylactically effective amount.
The invention provides application of a compound or pharmaceutically acceptable salt, stereoisomer, solvate, hydrate and pharmaceutical composition thereof in preparing a medicament for treating and/or preventing Bcr-Abl-caused diseases in a subject.
In a particular embodiment of the invention, the Bcr-Abl caused disease is a proliferative disease selected from the group consisting of: solid tumors, sarcomas, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, gastrointestinal stromal tumors, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia and other proliferative or proliferative diseases. In a particular embodiment of the invention, the Bcr-Abl caused disease is metastatic invasive cancer, a viral infection or a CNS disorder.
Pharmacological experiments show that the compound can generate good antiproliferative effect on human chronic myelogenous leukemia cell lines K562 and KBM5, can be used for preparing medicines for treating cancers such as chronic myelogenous leukemia, acute myelogenous leukemia and the like, and has good application prospect.
Detailed Description
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are carried out, prepared, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what is claimed herein.
The structure of the compounds of the invention is determined by Mass Spectrometry (MS) and/or nuclear magnetic resonance (M) 1 HNMR) device.
Synthesis method
The compounds of the present invention may be prepared according to conventional methods in the art, using appropriate reagents, starting materials and purification methods known to those skilled in the art. The following more specifically describes the preparation of the compounds of the present invention, but these specific methods do not set any limit to the present invention. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
In general, in the preparation, each reaction is usually carried out in an inert solvent at a temperature ranging from room temperature to reflux temperature (e.g., from 0 ℃ to 100 ℃, preferably from 0 ℃ to 80 ℃). The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 24 hours.
EXAMPLE 1 preparation of (R, E) -5- (((5-bromothien-2-yl) methylene) amino) -N- (4- (chlorodifluoromethoxy) Phenyl) -6- (3-Hydroxypyrrolidin-1-yl nicotinamide (Compound 1)
Figure BDA0003790398760000081
Step 1: synthesis of 2-hydroxy-5-methyl-3-nitropyridine (Compound 1 b).
To a reaction flask, 300mL of concentrated sulfuric acid was added, and 2-amino-5-methylpyridine (1a, 60.0g, 554.8mmol), 70mL of concentrated sulfuric acid and a mixed concentrated nitric acid (V: V ═ 1:1) were added under ice bath, and the mixture was stirred at room temperature for 1 hour, and then heated to 55 ℃ and stirred for 2 hours. The reaction solution was poured into ice water, 77g of sodium nitrite was added in portions under ice bath, and stirring was carried out for 4 hours while maintaining the temperature, yielding a large amount of yellow solid. Suction filtration, filter cake drying, yellow solid 45.2g, yield: 52.9 percent.
Step 2: synthesis of 2-chloro-5-methyl-3-nitropyridine (Compound 1 c).
2-hydroxy-5-methyl-3-nitropyridine (1b, 45.2g, 272.5mmol), 750mL phosphorus oxychloride were added to the reaction flask and heated under reflux for 8 h. And (3) after the reaction liquid is decompressed and concentrated, pouring the reaction liquid into crushed ice, separating out a large amount of yellow solids, performing suction filtration, washing and drying to obtain 42.1g of a product, wherein the yield is as follows: 89.5 percent.
And step 3: synthesis of 6-chloro-5-nitronicotinic acid (Compound 1 d).
2-chloro-5-methyl-3-nitropyridine (1c, 42.1g, 197.4mmol) and 500mL of concentrated sulfuric acid were added to a reaction flask to dissolve, and stirred at room temperature, potassium dichromate (92.3g, 313.8mmol) was added in portions, and stirred at room temperature for 16 hours. Pouring the reaction solution into crushed ice, stirring and cooling, extracting for 3 times by ethyl acetate, combining organic phases, concentrating under reduced pressure, and recrystallizing to obtain 36.72g of a product with yield: 74.3 percent.
And 4, step 4: synthesis of 6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -5-nitronicotinamide (Compound 1 e).
6-chloro-5-nitronicotinic acid (1d, 36.53g, 180.35mmol) was added to the reaction flask, and thionyl chloride (SOCl) was added 2 550mL) was reacted at 80 ℃ for 4 hours with stirring, dried in vacuo, dissolved in 500mL of anhydrous DCM, and then 4- (chlorodifluoromethoxy) aniline (34.91g, 180.35mmol) was added, reacted at room temperature with stirring for 1 hour, and then the reaction mixture was reduced in pressureConcentration gave 52.13g of product, yield: 76.4 percent.
And 5: synthesis of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5-nitronicotinamide (Compound 1 f).
Adding compound 1e (52.06g, 137.6mmol) and (R) -3 hydroxypyrrolidine (12.00g, 137.6mmol) into a reaction flask, adding 400mL of anhydrous DMSO, adding DIEA (35.57g, 275.3mmol), heating to 100 ℃, stirring for reaction for 2 hours, adding excessive water for dilution, extracting with ethyl acetate for 3 times, combining organic phases, washing with saturated sodium chloride solution, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain 45.73g of a product, yield: 77.4 percent.
Step 6: synthesis of (R) -5-amino-N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 1g)
To a reaction flask was added compound 1f (45.7g, 106.5mmol), palladium on carbon (Pd/C,2g), and 300mL anhydrous MeOH, H 2 Replacement, stirring at 40 ℃ for reaction for 12 hours, suction filtration, and decompression concentration of the filtrate to obtain 33.4g of a product, yield: 78.63 percent.
And 7: synthesis of (R, E) -5- (((5-bromothien-2-yl) methylene) amino) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidine-1) nicotinamide (Compound 1)
To a reaction flask were added 1g (200mg, 0.5mmol) of the compound, 5-bromothiophene-2-carbaldehyde (190mg, 1mmol), formic acid (2.3mg, 0.05mmol) and 3mL of anhydrous methanol, and the mixture was stirred at 50 ℃ for 2 hours. Purifying by silica gel column chromatography and reversed phase column chromatography to obtain 61.6mg product, yield: 21.4 percent. LC-ms (esi) m/z 570.99; 1 H-NMR(300MHz,DMSO-d 6 )δ10.18(s,1H),8.75(s,1H),8.62(d,J＝2.1Hz,1H),7.90-7.85(m,2H),7.82(d,J＝2.2Hz,1H),7.54(d,J＝3.9Hz,1H),7.40(d,J＝3.9Hz,1H),7.38-7.33(m,2H),4.95(d,J＝3.3Hz,1H),4.34(s,1H),3.81-3.78(m,3H),3.68(s,1H),1.98-1.82(m,2H)。
EXAMPLE 2 preparation of (R, E) -5- (((5-bromofuran-2-yl) methylene) amino) -N- (4- (chlorodifluoromethoxy) Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 2)
Figure BDA0003790398760000101
Referring to the procedure of example 1, 5-bromothiophene-2-carbaldehyde was replaced with 5-bromo-2-furancarbaldehyde to finally obtain 72.8mg of a product in yield: 26.2 percent. LC-MS (ESI) M/z 555.02[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.15(s,1H),8.61(d,J＝2.1Hz,1H),8.41(s,1H),7.87(d,J＝9.1Hz,2H),7.75(d,J＝2.2Hz,1H),7.35(d,J＝8.6Hz,2H),7.21(d,J＝3.5Hz,1H),6.89(d,J＝3.5Hz,1H),4.94(d,J＝3.3Hz,1H),4.33(s,1H),3.88-3.75(m,3H),3.66-3.62(m,1H),1.96-1.82(m,2H)。
EXAMPLE 3 preparation of (R, E) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (((5- (hydroxymethyl) furan-2-yl) ylidene) Methyl) amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 3)
Figure BDA0003790398760000102
Referring to the method of example 1, 5-bromothiophene-2-carbaldehyde was replaced with 5-hydroxymethylfurfural to give 80.0mg of the final product in yield: 31.6 percent. LC-MS (ESI) M/z 507.12[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.14(s,1H),8.59(d,J＝2.1Hz,1H),8.41(s,1H),7.91-7.84(m,2H),7.71(d,J＝2.2Hz,1H),7.38-7.31(m,2H),7.12(d,J＝3.4Hz,1H),6.56(d,J＝3.4Hz,1H),5.48(t,J＝5.8Hz,1H),4.93(d,J＝3.3Hz,1H),4.51(d,J＝5.8Hz,2H),4.32(s,1H),3.79-3.76(m,3H),3.65-3.62(m,1H),1.98-1.80(m,2H)。
Example 4 preparation of (R, E) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((5-methoxypyridin-3-yl) methylene) amino) nicotinamide (Compound 4)
Figure BDA0003790398760000103
Referring to the procedure of example 1, 5-bromothiophene-2-carbaldehyde was preparedSubstitution with 5-methoxy-pyridine-3-carbaldehyde to give 49.0mg of the final product, yield: 18.9 percent. LC-MS (ESI) M/z 518.14[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.20(s,1H),8.76(s,1H),8.70(d,J＝1.6Hz,1H),8.65(d,J＝2.1Hz,1H),8.46(d,J＝2.9Hz,1H),7.90(s,1H),7.87(s,1H),7.83(d,J＝2.1Hz,2H),7.36(d,J＝8.6Hz,2H),4.95(d,J＝3.3Hz,1H),4.34(s,1H),3.92(s,3H),3.85-3.81(m,3H),3.70-3.67(m,1H),1.97-1.81(m,2H)。
Example 5 preparation of (R, E) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((pyridin-4-ylmethylene) amino) nicotinamide (Compound 5)
Figure BDA0003790398760000104
Referring to the procedure of example 1, 5-bromothiophene-2-carbaldehyde was replaced with 4-pyridinecarbaldehyde to give 39.3mg of the final product in yield: 16.1 percent. LC-MS (ESI) M/z 488.13[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.21(s,1H),8.81-8.77(m,2H),8.75(s,1H),8.67(d,J＝2.2Hz,1H),7.89(d,J＝2.2Hz,1H),7.87(d,J＝1.3Hz,3H),7.85(d,J＝1.7Hz,1H),7.41-7.31(m,2H),4.95(d,J＝3.3Hz,1H),4.34(s,1H),3.86-3.81(m,3H),3.70-3.65(m,1H),1.99-1.84(m,2H)。
EXAMPLE 6 preparation of (R, E) -5- (((6-bromopyridin-3-yl) methylidene) amino) -N- (4- (chlorodifluoromethoxy) Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 6)
Figure BDA0003790398760000111
Referring to the procedure of example 1, 5-bromothiophene-2-carbaldehyde was replaced with 5-bromopyridine-3-carbaldehyde to obtain compound 6. LC-MS (ESI) M/z 566.04[ M + H ]] + 。
EXAMPLE 7 preparation of (R, E) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-hydroxy-5-nitrobenzylidene) ammonia 6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 7)
Figure BDA0003790398760000112
Referring to the procedure of example 1, 5-bromothiophene-2-carbaldehyde was replaced with 5-nitrosalicylaldehyde to prepare compound 7. LC-MS (ESI) M/z 548.12[ M + H ]] + 。
EXAMPLE 8 preparation of (R) -5- (((5-bromothien-2-yl) methyl) amino) -N- (4- (chlorodifluoromethoxy) benzene 6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 8)
Figure BDA0003790398760000113
To a reaction flask were added 1g (200mg, 0.5mmol) of the compound, 5-bromothiophene-2-carbaldehyde (190mg, 1mmol), formic acid (2.3mg, 0.05mmol) and 3mL of anhydrous methanol, heated and stirred at 50 ℃ for 2 hours, and added sodium cyanoborohydride (NaBH) 3 CN,128mg, 2mmol), stirring at room temperature for 1 hour, diluting with water, extracting with ethyl acetate for 3 times, combining organic phases, washing with saturated sodium chloride solution, concentrating under reduced pressure, purifying by silica gel column chromatography to obtain 113.4mg of product, yield: 39.6 percent. LC-MS (ESI) M/z 573.02[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.13(s,1H),8.21(d,J＝1.9Hz,1H),7.90-7.81(m,2H),7.33-7.29(m,2H),7.21(d,J＝2.0Hz,1H),7.08(d,J＝3.7Hz,1H),6.95(d,J＝3.7Hz,1H),5.64(t,J＝5.5Hz,1H),4.93(d,J＝3.6Hz,1H),4.47(d,J＝5.4Hz,2H),4.37(d,J＝3.7Hz,1H),3.88-3.68(m,2H),3.47-3.42(m,1H),3.30-3.25(m,1H),2.05-1.77(m,2H)。
EXAMPLE 9 preparation of (R) -5- (((5-bromofuran-2-yl) methyl) amino) -N- (4- (chlorodifluoromethoxy) benzene 6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 9)
Figure BDA0003790398760000121
Referring to the procedure of example 8, 5-bromothiophene-2-carbaldehyde was replaced with 5-bromo-2-furaldehyde to prepare compound 9. LC-MS (ESI) M/z 557.04[ M + H ]] + 。
EXAMPLE 10 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (((5- (hydroxymethyl) furan-2-yl) methane Yl) amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 10)
Figure BDA0003790398760000122
Referring to the method of example 8, 5-bromothiophene-2-carbaldehyde was replaced with 5-hydroxymethylfurfural to finally obtain 35.0mg of a product, yield: 13.7 percent. LC-MS (ESI) M/z 509.16[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.15(s,1H),8.19(d,J＝2.0Hz,1H),7.86(d,J＝9.1Hz,2H),7.34(d,J＝9.3Hz,2H),7.27(d,J＝2.0Hz,1H),6.20(s,2H),5.30(t,J＝5.8Hz,1H),5.17(t,J＝5.7Hz,1H),4.91(d,J＝3.7Hz,1H),4.36(s,2H),4.34(s,2H),3.74-3.70(m,2H),3.49-3.39(m,1H),3.31-3.26(m,1H),2.04-1.74(m,2H)。
Example 11 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((5-methoxypyridin-3-yl) methyl) amino) nicotinamide (Compound 11)
Figure BDA0003790398760000123
Referring to the procedure of example 8, 5-bromothiophene-2-carbaldehyde was replaced with 5-methoxy-pyridine-3-carbaldehyde to give 64.0mg of the final product in yield: 24.6 percent. LC-MS (ESI) M/z 520.15[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.12(s,1H),8.23(d,J＝1.7Hz,1H),8.18-8.13(m,2H),7.88-7.80(m,2H),7.39-7.35(m,1H),7.32-7.26(m,2H),7.10(d,J＝2.0Hz,1H),5.55(t,J＝5.7Hz,1H),4.93(d,J＝3.6Hz,1H),4.36(s,3H),3.81(s,5H),3.49-3.45(m,1H),3.33-3.28(m,1H),2.05-1.79(m,2H)。
EXAMPLE 12 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((pyrazine) Pyridin-4-ylmethyl) amino) nicotinamide (Compound 12)
Figure BDA0003790398760000124
Referring to the procedure of example 8, 5-bromothiophene-2-carbaldehyde was replaced with 4-pyridinecarbaldehyde to finally obtain 55.0mg of a product, yield: 22.4 percent. LC-MS (ESI) M/z 490.16[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.11(s,1H),8.52(d,J＝5.0Hz,2H),8.18(d,J＝1.9Hz,1H),7.82(d,J＝2.1Hz,1H),7.80(d,J＝2.3Hz,1H),7.42-7.37(m,2H),7.31(d,J＝8.7Hz,2H),6.95(d,J＝2.0Hz,1H),5.66(t,J＝5.7Hz,1H),4.94(d,J＝3.5Hz,1H),4.40-4.36(m,3H),3.92-3.73(m,2H),3.52-3.48(m,2H),2.06-1.80(m,2H)。
EXAMPLE 13 preparation of (R) -5- (((6-bromopyridin-3-yl) methyl) amino) -N- (4- (chlorodifluoromethoxy) benzene 6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 13)
Figure BDA0003790398760000131
Referring to the procedure of example 8, 5-bromothiophene-2-carbaldehyde was replaced with 5-bromopyridine-3-carbaldehyde to finally obtain 127.5mg, yield: 44.9 percent. LC-MS (ESI) M/z 568.06[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.12(s,1H),8.43(d,J＝2.5Hz,1H),8.19(d,J＝2.0Hz,1H),7.88-7.80(m,2H),7.76-7.72(m,1H),7.63-7.58(m,1H),7.32-7.28(m,2H),7.06(d,J＝2.0Hz,1H),5.58(d,J＝5.7Hz,1H),4.92(d,J＝3.6Hz,1H),4.36(d,J＝5.6Hz,3H),3.84-3.73(m,2H),3.49-3.45(m,1H),3.33-3.29(m,1H),2.07-1.74(m,2H)。
EXAMPLE 14 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-hydroxy-5-nitrobenzyl) amino) - 6- (3-Hydroxypyrrolidin-1-yl) nicotinamide (Compound 14)
Figure BDA0003790398760000132
Referring to the procedure of example 8, 5-bromothiophene-2-carbaldehyde was replaced with 5-nitrosalicylaldehyde to give 98.0mg of final product in yield: 35.7 percent. LC-MS (ESI) M/z 550.13[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ11.44(s,1H),10.14(s,1H),8.18(d,J＝1.9Hz,1H),8.11(d,J＝2.9Hz,1H),8.05(d,J＝8.9Hz,1H),7.81(d,J＝9.1Hz,2H),7.31(d,J＝8.6Hz,2H),7.08-6.94(m,2H),5.61(s,1H),4.97(s,1H),4.36(d,J＝19.7Hz,3H),3.84-3.80(m,2H),3.52-3.49(m,1H),3.33-3.28(m,1H),2.09-1.77(m,2H)。
EXAMPLE 15 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (2- Nitrobenzoylamino) nicotinamide (Compound 15)
Figure BDA0003790398760000133
Adding o-nitrobenzoic acid (84mg, 0.5mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 228mg, 0.6mmol), N, N-diisopropylethylamine (DIEA, 129mg, 1mmol) and 3mL DMF into a reaction bottle, stirring for 1 hour at room temperature, adding compound 1g (200mg, 0.5mmol), stirring for 4 hours at room temperature, adding water for dilution, extracting for 3 times with ethyl acetate, combining organic phases, washing with saturated sodium chloride solution, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain the product 36.0mg, yield: 13.16 percent. LC-MS (ESI) M/z 548.12[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.36(s,1H),10.30(d,J＝1.8Hz,1H),8.73(d,J＝2.1Hz,1H),8.15-8.11(m,1H),7.99(d,J＝2.2Hz,1H),7.92-7.87(m,3H),7.82-7.76(m,2H),7.39-7.32(m,2H),5.01-4.97(m,1H),4.37(s,1H),3.82-3.71(m,3H),3.55-3.48(m,1H),2.00-1.83(m,2H)。
EXAMPLE 16 preparation of (R) -N- (4- (chlorobis)Fluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (thia-zo Phen-2-carboxamido) nicotinamide (Compound 16)
Figure BDA0003790398760000141
Referring to the procedure of example 15, replacing o-nitrobenzoic acid with thiophene-2-carboxylic acid gave 37.0mg of the final product in yield: 14.5 percent. LC-MS (ESI) M/z 509.11[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.18(s,1H),10.17(s,1H),8.72(d,J＝2.3Hz,1H),8.06-7.94(m,2H),7.94-7.81(m,3H),7.46-7.33(m,2H),7.25-7.21(m,1H),4.99(d,J＝3.3Hz,1H),4.32-4.28(m,1H),3.70-3.67(m,3H),3.55-3.43(m,1H),1.98-1.74(m,2H)。
EXAMPLE 17 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (furan-2-carboxamido) -6- (3-hydroxy Methylpyrrolidin-1-yl nicotinamide (Compound 17)
Figure BDA0003790398760000142
Referring to the procedure of example 15, replacing o-nitrobenzoic acid with furoic acid provided 69.0mg of product in yield: 28.0 percent. LC-MS (ESI) M/z 493.12[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.19(s,1H),10.10(s,1H),8.71(d,J＝2.3Hz,1H),7.95(m,2H),7.90-7.87(m,2H),7.39-7.28(m,3H),6.71(dd,J＝3.5,1.8Hz,1H),4.99(d,J＝3.3Hz,1H),4.32-4.29(m,1H),3.76-3.62(m,3H),3.47-3.42(m,1H),1.97-1.77(m,2H)。
EXAMPLE 18 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) picolinamides (Compound 18)
Figure BDA0003790398760000143
Referring to the procedure of example 15, replacing o-nitrobenzoic acid with 2-picolinic acid gave 59.0mg of product, yield: 23.4 percent. LC-MS (ESI) M/z 504.14[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.55(s,1H),10.20(s,1H),8.80-8.67(m,2H),8.15-8.11(m,1H),8.08-8.06(m,1H),8.05-8.00(m,1H),7.94-7.84(m,2H),7.69-7.64(m,1H),7.34-7.31(m,2H),4.95(d,J＝3.4Hz,1H),4.29-4.25(m,1H),3.79-3.62(m,3H),3.47-3.42(m,1H),1.96-1.72(m,2H)。
EXAMPLE 19 preparation of N- {4- [ (chlorodifluoromethyl) oxy]Phenyl } -4- [ (3R) -3-hydroxytetrahydro-1H-pyrrole- 1-radical]-3- [ (pyridin-4-ylcarbonyl) amino]Benzamide (Compound 19)
Figure BDA0003790398760000144
Compound 19 was prepared by substituting isonicotinic acid for o-nitrobenzoic acid according to the procedure of example 15. LC-MS (ESI) M/z 504.15[ M + H ]] + 。
EXAMPLE 20 preparation of (R) -5- (5-bromonicotinamide) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrole Alk-1-yl) nicotinamide (Compound 20)
Figure BDA0003790398760000151
Compound 20 was obtained by substituting 5-bromonicotinic acid with o-nitrobenzoic acid according to the procedure of example 15. LC-MS (ESI) M/z 582.03[ M + H ]] + 。
EXAMPLE 21 preparation of (R) -5- (2-bromonicotinamide) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrole Alk-1-yl) nicotinamide (Compound 21)
Figure BDA0003790398760000152
Compound 21 was obtained by substituting o-nitrobenzoic acid for 2-bromonicotinic acid according to the procedure of example 15. LC-MS (ESI) M/z 582.03[ M + H ]] + 。
EXAMPLE 22 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (4- Nitrobenzoylamino) nicotinamide (Compound 22)
Figure BDA0003790398760000153
Referring to the procedure of example 15, replacing o-nitrobenzoic acid with 2-bromonicotinic acid gave 23.0mg of final product in yield: 8.4 percent. LC-MS (ESI) M/z 548.13[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.52(s,1H),10.22(s,1H),8.74(d,J＝2.2Hz,1H),8.44-8.38(m,2H),8.27-8.21(m,2H),7.99(d,J＝2.2Hz,1H),7.92-7.85(m,2H),7.39-7.30(m,2H),4.98(d,J＝3.3Hz,1H),4.30(d,J＝4.9Hz,1H),3.78-3.61(m,3H),3.53-3.44(m,1H),1.95-1.76(m,2H)。
EXAMPLE 23 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (3- (4-Nitrophenyl) thioureido) nicotinamide (Compound 23)
Figure BDA0003790398760000154
To a reaction flask were added isothiocyano 4-nitrophenyl ester (108mg, 0.6mmol), triethylamine (TEA, 101mg, 1mmol), 1g of the compound (200mg, 0.5mmol) and 2mL of absolute ethanol, and the mixture was stirred at 80 ℃ for 4 hours. Vacuum concentrating, purifying by silica gel column chromatography to obtain product 162.3mg, yield: 56.1 percent. LC-MS (ESI) M/z 579.23[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.62(s,1H),10.16(s,1H),9.75(s,1H),8.72(d,J＝2.2Hz,1H),8.30-8.16(m,2H),7.95(d,J＝5.5Hz,2H),7.91-7.70(m,3H),7.41-7.28(m,2H),5.01(d,J＝3.3Hz,1H),4.35(s,1H),3.76-3.72(m,3H),3.55-3.51(m,1H),1.96-1.84(m,2H)。
Example 24 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (3- (pyridin-3-yl) thioureido) nicotinamide (Compound 24)
Figure BDA0003790398760000161
Referring to the procedure of example 23, substituting isothiocyano 4-nitrophenyl ester with 3-pyridyl isothiocyanate gave 92.9mg, yield: 34.7 percent. LC-MS (ESI) M/z 535.22[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.15(s,1H),9.63(s,2H),8.72(d,J＝2.2Hz,1H),8.60(s,1H),8.36-8.32(m,1H),7.97(s,2H),7.94-7.86(m,2H),7.37-3.34(m,3H),4.38(s,1H),3.75-3.71(m,4H),3.57-3.52(m,1H),2.03-1.83(m,3H)。
EXAMPLE 25 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (3- (p-tolyl) thioureido) nicotinamide (compound 25)
Figure BDA0003790398760000162
Referring to the procedure of example 23, substituting isothiocyano 4-nitrophenyl ester for para-toluene isothiocyanate produced 215.6mg, yield: 78.8 percent. LC-MS (ESI) M/z 548.12[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.14(s,1H),9.68(s,1H),9.28(s,1H),8.68(d,J＝2.2Hz,1H),7.91(d,J＝3.5Hz,2H),7.87(d,J＝2.2Hz,1H),7.36(d,J＝1.2Hz,1H),7.35-7.29(m,3H),7.16(d,J＝8.1Hz,2H),5.01(d,J＝3.3Hz,1H),4.36(s,1H),3.84-3.68(m,3H),3.55-3.51(m,1H),2.29(s,3H),1.99-1.80(m,2H)。
EXAMPLE 26 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (3- Phenyl thiourea based) nicotinamide (compound 26)
Figure BDA0003790398760000163
Referring to the procedure of example 23, substituting isothiocyano 4-nitrophenyl ester with thiophenyl isocyanate, 48.8mg of the product was finally obtained in yield: 18.3 percent. LC-MS (ESI) M/z 534.14[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.15(s,1H),9.79(s,1H),9.37(s,1H),8.69(d,J＝2.3Hz,1H),7.93(s,1H),7.91-7.85(m,2H),7.47(d,J＝7.9Hz,2H),7.38(s,1H),7.37-7.34(m,2H),7.33-7.28(m,1H),7.21-7.13(m,1H),5.02(d,J＝3.3Hz,1H),4.36(s,1H),3.76-3.72(m,3H),3.56-3.51(m,1H),2.00-1.80(m,2H)。
Example 27 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (3- (4-cyanophenyl) thioureido) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 27)
Figure BDA0003790398760000171
Referring to the procedure of example 23, substituting isothiocyano 4-nitrophenyl ester with 4-cyanophenyl isothiocyanate gave 59.9mg, yield: 21.5 percent. LC-MS (ESI) M/z 559.11[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.23(s,1H),10.16(s,1H),9.68(s,1H),8.80-8.65(m,1H),7.94(s,1H),7.89(d,J＝2.2Hz,1H),7.89-7.83(m,2H),7.79-7.74(m,3H),7.39-7.30(m,2H),5.01(d,J＝3.3Hz,1H),4.35(s,1H),3.75-3.71(m,3H),3.55-3.51(m,1H),1.96-1.82(m,2H)。
EXAMPLE 28 preparation of (R) -5- (3- (3, 5-bis (trifluoromethyl) phenyl) thioureido) -N- (4- (chlorodifluoromethoxy) urea Yl) phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 28)
Figure BDA0003790398760000172
By reference to the procedure in example 23, the isothiocyano 4-nitrophenyl ester was replaced3, 5-bis (trifluoromethyl) phenyl isothiocyanate was finally obtained as the product 196.3mg, yield: 58.7 percent. LC-MS (ESI) M/z 670.08[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.61(s,1H),10.15(s,1H),9.74(s,1H),8.74(d,J＝2.2Hz,1H),8.29(d,J＝19.2Hz,2H),7.99(s,1H),7.89(d,J＝2.2Hz,1H),7.87(d,J＝2.1Hz,1H),7.84(s,1H),7.41-7.30(m,2H),5.02(d,J＝3.2Hz,1H),4.37(s,1H),3.76-3.71(m,3H),3.56-3.51(m,1H),2.00-1.84(m,2H)。
Example 29 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (3- (4-fluorophenyl) thioureido) -6- (3-) Hydroxypyrrolidin-1-yl) nicotinamide (Compound 29)
Figure BDA0003790398760000173
Referring to the procedure of example 23, substituting isothiocyano 4-nitrophenyl ester with 4-fluorophenyl isothiocyanate gave 81.9mg, yield: 29.7 percent. LC-MS (ESI) M/z 552.10[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.14(s,1H),9.67(s,1H),9.40(s,1H),8.69(d,J＝2.2Hz,1H),7.93(s,1H),7.92-7.85(m,2H),7.44(s,2H),7.35-7.31(m,2H),7.18-7.14(m,2H),5.02(d,J＝3.3Hz,1H),4.36(s,1H),3.75-3.71(m,3H),3.55-3.51(m,1H),1.98-1.82(m,2H)。
EXAMPLE 30 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (3- (4- (trifluoromethyl) phenyl) thioureido) nicotinamide (Compound 30)
Figure BDA0003790398760000181
Referring to the procedure of example 23, substituting phenyl 4- (trifluoromethyl) isothiocyanate with 4-nitrophenylisothiocyano provided the product, 162.5mg, in yield: 54.0 percent. LC-MS (ESI) M/z 602.10[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.37(s,1H),10.23(s,1H),10.16(s,1H),9.62(s,1H),8.71(d,J＝2.2Hz,1H),7.95(s,1H),7.92-7.85(m,2H),7.78(s,1H),7.70(d,J＝8.5Hz,2H),7.44-7.24(m,2H),5.01(d,J＝3.3Hz,1H),4.36(s,1H),3.84-3.70(m,3H),3.56-3.51(m,1H),2.00-1.79(m,2H)。
EXAMPLE 31 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (3- (3, 5-dichlorophenyl) thioureido) 6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 31)
Figure BDA0003790398760000182
Referring to the procedure of example 23, phenyl 3, 5-dichloroisothiocyanate was substituted with isothiocyano 4-nitrophenyl ester to give compound 31. LC-MS (ESI) M/z 602.03[ M + H ]] + 。
EXAMPLE 32 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (3- (4-methoxyphenyl) thioureido) nicotinamide (Compound 32)
Figure BDA0003790398760000183
Referring to the procedure of example 23, isothiocyano 4-nitrophenyl ester was replaced with 4-methoxyphenyl isothiocyanate to provide compound 32. LC-MS (ESI) M/z 548.15[ M + H ]] + 。
EXAMPLE 33 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) -6-fluoropyridinamide (Compound 33)
Figure BDA0003790398760000184
Referring to the procedure of example 15, replacing o-nitrobenzoic acid with 2-fluoropyridine-6-carboxylic acid gave 40.0mg of final product in yield: 15.3 percent. LC-MS (ESI) M/z 522.11[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.48(s,1H),10.19(s,1H),8.70(d,J＝2.3Hz,1H),8.25(t,J＝7.9Hz,1H),8.09(d,J＝2.1Hz,1H),7.98(d,J＝2.3Hz,1H),7.90-7.86(m,2H),7.58-7.49(m,1H),7.42-7.30(m,2H),4.95(d,J＝3.3Hz,1H),4.29(s,1H),3.67-3.61(m,3H),3.46-3.42(m,1H),1.93-1.75(m,2H)。
EXAMPLE 34 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) -5-fluoropyridinamide (Compound 34)
Figure BDA0003790398760000191
Referring to the procedure of example 15, substituting o-nitrobenzoic acid for 5-fluoro-2-pyridinecarboxylic acid, 53.0mg of the product was finally obtained in yield: 20.3 percent. LC-MS (ESI) M/z 522.12[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.52(s,1H),10.19(s,1H),8.76(d,J＝2.8Hz,1H),8.70(d,J＝2.4Hz,1H),8.22-8.16(m,1H),7.99-7.94(m,2H),7.94-7.84(m,2H),7.34(d,J＝8.5Hz,2H),4.94(d,J＝3.3Hz,1H),4.28(s,1H),3.68-3.64(m,3H),3.46-3.42(m,1H),1.98-1.68(m,2H)。
EXAMPLE 35 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) -3-fluoropyridinamide (Compound 35)
Figure BDA0003790398760000192
Referring to the procedure of example 15, replacing o-nitrobenzoic acid with 3-fluoropyridine-2-carboxylic acid gave 128.0mg of final product in yield: 49.12 percent. LC-MS (ESI) M/z 522.11[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.46(s,1H),10.22(s,1H),8.71(d,J＝2.3Hz,1H),8.59-8.57(m,1H),7.99-7.96(m,1H),7.97-7.92(m,1H),7.91-7.85(m,2H),7.77-7.73(m,1H),7.38-7.32(m,2H),4.97(d,J＝3.3Hz,1H),4.31(s,1H),3.73-3.65(m,3H),3.50-3.45(m,1H),1.95-1.79(m,2H)。
EXAMPLE 36 preparation of (R) -5- (2-Bromoiisonicotinamide) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrazine Pyrrolidin-1-yl) nicotinamide (compound 36)
Figure BDA0003790398760000193
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with 2-bromo-4-pyridinecarboxylic acid to give compound 36. LC-MS (ESI) M/z 582.03[ M + H ]] + 。
Example 37 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (6- (trifluoromethyl) nicotinamide (Compound 37)
Figure BDA0003790398760000201
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with 6-trifluoromethylnicotinic acid to finally obtain compound 37. LC-MS (ESI) M/z 572.11[ M + H ]] + 。
Example 38 preparation of (R) -2, 6-dichloro-N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-Hydroxypyrrolidin-1-yl) pyridin-3-yl) nicotinamide (Compound 38)
Figure BDA0003790398760000202
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with 2, 6-dichloronicotinic acid to give compound 38. LC-MS (ESI) M/z 572.05[ M + H ]] + 。
Example 39 preparation of (R) -3, 5-dichloro-N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrolidin-1-yl) pyridin-3-yl) picolinamide (Compound 39)
Figure BDA0003790398760000203
Referring to the procedure of example 15, the o-nitrobenzoic acid was replaced with 1H-benzimidazole-2-carboxylic acid to give 78.0mg of the final product in yield: 27.3 percent. LC-MS (ESI) M/z 572.03[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.45(s,1H),10.27(s,1H),8.77(d,J＝2.0Hz,1H),8.73(d,J＝2.3Hz,1H),8.46(d,J＝2.0Hz,1H),7.96(d,J＝2.4Hz,1H),7.92-7.86(m,2H),7.38-7.31(m,2H),4.98(d,J＝3.3Hz,1H),4.34(s,1H),3.79-3.71(m,3H),3.52-3.47(m,1H),1.95-1.83(m,2H)。
EXAMPLE 40 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) -6-hydroxypicolinamide (Compound 40)
Figure BDA0003790398760000204
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with 6-hydroxypyridine-2-carboxylic acid to finally obtain compound 40. LC-MS (ESI) M/z 520.12[ M + H ]] + 。
EXAMPLE 41 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) pyrimidine-2-carboxamides (Compound 41)
Figure BDA0003790398760000211
Referring to the procedure of example 15, substitution of o-nitrobenzoic acid for pyrimidine-2-carboxylic acid ultimately provided compound 41. LC-MS (ESI) M/z 505.12[ M + H ]] + 。
EXAMPLE 42 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) pyrazine-2-carboxamide (Compound 42)
Figure BDA0003790398760000212
By following the procedure of example 15, o-nitrobenzoic acid was replaced with 2-pyrazine formate to obtain compound 42. LC-MS (ESI) M/z 505.13[ M + H ]] + 。
EXAMPLE 43 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) pyrimidine-4-carboxamide (Compound 43)
Figure BDA0003790398760000213
By following the procedure of example 15, o-nitrobenzoic acid was replaced with 4-pyrimidinecarboxylic acid to obtain compound 43. LC-MS (ESI) M/z 505.12[ M + H ]] + 。
EXAMPLE 44 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (Smoke Amide) Nicotinamide (Compound 44)
Figure BDA0003790398760000214
Referring to the procedure of example 15, substitution of o-nitrobenzoic acid for nicotinic acid resulted in the final preparation of compound 44. LC-MS (ESI) M/z 504.12[ M + H ]] + 。
EXAMPLE 45 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (iso-propyl) phenyl Nicotinamide) nicotinamide (compound 45)
Figure BDA0003790398760000215
Compound 45 was finally obtained by replacing o-nitrobenzoic acid with isonicotinic acid according to the procedure of example 15. LC-MS (ESI) M/z 504.13[ M + H ]] + 。
EXAMPLE 46 preparation of (R) -5-bromo-N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxy PYRROLIDIN-1-YL) PYRIDIN-3-YL) -2- (METHYLTHIO) PYRIMIDINE-4-CARBOXAMIDE (COMPOUND 46)
Figure BDA0003790398760000221
Referring to the procedure of example 15, the o-nitrobenzoic acid was replaced with 5-bromo-2- (methylthio) -4-pyrimidinecarboxylic acid to give 96.0mg of the final product in yield: 30.5 percent. LC-MS (ESI) M/z 629.02[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.55(s,1H),10.29(s,1H),9.02(s,1H),8.74(d,J＝2.2Hz,1H),7.94(d,J＝2.3Hz,1H),7.91-7.86(m,2H),7.35(d,J＝8.7Hz,2H),5.00(d,J＝3.3Hz,1H),4.35(s,1H),3.78-3.74(m,3H),3.57-3.52(m,1H),2.60(s,3H),1.99-1.83(m,2H)。
EXAMPLE 47 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) -5-methylpyrazine-2-carboxamide (Compound 47)
Figure BDA0003790398760000222
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid for 5-methylpyrimidine-2-carboxylic acid provided 89.0mg of the final product in yield: 34.3 percent. LC-MS (ESI) M/z 519.13[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.61(s,1H),10.20(s,1H),9.15(d,J＝1.4Hz,1H),8.73(d,J＝1.4Hz,1H),8.71(d,J＝2.3Hz,1H),7.99(d,J＝2.3Hz,1H),7.92-7.85(m,2H),7.37-7.32(m,2H),4.95(s,1H),4.27(s,1H),3.73-3.64(m,3H),3.46-3.41(m,1H),2.65(s,3H),1.94-1.75(m,2H)。
EXAMPLE 48 preparation of (R) -N- (4- (chlorodifluoro)Methoxy) phenyl) -5- (cyclopropanecarboxamido) -6- (3-hydroxy Pyrrolidin-1-yl) nicotinamide (Compound 48)
Figure BDA0003790398760000223
To a reaction flask were added compound 1g (200mg, 0.5mmol), triethylamine (TEA, 50.7mg, 0.75mmol), cyclopropylcarbonyl chloride (104.9mg, 1mmol) and 3mL anhydrous acetonitrile. Stirred at room temperature for 2 hours, purified by silica gel column chromatography to give 23.3mg, yield: 9.9 percent. LC-MS (ESI) M/z 467.12[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.17(s,1H),9.40(s,1H),8.64(d,J＝2.3Hz,1H),7.91-7.85(m,2H),7.83(d,J＝2.3Hz,1H),7.34-7.31(m,2H),4.97(d,J＝3.3Hz,1H),4.32(s,1H),3.73-3.56(m,3H),3.41(m,1H),3.24-3.17(m,1H),2.31-2.08(m,4H),2.05-1.69(m,2H)。
EXAMPLE 49 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (cyclobutanecarboxamido) -6- (3-hydroxy Pyrrolidin-1-yl) nicotinamide (compound 49)
Figure BDA0003790398760000231
Referring to the procedure of example 48, substituting cyclopropylcarbonyl chloride for cyclobutylcarbonyl chloride, the final product was prepared in 53.0mg, yield: 22.0 percent. LC-MS (ESI) M/z 481.15[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.17(s,1H),9.82(s,1H),8.64(s,1H),7.87(d,J＝9.9Hz,3H),7.34(d,J＝8.5Hz,2H),5.00(d,J＝2.9Hz,1H),4.35(s,1H),3.70-3.65(m,3H),3.45(d,J＝11.8Hz,1H),3.24-3.18(m,1H),2.31-2.08(m,4H),2.05-1.76(m,4H)。
EXAMPLE 50 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (cyclopentanecarboxamido) -6- (3-hydroxy Pyrrolidin-1-yl) nicotinamide (compound 50)
Figure BDA0003790398760000232
Referring to the procedure of example 48, substituting cyclopropylcarbonyl chloride for cyclopentylcarbonyl chloride yielded the final product 130.0mg, yield: 52.6 percent. LC-MS (ESI) M/z 495.16[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.19(d,J＝4.1Hz,1H),9.52(d,J＝3.6Hz,1H),8.64(dt,J＝3.9,2.3Hz,1H),7.89-7.85(m,3H),7.35(d,J＝9.2Hz,2H),5.00-4.97(m,1H),4.34(s,1H),3.69(d,J＝9.0Hz,3H),3.44(d,J＝11.6Hz,1H),2.79-2.72(m,1H),1.97-1.80(m,4H),1.79-1.62(m,4H),1.61-1.50(m,2H)。
EXAMPLE 51 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (cyclohexanecarboxamido) -6- (3-hydroxy Pyrrolidin-1-yl) nicotinamide (Compound 51)
Figure BDA0003790398760000233
Referring to the procedure of example 48, substituting cyclopropylcarbonyl chloride for cyclohexylcarbonyl chloride, the final product was prepared in 18.0mg, yield: 7.3 percent. LC-MS (ESI) M/z 509.18[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.20(d,J＝4.2Hz,1H),9.44(d,J＝4.1Hz,1H),8.69-8.60(m,1H),7.86-7.83(m,2H),7.77(q,J＝2.4Hz,1H),7.38-7.30(m,2H),4.97(s,1H),4.33(s,1H),3.67(d,J＝13.2Hz,3H),3.43(d,J＝11.7Hz,1H),2.34(s,1H),1.94-1.58(m,8H),1.47-1.12(m,4H)。
EXAMPLE 52 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (cycloheptanecarboxamido) -6- (3-hydroxy Pyrrolidin-1-yl) nicotinamide (compound 52)
Figure BDA0003790398760000234
Referring to the procedure of example 48, cyclopropylcarbonyl chloride was substituted for cycloheptylcarbonyl chloride to afford compound 52. LC-MS (ESI) M/z 523.17[ M + H ]] + 。
EXAMPLE 53 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (tetra-N-ethyl) phenyl Hydrogen-2H-pyran-4-carboxamido) nicotinamide (Compound 53)
Figure BDA0003790398760000241
Referring to the procedure of example 15, the o-nitrobenzoic acid was replaced with tetrahydropyran-4-carboxylic acid to give 92.0mg of the final product in yield: 36.0 percent. LC-MS (ESI) M/z 511.16[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d6)δ10.20(s,1H),9.53(s,1H),8.65(d,J＝2.3Hz,1H),7.90-7.84(m,2H),7.79(d,J＝2.2Hz,1H),7.34(d,J＝8.8Hz,2H),4.98(d,J＝3.2Hz,1H),4.34(s,1H),3.97-3.88(m,2H),3.65-3.61(m,3H),3.47-3.38(m,1H),3.32-3.27(m,2H),2.66-2.54(m,1H),1.90-1.64(m,6H)。
EXAMPLE 54 preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- ((R) -3-hydroxypyrrolidin-1-yl) -5- (tetra-N-methyl-pyrrolidine Hydrofuran-2-carboxamido) nicotinamide (compound 54)
Figure BDA0003790398760000242
Referring to the procedure of example 48, substituting cyclopropanecarbonyl chloride with tetrahydrofuran-2-carbonyl chloride provided the final product, 55.0mg, yield: 22.17 percent. LC-MS (ESI) M/z 497.13[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.19(s,1H),9.55(d,J＝2.7Hz,1H),8.66(d,J＝2.2Hz,1H),7.91-7.86(m,2H),7.83(t,J＝2.9Hz,1H),7.34(d,J＝8.8Hz,2H),4.99(t,J＝3.0Hz,1H),4.41-4.37(m,1H),4.33(s,1H),4.06-3.94(m,1H),3.84-3.80(m,1H),3.72-3.61(m,3H),3.45(t,J＝11.2Hz,1H),2.23-2.18(m,1H),2.01-1.93(m,1H),1.89-1.75(m,4H)。
EXAMPLE 55 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) -6-methylpyridinoylAmine (Compound 55)
Figure BDA0003790398760000243
Referring to the procedure of example 15, replacing o-nitrobenzoic acid with 6-methyl-2-pyridinecarboxylic acid gave 128.0mg of the final product in yield: 49.5 percent. LC-MS (ESI) M/z 518.14[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.42(s,1H),10.21(s,1H),8.69(d,J＝2.3Hz,1H),8.12(d,J＝2.2Hz,1H),7.95(d,J＝1.9Hz,1H),7.94(s,1H),7.92-7.87(m,2H),7.56-7.52(m,1H),7.34(d,J＝10.8Hz,2H),4.96(d,J＝3.4Hz,1H),4.30(s,1H),3.71-3.67(m,3H),3.47-3.43(m,1H),2.62(s,3H),1.98-1.76(m,2H)。
EXAMPLE 56 preparation of N- {4- [ (chlorodifluoromethyl) oxy]Phenyl } -4- [ (3R) -3-hydroxytetrahydro-1H-pyrrole- 1-radical]-3- [ (1H-pyrrol-2-ylcarbonyl) amino]Benzamide (Compound 56)
Figure BDA0003790398760000244
Referring to the procedure of example 15, substitution of o-nitrobenzoic acid for pyrrole-2-carboxylic acid ultimately provided compound 56. LC-MS (ESI) M/z 492.13[ M + H ]] + 。
EXAMPLE 57 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (5-hydroxyfuran-2-carboxamido) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 57)
Figure BDA0003790398760000251
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with 5-hydroxyfuran-2-carboxylic acid to finally obtain compound 57. LC-MS (ESI) M/z 509.11[ M + H ]] + 。
EXAMPLE 58 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (5-chlorofuranPyran-2-carboxamide) -6- (3- Hydroxypyrrolidin-1-yl) nicotinamide (Compound 58)
Figure BDA0003790398760000252
Referring to the procedure of example 15, replacing o-nitrobenzoic acid with 5-chloro-2-furoic acid gave 72.0mg of final product in yield: 27.3 percent. LC-MS (ESI) M/z 527.06[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.18(d,J＝3.0Hz,2H),8.71(d,J＝2.3Hz,1H),7.94(d,J＝2.3Hz,1H),7.90-7.85(m,2H),7.41(d,J＝3.6Hz,1H),7.35(d,J＝8.8Hz,2H),6.78(d,J＝3.6Hz,1H),4.98(d,J＝3.2Hz,1H),4.32(s,1H),3.67-3.62(m,3H),3.45-3.40(m,1H),1.96-1.79(m,2H)。
EXAMPLE 59 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (furan-3-carboxamido) -6- (3-hydroxy Methylpyrrolidin-1-yl nicotinamide (compound 59)
Figure BDA0003790398760000253
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with 3-furoic acid to obtain compound 59. LC-MS (ESI) M/z 493.11[ M + H ]] + 。
EXAMPLE 60 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (thia-zo-l) Phen-3-carboxamido) nicotinamide (compound 60)
Figure BDA0003790398760000254
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with 3-thiophenecarboxylic acid to give compound 60. LC-MS (ESI) M/z 509.09[ M + H ]] + 。
EXAMPLE 61 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrazinePyrrolidin-1-yl) -5- (5- Methylthiophene-2-carboxamide nicotinamide (Compound 61)
Figure BDA0003790398760000261
Referring to the procedure of example 15, the o-nitrobenzoic acid was replaced with 5-methyl-2-thiophenecarboxylic acid to give 67.0mg of the final product in yield: 25.6 percent. LC-MS (ESI) M/z 523.08[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.19(s,1H),10.05(s,1H),8.70(d,J＝2.3Hz,1H),7.96(d,J＝2.3Hz,1H),7.90-7.86(m,2H),7.77(d,J＝3.7Hz,1H),7.34-7.31(m,2H),6.94-6.92(m,1H),4.98(d,J＝3.2Hz,1H),4.31(s,1H),3.68-3.63(m,3H),3.47-3.41(m,1H),2.51(s,3H),1.93-1.79(m,2H)。
EXAMPLE 62 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (5-chlorothiophene-2-carboxamide) -6- (3- Hydroxypyrrolidin-1-yl) nicotinamide (Compound 62)
Figure BDA0003790398760000262
Referring to the procedure of example 15, replacing o-nitrobenzoic acid with 2-chlorothiophene-5-carboxylic acid gave 79.0mg of final product in yield: 29.1 percent. LC-MS (ESI) M/z 543.04[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.29(s,1H),10.19(s,1H),8.71(d,J＝2.2Hz,1H),7.98(d,J＝2.3Hz,1H),7.89-7.86(m,2H),7.85(d,J＝4.2Hz,1H),7.35(d,J＝8.7Hz,2H),7.31(d,J＝4.1Hz,1H),4.99(d,J＝3.2Hz,1H),4.32(s,1H),3.76-3.60(m,3H),3.48-3.41(m,1H),1.92-1.81(m,2H)。
Example 63 preparation of (R) -5- (4-bromothiophene-2-carboxamido) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 63)
Figure BDA0003790398760000263
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with 4-bromothiophene-2-carboxylic acid to give compound 63. LC-MS (ESI) M/z 586.98[ M + H ]] + 。
EXAMPLE 64 preparation of (R) -5- (5-bromothiophene-2-carboxamido) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 64)
Figure BDA0003790398760000264
Referring to the procedure of example 15, substituting o-nitrobenzoic acid for 5-bromo-2-carboxythiophene, 54.0mg of the product was finally obtained in yield: 18.4 percent. LC-MS (ESI) M/z 586.99[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ10.27(s,1H),10.19(s,1H),8.71(d,J＝2.3Hz,1H),7.98(d,J＝2.3Hz,1H),7.92-7.85(m,2H),7.80(d,J＝4.0Hz,1H),7.40(d,J＝4.0Hz,1H),7.37-7.32(m,2H),4.98(d,J＝3.2Hz,1H),4.31(s,1H),3.73-3.62(m,3H),3.46-3.42(m,1H),1.92-1.80(m,2H)。
EXAMPLE 65 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) thiazole-2-carboxamide (Compound 65)
Figure BDA0003790398760000271
Referring to the procedure of example 15, substituting o-nitrobenzoic acid for thiazole-2-carboxylic acid, the final product was prepared in 79.0mg, yield: 31.0 percent. LC-MS (ESI) M/z 510.08[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.64(s,1H),10.19(s,1H),8.72(d,J＝2.3Hz,1H),8.15(q,J＝3.1Hz,2H),7.99(d,J＝2.3Hz,1H),7.92-7.84(m,2H),7.39-7.31(m,2H),4.97(d,J＝3.3Hz,1H),4.30(s,1H),3.74-3.66(m,3H),3.49-3.42(m,1H),1.95-1.78(m,2H)。
Example 66 preparation of (R) -N-(5- ((4- (Chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) -2-methylthiazole-5-carboxamide (Compound 66)
Figure BDA0003790398760000272
Referring to the procedure of example 15, substitution of o-nitrobenzoic acid for 2-methylthiazole-5-carboxylic acid ultimately provided compound 66. LC-MS (ESI) M/z 524.09[ M + H ]] + 。
EXAMPLE 67 preparation of (R) -2-bromo-N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxy PYRROLIDIN-1-YL) PYRIDIN-3-YL) THIAZOLE-5-CARBOXAMIDE (COMPOUND 67)
Figure BDA0003790398760000273
Referring to the procedure of example 15, replacing o-nitrobenzoic acid with 2-bromo-4-thiazolecarboxylic acid produced 74.0mg of product in final yield: 25.2 percent. LC-MS (ESI) M/z 587.98[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.31(s,1H),10.18(s,1H),8.70(d,J＝2.3Hz,1H),8.46(s,1H),7.93(d,J＝2.2Hz,1H),7.91-7.86(m,2H),7.39-7.29(m,2H),4.96(d,J＝3.3Hz,1H),4.30(s,1H),3.73-3.60(m,3H),3.45-3.41(m,1H),1.95-1.77(m,2H)。
EXAMPLE 68 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridinePyridin-3-yl) isoxazole-5-carboxamides (Compound 68)
Figure BDA0003790398760000274
Referring to the procedure of example 15, replacing o-nitrobenzoic acid with isoxazole-5-carboxylic acid gave 53.0mg of final product in yield: 21.5 percent. LC-MS (ESI) M/z 494.11[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.70(s,1H),10.20(s,1H),8.86(d,J＝1.9Hz,1H),8.73(d,J＝2.3Hz,1H),8.00(d,J＝2.2Hz,1H),7.93-7.83(m,2H),7.35-7.31(m,1.0Hz,2H),7.27(d,J＝2.0Hz,1H),4.99(d,J＝3.3Hz,1H),4.32(s,1H),3.66-3.61(m,3H),3.46-3.41(m,1H),1.97-1.79(m,2H)。
EXAMPLE 69 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (1H- Pyrazole-4-carboxamide nicotinamide (Compound 69)
Figure BDA0003790398760000281
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with 1H-pyrazole-4-carboxylic acid to give compound 69. LC-MS (ESI) M/z 493.12[ M + H ]] + 。
EXAMPLE 70 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (1H- Pyrazole-3-carboxamide nicotinamide (Compound 70)
Figure BDA0003790398760000282
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with pyrazole-3-carboxylic acid to give compound 70. LC-MS (ESI) M/z 493.12[ M + H ]] + 。
EXAMPLE 71 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (1- methyl-1H-pyrazole-4-carboxamido) nicotinamide (Compound 71)
Figure BDA0003790398760000283
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with 1-methylpyrazole-4-carboxylic acid to give compound 71. LC-MS (ESI) M/z 507.14[ M + H ]] + 。
EXAMPLE 72 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (1- methyl-1H-imidazole-4-carboxamido) nicotinamide (compound 72)
Figure BDA0003790398760000284
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with 1-methyl-4-imidazolecarboxylic acid to give compound 72. LC-MS (ESI) M/z 507.13[ M + H ]] + 。
EXAMPLE 73 preparation of (R) -5- (benzo [ b ]]Thiophene-2-carboxamido) -N- (4- (chlorodifluoromethoxy) phenyl) - 6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 73)
Figure BDA0003790398760000291
Referring to the procedure of example 15, substitution of o-nitrobenzoic acid for benzothiophene-2-carboxylic acid provided 67.0mg of the final product in yield: 24.0 percent. LC-MS (ESI) M/z 559.09[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.48(s,1H),10.22(s,1H),8.74(d,J＝2.3Hz,1H),8.30(s,1H),8.12-8.06(m,1H),8.04(s,1H),8.02(d,J＝2.2Hz,1H),7.92-7.85(m,2H),7.55-7.45(m,2H),7.39-7.28(m,2H),4.98(d,J＝3.2Hz,1H),4.31(s,1H),3.78-3.65(m,J＝4.1Hz,3H),3.51-3.45(m,1H),2.00-1.74(m,2H)。
EXAMPLE 74 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) -1H-indole-2-carboxamides (Compound 74)
Figure BDA0003790398760000292
By reference to the procedure of example 15, o-nitrobenzoic acid was substitutedTo obtain the 2-indole carboxylic acid, and finally obtaining the product 78.0mg with the yield: 28.8 percent. LC-MS (ESI) M/z 542.12[ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )δ11.77(s,1H),10.22(s,1H),10.17(s,1H),8.73(d,J＝2.3Hz,1H),8.03(d,J＝2.2Hz,1H),7.94-7.85(m,2H),7.68(d,J＝8.0Hz,1H),7.47-7.42(m,1H),7.37-7.34(m,3H),7.23-7.19(m,1H),7.08-7.05(m,1H),4.96(d,J＝3.3Hz,1H),4.30(s,1H),3.71-3.67(m,3H),3.50-3.45(m,1H),1.90-1.80(m,2H)。
EXAMPLE 75 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) -1H-indazole-3-carboxamide (Compound 75)
Figure BDA0003790398760000293
Referring to the procedure of example 15, substituting o-nitrobenzoic acid for indazole-3-carboxylic acid, the final product was prepared in 46.0mg, yield: 16.9 percent. LC-MS (ESI) M/z 543.13[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ13.79(s,1H),10.20(d,J＝5.5Hz,2H),8.71(d,J＝2.3Hz,1H),8.19(m,1H),8.03(d,J＝2.3Hz,1H),7.92-7.88(m,2H),7.68-7.62(m,1H),7.46-7.42(m,1H),7.37-7.32(m,2H),7.29-7.26(m,1H),4.94(d,J＝3.3Hz,1H),4.28(s,1H),3.74-3.71(m,3H),3.58-3.48(m,1H),1.94-1.77(m,2H)。
EXAMPLE 76 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) -1H-benzo [ d]Imidazole-2-carboxamide (Compound 76)
Figure BDA0003790398760000294
Referring to the procedure of example 15, the o-nitrobenzoic acid was replaced with 1H-benzimidazole-2-carboxylic acid to give 37.0mg of the final product in yield: 13.6 percent. LC-MS (ESI) M/z 543.13[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ13.46(s,1H),10.78(s,1H),10.21(s,1H),8.73(d,J＝2.2Hz,1H),8.01(d,J＝2.3Hz,1H),7.92-7.85(m,2H),7.82(d,J＝7.8Hz,1H),7.59(d,J＝7.8Hz,1H),7.38-7.32(m,4H),4.95(d,J＝3.4Hz,1H),4.29(s,1H),3.75-3.69(m,3H),3.51-3.46(m,1H),1.92-1.78(m,2H)。
EXAMPLE 77 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (5-hydroxynicotinamide) -6- (3-hydroxypyrazine Pyrrolidin-1-yl) nicotinamide (compound 77)
Figure BDA0003790398760000301
By following the procedure of example 15, o-nitrobenzoic acid was replaced with 5-hydroxynicotinic acid to obtain compound 77. LC-MS (ESI) M/z 520.12[ M + H ]] + 。
EXAMPLE 78 preparation of (R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole Alk-1-yl) pyridin-3-yl) -4-fluoropyridinamides (Compound 78)
Figure BDA0003790398760000302
Referring to the procedure of example 15, replacing o-nitrobenzoic acid with 5-fluoro-2-pyridinecarboxylic acid gave 57.0mg of the final product in yield: 21.8 percent. LC-MS (ESI) M/z 522.11[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.53(s,1H),10.19(s,1H),8.76(d,J＝2.8Hz,1H),8.70(d,J＝2.2Hz,1H),8.22-8.20(m,1H),8.01-8.98(m,2H),7.91-7.86(m,2H),7.34(d,J＝8.8Hz,2H),4.94(d,J＝3.3Hz,1H),4.28(s,1H),3.68-3.65(m,3H),3.46-3.42(m,1H),1.96-1.74(m,2H)。
EXAMPLE 79 preparation of (R) -4-chloro-N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxyj-ydroxygen) Pyrrolidin-1-yl) pyridin-3-yl) picolinamide (Compound 79)
Figure BDA0003790398760000303
Referring to the procedure of example 15, replacing o-nitrobenzoic acid with 4-chloro-2-pyridinecarboxylic acid gave 88.0mg of the final product in yield: 32.7 percent. LC-MS (ESI) M/z 538.08[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.65(s,1H),10.20(s,1H),8.75-8.71(m,1H),8.71(d,J＝2.3Hz,1H),8.14-8.11(m,1H),8.00(d,J＝2.3Hz,1H),7.89(d,J＝2.2Hz,1H),7.87(d,J＝1.3Hz,2H),7.34-7.31(m,2H),4.94(d,J＝3.3Hz,1H),4.28(s,1H),3.68-3.62(m,3H),3.47(s,1H),1.93-1.77(m,2H)。
EXAMPLE 80 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (2-chloroisonicotinamide) -6- (3-hydroxypyrazine Pyrrolidin-1-yl) nicotinamide (compound 80)
Figure BDA0003790398760000311
Referring to the procedure of example 15, replacing o-nitrobenzoic acid with 2-chloroisonicotinic acid gave 93.0mg of final product in yield: 34.6 percent. LC-MS (ESI) M/z 538.07[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.56(s,1H),10.22(s,1H),8.74(d,J＝2.2Hz,1H),8.67-8.65(m,1H),8.02-8.00(m,1H),7.99(d,J＝2.3Hz,1H),7.92-7.90(m,1H),7.90-7.86(m,2H),7.39-7.28(m,3H),4.97(d,J＝3.2Hz,1H),4.31(s,1H),3.65-3.62(m,3H),3.44-3.41(m,1H),1.92-1.80(m,2H)。
EXAMPLE 81 preparation of (R) -3-chloro-N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxy PYRROLIDIN-1-YL) PYRIDIN-3-YL) PYRIDINE AMIDE (COMPOUND 81)
Figure BDA0003790398760000312
Referring to the procedure of example 15, the o-nitrobenzoic acid was replaced with 3-chloro-2-pyridinecarboxylic acid to give 48.0mg of the final product in yield: 17.8 percent. LC-MS (ESI) M/z 538.08[ M +H] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.41(s,1H),10.27(s,1H),8.72(d,J＝2.3Hz,1H),8.66-8.63(m,1H),8.13-8.11(m,1H),7.96(d,J＝2.2Hz,1H),7.89(d,J＝9.1Hz,2H),7.64-7.61(m,1H),7.35-7.32(m,2H),4.99(d,J＝3.3Hz,1H),4.34(s,1H),3.77-3.72(m,,3H),3.54-3.50(m,1H),1.97-1.82(m,2H)。
EXAMPLE 82 preparation of (R) -6-bromo-N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxy PYRROLIDIN-1-YL) PYRIDIN-3-YL) PYRIDINE AMIDE (COMPOUND 82)
Figure BDA0003790398760000313
Referring to the procedure of example 15, replacing o-nitrobenzoic acid with 6-bromo-2-pyridinecarboxylic acid gave 65.0mg of final product in yield: 22.4 percent. LC-MS (ESI) M/z 582.03[ M + H ]] + ； 1 H-NMR(300MHz,DMSO-d 6 )δ10.45(s,1H),10.19(s,1H),8.70(d,J＝2.3Hz,1H),8.14-8.11(m,1H),8.03-8.00(m,2H),8.00-7.93(m,1H),7.91-7.85(m,2H),7.34(m,2H),4.96(d,J＝3.3Hz,1H),4.30(s,1H),3.74-3.64(m,3H),3.45-3.41(m,1H),1.95-1.79(m,2H)。
EXAMPLE 83 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (6- Methylnicotinamide) nicotinamide (compound 83)
Figure BDA0003790398760000321
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with 6-methylnicotinic acid to obtain compound 83. LC-MS (ESI) M/z 518.13[ M + H ]] + 。
Biological activity assay
Example 84 in vitro tumor cell (K562, KBM5) antiproliferative Activity assay
1. Experiments were performed on K562, KBM5 human chronic myelogenous leukemia cell line in 1640+ 10% FBS (Gibco) complete mediumAt 37 ℃ and 5% CO 2 Suspension culture in 95% humidity.
2. The following is a general experimental method: taking logarithmically growing K562 and KBM5 cells, centrifuging to obtain cell precipitates, adding a fresh culture medium for resuspension, performing staining counting on a platform blue, diluting the cells to a proper concentration, taking 50uL of the cells, respectively planting the cells in a 96-well plate at 3000 cells/well, and placing the cell plate in a carbon dioxide incubator for overnight culture; test compound stocks were prepared at 10mM DMSO stock for all compounds, stored at-80 ℃ and dispensed for use. Diluting the compound mother liquor to a proper concentration by using a culture medium according to the required working concentration, adding 50uL of a compound solution to be detected into a cell hole, and setting three multiple holes for each compound to be detected; the cell plates were placed in a carbon dioxide incubator for 3 additional days.
3. Reading the plate at the end: 10uL Cell Counting Kit-8 reagent is incubated for 2-4 hours at room temperature in each well, the absorbance value is read by an enzyme-labeling instrument at 450nm, and the Cell growth inhibition efficiency is calculated.
4. Data processing
Data were analyzed using GraphPad Prism 9.0 software, and dose-effect curves were derived by fitting the data using nonlinear sigmoidal regression, and IC was calculated therefrom 50 The value is obtained. Cell survival rate (%) { (OD test drug-OD culture medium control)/(OD cell control-OD culture medium control) } × 100%.
The results of the in vitro antiproliferative activity preliminary screening of the cells in the examples are summarized in Table 2 below.
TABLE 2 cytotoxic Effect of the preliminary screening of the Compounds of the examples
Figure BDA0003790398760000322
Figure BDA0003790398760000331
Figure BDA0003790398760000341
As shown in Table 2, the experimental results show that the compounds of the invention all have certain anti-tumor cell (K562/KBM5) proliferation activity. Of these, compounds 16, 33, 35 and 67 showed significant antiproliferative activity against K562 and KBM 5. From the above examples, it is clear that some of the (hetero) arylamides of the present invention can exert a good antiproliferative effect on human chronic myelogenous leukemia cell lines K562, KBM5, and can be used to prepare drugs for treating cancers such as chronic myelogenous leukemia and acute myelogenous leukemia.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims (10)

1. A compound of formula I:
Figure FDA0003790398750000011
or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein:
y is selected from CH or N;
R 1 independently selected from hydrogen, halogen, nitrile group and hydroxyl, and can be mono, bi or polysubstituted;
R 2 is selected from-CF 2 -Y 1 ；
Y 1 Selected from hydrogen, chloro, fluoro, methyl, difluoromethyl and trifluoromethyl;
z is selected from the group consisting of a bond, O and S (O) 0-2 ；
or-Z-R 2 Together represent-SF 5 ；
Het is pyrrolidinyl; wherein said pyrrolidinyl is substituted with 1 or more R a Substituted by groups;
R a selected from hydrogen, hydroxy, methyl, halogen, methoxy, hydroxy-methyl, ammoniaMethyl-amino, amino-methyl, trifluoromethyl, cyano and amino-carbonyl;
link is urea, thiourea,
Figure FDA0003790398750000012
Figure FDA0003790398750000013
R 3 Is composed of
Figure FDA0003790398750000014
Wherein X 1 -X 9 Independently selected from CR c Or N, and X 6 ，X 7 ，X 8 And X 9 One of them being a mother-nuclear-bound C atom, X 10 Selected from O, S or NR b ，X 11 Selected from O, S, NR b Or C (R) c ) 2 ；
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3, 4, 5, 6 or 7;
R b independently selected from hydrogen, acetyl, C 1-6 Alkyl or C 1-6 A haloalkyl group;
r and R c Independently selected from hydrogen, halogen, nitrile group, nitro group, hydroxyl group, aldehyde group, carboxyl group, acetamido group, ethoxycarbonyl group, aminoacyl group and-NH 2 、-NHC 1-6 Alkyl, -N (C) 1-6 Alkyl radical) 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Haloalkoxy, C 3-7 Heterocycloalkyl radical, C 6-10 Aryl or C 5-10 A heteroaryl group;
or two R groups on the same atom or on adjacent atoms may together form C 3-7 Cycloalkyl radical, C 3-7 Heterocycloalkyl radical, C 6-10 Aryl or C 5-10 A heteroaryl group;
the halogen is F, Cl or Br.
2. The compound of claim 1, having formula (II):
Figure FDA0003790398750000015
or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein:
R 1 independently selected from hydrogen, halogen, nitrile group and hydroxyl, and can be mono, bi or polysubstituted;
R a independently selected from hydrogen, hydroxyl, halogen, nitrile group and carboxyl, and can be mono, bi or polysubstituted;
link is urea, thiourea,
Figure FDA0003790398750000021
Figure FDA0003790398750000022
R 3 Is composed of
Figure FDA0003790398750000023
Wherein X 1 -X 9 Independently selected from CR c Or N, and X 6 ,X 7 ,X 8 And X 9 One of them being a mother-nuclear-bound C atom, X 10 Selected from O, S or NR b ，X 11 Selected from O, S, NR b Or C (R) c ) 2 ；
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3, 4, 5, 6 or 7;
R b independently selected from hydrogen, acetyl, C 1-6 Alkyl or C 1-6 A haloalkyl group;
r and R c Independently selected from hydrogen, halogen, nitrile group, nitro group, hydroxyl group, aldehyde group, carboxyl group, acetamido group, ethoxycarbonyl group and aminoacyl groupRadical, -NH 2 、-NHC 1-6 Alkyl, -N (C) 1-6 Alkyl radical) 2 、C 1-6 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylthio radical, C 1-6 Haloalkoxy, C 3-7 Heterocycloalkyl radical, C 6-10 Aryl or C 5-10 A heteroaryl group;
two R groups on either the same atom or on adjacent atoms may together form C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl radical, C 6-10 Aryl or C 5-10 A heteroaryl group;
the halogen is F, Cl or Br.
3. The compound of claim 2, wherein:
the R is 1 Independently selected from hydrogen and halogen;
R a independently selected from hydrogen and hydroxyl;
link is urea, thiourea,
Figure FDA0003790398750000024
R b Independently selected from hydrogen, acetyl, C 1-3 Alkyl or C 1-3 A haloalkyl group;
r and R c Independently selected from hydrogen, halogen, nitrile group, nitro group, hydroxyl group, aldehyde group, carboxyl group, acetamido group, ethoxycarbonyl group, aminoacyl group and-NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl radical) 2 、C 1-3 Alkyl radical, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy radical, C 1-3 Alkylthio radical, C 1-3 Haloalkoxy, C 3-7 Heterocycloalkyl radical, C 6-10 Aryl or C 5-10 A heteroaryl group;
or two R groups on the same atom or on adjacent atoms may together form C 3-7 Cycloalkyl radical, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 A heteroaryl group.
4. The compound of claim 1, having formula (III):
Figure FDA0003790398750000025
or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein:
R a independently selected from hydrogen and hydroxyl;
link is urea, thiourea,
Figure FDA0003790398750000026
R 3 Selected from the following groups optionally substituted with one, two or three R:
Figure FDA0003790398750000031
R b independently selected from hydrogen, acetyl or C 1-3 An alkyl group;
r is independently selected from hydrogen, halogen, nitrile group, nitryl, hydroxyl, aldehyde group, carboxyl, acetamido, ethoxycarbonyl, aminoacyl and-NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl radical) 2 、C 1-3 Alkyl radical, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy radical, C 1-3 Alkylthio radical, C 1-3 Haloalkoxy, C 3-7 Heterocycloalkyl radical, C 6-10 Aryl or C 5-10 A heteroaryl group.
5. The compound of claim 4,
the R is a Is a hydroxyl group;
link is thiourea,
Figure FDA0003790398750000032
R is independently selected from hydrogen, halogen, nitrile group, nitro group, hydroxyl group, aldehyde group, carboxyl group, acetamido group, ethoxycarbonyl group, aminoacyl group and-NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl radical) 2 、C 1-3 Alkyl radical, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy radical, C 1-3 Alkylthio radical, C 1-3 A haloalkoxy group.
6. The compound according to any one of claims 2-5, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, selected from:
Figure FDA0003790398750000033
Figure FDA0003790398750000041
Figure FDA0003790398750000051
Figure FDA0003790398750000061
Figure FDA0003790398750000071
7. a process for the preparation of a compound of formula (XI) comprising the steps of:
Figure FDA0003790398750000072
(1) preparation of intermediate (V)
Dissolving 2-amino-5-methylpyridine (IV) in concentrated sulfuric acid, and adding a mixture of the two in a volume ratio of 1:1, heating the mixed acid solution of concentrated sulfuric acid and concentrated nitric acid to 55 ℃, pouring the reaction solution into crushed ice, adding sodium nitrite, and stirring in an ice bath to obtain an intermediate (V);
(2) preparation of intermediate (VI)
Adding 2-hydroxy-5-methyl-3-nitropyridine (V) into a reaction bottle, adding phosphorus oxychloride, and heating and refluxing for 8 hours to obtain an intermediate (VI);
(3) preparation of intermediate (VII)
Dissolving 2-chloro-5-methyl-3-nitropyridine (VI) in concentrated sulfuric acid, adding potassium dichromate in batches under an ice bath condition, and stirring at room temperature for 16h to obtain an intermediate (VII);
(4) preparation of intermediate (VIII)
6-chloro-5-nitronicotinic acid (VII) was dissolved in anhydrous DCM, and thionyl chloride (SOCl) was added 2 ) Heating and stirring for reaction for 4 hours, drying in vacuum, adding anhydrous DCM for dissolution, adding corresponding substituted aniline, and stirring for reaction at room temperature to obtain an intermediate (VIII);
(5) preparation of Intermediate (IX)
Dissolving the intermediate (VIII) in anhydrous DMSO, adding N, N-Diisopropylethylamine (DIEA) and corresponding substituted pyrrolidine, and heating to react to obtain an Intermediate (IX);
(6) preparation of intermediate (X)
Intermediate (IX) was dissolved in anhydrous MeOH and palladium on carbon (Pd/C) was added, followed by addition of hydrogen 2 Heating and reacting under the condition to obtain an intermediate (X);
(7) preparation of the desired product (XI)
A condensation reaction, which comprises the specific steps of dissolving the intermediate (X) in anhydrous acetonitrile, adding various substituted acyl chlorides, adding Triethylamine (TEA), and stirring at room temperature for 1h to obtain a target product (XI);
or an addition reaction, specifically comprising the steps of dissolving the intermediate (X) in anhydrous methanol, adding various substituted cycloalkyl ketones, heating and stirring for reaction to obtain a target product (XI);
or a reductive amination reaction is carried out on the raw materials,the preparation method comprises the following specific steps of dissolving the intermediate (X) in absolute methanol, adding various substituted cycloalkyl ketones, heating and stirring for reaction for 2 hours, and adding sodium cyanoborohydride (NaBH) 3 CN), heating to react to obtain a target product (XI);
or addition reaction, which comprises the specific steps of dissolving the intermediate (X) in absolute ethyl alcohol, adding various substituted isothiocyanates and TEA, and stirring at 80 ℃ for 4h to obtain a target product (XI);
or condensation reaction, specifically comprising the steps of dissolving the intermediate (X) in N, N-dimethylformamide, adding various substituted carboxylic acids, adding 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) and DIEA, and stirring at room temperature for 18 hours to obtain the target product (XI).
8. A pharmaceutical composition comprising a compound of any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.
9. Use of a compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for the treatment and/or prevention of a Bcr-Abl caused disease in a subject.
10. The use according to claim 9, wherein the Bcr-Abl caused disease is a proliferative disease selected from the group consisting of: solid tumors, sarcomas, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, gastrointestinal stromal tumors, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia and other proliferative or proliferative diseases; the Bcr-Abl caused disease is metastatic invasive cancer, viral infection or CNS disorder.
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