CN115109048B - (hetero) aryl amide compound - Google Patents

(hetero) aryl amide compound Download PDF

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CN115109048B
CN115109048B CN202210953698.3A CN202210953698A CN115109048B CN 115109048 B CN115109048 B CN 115109048B CN 202210953698 A CN202210953698 A CN 202210953698A CN 115109048 B CN115109048 B CN 115109048B
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CN115109048A (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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    • 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
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    • 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

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Abstract

The invention belongs to the field of medicinal chemistry, and relates to (hetero) aryl amide compounds or pharmaceutically acceptable stereoisomers thereof, or crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, which can inhibit the activity of Abelson protein (Abl 1), abelson related protein (Abl 2) and related chimeric proteins, in particular Bcr-Abl1, as well as preparation methods of the compounds, pharmaceutical compositions containing the compounds and application of the compounds or the compositions in preparation of medicaments. The compound of the invention has better Bcr-Abl kinase inhibition activity and pharmacodynamic performance, and can be used for treating and/or preventing Bcr-Abl caused diseases in subjects.

Description

(hetero) aryl amide compound
Technical Field
The invention relates to the technical field of medicines, in particular to a (hetero) aryl amide compound capable of inhibiting the tyrosine kinase enzyme activity of Abelson protein (Abl 1), abelson related protein (Abl 2) and related chimeric proteins, especially Bcr-Abl1, a pharmaceutical composition containing the (hetero) aryl amide compound, and a preparation method and application thereof.
Background
The known (hetero) aryl amide compounds are Bcr-Abl kinase inhibitory active compounds and are allosteric inhibitors of Bcr-Abl tyrosine kinase. The Bcr-Abl fusion gene is caused by the reciprocal translocation between chromosomes 9 and 22 in human hematopoietic stem cells, and the fusion of Bcr and Abl1 genes on Philadelphia chromosome (Ph). The expressed tyrosine kinase enables a series of signal paths for regulating cell growth, differentiation and death to be abnormally activated, so that the proliferation, adhesion and survival properties of cells are changed, and various tumors are generated, and therefore, the Bcr-Abl tyrosine kinase can be inhibited effectively to 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), which are ABL1 kinase allosteric inhibitors developed by the nohua pharmaceutical company, are inactivated by targeting the myristoyl pocket at the allosteric site of ABL1, and can be used in combination with ATP competitive Bcr-ABL tyrosine kinase inhibitors to effectively prevent the emergence of ATP competition inhibitors and/or drug resistance for allosteric inhibitor applications. ABL-001 has been shown to act as a radical cure for CML in a mouse model in combination with the second generation Bcr-ABL inhibitor nilotinib. North is developing a therapeutic regimen for ABL001 in combination with a number of ATP-competitive Bcr-ABL inhibitors, including imatinib, nilotinib, and dasatinib. The drug is marketed in the united states at 2021.
TGRX-678 is a fourth-generation Bcr-Abl1 allosteric inhibitor developed by Tajirui pharmaceutical company and developed in China first and the fastest development, and is also a global second-generation Bcr-Abl1 allosteric inhibitor, and the in-vitro and in-vivo clinical research results show that compared with ABL001, the activity and the selectivity of TGRX-678 on Bcr-AblT315I cells are higher, the oral bioavailability is better, and the in-vivo safety of animals is better than that of ABL001.
However, there remains a need in the art to develop compounds that have inhibitory activity, or better pharmacodynamic properties, against 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 thereof or a crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which can be used for treating/preventing Bcr-Abl caused diseases in a subject.
The invention also provides a preparation method of the (hetero) aryl amide compound and an intermediate thereof.
The invention also provides a pharmaceutical composition comprising at least one compound of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.
The invention also provides the use of the compound of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof or the pharmaceutical composition of the invention for the preparation of a medicament.
In this regard, the technical scheme adopted by the invention is as follows:
in a first aspect of the present invention there is provided a compound of formula (I), 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, hydroxy, which may be mono-, di-or polysubstituted; r is R 2 Selected from-CF 2 -Y 1 ；
Y 1 Selected from hydrogen, chlorine, fluorine, methyl, difluoromethyl and trifluoromethyl;
z is selected from the group consisting of a bond, O and S (O) 0-2 The method comprises the steps of carrying out a first treatment on the surface of the or-Z-R 2 Together represent-SF 5 ；
Het is pyrrolidinyl; wherein the pyrrolidinyl is substituted with 1 or more R a Group substitution;
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,
R 3 Is thatWherein X is 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 C atom, X, bound to the parent nucleus 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, nitro, hydroxy, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH 2 、-NHC 1-6 Alkyl, -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxy alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-7 Heterocycloalkyl group,C 6-10 Aryl or C 5-10 Heteroaryl;
Or two R groups on 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 Heteroaryl;
the halogen is F, cl or Br.
In certain preferred embodiments, formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, is disclosed:
wherein R is 1 Independently selected from hydrogen, halogen, nitrile, hydroxy, which may be mono-, di-or polysubstituted;
R a independently selected from hydrogen, hydroxy, halogen, nitrile, carboxyl, which may be mono-, di-or polysubstituted;
link is urea, thiourea,
R 3 Is that
Wherein X is 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 C atom, X, bound to the parent nucleus 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 orC 1-6 A haloalkyl group;
r and R c Independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH 2 、-NHC 1-6 Alkyl, -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxy alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl;
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 Heteroaryl;
the halogen is F, cl or Br.
Further, the R 1 Independently selected from hydrogen and halogen; r is R a Independently selected from hydrogen and hydroxy;
link is urea, thiourea,
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, nitro, hydroxy, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxy alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl;
or two R groups on 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 Heteroaryl groups.
In certain preferred embodiments, formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, is disclosed:
wherein R is a Independently selected from hydrogen and hydroxy;
link is urea, thiourea,
R 3 Selected from the following groups optionally substituted with one, two or three R:
R b Independently selected from hydrogen, acetyl or C 1-3 An alkyl group;
r is independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxy alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl groups.
Further, the R a Is hydroxyl;
link is thiourea,
R is independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxy alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy groups.
In certain more preferred embodiments, the (hetero) arylamide compounds of the present invention are any one of the compounds in table 1 below, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof:
table 1 shows some of the compounds of the invention
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:
(1) Preparation of intermediate (V): 2-amino-5-methylpyridine (IV) is dissolved in concentrated sulfuric acid, and the volume ratio of the 2-amino-5-methylpyridine (IV) to the concentrated sulfuric acid is 1:1, heating 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 ice bath condition, and stirring at room temperature for 16h to obtain an intermediate (VII);
(4) Preparation of intermediate (VIII): dissolving 6-chloro-5-nitronicotinic acid (VII) in anhydrous DCM, adding thionyl chloride (SOCl) 2 ) Heating and stirring for reaction for 4 hours, vacuum drying, adding anhydrous DCM for dissolution, then adding corresponding substituted aniline, and stirring at room temperature for reaction 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, palladium on carbon (Pd/C) was added to the mixture at H 2 Heating and reacting under the condition to obtain an intermediate (X);
(7) Preparation of the target product (XI):
the condensation reaction comprises the specific steps of dissolving an 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 to obtain a target product (XI);
or reductive amination reaction, which comprises 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 and reacting to obtain a target product (XI);
or an addition reaction, specifically comprising the steps of dissolving the intermediate (X) in absolute ethanol, adding various substituted isothiocyanates and TEA, and stirring at 80 ℃ for 4 hours to obtain a target product (XI);
or condensation reaction, specifically, the steps are that the intermediate (X) is dissolved in N, N-dimethylformamide, various substituted carboxylic acids are added, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethyl urea Hexafluorophosphate (HATU) and DIEA are added, and stirring is carried out at room temperature for 18 hours, thus obtaining the target product (XI).
In yet another aspect, the invention provides a pharmaceutical composition comprising a compound of any one of the 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 medicinal preparations such as tablets, capsules, syrup, suspending agents and injection, and can be added with common medicinal auxiliary materials such as spice, sweetener, liquid or solid filler or diluent and the like. In a specific embodiment, the compounds of the present invention are provided in the pharmaceutical composition in an effective amount. 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 the use of a compound of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate and pharmaceutical composition thereof for the manufacture of a medicament for the treatment and/or prophylaxis of a Bcr-Abl induced disease in a subject.
In a specific embodiment of the present invention, the Bcr-Abl-caused disease is a proliferative disease selected from the group consisting of: solid tumors, sarcomas, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumors, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia, and other proliferative or proliferative diseases. In a specific embodiment of the present invention, the Bcr-Abl caused disease is metastatic invasive cancer, viral infection or CNS disorder.
Pharmacological experiments show that the compound of the invention can generate good antiproliferation 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 merely illustrative of the invention and are not intended to limit the scope of what is claimed.
The structure of the compound in the invention is that the compound is prepared by Mass Spectrum (MS) and/or nuclear magnetic resonance 1 HNMR) device.
Synthesis method
The compounds of the present invention may be prepared according to methods conventional in the art, using suitable reagents, starting materials and purification methods known to those skilled in the art. The following more specifically describes the preparation method of the compound of the present invention, but these specific methods do not limit the present invention in any way. The compounds of the present invention may also be conveniently prepared by optionally combining the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present invention pertains.
Typically, in the preparation, each reaction is carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ℃ C. To 100 ℃ C., preferably 0 ℃ C. To 80 ℃ C.). The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 24 hours.
Example 1 preparation of (R, E) -5- (((5-bromothiophen-2-yl) methylene) amino) -N- (4- (chlorodifluoromethoxy) amino) Phenyl) -6- (3-Hydroxypyrrolidin-1-yl) nicotinamide (compound 1)
Step 1: synthesis of 2-hydroxy-5-methyl-3-nitropyridine (Compound 1 b).
To the reaction flask was added 300mL of concentrated sulfuric acid, 2-amino-5-methylpyridine (1 a,60.0g,554.8 mmol) was added under ice bath, 70mL of a mixed acid of concentrated sulfuric acid and concentrated nitric acid (V: V=1:1), stirred at room temperature for 1h, and then heated to 55℃and stirred for 2h. The reaction solution was poured into ice water, 77g of sodium nitrite was added in portions under ice bath, and stirred for 4 hours under heat preservation, resulting in a large amount of yellow solid. Suction filtration and filter cake drying are carried out, 45.2g of yellow solid is obtained, and the yield is: 52.9%.
Step 2: synthesis of 2-chloro-5-methyl-3-nitropyridine (Compound 1 c).
To the reaction flask was added 2-hydroxy-5-methyl-3-nitropyridine (1 b,45.2g,272.5 mmol), 750mL phosphorus oxychloride, and heated under reflux for 8h. The reaction solution is decompressed, concentrated and poured into crushed ice, a large amount of yellow solid is separated out, the product is 42.1g after suction filtration, washing and drying, and the yield is: 89.5%.
Step 3: synthesis of 6-chloro-5-nitronicotinic acid (Compound 1 d).
To the reaction flask was added 2-chloro-5-methyl-3-nitropyridine (1 c,42.1g,197.4 mmol), dissolved 500mL of concentrated sulfuric acid, stirred at room temperature, potassium dichromate (92.3 g,313.8 mmol) was added in portions, and stirred at room temperature for 16h. Pouring the reaction solution into crushed ice, stirring and cooling, extracting with ethyl acetate for 3 times, combining organic phases, concentrating under reduced pressure, and recrystallizing to obtain 36.72g of a product, wherein the yield is: 74.3%.
Step 4: synthesis of 6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -5-nitronicotinamide (Compound 1 e).
Into a reaction flask was charged 6-chloro-5-nitronicotinic acid (1 d,36.53g,180.35 mmol) and thionyl chloride (SOCl) 2 550 mL), stirring at 80 ℃ for 4 hours, vacuum drying, adding 500mL of anhydrous DCM for dissolution, adding 4- (chlorodifluoromethoxy) aniline (34.91 g,180.35 mmol), stirring at room temperature for 1 hour, and concentrating under reduced pressure to obtain a product of 52.13g, yield: 76.4%.
Step 5: synthesis of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5-nitronicotinamide (Compound 1 f).
To a reaction flask were added compound 1e (52.06 g,137.6 mmol) and (R) -3 hydroxypyrrolidine (12.00 g,137.6 mmol), 400mL of anhydrous DMSO was added, DIEA (35.57 g,275.3 mmol) was added, the reaction was heated to 100deg.C and stirred for 2 hours, excess water was added for dilution, ethyl acetate was extracted for 3 times, the organic phases were combined, washed with saturated sodium chloride solution, concentrated under reduced pressure, and purified by silica gel column chromatography to give 45.73g of the product, yield: 77.4%.
Step 6: synthesis of (R) -5-amino-N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 1 g)
Into a reaction flask were charged compound 1f (45.7 g,106.5 mmol), palladium on carbon (Pd/C, 2 g) and 300mL anhydrousMeOH，H 2 The reaction is stirred for 12 hours at 40 ℃, suction filtration is carried out, the filtrate is decompressed and concentrated to obtain 33.4g of product, and the yield is: 78.63%.
Step 7: synthesis of (R, E) -5- (((5-bromothiophen-2-yl) methylene) amino) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidine-1) nicotinamide (Compound 1)
To the reaction flask was added 1g (200 mg,0.5 mmol) of the compound, 5-bromothiophene-2-carbaldehyde (190 mg,1 mmol), formic acid (2.3 mg,0.05 mmol) and 3mL of anhydrous methanol, and the mixture was heated and stirred at 50℃for 2 hours. Purifying by silica gel column chromatography and reversed phase column chromatography to obtain 61.6mg of the product, yield: 21.4%. 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) amino) Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 2)
Referring to the procedure of example 1, substituting 5-bromothiophene-2-carbaldehyde with 5-bromo-2-carbaldehyde, 72.8mg of the product was finally produced in the yield: 26.2%. 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)
Referring to the procedure of example 1, 5-bromothiophene-2-carbaldehyde was replaced with 5-hydroxymethylfurfural to give 80.0mg of the final product in the yield: 31.6%. 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)
Referring to the procedure of example 1, substituting 5-bromothiophene-2-carbaldehyde with 5-methoxy-pyridine-3-carbaldehyde gave 49.0mg of the final product, yield: 18.9%. 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)
Referring to the procedure of example 1, substituting 5-bromothiophene-2-carbaldehyde with 4-pyridinecarbaldehyde gave the final product 39.3mg, yield: 16.1%. 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) methylene) amino) -N- (4- (chlorodifluoromethoxy) amino) Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 6)
Referring to the procedure of example 1, 5-bromothiophene-2-carbaldehyde was replaced with 5-bromopyridine-3-carbaldehyde to give 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 Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 7)
Referring to the procedure of example 1, 5-bromothiophene-2-carbaldehyde was replaced with 5-nitrosalicylaldehyde to produce compound 7.LC-MS (ESI) m/z=548.12 [ M+H ]] + 。
Example 8 preparation of (R) -5- (((5-bromothiophen-2-yl) methyl) amino) -N- (4- (chlorodifluoromethoxy) benzene Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 8)
Into a reaction flask, 1g (200 mg,0.5 mmol) of the compound, 5-bromothiophene-2-carbaldehyde (190 mg,1 mmol), formic acid (2.3 mg,0.05 mmol) and 3mL of anhydrous methanol were added, and the mixture was heated and stirred at 50℃for 2 hours, followed by addition of sodium cyanoborohydride (NaBH) 3 CN,128mg,2 mmol), stirring at room temperature, reacting 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 the product, yield: 39.6%. 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 Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 9)
Referring to the procedure of example 8, 5-bromothiophene-2-carbaldehyde was replaced with 5-bromo-2-carbaldehyde to give 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) methyl) Group) amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 10)
Referring to the procedure of example 8, 5-bromothiophene-2-carbaldehyde was replaced with 5-hydroxymethylfurfural to give 35.0mg of the final product in yield: 13.7%. 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)
Referring to the procedure of example 8, substituting 5-bromothiophene-2-carbaldehyde with 5-methoxy-pyridine-3-carbaldehyde gave 64.0mg of the final product in yield: 24.6%. 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- ((pir-idine Pyridin-4-ylmethyl) amino) nicotinamide (compound 12)
Referring to the procedure of example 8, substituting 5-bromothiophene-2-carbaldehyde with 4-pyridinecarbaldehyde gave the final product 55.0mg, yield: 22.4%. 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 Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 13)
Referring to the procedure of example 8, substituting 5-bromothiophene-2-carbaldehyde with 5-bromopyridine-3-carbaldehyde gave 127.5mg of the final product in yield: 44.9%. 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)
Referring to the procedure of example 8, substituting 5-bromothiophene-2-carbaldehyde with 5-nitrosalicylaldehyde yielded 98.0mg of the final product in yield: 35.7%. 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-) Nitrophenyl carboxamido) nicotinamide (Compound 15)
To the reaction flask was added o-nitrobenzoic acid (84 mg,0.5 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 228mg,0.6 mmol), N, N-diisopropylethylamine (DIEA, 129mg,1 mmol) and 3 mL-DMF, stirred at room temperature for 1 hour, 1g (200 mg,0.5 mmol) of the compound was added, stirred at room temperature for 4 hours, diluted with water, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, concentrated under reduced pressure, and purified by silica gel column chromatography to give 36.0mg of the product, yield: 13.16%. 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- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (thia-point) Phenant-2-carboxamide nicotinamide (Compound 16)
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Referring to the procedure of example 15, substituting o-nitrobenzoic acid for thiophene-2-carboxylic acid produced 37.0mg of product in yield: 14.5%. 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) benzenePhenyl) -5- (furan-2-carboxamido) -6- (3-hydroxy Pyrrolidin-1-yl) nicotinamide (compound 17)
Referring to the procedure of example 15, substituting furoic acid for o-nitrobenzoic acid, 69.0mg of the product was finally obtained in the yield: 28.0%. 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 Alkan-1-yl) pyridin-3-yl picolinamide (Compound 18)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 2-picolinic acid produced 59.0mg of product in yield: 23.4%. 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-yl group]-3- [ (pyridin-4-ylcarbonyl) amino group]Benzamide (Compound 19)
Referring to the procedure of example 15, the substitution of ortho-nitrobenzoic acid to isonicotinic acid produced compound 19.LC-MS (ESI) m/z=504.15 [ M+H ] ] + 。
EXAMPLE 20 preparation of (R) -5- (5-bromonicotinamide) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrole Alkan-1-yl) nicotinamide (compound 20)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to 5-bromonicotinic acid produced compound 20.LC-MS (ESI) m/z=582.03 [ M+H ]] + 。
EXAMPLE 21 preparation of (R) -5- (2-bromonicotinamide) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrole Alkan-1 yl) nicotinamide (compound 21)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to 2-bromonicotinic acid produced compound 21.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- Nitrophenyl carboxamido) nicotinamide (Compound 22)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 2-bromonicotinic acid, 23.0mg of the product was finally obtained in the yield: 8.4%. 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) thiourea nicotinamide (Compound 23)
To the reaction flask was added isothiocyanato 4-nitrophenyl ester (108 mg,0.6 mmol), triethylamine (TEA, 101mg,1 mmol), 1g (200 mg,0.5 mmol) of the compound and 2mL of absolute ethanol, and stirred at 80℃for 4 hours. Concentrating under reduced pressure, purifying by silica gel column chromatography to obtain 162.3mg of product, yield: 56.1%. 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) Thiourea nicotinamide (Compound 24)
Referring to the procedure of example 23, substituting isothiocyanato 4-nitrophenyl ester for 3-pyridylthioisothiocyanate, 92.9mg of the product was finally obtained in yield: 34.7%. 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) Thiourea group) nicotinamide (Compound 25)
Referring to the procedure of example 23, substituting isothiocyanato 4-nitrophenyl ester for p-toluene isothiocyanate, 215.6mg of the product was finally obtained in the yield: 78.8%. 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- Phenylthiourea) nicotinamide (compound 26)
Referring to the procedure of example 23, substituting phenyl thioisocyanate with isocyanatophenyl isothiocyanato 4-nitrophenyl ester, 48.8mg of the product was finally obtained in the yield: 18.3%. 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) thiourea) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 27)
Referring to the procedure of example 23, substituting isothiocyanato 4-nitrophenyl isothiocyanate with 4-cyanophenyl isothiocyanate, 59.9mg of the product was finally obtained in yield: 21.5%. 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, 5-bis (trifluoromethyl) phenyl) thiourea) -N- (4- (chlorodifluoromethoxy) Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 28)
Referring to the procedure of example 23, substituting isothiocyanato 4-nitrophenyl ester with 3, 5-bis (trifluoromethyl) phenylisothiocyanato ester, 196.3mg of the product was finally produced in the yield: 58.7%. 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) thiourea) -6- (3- Hydroxypyrrolidin-1-yl) nicotinamide (compound 29)
Referring to the procedure of example 23, substituting isothiocyanato 4-nitrophenyl isothiocyanate with 4-fluorophenyl isothiocyanate, 81.9mg of the product was obtained in yield: 29.7%. 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) thiourea) nicotinamide (compound 30)
Referring to the procedure of example 23, substituting isothiocyanato 4-nitrophenyl ester with 4- (trifluoromethyl) phenyl isothiocyanate, 162.5mg of the product was finally obtained in yield: 54.0%. 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, 5-dichlorophenyl) thiourea) 6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 31)
Referring to the procedure of example 23, replacement of isothiocyanato 4-nitrophenyl ester with 3, 5-dichlorophenyl isothiocyanate gives compound 31.LC-MS (ESI) m/z=602.03 [ M+H ]] + 。
Example 32 preparation (R)) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (3-) (4-methoxyphenyl) thiourea nicotinamide (Compound 32)
Referring to the procedure of example 23, replacement of isothiocyanato 4-nitrophenyl ester with 4-methoxyphenyl isothiocyanate gives 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 Alkan-1-yl) pyridin-3-yl) -6-fluoropyridine amide (compound 33)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 2-fluoropyridine-6-carboxylic acid produced 40.0mg of product in yield: 15.3%. 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 Alkan-1-yl) pyridin-3-yl) -5-fluoropyridine amide (compound 34)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 5-fluoro-2-pyridinecarboxylic acid, 53.0mg of the product was finally produced in the yield: 20.3%。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 Alkan-1-yl) pyridin-3-yl) -3-fluoropyridine amide (compound 35)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 3-fluoropyridine-2-carboxylic acid produced 128.0mg of product in yield: 49.12%. 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-Bromoisonicotinamide) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyramid Pyrrolidin-1-yl) nicotinamide (compound 36)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to 2-bromo-4-pyridinecarboxylic acid ultimately produces 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 group) nicotinamide (compound 37)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid with 6-trifluoromethyl nicotinic acid resulted in 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)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to 2, 6-dichloronicotinic acid eventually produced 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)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 1H-benzimidazole-2-carboxylic acid, 78.0mg of the product was finally produced in the yield: 27.3%. 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-Hydroxypyridine carboxamide (Compound 40)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to 6-hydroxypyridine-2-carboxylic acid resulted in 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 Alkan-1-yl) pyridin-3-yl pyrimidine-2-carboxamide (Compound 41)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to pyrimidine-2-carboxylic acid resulted in 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 Alkan-1-yl) pyridin-3-yl pyrazine-2-carboxamide (Compound 42)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to 2-carboxypyrazine eventually produced 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 Alkan-1-yl) pyridin-3-yl pyrimidine-4-carboxamide (Compound 43)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to 4-pyrimidinecarboxylic acid resulted in 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- (cigarette Amide) nicotinamide (Compound 44)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to nicotinic acid resulted in 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- Nicotinamide (compound 45)
Referring to the procedure of example 15, the substitution of ortho-nitrobenzoic acid with isonicotinic acid produced compound 45.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)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 5-bromo-2- (methylthio) -4-pyrimidinecarboxylic acid, 96.0mg of the product was finally obtained in the yield: 30.5%. 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 Alkan-1-yl) pyridin-3-yl) -5-methylpyrazine-2-carboxamide (Compound 47)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 5-methylpyrimidine-2-carboxylic acid, 89.0mg of the product was finally obtained in the yield: 34.3%. 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- (chlorodifluoromethoxy) phenyl) -5- (cyclopropanecarboxamide) -6- (3-hydroxy) Pyrrolidin-1-yl) nicotinamide (compound 48)
To the reaction flask was added 1g (200 mg,0.5 mmol), triethylamine (TEA, 50.7mg,0.75 mmol), cyclopropylcarbonyl chloride (104.9 mg,1 mmol) and 3mL anhydrous acetonitrile. Stirring for 2 hours at room temperature, purifying by silica gel column chromatography to obtain 23.3mg of a product, and obtaining the yield: 9.9%. 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- (cyclobutanecarboxamide) -6- (3-hydroxy) Pyrrolidin-1-yl) nicotinamide (compound 49)
Referring to the procedure of example 48, substituting cyclopropylcarbonyl chloride with cyclobutylcarbonyl chloride produced 53.0mg of the final product in yield: 22.0%. 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- (cyclopentanecarboxamide) -6- (3-hydroxy) Pyrrolidin-1-yl) nicotinamide (compound 50)
Referring to the procedure of example 48, substituting cyclopropylcarbonyl chloride with cyclopentylcarbonyl chloride produced 130.0mg of the final product in yield: 52.6%. 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- (cyclohexanecarboxamide) -6- (3-hydroxy) Pyrrolidin-1-yl) nicotinamide (compound 51)
Referring to the procedure of example 48, substituting cyclopropylcarbonyl chloride with cyclohexylcarbonyl chloride produced 18.0mg of the final product in yield: 7.3%. 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- (cycloheptanecarboxamide) -6- (3-hydroxy) Pyrrolidin-1-yl) nicotinamide (compound 52)
Referring to the procedure of example 48, cyclopropylcarbonyl chloride was substituted for Cheng Huangeng ylcarbonyl chloride to finally produce 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-fluoro) Hydrogen-2H-pyran-4-carboxamide nicotinamide (Compound 53)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with tetrahydropyran-4-carboxylic acid produced 92.0mg of product in yield: 36.0%. 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- (tetraf- Hydrofuran-2-carboxamide nicotinamide (Compound 54)
Referring to the procedure of example 48, substituting cyclopropylcarbonyl chloride with tetrahydrofuran-2-carboxylic acid chloride, 55.0mg of product was finally obtained in yield: 22.17%. 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 Alkan-1-yl) pyridin-3-yl) -6-methylpyridine amide (compound 55)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 6-methyl-2-picolinic acid produced 128.0mg of product in yield: 49.5%. 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-yl group]-3- [ (1H-pyrrol-2-ylcarbonyl) amino group ]Benzamide (Compound 56)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to pyrrole-2-carboxylic acid ultimately produced compound 56.LC-MS (ESI) m/z=492.13 [ M+H ]] + 。
EXAMPLE 57 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (5-hydroxyfuran-2-carboxamide) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 57)
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with 5-hydroxyfuran-2-carboxylic acid to finally produce compound 57.LC-MS (ESI) m/z=509.11 [ M+H ]] + 。
EXAMPLE 58 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (5-chlorofuran-2-carboxamide) -6- (3- Hydroxypyrrolidin-1-yl) nicotinamide (compound 58)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 5-chloro-2-furoic acid, 72.0mg of the product was finally produced in the yield: 27.3%. 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) benzenePhenyl) -5- (furan-3-carboxamido) -6- (3-hydroxy Pyrrolidin-1-yl) nicotinamide (compound 59)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to 3-furoic acid eventually produced 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-point) Phenant-3-carboxamide nicotinamide (Compound 60)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to 3-thiophenecarboxylic acid resulted in compound 60.LC-MS (ESI) m/z=509.09 [ M+H ]] + 。
EXAMPLE 61 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (5- Methylthiophene-2-carboxamide nicotinamide (compound 61)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 5-methyl-2-thiophenecarboxylic acid, 67.0mg of the product was obtained in the yield: 25.6%. 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- (chlorodifluoromethyl)Oxy) phenyl) -5- (5-chlorothiophene-2-carboxamide) -6- (3-) Hydroxypyrrolidin-1-yl) nicotinamide (compound 62)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 2-chlorothiophene-5-carboxylic acid produced 79.0mg of product in yield: 29.1%. 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)
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with 4-bromothiophene-2-carboxylic acid to finally produce 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)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 5-bromo-2-carboxythiophene, 54.0mg of the product was finally obtained in the yield: 18.4%. 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 Alkan-1-yl) pyridin-3-yl thiazole-2-carboxamide (Compound 65)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with thiazole-2-carboxylic acid produced 79.0mg of product in yield: 31.0%. 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 Alkan-1-yl) pyridin-3-yl) -2-methylthiazole-5-carboxamide (Compound 66)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to 2-methylthiazole-5-carboxylic acid eventually produced 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)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 2-bromo-4-thiazolecarboxylic acid, 74.0mg of the product was finally obtained in the yield: 25.2%. 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) Alkan-1-yl) pyri-dinePyridin-3-yl) isoxazole-5-carboxamide (Compound 68)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with isoxazole-5-carboxylic acid produced 53.0mg of product in yield: 21.5%. 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)
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Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to 1H-pyrazole-4-carboxylic acid resulted in 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)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to pyrazole-3-carboxylic acid ultimately produced 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-carboxamide nicotinamide (Compound 71)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid to 1-methylpyrazole-4-carboxylic acid eventually produced 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-carboxamide nicotinamide (Compound 72)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid with 1-methyl-4-imidazole carboxylic acid resulted in 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) propanoic acid 6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 73)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with benzothiophene-2-carboxylic acid, 67.0mg of the product was finally obtained in the yield: 24.0%. 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-carboxamide (Compound 74)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 2-indolecarboxylic acid, 78.0mg of the product was finally obtained in the yield: 28.8%. 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) Alkan-1-yl) pyridin-3-yl) -1H-indazole-3-carboxamide (Compound 75)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with indazole-3-carboxylic acid produced 46.0mg of product in yield: 16.9%. 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)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 1H-benzimidazole-2-carboxylic acid produced 37.0mg of product in yield: 13.6%. 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-hydroxypyrazole) Pyrrolidin-1-yl) nicotinamide (compound 77)
Referring to the procedure of example 15, the substitution of ortho-nitrobenzoic acid with 5-hydroxynicotinic acid ultimately produced compound 77.LC-MS (ESI) m/z=520.12 [ M+H ]] + 。
Example 78 preparation(R) -N- (5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrole) Alkan-1-yl) pyridin-3-yl) -4-fluoropyridine amide (compound 78)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 5-fluoro-2-pyridinecarboxylic acid produced 57.0mg of the product in yield: 21.8%. 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-hydroxy) Pyrrolidin-1-yl) pyridin-3-yl picolinamide (Compound 79)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 4-chloro-2-picolinic acid produced 88.0mg of product in yield: 32.7%. 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-hydroxypyra-zine Pyrrolidin-1-yl) nicotinamide (compound 80)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 2-chloroisonicotinic acid produced 93.0mg of product in yield: 34.6%. 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 picolinamide (Compound 81)
Referring to the procedure of example 15, substituting o-nitrobenzoic acid with 3-chloro-2-picolinic acid produced 48.0mg of the final product in yield: 17.8%. 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 picolinamide (Compound 82)
Referring to the procedure of example 15, o-nitrobenzoic acid was replaced with 6-bromo-2-pyridinecarboxylic acid to give 65.0mg of the final product, which was recoveredThe rate is as follows: 22.4%. 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- Nicotinamide (compound 83) nicotinamide (methylnicotinamide)
Referring to the procedure of example 15, the substitution of o-nitrobenzoic acid with 6-methylnicotinic acid eventually produced compound 83.LC-MS (ESI) m/z=518.13 [ M+H ]] + 。
Biological Activity test
EXAMPLE 84 in vitro tumor cell (K562, KBM 5) antiproliferative Activity assay
1. Experiments were performed on a KBM5 human chronic myelogenous leukemia cell line in 1640+10% FBS (Gibco) complete medium at 37℃in 5% CO 2 Suspension culture in 95% humidity.
2. The following is a general experimental procedure: taking logarithmic growth K562 and KBM5 cells, centrifuging to obtain cell precipitates, adding fresh culture medium to resuspend, performing dyeing counting on the cells by using a table blue, diluting the cells to a proper concentration, respectively planting 50uL of cells in 96-well plates, 3000 cells/well, and placing the cell plates in a carbon dioxide incubator for overnight culture; preparing mother liquor of the compound to be tested, wherein the DMSO mother liquor of all the compounds is 10mM, storing at-80 ℃, and sub-packaging for use. Diluting the compound mother solution to a proper concentration by using a culture medium according to the required working concentration, taking 50uL of compound solution to be tested, adding the compound solution to be tested into cell holes, and arranging three compound holes for each compound to be tested; the cell plates were placed in a carbon dioxide incubator for 3 days.
3. End point reading plate: the reagents were incubated at room temperature for 2-4 hours at 10-uL Cell Counting Kit-8 per well, absorbance was read at 450nm by an enzyme-labeled instrument, and cell growth inhibition efficiency was calculated.
4. Data processing
Analysis of data using GraphPad Prism 9.0 software, fitting data using non-linear S-curve regression to derive dose-response curves, and calculating IC therefrom 50 Values. Cell viability (%) = { (OD test drug-OD culture solution control)/(OD cell control-OD culture solution control) } ×100%.
The results of the in vitro antiproliferative activity primary screening of cells in the examples are summarized in Table 2 below.
TABLE 2 cytotoxicity of example Compound Primary screening
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As shown in Table 2, the experimental results show that the compounds of the invention have certain anti-tumor cell (K562/KBM 5) proliferation activity. Of these, compounds 16, 33, 35 and 67 exhibited significant antiproliferative activity against K562 and KBM 5. From the above examples, it is clear that the partial compounds of the (hetero) aryl amides of the present invention can exert a good antiproliferative effect on human chronic myelogenous leukemia cell lines K562, KBM5, and can be used for preparing medicaments for treating cancers such as chronic myelogenous leukemia, acute myelogenous leukemia, etc.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein 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:
or a pharmaceutically acceptable salt, stereoisomer thereof, wherein:
y is selected from CH or N;
R 1 independently selected from hydrogen, halogen, nitrile, hydroxy, which may be mono-, di-or polysubstituted;
R 2 selected from-CF 2 -Y 1 ；
Y 1 Selected from hydrogen, chlorine, fluorine, 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 the pyrrolidinyl is substituted with 1 or more R a Group substitution;
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 thiourea,
R 3 Selected from the following groups optionally substituted with one, two or three R:
R b independently selected from hydrogen, acetyl, C 1-6 Alkyl or C 1-6 A haloalkyl group;
r is independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxy alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy groups;
the halogen is F, cl or Br.
2. The compound of claim 1, having formula (II):
Or a pharmaceutically acceptable salt, stereoisomer thereof, wherein:
R 1 independently selected from hydrogen, halogen, nitrile, hydroxy, which may be mono-, di-or polysubstituted;
R a independently selected from hydrogen, hydroxy, halogen, nitrile, carboxyl, which may be mono-, di-or polysubstituted; link is thiourea,
R 3 The method of claim 1.
3. The compound according to claim 2, wherein:
the R is 1 Independently selected from hydrogen and halogen;
R a independently selected from hydrogen and hydroxy;
link is thiourea,
R b Independently selected from hydrogen, acetyl, C 1-3 Alkyl or C 1-3 A haloalkyl group.
4. The compound of claim 1, having formula (III):
or a pharmaceutically acceptable salt, stereoisomer thereof, wherein:
R a independently selected from hydrogen and hydroxy;
link is thiourea,
R 3 Selected from the following groups optionally substituted with one, two or three R:
R b independently selected from hydrogen, acetyl or C 1-3 An alkyl group;
r is as defined in claim 1.
5. A compound according to claim 4, wherein,
the R is a Is hydroxyl;
link is thiourea,
R is independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxy alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy groups.
6. A compound according to any one of claims 2-5, or a pharmaceutically acceptable salt, stereoisomer thereof, selected from the group consisting of:
7. a pharmaceutical composition comprising a compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, and pharmaceutically acceptable excipient thereof.
8. Use of a compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, or pharmaceutical composition according to claim 7, for the manufacture of a medicament for the treatment and/or prevention of a Bcr-Abl-induced disease in a subject.
9. The use of claim 8, wherein the Bcr-Abl-caused disease is a proliferative disease selected from the group consisting of: solid tumors, sarcomas, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumors, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia, and other proliferative or proliferative diseases.
10. The use of claim 8, wherein the Bcr-Abl-caused disease is metastatic invasive cancer, a viral infection, or a CNS disorder.
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