CN111620854A - 4-aminopyrimidine substituted phenylamide compound and preparation method thereof - Google Patents
4-aminopyrimidine substituted phenylamide compound and preparation method thereof Download PDFInfo
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- CN111620854A CN111620854A CN201910152430.8A CN201910152430A CN111620854A CN 111620854 A CN111620854 A CN 111620854A CN 201910152430 A CN201910152430 A CN 201910152430A CN 111620854 A CN111620854 A CN 111620854A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic System
Abstract
The invention discloses a 4-aminopyrimidine substituted phenylamide compound and a preparation method thereof. The structure of the 4-aminopyrimidine substituted phenylamide compound is shown in formula I. The 4-aminopyrimidine substituted phenylamide compound has low toxicity to normal cells and good selectivity to EGFR mutant strains.
Description
Technical Field
The invention relates to a 4-aminopyrimidine substituted phenylamide compound and a preparation method thereof.
Background
Specific cysteine (Cys797) residues exist near openings of ATP binding domains of EGFR receptor family, and cysteine residues at similar positions exist only in 11 kinases such as EGFR, HER2, HER4, Jak3, Blk, Lkb1, 95Bmx, Btk, Itk, Tec and Txk. The specific cysteine residue, unlike the glutamate or serine residues of other kinases, is nucleophilic and can undergo a michael addition reaction with an electrophilic michael acceptor group. The introduction of an electrophilic michael acceptor group into the inhibitor to react with nucleophilic Cys797 through michael addition irreversibly prevents the binding of the kinase to ATP, thus realizing irreversible selective inhibition of EGFR kinase and improving the action strength of the inhibitor.
Currently, EGFR inhibitors and the mainstream drugs developed by the EGFR inhibitors are designed based on the above mechanisms, such as the second generation EGFR inhibitor afatinib, the structural formula of which is shown in the specificationAlso for example, the third generation EGFR inhibits oxitinib, which has the structural formulaHowever, second generation EGFR inhibitors have a deficiency in that they lack selectivity for EGFR mutant T790M and wild-type EGFR kinase. On the basis, the developed third-generation EGFR inhibitor oxitinib has good selectivity on T790M mutant and wild-type EGFR kinase. Therefore, the third-generation EGFR inhibitor, obitinib, has received extensive attention after marketing.
However, the allyl structure of the EGFR inhibitor also has the defect of certain toxicity to wild-type EGFR kinase, and the defect of drug resistance brought by the single main bond functional group is inevitable.
There is therefore a great need in the art to develop new classes of EGFR inhibitors.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defects that the existing EGFR inhibitor has certain toxicity and drug resistance to wild EGFR kinase in the prior art, and provides a 4-aminopyrimidine substituted phenylamide compound and a preparation method thereof. The inhibitor has low toxicity to normal cells and good selectivity to EGFR mutant strains.
The invention provides a compound shown as a formula I or a pharmaceutically acceptable salt thereof:
R1Is C1~10Alkyl, halogen substituted C1~10Alkyl radical, C3~10Cycloalkyl radical, C6~30Aryl radical, R1-1Substituted C6~30Aryl, 3-to 30-membered heteroaryl orThe heteroatoms in the 3-30 membered heteroaryl are N, O or S independently, and the number of the heteroatoms is 1,2 or 3; when the number of the hetero atoms is plural, the species of the hetero atoms are the same or different;
said halogen substituted C1~10The number of halogen substitution in the alkyl group is 1 or more; when the number of the halogen substitution is plural, the halogens are independently the same or different;
each R1-1Independently of one another, halogen, C1~10Alkyl radical, C1~10Alkoxy orThe R is1-11,2, 3 or 4; when said R is1-1When plural, R is1-1Independently the same or different;
the R is1-1-1aAnd R1-1-1bIndependently is C1~4An alkyl group;
R2is C6~30Aryl or R2-1Substituted C6~30An aryl group;
each R2-1Independently of one another, halogen, C1~10Alkyl or C1~10An alkoxy group; the R is2-1Is 1 or more; when said R is2-1When there are plural, R is2-1The same or different.
Wherein, the pharmaceutically acceptable salt of the compound shown in formula I can be a salt which is conventional in the field, preferably a methanesulfonate, ethanesulfonate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, lactate, malate, citrate, tartrate, picrate, glutamate, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate or phosphate, preferably a methanesulfonate.
Wherein when R is1Is halogen substituted C1~10When alkyl, said halogen being substituted by C1~10C in alkyl1~10The alkyl group may be C1~6Alkyl, preferably C1~3An alkyl group. Said C is1~3The alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably ethyl.
Wherein when R is1Is halogen substituted C1~10When alkyl, said halogen being substituted by C1~10The halogen in the alkyl group may be F, Cl, Br or I, preferably Cl.
Wherein when R is1Is halogen substituted C1~10When alkyl, said halogen being substituted by C1~10The number of halogen substitutions in the alkyl group may be1 or more, preferably 1.
Wherein, when said halogen is substituted C1~10When the alkyl group has a chiral center, the halogen is substituted C1~10The steric configuration of the alkyl group may be R-type.
Wherein when R is1Is halogen substituted C1~10When alkyl, said halogen being substituted by C1~10Alkyl chloride substituted C1~3Alkyl, more preferablyFurther preferred is
Wherein when R is1Is C3~10When a cycloalkyl group is present, C is3~10Cycloalkyl radicals may be C3~6A cycloalkyl group. Said C is3~6Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.
Wherein when R is1Is R1-1Substituted C6~30When aryl is said to R1-1Substituted C6~30C in aryl6~30Aryl may be C6~20Aryl, preferably C6~14And (4) an aryl group. Said C is6~14Aryl can be phenyl, naphthyl, phenanthryl or anthracyl, preferably phenyl.
Wherein when R is1Is R1-1Substituted C6~30When aryl is said to R1-1The number of (a) may be1, 2 or 3.
Wherein when R is1Is R1-1Substituted C6~30When aryl is said to R1-1Substituted C6~30Aryl may be "substituted by 1,2 or 3 times", halogen or"substituted phenyl radical, further preferred
Wherein when R is1In the case of a 3-to 30-membered heteroaryl group, the 3-to 30-membered heteroaryl group may be a 3-to 10-membered heteroaryl group, preferably a 3-to 6-membered heteroaryl group, and more preferably a 5-membered heteroaryl group.
Wherein when R is1In the case of a 3-to 30-membered heteroaryl group, the heteroatom in the 3-to 30-membered heteroaryl group may be N and/or O, preferably N.
Wherein when R is1In the case of a 3-to 30-membered heteroaryl group, the number of heteroatoms in the 3-to 30-membered heteroaryl group may be1 or 2, preferably 1.
Wherein when R is1In the case of the 3-to 30-membered heteroaryl group, the 3-to 30-membered heteroaryl group may be a "3-to 10-membered heteroaryl group in which the number of hetero atoms is 1 or 2", preferably a "3-to 6-membered heteroaryl group in which the number of hetero atoms is 1", and more preferably a pyrrolyl group.
Wherein when each R is1-1Independently halogen, the halogen may be F, Cl, Br or I, preferably F, Cl or Br.
Wherein when each R is1-1Independently is C1~10At alkoxy, the C1~10Alkoxy may be C1~6Alkoxy, preferably C1~3An alkoxy group. Said C is1~3The alkoxy group may be methoxy, ethoxy, n-propoxy or isopropoxy, with methoxy being preferred.
Wherein when said R is1-1-1aAnd R1-1-1bIndependently is C1~4When alkyl, said C1~4The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.
Wherein when R is2Is R2-1Substituted C6~30When aryl is said to R2-1Substituted C6~30C in aryl6~30Aryl may be C6~20Aryl, preferably C6~14And (4) an aryl group. Said C is6~14Aryl can be phenyl, naphthyl, phenanthryl or anthracyl, preferably phenyl.
Wherein when each R is2-1Independently is C1~10When alkyl, said C1~10The alkyl group may be C1~6Alkyl, preferably C1~3An alkyl group. Said C is1~3The alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably methyl.
In one embodiment, when R isWhen R is in the above-mentioned range1Is halogen substituted C1~10Alkyl radical, C3~10Cycloalkyl radical, R1-1Substituted C6~30Aryl, 3-to 30-membered heteroaryl or
In one embodiment, when R isWhen R is in the above-mentioned range1Is halogen substituted C1~10An alkyl group.
In one embodiment, when R isR1Is R1-1Substituted C6~30When aryl is said each R1-1Independently of one another, halogen, C1~10Alkyl or
In one embodiment, when R isWhen R is in the above-mentioned range2Is R2-1Substituted C6~30And (4) an aryl group.
In one embodiment, when R isR2Is R2-1Substituted C6~30When aryl is said each R2-1Independently is C1~10An alkyl group.
In a certain implementationIn the scheme, R1Is halogen substituted C1~10Alkyl radical, C3~10Cycloalkyl radical, R1-1Substituted C6~30Aryl, 3-to 30-membered heteroaryl or
R2Is R2-1Substituted C6~30And (4) an aryl group.
In one embodiment, R1Is halogen substituted C1~10An alkyl group; r2Is R2-1Substituted C6~30And (4) an aryl group.
The compound shown in the formula I or the pharmaceutically acceptable salt thereof is preferably any one of the following compounds:
the invention also provides a preparation method of the compound shown in the formula I or the pharmaceutically acceptable salt thereof, which is a method 1, a method 2 or a method 3:
the method comprises the following steps: the method comprises the following steps of carrying out condensation reaction of a compound shown in a formula II and a compound shown in a formula III in an organic solvent under the action of a condensing agent and an alkaline reagent to obtain a compound shown in a formula I;
the method 2 comprises the following steps: the method comprises the following steps of carrying out acylation reaction on a compound shown in a formula II and a compound shown in a formula IV in an organic solvent in the presence of an acid binding agent to obtain a compound shown in a formula I;
the method 3 comprises the following steps: the method comprises the following steps of reacting a compound shown as a formula I with acid in a solvent to obtain a salt of the compound shown as the formula I;
wherein R in the method 1, the method 2 and the method 3 is the same as the above.
In method 1, the conditions and operation of the condensation reaction may be those conventional in the art.
In method 1, the condensing agent may be a condensing agent conventional in this reaction in the art, preferably 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), Dicyclohexylcarbodiimide (DCC) or Carbonyldiimidazole (CDI), such as HATU.
In the method 1, the molar ratio of the condensing agent to the compound II can be a molar ratio which is conventional in the art for this reaction, and is preferably 1.0 to 2.0, for example 1.5.
In method 1, the basic reagent may be a reagent conventional in the art, preferably Triethylamine (TEA) and/or N, N-Diethylisopropylamine (DIEA), such as TEA.
In the method 1, the molar ratio of the alkaline agent to the compound II can be a molar ratio which is conventional in the art for this reaction, and is preferably 1.0 to 5.0, for example 3.0.
In the method 1, the molar ratio of the compound III to the compound II can be a molar ratio which is conventional in the reaction in the field, and is preferably 1.0-2.0, such as 1.0.
In the method 1, the organic solvent may be an organic solvent that is conventional in this reaction in the art, preferably one or more of a halogenated hydrocarbon solvent, an amide solvent and a sulfone solvent, more preferably a halogenated hydrocarbon solvent. The halogenated hydrocarbon solvent may be one or more of dichloromethane, dichloroethane and chloroform, preferably dichloromethane.
In method 1, the condensation reaction may be at a temperature conventional in the art for such reactions, preferably 10-40 deg.C, for example 25 deg.C.
In method 1, the progress of the condensation reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, LCMS), and the end point of the reaction is generally the disappearance or no longer reaction of compound II. The reaction time is preferably 3 to 10 hours, for example 5 hours.
In the method 1, after the condensation reaction is finished, the method may further include a post-treatment step: and (3) washing, drying, concentrating and carrying out column chromatography on the reaction solution after the reaction is finished.
In method 2, the conditions and operation of the acylation reaction may be those conventional in the art for such reactions.
In the method 2, the acid-binding agent can be a reagent conventional in the art, and is preferably an organic weak base. The weak organic base may be one or more of pyridine, Triethylamine (TEA) and N, N-Diethylisopropylamine (DIEA), such as TEA.
In the method 2, the molar ratio of the acid-binding agent to the compound II may be a molar ratio conventional in this reaction in the art, and is preferably 1.0-5.0, for example 2.0.
In the method 2, the molar ratio of the compound IV to the compound II can be a molar ratio which is conventional in the reaction in the field, and is preferably 1.0-2.0, such as 1.0.
In method 2, the organic solvent may be an organic solvent conventional in this reaction in the art, preferably one or more of a halogenated hydrocarbon solvent, an amide solvent and a sulfone solvent, more preferably a halogenated hydrocarbon solvent. The halogenated hydrocarbon solvent may be one or more of dichloromethane, dichloroethane and chloroform, preferably dichloromethane.
In method 2, the temperature of the acylation reaction may be a temperature conventional in the art for such reactions, preferably 0 to 40 ℃, e.g. 25 ℃.
In method 2, the progress of the acylation reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, LCMS), and the end point of the reaction is generally the disappearance or no longer reaction of compound II. The reaction time is preferably 1 to 5 hours, for example, 1 hour.
After the condensation reaction is finished, the method can further comprise the following post-treatment steps: and (3) washing, drying, concentrating and carrying out column chromatography on the reaction solution after the reaction is finished.
In the method 3, the salt of the compound shown in the formula I can be prepared according to the conventional method and conditions of salt forming reaction in the field.
In method 3, the acid may be an organic acid or an inorganic acid capable of salt formation, which is conventional in the art. The organic acid can be one or more of methanesulfonic acid, ethanesulfonic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, picric acid and glutamic acid, and preferably methanesulfonic acid. The inorganic acid may be one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid.
In the method 3, the molar ratio of the acid to the compound represented by the formula I may be1 to 3, for example, 1.
In method 3, the solvent may be a ketone solvent, such as acetone.
In the method 3, the reaction temperature may be 10 to 60 ℃, for example, 50 ℃.
The invention also provides an application of the compound shown as the formula I or the pharmaceutically acceptable salt thereof in preparing an EGFR inhibitor.
The invention also provides the application of the compound shown as the formula I or the pharmaceutically acceptable salt thereof in preparing medicaments for preventing and/or treating diseases related to EGFR mediation.
In the above application, preferably, the medicament is used for preventing and/or treating diseases related to EGFR mutation mediation. The disease may be ovarian cancer, cervical cancer, colorectal cancer, breast cancer, membrane adenocarcinoma, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, Acute Myeloid Leukemia (AML), multiple myeloma, melanoma, or mesothelioma; preferably lung cancer, and more preferably non-small cell lung cancer.
The invention also provides a pharmaceutical composition, which comprises the compound shown as the formula I or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The pharmaceutical composition can also consist of the compound shown as the formula I or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In the present invention, the pharmaceutically acceptable carrier may be a carrier conventional in the art, including one or more of a lubricant, a binder, a filler and a disintegrant. The lubricant is selected from one or more of magnesium stearate, aerosil, silicon dioxide and talcum powder; the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, starch and crospovidone; the binder is selected from one or more of hydroxypropyl cellulose, polyvinylpyrrolidone and methyl cellulose; the filler is selected from one or more of lactose, pregelatinized starch and microcrystalline cellulose.
In the present invention, the amount of the pharmaceutically acceptable carrier is not particularly limited as long as it meets the requirements of a formulation which is conventional in the art.
In the invention, the pharmaceutical composition can be prepared into various dosage forms, such as tablets, capsules, pills, powder, emulsion, granules, suppositories, injections and the like.
In the present invention, the term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to occur in a subject who may be exposed to a disease causing agent or predisposing disease prior to the onset of the disease).
In the invention: the term "R-S configuration" is the term used to designate the R-S system nomenclature in the nomenclature of chiral C. The specific nomenclature of the R-S system is as follows: when a, b, c, d attached to the central carbon atom are different groups, the molecule is chiral. Assuming that the four substituents in the molecule are arranged in the CIP order rule in the order a > b > c > d, if the smallest d group is placed at the position furthest from the viewer, the other three groups are viewed in a-b-c precedence order, with a → b → c being observed in a clockwise direction, the configuration of this carbon center is defined as R (latin recatus); otherwise, S (Latin Sinister) is identified.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and raw materials used in the invention are commercially available, wherein S-2-chloropropionic acid is purchased from Annaiji (batch number: BE170142), the purity is 98%, and the specific rotation degree is-13.5 degrees; r-2-chloropropionic acid was purchased from Annaiji (batch No.: EE040098) and had a purity of 98% and a specific rotation of +13.4 o.
The positive progress effects of the invention are as follows: the 4-aminopyrimidine substituted phenylamide compound has low toxicity to normal cells and good selectivity and activity to EGFR mutant strains.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
EXAMPLE 1 preparation of N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (3-N, N-dimethylamino) benzamide
The compound N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (1.0g,2.24mmol,1eq), 3- (N, N-dimethylamino) benzoic acid (445mg, 2.69mmol, 1.2eq) and HATU (1.28g, 3.37mmol,1.5eq) were dissolved in dichloromethane (20ml), DIPEA (1.11ml,6.73mmol,3.0eq) was added, after stirring at room temperature for 4 hours, the reaction solution was washed with water three times, dried and concentrated, and the crude product was column chromatographed (dichloromethane/methanol) to give a product (1.33 g).
1H NMR(400MHz,DMSO-d6) 10.37(s,1H),9.30(s,1H),8.79(s,1H),8.36(d, J, 5.2Hz,1H),8.25(d, J, 8.0Hz,1H),7.91(s,1H),7.53(d, J, 8.0Hz,1H),7.36(t, J, 8.0Hz,1H),7.29-7.19(m,4H),7.19-7.12(m,1H),7.11(s,1H),6.95(dd, J, 8.0,2.4Hz,1H),3.94(s,3H),3.89(s,3H),3.00(m,2H),2.98(s,6H),2.73(s,3H),2.25(s,2H),2.02 (s, 6H); ES-API (m/z) calculated value C34H40N8O2[M+H]+, 593.3; theoretical value, 593.3.
Example 2 preparation of N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2-chloro) benzamide
Preparation of N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2-chloro) benzamide (1.31g) prepared in reference example 1
1H NMR(400MHz,DMSO-d6) 10.91(s,1H),9.22(s,1H),8.70(s,1H),8.35(d, J) 5.2Hz,1H),8.25(d, J) 8.0Hz,1H),7.96(s,1H),7.63(dd, J) 7.2,2.4Hz,1H),7.59(dd, J) 7.6,1.6Hz,1H),7.55-7.45(m,3H),7.28-7.21(m,2H),7.19-7.12(m,1H),7.10(s,1H),3.87(s,3H),3.86(s,3H),2.89(s,2H),2.74(s,3H),2.16(s,2H),1.76 (s, 6H); ES-API (m/z) calculated value C32H34ClN7O2[M+H]+, 584.2; theoretical value, 584.2.
Example 3N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2, 6-difluoro) benzamide
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2, 6-difluoro) benzamide (1.29g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 11.12(s,1H),9.17(s,1H),8.64(1H),8.35(d, J) 5.2Hz,1H),8.24(d, J) 8.0Hz,1H),7.97(s,1H),7.65-7.55(m,1H),7.52(d, J) 8.0Hz,1H),7.33-7.21(m,4H),7.20-7.12(m,1H),7.10(s,1H),3.87(s,3H),3.85(s,3H),2.89(t, J) 5.6Hz,2H),2.74, (s,3H),2.19(t, J) 5.6Hz,2H),1.81ppm (s, 6H); ES-API (m/z) calculated value C32H33F2N7O2[M+H]+, 586.3; theoretical value, 586.3.
Example 4N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (4-methoxy) benzamide
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (4-methoxy) benzamide (1.30g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 10.38(s,1H),9.25(s,1H),8.72(s,1H),8.35(d, J, 5.2Hz,1H),8.26(d, J, 8.0Hz,1H),8.00-7.90(m,3H),7.52(d, J, 8.0Hz,1H),7.25(d, J, 5.2Hz,1H),7.24-7.18(m,1H),7.16-7.07(m,4H),3.91(s,3H),3.88(s,3H),3.86(s,3H),3.99(t, J, 5.6Hz,2H),2.73(s,3H),2.22(t, J, 5.6Hz,2H),2.04 (s,6 ppm); ES-API (m/z) calculated value C33H37N7O3[M+H]+, 580.3; theoretical value, 580.3.
Example 5N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2-bromo-3, 5-dimethoxy) benzamide
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2-bromo-3, 5-dimethoxy) benzamide (1.55g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 10.79(s,1H),9.19(s,1H),8.72(s,1H),8.34(d, J, 5.2Hz,1H),8.24(d, J, 8.0Hz,1H),7.95(s,1H),7.52(d, J, 8.0Hz,1H),7.30-7.22(m,2H),7.20-7.12(m,1H),7.13-7.05(m,1H),6.78(d, J, 2.8Hz,1H),6.73(d, J, 2.8Hz,1H),3.89(s,3H),3.87(s,3H),3.86(s,3H),3.82(s,3H),2.90(t, J, 6.5, 2H), 2.84 (s,3H), 6.84 ppm); ES-API (m/z) calculated value C34H38BrN7O4[M+H]+,688.2,690.2; theoretical value, 688.2,690.2.
Example 6N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-ferrocenecarboxamide
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-ferrocenecarboxamide (1.48g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 9.63(s,1H),9.18(s,1H),8.80(s,1H),8.37(s,1H),8.23(d, J ═ 8.0Hz,1H),7.89(s,1H),7.53(d, J ═ 8.0Hz,1H),7.31-7.21(m,2H),7.17(t, J ═ 7.6Hz,1H),7.11(s,1H),4.88(t, J ═ 2.0, 2H),4.49(t, J ═ 2.0Hz,2H),4.25(s,5H),3.97(s,3H),3.88(s,3H),3.06(t, J ═ 5.6Hz,2H),2.75(s,3H),2.27(t, J ═ 2H), 6.6 (s,2H), 18.6 (s, 6H); ES-API (m/z) calculated value C36H39FeN7O2[M+H]+, 657.2; theoretical value, 657.2.
Example 7N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2, 4-dichloro) benzamide
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2, 4-dichloro) benzamide (1.39g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 10.94(s,1H),9.20(s,1H),8.68(s,1H),8.34(d, J, 5.2Hz,1H),8.25(d, J, 8.0Hz,1H),7.96(s,1H),7.78(d, J, 2.0Hz,1H),7.66(d, J, 8.0Hz,1H),7.59(dd, J, 8.0,2.0Hz,1H),7.51(d, J, 8.0Hz,1H),7.30-7.20(m,2H),7.19-7.12(m,1H),7.10(s,1H),3.87(s,3H),3.86(s,3H),2.89(t, 6.4, 2H), 3.17 (t, 6.17H), 4.17H, 4(s, 6H), 4.17H); ES-API (m/z) calculated value C32H33Cl2N7O2[M+H]+, 618.2; theoretical value, 618.2.
Example 8N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (3-pyrrolyl) carboxamide
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (3-pyrrolyl) carboxamide (1.18g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6):=11.34(s,1H),9.62(s,1H),9.16(s,1H),8.77(s,1H),8.34(d,J=5.2Hz,1H),8.25(d,J=8.0Hz,1H),7.88(s,1H),7.52(d,J=8.0Hz,1H),7.48-7.32(m,1H),7.29-7.20(m,2H),7.20-7.12(m,1H),7.05(s,1H),6.87(dd,J=2.4Hz,1H),6.58(dd,J=2.4Hz,1H),3.94(s,3H),3.88(s,3H),3.05(m,2H),269(s,3H),2.40(s,2H),2.21ppm (s, 6H); ES-API (m/z) calculated value C30H34N8O2[M+H]+, 539.3; theoretical value, 539.3.
Example 9N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (3, 4-dimethoxy) benzamide
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (3, 4-dimethoxy) benzamide (1.37g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 10.31(s,1H),9.23(s,1H),8.75(s,1H),8.35(d, J, 5.2Hz,1H),8.26(d, J, 8.0Hz,1H),7.91(s,3H),7.60(dd, J, 8.0Hz,1H), 7.57-7.49(m,2H),7.26(d, J, 5.2Hz,1H),7.24-7.19(m,1H),7.18-7.11(m,2H),7.10(s,1H),3.93(s,3H),3.89(s,3H),3.86(s,3H),3.85(s,3H),3.02(t, J, 6.0, 2H), 3.73 (s,2H), 6.73 (s,2H), 6.09 (s,2H), 2H, 6.09 (m, 2H); ES-API (m/z) calculated value C34H39N7O4[M+H]+, 610.3; theoretical value, 610.3.
Example 10N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2-pyrrolyl) carboxamide
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2-pyrrolyl) carboxamide (1.15g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6):=11.62(s,1H),9.76(s,1H),9.00(s,1H),8.50(s,1H),8.36-8.25(m,2H),7.94(s,1H),7.51(d,J=8.0Hz,1H),7.24-7.15(m,2H),7.16-7.09(m,1H),7.06(s,1H),7.00-6.94(m,1H) 6.88-6.79(m,1H),6.24-6.17(m,1H),3.87(s,3H),3.86(s,3H),3.01(t, J ═ 6.0Hz,2H),2.71(s,3H),2.33(t, J ═ 6.0Hz,2H),2.16ppm (s, 6H); ES-API (m/z) calculated value C30H34N8O2[M+H]+, 539.3; theoretical value, 539.3.
Example 11N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-cyclopropylcarboxamide
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-cyclopropanecarboxamide (1.15g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 10.21(s,1H),9.05(s,1H),8.66(s,1H),8.32(d, J, 5.2Hz,1H),8.23(d, J, 8.0Hz,1H),7.85(s,1H),7.53(d, J, 8.0Hz,1H),7.29-7.23(m,1H),7.22(d, J, 5.2Hz,1H),7.20-7.13(m,1H),7.02(s,1H),3.90(s,3H),3.85(s,3H),2.92(t, J, 6.0Hz,2H),2.72(s,3H),2.37(t, J, 6.0, 2H),2.28(s,6H), 1.83-1H), 1.70(m, 0 ppm), 4.75-m, 1H); ES-API (m/z) calculated value C29H35N7O2[M+H]+, 514.3; theoretical value, 514.3.
Example 12N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-p-toluenesulphonic acid amine
The compound N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (1.0g,2.24mmol,1eq), DIPEA (0.74ml,4.49mmol,2.0eq) were dissolved in dichloromethane, the corresponding p-toluenesulfonyl chloride (428mg,2.24mmol,1.0eq) was added dropwise, after stirring at room temperature for 1 hour, the reaction was washed twice with water, dried and concentrated, and the crude product was subjected to column chromatography (dichloromethane/methanol) to give a product (1.27 g).
1H NMR(400MHz,DMSO-d6) 12.03(s,1H),8.49(s,1H),8.37(s,1H),8.36-8.29(m,2H),7.89(s,1H),7.61-7.49(m,3H),7.30-7.21(m,4H),7.20-7.13(m,1H),6.87(s,1H),3.89(s,3H),3.78(s,3H),2.74(t, J ═ 5.2Hz,2H),2.33(s,6H),2.28(s,3H),2.24(t, J ═ 5.2Hz,2H),2.20ppm (s, 3H); ES-API (m/z) calculated value C32H37N7O3S[M+H]+, 600.3; theoretical value, 600.3.
Example 13N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- ((S) -2-chloro) propanamide
S-2-chloropropionic acid (365mg, 3.37mmol,1.5eq) was dissolved in 50mL DCM, starting material (1g, 2.24mol,1eq) was added, the mixture was stirred for 10min under ice-bath, EDCI (1.5g, 4.49mmol,2eq) and DMAP (110mg,0.90mmol,0.4eq) were added, and the mixture was stirred to room temperature under ice-bath and reacted overnight. After the reaction was complete, extraction was performed with water and DCM, and the organic phase was taken, spin dried and purified by silica gel chromatography to give the product (700 mg). .
1H NMR(400MHz,DMSO-d6)10.10(s,1H),8.95(s,1H),8.62(s,1H),8.33(d, J ═ 4.4Hz,1H),8.25(d, J ═ 6.4Hz,1H),7.91(s,1H),7.53(d, J ═ 6.8Hz,1H),7.27-7.23(m,2H),7.18(t, J ═ 6.4Hz,1H),7.02(s,1H),5.08(br,1H),3.93(s,3H),3.88(s,3H),3.10(brs,2H),2.67(s,3H),2.42(br,8H),1.64(d, J ═ 5.2Hz, 3H); ES-API (m/z) calculated value C28H34ClN7O2[M+H]+, 536.1; theoretical value, 536.1.
Example 14N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- ((R) -2-chloro) propanamide
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- ((R) -2-chloro) propionamide (665mg) was prepared according to example 13.
1H NMR(400MHz,DMSO-d6)10.16(s,1H),9.01(s,1H),8.64(s,1H),8.33(d, J ═ 5.2Hz,1H),8.23(d, J ═ 8.0Hz,1H),7.90(s,1H),7.53(d, J ═ 8.4Hz,1H),7.27-7.23(m,2H),7.17(t, J ═ 7.6Hz,1H),7.05(s,1H),4.85(br,1H),3.93(s,3H),3.87(s,3H),2.99(br, 2H),2.69(s,3H),2.35(br,2H),2.25(br,6H),1.66(d, J ═ 6.8, 3H); ES-API (m/z) calculated value C28H34ClN7O2[M+H]+, 536.1; theoretical value, 536.1.
Example 15N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- ((S) -2-chloro) propanamide methanesulfonate
The product from example 13 (535mg, 1.0mmol, 1eq) was dissolved in 5ml of acetone and gradually stirred to 50 ℃ and the prepared methanesulfonic acid solution (96mg, 1.0mol, 1eq, methanesulfonic acid in 96mg, 0.5ml of acetone) was added and reacted for about 3 h. After the reaction was completed, suction filtration and drying were carried out to obtain a product (86 mg).
1H NMR(400MHz,DMSO-d6) 9.98(s,1H),9.92(s,1H),8.75(s,1H),8.40(s,2H),8.24(s,2H),7.59(d, J ═ 8.2Hz,1H),7.38(d, J ═ 6.3Hz,1H),7.31(t, J ═ 7.5Hz,1H),7.23(t, J ═ 7.2Hz,1H),7.05(s,1H),5.32(t, J ═ 4.7Hz,1H),3.94(s,3H),3.87(s,3H), 3.33-3.30 (m,4H),2.79(s,6H),2.67(s,3H),2.32(s,3H),1.58(d, J ═ 6, 3 Hz); ES-API (m/z): calculated value, C29H38ClN7O5S[M-CH3SO3]+, 536.1; theoretical value, 536.1.
Example 16N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- ((R) -2-chloro) propanamide methanesulfonate
The product obtained in example 14 was prepared according to the preparation method of example 15 to give N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- ((R) -2-chloro) propionamide methanesulfonate (79 mg).
1H NMR(400MHz,DMSO-d6)10.17(s,1H),9.97(s,1H),8.75(s,1H),8.46(s,1H),8.4-8.1(br,3H),7.59(d, J ═ 8.1Hz,1H),7.38(d, J ═ 6.3Hz,1H),7.31(t, J ═ 7.5Hz,1H),7.24(t, J ═ 7.4Hz,1H),7.04(s,1H),5.41(q, J ═ 6.6Hz,1H),3.95(s,3H),3.88(s,3H),3.39-3.35(m,2H),3.35-3.31(m,2H),2.79(s,6H),2.68(s,3H),2.34(s,3H),1.59 (s,6H), 6.59 (d, 6H); ES-API (m/z): calculated value, C29H38ClN7O5S[M-CH3SO3]+, 536.1; theoretical value, 536.1.
Effects of the embodiment
1. Test method
Cells in logarithmic growth phase were seeded at 3-6 ten thousand per mL per well in 96-well culture plates in a volume of 100. mu.L per well, and the plates were then transferred to CO2In an incubator at 37 deg.C and 5% CO2Culturing for 24h under saturated humidity condition, diluting the tested compound in gradient, adding the diluted tested compound into corresponding wells of a 96-well plate, incubating with cells, culturing and incubating for 72h in a cell culture box, adding 10 mu L of CCK8 reagent into each well after the incubation is finished, incubating for 2-4 h in the culture box, measuring OD value at 450nm, calculating the survival rate of the drug on the cell growth according to the following formula of (survival rate (%) - (OD drug-OD blank)/(OD control-OD blank) × 100%, fitting to obtain an inhibition curve, and calculating corresponding IC50See table 1 for details.
2. Primary reagent
TABLE 1 test Compounds IC50Test results
TABLE 2 selectivity of test compounds HWB 14-17 for different cell lines
Remarking: h1975 in tables 1 and 2 is EGFR mutant non-small cell lung cancer cell; HCC827 is EGFR mutant non-small cell lung cancer cell; a431 is a tumor cell with high expression of normal EGFR; wi38 was normal cells.
As can be seen from Table 1, the compounds of the present application have inhibitory effects on EGFR-mutated H1975 and HCC827, and normal EGFR-overexpressed A431, and IC thereof50The values are all below 1000nM, and the toxicity to normal cell Wi38 is extremely low, and the IC is50The value can be as high as 10000nM or more, and the medicine has better patent medicine prospect; in particular, it represents the compound HWB17, the inhibitory activity against EGFR mutated H1975 and HCC827 is of the same order of magnitude as that of the marketed drug AZD9291 (control drug, ocitinib), and it is more selective for a431 of non-mutated EGFR.
As can be seen from table 2, the compounds of the present application have higher selectivity for EGFR mutant cancer cells than EGFR highly expressed cancer cells. In particular, compound HWB17 (example 16) was 107-fold selective for a431/H1975 and a431/HCC827 was 1337-fold more selective than AZD9291 (control, ocitinib) by 1-fold; HWB16 also showed comparable selectivity to AZD9291 for EGFR-highly expressed cancer cells and mutant cancer cells.
Claims (10)
1. A compound of formula I or a pharmaceutically acceptable salt thereof:
R1Is C1~10Alkyl, halogen substituted C1~10Alkyl radical, C3~10Cycloalkyl radical, C6~30Aryl radical, R1-1Substituted C6~30Aryl, 3-to 30-membered heteroaryl orThe heteroatoms in the 3-30 membered heteroaryl are N, O or S independently, and the number of the heteroatoms is 1,2 or 3; when the number of the hetero atoms is plural, the species of the hetero atoms are the same or different;
said halogen substituted C1~10The number of halogen substitution in the alkyl group is 1 or more; when the number of the halogen substitution is plural, the halogens are independently the same or different;
each R1-1Independently of one another, halogen, C1~10Alkyl radical, C1~10Alkoxy orThe R is1-11,2, 3 or 4; when said R is1-1When there are plural, R is1-1The same or different;
the R is1-1-1aAnd R1-1-1bIndependently is C1~4An alkyl group;
R2is C6~30Aryl or R2-1Substituted C6~30An aryl group;
each R2-1Independently of one another, halogen, C1~10Alkyl or C1~10An alkoxy group; the R is2-1Is 1 or more; when said R is2-1When there are plural, R is2-1The same or different.
2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I is a mesylate, esylate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, lactate, malate, citrate, tartrate, picrate, glutamate, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate or phosphate salt, preferably a mesylate salt;
when R is1Is halogen substituted C1~10When alkyl, said halogen being substituted by C1~10C in alkyl1~10Alkyl is C1~6Alkyl, preferably C1~3An alkyl group;
when R is1Is halogen substituted C1~10When alkyl, said halogen being substituted by C1~10Halogen in the alkyl is F, Cl, Br or I, preferably Cl;
when R is1Is halogen substituted C1~10When alkyl, said halogen being substituted by C1~10The number of halogen substitution in the alkyl group is 1 or more, preferably 1;
when said halogen is substituted C1~10When the alkyl group has a chiral center, the halogen is substituted C1~10The spatial configuration of the alkyl is R type;
when R is1Is C3~10When a cycloalkyl group is present, C is3~10Cycloalkyl being C3~6A cycloalkyl group;
when R is1Is R1-1Substituted C6~30When aryl is said to R1-1Substituted C6~30C in aryl6~30Aryl is C6~20Aryl, preferably C6~14An aryl group;
when R is1Is R1-1Substituted C6~30When aryl is said to R1-1The number of (a) is 1,2 or 3;
when R is1In the case of a 3-to 30-membered heteroaryl group, the 3-to 30-membered heteroaryl group is a 3-to 10-membered heteroaryl group, preferably a 3-to 6-membered heteroaryl group, and more preferably a 5-membered heteroaryl group;
when R is1In the case of 3-30-membered heteroaryl, the heteroatom in the 3-30-membered heteroaryl is N and/or O, preferably N;
when R is1In the case of a 3-to 30-membered heteroaryl group, the number of heteroatoms in the 3-to 30-membered heteroaryl group is 1 or 2, preferably1, the number of the active ingredients is 1;
when each R is1-1Independently halogen, said halogen is F, Cl, Br or I, preferably F, Cl or Br;
when each R is1-1Independently is C1~10At alkoxy, the C1~10Alkoxy is C1~6Alkoxy, preferably C1~3An alkoxy group;
when said R is1-1-1aAnd R1-1-1bIndependently is C1~4When alkyl, said C1~4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl;
when R is2Is R2-1Substituted C6~30When aryl is said to R2-1Substituted C6~30C in aryl6~30Aryl is C6~20Aryl, preferably C6~14An aryl group;
when each R is2-1Independently is C1~10When alkyl, said C1~10Alkyl is C1~6Alkyl, preferably C1~3An alkyl group.
3. The compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 2, wherein when R is1Is halogen substituted C1~10Alkyl, said halogen substituted C1~10C in alkyl1~10Alkyl is C1~3When alkyl, said C1~3Alkyl is methyl, ethyl, n-propyl or isopropyl, preferably ethyl;
when R is1Is C3~10Cycloalkyl radical, said C3~10Cycloalkyl being C3~6When a cycloalkyl group is present, C is3~6Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl;
when R is1Is R1-1Substituted C6~30Aryl radical, said R1-1Substituted C6~30C in aryl6~30Aryl is C6~14Aryl is said to C6~14Aryl is phenyl, naphthyl, phenanthryl or anthracyl, preferably phenyl;
when each R is1-1Independently is C1~10Alkoxy radical, said C1~10Alkoxy is C1~3At alkoxy, the C1~3Alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy, preferably methoxy;
when R is2Is R2-1Substituted C6~30When aryl is said to R2-1Substituted C6~30C in aryl6~30Aryl is C6~14Aryl radical, said C6~14Aryl is phenyl, naphthyl, phenanthryl or anthracyl, preferably phenyl.
6. A compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereofAn acceptable salt, wherein when R isR1Is R1-1Substituted C6~30When aryl is said each R1-1Independently of one another, halogen, C1~10Alkyl or
7. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, wherein when R isR1Is halogen substituted C1~10When alkyl, said halogen being substituted by C1~10Alkyl chloride substituted C1~3Alkyl, more preferablyFurther preferred is
When R isR1Is R1-1Substituted C6~30When aryl is said to R1-1Substituted C6~30Aryl is "substituted by 1,2 or 3, halogen orSubstituted phenyl, further preferred
When R isR1In the case of the 3-to 30-membered heteroaryl group, the 3-to 30-membered heteroaryl group may be a "3-to 10-membered heteroaryl group in which the number of hetero atoms is 1 or 2", preferably a "3-to 6-membered heteroaryl group in which the number of hetero atoms is 1", and more preferably a pyrrolyl group.
9. the process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, which is process 1, process 2 or process 3:
the method comprises the following steps: the method comprises the following steps of carrying out condensation reaction of a compound shown in a formula II and a compound shown in a formula III in an organic solvent under the action of a condensing agent and an alkaline reagent to obtain a compound shown in a formula I;
the method 2 comprises the following steps: the method comprises the following steps of carrying out acylation reaction on a compound shown in a formula II and a compound shown in a formula IV in an organic solvent in the presence of an acid binding agent to obtain a compound shown in a formula I;
the method 3 comprises the following steps: the method comprises the following steps of reacting a compound shown as a formula I with acid in a solvent to obtain a salt of the compound shown as the formula I;
wherein R in the methods 1,2 and 3 is as defined in any one of claims 1 to 8.
10. The method of claim 9, wherein in method 1, the condensing agent is 2- (7-oxybenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate, dicyclohexylcarbodiimide, or carbonyldiimidazole;
and/or in the method 1, the molar ratio of the condensing agent to the compound II is 1.0-2.0;
and/or, in method 1, the basic reagent is triethylamine and/or N, N-diethylisopropylamine;
and/or in the method 1, the molar ratio of the alkaline reagent to the compound II is 1.0-5.0;
and/or in the method 1, the molar ratio of the compound III to the compound II is 1.0-2.0;
and/or, in the method 1, the organic solvent is one or more of halogenated hydrocarbon solvent, amide solvent and sulfone solvent, preferably halogenated hydrocarbon solvent; further preferably one or more of dichloromethane, dichloroethane and chloroform, still further preferably dichloromethane;
And/or in the method 1, the condensation reaction temperature is 10-40 ℃;
and/or in the method 2, the acid-binding agent is an organic weak base, and the organic weak base is one or more of pyridine, triethylamine and N, N-diethyl isopropylamine;
and/or in the method 2, the molar ratio of the acid-binding agent to the compound II is 1.0-5.0;
and/or in the method 2, the molar ratio of the compound IV to the compound II is 1.0-2.0;
and/or, in the method 2, the organic solvent is one or more of a halogenated hydrocarbon solvent, an amide solvent and a sulfone solvent, preferably a halogenated hydrocarbon solvent, more preferably one or more of dichloromethane, dichloroethane and chloroform, and still more preferably dichloromethane;
And/or in the method 2, the temperature of the acylation reaction is 0-40 ℃;
and/or, in the method 3, the acid is an organic acid or an inorganic acid; the organic acid is one or more of methanesulfonic acid, ethanesulfonic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, picric acid and glutamic acid, and preferably methanesulfonic acid; the inorganic acid is one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid;
and/or in the method 3, the molar ratio of the acid to the compound shown in the formula I is 1-3;
and/or, in method 3, the solvent is a ketone solvent;
and/or in the method 3, the reaction temperature is 10-60 ℃.
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