CN111484484B - 2, 4-diaryl aminopyrimidine derivative containing aromatic heterocycle and preparation and application thereof - Google Patents

2, 4-diaryl aminopyrimidine derivative containing aromatic heterocycle and preparation and application thereof Download PDF

Info

Publication number
CN111484484B
CN111484484B CN202010283698.8A CN202010283698A CN111484484B CN 111484484 B CN111484484 B CN 111484484B CN 202010283698 A CN202010283698 A CN 202010283698A CN 111484484 B CN111484484 B CN 111484484B
Authority
CN
China
Prior art keywords
amino
pyrimidin
chloro
methyl
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202010283698.8A
Other languages
Chinese (zh)
Other versions
CN111484484A (en
Inventor
翟鑫
郭明
左代英
邢凌云
曹猛
赵天铭
陈煜翔
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenyang Pharmaceutical University
Original Assignee
Shenyang Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenyang Pharmaceutical University filed Critical Shenyang Pharmaceutical University
Priority to CN202010283698.8A priority Critical patent/CN111484484B/en
Publication of CN111484484A publication Critical patent/CN111484484A/en
Application granted granted Critical
Publication of CN111484484B publication Critical patent/CN111484484B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

The invention relates to 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocyclic rings shown in a general formula I, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, a preparation method thereof and a pharmaceutical composition taking the compounds shown in the general formula I as active ingredients, wherein a substituent R is1、R2、R3、R4、R5、R6X, Y, Z have the meaning given in the description. The invention also relates to a compound of the general formula I, which has strong ALK and ROS1 kinase inhibition effect, and also relates to an application of the compound, an optical isomer and a pharmaceutically acceptable salt thereof in preparing a medicament for treating and/or preventing diseases caused by abnormal expression of ALK and ROS1, in particular to an application in preparing a medicament for treating and/or preventing cancers.

Description

2, 4-diaryl aminopyrimidine derivative containing aromatic heterocycle and preparation and application thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocycles, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, a preparation method of the derivatives and a pharmaceutical composition containing the compounds. The invention also relates to a strong ALK and ROS1 kinase inhibition effect of the compound and an application of the compound in preparing a medicament for treating and/or preventing diseases caused by abnormal expression of ALK and ROS1, in particular to an application in preparing a medicament for treating and/or preventing cancers.
Background
The research of kinase target drugs has become an important direction for the research and development of current antitumor drugs, and among them, protein kinases are the most studied class. The dysfunction or abnormality of the signal transduction process due to mutation or rearrangement of protein kinases may lead to abnormal cell growth, differentiation, metabolism and biological behavior, which in turn may induce various tumors.
Protein Kinases (PKs), which are enzymes catalyzing phosphorylation of hydroxyl groups on tyrosine, Serine, and threonine residues of proteins by transfer of terminal phosphate of ATP, mainly include Protein Tyrosine Kinase (PTK) and Serine-threonine kinase (STK). These enzymes regulate cell growth, differentiation, proliferation, and the like through signal transduction pathways.
Anaplastic Lymphoma Kinase (ALK) is a member of the insulin receptor tyrosine kinase family, first discovered in 1994 in anaplastic large cell lymphoma AMS3 cells, and is a single-chain transmembrane protein consisting of 1620 amino acids. ALK is expressed at high levels during embryonic development, with a subsequent gradual decline in expression levels and little expression during adulthood. The protein consists of an external membrane part, a transmembrane region and an internal membrane catalytic region, and the downstream signal pathways are Ras-ERK, JAK3-STAT3, PI3-K/Akt and the like, and are closely related to cell proliferation, survival and migration.
Morri et al, 1994 found that the ALK gene on chromosome 2 is fused with nucleolar phosphoprotein NPM (nucleophosphosmin) gene on chromosome 5 in a staggered manner, and the rearranged mutant gene NPM-ALK has carcinogenicity. The japanese scientist Soda et al found ALK gene mutations in lung adenocarcinoma tissue for the first time in 2007: inverted mutation occurs in the short arm of chromosome 2, so that NIH-3T3 fibroblasts of which the EML4-ALK fusion gene is transfected by fusion of exons 1-13 of echinoderm microtubule-associated protein 4(EML4) gene and exons 20-29 of ALK gene to form EML4-ALK fusion gene have malignant transformation capability. The EML4-ALK fusion gene is present in approximately 3% to 7% of NSCLC patients. In addition, studies have shown that ALK gene mutations are involved in the pathogenesis of a variety of tumors, including anaplastic large cell lymphoma, inflammatory myofibroblastoma, neuroblastoma. Therefore, the target ALK inhibitor can achieve the anti-tumor purpose by inhibiting ALK downstream related signals.
The c-ROS sarcoma carcinogen receptor tyrosine kinase ROS1(ROS proto-oncogene 1) is also a haplotype receptor tyrosine kinase. Fusion, overexpression and mutation of the ROS1 gene all result in the dysregulation of the ROS1 protein. Abnormal ROS1 protein kinase will activate multiple downstream oncogenic signaling pathways, controlling pathways for cell proliferation, survival and cell cycle. ROS1 is highly expressed in a variety of tumor cells, with 49% amino acid sequence homology to ALK and up to 77% homology in the ATP binding region. A variety of ALK inhibitors can inhibit the activity of ROS1 in vitro.
The invention designs and synthesizes a series of 2, 4-diaryl aminopyrimidine derivatives containing aromatic heterocycle. In vitro activity screening shows that the compounds have obvious antitumor activity.
Disclosure of Invention
The invention relates to 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocycle shown in a general formula I, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
Figure BDA0002447676200000021
wherein the content of the first and second substances,
n is 1 or 2
X is independently C, N, O or S, and may be substituted by R5Substitution;
y is independently C, N, O or S, and may be substituted with R4Substitution;
z is independently C, N, O or S, and may be substituted by R6Substitution;
R1is hydroxy, halogen, nitro, amino, cyano, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, (C)1-C6) Alkyl acyl group, (C)1-C6) Alkylamido radical, (C)1-C6) Alkylsulfonylamino group by 1-2 (C)1-C6) Alkyl-substituted carbamyl (acetyl) acyl, substituted by 1-2 hydroxy (C)1-C6) Alkyl-substituted aminomethylformyl, (C)1-C3) An alkylenedioxy group;
R2is halogen, halogenated or not halogenated (C)1-C6) Alkyl, hydroxy, cyano, amino, nitro;
R3is H, halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkylthio, halogen or/and hydroxy or/and amino substituted (C)1-C6) Alkyl, halogen and/or hydroxy and/or amino substituted (C)1-C6) Alkoxy, halogen and/or hydroxy and/or amino substituted (C)1-C6) An alkylthio group;
R4is H, (C)1-C6) Alkyl, 3-6 membered saturated or partially saturated carbocyclic ring, (C)1-C6) Alkyl acyl or (C)1-C6) An alkylsulfonyl group;
R5is H, (C)1-C6) Alkyl, 3-6 membered saturated or partially saturated carbocyclic ring, (C)1-C6) An alkanoyl or alkylsulfonyl group; or NR7R8、NHmCOR7R8、NHmCONHmR7R8、SO2(CH2)mNR7R8、 SO2(CH2)mCONR7R8、CONHmR7R8、(CH2)pR7R8、(CH2)pNmR7R8、CO(CH2)pR7R8、 NHmCO(CH2)pR7R8、NHm(CH2)pCOR7R8、NHmCO(CH2)pNHmR7R8、COR7；
R6Is H, (C)1-C6) Alkyl, 3-6 membered saturated or partially saturated carbocyclic ring, (C)1-C6) Alkyl acyl or (C)1-C6) An alkylsulfonyl group; or NR7R8、NHmCOR7R8、NHmCONHmR7R8、SO2(CH2)mNR7R8、 SO2(CH2)mCONR7R8、CONHmR7R8、(CH2)pR7R8、(CH2)pNmR7R8、CO(CH2)pR7R8、 NHmCO(CH2)pR7R8、NHm(CH2)pCOR7R8、NHmCO(CH2)pNHmR7R8；
R7And R8The same or different, are respectively and independently selected from H and (C)1-C10) Alkyl, (C)3-C7) Cycloalkyl group, (C)1-C10) Alkoxy group, (C)2-C10) Alkenyl, (C)2-C10) Alkynyl, cyano, carboxyl, hydroxyl, amino, hydroxyl and/or amino substituted (C)1-C10) Alkyl, hydroxy and/or amino substituted (C)1-C10) An alkoxy group;
or R7And R8Together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl group, other than R7And R8Optionally containing 0 to 4 heteroatoms selected from N, O and/or S in addition to the nitrogen atom to which it is attached, said heterocyclyl or heteroaryl group optionally being substituted with 0 to 3R, which may be the same or different9Substitution;
R9is (C)1-C10) Alkyl, (C)3-C7) Cycloalkyl group, (C)1-C10) Alkoxy, hydroxy, carboxyl, amino, hydroxy and/or amino substituted (C)1-C10) Alkyl, hydroxy and/or amino substituted (C)1-C10) Alkoxy, halogen, halo (C)1-C10) Alkyl, halo (C)1-C10) Alkoxy, nitro;
m is independently 0-2 and p is independently 0-6.
The invention relates to 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocycle shown in a general formula I, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein the content of the first and second substances,
n is 1 or 2
X is independently C, N, O or S, and may be substituted by R5Substitution;
y is independently C, N, O or S, and may be substituted with R4Substitution;
z is independently C, N, O or S, and may be substituted by R6Substitution;
R1is hydroxy, halogen, nitro, amino, cyano, (C)1-C3) Alkylsulfinyl (C)1-C3) Alkylsulfonyl group, (C)1-C3) Alkoxy group, (C)1-C3) Alkyl, (C)1-C3) Alkyl acyl group, (C)1-C3) Alkylamido radical, (C)1-C3) Alkylsulfonylamino group by 1-2 (C)1-C3) Alkyl-substituted carbamyl (acetyl) acyl, substituted by 1-2 hydroxy (C)1-C3) Alkyl substituted aminomethylcarbonyl, alkylenedioxy;
R2is halogen, halogenated or not halogenated (C)1-C3) Alkyl, hydroxy, cyano, amino, nitro;
R3is H, halogen, (C)1-C3) Alkyl, (C)1-C3) Alkoxy group, (C)1-C3) Alkylthio, halogen or/and hydroxy or/and amino substituted (C)1-C3) Alkyl, halogen and/or hydroxy and/or amino substituted (C)1-C3) Alkoxy, halogen and/or hydroxy and/or amino substituted (C)1-C3) An alkylthio group;
R4is H, (C)1-C3) Alkyl, 3-6 membered saturated or partially saturated carbocyclic ring, (C)1-C3) Alkyl acyl or (C)1-C3) An alkylsulfonyl group;
R5is H, (C)1-C3) Alkyl, 3-6 membered saturated or partially saturated carbocyclic ring, (C)1-C3) Alkyl acyl or (C)1-C3) An alkylsulfonyl group; or NR7R8、NHmCOR7R8、NHmCONHmR7R8、SO2(CH2)mNR7R8、 SO2(CH2)mCONR7R8、CONHmR7R8、(CH2)pR7R8、(CH2)pNmR7R8、CO(CH2)pR7R8、 NHmCO(CH2)pR7R8、NHm(CH2)pCOR7R8、NHmCO(CH2)pNHmR7R8、COR7；
R6Is H, (C)1-C3) Alkyl, 3-6 membered saturated or partially saturated carbocyclic ring, (C)1-C3) Alkyl acyl or (C)1-C3) An alkylsulfonyl group; or NR7R8、NHmCOR7R8、NHmCONHmR7R8、SO2(CH2)mNR7R8、 SO2(CH2)mCONR7R8、CONHmR7R8、(CH2)pR7R8、(CH2)pNmR7R8、CO(CH2)pR7R8、 NHmCO(CH2)pR7R8、NHm(CH2)pCOR7R8、NHmCO(CH2)pNHmR7R8；
R7And R8The same or different, are respectively and independently selected from H and (C)1-C3) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C3) Alkoxy group, (C)2-C4) Alkenyl, (C)2-C4) Alkynyl, cyano, carboxyl, hydroxyl, amino, hydroxyl and/or amino substituted (C)1-C3) Alkyl, hydroxy and/or amino substituted (C)1-C3) An alkoxy group;
or R7And R8Together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl group, other than R7And R8Optionally containing 0 to 4 heteroatoms selected from N, O and/or S in addition to the nitrogen atom to which it is attached, said heterocyclyl or heteroaryl group optionally being substituted with 0 to 3R, which may be the same or different9Substitution;
R9is (C)1-C3) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C3) Alkoxy radicalSubstituted by radicals, hydroxy, carboxy, amino, hydroxy and/or amino (C)1-C3) Alkyl, hydroxy and/or amino substituted (C)1-C3) Alkoxy, halogen, halo (C)1-C3) Alkyl, halo (C)1-C3) Alkoxy, nitro;
m is independently 0-2 and p is independently 0-6.
The invention relates to 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocycle shown in a general formula I, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein the content of the first and second substances,
n＝1
x is independently C, N, O or S, and may be substituted by R5Substitution;
y is independently C, N, O or S, and may be substituted with R4Substitution;
z is independently C, N, O or S, and may be substituted by R6Substitution;
R1is (C)1-C3) Alkylsulfinyl (C)1-C3) Alkylsulfonyl group, (C)1-C3) Alkoxy group, (C)1-C3) Alkyl, (C)1-C3) Alkyl acyl group, (C)1-C3) Alkylamido radical, (C)1-C3) Alkylsulfonylamino group by 1-2 (C)1-C3) Alkyl-substituted carbamyl (acetyl) acyl, substituted by 1-2 hydroxy (C)1-C3) Alkyl substituted aminomethylcarbonyl, alkylenedioxy;
R2is halogen, hydroxyl, cyano, amino, nitro;
R3is H, halogen, (C)1-C3) Alkyl, (C)1-C3) Alkoxy, halogen and/or hydroxy and/or amino substituted (C)1-C3) Alkyl, halogen and/or hydroxy and/or amino substituted (C)1-C3) An alkoxy group;
R4is H, (C)1-C3) Alkyl, (C)1-C3) Alkyl acyl or (C)1-C3) Alkyl sulfonic acidAn acyl group;
R5is H, (C)1-C3) An alkyl group; or NHmCONHmR7R8、CONHmR7R8、(CH2)pR7R8、 (CH2)pNmR7R8、CO(CH2)pR7R8、NHmCO(CH2)pR7R8、NHm(CH2)pCOR7R8、 NHmCO(CH2)pNHmR7R8、COR7；
R6Is H, (C)1-C3) An alkyl group; or NHmCONHmR7R8、CONHmR7R8、(CH2)pR7R8、 (CH2)pNmR7R8、CO(CH2)pR7R8、NHmCO(CH2)pR7R8、NHm(CH2)pCOR7R8、 NHmCO(CH2)pNHmR7R8；
R7And R8The same or different, are respectively and independently selected from H and (C)1-C3) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C3) Alkoxy group, (C)2-C4) Alkenyl, (C)2-C4) Alkynyl, cyano, carboxyl, hydroxyl, amino, hydroxyl and/or amino substituted (C)1-C3) An alkyl group;
or R7And R8Together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl or 4-6 membered heteroaryl group, other than R7And R8Optionally containing 0 to 4 heteroatoms selected from N, O and/or S in addition to the nitrogen atom to which it is attached, said heterocyclyl or heteroaryl group optionally being substituted by 0 to 2R, which may be the same or different9Substitution；
R9Is (C)1-C3) Alkyl, (C)1-C3) Alkoxy, hydroxy, carboxyl, amino, hydroxy and/or amino substituted (C)1-C3) An alkyl group;
m is independently 0-2 and p is independently 0-6.
The invention relates to 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocycle shown in a general formula I, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein the content of the first and second substances,
n＝1
x is independently C, N, O or S, and may be substituted by R5Substitution;
y is independently C, N, O or S, and may be substituted with R4Substitution;
z is independently C, N, O or S, and may be substituted by R6Substitution;
R1is (C)1-C3) Alkylamido radical, (C)1-C3) Alkylsulfonylamino group by 1-2 (C)1-C3) An alkyl-substituted carbamoyl group;
R2is halogen, hydroxy, cyano;
R3is H, halogen, (C)1-C3) Alkyl, (C)1-C3) An alkoxy group;
R4is H, (C)1-C3) Alkyl, (C)1-C3) Alkyl acyl or (C)1-C3) An alkylsulfonyl group;
R5is H, NHmCONHmR7R8、CONHmR7R8、(CH2)pNmR7R8、 NHmCO(CH2)pNHmR7R8、COR7；
R6Is H, (C)1-C3) An alkyl group; or NHmCONHmR7R8、CONHmR7R8、(CH2)pNmR7R8、 NHmCO(CH2)pNHmR7R8；
R7And R8The same or different, are respectively and independently selected from H and (C)1-C3) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C3) Alkoxy, hydroxy substituted (C)1-C3) Alkyl, hydroxy;
or R7And R8Together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, except for R7And R8Optionally containing 0 to 2 heteroatoms selected from N, O and/or S in addition to the nitrogen atom to which it is attached, said heterocyclic group optionally being substituted with 0 to 1 identical or different R9Substitution;
R9is (C)1-C3) Alkyl, hydroxy-substituted (C)1-C3) An alkyl group;
m is independently 0-1 and p is independently 0-3.
The invention relates to 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocycle shown in a general formula I, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein the content of the first and second substances,
n＝1
x is independently C or N, and may be substituted by R5Substitution;
y is N and may be R4Substitution;
z is independently C or N, and may be substituted by R6Substitution;
R1is (C)1-C3) Alkylamido radical, (C)1-C3) Alkylsulfonylamino group by 1-2 (C)1-C3) An alkyl-substituted carbamoyl group;
R2is halogen;
R3is H;
R4is H;
R5is NHmCONHmR7R8、CONHmR7R8、(CH2)pNmR7R8、COR7；
R6Is (C)1-C3) An alkyl group; or (CH)2)pNmR7R8；
R7And R8The same or different, are respectively and independently selected from H and (C)1-C3) Alkyl, (C)1-C3) Alkoxy, hydroxy substituted (C)1-C3) Alkyl, hydroxy;
or R7And R8Together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, except for R7And R8Optionally containing 0 to 1 heteroatom selected from N, O and/or S in addition to the attached nitrogen atom, said heterocyclic group being optionally substituted by 0 to 1R which may be the same or different9Substitution;
R9is (C)1-C3) Alkyl, hydroxy-substituted (C)1-C3) An alkyl group;
m is independently 0-1 and p is independently 0-3.
The invention relates to 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocycle shown in a general formula I, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein the content of the first and second substances,
n＝1
x is independently C or N, and may be substituted by R5Substitution;
y is N and may be R4Substitution;
z is independently C or N, and may be substituted by R6Substitution;
R1is acetylamino, methylsulfonylamino, N-methylcarbamoyl, N-dimethylcarbamoyl;
R2is Cl;
R3is H;
R4is H;
R5is CONHmR7R8、COR7；
R6Is methyl; or (CH)2)pNmR7R8；
R7And R8The same or different, are respectively and independently selected from H and (C)1-C3) Alkyl, (C)1-C3) Alkoxy, hydroxy substituted (C)1-C3) Alkyl, hydroxy;
or R7And R8Together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, except for R7And R8Optionally containing 0 to 1 heteroatom selected from N, O and/or S in addition to the attached nitrogen atom, said heterocyclic group being optionally substituted by 0 to 1R which may be the same or different9Substitution;
R9is (C)1-C3) Alkyl, hydroxy-substituted (C)1-C3) An alkyl group;
m is independently 0-1 and p is independently 0-3.
The invention relates to 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocycle shown in a general formula I, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein the content of the first and second substances,
n＝1
x is N;
y is N and may be R4Substitution;
z is C and may be R6Substitution;
R1is acetylamino, methylsulfonylamino, N-methylcarbamoyl, N-dimethylcarbamoyl;
R2is Cl;
R3is H;
R4is H;
R6is (CH)2)pNmR7R8；
R7And R8The same or different, are respectively and independently selected from H and (C)1-C3) Alkyl, hydroxy substituted (C)1-C3) An alkyl group;
or R7And R8Together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, except for R7And R8Optionally containing 0 to 1 heteroatom selected from N, O and/or S in addition to the attached nitrogen atom, said heterocyclic group being optionally substituted by 0 to 1R which may be the same or different9Substitution;
R9is (C)1-C3) Alkyl, hydroxy-substituted (C)1-C3) An alkyl group;
m is independently 1 and p is independently 1.
The invention relates to 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocycle shown in a general formula I, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein the content of the first and second substances,
n＝1
x is N;
y is N and may be R4Substitution;
z is C and may be R6Substitution;
R1is acetylamino, methylsulfonylamino, N-methylcarbamoyl, N-dimethylcarbamoyl;
R2is Cl;
R3is H;
R4is H;
R6is composed of
Figure BDA0002447676200000061
Figure BDA0002447676200000062
The invention relates to 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocycle shown in a general formula I, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein the content of the first and second substances,
n＝1
x is C and may be R5Substitution;
y is N, and Y is N,and can be substituted by R4Substitution;
z is C and may be R6Substitution;
R1is methylsulfonylamino, N-methylcarbamoyl;
R2is Cl;
R3is H;
R4is H;
R5is CONHmR7R8、COR7；
R6Is methyl;
R7and R8The same or different, are respectively and independently selected from H and (C)1-C3) Alkyl, (C)1-C3) Alkoxy, hydroxy substituted (C)1-C3) Alkyl, hydroxy;
or R7And R8Together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, except for R7And R8Optionally containing 0 to 1 heteroatom selected from N, O and/or S in addition to the attached nitrogen atom, said heterocyclic group being optionally substituted by 0 to 1R which may be the same or different9Substitution;
R9is (C)1-C3) Alkyl, hydroxy-substituted (C)1-C3) An alkyl group;
m is independently 1.
The invention relates to 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocycle shown in a general formula I, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
wherein the content of the first and second substances,
n＝1
x is C and may be R5Substitution;
y is N and may be R4Substitution;
z is C and may be R6Substitution;
R1is methylsulfonylamino, N-methylcarbamoyl;
R2is Cl;
R3is H;
R4is H;
R5is composed of
Figure BDA0002447676200000071
Figure BDA0002447676200000072
R6Is methyl.
The compounds of the present invention and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof are preferably the following compounds, but these compounds are not meant to limit the present invention in any way:
n- (2- ((5-chloro-2- ((2- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
2- (5-chloro-2- ((2- (((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
N- (2- ((5-chloro-2- ((2- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) acetamide
2- ((5-chloro-2- ((2- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylphenylcarboxamide
N- (2- ((5-chloro-2- ((2- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
2- ((5-chloro-2- ((2- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
N- (2- ((5-chloro-2- ((2- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) acetamide
2- ((5-chloro-2- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
N- (2- ((5-chloro-2- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
2- ((5-chloro-2- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
N- (2- ((5-chloro-2- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) acetamide
N- (2- ((5-chloro-2- ((2- (piperidin-1-ylmethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2- ((4-ethylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2- (pyrrolidin-1-ylmethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
2- ((5-chloro-2- ((2- ((4-methylpiperidin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
N- (2- ((5-chloro-2- ((2- ((4-methylpiperidin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2- ((4-methylpiperidin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) acetamide
N- (2- ((5-chloro-2- ((2- ((4-hydroxypiperidin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- (((2- ((diisopropylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2- (morpholinomethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2- ((diethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2- (thiomorpholinomethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
2- ((5-chloro-2- ((2- (piperidin-1-ylmethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
2- ((5-chloro-2- ((2- ((4-ethylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
2- ((5-chloro-2- ((2- (pyrrolidin-1-ylmethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
2- ((5-chloro-2- ((2- (morpholinomethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
2- ((5-chloro-2- ((2- ((diethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
2- ((5-chloro-2- ((2- (thiomorpholinomethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
6- ((5-chloro-4- ((2- (methylsulfonylamino) phenyl) amino) pyrimidin-2-yl) amino) -2-methyl-1H-indole-3-carboxylic acid ethyl ester
6- ((5-chloro-4- ((2- (methylsulfonylamino) phenyl) amino) pyrimidin-2-yl) amino) -2-methyl-1H-indole-3-carboxylic acid methyl ester
N- (2- ((5-chloro-2- ((2-methyl-3- (4-methylpiperazine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((3- (4- (2-hydroxyethyl) piperazine-1-carbonyl) -2-methyl-1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
6- ((5-chloro-4- ((2- (methylsulfonylamino) phenyl) amino) pyrimidin-2-yl) amino) -N- (2-hydroxyethyl) -2-methyl-1H-indole-3-carboxamide
N- (2- ((5-chloro-2- ((3- (4-ethylpiperazine-1-carbonyl) -2-methyl-1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2-methyl-3- (4-methylpiperidine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((3- (4-hydroxypiperidine-1-carbonyl) -2-methyl-1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2-methyl-3- (piperidine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2-methyl-3- (morpholine-4-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2-methyl-3- (thiomorpholine-4-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2-methyl-3- (pyrrolidine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
(R) -N- (2- ((5-chloro-2- ((3- (2- (hydroxymethyl) pyrrolidine-1-carbonyl) -2-methyl-1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((3- (3-hydroxyazetidin-1-carbonyl) -2-methyl-1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
6- ((5-chloro-4- ((2- (methylsulfonylamino) phenyl) amino) pyrimidin-2-yl) amino) -N, 2-trimethyl-1H-indole-3-carboxamide
2- ((5-chloro-2- ((2-methyl-3- (4-methylpiperazine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
6- ((5-chloro-4- ((2- (methylcarbamoyl) phenyl) amino) pyrimidin-2-yl) amino) -N, 2-trimethyl-1H-indole-3-carboxamide
2- ((5-chloro-2- ((2-methyl-3- (morpholine-4-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
2- ((5-chloro-2- ((2-methyl-3- (4-methylpiperidine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
2- ((5-chloro-2- ((3- (4-hydroxypiperidine-1-carbonyl) -2-methyl-1H-indol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
6- ((5-chloro-4- ((2- (methylcarbamoyl) phenyl) amino) pyrimidin-2-yl) amino) -N, N-diethyl-2-methyl-1H-indole-3-carboxamide
6- ((5-chloro-4- ((2- (methylsulfonylamino) phenyl) amino) pyrimidin-2-yl) amino) -2-methyl-1H-indole-3-carboxylic acid
Furthermore, the 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocyclic rings of the general formula I of the present invention can form pharmaceutically acceptable salts with acids according to some common methods in the art to which the present invention pertains. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. The prodrug of the derivative is pyrimidine derivatives with the general formula I, wherein R contains hydroxyl5Or R6The group is esterified with a carboxyl compound to obtain the ester prodrug. They may themselves have a weak or even no activity, but are converted to the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) after administration.
"halogen" in the present invention means fluoro, chloro, bromo or iodo; "alkyl" refers to straight, branched alkyl or cycloalkyl; "alkylene" refers to straight or branched chain alkylene.
We have found that the compounds of the present invention have activity in inhibiting the growth of tumor cells in vitro and therefore, it can be used for the preparation of a medicament for the treatment and/or prevention of cancers, such as breast, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, pancreas, bone marrow, testis, ovary, lymph, soft tissues, head and neck, thyroid, esophageal cancers and leukemias, neuroblastoma and the like.
Through the activity test of inhibiting human anaplastic large cell lymphoma cells Karpas299 with high expression of NPM-ALK protein and human lung adenocarcinoma cells NCI-H2228 with high expression of EML4-ALK protein in vitro, the compound has obvious inhibiting effect on lung cancer cells and lymphoma cells, and is particularly used for preparing the medicines for treating and/or preventing lung cancer and lymphoma.
The active compound or the medicinal salt and the solvate thereof can be used alone as a unique antitumor medicament or can be used together with the antitumor medicaments (such as platinum medicaments cisplatin, camptothecin medicaments irinotecan, vinblastine medicaments navelbine and the like) on the market. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way.
The following synthetic schemes outline and describe the preparation of the derivatives of formula I of the present invention, all starting materials being prepared by the means described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or being commercially available. All final derivatives of the invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variables used in these routes are as defined below or in the claims.
Figure BDA0002447676200000111
The derivatives of formula I according to the invention can be prepared by nucleophilic substitution of intermediates M-1 and M-2 in the corresponding solvents according to the methods of schemes 1 and 2 or by intermediate M-3 and the corresponding HNR7R8In the corresponding solvent, through N-acylation reaction. Wherein R in the compound1、R2、R3、R4、R6、R7And R8As defined in the claims.
Figure BDA0002447676200000112
Intermediate M--1 can follow the wayLine 3 is obtained by condensation of intermediate XII with substituted dichloropyrimidines. Wherein R in the compound1And R2As defined in the claims.
Intermediate M-2 can be obtained by cyclizing intermediate XIII and chloroacetic acid to obtain intermediate XIV according to scheme 4, then carrying out N-alkylation reaction with corresponding small molecular amine to obtain intermediate XV, and finally carrying out nitro reduction. Wherein R in the compound3、R4、R7And R8The reduction process, as defined in the claims, comprises a hydrogen/Pd-C/alcohol system, a hydrazine hydrate/ferric chloride hexahydrate/activated carbon/alcohol system, a metal/acid or ammonium chloride system, a stannous chloride dihydrate/alcohol system.
Intermediate M-3 can be prepared according to scheme 5 from intermediates XVI and R6The intermediate XVII is obtained by substitution reaction of substituted acyl methyl/ethyl acetate, the intermediate XVIII is obtained by reduction method, the intermediate XVIII and the intermediate M-1 are subjected to nucleophilic substitution reaction to obtain the intermediate XIX, and finally the intermediate XIX is obtained by hydrolysis method. Wherein R in the compound1、 R2、R3And R6The reduction process, as defined in the claims, comprises a hydrogen/Pd-C/alcohol system, a hydrazine hydrate/ferric chloride hexahydrate/activated carbon/alcohol system, a metal/acid or ammonium chloride system, a stannous chloride dihydrate/alcohol system. The hydrolysis method comprises a solvent system of inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide and alcohol/water or tetrahydrofuran.
When R is1When it is methylsulfonylamino or acetylamino, R2When Cl is present, intermediate M1-1 and M2The preparation of (E) -1 is shown in scheme 6.
Figure BDA0002447676200000121
When R is1In the case of N-methylcarbamoyl or N, N-dimethylcarbamoyl, R2When Cl is present, intermediate M3-1 and M4The preparation of (E) -1 is shown in scheme 7.
Figure BDA0002447676200000122
When R is3Is H, R4The preparation of intermediate M-2 for H is shown in scheme 8.
Figure BDA0002447676200000123
When R is1When it is methylsulfonylamino or N-methylcarbamoyl, R3Is H, R6Intermediate M when being methyl1-3 and M2The preparation of (E) -3 is shown in scheme 9.
Figure BDA0002447676200000131
The specific implementation mode is as follows:
the examples are intended to illustrate, but not to limit, the scope of the invention. The NMR of the compound was measured by Bruker ARX-400 and the mass spectrum by Agilent 1100 LC/MSD; all reagents used were analytically or chemically pure.
Figure BDA0002447676200000132
Wherein R is2Is Cl, R3Is H, R4Is H, Z is C, and n is 1.
Watch 1
Figure BDA0002447676200000133
Figure BDA0002447676200000141
Figure BDA0002447676200000151
Example 1:
step A N- (2, 5-dichloropyrimidin-4-yl) -1, 2-diphenylamine (III)
30.00g (0.16mol) of o-phenylenediamine (II) and 17.70g (0.16mol) of 2,4, 5-trichloropyrimidine are added to 300mL of dry isopropanol (i-PrOH), 42.30g (0.33mol) of N, N-diisopropylethylamine are slowly added, and the temperature is raised to 80 ℃ for reaction for 1.5 h. Vacuum-filtering while hot to obtain 37.35g of white powder solid with the yield of 89.7 percent.
Step B N- (2- ((2, 5-dichloropyrimidin-4-yl) amino) phenyl) methanesulfonamide (M)1-1)
10g (0.04mol) of intermediate III and 9.3g (0.12mol) of pyridine (Py) are added to 50mL of dry tetrahydrofuran under ice-bath conditions, and 5.4g (0.05mol) of methanesulfonyl chloride is slowly added dropwise. After dropping, the reaction was carried out at room temperature for 2.5 hours, followed by suction filtration and washing with tetrahydrofuran (10 mL. times.3) to obtain 11.7g of a white powdery solid with a yield of 89.3%.
Step C2- (chloromethyl) -6-nitro-1H-benzo [ d ] imidazole (VI)
10.0g (0.07mol) of 4-nitrophthalenediamine (V), 12.3g (0.13mol) of chloroacetic acid and 50mL of water were added to 133mL of concentrated hydrochloric acid at room temperature, and the reaction was refluxed for 4 hours. The reaction solution was left at room temperature, the pH was adjusted to 9 with ammonia, and an orange-red solid was obtained by suction filtration, and the obtained solid was recrystallized from methanol to obtain 8.9g of a pale yellow solid with a yield of 64.5%.
Step D2- ((4-Methylpiperazin-1-yl) methyl) -6-nitro-1H-benzo [ D ] imidazole (VII-1)
9.0g (0.04mol) of VI was dissolved in 100mL of Tetrahydrofuran (THF) at room temperature, and 8.5 g (0.09mol) of N-methylpiperazine and 11.8g (0.09mol) of anhydrous potassium carbonate were added to react at 50 ℃ for 2 hours. The reaction solution was cooled to room temperature, poured into 20mL of water, stirred for 30 minutes, and filtered by suction to obtain a light brown solid (8.0 g, yield 68.3%)
Step E2- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d]Imidazole-6-amines (M)1-2)
5.0g (0.02mol) of VII-1 was dissolved in 50mL of a 90% ethanol solution at room temperature, and 0.74 g (2.7mmol) of ferric trichloride hexahydrate and 0.07g (5.5mmol) of activated carbon powder were added thereto. After the temperature is raised to 40 ℃, 50mL of 80% hydrazine hydrate is dripped, and the temperature is raised to reflux reaction for 1 hour after dripping. Vacuum filtering while hot, evaporating the filtrate to dryness to obtain off-white solid 4.3g, yield 97.0%
Step F N- (2- ((5-chloro-2- ((2- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide (example I)
0.7g (2.9mmol) of M are added at room temperature1-2 dissolved in 10mL of isopropanol and 0.85g (2.9mmol) of M added1Reaction of-1 with 0.50g (2.9mmol) of p-toluenesulfonic acid at 80 ℃ for 6 hours. The reaction solution is placed at room temperature, 20mL of water is added, the pH value is adjusted to 8 by using a saturated sodium bicarbonate solution, extraction is carried out for three times by using 60mL of ethyl acetate, organic phases are combined and evaporated to dryness to obtain light brown solid 0.46g, the yield is 31.9%, and column chromatography is carried out to obtain light yellow solid.
m.p.:232.5-233.4℃；ESI-MS[M+H]+(m/z):542.38；1H NMR(400MHz,DMSO-d6) δ9.27(s,1H),8.74(s,1H),8.21(d,J＝7.6Hz,1H),8.15(s,1H),7.78(s,1H),7.35 (d,J＝5.8Hz,2H),7.33(s,2H),7.13(d,J＝7.0Hz,1H),7.09(dd,J＝7.5,1.7Hz, 2H),3.67(s,2H),2.89(s,3H),2.50–2.42(m,3H),2.38(s,4H),2.18(s,4H).
Example 2N- (2- ((5-chloro-2- ((2- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
2- (4- ((6-nitro-1H-benzo [ D ] imidazol-2-yl) methyl) piperazin-1-yl) ethyl-1-ol (VII-2) was prepared according to the method of step D in example 1, starting from VI, by N-alkylation with N-hydroxyethylpiperazine. The yield thereof was found to be 83.0%.
2- (4- ((6-amino-1H-benzo [ d ] was obtained by reduction reaction using VII-2 as a starting material in accordance with the procedure of step E in example 1]Imidazol-2-yl) methyl) piperazin-1-yl) ethyl-1-ol (M)2-2), the yield was 97.8%.
Following the procedure of step F in example 1, with M1-1 and M2Example 2 was prepared in 80.5% yield starting from-2.
m.p.:237.6-240.2℃；ESI-MS[M+H]+(m/z):572.46；1H NMR(400MHz,DMSO-d6) δ12.05(s,1H),9.27(s,1H),8.63(s,1H),8.18(d,J＝7.8Hz,1H),8.15(s,1H),7.76 (s,1H),7.35(d,J＝7.9Hz,2H),7.32(s,2H),7.19(t,J＝7.4Hz,1H),7.12(t,J＝7.0 Hz,1H),4.38(s,1H),3.66(s,2H),3.50(d,J＝4.0Hz,2H),3.47(d,J＝6.1Hz,2H), 2.92(s,3H),2.47(s,4H),2.39(t,J＝6.2Hz,4H).
Example 3N- (2- ((5-chloro-2- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N, N-dimethyl-1- (6-nitro-1H-benzo [ D ] imidazol-2-yl) methylamine (VII-3) was prepared by the method of step D in example 1, starting from VI and reacting with dimethylamine (40% aqueous solution) by N-alkylation. The yield thereof was found to be 96.2%.
2- ((dimethylamino) methyl) -1H-benzo [ d ] is obtained by reduction according to the method of step E in example 1, starting from VII-3]Imidazole-6-amines (M)3-2) yield 92.6%.
Following the procedure of step F in example 1, with M1-1 and M3Example 3 was prepared starting from-2 in 95.9% yield.
m.p.:212.3-215.1℃；ESI-MS[M+H]+(m/z):487.28；1H NMR(400MHz,DMSO-d6) δ12.14(s,1H),9.27(s,1H),8.57(s,1H),8.16(s,1H),8.15(s,1H),7.74(s,1H), 7.36(d,J＝7.8Hz,2H),7.33(s,1H),7.29(d,J＝9.7Hz,1H),7.25(d,J＝7.7Hz, 1H),7.16(t,J＝7.1Hz,1H),3.63(s,3H),2.94(s,2H),2.24(s,6H).
Example 4N- (2- ((5-chloro-2- ((2- (piperidin-1-ylmethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
6-Nitro-2- (piperidin-1-ylmethyl) -1H-benzo [ D ] imidazole (VII-4) was prepared by N-alkylation of VI with piperidine as a starting material in step D of example 1. The yield thereof was found to be 85.7%.
2- (piperidin-1-ylmethyl) -1H-benzo [ d ] is obtained by reduction starting from VII-4 as in step E of example 1]Imidazole-6-amines (M)4-2) yield 90.5%.
Following the procedure of step F in example 1, with M1-1 and M4Example 4 was prepared in 91.7% yield starting from 2.
m.p.:228.5-230.7℃；ESI-MS[M+H]+(m/z):527.35；1H NMR(400MHz,DMSO-d6) δ12.04(s,1H),9.26(s,1H),8.63(s,1H),8.18(d,J＝8.0Hz,1H),8.15(s,1H),7.75 (s,1H),7.35(dd,J＝7.8,1.2Hz,2H),7.32(s,2H),7.19(t,J＝7.4Hz,1H),7.11(t,J ＝7.1Hz,1H),3.63(s,2H),2.92(s,3H),2.41(s,4H),1.55–1.52(m,4H),1.40(d,J ＝4.4Hz,2H).
Example 5N- (2- ((5-chloro-2- ((2- ((4-ethylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
2- ((4-ethylpiperazin-1-yl) methyl) -6-nitro-1H-benzo [ D ] imidazole (VII-5) was prepared by the method of step D in example 1, using VI as a starting material, and carrying out N-alkylation reaction with N-ethylpiperazine. The yield thereof was found to be 83.0%.
2- ((4-ethylpiperazin-1-yl) methyl) -1H-benzo [ d ] was obtained by a reduction reaction using VII-5 as a starting material in accordance with the procedure of step E in example 1]Imidazole-6-amines (M)5-2) yield was 92.2%.
Following the procedure of step F in example 1, with M1-1 and M5Example 5 was prepared starting from-2 in 81.9% yield.
m.p.:232.9-234.2℃；ESI-MS[M+H]+(m/z):556.48；1H NMR(400MHz,DMSO-d6) δ12.03(s,1H),9.28(s,1H),8.64(s,1H),8.18(d,J＝7.9Hz,1H),8.16(s,1H),7.77 (s,1H),7.35(d,J＝7.7Hz,2H),7.32(s,1H),7.19(dd,J＝15.2,7.3Hz,2H),7.15– 7.09(m,1H),3.57(s,2H),2.93(s,3H),2.85(dd,J＝14.3,7.1Hz,2H),2.44(s,4H), 2.40–2.27(m,4H),0.99–0.97(m,3H).
Example 6N- (2- ((5-chloro-2- ((2- (pyrrolidin-1-ylmethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
6-Nitro-2- (pyrrolidin-1-ylmethyl) -1H-benzo [ D ] imidazole (VII-6) was prepared by N-alkylation of VI with tetrahydropyrrole as starting material in step D of example 1. The yield thereof was found to be 85.9%.
2- (pyrrolidin-1-ylmethyl) -1H-benzo [ d ] was obtained by reduction starting from VII-6 as in step E of example 1]Imidazole-6-amine (M)6-2), yield 95.0%.
Following the procedure of step F in example 1, with M1-1 and M6Example 6 was prepared starting from 2, yield 85.5%.
m.p.:215.9-219.0℃；ESI-MS[M+H]+(m/z):513.40；1H NMR(600MHz,DMSO-d6) δ12.08(s,1H),9.26(s,1H),8.65(s,1H),8.19(d,J＝7.5Hz,1H),8.15(s,1H),7.75 (s,0H),7.34(d,J＝7.5Hz,2H),7.33(s,2H),7.18(t,J＝7.1Hz,1H),7.11(t,J＝7.5 Hz,1H),3.79(s,2H),2.92(s,3H),2.54(s,4H),1.73(s,4H).
Example 7N- (2- ((5-chloro-2- ((2- ((4-methylpiperidin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
2- ((4-methylpiperidin-1-yl) methyl) -6-nitro-1H-benzo [ D ] imidazole (VII-7) was prepared by the method of step D in example 1 using VI as a starting material and 4-methylpiperidine through N-alkylation reaction. The yield thereof was found to be 76.9%.
2- ((4-Methylpiperidin-1-yl) methyl) -1H-benzo [ d ] was obtained by reduction of VII-7 as the starting material in accordance with the procedure of step E in example 1]Imidazole-6-amines (M)7-2) yield was 93.9%.
Following the procedure of step F in example 1, with M1-1 and M7Example 7 was prepared starting from 2, yield 89.6%.
m.p.:219.6-221.2℃；ESI-MS[M+H]+(m/z):541.48；1H NMR(600MHz,DMSO-d6) δ12.07(s,1H),9.24(s,1H),8.98(s,1H),8.30(s,1H),8.12(s,1H),7.80(s,1H), 7.34(s,2H),7.27(d,J＝7.8Hz,2H),6.95(t,J＝7.3Hz,1H),6.89(s,1H),3.65(s, 2H),2.83(s,3H),2.80(s,4H),2.04(t,J＝11.1Hz,2H),1.59(d,J＝11.9Hz,2H), 1.19(dd,J＝10.6,1.4Hz,1H),0.90(d,J＝6.5Hz,3H).
Example 8N- (2- ((5-chloro-2- ((2- ((4-hydroxypiperidin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
1- ((6-nitro-1H-benzo [ D ] imidazol-2-yl) methyl) piperidin-4-ol (VII-8) is prepared by N-alkylation of VI with 4-hydroxypiperidine according to the method of step D in example 1. The yield thereof was found to be 97.0%.
1- ((6-amino-1H-benzo [ d ] is obtained by reduction starting from VII-8 as example 1, step E]Imidazol-2-yl) methyl) piperidin-4-ol (M)8-2), yield 95.0%.
Following the procedure of step F in example 1, with M1-1 and M8Example 8 was prepared in 83.2% yield from 2.
m.p.:240.2-243.7℃；ESI-MS[M+H]+(m/z):543.57；1H NMR(400MHz,DMSO-d6) δ12.09(s,1H),9.29(s,1H),8.50(s,1H),8.18(s,1H),8.13(d,J＝7.8Hz,1H),7.77 (s,1H),7.39(d,J＝7.8Hz,2H),7.33(s,2H),7.30(d,J＝8.5Hz,1H),7.19(t,J＝7.1 Hz,1H),4.66(s,1H),3.77(s,1H),2.97(s,3H),2.81(s,2H),2.30(s,2H),1.76(d,J ＝11.2Hz,2H),1.48(d,J＝9.2Hz,2H).
Example 9N- (2- ((5-chloro-2- ((2- ((diisopropylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
According to the method of the step D in the embodiment 1, the N-isopropyl-N- ((6-nitro-1H-benzo [ D ] imidazol-2-yl) methyl) propane-2-amine (VII-9) is prepared by taking VI as a raw material and carrying out N-alkylation reaction with diisopropylamine. The yield thereof was found to be 70.2%.
2- ((diisopropylamino) methyl) -1H-benzo [ d ] was obtained by reduction according to the procedure of step E in example 1, starting from VII-9]Imidazole-6-amines (M)9-2) yield was 89.0%.
Following the procedure of step F in example 1, with M1-1 and M9Example 9 was prepared in 75.2% yield starting from-2.
m.p.:240.2-243.7℃；ESI-MS[M+H]+(m/z):543.60；1H NMR(400MHz,DMSO-d6) δ11.56(s,1H),9.26(s,1H),8.69(s,1H),8.21(d,J＝6.1Hz,1H),8.14(s,1H),7.78 (s,1H),7.34(d,J＝6.6Hz,2H),7.30(s,2H),7.12(dd,J＝11.6,8.1Hz,2H),3.79(s, 2H),3.04(d,J＝6.1Hz,2H),2.91(s,3H),1.03(d,J＝5.8Hz,12H).
Example 10N- (2- ((5-chloro-2- ((2- (morpholinomethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
4- ((6-nitro-1H-benzo [ D ] imidazol-2-yl) methyl) morpholine (VII-10) was prepared by N-alkylation of VI with morpholine as starting material in step D of example 1. The yield thereof was found to be 91.5%.
2- (Morpholinomethyl) -1H-benzo [ d ] was obtained by reduction according to the procedure of step E in example 1, starting from VII-10]Imidazole-6-amines (M)10-2) yield was 93.7%.
Following the procedure of step F in example 1, with M1-1 and M10Example 10 was prepared starting from 2, yield 85.3%.
m.p.:222.8-223.9℃；ESI-MS[M+H]+(m/z):529.39；1H NMR(400MHz,DMSO-d6) δ12.08(s,1H),9.27(s,1H),8.71(s,1H),8.21(d,J＝7.3Hz,1H),8.15(s,1H),7.79 (s,1H),7.33(s,2H),7.33(s,22H),7.17–7.05(m,2H),3.68(s,2H),3.62–3.60(m, 4H),2.90(s,3H),2.46(s,4H).
Example 11N- (2- ((5-chloro-2- ((2- ((diethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
According to the method of the step D in the embodiment 1, the N-ethyl-N- ((6-nitro-1H-benzo [ D ] imidazol-2-yl) methyl) ethylamine (VII-11) is prepared by taking VI as a raw material and carrying out N-alkylation reaction with diethylamine. The yield thereof was found to be 85.2%.
2- ((diethylamino) methyl) -1H-benzo [ d ] was obtained by reduction from VII-11 as starting material in accordance with the procedure described in example 1 for step E]Imidazole-6-amines (M)11-2) yield 90.1%.
Following the procedure of step F in example 1, with M1-1 and M11Example 11 was prepared in 65.2% yield starting from-2.
m.p.:202.1-205.4℃；ESI-MS[M+H]+(m/z):515.51；1H NMR(400MHz,DMSO-d6) δ11.96(s,1H),9.68(s,1H),9.23(s,1H),9.05(s,1H),8.33(d,J＝7.7Hz,1H),8.11 (s,1H),7.82(s,1H),7.34(s,2H),7.26(d,J＝7.8Hz,2H),6.93(t,J＝7.1Hz,1H), 3.75(s,2H),2.78(s,3H),2.58–2.52(m,4H),1.03(t,J＝7.1Hz,6H).
Example 12N- (2- ((5-chloro-2- ((2- (thiomorpholinomethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
4- ((6-nitro-1H-benzo [ D ] imidazol-2-yl) methyl) thiomorpholine (VII-12) was prepared by N-alkylation of VI with thiomorpholine according to the procedure of step D in example 1. The yield thereof was found to be 81.9%.
2- (Thiomorpholinomethyl) -1H-benzo [ d ] was obtained by reduction starting from VII-12 as in step E of example 1]Imidazole-6-amines (M)12-2) yield was 92.2%.
Following the procedure of step F in example 1, with M1-1 and M12Example 2 was prepared starting from (E2) in 81.9% yield.
m.p.:222.9-224.2℃；ESI-MS[M+H]+(m/z):545.58；1H NMR(400MHz,DMSO-d6) δ11.44(s,1H),9.37(s,1H),8.98(s,1H),8.84–8.56(m,1H),8.43(s,1H),8.23(s, 1H),8.08(d,J＝12.0Hz,1H),7.53(d,J＝6.9Hz,1H),7.34(d,J＝47.6Hz,2H), 7.12(d,J＝51.4Hz,2H),3.51(s,2H),3.02(d,J＝3.5Hz,4H),2.92(s,34H),2.51(s, 4H).
Example 13N- (2- ((5-chloro-2- ((2- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) acetamide
The N- (2- ((2, 5-dichloropyrimidin-4-yl) amino) phenyl) acetamide (M) is prepared by the method of step B in example 1 by starting from III and acetyl chloride in an N-acylation reaction2-1)。
Following the procedure of step F in example 1, with M2-1 and M1Example 13 was prepared in 78.6% yield starting from-2.
m.p.:230.2-235.5℃；ESI-MS[M+H]+(m/z):506.39；1H NMR(400MHz,DMSO-d6) δ9.28(s,1H),8.63(s,1H),8.18(d,J＝8.3Hz,1H),8.16(s,1H),7.77(s,1H),7.36
(d,J＝7.8Hz,1H),7.32(s,1H),7.23–7.17(m,1H),7.13(dd,J＝13.7,7.8Hz,2H), 6.61(s,1H),6.46(d,J＝8.4Hz,1H),3.57(s,2H),2.93(s,3H),2.85(dd,J＝14.4, 7.2Hz,3H),2.44(s,4H),2.34(dt,J＝13.8,7.0Hz,4H).
Example 14N- (2- ((-chloro-2- ((2- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) acetamide
Following the procedure of step F in example 1, with M2-1 and M2Example 14 was prepared in 92.0% yield starting from 2.
m.p.:270.9-273.0℃；ESI-MS[M+H]+(m/z):536.58；1H NMR(400MHz,DMSO-d6) δ12.00(s,1H),10.09(s,1H),9.18(s,1H),8.42(s,1H),8.11(s,1H),7.84(d,J＝7.2 Hz,1H),7.69(s,1H),7.31(s,2H),7.28(d,J＝7.9Hz,2H),7.17(t,J＝7.5Hz,1H), 4.44(s,1H),3.66(s,2H),3.51(s,2H),3.48(d,J＝6.0Hz,2H),2.49–2.45(m,4H), 2.45–2.39(m,4H),2.10(s,3H).
Example 15N- (2- ((5-chloro-2- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) acetamide
Following the procedure of step F in example 1, with M2-1 and M3Example 15 was prepared in 85.5% yield from 2.
m.p.:212.7.9-213.2℃；ESI-MS[M+H]+(m/z):451.39；1H NMR(400MHz,DMSO-d6) δ12.08(s,1H),10.13(s,1H),9.18(s,1H),8.43(s,1H),8.12(s,1H),7.85(d,J＝7.7 Hz,1H),7.70(d,J＝36.2Hz,1H),7.38–7.30(m,2H),7.28(d,J＝7.6Hz,2H),7.17 (t,J＝7.5Hz,1H),3.61(s,2H),2.23(s,6H),2.11(s,3H).
Example 16N- (2- ((5-chloro-2- ((2- ((4-methylpiperidin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) acetamide
Following the procedure of step F in example 1, with M2-1 and M7Example 16 was prepared in 92.8% yield starting from 2.
m.p.:215.7.9-218.0℃；ESI-MS[M+H]+(m/z):505.58；1H NMR(400MHz,DMSO-d6) δ12.04(s,1H),10.15(s,1H),9.16(s,1H),8.43(s,1H),8.11(s,1H),7.84(d,J＝7.9 Hz,1H),7.69(s,1H),7.30(d,J＝7.1Hz,2H),7.27(d,J＝7.6Hz,2H),7.15(t,J＝ 7.5Hz,1H),3.63(s,2H),2.81(d,J＝11.2Hz,2H),2.10(s,3H),1.56(t,J＝20.4Hz, 2H),1.23(s,4H),1.17(s,1H),0.89(d,J＝6.3Hz,3H).
Example 172- ((5-chloro-2- ((2- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
Step A: 2-amino-N-methylbenzamide (XII-1)
20.0g (0.12mol) of isatoic anhydride (IV) is dissolved in 100.0mL of ethanol at room temperature, stirring is started, 14.45mL (0.15mol) of 40% methylamine aqueous solution is slowly dripped, and the reaction is finished. To the reaction mixture was added 50mL of saturated saline, and the mixture was stirred for 20 minutes. Extracting with 750mL ethyl acetate for three times, combining organic phases, evaporating the solvent to dryness, and drying to obtain 15.8g of light yellow solid. The yield thereof was found to be 85.7%.
2- ((2, 5-dichloropyrimidin-4-yl) amino) -N-methylbenzamide (M) was prepared by the method of step A in example 1, starting from XII-1 and 2,4, 5-trichloropyrimidine3-1), yield 79.5%.
Following the procedure of step F in example 1, with M3-1 and M2Example 17 was prepared starting from-2 in 31.9% yield.
m.p.:282.9-285.0℃；ESI-MS[M+H]+(m/z):536.56；1H NMR(400MHz,DMSO-d6) δ12.16(s,1H),11.69(s,1H),9.38(s,1H),8.83(s,1H),8.78(s,1H),8.20(s,1H), 7.83(s,1H),7.75(d,J＝7.6Hz,1H),7.39(s,2H),7.33(d,J＝8.7Hz,1H),7.09(t,J ＝7.4Hz,1H),5.70(d,J＝7.7Hz,1H),3.68(s,2H),3.50(d,J＝4.7Hz,2H),3.47(d, J＝6.1Hz,2H),2.81(d,J＝4.1Hz,3H),2.47(s,4H),2.38(t,J＝6.1Hz,4H).
Example 182- ((5-chloro-2- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
Following the procedure of step F in example 1, with M3-1 and M3Example 18 was prepared starting from 2 in 50.0% yield.
m.p.:216.7-218.0℃；ESI-MS[M+H]+(m/z):451.49；1H NMR(400MHz,DMSO-d6) δ12.22(s,1H),11.69(s,1H),9.38(s,1H),8.85(d,J＝6.2Hz,1H),8.78(d,J＝4.0
Hz,1H),8.20(s,1H),7.82(s,1H),7.76(d,J＝7.7Hz,1H),7.39(d,J＝12.0Hz,2H), 7.35(s,1H),7.10(t,J＝7.4Hz,1H),3.65(s,2H),2.82(d,J＝4.2Hz,3H),2.25(s, 6H).
Example 192- ((5-chloro-2- ((2- ((4-methylpiperidin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
Following the procedure of step F in example 1, with M3-1 and M7Example 19 was prepared in 72.5% yield starting from-2.
m.p.:225.3-226.9℃；ESI-MS[M+H]+(m/z):505.68；1H NMR(600MHz,DMSO-d6) δ12.17(s,1H),11.68(s,1H),9.37(s,1H),8.84(s,1H),8.79(s,1H),8.19(s,1H), 7.82(s,1H),7.75(d,J＝7.7Hz,1H),7.39(s,2H),7.33(d,J＝8.3Hz,1H),7.08(t,J ＝7.4Hz,1H),3.66(s,2H),2.83(s,3H),2.81(d,J＝4.1Hz,4H),2.04(t,J＝11.1Hz, 2H),1.59(d,J＝12.5Hz,2H),1.19(dd,J＝11.7,2.0Hz,1H),0.90(d,J＝6.4Hz, 3H).
Example 202- ((5-chloro-2- ((2- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
2-amino-N, N-dimethylbenzamide (XII-2) was prepared in 99.4% yield by N-acylation of IV and dimethylamine as starting materials in the procedure of step A of example 17.
2- ((2, 5-dichloropyrimidin-4-yl) amino) -N, N-dimethylbenzamide (M) was prepared by the method of step A in example 1, starting from XII-2 and 2,4, 5-trichloropyrimidine4-1), yield 71.8%.
Following the procedure of step F in example 1, with M4-1 and M1Example 20 was prepared starting from 2, yield 74.5%.
m.p.:227.3-229.2℃；ESI-MS[M+H]+(m/z):520.45；1H NMR(400MHz,DMSO-d6) δ9.29(s,1H),9.16(s,1H),8.37(d,J＝7.8Hz,1H),8.17(s,1H),7.80(s,1H),7.41 (d,J＝7.4Hz,2H),7.34(d,J＝8.7Hz,1H),7.14(t,J＝7.5Hz,1H),6.07(s,1H), 5.64(s,1H),3.67(s,2H),3.51(s,4H),2.98(s,4H),2.36(s,6H),2.16(s,3H).
Example 212- ((5-chloro-2- ((2- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-amino) -N, N-dimethylbenzamide
Following the procedure of step F in example 1, with M4-1 and M2Example 21 was prepared in 65.0% yield starting from 2.
m.p.:275.6-278.6℃；ESI-MS[M+H]+(m/z):550.56；1H NMR(400MHz,DMSO-d6) δ12.14(s,1H),9.30(s,1H),9.18(s,1H),8.38(d,J＝8.0Hz,1H),8.17(s,1H),7.80 (s,1H),7.42(d,J＝7.6Hz,2H),7.37(d,J＝12.9Hz,1H),7.33(s,1H),7.15(t,J＝ 7.2Hz,1H),4.66(s,1H),3.67(s,2H),3.50(d,J＝5.8Hz,2H),3.47(d,J＝6.0Hz, 2H),2.99(s,6H),2.46(s,4H),2.40–2.35(m,4H).
Example 222- ((5-chloro-2- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
Following the procedure of step F in example 1, with M4-1 and M3Example 22 was prepared with a yield of 69.3% using-2 as the starting material.
m.p.:212.9-214.5℃；ESI-MS[M+H]+(m/z):465.32；1H NMR(400MHz,DMSO-d6) δ12.20(s,1H),9.29(s,1H),9.17(s,1H),8.38(d,J＝8.6Hz,1H),8.17(s,1H),7.79 (s,1H),7.44–7.39(m,2H),7.34(s,2H),7.15(t,J＝7.4Hz,1H),3.62(s,2H),2.99 (s,6H),2.23(s,6H).
Example 232- ((5-chloro-2- ((2- (piperidin-1-ylmethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
Following the procedure of step F in example 1, with M4-1 and M4Example 23 was prepared in 80.0% yield starting from-2.
m.p.:222.7-223.6℃；ESI-MS[M+H]+(m/z):505.32；1H NMR(400MHz,DMSO-d6) δ12.09(s,1H),9.29(s,1H),9.16(s,1H),8.38(d,J＝8.2Hz,1H),8.17(s,1H),8.09 (d,J＝15.0Hz,1H),7.80(s,1H),7.41(d,J＝7.6Hz,2H),7.39(s,1H),7.32(s,1H), 3.66(s,2H),2.99(s,6H),2.44(s,4H),1.54(d,J＝5.1Hz,4H),1.40(s,2H).
Example 242- ((5-chloro-2- ((2- ((4-ethylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
Following the procedure of step F in example 1, with M4-1 and M5Example 24 was prepared in 70.2% yield from 2.
m.p.:225.6.9-226.9℃；ESI-MS[M+H]+(m/z):534.42；1H NMR(400MHz,DMSO-d6) δ9.40(s,1H),9.21(s,1H),8.36(d,J＝7.9Hz,1H),8.19(s,1H),8.01(d,J＝49.2 Hz,1H),7.50(d,J＝7.7Hz,2H),7.43(d,J＝8.6Hz,2H),7.12(d,J＝7.7Hz,2H), 3.89(s,2H),3.10(s,2H),2.99(s,6H),2.52(s,4H),2.29(s,4H),1.17(t,J＝7.1Hz, 3H).
Example 252- ((5-chloro-2- ((2- (pyrrolidin-1-ylmethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
Following the procedure of step F in example 1, with M4-1 and M6Example 25 was prepared in 76.9% yield from-2.
m.p.:221.2.9-223.2℃；ESI-MS[M+H]+(m/z):491.50；1H NMR(400MHz,DMSO-d6) δ12.20(s,1H),9.32(s,1H),9.17(s,1H),8.37(d,J＝8.4Hz,1H),8.18(s,1H),7.85 (s,1H),7.47–7.41(m,2H),7.37(s,2H),7.16(t,J＝7.3Hz,1H),4.05(s,2H),2.99 (s,6H),2.81(s,4H),1.81(s,4H).
Example 262- ((5-chloro-2- ((2- (morpholinomethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
Following the procedure of step F in example 1, with M4-1 and M10Example 26 was prepared starting from-2 with a yield of 71.6%.
m.p.:234.6.9-237.8℃；ESI-MS[M+H]+(m/z):507.49；1H NMR(400MHz,DMSO-d6) δ12.17(s,1H),9.31(s,1H),9.18(s,1H),8.38(d,J＝8.4Hz,1H),8.17(s,1H),7.82 (s,1H),7.42(d,J＝7.6Hz,2H),7.34(t,J＝7.4Hz,2H),7.15(t,J＝7.4Hz,1H), 3.69(s,2H),3.63–3.60(m,4H),2.98(d,J＝8.1Hz,6H),2.46(s,4H).
Example 272- ((5-chloro-2- ((2- ((diethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
Following the procedure of step F in example 1, with M4-1 and M11Example 27 was prepared starting from-2 with a yield of 71.6%.
m.p.:214.6.9-217.5℃；ESI-MS[M+H]+(m/z):493.66；1H NMR(400MHz,DMSO-d6) δ12.02(s,1H),9.31(s,1H),9.18(s,1H),8.38(d,J＝8.5Hz,1H),8.18(s,1H),7.84 (s,1H),7.42(dd,J＝7.6,1.5Hz,2H),7.33(dd,J＝8.6,1.7Hz,2H),7.15(t,J＝7.5 Hz,1H),3.87(s,2H),2.99(s,6H),2.64(d,J＝6.9Hz,4H),1.06(t,J＝7.1Hz,6H).
Example 282- ((5-chloro-2- ((2- (thiomorpholinomethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
Following the procedure of step F in example 1, with M4-1 and M12Example 28 was prepared starting from-2 with a yield of 59.8%.
m.p.:227.0-230.2℃；ESI-MS[M+H]+(m/z):523.51；1H NMR(400MHz,DMSO-d6) δ12.11(s,1H),9.34(s,1H),9.18(s,1H),8.37(d,J＝8.5Hz,1H),8.18(s,1H),7.86 (s,1H),7.42(d,J＝6.4Hz,2H),7.37(t,J＝7.7Hz,2H),7.16(t,J＝7.4Hz,1H), 3.80(s,2H),2.99(s,6H),2.78(d,J＝3.0Hz,4H),2.68(d,J＝3.9Hz,4H).
Example 296- ((5-chloro-4- ((2- (methylsulfonylamino) phenyl) amino) pyrimidin-2-yl) amino) -2-methyl-1H-indole-3-carboxylic acid ethyl ester
Step A Ethyl 2- (2, 4-dinitrophenyl) -3-oxobutyrate (IX-1)
1.31g (11.3mmol) of ethyl acetoacetate and 1.26g (11.3mmol) of potassium tert-butoxide were added to 10mL of tetrahydrofuran at room temperature, and the mixture was stirred at room temperature for 2 hours, followed by addition of 1.0g (5.4mmol) of 2, 4-dinitrofluorobenzene (VIII) and reaction for 1 hour. After adjusting pH to 2 by adding 1.2M hydrochloric acid, the mixture was allowed to stand for layer separation, the upper organic phase was collected, the organic solvent was evaporated to dryness, and drying was performed to obtain 1.4g of a yellow solid with a yield of 91.19%.
Step B6-amino-2-methyl-1H-indole-3-carboxylic acid ethyl ester (X-1)
0.5g (1.7mmol) of IX was dissolved in 15mL of ethanol at room temperature, and then 2.29g (10.1mmol) of stannous chloride dihydrate and 1.2mL of concentrated hydrochloric acid were added to conduct a reflux reaction for 4 hours. Pouring the reaction solution into 30% sodium hydroxide solution, stirring for 30 minutes, extracting with ethyl acetate, combining organic phases, and evaporating to dryness. 0.2g of dry brown solid, yield 54.1%.
Following the procedure of step F in example 1, with M1Preparation example 29, starting from-1 and X-1, gives a yield of 58.3%.
m.p.:172.9-173.7℃；ESI-MS[M+H]+(m/z):515.36；1H NMR(400MHz,DMSO-d6) 11.66(s,1H),9.29(s,1H),8.93(s,1H),8.30(d,J＝7.2Hz,1H),8.14(s,1H),7.78(s, 1H),7.73(d,J＝8.8Hz,1H),7.35(d,J＝8.5Hz,1H),7.30(d,J＝7.4Hz,1H),7.07 –6.93(m,2H),4.26(dd,J＝13.9,6.8Hz,2H),2.83(s,3H),2.62(s,3H),1.34(dd,J ＝18.6,11.7Hz,3H).
Example 306- ((5-chloro-4- ((2- (methylsulfonylamino) phenyl) amino) pyrimidin-2-yl) amino) -2-methyl-1H-indole-3-carboxylic acid methyl ester
Methyl 2- (2, 4-dinitrophenyl) -3-oxobutanoate (IX-2) was prepared by a C-alkylation reaction of methyl acetoacetate with VIII as the starting material in accordance with the procedure described in step A of example 29. The yield thereof was found to be 98.9%.
According to the method of step B in example 29, methyl 6-amino-2-methyl-1H-indole-3-carboxylate (X-2) was obtained in 90.5% yield by reduction using IX-2 as a starting material.
Following the procedure of step F in example 1, with M1Preparation example 30 starting from-1 and X-2 with a yield of 90.98%.
m.p.:174.7-176.2℃；ESI-MS[M+H]+(m/z):501.30；1H NMR(600MHz,DMSO-d6) δ11.64(s,1H),9.38(s,1H),9.30(s,1H),8.53(s,1H),8.19(s,1H),8.17(s,1H),7.79 (d,J＝8.4Hz,1H),7.69(d,J＝8.6Hz,1H),7.39(d,J＝7.7Hz,1H),7.33(d,J＝8.6 Hz,1H),7.30(t,J＝7.6Hz,1H),7.21(t,J＝7.5Hz,1H),3.80(s,3H),2.97(s,3H), 2.62(s,3H).
Example 316- ((5-chloro-4- ((2- (methylsulfonylamino) phenyl) amino) pyrimidin-2-yl) amino) -2-methyl-1H-indole-3-carboxylic acid
0.5g (1.0mmol) of example 30 was put into 10mL of methanol at room temperature, 0.32g (8.0 mmol) of sodium hydroxide was dissolved in 1mL of water, and the prepared sodium hydroxide solution was dropped into methanol to conduct a reflux reaction for 6 hours. The reaction solution was left at room temperature, and 1M hydrochloric acid was added dropwise to adjust pH to 1, followed by suction filtration and drying to obtain 0.46g of a dark purple solid with a yield of 94.9%. The crude product is purified by column chromatography to obtain a white-like solid.
m.p.:207.2-210.3℃；ESI-MS[M+H]+(m/z):487.39；1H NMR(600MHz,DMSO-d6) δ11.96(s,1H),11.64(s,1H),9.38(s,1H),9.30(s,1H),8.53(s,1H),8.19(s,1H), 8.17(s,1H),7.79(d,J＝8.4Hz,1H),7.69(d,J＝8.6Hz,1H),7.39(d,J＝7.7Hz, 1H),7.33(d,J＝8.6Hz,1H),7.30(t,J＝7.6Hz,1H),7.21(t,J＝7.5Hz,1H),2.97(s, 3H),2.62(s,3H).
Example 32N- (2- ((5-chloro-2- ((2-methyl-3- (4-methylpiperazine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenylmethanesulfonamide
0.5g (1.02mmol) of example 31, 0.20g (2.05mmol) of N-methylpiperazine, 0.78g (2.05mmol) of HATU, 0.012g (0.10mmol) of 4-Dimethylaminopyridine (DMAP) and 0.53g (4.12mmol) of N, N-Diisopropylethylamine (DIPEA) were dissolved in 10mL of N, N-Dimethylformamide (DMF) and reacted at room temperature for 1 hour. 20mL of water was added to the reaction solution, followed by stirring, extraction with 60mL of ethyl acetate was carried out three times, and the organic phases were combined. The mixture was washed once with a 5% lithium chloride solution and once with saturated brine, and then 0.12g of a brown solid in which the solvent was evaporated was obtained in 34.3% yield. The crude product is purified by column chromatography to obtain a light yellow solid.
m.p.:223.2-225.7℃；ESI-MS[M+H]+(m/z):569.39；1H NMR(400MHz,DMSO-d6) δ11.22(s,1H),9.25(s,1H),8.81(s,1H),8.32-8.09(m,2H),7.67(s,1H),7.33(s, 2H),7.20(s,1H),7.07(s,1H),6.61(s,1H),3.49(s,4H),2.96(s,3H),2.87(s,3H), 2.36(d,J＝19.2Hz,4H),2.22(s,3H).
Example 33N- (2- ((5-chloro-2- ((3- (4- (2-hydroxyethyl) piperazine-1-carbonyl) -2-methyl-1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
Example 33 was prepared according to the procedure for example 32, starting from example 31 and N-hydroxyethylpiperazine, in 94.6% yield.
m.p.:239.6.2-242.7℃；ESI-MS[M+H]+(m/z):599.69；1H NMR(400MHz,DMSO-d6) δ11.21(s,1H),9.39(s,1H),9.27(s,1H),8.52(s,1H),8.17(s,1H),8.14(d,J＝8.0 Hz,1H),7.62(s,1H),7.40(dd,J＝7.9,1.3Hz,1H),7.32(d,J＝1.8Hz,1H),7.31– 7.28(m,1H),7.22(dd,J＝7.6,1.2Hz,1H),7.17(d,J＝8.7Hz,1H),4.49(s,1H), 3.53(dd,J＝11.6,5.6Hz,4H),3.49(s,4H),3.38(dd,J＝14.0,7.0Hz,2H),2.96(d, J＝5.2Hz,3H),2.47(s,2H),2.38(s,3H).
Example 346- ((5-chloro-4- ((2- (methylsulfonylamino) phenyl) amino) pyrimidin-2-yl) amino) -N- (2-hydroxyethyl) -2-methyl-1H-indole-3-carboxamide
Example 34 was prepared according to the procedure for example 32, starting from example 31 and ethanolamine in 92.5% yield.
m.p.:232.3.2-234.9℃；ESI-MS[M+H]+(m/z):530.37；1H NMR(400MHz,DMSO-d6) δ11.25(s,1H),9.61(s,1H),9.27(s,1H),8.62(s,1H),8.22(d,J＝7.9Hz,1H),8.17 (s,1H),7.72(s,1H),7.57(d,J＝8.7Hz,1H),7.37(d,J＝7.1Hz,1H),7.29(d,J＝ 8.7Hz,1H),7.24(d,J＝7.6Hz,1H),7.21–7.17(m,1H),7.16(d,J＝7.4Hz,1H), 4.79(s,1H),3.55(t,J＝5.9Hz,2H),3.37(dd,J＝11.5,5.7Hz,2H),2.95(s,3H), 2.55(s,3H).
Example 35N- (2- ((5-chloro-2- ((2-methyl-3- (4-ethylpiperazine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
Example 35 was prepared according to the procedure for example 32, starting from example 31 and N-ethylpiperazine, in 78.9% yield.
m.p.:221.6.2-224.0℃；ESI-MS[M+H]+(m/z):583.47；1H NMR(400MHz,DMSO-d6) δ11.21(s,1H),9.28(s,1H),8.51(s,1H),8.18(s,1H),8.14(d,J＝7.8Hz,1H),7.62 (s,1H),7.40(d,J＝7.6Hz,1H),7.31(d,J＝7.9Hz,2H),7.22(d,J＝7.4Hz,1H), 7.18(d,J＝8.8Hz,1H),3.51(s,6H),2.97(s,3H),2.49–2.44(m,4H),2.39(s,3H), 1.05(t,J＝6.7Hz,3H).
Example 36N- (2- ((5-chloro-2- ((2-methyl-3- (4-methylpiperidin-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
Example 36 was prepared according to the procedure for example 32, starting from example 31 and 4-methylpiperidine, in 75.3% yield.
m.p.:217.6.2-219.6℃；ESI-MS[M+H]+(m/z):568.40；1H NMR(400MHz,DMSO-d6) δ11.21(s,1H),9.30(s,1H),9.21(s,1H),8.09(s,1H),7.75(s,1H),7.31(d,J＝8.4 Hz,1H),7.25–7.15(m,2H),6.83(t,J＝7.7Hz,1H),6.65(t,J＝7.5Hz,1H),6.09– 6.04(m,2H),2.89(s,3H),2.70(s,4H),2.37(s,3H),1.63(d,J＝10.9Hz,4H),0.94 (d,J＝5.6Hz,3H),0.86(dd,J＝9.5,6.1Hz,1H).
Example 37N- (2- ((5-chloro-2- ((2-methyl-3- (4-hydroxypiperidine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
Example 37 was prepared according to the procedure for example 32, starting from example 31 and 4-hydroxypiperidine, in 85.2% yield.
m.p.:230.2.2-232.9℃；ESI-MS[M+H]+(m/z):570.56；1H NMR(400MHz,DMSO-d6) δ11.14(s,1H),9.30(s,1H),9.25(s,1H),8.49(s,1H),8.17(s,1H),8.13(d,J＝7.5 Hz,1H),7.61(s,1H),7.39(d,J＝7.9Hz,1H),7.30(dd,J＝18.9,8.7Hz,2H),7.21(t, J＝7.6Hz,1H),7.15(d,J＝8.4Hz,1H),4.75(s,1H),3.77(d,J＝47.9Hz,4H),3.51 (s,1H),3.13(dd,J＝21.1,10.5Hz,4H),2.97(s,3H),2.37(s,3H).
Example 38N- (2- ((5-chloro-2- ((2-methyl-3- (piperidine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
Example 38 was prepared according to the procedure for example 32, starting from example 31 and piperidine in 95.6% yield.
m.p.:216.9.2.2-219.2℃；ESI-MS[M+H]+(m/z):554.57；1H NMR(600MHz, DMSO-d6)δ11.14(s,1H),9.40(s,1H),9.24(s,1H),8.58(s,1H),8.17(s,1H),8.16 (s,1H),7.63(s,1H),7.37(d,J＝7.9Hz,1H),7.27(dd,J＝8.6,1.5Hz,1H),7.25– 7.22(m,1H),7.17(d,J＝4.3Hz,1H),7.16(s,1H),3.46(s,4H),2.94(s,3H),2.37(s, 3H),1.61(s,2H),1.50(s,4H).
Example 39N- (2- ((5-chloro-2- ((2-methyl-3- (morpholine-4-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
Example 39 was prepared according to the procedure for example 32, starting from example 31 and morpholine in 56.5% yield.
m.p.:222.2-225.9℃；ESI-MS[M+H]+(m/z):556.49；1H NMR(400MHz,DMSO-d6) δ11.23(s,1H),9.30(s,1H),9.27(s,1H),8.52(s,1H),8.17(s,1H),8.15(d,J＝8.0 Hz,1H),7.65(s,1H),7.39(d,J＝7.8Hz,1H),7.30(d,J＝8.3Hz,2H),7.21(t,J＝ 7.6Hz,2H),3.62(s,4H),3.49(s,4H),2.97(s,3H),2.39(s,3H).
Example 40N- (2- ((5-chloro-2- ((2-methyl-3- (thiomorpholine-4-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
Example 40 was prepared according to the procedure for example 32, starting from example 31 and thiomorpholine, in 47.8% yield.
m.p.:221.3-223.5℃；ESI-MS[M+H]+(m/z):572.38；1H NMR(400MHz,DMSO-d6) δ11.20(s,1H),9.31(s,1H),9.26(s,1H),8.50(s,1H),8.18(s,1H),8.15(d,J＝8.0 Hz,1H),7.65(s,1H),7.39(d,J＝7.8Hz,1H),7.33(t,J＝7.7Hz,1H),7.28(dd,J＝ 8.7,1.5Hz,1H),7.22(d,J＝7.7Hz,1H),7.18(d,J＝8.8Hz,1H),3.76(s,4H),2.98 (s,3H),2.60(s,4H),2.38(s,3H).
Example 41N- (2- ((5-chloro-2- ((2-methyl-3- (pyrrolidine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
Example 41 was prepared according to the procedure for example 32, starting from example 31 and tetrahydropyrrole in 98.0% yield.
m.p.:213.9-216.5℃；ESI-MS[M+H]+(m/z):540.50；1H NMR(400MHz,DMSO-d6) δ11.16(s,1H),9.22(s,1H),9.12(s,1H),8.38(s,1H),8.11(s,1H),7.73(s,1H),7.27 (d,J＝8.7Hz,1H),7.22(dd,J＝14.8,9.2Hz,1H),6.92(s,1H),6.79(s,1H),6.21– 5.98(m,2H),2.76(s,3H),2.38(s,3H),1.84(s,4H),0.86(s,4H).
Example 42(R) -N- (2- ((5-chloro-2- ((3- (2- (hydroxymethyl) pyrrolidine-1-carbonyl) -2-methyl-1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
Example 42 was prepared according to the procedure for example 32, starting from example 31 and L-prolinol, in a yield of 95.7%.
m.p.:233.6-235.3℃；ESI-MS[M+H]+(m/z):570.42；1H NMR(400MHz,DMSO-d6) δ11.10(s,1H),9.28(s,1H),9.24(s,1H),8.53(s,1H),8.17(d,J＝2.9Hz,1H),8.16 (s,1H),7.62(s,1H),7.38(d,J＝7.7Hz,1H),7.25(d,J＝8.9Hz,2H),7.17(dd,J＝ 12.8,6.5Hz,2H),4.83(s,1H),3.42(d,J＝5.2Hz,2H),2.96(s,3H),2.72(s,1H), 2.37(s,3H),2.07–1.94(m,2H),1.94–1.81(m,2H),0.95–0.75(m,2H).
Example 43N- (2- ((5-chloro-2- ((3- (3-hydroxyazetidin-1-carbonyl) -2-methyl-1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
Example 43 was prepared according to the procedure for example 32, starting from example 31 and N-azetidin-3-ol, in 32.1% yield.
m.p.:228.6-231.7℃；ESI-MS[M+H]+(m/z):542.39；1H NMR(400MHz,DMSO-d6) δ11.27(s,1H),9.30(d,J＝20.4Hz,1H),9.27(s,1H),8.50(s,1H),8.18(s,1H),8.15 (d,J＝8.1Hz,1H),7.63(s,1H),7.40(d,J＝7.7Hz,1H),7.36–7.30(m,1H),7.29(s, 1H),7.23(dd,J＝17.1,9.5Hz,2H),5.69(d,J＝6.2Hz,1H),4.16(t,J＝7.7Hz,2H), 3.75(dd,J＝9.5,4.4Hz,2H),3.48(d,J＝17.9Hz,1H),2.98(s,3H),2.45(s,3H).
Example 446- ((5-chloro-4- ((2- (methylsulfonylamino) phenyl) amino) pyrimidin-2-yl) amino) -N, N, 2-trimethyl-1H-indole-3-carboxamide
Example 44 was prepared according to the procedure for example 32, starting from example 31 and dimethylamine (40% in water), in 32.1% yield.
m.p.:212.3-216.0℃；ESI-MS[M+H]+(m/z):514.59；1H NMR(400MHz,DMSO-d6) δ11.14(s,1H),9.90(s,1H),9.25(s,1H),8.50(s,1H),8.18(s,1H),8.15(s,1H),7.64 (s,1H),7.39(d,J＝7.6Hz,1H),7.31(t,J＝7.5Hz,1H),7.28–7.22(m,1H),7.17 (dd,J＝18.5,7.9Hz,2H),2.98(s,9H),2.36(s,3H).
Example 452- ((5-chloro-2- ((2-methyl-3- (4-methylpiperazine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
Following the procedure of step F in example 1, with M3-1 and X-2 were used as starting materials to prepare methyl 6- ((5-chloro-4- ((2- (methylcarbamoyl) phenyl) amino) pyrimidin-2-yl) amino) -2-methyl-1H-indole-3-carboxylate (XI-2) in 73.75% yield.
Hydrolysis of XI-2 as starting Material according to the procedure in example 31 gave 6- ((5-chloro-4- ((2- (methylcarbamoyl) phenyl) amino) pyrimidin-2-yl) amino) -2-methyl-1H-indole-3-carboxylic acid (M)2-3), yield: 92.30 percent.
Method according to example 32, with M2Example 45 was prepared in 91.9% yield starting from-3 and N-methylpiperazine.
m.p.:208.9-210.4℃；ESI-MS[M+H]+(m/z):533.62；1H NMR(400MHz,DMSO-d6) δ11.70(s,1H),11.29(s,1H),9.36(s,1H),8.87(d,J＝8.1Hz,1H),8.77(d,J＝4.4 Hz,1H),8.20(s,1H),7.76(d,J＝7.9Hz,1H),7.71(s,1H),7.40(d,J＝7.4Hz,1H), 7.32(dd,J＝8.6,1.5Hz,1H),7.27(d,J＝8.5Hz,1H),7.11(t,J＝7.5Hz,1H),3.51 (s,3H),2.81(d,J＝4.5Hz,3H),2.39(s,3H),2.33(s,4H),2.21(s,4H).
Example 466- ((5-chloro-4- ((2- (methylcarbamoyl) phenyl) amino) pyrimidin-2-yl) amino) -N, N, 2-trimethyl-1H-indole-3-carboxamide
Method according to example 32, with M2Preparation example 46 starting from-3 and dimethylamine (40% in water) in 80.92% yield.
m.p.:206.3-208.9℃；ESI-MS[M+H]+(m/z):478.63；1H NMR(400MHz,DMSO-d6) δ11.71(s,1H),11.22(s,1H),9.34(s,1H),8.89(d,J＝8.0Hz,1H),8.76(d,J＝4.6 Hz,1H),8.20(s,1H),7.76(s,1H),7.74(s,1H),7.40(t,J＝8.1Hz,1H),7.28(dd,J＝ 8.6,1.3Hz,1H),7.24(d,J＝8.5Hz,1H),7.11(t,J＝7.5Hz,1H),2.99(s,6H),2.81 (d,J＝4.4Hz,3H),2.38(s,3H).
Example 472- ((5-chloro-2- ((2-methyl-3- (morpholine-4-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
Method according to example 32, with M2Example 47 was prepared starting from-3 and morpholine in 50.39% yield. 216.9-219.3 ℃ in m.p.; ESI-MS [ M + H ]]+(m/z):520.38；1H NMR(400MHz,DMSO-d6) δ11.72(s,1H),11.35(s,1H),9.38(s,1H),8.89(d,J＝7.6Hz,1H),8.80(d,J＝4.5 Hz,1H),8.21(s,1H),8.15(s,1H),7.77(d,J＝7.9Hz,1H),7.42(t,J＝7.3Hz,1H), 7.31(s,1H),7.12(t,J＝7.5Hz,1H),6.77(d,J＝6.2Hz,1H),3.51(s,4H),3.05(s, 4H),2.82(d,J＝4.5Hz,3H),2.42(s,3H).
Example 482- ((5-chloro-2- ((2-methyl-3- (4-methylpiperidine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
Method according to example 32, with M2Preparation example 48, starting from-3 and morpholine, gave a yield of 91.23%. 212.9-215.8 ℃ in m.p.; ESI-MS [ M + H ]]+(m/z):532.67；1H NMR(400MHz,DMSO-d6) δ11.69(s,1H),11.23(s,1H),9.35(s,1H),8.86(s,1H),8.77(s,1H),8.20(s,1H), 7.75(d,J＝7.5Hz,1H),7.70(s,1H),7.40(s,1H),7.27(dd,J＝19.0,8.6Hz,2H), 7.10(t,J＝7.5Hz,1H),2.89(s,4H),2.81(d,J＝4.3Hz,3H),2.38(s,3H),1.63(d,J ＝10.2Hz,4H),1.07(s,1H),0.94(d,J＝5.4Hz,3H).
Example 492- ((5-chloro-2- ((2-methyl-3- (4-hydroxypiperidine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
Method according to example 32, with M2Preparation example 49 with morpholine in 83.65% yield starting from 3. 231.8-234.2 ℃ in m.p.; ESI-MS [ M + H ]]+(m/z):534.61；1H NMR(400MHz,DMSO-d6) δ11.69(s,1H),11.24(s,1H),9.35(s,1H),8.87(d,J＝7.5Hz,1H),8.76(d,J＝4.3 Hz,1H),8.20(s,1H),8.07(s,1H),7.75(d,J＝7.8Hz,1H),7.40(s,1H),7.26(q,J＝8.4Hz,2H),7.11(t,J＝7.3Hz,1H),4.76(s,1H),3.51(s,1H),3.20–3.07(m,4H), 2.81(d,J＝4.0Hz,3H),2.38(s,3H),1.30(d,J＝37.7Hz,4H).
Research on antitumor activity of product of the invention
In vitro antitumor cell Activity
The pyrimidine derivatives of the formula I are subjected to activity screening for inhibiting human anaplastic large cell lymphoma cells Karpas299 of high-surface NPM-ALK protein, human lung adenocarcinoma cells NCI-H2228 of high-expression EML4-ALK protein and human lung adenocarcinoma cells A549 of high-expression EGFR in vitro.
(1) After cells were thawed and passaged for 2-3 stabilities, they were digested from the bottom of the flask with trypsin solution (0.25%). The cell digest was poured into a centrifuge tube, after which culture broth was added to stop the digestion. Centrifuging the centrifuge tube at 800r/min for 10min, discarding supernatant, adding 5mL culture solution, blowing and beating the mixed cells, sucking 10 μ L cell suspension, adding into cell counting plate, counting, and adjusting cell concentration to 104Per well. 100. mu.L of the cell suspension was added to the 96-well plate except that the A1 well was a blank well and no cells were added. The 96-well plate was placed in an incubator for 24 h.
(2) The test sample was dissolved in 50. mu.L of dimethyl sulfoxide, and then an appropriate amount of culture medium was added to dissolve the sample to 2mg/mL of the liquid, and then the sample was diluted to 20, 4, 0.8, 0.16, 0.032. mu.g/mL in a 24-well plate.
3 wells were added for each concentration, two rows and two columns of cells around the perimeter of which were greatly influenced by the environment and were used only for blank wells. The 96-well plate was placed in an incubator for 72 h.
(3) The drug-containing culture medium in the 96-well plate was discarded, the cells were washed twice with Phosphate Buffered Saline (PBS), 100. mu.L of MTT (0.5mg/mL) was added to each well, and the mixture was placed in an incubator for 4 hours, and then the MTT solution was discarded, and 100. mu.L of dimethyl sulfoxide was added thereto. And oscillating on a magnetic oscillator to fully dissolve the viable cells and the MTT reaction product formazan, and putting the formazan into an enzyme labeling instrument to measure the result. Determination of drug IC by Bliss method50The value is obtained.
The results of the compound for inhibiting the activity of the lymphoma Karpas299 and the lung adenocarcinoma cells A549 are shown in the table 1.
TABLE 1
Figure BDA0002447676200000281
Figure BDA0002447676200000291
L1196M ALK and ROS1 enzyme Activity assay
The assay used to measure the enzymatic activity of L1196M ALK is based on an enzyme-linked immunosorbent assay. The specific operation is as follows:
the example compounds, 50pM L1196M ALK and 5uM ATP were placed in assay buffer (25mM MOPS, Ph 7.4,1mM DTT,5mM MgCl) on 0.25mg/mL PGT coated plates at room temperature2,1mM MnCl2,0.1％NaN3) Incubate for 20 min. The reaction mixture was removed by washing and the phosphopolymer substrate was detected with 0.2ug/mL of horseradish peroxidase conjugated phosphotyrosine specific monoclonal antibody. After the color development was stopped by adding 1M phosphoric acid, the developed substrate color was quantified spectrophotometrically at 450 nm.
The ROS1 enzyme activity assay was performed as described for the enzyme activity assay L1196M ALK.
The inhibition data of the example compounds on L1196M ALK and ROS1 are shown in table 2.
TABLE 2
Figure BDA0002447676200000292
The compounds of general formula I of the present invention can be administered alone, but usually are administered in admixture with a pharmaceutically acceptable carrier selected according to the desired route of administration and standard pharmaceutical practice, and their novel use is illustrated below in the context of methods for the preparation of various pharmaceutical dosage forms of the compounds, e.g., tablets, capsules, injections, aerosols, suppositories, films, dripping pills, liniments for external use and ointments, as appropriate.

Claims (7)

1.2, 4-diarylaminopyrimidine derivatives containing aromatic heterocyclic rings shown in a general formula I, optical isomers and pharmaceutically acceptable salts thereof,
Figure FDA0003227695940000011
wherein the content of the first and second substances,
x is independently C, N, and may be R5Substitution;
y is independently N and may be substituted by R4Substitution;
z is independently C and may be substituted by R6Substitution;
n＝1；
R1is (C)1-C3) Alkylamido radical, (C)1-C3) Alkylsulfonylamino group by 1-2 (C)1-C3) An alkyl-substituted carbamoyl group; r2Is Cl; r3Is H; r4Is H;
R5is CONR7R8、COR7；
R6Is (C)1-C3) Alkyl radical, CH2NR7R8；
R7And R8The same or different, are respectively and independently selected from H and (C)1-C3) Alkyl, (C)1-C3) Alkoxy, hydroxy substituted (C)1-C3) An alkyl group;
or R7And R8Together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, except for R7And R8Optionally containing 0-1 heteroatoms selected from N, O and/or S in addition to the nitrogen atom to which it is attached, said heterocyclic group optionally being substituted with 0-1R9Substitution;
R9is (C)1-C3) Alkyl, hydroxy-substituted (C)1-C3) An alkyl group.
2.2, 4-diarylaminopyrimidine derivatives containing aromatic heterocyclic rings shown in the general formula I in claim 1, and optical isomers, pharmaceutically acceptable salts thereof,
wherein R is5Comprises the following steps:
Figure FDA0003227695940000012
Figure FDA0003227695940000013
R6is methyl,
Figure FDA0003227695940000014
Figure FDA0003227695940000015
3.2, 4-diarylaminopyrimidine derivatives containing aromatic heterocyclic ring, and optical isomers and pharmaceutically acceptable salts thereof, N- (2- ((5-chloro-2- ((2- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
2- (5-chloro-2- ((2- (((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
N- (2- ((5-chloro-2- ((2- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) acetamide
2- ((5-chloro-2- ((2- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylphenylcarboxamide
N- (2- ((5-chloro-2- ((2- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
2- ((5-chloro-2- ((2- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
N- (2- ((5-chloro-2- ((2- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) acetamide
2- ((5-chloro-2- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
N- (2- ((5-chloro-2- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
2- ((5-chloro-2- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
N- (2- ((5-chloro-2- ((2- ((dimethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) acetamide
N- (2- ((5-chloro-2- ((2- (piperidin-1-ylmethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2- ((4-ethylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2- (pyrrolidin-1-ylmethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
2- ((5-chloro-2- ((2- ((4-methylpiperidin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
N- (2- ((5-chloro-2- ((2- ((4-methylpiperidin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2- ((4-methylpiperidin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) acetamide
N- (2- ((5-chloro-2- ((2- ((4-hydroxypiperidin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- (((2- ((diisopropylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2- (morpholinomethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2- ((diethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2- (thiomorpholinomethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
2- ((5-chloro-2- ((2- (piperidin-1-ylmethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
2- ((5-chloro-2- ((2- ((4-ethylpiperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
2- ((5-chloro-2- ((2- (pyrrolidin-1-ylmethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
2- ((5-chloro-2- ((2- (morpholinomethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
2- ((5-chloro-2- ((2- ((diethylamino) methyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
2- ((5-chloro-2- ((2- (thiomorpholinomethyl) -1H-benzo [ d ] imidazol-6-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzamide
6- ((5-chloro-4- ((2- (methylsulfonylamino) phenyl) amino) pyrimidin-2-yl) amino) -2-methyl-1H-indole-3-carboxylic acid ethyl ester
6- ((5-chloro-4- ((2- (methylsulfonylamino) phenyl) amino) pyrimidin-2-yl) amino) -2-methyl-1H-indole-3-carboxylic acid methyl ester
N- (2- ((5-chloro-2- ((2-methyl-3- (4-methylpiperazine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((3- (4- (2-hydroxyethyl) piperazine-1-carbonyl) -2-methyl-1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
6- ((5-chloro-4- ((2- (methylsulfonylamino) phenyl) amino) pyrimidin-2-yl) amino) -N- (2-hydroxyethyl) -2-methyl-1H-indole-3-carboxamide
N- (2- ((5-chloro-2- ((3- (4-ethylpiperazine-1-carbonyl) -2-methyl-1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2-methyl-3- (4-methylpiperidine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((3- (4-hydroxypiperidine-1-carbonyl) -2-methyl-1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2-methyl-3- (piperidine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2-methyl-3- (morpholine-4-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2-methyl-3- (thiomorpholine-4-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((2-methyl-3- (pyrrolidine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
(R) -N- (2- ((5-chloro-2- ((3- (2- (hydroxymethyl) pyrrolidine-1-carbonyl) -2-methyl-1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
N- (2- ((5-chloro-2- ((3- (3-hydroxyazetidin-1-carbonyl) -2-methyl-1H-indol-6-yl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide
6- ((5-chloro-4- ((2- (methylsulfonylamino) phenyl) amino) pyrimidin-2-yl) amino) -N, 2-trimethyl-1H-indole-3-carboxamide
2- ((5-chloro-2- ((2-methyl-3- (4-methylpiperazine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
6- ((5-chloro-4- ((2- (methylcarbamoyl) phenyl) amino) pyrimidin-2-yl) amino) -N, 2-trimethyl-1H-indole-3-carboxamide
2- ((5-chloro-2- ((2-methyl-3- (morpholine-4-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
2- ((5-chloro-2- ((2-methyl-3- (4-methylpiperidine-1-carbonyl) -1H-indol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
2- ((5-chloro-2- ((3- (4-hydroxypiperidine-1-carbonyl) -2-methyl-1H-indol-6-yl) amino) pyrimidin-4-yl) amino) -N-methylbenzamide
6- ((5-chloro-4- ((2- (methylcarbamoyl) phenyl) amino) pyrimidin-2-yl) amino) -N, N-diethyl-2-methyl-1H-indole-3-carboxamide
6- ((5-chloro-4- ((2- (methylsulfonamido) phenyl) amino) pyrimidin-2-yl) amino) -2-methyl-1H-indole-3-carboxylic acid.
4. A pharmaceutical composition comprising the 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocyclic rings of claims 1-3 and optical isomers, pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers.
5. Use of 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocycles of claims 1-3 and their optical isomers, pharmaceutically acceptable salts or pharmaceutical compositions of claim 4 for the preparation of ALK and ROS1 kinase inhibitors.
6. Use of 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocycles as claimed in claims 1-3 and optical isomers, pharmaceutically acceptable salts thereof or pharmaceutical compositions as claimed in claim 4 in preparing antitumor drugs.
7. The use of claim 6, wherein the neoplasm is lymphoma or lung cancer.
CN202010283698.8A 2020-04-13 2020-04-13 2, 4-diaryl aminopyrimidine derivative containing aromatic heterocycle and preparation and application thereof Active CN111484484B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010283698.8A CN111484484B (en) 2020-04-13 2020-04-13 2, 4-diaryl aminopyrimidine derivative containing aromatic heterocycle and preparation and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010283698.8A CN111484484B (en) 2020-04-13 2020-04-13 2, 4-diaryl aminopyrimidine derivative containing aromatic heterocycle and preparation and application thereof

Publications (2)

Publication Number Publication Date
CN111484484A CN111484484A (en) 2020-08-04
CN111484484B true CN111484484B (en) 2021-11-23

Family

ID=71811724

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010283698.8A Active CN111484484B (en) 2020-04-13 2020-04-13 2, 4-diaryl aminopyrimidine derivative containing aromatic heterocycle and preparation and application thereof

Country Status (1)

Country Link
CN (1) CN111484484B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023178094A2 (en) * 2022-03-14 2023-09-21 Purdue Research Foundation Spleen tyrosine kinase inhibitor, composition, and methods of use

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003030909A1 (en) * 2001-09-25 2003-04-17 Bayer Pharmaceuticals Corporation 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer
WO2003078404A1 (en) * 2002-03-15 2003-09-25 Novartis Ag Pyrimidine derivatives
WO2005026158A1 (en) * 2003-09-16 2005-03-24 Novartis Ag 2,4 di (hetero) -arylamino-pyrimidine derivatives as zap-70 and/or syk inhibitors
CN1852900A (en) * 2003-09-18 2006-10-25 诺瓦提斯公司 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders
WO2008073687A2 (en) * 2006-12-08 2008-06-19 Irm Llc Compounds and compositions as protein kinase inhibitors
WO2008118822A1 (en) * 2007-03-23 2008-10-02 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
WO2009032703A1 (en) * 2007-08-28 2009-03-12 Irm Llc 2- (het) arylamino-6-aminopyridine derivatives and fused forms thereof as anaplastic lymphoma kinase inhibitors
WO2009080638A2 (en) * 2007-12-20 2009-07-02 Cellzome Limited Sulfamides as zap-70 inhibitors
WO2009112490A1 (en) * 2008-03-11 2009-09-17 Cellzome Limited Sulfonamides as zap-70 inhibitors
WO2009126515A1 (en) * 2008-04-07 2009-10-15 Irm Llc Compounds and compositions as protein kinase inhibitors
WO2012106540A1 (en) * 2011-02-02 2012-08-09 Irm Llc Methods of using alk inhibitors
WO2016033100A1 (en) * 2014-08-25 2016-03-03 Salk Institute For Biological Studies Novel ulk1 inhibitors and methods using same
CN105524045A (en) * 2014-10-22 2016-04-27 山东轩竹医药科技有限公司 Tetracyclic anaplastic lymphoma kinase inhibitor

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003030909A1 (en) * 2001-09-25 2003-04-17 Bayer Pharmaceuticals Corporation 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer
WO2003078404A1 (en) * 2002-03-15 2003-09-25 Novartis Ag Pyrimidine derivatives
WO2005026158A1 (en) * 2003-09-16 2005-03-24 Novartis Ag 2,4 di (hetero) -arylamino-pyrimidine derivatives as zap-70 and/or syk inhibitors
CN1852900A (en) * 2003-09-18 2006-10-25 诺瓦提斯公司 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders
WO2008073687A2 (en) * 2006-12-08 2008-06-19 Irm Llc Compounds and compositions as protein kinase inhibitors
WO2008118822A1 (en) * 2007-03-23 2008-10-02 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
WO2009032703A1 (en) * 2007-08-28 2009-03-12 Irm Llc 2- (het) arylamino-6-aminopyridine derivatives and fused forms thereof as anaplastic lymphoma kinase inhibitors
WO2009032694A1 (en) * 2007-08-28 2009-03-12 Dana Farber Cancer Institute Amino substituted pyrimidine, pyrollopyridine and pyrazolopyrimidine derivatives useful as kinase inhibitors and in treating proliferative disorders and diseases associated with angiogenesis
WO2009080638A2 (en) * 2007-12-20 2009-07-02 Cellzome Limited Sulfamides as zap-70 inhibitors
WO2009112490A1 (en) * 2008-03-11 2009-09-17 Cellzome Limited Sulfonamides as zap-70 inhibitors
WO2009126515A1 (en) * 2008-04-07 2009-10-15 Irm Llc Compounds and compositions as protein kinase inhibitors
WO2012106540A1 (en) * 2011-02-02 2012-08-09 Irm Llc Methods of using alk inhibitors
WO2016033100A1 (en) * 2014-08-25 2016-03-03 Salk Institute For Biological Studies Novel ulk1 inhibitors and methods using same
CN105524045A (en) * 2014-10-22 2016-04-27 山东轩竹医药科技有限公司 Tetracyclic anaplastic lymphoma kinase inhibitor

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Discovery of N6-phenyl-1H -pyrazolo[3 ,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors using comm on-feature pharmacop hore model based virtual screening and hit-to-lead optimization;Ling-Ling Yang等;《Eu ropean Journal of Medicina l Chemistry》;20120814;Supporting information *
RN:511247-06-6;STN;《STN检索记录》;20030506;第1页 *
Substituted aminobenzimidazole pyrimidines as cyclin-dependent kinase inhibitors;Sharad Verma等;《Bioorganic & Medicinal Chemistry Letters》;20050415;第1975页Table 2.化合物19 *
Virtual Screening for Potential Allosteric Inhibitors of Cyclin-Dependent Kinase 2 from Traditional Chinese Medicine;Fang Lu等;《Molecules》;20160921;第9页Figure 8. *

Also Published As

Publication number Publication date
CN111484484A (en) 2020-08-04

Similar Documents

Publication Publication Date Title
US20210163464A1 (en) Pyridine compound
JP6606561B2 (en) Pyrimidopyrroles compound, preparation method thereof, pharmaceutical composition and application thereof
EP3323817B1 (en) Aniline pyrimidine derivatives and uses thereof
JP2015524448A (en) Alkynyl heteroaromatic compounds and their applications
WO2020200158A1 (en) N-heteroaromatic amide derivatives for treatment of cancer
JP2010505859A (en) Protein kinase inhibitors and methods for using the same
CN109071523A (en) A kind of carbamide compounds, preparation method and its medical usage
WO2019233459A1 (en) Human epidermal growth factor receptor inhibitor, preparation method therefor and use thereof
CN111484484B (en) 2, 4-diaryl aminopyrimidine derivative containing aromatic heterocycle and preparation and application thereof
CN107151233B (en) Hydrazone-containing pyrimidine derivative and application thereof
WO2017144025A1 (en) Pyrimido[4,5-d][1,3]oxazin-2-one derivative serving as egfr inhibitor, and application thereof
CN106866642B (en) Quinazoline compound containing aryl acylhydrazone structure and application thereof
TW201934547A (en) A pyrimidine compound and the preparation method and medical use thereof
CN110724137B (en) Thiophene derivative and preparation method and application thereof
CN113493436B (en) Amino substituted pyridine derivative and preparation method thereof, pharmaceutical composition and application
CN107721937B (en) Preparation method and application of compound containing pyrimidone skeleton
WO2016153394A1 (en) Use of novel chemical compounds (variants) as nuak1 kinase inhibitors for treating oncological diseases
WO2019233458A1 (en) Vegfr inhibitor, preparation method therefor and use thereof
CN117126142A (en) Heterocyclic EGFR mutation inhibitor and application thereof
WO2021259049A1 (en) Indole derivative, preparation method therefor and use thereof
CN117430586A (en) FGFR kinase inhibitor and pharmaceutical application thereof
CN116102575A (en) Cyclic 2-aminopyrimidine compound and application thereof
CN113880813A (en) 2-aminopyrimidine heterocyclic compound and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant