CN111484484A - 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

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CN111484484A
CN111484484A CN202010283698.8A CN202010283698A CN111484484A CN 111484484 A CN111484484 A CN 111484484A CN 202010283698 A CN202010283698 A CN 202010283698A CN 111484484 A CN111484484 A CN 111484484A
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amino
chloro
pyrimidin
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CN111484484B (en
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翟鑫
郭明
左代英
邢凌云
曹猛
赵天铭
陈煜翔
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—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 the conversion of the general formula IThe compound has strong A L K and ROS1 kinase inhibition effect, and also relates to the application of the compound, optical isomers and pharmaceutically acceptable salts thereof in preparing medicaments for treating and/or preventing diseases caused by abnormal expression of A L K and ROS1, in particular to the application in preparing medicaments 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 thereof and a pharmaceutical composition containing the compounds.
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 (A L K) is a member of the insulin receptor tyrosine kinase family, and is first discovered in 1994 to be a single-chain transmembrane protein consisting of 1620 amino acids in anaplastic large cell lymphoma AMS3 cells, A L K has high expression level in embryonic development period and then gradually decreases in expression level in adult period, the protein consists of an extramembranous part, a transmembrane region and an intramembranous catalytic region, downstream signaling pathways are Ras-ERK, JAK3-STAT3 and PI3-K/Akt and the like, and the pathways are closely related to cell proliferation, survival and migration.
In 1994, Morri et al found that A L K gene on chromosome 2 and nucleolar phosphoprotein NPM (nucleophosphosmin) gene on chromosome 5 were fused in a staggered manner, and the rearranged mutant gene NPM-A L K has carcinogenicity, in 2007, Japanese scientist Soda et al found A L K gene mutation in lung adenocarcinoma tissue for the first time, inversion mutation occurred in the short arm of chromosome 2, so that NIH-3T3 fibroblasts, which are obtained by transfecting NIH-3T3 of echinoderm microtubule-associated protein 4(EM L) gene with A L K gene 20-29 exon fusion form EM L-A L K fusion gene with EM L-A L K fusion gene, had malignant transformation capability, and in NSC L C patients, which had about 3% -7%, the presence of EM 464-A L K fusion gene, furthermore, research also showed that A L K gene mutation is involved in the development of various tumors, including the interstitial cell tumor suppressor, and anti-malignant tumor signal of large cell tumor, and further showed that the A target tumor suppressor can be achieved by targeting on tumor cell proliferation, tumor, and tumor target tumor.
The fusion, overexpression and mutation of ROS1 gene can result in the dysregulation of ROS1 protein, abnormal ROS1 protein kinase can activate downstream multiple oncogenic signal channels and control the channels of cell proliferation, survival and cell cycle, ROS1 is highly expressed in various tumor cells, and has 49% of amino acid sequence homology with A L K and 77% of homology with ATP binding region, and various A L K 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 radicalBase, (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, hydroxy, carboxyl, amino, hydroxy and/or amino substituted (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 radicalAcyl or (C)1-C3) An alkylsulfonyl 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 substituted0 to 2 identical or different R9Substitution;
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 may be 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 highly expressing NPM-A L K protein and human lung adenocarcinoma cells NCI-H2228 highly expressing EM L4-A L K protein in vitro, the compound has obvious inhibiting effect on lung cancer cells and lymph cancer cells, and is particularly used for preparing the medicines for treating and/or preventing lung cancer and lymph cancer.
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 be obtained by condensation of intermediate XII with substituted dichloropyrimidines according to scheme 3And (4) obtaining. 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 NMR spectra of the compounds were determined using BrukeraRx-400 and Agilent 1100L C/MSD, the reagents used being either 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 into 300m L dried isopropanol (i-PrOH), 42.30g (0.33mol) of N, N-diisopropylethylamine is slowly added, the temperature is increased to 80 ℃, the reaction is carried out for 1.5h, and the hot solution is filtered by suction, thus 37.35g of white powder solid is obtained, and the yield is 89.7%.
Step B N- (2- ((2, 5-dichloropyrimidin-4-yl) amino) phenyl) methanesulfonamide (M)1-1)
Under ice-bath conditions, 10g (0.04mol) of intermediate III and 9.3g (0.12mol) of pyridine (Py) are added into 50m L dried tetrahydrofuran, 5.4g (0.05mol) of methylsulfonyl chloride is slowly added dropwise, after dropwise addition, the reaction is carried out at room temperature for 2.5 hours, suction filtration is carried out, and tetrahydrofuran (10m L× 3) is washed to obtain 11.7g of white powder solid, wherein the yield is 89.3%.
Step C2- (chloromethyl) -6-nitro-1H-benzo [ d ] imidazole (VI)
At room temperature, 10.0g (0.07mol) of 4-nitrophthalenediamine (V), 12.3g (0.13mol) of chloroacetic acid and 50m of L water are added into 133m of L concentrated hydrochloric acid, reflux reaction is carried out for 4h, the reaction liquid is placed at room temperature, the pH value is adjusted to be 9 by ammonia water, suction filtration is carried out to obtain orange-red solid, the obtained solid is recrystallized by methanol to obtain 8.9g of light yellow solid, and the yield is 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 100m of L Tetrahydrofuran (THF) at room temperature, 8.5g (0.09mol) of N-methylpiperazine and 11.8g (0.09mol) of anhydrous potassium carbonate were added, and the mixture was reacted at 50 ℃ for 2 hours, after cooling the reaction mixture to room temperature, the mixture was poured into 20m of L water and stirred for 30 minutes, followed by suction filtration to obtain 8.0g of a pale brown solid with a yield of 68.3%
Step E2- ((4-methylpiperazin-1-yl) methyl) -1H-benzo [ d]Imidazole-6-amines (M)1-2)
At room temperature, 5.0g (0.02mol) of VII-1 is dissolved in 50m L90% ethanol solution, 0.74g (2.7mmol) of ferric trichloride hexahydrate and 0.07g (5.5mmol) of activated carbon powder are added, 50m L80% hydrazine hydrate is dripped after the temperature is raised to 40 ℃, the temperature is raised to reflux reaction for 1 hour after dripping, the hot solution is filtered, the filtrate is evaporated to dryness to obtain 4.3g of off-white solid, the yield is 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 was dissolved in 10M L isopropanol and 0.85g (2.9mmol) of M was added1-1 and 0.50g (2.9mmol) of p-toluenesulfonic acid react at 80 ℃ for 6 hours, the reaction solution is placed at room temperature, 20m L water is added, the pH value is adjusted to 8 by using saturated sodium bicarbonate solution, extraction is carried out for three times by using 60m L ethyl acetate, the combined organic phases are 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)9.27(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)12.05(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＝7.0Hz,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)12.14(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)12.04(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)12.03(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-amines (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)12.08(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＝7.5Hz,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)12.07(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)12.09(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＝7.1Hz,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)11.56(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)12.08(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)11.96(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)11.44(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)9.28(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 M2-2Starting from this, example 14 was prepared in 92.0% yield.
m.p.:270.9-273.0℃；ESI-MS[M+H]+(m/z):536.58；1H NMR(400MHz,DMSO-d6)12.00(s,1H),10.09(s,1H),9.18(s,1H),8.42(s,1H),8.11(s,1H),7.84(d,J＝7.2Hz,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)12.08(s,1H),10.13(s,1H),9.18(s,1H),8.43(s,1H),8.12(s,1H),7.85(d,J＝7.7Hz,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)12.04(s,1H),10.15(s,1H),9.16(s,1H),8.43(s,1H),8.11(s,1H),7.84(d,J＝7.9Hz,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)
At room temperature, 20.0g (0.12mol) of isatoic anhydride (IV) is dissolved in 100.0m L ethanol, stirring is started, 14.45m L (0.15mol) of 40% methylamine aqueous solution is slowly dripped to the solution, after the reaction is finished, 50m L saturated saline is added into the reaction solution, the solution is stirred for 20 minutes, three times of extraction are carried out by 750m L ethyl acetate, organic phases are combined, the solvent is evaporated to dryness, and light yellow solid 15.8g is obtained after drying, and the yield is 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)12.16(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)12.22(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)12.17(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)9.29(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 2 preparation of example 21, yield starting from65.0％。
m.p.:275.6-278.6℃；ESI-MS[M+H]+(m/z):550.56；1H NMR(400MHz,DMSO-d6)12.14(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)12.20(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)12.09(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)9.40(s,1H),9.21(s,1H),8.36(d,J＝7.9Hz,1H),8.19(s,1H),8.01(d,J＝49.2Hz,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)12.20(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)12.17(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)12.02(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＝7.5Hz,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)12.11(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)
At room temperature, 1.31g (11.3mmol) of ethyl acetoacetate and 1.26g (11.3mmol) of potassium tert-butoxide are added to 10M L tetrahydrofuran, stirred at room temperature for 2 hours, then 1.0g (5.4mmol) of 2, 4-dinitrofluorobenzene (VIII) is added, reaction is carried out for 1 hour, 1.2M hydrochloric acid is added to adjust the pH value to 2, and then the mixture is stood for layering, an upper organic phase is collected, the organic solvent is evaporated to dryness, and yellow solid 1.4g is obtained after drying, and the yield is 91.19%.
Step B6-amino-2-methyl-1H-indole-3-carboxylic acid ethyl ester (X-1)
0.5g (1.7mmol) of IX is dissolved in 15m L of ethanol at room temperature, then 2.29g (10.1mmol) of stannous chloride dihydrate and 1.2m L of concentrated hydrochloric acid are added, reflux reaction is carried out for 4 hours, the reaction liquid is poured into 30% sodium hydroxide solution, stirring is carried out for 30 minutes, ethyl acetate extraction is carried out, the organic phases are combined, evaporation is carried out, 0.2g of dried brown solid is obtained, and the yield is 54.1%.
Following procedure F in example 1Method 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)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),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
At room temperature, 0.5g (1.0mmol) of example 30 is put into 10M L methanol, 0.32g (8.0mmol) of sodium hydroxide is dissolved in 1M L water, the prepared sodium hydroxide solution is dripped into the methanol, reflux reaction is carried out for 6 hours, the reaction solution is placed at room temperature, 1M hydrochloric acid is added dropwise to adjust the pH value to be 1, suction filtration and drying are carried out, 0.46g of dark purple solid is obtained, the yield is 94.9%, and the crude product is purified by column chromatography to obtain the white-like solid.
m.p.:207.2-210.3℃；ESI-MS[M+H]+(m/z):487.39；1H NMR(600MHz,DMSO-d6)11.96(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 10m L N, N-Dimethylformamide (DMF), reacted at room temperature for 1 hour, the reaction mixture was stirred with 20m L water, extracted with 60m L ethyl acetate three times, the organic phases were combined, washed once with a 5% lithium chloride solution and once with saturated saline, and then 0.12g of a brown solid obtained by evaporation of the solvent was obtained, and the yield was 34.3%.
m.p.:223.2-225.7℃；ESI-MS[M+H]+(m/z):569.39；1H NMR(400MHz,DMSO-d6)11.22(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)11.21(s,1H),9.39(s,1H),9.27(s,1H),8.52(s,1H),8.17(s,1H),8.14(d,J＝8.0Hz,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)11.25(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)11.21(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)11.21(s,1H),9.30(s,1H),9.21(s,1H),8.09(s,1H),7.75(s,1H),7.31(d,J＝8.4Hz,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)11.14(s,1H),9.30(s,1H),9.25(s,1H),8.49(s,1H),8.17(s,1H),8.13(d,J＝7.5Hz,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)11.14(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)11.23(s,1H),9.30(s,1H),9.27(s,1H),8.52(s,1H),8.17(s,1H),8.15(d,J＝8.0Hz,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)11.20(s,1H),9.31(s,1H),9.26(s,1H),8.50(s,1H),8.18(s,1H),8.15(d,J＝8.0Hz,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)11.16(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)11.10(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)11.27(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)11.14(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.
Following the procedure of example 31, in XI-2Hydrolyzing the raw material to obtain 6- ((5-chloro-4- ((2- (methylcarbamoyl) phenyl) amino) pyrimidine-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)11.70(s,1H),11.29(s,1H),9.36(s,1H),8.87(d,J＝8.1Hz,1H),8.77(d,J＝4.4Hz,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)11.71(s,1H),11.22(s,1H),9.34(s,1H),8.89(d,J＝8.0Hz,1H),8.76(d,J＝4.6Hz,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)11.72(s,1H),11.35(s,1H),9.38(s,1H),8.89(d,J＝7.6Hz,1H),8.80(d,J＝4.5Hz,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)11.69(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)11.69(s,1H),11.24(s,1H),9.35(s,1H),8.87(d,J＝7.5Hz,1H),8.76(d,J＝4.3Hz,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-table NPM-A L K protein and human lung adenocarcinoma cells NCI-H2228 and human lung adenocarcinoma cells A549 of high-expression EGFR of high-expression EM L4-A L K protein 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. Centrifuge tube at 800r/mCentrifuging for 10min in, discarding supernatant, adding 5m L culture solution, blowing and mixing cells, sucking 10 μ L cell suspension, adding into cell counting plate, counting, and adjusting cell concentration to 104One/well, 100. mu. L of cell suspension was added to 96-well plates except for blank A1 wells, and the 96-well plates were incubated for 24 h.
(2) The test sample was dissolved in 50. mu. L DMSO, and then an appropriate amount of culture medium was added to dissolve the sample to 2mg/m L liquid, and then the sample was diluted to 20, 4, 0.8, 0.16, 0.032. mu.g/m L 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) Discarding the drug-carrying culture solution in a 96-well plate, washing cells twice by using Phosphate Buffer Solution (PBS), adding MTT (0.5mg/m L) 100 mu L into each well, putting the well into an incubator for 4 hours, discarding the MTT solution, adding dimethyl sulfoxide 100 mu L, oscillating on a magnetic oscillator to fully dissolve the surviving cells and MTT reaction product formazan, putting the formazan into an enzyme labeling instrument to determine the result, and determining the drug IC by a 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 A L K and ROS1 enzyme Activity assay
The assay used to measure the enzymatic activity of L1196M A L K is based on an enzyme-linked immunosorbent assay.
The example compounds, 50pM L1196M A L K and 5uMATP were placed in assay buffer (25mM MOPS, Ph 7.4,1mM DTT,5mM MgCl) on 0.25mg/m L PGT coated plates at room temperature2,1mM MnCl2,0.1％NaN3) Incubation for 20 min. the reaction mixture was removed by washing and the phosphopolymer substrate was detected with 0.2ug/M L horseradish peroxidase conjugated phosphotyrosine specific monoclonal antibody after addition of 1M phosphoric acid to stop the development, the developed substrate color was quantified spectrophotometrically at 450 nm.
The ROS1 enzyme activity was tested in the same manner as L1196M A L K enzyme activity test.
The inhibition data of the example compounds against L1196M A L K 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 (10)

1.2, 4-diarylaminopyrimidine derivatives containing aromatic heterocyclic rings shown in a general formula I, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
Figure FDA0002447676190000011
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-C4) 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) 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、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 to 2 and p is independently 0 to 6, preferably 0 to 4, more preferably 0 to 2.
2.2, 4-diarylaminopyrimidine derivatives containing aromatic heterocyclic ring of the general formula I of claim 1, and 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;
preferably, the first and second electrodes are formed of a metal,
n＝1；
x is independently C or N, and may be substituted by R5Substitution;
y is independently C or N, and may be substituted by R4Substitution;
z is independently C or N, and may be substituted by R6Substitution;
more preferably still, the first and second liquid crystal compositions are,
n＝1；
x is independently C or N, and may be substituted by R5Substitution;
y is N and may be R4Substitution;
z is C and may be R6And (4) substitution.
3.2, 4-diarylaminopyrimidine derivatives containing aromatic heterocyclic ring of the general formula I according to claim 1 or 2, and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
R1is (C)1-C6) Alkylamido radical, (C)1-C6) Alkylsulfonylamino group by 1-2 (C)1-C6) Alkyl-substituted carbamoyl.
4.2, 4-diarylaminopyrimidine derivatives containing aromatic heterocyclic rings represented by the general formula I as claimed in any one of claims 1 to 3, and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
R2is halogen, hydroxyl, cyano, amino, nitro;
R3is H, halogen, (C)1-C6) Alkyl, (C)1-C6) An alkoxy group;
R4is H, (C)1-C6) An alkyl group;
preferably, the first and second electrodes are formed of a metal,
R2is halogen;
R3is H, (C)1-C3) Alkyl, (C)1-C3) An alkoxy group;
R4is H, (C)1-C3) An alkyl group;
more preferably still, the first and second liquid crystal compositions are,
R2is Cl;
R3is H;
R4is H.
5.2, 4-diarylaminopyrimidine derivatives containing aromatic heterocyclic rings represented by the general formula I as claimed in any one of claims 1 to 4, and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
R5is 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、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、NHmCO(CH2)pNHmR7R8、NHm(CH2)pCOR7R8；
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;
preferably, the first and second electrodes are formed of a metal,
R5is CONHmR7R8、(CH2)pNmR7R8、NHmCONHmR7R8、COR7；
R6Is (C)1-C3) Alkyl group, (CH)2)pNmR7R8；NHmCO(CH2)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 heterocyclyl or heteroaryl group optionally being substituted with 0 to 1R which may be the same or different9Substitution;
R9is (C)1-C3) Alkyl, hydroxy substituted (C)1-C3) Alkyl radical
More preferably still, the first and second liquid crystal compositions are,
R5comprises the following steps:
Figure FDA0002447676190000031
Figure FDA0002447676190000032
R6is methyl, methyl,
Figure FDA0002447676190000033
Figure FDA0002447676190000034
6.2, 4-diarylaminopyrimidine derivatives containing aromatic heterocyclic rings shown in a general formula I, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs 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.
7. A pharmaceutical composition comprising the 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocyclic rings of any one of claims 1-6 and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof and a pharmaceutically acceptable carrier.
8. Use of 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocycles according to any one of claims 1-6 and their optical isomers, pharmaceutically acceptable salts, solvates or prodrugs or the pharmaceutical composition according to claim 7 for the preparation of inhibitors of a L K and ROS1 kinase.
9. Use of 2, 4-diarylaminopyrimidine derivatives containing aromatic heterocyclic ring as claimed in any one of claims 1 to 6 and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof or of the pharmaceutical composition as claimed in claim 7 for preparing antitumor drugs.
10. The use of claim 9, wherein the neoplasm is lymphoma or lung cancer.
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