CN117534631B - Phenylthiazole amine PI4KIII beta inhibitor, preparation method, pharmaceutical composition and application thereof - Google Patents
Phenylthiazole amine PI4KIII beta inhibitor, preparation method, pharmaceutical composition and application thereof Download PDFInfo
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- CN117534631B CN117534631B CN202410028674.6A CN202410028674A CN117534631B CN 117534631 B CN117534631 B CN 117534631B CN 202410028674 A CN202410028674 A CN 202410028674A CN 117534631 B CN117534631 B CN 117534631B
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- China
- Prior art keywords
- methylthiazol
- butyl ester
- acid tert
- methoxyphenyl
- dmso
- Prior art date
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- -1 Phenylthiazole amine Chemical class 0.000 title claims abstract description 106
- 239000003112 inhibitor Substances 0.000 title claims abstract description 40
- 101000730433 Homo sapiens Phosphatidylinositol 4-kinase beta Proteins 0.000 title claims abstract description 33
- 102100032619 Phosphatidylinositol 4-kinase beta Human genes 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 10
- 238000000034 method Methods 0.000 claims abstract description 60
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 230000008569 process Effects 0.000 claims abstract description 3
- WFWKNGZODAOLEO-UHFFFAOYSA-N 1-(4-Methoxyphenyl)-2-propanone Chemical compound COC1=CC=C(CC(C)=O)C=C1 WFWKNGZODAOLEO-UHFFFAOYSA-N 0.000 claims description 46
- 150000001875 compounds Chemical class 0.000 claims description 43
- ISTGQSQWSKCNFJ-UHFFFAOYSA-N tert-butyl n-ethylcarbamate Chemical compound CCNC(=O)OC(C)(C)C ISTGQSQWSKCNFJ-UHFFFAOYSA-N 0.000 claims description 42
- WEJRYKSUUFKMBC-UHFFFAOYSA-N 1-(4-chlorophenyl)propan-2-one Chemical compound CC(=O)CC1=CC=C(Cl)C=C1 WEJRYKSUUFKMBC-UHFFFAOYSA-N 0.000 claims description 39
- 239000000543 intermediate Substances 0.000 claims description 37
- 206010028980 Neoplasm Diseases 0.000 claims description 31
- ALBYIUDWACNRRB-UHFFFAOYSA-N hexanamide Chemical compound CCCCCC(N)=O ALBYIUDWACNRRB-UHFFFAOYSA-N 0.000 claims description 31
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 26
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 239000002994 raw material Substances 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 10
- LINZZISWCNKFEM-UHFFFAOYSA-N 3,3-dimethylbutanamide Chemical compound CC(C)(C)CC(N)=O LINZZISWCNKFEM-UHFFFAOYSA-N 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 claims description 9
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 6
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- 108091000080 Phosphotransferase Proteins 0.000 claims description 5
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- ZJVAWPKTWVFKHG-UHFFFAOYSA-N p-Methoxypropiophenone Chemical compound CCC(=O)C1=CC=C(OC)C=C1 ZJVAWPKTWVFKHG-UHFFFAOYSA-N 0.000 claims description 5
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- PRXNKYBFWAWBNZ-UHFFFAOYSA-N trimethylphenylammonium tribromide Chemical compound Br[Br-]Br.C[N+](C)(C)C1=CC=CC=C1 PRXNKYBFWAWBNZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 2
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- 239000011737 fluorine Substances 0.000 claims description 2
- LMYQWQCDUHNQLF-UHFFFAOYSA-N hexylthiourea Chemical compound CCCCCCNC(N)=S LMYQWQCDUHNQLF-UHFFFAOYSA-N 0.000 claims description 2
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims 1
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- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- KLKBCNDBOVRQIJ-UHFFFAOYSA-N tert-butyl 4-(aminomethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CN)CC1 KLKBCNDBOVRQIJ-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WUOQXNWMYLFAHT-MRVPVSSYSA-N tert-butyl n-[(3r)-piperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCCNC1 WUOQXNWMYLFAHT-MRVPVSSYSA-N 0.000 description 1
- DQQJBEAXSOOCPG-ZETCQYMHSA-N tert-butyl n-[(3s)-pyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCNC1 DQQJBEAXSOOCPG-ZETCQYMHSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- 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
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a phenylthiazole amine PI4KIII beta inhibitor, which is a substituted phenylthiazole amine compound shown in a general formula V, or a stereoisomer, a hydrate or a pharmaceutically acceptable salt thereof; the inhibitor has the characteristics of effectively inhibiting PI3K/Akt/mTOR signaling pathway of PI4KIII beta, has high-efficiency and excellent PI4KIII beta enzyme inhibition activity, and has low cost, good curative effect and low toxicity, and the intermediate product in the synthesis process has high yield, reduces the resource waste, and is further beneficial to reducing the cost; the application of the composition in antitumor drugs is small in dosage and remarkable in activity.
Description
Technical Field
The invention relates to a phenylthiazole amine PI4KIII beta inhibitor, and also relates to a preparation method, a pharmaceutical composition and application of the inhibitor, belonging to the technical field of medicines.
Background
Traditional methods of malignancy treatment mainly include surgical treatment, chemotherapy, and radiation therapy. Although surgical treatment is a better method, if other auxiliary treatments are not continued, the effect of prolonging the life of the patient is not ideal; the chemotherapy may have drug resistance, side effects of the drug, and frequent cases include suppression of bone marrow, suppression of intestinal functions, etc.; radiation therapy is a localized treatment that inhibits tumor growth, but on the other hand, affects and causes damage to surrounding tissue. Molecular targeting therapy is a novel method for treating cancers due to the characteristics of strong specificity, low toxicity and the like.
Lipid phosphatidylinositol is an important regulator of numerous cellular processes, including signaling, membrane transport, and cytokinesis. Phosphatidylinositol is produced by inositol ring phosphorylation of phosphatidylinositol. Phosphatidylinositol can be phosphorylated and dephosphorylated by a set of different enzymes, which results in a total of seven different mono-and polyphosphorylated phosphatidylinositol. The lipid class phosphatidylinositol 4-phosphate (PI 4P) is produced by the action of phosphatidylinositol 4 kinase (PI 4 Ks). PI4P is the major biosynthetic pathway for the multiple phosphorylated signaling lipids phosphatidylinositol 4, 5-diphosphate (PIP 2) and phosphatidylinositol 3,4, 5-triphosphate (PIP 3). In mammals, there are four different PI4K enzymes: two type II enzymes (PI 4kiiα and PI4kiiβ) and two type III enzymes (PI 4kiiα and PI4kiiβ).
PI4 kiilβ is a peripheral membrane protein, primarily localized to the golgi and trans-golgi network (TGN). Play a key role in mediating lipid transport cytokinesis, maintaining lysosomal identity and regulating membrane transport along with Rab gtpase. Deregulation of PI4 kiilβ is also associated with cancer. PI4 kiilβ is often amplified and oncogenically activated in tumors, and its expression can inhibit cancer cell apoptosis. Deletion of the PI4KIII beta subtype induces apoptosis in cancer cells. Although PI4 kiilβ has been demonstrated as a novel driver of cancer, little research into specific PI4 kiilβ inhibitors involved in cancer treatment has been reported. To date, several PI4 kiilβ small molecule inhibitors have been disclosed as potent antiviral drug candidates in preclinical studies. Many studies demonstrate the medicinal potential of PI4KIII β inhibitors, but much less attention has been paid to exploring PI4KIII β inhibitors as chemotherapies for cancer treatment. Therefore, it is a significant and valuable effort to develop a new class of PI4KIII β inhibitors and explore their use in cancer therapy.
Disclosure of Invention
The invention aims to: the invention aims to provide a high-activity phenylthiazole amine PI4KIII beta inhibitor, and also provides a preparation method, a pharmaceutical composition and application of the inhibitor.
The phenylthiazole amine PI4KIII beta inhibitor is a substituted phenylthiazole amine compound shown in a general formula V, or a stereoisomer or pharmaceutically acceptable salt thereof:wherein A isOr->；
R 1 Is a substituent on the benzene ring selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyC 1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxyC 1-C6 alkoxy or C1-C6 alkoxyC 1-C6 alkyl; r is R 2 Is that；R 3 Or R is 4 Is C1-C6 alkyl, C1-C6 alkyl containing one or more substituents, C1-C6 alkoxy containing one or more substituents, C1-C6 alkanoyl, C1-C6 alkylsulfonyl, C3-a C6 heterocyclyl, a C3-C6 heterocyclyl containing one or more substituents;
x is sulfonyl or carbonyl.
Preferably, the inhibitor is a compound represented by formula I or II:wherein R is 1 、R 2 、R 4 And X is as defined above; r is R 3 Is that. Preferably, in the inhibitor of formula V, the carbon-linked hydrogen is replaced with deuterium, an isotope of hydrogen.
It is further preferred that the alkyl group is replaced by a deuterated alkyl group, the alkoxy group is replaced by a deuterated epoxy group, the benzene ring is replaced by a deuterated benzene ring, and the aromatic ring is replaced by a deuterated aromatic ring.
Preferably, a pharmaceutically acceptable salt refers to the conversion of a basic group in the parent compound to a salt form; wherein the pharmaceutically acceptable salt is a basic group, and is further preferably an amino group or an inorganic or organic acid salt of an amino group; the basic group in the parent compound reacts with 1-4 equivalents of acid in a solvent system.
Preferably, the basic groups of the compounds of the present invention may form salts with acids, in particular with inorganic acids, especially with hydrohalic acids (e.g. hydrochloric, hydrobromic, hydroiodic), nitric, sulfuric, phosphoric, carbonic acids and the like; salts of lower alkyl sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid; salts with aryl sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; salts with organic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, maleic acid, malic acid or succinic acid; salts with amino acids, such as aspartic acid or glutamic acid.
Preferably, the compounds and pharmaceutically acceptable salts of the present invention also include the forms of solvates or hydrates.
Preferably, the structural formula of the compounds in the phenylthiazole amine PI4KIII beta inhibitor of the invention comprises isomeric forms, such as enantiomer, diastereomer and geometryIsomerism or conformational isomerism, in particular R, S configuration containing asymmetric center, double bondZ)、(E) Isomers, the mixture ofZ)、(E) Conformational isomer of (a).
Preferably, the inhibitor is one of the following:
(1) (2- (5- (2-acetamido-4-methylthiazol-5-yl) -2-chlorophenyl sulfamide) ethyl) carbamic acid tert-butyl ester;
(2) N- (5- (4-chloro-3- (N- (2-hydroxy-2-methylpropyl) sulfamoyl) phenyl) -4-methylthiazol-2-yl) acetamide;
(3) N- (2- (2-acetamido-4-methylthiazol-5-yl) -2-chlorophenyl sulfamide) ethyl propionamide;
(4) (2- (2-acetamido-4-methylthiazol-5-yl) -2-chlorophenyl sulfamide) ethylcarbamate;
(5) (2- ((5- (2-acetamido-4-methylthiazol-5-yl) -2-methoxyphenyl) sulfamide) ethyl) carbamic acid tert-butyl ester;
(6) N- (5- (4-chloro-3- (N- (3-hydroxy-4-methylphenyl) sulfamoyl) phenyl) -4-methylthiazol-2-yl) acetamide;
(7) N- (5- (3- (N- (2, 4-difluorophenyl) sulfamoyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) acetamide;
(8) (5- (2-propionylamino-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamide) ethylcarbamic acid tert-butyl ester;
(9) (5- (2-butyrylamino-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamide) ethylcarbamic acid tert-butyl ester;
(10) (5- (2-pentanoylamino-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamide) ethylcarbamic acid tert-butyl ester;
(11) (5- (2-hexanamido-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamido) ethylcarbamic acid tert-butyl ester;
(12) (5- (2-heptanamido-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamido) ethylcarbamic acid tert-butyl ester;
(13) (2- (2-methoxy-5- (4-methyl-2- (3-propylureido) thiazol-5-yl) phenyl) sulfamide) ethylcarbamic acid tert-butyl ester;
(14) (2- (5- (2- (3-butylureido) -4-methylthiazol-5-yl) -2-methoxyphenylsulphonamido) ethyl) carbamic acid tert-butyl ester;
(15) (2- (2-methoxy-5- (4-methyl-2- (3-methylbutanamide) thiazol-5-yl) phenyl) sulfamide) ethyl carbamic acid tert-butyl ester;
(16) (5- (2-isobutyrylamino-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamide) ethylcarbamic acid tert-butyl ester;
(17) (2- (2-methoxy-5- (4-methyl-2-pivaloylamide thiazol-5-yl) phenyl) sulphonamido) ethylcarbamic acid tert-butyl ester;
(18) (5- (2- (3, 3-dimethylbutyramide) -4-methylthiazol-5-yl) -2-methoxyphenylsulphonamide) ethylcarbamic acid tert-butyl ester;
(19) (2- (2-methoxy-5- (4-methyl-2- (4-methylpentanamide) thiazol-5-yl) phenyl) sulphonamido) ethylcarbamic acid tert-butyl ester;
(20) (2- (2-methoxy-5- (4-methyl-2- (5-methylhexanamido) thiazol-5-yl) phenyl) sulphonamido) ethylcarbamic acid tert-butyl ester
(21) (2- (5- (2- (cyclohexanecarboxamido) -4-methylthiazol-5-yl) -2-methoxyphenyl) sulfamide) ethylcarbamic acid tert-butyl ester;
(22) (2- (2-chloro-5- (4-methyl-2- (3-methylbutanamidyl) thiazol-5-yl) phenyl) sulfamide) ethylcarbamic acid tert-butyl ester;
(23) (2-chloro-5- (2- (3, 3-dimethylbutyramide) -4-methylthiazol-5-yl) phenylsulfonamide) ethylcarbamic acid tert-butyl ester;
(24) (2-chloro-5- (4-methyl-2-pentanoylamino-5-yl) phenylsulfonamide) ethylcarbamic acid tert-butyl ester;
(25) (2-chloro-5- (2-hexanamido-4-methylthiazol-5-yl) phenylsulfonamide) ethylcarbamic acid tert-butyl ester;
(26) (2- (5- (2- (3-acetamidopropionamido) -4-methylthiazol-5-yl) -2-methoxyphenyl) sulfamide) ethylcarbamic acid tert-butyl ester;
(27) (2- (2-methoxy-5- (4-methyl-2- (6-oxoheptanamido) thiazol-5-yl) phenyl) sulfamide) ethylcarbamic acid tert-butyl ester;
(28) (2- (2-methoxy-5- (4-methyl-2- (6-oxohexanamide) thiazol-5-yl) phenyl) sulphonamide) ethylcarbamic acid tert-butyl ester;
(29) (R) - (1- ((5- (2-hexanamido-4-methylthiazol-5-yl) -2-methoxyphenyl) sulfonyl) piperidin-3-yl) carbamic acid tert-butyl ester;
(30) (S) - (1- ((5- (2-hexanamido-4-methylthiazol-5-yl) -2-methoxyphenyl) sulfonyl) pyrrolidin-3-yl) carbamic acid tert-butyl ester;
(31) 4- ((2-hexanamido-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamido) piperidine-1-carboxylic acid tert-butyl ester;
(32) N- (5- (3- (2- (3, 3-dimethylbutyramide) ethylaminosulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide;
(33) N- (5- (3- (2-hydroxy-2-methylpropyl) sulfamoyl) -4-methoxyphenyl) -4-methylthiazol-2-yl hexanamide;
(34) N- (5- (3- (N- (2-inylethyl) sulfamoyl)) -4-methoxyphenyl) -4-methylthiazol-2-yl hexanamide;
(35) N- (5- (3- (((4-fluorophenyl) -l 2-nitroxyl) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide;
(36) N- (5- (3- (((4-chlorophenyl) -l 2-subunit) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide;
(37) N- (5- (3- (((4-fluorobenzyl) -l 2-subunit) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide;
(38) N- (5- (3- (((3-fluorobenzyl) -l 2-subunit) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide;
(39) N- (5- (3- (((2-fluorobenzyl) -l 2-diazonium) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide;
(40) N- (4- (3- (((2, 4-difluorobenzyl) -l 2-subunit) sulfonyl) -4-methoxyphenyl) -5-methylthiazol-2-yl) hexanamide;
(41) N- (5- (3- (((3, 4-difluorobenzyl) -l 2-subunit) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide;
(42) N- (5- (3- (((3-chloro-4-fluorobenzyl) -l 2-subunit) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide;
(43) N- (5- (3- (((4-fluoro-3- (trifluoromethyl) benzyl) -l 2-subunit) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide;
(44) N- (5- (4-methoxy-3- (((3, 4, 5-trifluorobenzyl) -l 2-diazonium) sulfonyl) phenyl) -4-methylthiazol-2-yl) hexanamide;
(45) N- (5- (3- (((4-fluorophenylethyl) -l 2-subunit) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide;
(46) (2- (2-hexanamido-4-methylthiazol-5-yl) -2-methoxybenzamide) ethylcarbamic acid tert-butyl ester;
(47) N- (4- (3- (((2, 4-difluorobenzyl) -l 2-subunit) sulfonyl) -4-methoxyphenyl) -5-methylthiazol-2-yl) hexanamide.
The preparation method of the inhibitor comprises the steps of taking 1- (4-chlorophenyl) -2-acetone or 1- (4-methoxyphenyl) -2-acetone as raw materials (1 a, 1 b), and carrying out substitution reaction on the raw materials (1 a, 1 b) and chlorosulfonic acid at the 3 rd position of a benzene ring to obtain intermediates (2 a, 2 b); on the basis of intermediates (2 a, 2 b) by Hins berg reaction, incorporating R 2
The groups give intermediates (3 a-3 g); the intermediate (3 a-3 g) and phenyl trimethyl ammonium tribromide undergo alpha-bromination reaction to obtain an intermediate (4 a-4 g); the intermediate (4 a-4 g) and N-acetylthiourea are condensed to obtain the target compound (5 a-5 g), and the synthetic route is as follows:
。
the preparation method of the inhibitor also comprises the steps of taking the intermediates (4 d, 4 e) as raw materials according to the preparation method of the target compounds (5 a-5 g), and simultaneously introducing thiourea and various acyl chlorides into R for substitution reaction 3 The N-substituted thiourea obtained by the group is used as another raw material; the target compounds (7 a-7 r) are obtained by condensation reaction of the two; or only takes the intermediate (4 e) as a raw material, and performs condensation reaction with thiourea to obtain an intermediate (8); the intermediate (8) respectively carries out substitution reaction with 3-acetamidopropionyl chloride, 6-carbonyl heptanoyl chloride and 5-carbonyl hexanoyl chloride to obtain target compounds (9 a-9 c), and the synthetic route is as follows:
or according to the preparation method of the target compound (5 a-5 g), the compound (4 h-4 x) is obtained as a raw material, and is subjected to condensation reaction with N-hexanylthiourea to obtain the target compound (10 a-10 q), wherein the synthetic route is as follows:
。
the preparation method of the inhibitor also comprises the steps of taking the compound (11) as a raw material, and obtaining an intermediate (12) through two-step reaction; the intermediate (12) is heated and refluxed in acetic acid to react with iron powder in a reduction way to obtain an intermediate (13); the intermediate (13) undergoes hydrolysis reaction under acidic condition to obtain an intermediate (14); intermediate (14) and (2-aminoethyl) carbamic acid tert-butyl ester react to obtain intermediate (15), and the target compound (17) is obtained through two steps of reactions, wherein the synthetic route is as follows:
。
Or 4' -methoxy propiophenone (18) is used as a raw material, and the target compound (22) is obtained through four steps of reactions, and the synthetic route is as follows:。
the invention also discloses a pharmaceutical composition which comprises at least one pharmaceutically acceptable auxiliary material, auxiliary agent or carrier and the phenylthiazole amine PI4KIII beta inhibitor.
The application of the phenylthiazole amine PI4KIII beta inhibitor or the pharmaceutical composition in preparing medicines for preventing, treating or assisting in treating proliferative diseases, metabolic diseases, nervous system diseases or tuberous sclerosis caused by excessive activation of PI4KIII beta kinase.
Preferably, the proliferative disease comprises colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, renal cancer, brain cancer, cervical cancer, cancer of the CNS, glioblastoma, myeloproliferative disease, hematological cancer or lymphoma.
The application of the phenylthiazole amine PI4KIII beta inhibitor or the pharmaceutical composition in preparing medicines for inhibiting the growth of cancer cells.
The principle of the invention: because PIK4KIII beta has weak inhibition activity and insufficient anti-tumor effect, PIK-93 is selected as a lead compound for further structural modification. The phenylthiazole amine is determined to be taken as a basic framework structure, and the substituent groups are screened, so that a high-efficiency inhibition effect is brought.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages: (1) The inhibitor has the characteristics of effectively inhibiting PI3K/Akt/mTOR signal paths of PI4KIII beta, and has high-efficiency and excellent PI4KIII beta enzyme inhibition activity; (2) Low cost, good curative effect, low toxicity, high yield of intermediate products in the synthesis process, and reduced resource waste, thereby being beneficial to reducing the cost; and (3) the antitumor activity is remarkable, and the dosage is small.
Drawings
FIG. 1 shows the results of in vivo anti-tumor efficacy and toxicity studies of examples 11 and 27, with A being the tumor volume change curve of mice, B being the growth curve of body weight, and C being representative images of tumor tissue of mice;
FIG. 2 shows the results of in vivo anti-tumor efficacy and toxicity studies of example 40, with A being the tumor volume change curve of the mice, B being the growth curve of body weight, and C being representative images of the tumor tissue of the mice;
FIG. 3 is a histopathological section staining image of tumor mice.
Detailed Description
The technical scheme of the invention is further described below with reference to the embodiment and the attached drawings.
Reagents were purchased from commercial suppliers such as Anhui Zealand technologies, balanuginos, aba Ding Shiji, beijing coupling technologies, etc., and were not further purified unless otherwise indicated. General reagents are purchased from the chemical company of the chemical industry of the ridge, the chemical company of the Nanjing, the chemical company of the national medicine group, the ocean chemical company of the Qingdao, and the like. All temperatures in the examples are given in degrees celsius unless otherwise indicated.
The chromatographic column in the examples described below uses a silica gel column, silica gel (200-300 mesh) available from Qingdao ocean chemical Co. Nuclear magnetic resonance spectroscopy with a ChloroformdOr DMSO-d 6 Solvent (in ppm)), TMS (0 ppm) was used as a reference standard. When multiple peaks occur, the following abbreviations will be used: s (single, singlet), d (doublet ), t (triplet, multiplet), m (multiplet ), br (broadside), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet). Coupling constants are expressed in hertz (Hz).
The low resolution Mass Spectrometry (MS) data in the examples described below were analyzed by an Agilent 6120 series LC-MS G1329B autosampler and G4212B detector equipped with a G1311B quaternary pump and G1316A column oven, and the ESI source was applied to the LC-MS spectrometer.
For convenience of description, some of the raw materials will be described in terms of their abbreviations, which are fully described below: DCM is CH 2 Cl 2 I.e. dichloromethane; chloroform (R)dWith CDC1 3 Deuterated chloroform; PE is petroleum ether; etOAc and EA were both ethyl acetate; meOH and CH 3 OH is methanol; clSO (ClSO) 3 H is chlorosulfonic acid; TEA and Et 3 N is triethylamine; DMSO (beta-methyl-vinyl acetate)d 6 Is hexadeuterated dimethyl sulfoxide; THF is tetrahydrofuran; naCl is sodium chloride; na (Na) 2 SO 4 Sodium sulfate; CDI is N, N-carbonyl diimidazole.
Example 1
The synthesis of (2- (5- (2-acetamido-4-methylthiazol-5-yl) -2-chlorophenyl sulfamido) ethyl) carbamic acid tert-butyl ester comprises the following steps:
step 1: synthesis of 2-chloro-5- (2-oxopropyl) benzenesulfonyl chloride:
ClSO of 10 mL is measured out 3 H (132 mmol,11.0 eq.) was added to a 25 mL eggplant reaction flask and precooled for 30 min under ice bath, 2.02 g (12.0 mmol) 4-chlorophenyl acetone was slowly added dropwise to ClSO 3 In H, the reaction was performed at room temperature of about 6H, and was completed by TLC until starting material 1a was completely consumed. Slowly dripping the reaction solution onto ice blocks to quench unreacted ClSO 3 H, the aqueous solution was extracted with ethyl acetate solution (3X 100 mL), the organic phase was collected, washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE: EA=4:1-2:1). White solid, yield: 60 Percent of the total weight of the composition. 1 H NMR (300 MHz, Chloroform-d)δ7.95 (d,J= 2.1 Hz, 1H), 7.63 (d,J= 8.2 Hz, 1H), 7.50 (dd,J= 8.2, 2.1 Hz, 1H), 3.86 (s, 2H), 2.30 (s, 3H).
Step 2: (2- (2-chloro-5- (2-oxopropyl) phenylsulfonamide) ethyl) Group) synthesis of tert-butyl carbamate:5 mmol of 2-chloro-5- (2-oxopropyl) benzenesulfonyl chloride was weighed out and dissolved in 20 mL dichloromethane, 7.5 mmol of tert-butyl (2-aminoethyl) carbamate (1.5 eq) and 1.01 g triethylamine (2.0 eq) were added to the reaction mixture and stirred at room temperature for 12 h until the 2-chloro-5- (2-oxopropyl) benzenesulfonyl chloride was completely consumed. The end of the reaction was purified by column chromatography (PE: ea=1:1). White solid, yield: 78 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 )δ7.85 (t,J= 5.9 Hz, 1H), 7.78 (d,J= 2.1 Hz, 1H), 7.60 (d,J= 8.1 Hz, 1H), 7.43 (dd,J= 8.2, 2.2 Hz, 1H), 6.78 (t,J= 5.8 Hz, 1H), 3.95 (s, 2H), 3.02–2.93 (m, 2H), 2.84 (dt,J= 8.2, 6.0 Hz, 2H), 2.18 (s, 3H), 1.35 (s, 9H); 13 C NMR (101 MHz, DMSO-d 6 )δ205.63, 155.97, 137.78, 135.79, 135.40, 132.09, 131.92, 129.09, 78.30, 48.54, 42.60, 30.21, 28.64.
Step 3: synthesis of tert-butyl (5- (1-bromo-2-oxopropyl) -2-chlorophenyl sulfamido) ethyl) carbamate:1 mmol (2- (2-chloro-5- (2-oxo propyl) phenyl sulfamido) ethyl) carbamic acid tert-butyl ester is weighed and dissolved in 5 mL tetrahydrofuran solution and placed in an eggplant-shaped bottle, 10 mL tetrahydrofuran solution containing 1.1 mmol of phenyl trimethyl ammonium tribromide is slowly added dropwise to the reaction liquid under the ice bath state, the ice bath is removed after the dropwise addition, the reaction is carried out at room temperature for 0.5 h until the reactants are completely consumed, and a brominated product is obtained after purification (PE: EA=1:1). Pale yellow oil, yield: 60 Percent of the total weight of the composition. 1 H NMR (300 MHz, Chloroform-d)δ8.11 (d,J= 2.3 Hz, 1H), 7.66 (dd,J= 8.3, 2.3 Hz, 1H), 7.57 (d,J= 8.3 Hz, 1H), 5.72 (s, 1H), 5.42 (s, 1H), 4.87 (s, 1H), 3.28 (q,J= 5.7 Hz, 2H), 3.08 (q,J= 5.8 Hz, 2H), 2.44 (s, 3H), 1.46 (s, 9H).
Step 4: (2- (5Synthesis of tert-butyl- (2-acetamido-4-methylthiazol-5-yl) -2-chlorophenyl sulfamido) ethyl) carbamate, the structural formula is as follows: Firstly, preparing N-acetylthiourea, namely 10 mmol of thiourea is dissolved in 30 mL of anhydrous toluene solution and placed in a 100 mL eggplant-shaped bottle, 15 mmol of acetyl chloride is weighed and dissolved in 2 mL of anhydrous toluene and slowly added into a reactor in a dropwise manner, the reaction is heated to 110 ℃ to reflux for 5 h, the reaction solution is cooled to room temperature after the reaction is finished, the reaction solution is concentrated, and the white solid N-acetylthiourea is obtained through column chromatography (PE: EA=8:1), the yield is: 71 Concentration of% 1 H NMR (400 MHz, Chloroform-d)δ9.88 (s, 1H), 8.99 (s, 1H), 7.14 (s, 1H), 2.19 (s, 3H). 1 mmol of intermediate 4d was weighed into a 25 mL eggplant-shaped bottle, 10 mL acetone solution was added, 1 mmol of N-acetylthiourea (1.0 eq.) was added to the reaction, the temperature was raised to 60℃for reflux reaction for 1h, TLC monitoring was carried out until the complete consumption of intermediate 4a (DCM: meOH=25:1), vacuum concentration, column chromatography purification was carried out. White solid, yield: 60 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 )δ12.25 (s, 1H), 8.04 (t,J= 5.7 Hz, 1H), 7.93 (t,J= 1.3 Hz, 1H), 7.72 (d,J= 1.3 Hz, 2H), 6.77 (t,J= 5.6 Hz, 1H), 2.97 (q,J= 6.4 Hz, 2H), 2.93 – 2.80 (m, 2H), 2.37 (s, 3H), 2.15 (s, 3H), 1.33 (s, 9H); 13 C NMR (101 MHz, DMSO-d 6 )δ175.44, 156.03, 155.52, 143.80, 138.28, 133.23, 132.53, 131.84, 129.39, 128.96, 121.44, 77.86, 42.22, 42.21, 28.19, 19.09, 16.13.ESI-HRMScalcdforC 19 H 25 ClN 4 O 5 S 2 m/z[M + H] + 489.1028, found [M + H] + 489.1032.
Example 2
N- (5- (4-chloro-3- (N- (2-hydroxy-2-methylpropyl) sulfamoyl) phenyl) -4-methylthiazol-2-yl) acetamide has the following structural formula:step in example 1The procedure of example 1 was followed except that the fragment t-butyl (2-aminoethyl) carbamate in step 2 was changed to 1-amino-2-methyl-2-propanol; white solid, yield: 25 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 )δ12.24 (s, 1H), 7.94 (s, 1H), 7.77 (t,J= 6.3 Hz, 1H), 7.72–7.68 (m, 2H), 4.45 (s, 1H), 2.83 (d,J= 6.2 Hz, 2H), 2.37 (s, 3H), 2.16 (s, 3H), 1.05 (s, 6H); 13 C NMR (101 MHz, DMSO-d 6 )δ166.42, 145.50, 138.51, 132.58, 132.11, 132.03, 128.42, 127.28, 114.92, 68.87, 53.89, 27.03, 16.48.ESI-HRMScalcdforC 16 H 20 ClN 3 O 4 S 2 m/z[M + H] + 418.0657, found [M + H] + 418.0663.
Example 3
N- (2- (2-acetamido-4-methylthiazol-5-yl) -2-chlorophenyl sulfamide) ethyl propionamide has the following structural formula:the procedure of example 1 was repeated except that the fragment (2-aminoethyl) carbamic acid tert-butyl ester in step 2 of example 1 was changed to N- (2-aminoethyl) propionamide; white solid, yield: 30%. 1 H NMR (400 MHz, DMSO-d 6 )δ7.93 (s, 1H), 7.76 (t,J= 5.7 Hz, 1H), 7.71 –7.69 (m, 2H), 3.09 (q,J= 6.4 Hz, 2H), 2.92 (t,J= 6.7 Hz, 2H), 2.37 (s, 3H), 2.15 (s, 3H), 2.00 (q,J= 7.5 Hz, 2H), 0.93 (td,J= 7.6, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ173.13, 168.66, 155.88, 143.79, 138.26, 133.20, 132.48, 131.80, 129.34, 128.92, 121.34, 42.07, 38.62, 28.39, 22.48, 16.16, 9.74. ESI-HRMScalcdforC 17 H 21 ClN 4 O 4 S 2 m/z[M + H] + 445.0766, found [M + H] + 445.0762.
Example 4
(2- (2-acetamido-4-methylthiazol-5-yl) -2-chlorophenyl sulfamide) ethylcarbamic acid methyl ester, structureThe formula is as follows:the procedure of example 1 was repeated except that the fragment t-butyl (2-aminoethyl) carbamate in step 2 of example 1 was changed to methyl (2-aminoethyl) carbamate; white solid, yield: 29 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 )δ12.24 (s, 1H), 8.06 (t,J= 5.8 Hz, 1H), 7.93 (s, 1H), 7.71 (d,J= 1.3 Hz, 2H), 7.07 (t,J= 5.7 Hz, 1H), 3.46 (s, 3H), 3.03 (q,J= 6.4 Hz, 2H), 2.93 (q,J= 6.4 Hz, 2H), 2.37 (s, 3H), 2.15 (s, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ168.66, 156.65, 155.90, 143.79, 138.28, 133.17, 132.47, 131.80, 129.33, 128.94, 121.38, 51.35, 42.12, 40.33, 22.48, 16.16.ESI-HRMScalcdforC 16 H 19 ClN 4 O 5 S 2 m/z[M + H] + 447.0558, found [M + H] + 447.0556.
Example 5
(2- ((5- (2-acetamido-4-methylthiazol-5-yl) -2-methoxyphenyl) sulfamido) ethyl) carbamic acid tert-butyl ester with the following structural formula:other steps and operations were the same as in example 1 except that 1- (4-chlorophenyl) -2-propanone was changed to 1- (4-methoxyphenyl) -2-propanone as the starting material in step 1 of example 1; white solid, yield: 28%. 1 H NMR (400 MHz, DMSO-d 6 )δ12.14 (s, 1H), 7.71 (d,J= 2.4 Hz, 1H), 7.68 (dd,J= 8.6, 2.4 Hz, 1H), 7.38 (t,J= 5.9 Hz, 1H), 7.31 (d,J= 8.6 Hz, 1H), 6.74 (t,J= 5.8 Hz, 1H), 3.94 (s, 3H), 2.95 (q,J= 6.5 Hz, 2H), 2.82 (q,J= 6.5 Hz, 2H), 2.32 (s, 3H), 2.14 (s, 3H), 1.34 (s, 9H); 13 C NMR (101 MHz, DMSO-d 6 )δ168.41, 155.46, 155.30, 155.01, 142.06, 134.26, 128.89, 128.17, 124.02, 122.27, 113.62, 77.80, 56.37, 42.38, 42.36, 28.19, 22.46, 15.85; ESI-HRMS calcd for C 20 H 28 N 4 O 6 S 2 m/z[M + H] + 485.1523, found [M + H] + 485.1519.
Example 6
N- (5- (4-chloro-3- (N- (3-hydroxy-4-methylphenyl) sulfamoyl) phenyl) -4-methylthiazol-2-yl) acetamide has the following structural formula: The procedure of example 1 was repeated except that the fragment (2-aminoethyl) carbamic acid tert-butyl ester in step 2 of example 1 was changed to 5-amino-2-methylphenol; white solid, yield: 25%. 1 H NMR (400 MHz, DMSO-d 6 ) δ12.20 (s, 1H), 9.89 (s, 1H), 9.72 (s, 1H), 7.84 (dd,J= 10.3, 2.1 Hz, 1H), 7.73 – 7.61 (m, 2H), 7.25 (s, 1H), 6.72 (s, 1H), 5.75 (d,J= 1.6 Hz, 1H), 2.22 (d,J= 4.8 Hz, 3H), 2.18 – 2.09 (m, 6H); 13 C NMR (101 MHz, DMSO-d 6 ) δ168.58, 155.90, 150.55, 143.61, 138.06, 135.64, 133.50, 132.38, 131.30, 129.72, 129.51, 128.46, 122.67, 121.26, 117.71, 111.63,22.44, 21.99, 15.78; ESI-HRMScalcdforC 19 H 18 ClN 3 O 4 S 2 m/z[M + H] + 452.0500, found [M + H] + 452.0511.
Example 7
N- (5- (3- (N- (2, 4-difluorophenyl) sulfamoyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) acetamide has the following structural formula:other steps and operations are the same as in example 1 except that the starting material in step 1 of example 1 is changed to 1- (4-chlorophenyl) -2-propanone to 1- (4-methoxyphenyl) -2-propanone and the fragment (2-aminoethyl) carbamic acid tert-butyl ester in step 2 is changed to 2, 4-difluoroaniline; white solid, yield: 39%. 1 H NMR (400 MHz, DMSO-d 6 )δ12.12 (d,J= 5.6 Hz, 1H), 9.89 (s, 1H), 7.81–7.53 (m, 2H), 7.37–7.16 (m, 3H), 7.11–6.87 (m, 1H), 3.90 (d,J= 22.1 Hz, 4H), 2.25–2.10 (m, 6H); 13 C NMR (101 MHz, DMSO)δ168.40, 155.64, 155.01, 142.09, 134.86, 129.78, 129.08, 128.91, 128.86, 128.80, 128.77, 127.48, 123.76, 122.01, 113.61, 111.63, 111.58, 104.70, 104.41, 104.17, 56.26, 22.43, 14.22; ESI-HRMScalcdfor C 19 H 17 F 2 N 3 O 4 S 2 m/z[M + H] + 454.0701, found [M + H] + 454.0709.
Example 8
(5- (2-propionylamino-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamide) ethylcarbamic acid tert-butyl ester, the structural formula is as follows:the procedure of example 1 was followed except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the acetyl chloride in step 4 was changed to propionyl chloride, and the procedure was otherwise as in example 1; white solid, yield: 32%. 1 H NMR (400 MHz, DMSO-d 6 ) δ12.09 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.5, 2.4 Hz, 1H), 7.38 (t,J= 5.9 Hz, 1H), 7.31 (d,J= 8.7 Hz, 1H), 6.75 (t,J= 5.7 Hz, 1H), 3.94 (s, 3H), 2.96 (q,J= 6.5 Hz, 2H), 2.83 (q,J= 6.6 Hz, 2H), 2.43 (q,J= 7.5 Hz, 2H), 2.32 (s, 3H), 1.34 (s, 9H), 1.09 (t,J= 7.6 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ172.07, 155.46, 155.30, 155.06, 142.07, 134.25, 128.90, 128.20, 124.06, 122.22, 113.63, 77.80, 56.37, 42.39, 28.23, 28.19, 15.84, 9.18; ESI-HRMS calcd for C 21 H 30 N 4 O 6 S 2 m/z[M + H] + 499.1680, found [M + H] + 499.1671.
Example 9
(5- (2-butyrylamino-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamide) ethylcarbamic acid tert-butyl ester, having the structural formula: The procedure of example 1 was repeated except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the acetyl chloride in step 4 was changed to butyryl chloride, and the procedure was repeated; white solid, yield: 34%. 1 H NMR (400 MHz, DMSO-d 6 ) δ12.11 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.6, 2.4 Hz, 1H), 7.37 (t,J= 6.9, 6.4 Hz, 1H), 7.31 (d,J= 8.6 Hz, 1H), 6.74 (t,J= 5.6 Hz, 1H), 3.94 (s, 3H), 2.96 (q,J= 6.5 Hz, 2H), 2.88–2.76 (m, 2H), 2.40 (t,J= 7.3 Hz, 2H), 2.32 (s, 3H), 1.66–1.57 (m, 2H), 1.34 (s, 9H), 0.89 (t,J= 7.4 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 ) δ171.24, 155.47, 155.31, 154.99, 142.07, 134.26, 128.93, 128.20, 124.06, 122.26, 113.62, 77.80, 56.37, 42.39, 36.78, 28.18, 18.23, 15.82, 13.50; ESI-HRMS calcd for C 22 H 32 N 4 O 6 S 2 m/z[M + H] + 513.1836, found [M + H] + 513.1841.
Example 10
(5- (2-valeramide-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamide) ethylcarbamic acid tert-butyl ester, the structural formula is as follows:the procedure of example 1 was followed except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, 1- (4-methoxyphenyl) -2-propanone, and the acetyl chloride in step 4 was changed to pentanoyl chloride; white solid, yield: 35 Percent of the total weight of the composition. 1 H NMR (300 MHz, DMSO-d 6 ) δ12.12 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.68 (dd,J= 8.5, 2.4 Hz, 1H), 7.46 (t,J= 5.9 Hz, 2H), 7.31 (d,J= 8.7 Hz, 1H), 3.94 (s, 3H), 3.15 – 3.03 (m, 2H), 2.83 (q,J= 6.6 Hz, 2H), 2.42 (t,J= 7.4 Hz, 2H), 2.32 (s, 3H), 1.63–1.53 (m, 2H), 1.36–1.24 (m, 2H), 1.04 (s, 9H), 0.88 (t,J= 7.3 Hz, 3H); 13 C NMR (101 MHz, DMSO) δ 171.42, 155.50, 155.33, 155.02, 142.10, 134.29, 128.94, 128.23, 124.08, 122.29, 113.66, 77.83, 56.40, 42.41, 40.17, 39.96, 39.75, 39.54, 39.33, 39.12, 38.92, 34.88, 28.20, 24.45, 21.85, 15.83, 13.85; ESI-HRMS calcd for C 23 H 34 N 4 O 6 S 2 m/z[M + H] + 527.1993, found [M + H] + 527.1995.
Example 11
(5- (2-hexanamido-4-methylthiazol-5-yl) -2-methoxy phenyl sulfamide) ethyl carbamic acid tert-butyl ester with the following structural formula:the procedure of example 1 was followed except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone and the acetyl chloride in step 4 was changed to caproyl chloride; white solid, yield: 34%. 1 H NMR (300 MHz, DMSO-d 6 )δ12.11 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.5, 2.4 Hz, 1H), 7.38 (t,J= 5.8 Hz, 1H), 7.31 (d,J= 8.7 Hz, 1H), 6.74 (t,J= 5.5 Hz, 1H), 3.94 (s, 3H), 3.03–2.90 (m, 2H), 2.90–2.76 (m, 2H), 2.41 (t,J= 7.3 Hz, 2H), 2.31 (s, 3H), 1.64–1.54 (m, 2H), 1.34 (s, 9H), 1.29–1.22 (m, 4H), 0.88–0.84 (m, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.40, 155.48, 155.31, 155.00, 142.08, 134.27, 128.92, 128.21, 124.06, 122.27, 113.64, 77.81, 56.38, 42.39, 34.86, 30.72, 28.18, 24.43, 21.83, 15.81, 13.83; ESI-HRMS calcd for C 24 H 36 N 4 O 6 S 2 m/z[M + H] + 541.2149, found [M + H] + 541.2147.
Example 12
(5- (2-heptanamido-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamide) ethylcarbamic acid tert-butyl ester, the structural formula is as follows: The procedure of example 1 was repeated except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, 1- (4-methoxyphenyl) -2-propanone was changed to heptanoyl chloride, and the acetyl chloride in step 4 was changed to heptanoyl chloride; white solid, yield: 35%. 1 H NMR (400 MHz, DMSO-d 6 ) δ12.11 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.6, 2.4 Hz, 1H), 7.38 (t,J= 5.8 Hz, 1H), 7.31 (d,J= 8.6 Hz, 1H), 6.74 (t,J= 5.7 Hz, 1H), 3.94 (s, 3H), 2.95 (q,J= 6.5 Hz, 2H), 2.86–2.77 (m, 2H), 2.41 (t,J= 7.4 Hz, 2H), 2.32 (s, 3H), 1.62–1.55 (m, 2H), 1.34 (s, 9H), 1.30–1.26 (m, 6H), 0.87–0.84 (m, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.36, 155.45, 155.29, 154.98, 142.06, 134.24, 128.91, 128.20, 124.04, 122.25, 113.62, 77.78, 56.35, 42.37, 34.88, 30.93, 28.17, 24.68, 21.95, 15.80, 13.91.; ESI-HRMS calcd for C 25 H 38 N 4 O 6 S 2 m/z[M + H] + 555.2306, found [M + H] + 555.2310.
Example 13
(2- (2-methoxy-5- (4-methyl-2- (3-propylureido) thiazol-5-yl) phenyl) sulfamide) ethylcarbamic acid tert-butyl ester with the following structural formula:the procedure of example 1 was followed except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, 1- (4-methoxyphenyl) -2-propanone, and the acetyl chloride in step 4 was changed to propylcarbamoyl chloride; white solid, yield: 36%. 1 H NMR (400 MHz, DMSO-d 6 )δ10.36 (s, 1H), 7.68 (d,J= 2.4 Hz, 1H), 7.63 (dd,J= 8.6, 2.4 Hz, 1H), 7.39 (t,J= 5.9 Hz, 1H), 7.29 (d,J= 8.7 Hz, 1H), 6.76 (t,J= 5.7 Hz, 1H), 6.57 (t,J= 5.9 Hz, 1H), 3.93 (s, 3H), 3.08 (q,J= 6.6 Hz, 2H), 2.95 (q,J= 6.5 Hz, 2H), 2.81 (q,J= 6.6 Hz, 2H), 2.26 (s, 3H), 1.49–1.40 (m, 2H), 1.33 (s, 9H), 0.86 (t,J= 7.4 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ156.83, 155.50, 155.05, 152.76, 141.76, 134.00, 128.72, 128.09, 124.51, 120.77, 113.60, 77.85, 65.01, 56.37, 50.02, 42.41, 28.81, 28.22, 15.96, 15.24; ESI-HRMS calcd for C 22 H 33 N 5 O 6 S 2 m/z[M + H] + 528.1945, found [M + H] + 528.1940.
Example 14
(2- (5- (2- (3-butylureido) -4-methylthiazol-5-yl) -2-methoxyphenylsulphonamido) ethyl) carbamic acid tert-butyl ester having the following structural formula:the procedure of example 1 was repeated except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, 1- (4-methoxyphenyl) -2-propanone was changed to acetyl chloride in step 4 to butylcarbamoyl chloride; white solid, yield: 42 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 )δ10.33 (s, 1H), 7.69 (d,J= 2.4 Hz, 1H), 7.63 (dd,J= 8.6, 2.4 Hz, 1H), 7.36 (t,J= 5.8 Hz, 1H), 7.29 (d,J= 8.7 Hz, 1H), 6.74 (t,J= 5.7 Hz, 1H), 6.56–6.53 (m, 1H), 3.93 (s, 3H), 3.12 (q,J= 6.5 Hz, 2H), 2.95 (q,J= 6.5 Hz, 2H), 2.82 (q,J= 6.5 Hz, 2H), 2.26 (s, 3H), 1.46–1.39 (m, 2H), 1.34 (s, 9H), 1.29 (t,J= 7.5 Hz, 2H), 0.89 (t,J= 7.3 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ164.06, 155.50, 155.08, 153.83, 141.81, 134.05, 128.73, 128.10, 124.45, 113.60, 77.85, 65.01, 56.37, 42.41, 41.05, 28.22, 22.82, 15.93, 15.24, 11.30; ESI-HRMS calcd for C 23 H 35 N 5 O 6 S 2 m/z[M + H] + 542.2102, found [M + H] + 542.2105.
Example 15
(2- (2-methoxy-5- (4-methyl-2- (3-methylbutanamide) thiazol-5-yl) phenyl) ) Sulfonamide) tert-butyl ethylcarbamate having the structural formula:the procedure of example 1 was repeated except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, 1- (4-methoxyphenyl) -2-propanone, and the acetyl chloride in step 4 was changed to 3-methylbutanoyl chloride; white solid, yield: 40%. 1 H NMR (400 MHz, DMSO-d 6 ) δ12.10 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.68 (dd,J= 8.6, 2.4 Hz, 1H), 7.37 (t,J= 5.8 Hz, 1H), 7.31 (d,J= 8.7 Hz, 1H), 6.73 (t,J= 5.7 Hz, 1H), 3.94 (s, 3H), 2.96 (q,J= 6.5 Hz, 2H), 2.83 (q,J= 6.3 Hz, 2H), 2.31 (d,J= 7.7 Hz, 5H), 2.11–2.03 (m, 1H), 1.34 (s, 9H), 0.92 (d,J= 6.7 Hz, 6H); 13 C NMR (75 MHz, DMSO-d 6 ) δ170.76, 155.49, 155.34, 154.95, 142.11, 134.31, 128.98, 128.19, 124.07, 122.31, 113.64, 77.83, 59.81, 56.39, 43.94, 42.41, 28.20, 25.59, 22.19, 15.83; ESI-HRMS calcd for C 23 H 34 N 4 O 6 S 2 m/z[M + H] + 527.1993, found [M + H] + 527.2001.
Example 16
(5- (2-isobutyrylamino-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamide) ethylcarbamic acid tert-butyl ester, having the structural formula:the procedure of example 1 was repeated except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the acetyl chloride in step 4 was changed to 2-methylpropanoyl chloride, and the procedure was repeated except that the starting material was changed to 1- (4-methoxyphenyl) -2-propanone; white solid, yield: 26%. 1 H NMR (400 MHz, DMSO-d 6 )δ12.11 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.6, 2.4 Hz, 1H), 7.39 (t,J= 5.9 Hz, 1H), 7.31 (d,J= 8.7 Hz, 1H), 6.75 (t,J= 5.7 Hz, 1H), 3.94 (s, 3H), 2.95 (q,J= 6.6 Hz, 2H), 2.82 (q,J= 6.5 Hz, 2H), 2.75–2.69 (m, 1H), 2.32 (s, 3H), 1.34 (s, 9H), 1.11 (d,J= 6.9 Hz, 6H); 13 C NMR (101 MHz, DMSO-d 6 )δ175.22, 155.47, 155.32, 155.15, 142.09, 134.29, 128.93, 128.23, 124.06, 122.35, 113.64, 77.80, 56.38, 42.40, 39.82, 33.82, 28.19, 19.11, 15.80; ESI-HRMScalcd for C 22 H 32 N 4 O 6 S 2 m/z[M + H] + 513.1836, found [M + H] + 513.1839.
Example 17
(2- (2-methoxy-5- (4-methyl-2-pivaloyl amide thiazol-5-yl) phenyl) sulfamide) ethylcarbamic acid tert-butyl ester, the structural formula is as follows:the procedure of example 1 was followed except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, 1- (4-methoxyphenyl) -2-propanone, and the acetyl chloride in step 4 was changed to 2, 2-dimethylpropionyl chloride; white solid, yield: 30%. 1 H NMR (300 MHz, DMSO-d 6 ) δ11.85 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.5, 2.4 Hz, 1H), 7.40 (t,J= 5.9 Hz, 1H), 7.32 (d,J= 8.6 Hz, 1H), 6.76 (t,J= 5.6 Hz, 1H), 3.94 (s, 3H), 3.05–2.90 (m, 2H), 2.83 (q,J= 6.8 Hz, 2H), 2.33 (s, 3H), 1.34 (s, 9H), 1.24 (s, 9H); 13 C NMR (101 MHz, DMSO) δ176.70, 155.79, 155.48, 155.32, 141.99, 134.28, 128.95, 128.26, 124.11, 122.42, 113.64, 77.81, 56.37, 42.43,38.77, 28.18, 26.60, 15.71; ESI-HRMS calcd for C 23 H 34 N 4 O 6 S 2 m/z[M + H] + 527.1993, found [M + H] + 527.2000.
Example 18
(5- (2- (3, 3-dimethylbutyramide) -4-methylthiazol-5-yl) -2-methoxyphenylsulphonamido) ethylcarbamic acid tert-butyl ester, the structural formula is as follows:the procedure of example 1 was repeated except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the acetyl chloride in step 4 was changed to 3, 3-dimethylbutyryl chloride, and the procedure was otherwise as in example 1; white solid, yield: 40 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 ) δ12.05 (s, 1H), 7.73 (d,J= 2.4 Hz, 1H), 7.68 (dd,J= 8.6, 2.4 Hz, 1H), 7.36 (t,J= 5.8 Hz, 1H), 7.31 (d,J= 8.6 Hz, 1H), 6.73 (t,J= 5.7 Hz, 1H), 3.94 (s, 3H), 2.95 (q,J= 6.5 Hz, 2H), 2.89–2.77 (m, 2H), 2.32 (d,J= 2.6 Hz, 5H), 1.34 (s, 9H), 1.00 (s, 9H); 13 C NMR (101 MHz, DMSO-d 6 ) δ174.22, 155.45, 155.29, 155.10, 142.05, 134.25, 128.90, 128.22, 124.07, 122.27, 113.62, 77.78, 56.35, 43.33, 42.38, 28.76, 28.17, 25.03, 15.78; ESI-HRMS calcd for C 24 H 36 N 4 O 6 S 2 m/z[M + H] + 541.2149, found [M + H] + 541.2152.
Example 19
(2- (2-methoxy-5- (4-methyl-2- (4-methylpentanamide) thiazol-5-yl) phenyl) sulphonamido) ethylcarbamic acid tert-butyl ester having the following structural formula:the procedure of example 1 was repeated except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, 1- (4-methoxyphenyl) -2-propanone, and the acetyl chloride in step 4 was changed to 4-methylpentanoyl chloride; white solid, yield: 34%. 1 H NMR (400 MHz, DMSO-d 6 ) δ12.14 (s, 1H), 7.71 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.6, 2.4 Hz, 1H), 7.40 (t,J= 5.9 Hz, 1H), 7.31 (d,J= 8.6 Hz, 1H), 6.76 (t,J= 5.7 Hz, 1H), 3.94 (s, 3H), 2.95 (q,J= 6.5 Hz, 2H), 2.86–2.75 (m, 2H), 2.43 (t,J= 7.3 Hz, 2H), 2.31 (s, 3H), 1.53–1.47 (m, 3H), 1.33 (s, 9H), 0.87 (d,J= 6.2 Hz, 6H); 13 C NMR (101 MHz, DMSO) δ 169.96, 155.44, 155.29, 154.81, 142.05, 134.24, 128.93, 128.18, 124.05, 122.26, 113.60, 77.77, 56.35, 47.91, 42.37, 30.98, 29.44, 28.16, 15.79; ESI-HRMS calcd for C 24 H 36 N 4 O 6 S 2 m/z[M + H] + 541.2149, found [M + H] + 541.2143.
Example 20
(2- (2-methoxy-5- (4-methyl-2- (5-methylhexanamido) thiazol-5-yl) phenyl) sulphonamido) ethylcarbamic acid tert-butyl ester with the following structural formula:the procedure of example 1 was repeated except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, 1- (4-methoxyphenyl) -2-propanone, and the acetyl chloride in step 4 was changed to 5-methylhexanoyl chloride; white solid, yield: 34 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 ) δ12.09 (s, 1H), 7.73 (t,J= 1.9 Hz, 1H), 7.67 (dt,J= 8.7, 2.1 Hz, 1H), 7.37 (t,J= 5.8 Hz, 1H), 7.31 (dd,J= 8.7, 1.8 Hz, 1H), 6.73 (t,J= 5.8 Hz, 1H), 3.94 (s, 3H), 2.96 (q,J= 6.6 Hz, 2H), 2.83 (q,J= 6.6 Hz, 2H), 2.45–2.36 (m, 2H), 2.32 (d,J= 1.7 Hz, 3H), 1.67–1.46 (m, 3H), 1.34 (s, 9H), 1.21–1.11 (m, 2H), 0.86 (dd,J= 6.7, 1.9 Hz, 6H); 13 C NMR (101 MHz, DMSO-d 6 ) δ171.37, 155.47, 155.31, 155.00, 142.07, 134.26, 128.93, 128.20, 124.06, 122.27, 113.62, 77.80, 56.37, 42.39 , 37.81, 35.11, 28.18, 27.25, 22.66, 22.42, 15.82; ESI-HRMS calcd for C 25 H 38 N 4 O 6 S 2 m/z[M + H] + 555.2306, found [M + H] + 555.2307.
Example 21
(2- (5- (2- (cyclohexanecarboxamido) -4-methylthiazol-5-yl) -2-methoxyphenyl) sulfamido) ethylcarbamic acid tert-butyl ester has the following structural formula:the procedure of example 1 was followed except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, to 1- (4-methoxyphenyl) -2-propanone, and the acetyl chloride in step 4 was changed to cyclohexanecarbonyl chloride; white solid, yield: 45 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 ) δ12.06 (s, 1H), 7.71 (d,J= 2.4 Hz, 1H), 7.66 (dd,J= 8.6, 2.4 Hz, 1H), 7.38 (t,J= 5.9 Hz, 1H), 7.31 (d,J= 8.7 Hz, 1H), 6.74 (t,J= 5.8 Hz, 1H), 3.94 (s, 3H), 2.95 (q,J= 6.5 Hz, 2H), 2.82 (q,J= 6.5 Hz, 2H), 2.45 (dt,J= 11.4, 3.5 Hz, 1H), 2.31 (s, 3H), 1.82–1.72 (m, 4H), 1.45 – 1.38 (m, 2H), 1.34 (s, 9H), 1.29 – 1.15 (m, 4H); 13 C NMR (101 MHz, DMSO-d 6 ) δ174.26, 155.48, 155.32, 155.12, 142.08, 134.29, 128.92, 128.21, 124.08, 122.29, 113.65, 77.82, 56.39, 43.36, 42.40, 39.82, 28.79, 28.20, 25.29, 25.06, 15.82; ESI-HRMS calcd for C 25 H 36 N 4 O 6 S 2 m/z[M + H] + 553.2149, found [M + H] + 553.2153.
Example 22
(2- (2-chloro-5- (4-methyl-2- (3-methylbutanamidyl) thiazol-5-yl) phenyl) sulfamide) ethylcarbamic acid tert-butyl ester with the following structural formula:the procedure of example 1 was repeated except that the acetyl chloride in step 4 of example 1 was changed to 3-methylbutyryl chloride; white solid, yield: 35 Percent of the total weight of the composition. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.23 (s, 1H), 8.05 (t,J= 5.6 Hz, 1H), 7.97 – 7.91 (m, 1H), 7.72 (t,J= 1.4 Hz, 2H), 6.79 (t,J= 5.5 Hz, 1H), 2.97 (dd,J= 12.2, 6.6 Hz, 2H), 2.91 (d,J= 6.7 Hz, 2H), 2.38 (s, 3H), 1.34 (s, 8H), 1.16 (dd,J = 18.6, 7.0 Hz, 8H); 13 C NMR (101 MHz, DMSO-d 6 ) δ 175.85, 156.46, 155.94, 144.22, 138.72, 133.64, 132.94, 132.27, 129.82, 129.38, 121.86, 78.28, 60.22, 42.65, 34.28, 28.62, 21.23, 19.52, 16.55, 14.55; ESI-HRMS calcd for C 22 H 31 N 4 O 5 S 2 m/z [M + H] + 531.1497, found [M + H] + 531.1495.
Example 23
(2-chloro-5- (2- (3, 3-dimethylbutyramide) -4-methylthiazol-5-yl) phenylsulfonamide) ethylcarbamic acid tert-butyl ester, having the structural formula:the procedure of example 1 was repeated except that the acetyl chloride in step 4 of example 1 was changed to 3, 3-dimethylbutyryl chloride; white solid, yield: 35%. 1 H NMR (300 MHz, DMSO-d 6 ) δ12.19 (s, 1H), 8.04 (t,J= 5.7 Hz, 1H), 7.94 (t,J= 1.3 Hz, 1H), 7.72 (d,J= 1.3 Hz, 2H), 6.78 (t,J= 5.6 Hz, 1H), 2.98–2.88 (m, 4H), 2.37 (s, 3H), 2.33 (s, 2H), 1.33 (s, 9H), 1.00 (s, 9H); 13 C NMR (101 MHz, DMSO-d 6 ) δ170.17, 155.67, 155.48, 143.75, 138.21, 133.18, 132.45, 131.82, 129.40, 128.90, 121.34, 77.81, 47.90, 42.17, 40.15, 39.94, 39.73, 39.52, 39.31, 39.10, 38.89, 31.01, 29.43, 28.16, 16.09; ESI-HRMS calcd for C 23 H 33 ClN 4 O 6 S 2 m/z[M + H] + 545.1654, found [M + H] + 545.1660.
Example 24
(2-chloro-5- (4-methyl-2-pentylamido-5-yl) phenylsulfamido) ethylcarbamic acid tert-butyl ester with the following structural formula: The procedure of example 1 was repeated except that the acetyl chloride in step 4 of example 1 was changed to pentanoyl chloride; white solid, yield: 35 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 )δ12.22 (s, 1H), 8.03 (t,J= 5.6 Hz, 1H), 7.93 (s, 1H), 7.73 – 7.69 (m, 2H), 6.77 (t,J= 5.6 Hz, 1H), 2.98 (q,J= 6.5 Hz, 2H), 2.90 (q,J= 6.8, 6.2 Hz, 2H), 2.43 (t,J= 7.4 Hz, 2H), 2.37 (s, 3H), 1.62–1.54 (m, 2H), 1.33 (s, 9H), 1.31–1.25 (m, 2H), 0.88 (t,J= 7.4 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.59, 155.87, 155.50, 143.77, 138.25, 133.19, 132.48, 131.82, 129.39, 128.92, 121.34, 77.84, 42.20, 34.61, 28.17, 26.81, 21.67, 16.11, 13.65; ESI-HRMS calcd for C 22 H 31 ClN 4 O 5 S 2 m/z[M + H] + 531.1497, found [M + H] + 531.1498.
Example 25
(2-chloro-5- (2-hexanamido-4-methylthiazol-5-yl) phenylsulfonamide) ethylcarbamic acid tert-butyl ester with the following structural formula:the procedure of example 1 was repeated except that acetyl chloride in step 4 of example 1 was changed to caproyl chloride; white solid, yield: 36%. 1 H NMR (400 MHz, DMSO-d 6 )δ12.20 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.71 (d,J= 1.8 Hz, 2H), 6.85–6.65 (m, 1H), 2.98 (q,J= 6.5 Hz, 2H), 2.91 (q,J= 6.6 Hz, 2H), 2.43 (t,J= 7.4 Hz, 2H), 2.37 (s, 3H), 1.64–1.56 (m, 2H), 1.33 (s, 9H), 1.30–1.24 (m, 4H), 0.86 (t,J= 6.8 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.56, 155.84, 155.47, 143.74, 138.24, 133.16, 132.46, 131.81, 129.37, 128.90, 121.32, 77.81, 42.18, 39.87, 34.84, 30.69, 28.15, 24.37, 21.80, 16.10, 13.81; ESI-HRMS calcd for C 23 H 33 ClN 4 O 5 S 2 m/z[M + H] + 545.1654, found [M + H] + 545.1645.
Example 26
(2- (5- (2- (3-acetamidopropionamido) -4-methylthiazol-5-yl) -2-methoxyphenyl) sulfamido) ethylcarbamic acid tert-butyl ester with the following structural formula:
the procedure of example 1 was repeated except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the acetyl chloride in step 4 was changed to 3-acetamidopropionyl chloride, and the procedure was as in example 1; white solid, yield: 30%. 1 H NMR (300 MHz, DMSO-d 6 )δ12.17 (s, 1H), 7.99 (t,J= 5.7 Hz, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.68 (dd,J= 8.5, 2.4 Hz, 1H), 7.39 (t,J= 5.8 Hz, 1H), 7.31 (d,J= 8.7 Hz, 1H), 6.83–6.67 (m, 1H), 3.94 (s, 3H), 3.31 (t,J= 6.2 Hz, 2H), 2.95 (q,J= 6.5 Hz, 2H), 2.82 (q,J= 6.4 Hz, 2H), 2.59 (t,J= 6.7 Hz, 2H), 2.32 (s, 3H), 1.78 (s, 3H), 1.34 (s, 9H); 13 C NMR (101 MHz, DMSO-d 6 )δ169.72, 169.36, 155.50, 155.36, 154.91, 142.14, 134.33, 128.97, 128.20, 124.02, 122.36, 113.68, 77.86, 56.42, 42.40, 39.83, 35.16, 34.66, 28.22, 22.60, 15.88; ESI-HRMS calcd for C 23 H 33 N 5 O 7 S 2 m/z[M + H] + 556.1894, found [M + H] + 556.1896.
Example 27
(2- (2-methoxy-5- (4-methyl-2- (6-oxoheptanamido) thiazol-5-yl) phenyl) sulfamide) ethylcarbamic acid tert-butyl ester having the following structural formula:the procedure of example 1 was repeated except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, 1- (4-methoxyphenyl) -2-propanone, and the acetyl chloride in step 4 was changed to 6-carbonyl heptanoyl chloride; white solid, yield: 35%. 1 H NMR (400 MHz, DMSO-d 6 )δ12.10 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.5, 2.4 Hz, 1H), 7.36 (t,J= 5.8 Hz, 1H), 7.31 (d,J= 8.6 Hz, 1H), 6.73 (t,J= 5.7 Hz, 1H), 3.94 (s, 3H), 2.96 (q,J= 6.5 Hz, 2H), 2.89–2.77 (m, 2H), 2.43 (dt,J= 13.9, 7.3 Hz, 4H), 2.32 (s, 3H), 2.07 (s, 3H), 1.63–1.41 (m, 4H), 1.34 (s, 9H); 13 C NMR (101 MHz, DMSO-d 6 )δ208.42, 171.28, 155.53, 155.36, 155.00, 142.13, 134.32, 128.96, 128.22, 124.07, 122.33, 113.67, 77.88, 56.41, 42.43, 42.36, 39.84, 34.77, 29.76, 28.21, 24.29, 22.71, 15.84; ESI-HRMS calcd for C 25 H 36 N 4 O 7 S 2 m/z[M + H] + 569.2098, found [M + H] + 569.2103.
Example 28
(2- (2-methoxy-5- (4-methyl-2- (6-oxohexanamide) thiazol-5-yl) phenyl) sulphonamide) ethylcarbamic acid tert-butyl ester with the following structural formula:the procedure of example 1 was repeated except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, 1- (4-methoxyphenyl) -2-propanone, and the acetyl chloride in step 4 was changed to 5-carbonyl chloride; white solid, yield: 35 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 )δ12.11 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.6, 2.4 Hz, 1H), 7.36 (t,J= 5.9 Hz, 1H), 7.31 (d,J= 8.7 Hz, 1H), 6.73 (t,J= 5.7 Hz, 1H), 3.94 (s, 3H), 2.96 (q,J= 6.5 Hz, 2H), 2.83 (q,J= 6.6 Hz, 2H), 2.46 (t,J= 3.6 Hz, 2H), 2.42 (t,J= 7.3 Hz, 2H), 2.32 (s, 3H), 2.08 (s, 3H), 1.77 (p,J= 7.4 Hz, 2H), 1.34 (s, 9H); 13 C NMR (101 MHz, DMSO-d 6 )δ208.03, 171.04, 155.50, 155.34, 154.98, 142.10, 134.28, 128.96, 128.23, 124.07, 122.32, 113.65, 77.84, 56.39, 41.86, 41.81, 34.01, 29.75, 28.20, 18.80, 15.83; ESI-HRMS calcd for C 24 H 34 N 4 O 7 S 2 m/z[M + H] + 555.1942, found [M + H] + 555.1946.
Example 29
(R) - (1- ((5- (2-hexyl)Amido-4-methylthiazol-5-yl) -2-methoxyphenyl) sulfonyl) piperidin-3-yl) carbamic acid tert-butyl ester having the structural formula:the procedure of example 1 was repeated except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, 1- (4-methoxyphenyl) -2-propanone, the fragment (2-aminoethyl) carbamic acid tert-butyl ester in step 2 was changed to (R) -piperidin-3-ylcarbamic acid tert-butyl ester, and the acetyl chloride in step 4 was changed to caproyl chloride; white solid, yield: 18%. 1 H NMR (400 MHz, DMSO-d 6 )δ12.09 (s, 1H), 7.73 (d,J= 2.3 Hz, 1H), 7.69 (dd,J= 8.6, 2.5 Hz, 1H), 7.33 (d,J= 8.6 Hz, 1H), 6.83 (d,J= 7.7 Hz, 1H), 3.93 (s, 3H), 3.55 (dd,J= 63.9, 12.2 Hz, 2H), 2.59 (t,J= 11.5 Hz, 1H), 2.41 (t,J= 7.4 Hz, 2H), 2.31 (s, 3H), 1.76 – 1.68 (m, 2H), 1.63 – 1.56 (m, 2H), 1.37 (s, 9H), 1.29 – 1.17 (m, 8H), 0.86 (t,J= 6.8 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.43, 155.65, 155.06, 154.87, 142.17, 134.71, 130.23, 126.27, 124.24, 122.14, 113.99, 77.96, 56.34, 50.00, 46.74, 45.50, 34.87, 30.74, 29.42, 28.23, 24.45, 23.70, 21.86, 15.83, 13.86; ESI-HRMS calcd for C 27 H 40 N 4 O 6 S 2 m/z[M + H] + 581.2462, found [M + H] + 581.2471.
Example 30
(S) - (1- ((5- (2-hexanamido-4-methylthiazol-5-yl) -2-methoxyphenyl) sulfonyl) pyrrolidin-3-yl) carbamic acid tert-butyl ester having the structural formula: The starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone to 1- (4-methoxyphenyl) -2-propanone, the fragment tert-butyl (2-aminoethyl) carbamate in step 2 was changed to tert-butyl (S) -pyrrolidin-3-ylcarbamate, and the acetyl chloride in step 4 was changed toHexanoyl chloride, other steps and operation as in example 1; white solid, yield: 20%. 1 H NMR (300 MHz, DMSO-d 6 )δ12.11 (s, 1H), 7.76 (d,J= 2.4 Hz, 1H), 7.69 (dd,J= 8.6, 2.4 Hz, 1H), 7.34 (d,J= 8.7 Hz, 1H), 7.11 (d,J= 6.5 Hz, 1H), 3.95 (s, 3H), 3.55 – 3.38 (m, 2H), 3.25 (q,J= 7.9 Hz, 1H), 2.41 (t,J= 7.4 Hz, 2H), 2.32 (s, 3H), 2.06 – 1.66 (m, 2H), 1.65 – 1.53 (m, 2H), 1.35 (s, 9H), 1.34 – 1.20 (m, 6H), 0.89 – 0.82 (m, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.39, 155.59, 155.21, 155.02, 142.11, 134.55, 130.65, 126.31, 124.17, 122.18, 113.83, 78.02, 56.36, 52.49, 49.98, 45.99, 34.85, 30.73, 30.56, 28.17, 24.43, 21.85, 15.82, 13.84; ESI-HRMScalcdforC 26 H 38 N 4 O 6 S 2 m/z[M + H] + 567.2306, found [M + H] + 567.2313.
Example 31
4- ((2-hexanamido-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamido) piperidine-1-carboxylic acid tert-butyl ester has the following structural formula:the procedure of example 1 was repeated except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the starting material in step 2 was changed to 1- (4-methoxyphenyl) -2-propanone, the tert-butyl (2-aminoethyl) carbamate in step 2 was changed to tert-butyl 4-aminomethylpiperidine-1-carboxylate, and the acetyl chloride in step 4 was changed to caproyl chloride; white solid, yield: 40%. 1 H NMR (300 MHz, DMSO-d 6 )δ12.11 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.67 (dd,J= 8.5, 2.4 Hz, 1H), 7.47 (t,J= 6.0 Hz, 1H), 7.30 (d,J= 8.6 Hz, 1H), 3.92 (s, 3H), 3.87 (t,J= 13.1 Hz, 2H), 2.69 (t,J= 6.3 Hz, 2H), 2.41 (t,J= 7.3 Hz, 2H), 2.31 (s, 3H), 1.64 – 1.49 (m, 5H), 1.36 (s, 9H), 1.28 – 1.14 (m, 6H), 0.96 – 0.83 (m, 5H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.46, 155.37, 155.02, 153.88, 142.07, 134.17, 129.00, 128.61, 124.03, 122.34, 113.61, 78.52, 59.82, 56.35, 47.98, 35.82, 34.89, 30.75, 28.12, 24.46, 21.86, 15.83, 13.86; ESI-HRMS calcd for C 28 H 42 N 4 O 6 S 2 m/z [M + H] + 595.2619,found [M + H] + 595.2624.
Example 32
N- (5- (3- (2- (3, 3-dimethylbutyramide) ethylaminosulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide, has the structural formula:other steps and operations are the same as in example 1 except that the starting material in step 1 of example 1 is changed to 1- (4-chlorophenyl) -2-propanone to 1- (4-methoxyphenyl) -2-propanone, the fragment (2-aminoethyl) carbamic acid tert-butyl ester in step 2 is changed to N- (2-aminoethyl) -3, 3-dimethylbutyramide, and the acetyl chloride in step 4 is changed to caproyl chloride; white solid, yield: 30%. 1 H NMR (300 MHz, DMSO-d 6 )δ12.11 (s, 1H), 7.84 – 7.59 (m, 3H), 7.42 (t,J= 5.9 Hz, 1H), 7.31 (d,J= 8.7 Hz, 1H), 3.93 (s, 3H), 3.37 (s, 3H), 3.07 (t,J= 6.6 Hz, 2H), 2.84 (q,J= 6.7 Hz, 2H), 2.41 (t,J= 7.4 Hz, 2H), 2.31 (s, 3H), 1.88 (s, 2H), 1.59 (t,J= 7.2 Hz, 2H), 1.32 – 1.21 (m, 4H), 0.97 – 0.83 (m, 9H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.39, 171.06, 155.33, 155.02, 142.07, 134.25, 128.94, 128.23, 124.09, 122.26, 113.64, 56.38, 48.83, 42.40, 38.46, 34.87, 30.73, 30.29, 29.64, 24.44, 21.84, 15.81, 13.82; ESI-HRMScalcdforC 25 H 38 N 4 O 5 S 2 m/z [M + H] + 539.2356, found [M + H] + 539.2358.
Example 33
N- (5- (3- (2-hydroxy-2-methylpropyl) sulfamoyl) -4-methoxyphenyl) -4-methylthiazol-2-yl hexanamide has the following structural formula:the procedure of example 1 was repeated except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the starting material in step 2 was changed to 1- (4-methoxyphenyl) -2-propanone, the tert-butyl (2-aminoethyl) carbamate in step 2 was changed to 1-amino-2-methyl-2-propanol, and the acetyl chloride in step 4 was changed to hexanoyl chloride; white solid, yield: 31%. 1 H NMR (400 MHz, DMSO-d 6 ) δ12.12 (s, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.68 (dd,J= 8.6, 2.4 Hz, 1H), 7.32 (d,J= 8.7 Hz, 1H), 6.96 (t,J= 6.4 Hz, 1H), 3.94 (s, 3H), 2.70 (d,J= 6.4 Hz, 2H), 2.41 (t,J= 7.4 Hz, 2H), 2.32 (s, 3H), 1.59 (p,J= 7.4 Hz, 2H), 1.32 – 1.23 (m, 4H), 1.06 (s, 6H), 0.92 – 0.81 (m, 3H); 13 C NMR (101 MHz, DMSO-d 6 ) δ171.37, 155.23, 154.97, 142.04, 134.12, 128.94, 128.23, 124.05, 122.25, 113.60, 68.74, 56.39, 53.89, 34.84, 30.71, 27.06, 24.40, 21.81, 15.81, 13.81; ESI-HRMS calcd for C 21 H 30 N 3 O 5 S 2 m/z[M + H] + 470.1778, found [M + H] + 470.1785.
Example 34
N- (5- (3- (N- (2-linoethyl) sulfamoyl)) -4-methoxyphenyl) -4-methylthiazol-2-yl hexanamide, the structural formula is as follows:the procedure of example 1 was followed except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the fragment of (2-aminoethyl) carbamic acid tert-butyl ester in step 2 was changed to N- (2-aminoethyl) morpholine, the acetyl chloride in step 4 was changed to hexanoyl chloride; white solid, yield: 20%. 1 H NMR (400 MHz, DMSO-d 6 )δ12.12 (s, 1H), 7.73 (d,J= 2.3 Hz, 1H), 7.68 (dd,J= 8.6, 2.4 Hz, 1H), 7.32 (d,J= 8.7 Hz, 1H), 7.16 – 7.04 (m, 1H), 3.96 (s, 3H), 3.45 (t,J= 4.7 Hz, 4H), 2.96 (q,J= 6.3 Hz, 2H), 2.42 (t,J= 7.4 Hz, 2H), 2.32 (s, 3H), 2.28 – 2.19 (m, 6H), 1.79 – 1.73 (m, 2H), 1.37 – 1.17 (m, 4H), 0.90 – 0.85 (m, 3H); 13 C NMR (101 MHz, DMSO) δ 155.35, 154.96, 136.08, 134.65, 130.56, 129.14, 126.96, 126.53, 113.86, 112.90, 63.17, 56.35, 55.51, 51.35, 47.92, 36.94, 30.70, 24.40, 21.80, 15.85, 13.82.ESI-HRMS calcd for C 23 H 34 N 4 O 5 S 2 m/z[M + H] + 511.2043, found [M + H] + 511.2044.
Example 35
N- (5- (3- (((4-fluorophenyl) -l 2-nitroxyl) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide, has the structural formula: The procedure of example 1 was followed except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the fragment tert-butyl (2-aminoethyl) carbamate in step 2 was changed to 4-fluoroaniline, and the acetyl chloride in step 4 was changed to caproyl chloride; white solid, yield: 55 Percent of the total weight of the composition. 1 H NMR (300 MHz, DMSO-d 6 )δ12.10 (s, 1H), 10.10 (s, 1H), 7.71–7.67 (m, 1H), 7.65–7.59 (m, 1H), 7.24 (dd,J= 9.1, 3.3 Hz, 1H), 7.15–7.01 (m, 4H), 3.91 (d,J= 2.0 Hz, 3H), 2.46–2.35 (m, 2H), 2.22 (q,J= 2.7, 1.9 Hz, 3H), 1.57 (d,J= 7.4 Hz, 2H), 1.30–1.19 (m, 4H), 0.88–0.82 (m, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.47, 160.10 (d,J= 241.4 Hz), 155.43, 155.05, 142.21, 134.97, 134.01, 129.75, 126.46, 124.04, 122.19(d,J= 8.1 Hz), 122.00, 115.91(d,J= 23.2 Hz), 113.70, 56.42, 34.87, 30.75, 24.46, 21.87, 15.72, 13.87; ESI-HRMS calcd for C 23 H 25 FN 3 O 4 S 2 m/z[M + H] + 492.1422, found [M + H] + 492.1420.
Example 36
N- (5- (3- (((4-chlorophenyl) -l 2-subunit) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide has the structural formula:the procedure of example 1 was followed except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the fragment tert-butyl (2-aminoethyl) carbamate in step 2 was changed to 4-chloroaniline, and the acetyl chloride in step 4 was changed to caproyl chloride; white solid, yield: 49 Percent of the total weight of the composition. 1 H NMR (300 MHz, DMSO-d 6 ) δ12.11 (s, 1H), 10.32 (s, 1H), 7.74 (d,J= 2.4 Hz, 1H), 7.63 (dd,J= 8.6, 2.4 Hz, 1H), 7.29–7.22 (m, 3H), 7.15–7.10 (m, 2H), 3.89 (s, 3H), 2.40 (t,J= 7.4 Hz, 2H), 2.24 (s, 3H), 1.58 (p,J= 7.3 Hz, 2H), 1.37–1.12 (m, 4H), 0.84 (t,J= 6.8 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 ) δ171.45, 155.43, 155.09, 142.25, 136.83, 135.06, 129.79,129.03, 127.86, 126.45, 124.12, 121.98, 121.06, 113.77, 56.44, 34.88, 30.75, 24.45, 21.86, 15.72, 13.85; ESI-HRMS calcd for C 23 H 25 ClN 3 O 4 S 2 m/z[M + H] + 508.1126, found [M + H] + 508.1133.
Example 37
N- (5- (3- (((4-fluorobenzyl) -l 2-nitrous) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide has the structural formula:the procedure of example 1 was followed except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the fragment (2-aminoethyl) carbamic acid tert-butyl ester in step 2 was changed to 4-fluorobenzylamine, the acetyl chloride in step 4 was changed to caproyl chloride, and the procedure was followed; white solid, yield: 54 Percent of the total weight of the composition. 1 H NMR (300 MHz, DMSO-d 6 )δ12.11 (s, 1H), 7.96 (t,J= 6.4 Hz, 1H), 7.64–7.52 (m, 2H), 7.23–7.09 (m, 3H), 6.96 (dd,J= 10.1, 7.7 Hz, 2H), 4.08 (d,J= 6.4 Hz, 2H), 3.85 (s, 3H), 2.41 (t,J= 7.4 Hz, 2H), 2.29 (s, 3H), 1.65–1.54 (m, 2H), 1.26 (dd,J= 6.4, 2.9 Hz, 4H), 0.86 (t,J= 6.7 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.41, 162.40 (d,J= 244.4 Hz), 155.11, 155.00, 141.96, 134.01, 133.71, 133.68, 129.71(d,J= 8.1 Hz), 128.84, 123.78, 122.38, 114.68(d,J= 21.2 Hz), 113.18, 56.15, 45.63, 34.88, 30.74, 24.45, 21.85, 15.72, 13.85; ESI-HRMS calcd for C 24 H 28 FN 3 O 4 S 2 m/z[M + H] + 506.1578, found [M + H] + 506.1581.
Example 38
N- (5- (3- (((3-fluorobenzyl) -l 2-nitrous) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide has the structural formula:the procedure of example 1 was followed except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the fragment (2-aminoethyl) carbamic acid tert-butyl ester in step 2 was changed to 3-fluorobenzylamine, the acetyl chloride in step 4 was changed to caproyl chloride, and the procedure was followed; white solid, yield: 48 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 )δ12.10 (s, 1H), 8.03 (t,J= 6.5 Hz, 1H), 7.62 (d,J= 2.4 Hz, 1H), 7.54 (dd,J= 8.6, 2.4 Hz, 1H), 7.21–7.16 (m, 1H), 7.11 (d,J= 8.8 Hz, 1H), 7.00–6.91 (m, 3H), 4.12 (d,J= 6.5 Hz, 2H), 3.85 (s, 3H), 2.41 (t,J= 7.4 Hz, 2H), 2.28 (s, 3H), 1.62–1.56 (m, 2H), 1.38–1.16 (m, 4H), 0.85 (d,J= 7.1 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.43, 163.11(d,J= 244.4 Hz), 155.15, 155.02, 142.00, 140.54(d,J= 7.1 Hz), 134.17, 129.89(d,J= 9.1 Hz), 128.86(d,J= 10.1 Hz), 123.81, 123.66(d,J= 3.0 Hz), 122.38, 114.34, 114.12, 113.82(d,J= 21.2 Hz), 113.15, 56.15, 45.77, 34.89, 30.77, 24.48, 21.89, 15.74, 14.02, 13.89; ESI-HRMS calcd for C 24 H 28 FN 3 O 4 S 2 m/z[M + H] + 506.1578, found [M + H] + 506.1584.
Example 39
N- (5- (3- (((2-fluorobenzyl) -l 2-nitrous) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide has the structural formula:the procedure of example 1 was followed except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the fragment (2-aminoethyl) carbamic acid tert-butyl ester in step 2 was changed to 2-fluorobenzylamine, the acetyl chloride in step 4 was changed to caproyl chloride, and the procedure was followed; white solid, yield: 42 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 ) δ12.10 (s, 1H), 7.93 (t,J= 6.4 Hz, 1H), 7.63 (d,J= 2.4 Hz, 1H), 7.56–7.49 (m, 1H), 7.32 (td,J= 7.6, 1.8 Hz, 1H), 7.22–7.13 (m, 1H), 7.09–6.97 (m, 2H), 6.93–6.89 (m, 1H), 4.12 (dd,J= 28.1, 6.3 Hz, 2H), 3.82 (s, 3H), 2.41 (t,J= 7.4 Hz, 2H), 2.29 (s, 3H), 1.60 (p,J= 7.4 Hz, 2H), 1.36–1.21 (m, 4H), 0.90–0.81 (m, 3H); 13 C NMR (101 MHz, DMSO-d 6 ) δ171.41, 160.78 (d,J= 245.4 Hz), 155.09, 155.02, 141.94, 134.14, 130.37(d,J= 3.0 Hz), 129.69(d,J= 132.3 Hz), 129.33(d,J= 8.1 Hz), 128.88, 124.29(d,J= 15.2 Hz), 123.97(d,J= 3.0 Hz), 123.72, 122.40, 114.79(d,J= 21.2 Hz), 113.04, 56.06, 55.90(d,J= 788.8 Hz), 34.88, 30.76, 24.47, 21.88, 15.71, 13.87; ESI-HRMS calcd for C 24 H 28 FN 3 O 4 S 2 m/z[M + H] + 506.1578, found [M + H] + 506.1575.
Example 40
N-（4-（3-（((2, 4-difluorobenzyl) -l 2-sulfinyl) -4-methoxyphenyl) -5-methylthiazol-2-yl) hexanamide, which has the following structural formula: The procedure of example 1 was followed except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the fragment (2-aminoethyl) carbamic acid tert-butyl ester in step 2 was changed to 2, 4-difluorobenzylamine, and the acetyl chloride in step 4 was changed to caproyl chloride; white solid, yield: 52 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 )δ12.09 (s, 1H), 7.92 (t,J= 6.4 Hz, 1H), 7.60 (d,J= 2.4 Hz, 1H), 7.54 (dd,J= 8.6, 2.4 Hz, 1H), 7.35 (td,J= 8.7, 8.3, 6.6 Hz, 1H), 7.07 (d,J= 8.7 Hz, 1H), 6.96–6.84 (m, 2H), 4.13 (d,J= 6.4 Hz, 2H), 3.83 (s, 3H), 2.42 (t,J= 7.4 Hz, 2H), 2.30 (s, 3H), 1.60 (p,J= 7.4 Hz, 2H), 1.32–1.25 (m, 4H), 0.87 (t,J= 6.9 Hz, 3H); 13 C NMR (101 MHz, DMSO)δ171.35, 162.73(dd,J= 189.9, 12.1 Hz), 160.28(dd,J= 192.9, 11.1 Hz), 154.98, 141.93, 134.04, 131.70(dd,J= 15.2, 5.1 Hz), 128.79, 128.35, 123.73, 122.32, 120.67(d,J= 4.0 Hz), 120.54(m), 112.97, 111.09(dd,J= 18.2, 2.0 Hz), 103.03(t,J= 51.5 Hz), 56.04, 34.84, 30.72, 24.42, 21.82, 15.65, 13.82.; ESI-HRMS calcd for C 24 H 27 F 2 N 3 O 4 S 2 m/z[M + H] + 524.1484, found [M + H] + 524.1489.
Example 41
N- (5- (3- (((3, 4-difluorobenzyl) -l 2-nitrosyl) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide, having the structural formula:the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone and 1- (4-methoxyphenyl) -2-propanone, and the fragment in step 2 was tert-butyl (2-aminoethyl) carbamateThe ester was changed to 3, 4-difluorobenzylamine and the acetyl chloride in step 4 was changed to caproyl chloride, and the other steps and operations were the same as in example 1; white solid, yield: 54 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 )δ12.09 (s, 1H), 8.00 (t,J= 6.5 Hz, 1H), 7.60 (d,J= 2.4 Hz, 1H), 7.55 (dd,J= 8.6, 2.4 Hz, 1H), 7.20–7.09 (m, 3H), 7.04–6.96 (m, 1H), 4.10 (d,J= 6.5 Hz, 2H), 3.86 (s, 3H), 2.41 (t,J= 7.4 Hz, 2H), 2.29 (s, 2H), 1.63–1.56 (m, 2H), 1.27 (dt,J= 10.3, 4.9, 4H), 0.87 (t,J= 6.9 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.36, 155.02, 154.99, 141.96, 135.32 (dd,J= 4.0,3.0Hz), 134.05, 129.65, 128.82, 128.74, 124.50 (dd,J= 3.0, 3.0 Hz), 123.80, 122.29, 116.86(d,J= 17.2 Hz), 116.62(d,J= 17.2 Hz), 113.03, 56.12, 45.27, 34.85, 30.72, 24.42, 21.83, 15.65, 13.82; ESI-HRMS calcd for C 24 H 27 F 2 N 3 O 4 S 2 m/z[M + H] + 524.1484, found [M + H] + 524.1480.
Example 42
N- (5- (3- (((3-chloro-4-fluorobenzyl) -l 2-nitrous) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide has the structural formula:the procedure of example 1 was followed except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the tert-butyl (2-aminoethyl) carbamate in step 2 was changed to 3-chloro-4-fluorobenzylamine, the acetyl chloride in step 4 was changed to caproyl chloride, and the procedure was followed; white solid, yield: 50 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 )δ12.08 (s, 1H), 8.00 (t,J= 6.6 Hz, 1H), 7.61–7.50 (m, 2H), 7.31 (d,J= 7.3 Hz, 1H), 7.15 (d,J= 7.3 Hz, 2H), 7.10 (d,J= 8.6 Hz, 1H), 4.11 (d,J= 6.5 Hz, 2H), 3.86 (s, 3H), 2.41 (t,J= 7.3 Hz, 2H), 2.29 (s, 3H), 1.63–1.56 (m, 2H), 1.32–1.25 (m, 4H), 0.86 (t,J= 6.8 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.35, 157.31(d,J= 247.4 Hz), 154.97, 154.94, 141.94, 135.29(d,J= 3.0 Hz), 134.03, 129.66, 128.76, 128.70, 128.41(d,J= 7.1 Hz), 123.84, 122.29, 118.86(d,J= 17.2 Hz), 116.23(d,J= 20.2 Hz), 112.96, 56.11, 45.14, 34.85, 30.72, 24.42, 21.82, 15.71, 13.82; ESI-HRMS calcd for C 24 H 27 ClFN 3 O 4 S 2 m/z[M + H] + 540.1188, found [M + H] + 540.1182.
Example 43
N- (5- (3- (((4-fluoro-3- (trifluoromethyl) benzyl) -l 2-subunit) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide, having the structural formula:the procedure of example 1 was repeated except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the starting material in step 2 was changed to 1- (4-methoxyphenyl) -2-propanone, the tert-butyl (2-aminoethyl) carbamate in step 2 was changed to 3-fluoro-4- (trifluoromethyl) benzylamine, and the acetyl chloride in step 4 was changed to caproyl chloride; white solid, yield: 44 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 )δ12.08 (s, 1H), 8.05 (t,J= 6.5 Hz, 1H), 7.58 (d,J= 2.4 Hz, 1H), 7.56–7.50 (m, 3H), 7.32–7.24 (m, 1H), 7.08 (d,J= 8.7 Hz, 1H), 4.19 (d,J= 6.5 Hz, 2H), 3.83 (s, 3H), 2.41 (t,J= 7.4 Hz, 2H), 2.28 (s, 3H), 1.60 (p,J= 7.4 Hz, 2H), 1.36–1.18 (m, 4H), 0.87 (t,J= 6.9 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.44, 156.56 (d,J= 194.9 Hz), 155.03, 154.90, 142.00, 134.65(d,J= 54.5 Hz), 134.61 (d,J= 5.0 Hz), 130.20(d,J= 49.5 Hz), 128.74, 128.67, 127.92, 126.60, 126.27 (m), 123.90, 122.29, 116.68(d,J= 20.2 Hz), 113.00, 56.06, 45.15, 34.90, 30.79, 24.50, 21.91, 15.75, 13.90; ESI-HRMS calcd for C 25 H 27 F 4 N 3 O 4 S 2 m/z[M + H] + 574.1452, found [M + H] + 574.1444.
Example 44
N- (5- (4-methoxy-3- (((3, 4, 5-trifluorobenzyl) -l 2-diazonium) sulfonyl) phenyl) -4-methylthiazol-2-yl) hexanamide has the structural formula:the procedure of example 1 was followed except that the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone, the tert-butyl (2-aminoethyl) carbamate in step 2 was changed to 3,4, 5-trifluorobenzylamine, and the acetyl chloride in step 4 was changed to caproyl chloride; white solid, yield: 31 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 )δ12.09 (s, 1H), 8.06 (t,J= 6.6 Hz, 1H), 7.60 (d,J= 2.3 Hz, 1H), 7.57 (dd,J= 8.5, 2.4 Hz, 1H), 7.14 (d,J= 8.7 Hz, 1H), 7.09 (dd,J= 8.9, 6.7 Hz, 2H), 4.12 (d,J= 6.6 Hz, 2H), 3.87 (s, 3H), 2.41 (t,J= 7.4 Hz, 2H), 2.28 (s, 3H), 1.60 (p,J= 7.2 Hz, 2H), 1.33–1.23 (m, 4H), 0.87 (t,J= 6.8 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.37, 155.04, 154.99, 154.72, 141.98, 135.49, 134.15, 130.23, 128.87, 128.66, 127.85, 126.62, 123.87, 122.22, 112.96(d,J= 72.7 Hz), 112.03 (m), 56.14(d,J= 22.2 Hz), 47.94, 45.10, 45.00, 34.85, 30.72, 24.43, 21.83, 15.59, 13.82; ESI-HRMS calcd for C 24 H 26 F 3 N 3 O 4 S 2 m/z[M + H] + 542.1390, found [M + H] + 542.1395.
Example 45
N- (5- (3- (((4-fluorophenethyl) -l 2-nitrosyl) sulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide having the structural formula: Will be described in detail below1, 1- (4-chlorophenyl) -2-propanone is changed to 1- (4-methoxyphenyl) -2-propanone, 2-carbamic acid tert-butyl ester is changed to 4-fluorophenylethylamine, acetyl chloride is changed to caproyl chloride, and other steps and operations are the same as in example 1; white solid, yield: 32 Percent of the total weight of the composition. 1 H NMR (400 MHz, DMSO-d 6 )δ12.12 (s, 1H), 7.70 (d,J= 2.4 Hz, 1H), 7.65 (dd,J= 8.6, 2.4 Hz, 1H), 7.43 (t,J= 5.8 Hz, 1H), 7.26 (d,J= 8.7 Hz, 1H), 7.17–7.13 (m, 2H), 7.06–7.01 (m, 2H), 3.89 (s, 3H), 3.06 (q,J= 6.8 Hz, 2H), 2.68 (t,J= 7.1 Hz, 2H), 2.41 (t,J= 7.4 Hz, 2H), 2.31 (s, 3H), 1.59 (p,J= 7.2 Hz, 2H), 1.27 (td,J= 8.5, 7.4, 5.0 Hz, 4H), 0.86 (t,J= 6.8 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 )δ171.54, 162.12(d,J= 242.4 Hz), 155.38, 155.07, 142.11, 135.00(d,J= 3.0 Hz),134.22, 130.55, 130.47, 128.93(d,J= 53.5 Hz),, 124.05, 122.40, 115.10(d,J= 20.2 Hz), 113.65, 56.36, 44.20, 34.94, 34.49, 30.81, 24.53, 21.93, 15.87, 13.92; ESI-HRMS calcd for C 25 H 30 FN 3 O 4 S 2 m/z[M + H] + 520.1735, found [M + H] + 520.1735.
Example 46
(2- (2-hexanamido-4-methylthiazol-5-yl) -2-methoxybenzamido) ethylcarbamate tert-butyl ester:
step 1: synthesis of 2-methoxy-5- (2-oxopropyl) benzoic acid:the starting material 10 mmol of methyl 5-formyl-2-methoxybenzoate and butylamine (2.0 eg) were dissolved in toluene and reacted at reflux for 3 h, distilled under reduced pressure to dryness and then dissolved in 10 mL of acetic acid, 1.14 mL nitroethane (1.5 eq) was slowly added to the reaction solution, and the mixture was heated to 100℃and reacted for 3 h. After the reaction, the reaction mixture was cooled to room temperature and slowly poured into 40 mL ice water solution (stirring vigorously throughout), using ethyl acetateThe mixture was extracted with ethyl acetate solution (2x40 mL), the organic phase was collected, washed with water (2x40 mL), 10% sodium bicarbonate solution (2x30 mL) and brine in this order, dried over anhydrous magnesium sulfate, and purified by column chromatography (PE: ea=2:1) to give [ (] Z) -methyl 2-methoxy-5- (2-nitropropen-1-yl) benzoate, yield: 80 The%; 100 mmol of iron powder was added to a reaction flask of 22 mL acetic acid, a solution of 12 mL acetic acid in which methyl (Z) -2-methoxy-5- (2-nitropropen-1-yl) benzoate (8 mmol) was dissolved was slowly dropped into the above reactor under nitrogen protection, after refluxing reaction 2 h, the reaction solution was cooled to room temperature, the iron powder was filtered, 30 mL water was added to the filtrate, the mixture was extracted with ethyl acetate solution (3×40 mL), the organic phase was collected, the organic phase was washed with water (2×30 mL), 10% sodium bicarbonate solution (2×30 mL) and brine (30 mL) in this order, dried over anhydrous magnesium sulfate, and purified by column chromatography (PE: EA=1:1) to give methyl 2-methoxy-5- (2-oxopropyl) benzoate, yield: 90 Percent of the total weight of the composition. 2 mmol of methyl 2-methoxy-5- (2-oxo-propyl) benzoate is weighed and acidolysis is carried out to obtain white solid 2-methoxy-5- (2-oxo-propyl) benzoate, and the yield is: 95% (1.0 mL hydrochloric acid solution (mixed solution of 1 mol/L and 4 mL acetic acid)) was used as acidolysis solution. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.58 (s, 1H), 7.46 (d,J= 2.3 Hz, 1H), 7.30 (dd,J= 8.5, 2.4 Hz, 1H), 7.07 (d,J= 8.6 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 2H), 2.13 (s, 3H).
Step 2: the synthesis of (2- (2-caproamide-4-methylthiazol-5-yl) -2-methoxybenzamide) ethyl carbamic acid tert-butyl ester has the following structural formula: 2-methoxy-5- (2-oxopropyl) benzoic acid (1 mmol) and CDI (1 mmol) were pre-reacted in 10 mL DCM solution for 1 h, after which 1.5 mmol of tert-butyl (2-aminoethyl) carbamate was added to the reaction solution for room temperature reaction. Purifying after the reaction is finished to obtain (2- (2-methoxy-5- (2-oxo propyl) benzamide) ethyl) carbamic acid tert-butyl ester; the white solid (2- (2-hexanamido-4-methylthiazol-5-yl) -2-methoxy) was then obtained according to steps 3 and 4 of example 1Benzamide) tert-butyl ethylcarbamate, yield: 40%. 1 H NMR (400 MHz, DMSO-d 6 )δ12.12 (s, 1H), 7.73 (d,J= 2.3 Hz, 1H), 7.68 (dd,J= 8.6, 2.4 Hz, 1H), 7.32 (d,J= 8.7 Hz, 1H), 7.16 – 7.04 (m, 1H), 3.96 (s, 3H), 3.45 (t,J= 4.7 Hz, 4H), 2.96 (q,J= 6.3 Hz, 2H), 2.42 (t,J= 7.4 Hz, 2H), 2.32 (s, 3H), 2.28 – 2.19 (m, 6H), 1.79 – 1.73 (m, 2H), 1.37 – 1.17 (m, 4H), 0.90 – 0.85 (m, 3H); 13 C NMR (101 MHz, DMSO) δ 155.35, 154.96, 136.08, 134.65, 130.56, 129.14, 126.96, 126.53, 113.86, 112.90, 63.17, 56.35, 55.51, 51.35, 47.92, 36.94, 30.70, 24.40, 21.80, 15.85, 13.82.ESI-HRMS calcd for C 23 H 34 N 4 O 5 S 2 m/z[M + H] + 511.2043, found [M + H] + 511.2044.
Example 47
N- (4- (3- (((2, 4-difluorobenzyl) -l 2-nitrosyl) sulfonyl) -4-methoxyphenyl) -5-methylthiazol-2-yl) hexanamide, having the structural formula:in analogy to the preparation of example 1, the starting material in step 1 of example 1 was changed to 1- (4-chlorophenyl) -2-propanone to 4' -methoxyphenylpropanone, the fragment (2-aminoethyl) carbamic acid tert-butyl ester in step 2 was changed to 2, 4-difluorobenzylamine, and the acetyl chloride in step 4 was changed to caproyl chloride and the other steps and operations were identical to those of example 1. White solid, yield: 51 Percent of the total weight of the composition. 1 H NMR (300 MHz, DMSO-d 6 )δ12.08 (s, 1H), 8.01 (d,J= 2.3 Hz, 1H), 7.84 (d,J= 6.4 Hz, 1H), 7.75 (dd,J= 8.7, 2.3 Hz, 1H), 7.39–7.31 (m, 1H), 7.09 (d,J= 8.7 Hz, 1H), 6.97–6.89 (m, 2H), 4.09 (d,J= 6.3 Hz, 2H), 3.84 (s, 3H), 2.45 (s, 3H), 2.40 (t,J= 7.4 Hz, 2H), 1.64–1.56 (m, 2H), 1.26 (td,J= 6.4, 6.0, 3.0 Hz, 4H), 0.89–0.84 (m, 3H); 13 C NMR (101 MHz, DMSO)δ171.33, 162.77 (d,J= 204.0 Hz), 160.17 (d,J= 177.8 Hz), 154.88, 154.01, 142.26, 132.99, 131.58 (d,J= 6.1 Hz), 128.78, 127.96, 126.88, 120.88 (dd,J= 15.2, 3.0 Hz), 120.26, 112.27, 111.08 (dd,J= 18.2, 3.0 Hz), 103.12 (t,J= 52.5 Hz), 55.98, 34.81, 30.74, 24.43, 21.82, 13.82, 11.77.; ESI-HRMS calcd for C 24 H 27 F 2 N 3 O 4 S 2 m/z[M + H] + 524.1484, found [M + H] + 524.1491.
PI4KIII beta kinase inhibition experiments were performed on the inhibitors of the invention: the reagents used for the kinase reaction were as follows, tested using the ADP-Glo Luminescent Kinase Assay method: HEPES (50 mM) pH 7.5 with NaCl (100 mM), EGTA (1.0 mM), mgCl 2 (3.0 mM), DTT (2.0 mM) and CHAPS (0.03%). During the reaction, 50. Mu.M PIP2 and 25. Mu.M ATP were added to each 10. 10 mL of the test compound (0.05 nM-1.0. Mu.M). The reaction system was incubated at room temperature for 1h, and then 10. Mu.L of the reagent ADP-Glo was added to terminate the enzyme reaction. Data collection using Envision software and IC analysis and fitting of compounds using Graphpad Prism 5 50 Values.
TABLE 1 PI4KIII beta enzyme inhibitory Activity of the Compounds of the examples (IC 50 ，nM)
As shown in Table 1, the compounds of the present invention have nanomolar inhibitory activity against PI4KIII beta kinase, and some of the compounds are significantly better than the positive control PIK-93, especially examples 10, 11, 12, 14, 20, 21, 24, 27 and example 33 have significantly better inhibitory activity against PI4KIII beta kinase than the positive control PIK-93. Thus, the compounds of the examples of the present invention are highly potent inhibitors of PI4KIII beta.
Anti-proliferation activity experiments of tumor cell lines were performed against the inhibitors of the present invention:
evaluation of proliferation inhibition Activity of Compounds on cells Using CCK-8 method, half inhibition concentration IC was determined by single concentration Activity initial screening and multiple concentration 50 Values. The detection principle is as follows: cytotoxicity (CCK-8 method) detection principle: CCK-8 reagentComprises WST-8 which is reduced into yellow Formazan product (Formazan) with high water solubility by dehydrogenase in cell mitochondria under the action of electron carrier 1-Methoxy-5-methylphenazine dimethyl sulfate (1-Methoxy PMS). The amount of formazan produced is proportional to the number of living cells.
The experimental method is as follows:
(1) Inoculating cells: cells were prepared as single cell suspensions with 10% fetal bovine serum in culture medium and 90 μl of 5×10 cells were inoculated per well in 96 well plates 4 Wall-attached cells/mL and 9X 10 4 Suspension cells per mL at 5% CO 2 Pre-incubation at 37 ℃ was 24 h.
(2) Adding a sample solution to be tested: adding 10 mu L of sample solution into each hole, setting 1 concentration of each sample by an active primary screen, and setting 3 compound holes; IC (integrated circuit) 50 8 concentrations (containing 0 concentration) were measured, each concentration being provided with 3 multiplex wells; placed in an incubator for cultivation 48 and h. Experiments set up Blank (Blank), control and Drug.
(3) Color development: the adherent cells aspirate the old medium and drug solution (suspension cells were directly added to 10. Mu.L of CCK-8 stock solution), 100. Mu.L of CCK-8 solution diluted ten times per well was added at 37℃with 5% CO 2 Cultivation was continued for 1-4 h (operation, real-time observation).
(4) And (3) detection: the absorbance at 450 and nm was measured with a microplate reader and the raw data results were recorded.
(5) Raw data normalization was performed using Excel software, and cell proliferation inhibition was calculated by primary screening through OD values per well (formula= (OD) Control -OD Drug )/(OD Control -OD Blank ) X 100%) and the inhibition rate was counted. IC (integrated circuit) 50 Calculated by GraphPad Prism 8.
Table 2 tumor cell line proliferation inhibiting Activity (IC 50, μM) of the Compounds of the examples
| Examples | MCF-7 | MDA-MB-231 | A549 | H446 | DU145 | PC3 | HT29 | HCT116 |
| Example 1 | 2.36 | 2.05 | 2.91 | 0.44 | 1.97 | 1.24 | 2.04 | 1.54 |
| Example 2 | 2.83 | 2.87 | 3.3 | 0.79 | 3.53 | 2.98 | 2.64 | 2.31 |
| Example 3 | ＞4 | ＞4 | ＞4 | 2.09 | ＞4 | ＞4 | ＞4 | ＞4 |
| Example 4 | ＞4 | ＞4 | ＞4 | 0.80 | ＞4 | ＞4 | ＞4 | ＞4 |
| Example 5 | 2.11 | 3.94 | 3.87 | 0.70 | ＞4 | 2.4 | 2.98 | 2.38 |
| Example 6 | ＞4 | ＞4 | ＞4 | 3.32 | ＞4 | ＞4 | ＞4 | 3.89 |
| Example 7 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 |
| Example 8 | 1.16 | 1.04 | 1.87 | 0.21 | 1.51 | 0.84 | 0.80 | 0.38 |
| Example 9 | 0.42 | 0.62 | 0.54 | 0.094 | 0.56 | 0.42 | 0.16 | 0.29 |
| Example 10 | 0.31 | 0.49 | 0.48 | 0.067 | 0.43 | 0.28 | 0.12 | 0.25 |
| Example 11 | 0.097 | 0.15 | 0.16 | 0.038 | 0.082 | 0.074 | 0.049 | 0.074 |
| Example 12 | 0.14 | 0.18 | 0.24 | 0.05 | 0.12 | 0.13 | 0.078 | 0.14 |
| Example 13 | 0.68 | 0.54 | 0.95 | 0.14 | 0.87 | 0.63 | 0.45 | 0.60 |
| Example 14 | 0.50 | 0.47 | 0.63 | 0.095 | 0.58 | 0.45 | 0.28 | 0.35 |
| Example 15 | 0.34 | 0.44 | 0.74 | 0.062 | 0.31 | 0.24 | 0.05 | 0.29 |
| Example 16 | ＞2 | ＞2 | ＞2 | 0.71 | ＞2 | ＞2 | 1.45 | ＞2 |
| Example 17 | ＞2 | ＞2 | ＞2 | 1.10 | ＞2 | ＞2 | ＞2 | ＞2 |
| Example 18 | 0.36 | 0.46 | 0.81 | 0.058 | 0.32 | 0.24 | 0.064 | 0.38 |
| Example 19 | 0.75 | 0.93 | 1.56 | 0.17 | 0.74 | 0.43 | 0.062 | 0.64 |
| Example 20 | 0.55 | 0.68 | 1.59 | 0.11 | 0.53 | 0.38 | 0.10 | 0.42 |
| Example 21 | 0.77 | 1.15 | 1.98 | 0.16 | 1.35 | 0.70 | 0.24 | 0.99 |
| Example 22 | 0.86 | 0.77 | 0.92 | 0.071 | 0.48 | 0.37 | 0.094 | 0.53 |
| Example 23 | 1.10 | 0.91 | 0.86 | 0.042 | 0.40 | 0.31 | 0.076 | 0.18 |
| Example 24 | 1.17 | 1.92 | 1.38 | 0.07 | 0.94 | 0.64 | 0.096 | 0.36 |
| Example 25 | 1.04 | 1.07 | 1.21 | 0.062 | 0.64 | 0.45 | 0.078 | 0.28 |
| Example 26 | ＞2 | ＞2 | ＞2 | ＞2 | ＞2 | ＞2 | ＞2 | ＞2 |
| Example 27 | 0.28 | 0.39 | 0.42 | 0.086 | 0.29 | 0.31 | 0.096 | 0.23 |
| Example 28 | ＞2 | ＞2 | ＞2 | ＞2 | ＞2 | ＞2 | ＞2 | ＞2 |
| Example 29 | ＞4 | ＞4 | ＞4 | 0.45 | ＞4 | 0.92 | 0.70 | ＞4 |
| Example 30 | 0.89 | 1.47 | 1.86 | 0.32 | 1.28 | 0.67 | 0.52 | 0.80 |
| Example 31 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 |
| Example 32 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 |
| Example 33 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 |
| Example 34 | 0.82 | 1.57 | ＞2 | 0.34 | 1.73 | 0.76 | 0.52 | 1.46 |
| Example 35 | 0.46 | 0.87 | 2.76 | 0.20 | 0.32 | 0.21 | 0.14 | 0.52 |
| Example 36 | 1.05 | 2.41 | ＞4 | 0.43 | 0.57 | 0.84 | 0.38 | 0.94 |
| Example 37 | 0.20 | 0.34 | 0.59 | 0.12 | 0.37 | 0.19 | 0.18 | 0.20 |
| Example 38 | 0.21 | 0.74 | 1.24 | 0.35 | 0.68 | 0.43 | 0.42 | 0.38 |
| Example 39 | 0.20 | 0.68 | 1.07 | 0.24 | 0.53 | 0.22 | 0.31 | 0.27 |
| Example 40 | 0.13 | 0.18 | 0.24 | 0.098 | 0.19 | 0.16 | 0.14 | 0.15 |
| Example 41 | 0.20 | 0.28 | 0.34 | 0.22 | 0.30 | 0.21 | 0.25 | 0.19 |
| Example 42 | 0.19 | 0.26 | 0.30 | 0.18 | 0.24 | 0.19 | 0.21 | 0.24 |
| Example 43 | 0.32 | 0.53 | 0.79 | 0.30 | 0.60 | 0.24 | 0.40 | 0.29 |
| Example 44 | 0.21 | 0.35 | 0.40 | 0.38 | 0.42 | 0.18 | 0.17 | 0.19 |
| Example 45 | 0.42 | 1.02 | 1.84 | 0.16 | 0.87 | 0.48 | 0.46 | 0.75 |
| Example 46 | ＞2 | ＞2 | ＞2 | ＞2 | ＞2 | ＞2 | ＞2 | ＞2 |
| Example 47 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 | ＞4 |
| PIK-93 | 3.30 | 3.12 | ＞4 | 0.68 | ＞4 | 3.53 | 1.94 | 3.73 |
As can be seen from Table 2, the compounds of the present invention have micromolar levels of proliferation inhibitory activity against different tumor strains, and particularly most of the compounds of the examples have higher sensitivity against human small cell lung cancer cell strain H446 and human colon cancer cell strain HT 29. Wherein, 12 compounds of example 9 and the like show nanomolar level inhibitory activity on various cell strains in table 2, which is significantly better than positive control PIK-93; among them, example 11 had nanomolar inhibitory activity against 6 of the 8 cell lines in table 2, and inhibitory activity against cell lines H446 and HT29 were 38 nM and 49 nM, respectively, which was significantly superior to the positive control PIK-93. It follows that the compounds of the present embodiments may be potentially useful in the clinical treatment of the aforementioned neoplasms.
PI4KIII beta pharmacokinetic experiments were performed on the inhibitors of the invention:
weighing a test sample, placing the test sample into a thousand sterile vials, adding 250 mu L of DMSO, adding 10 mu L of methanesulfonic acid, dissolving, adding 4.78 mL of 5% glucose injection, and uniformly mixing by ultrasonic and vibration to prepare a test sample solution of 2 mg/mL, wherein the solution is used as a stomach-lavage administration preparation. In addition, 0.5mL of 2 mg/mL of the sample solution was taken, and 4.5. 4.5 mL of 5% glucose injection was added thereto, followed by shaking and mixing to prepare a sample solution of 0.2. 0.2 mg/mL, which was used as an intravenous injection preparation.
The 20 SD rats were divided into four groups, and examples 11 and 27 were given only tail vein injection (5 mg/kg) and example 40 was given tail vein injection (5 mg/kg) and lavage (50 mg/kg), respectively, due to instability of the structures of examples 11 and 27 under acidic conditions, intravenous injection groups were administered 2 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h after administration; the gavage group took blood samples of about 0.25 mL from the retroorbital venous plexus 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h after dosing. The concentrations of examples 11, 27 and 40 in SD rat plasma samples were determined by LC-MS/MS method and pharmacokinetic parameters were calculated using WinNolin software and the results are shown in Table 3.
The results are shown in Table 3, and examples 11, 27 and 40 of the present invention are better metabolized in rats, have better absorption and exposure, and example 40 has higher bioavailability.
Table 3 pharmacokinetic parameter recordings
In Table 3, C max Representing blood concentration; CL represents the total clearance; v (V) ss Representing a steady state distribution volume; v (V) z Representing a distribution volume; t (T) 1/2 Indicating elimination half-life; MRT (media-radio head) INF Mean time of drug transport from blood circulation to tissues and organs; AUC (AUC) 0-t The area under the plasma concentration-time curve from time 0 to the final quantifiable time point; AUC (AUC) 0-∞ Represents the area under the plasma concentration-time curve from 0 to infinity;Findicating bioavailability.
The PI4KIII beta anti-tumor curative effect and toxicity research experiment is carried out on the inhibitor:
the drugs are examples 11, 27 and 40. The cell line is cultured in RPMI-1640 culture medium containing 10% of fetal calf serum of human small cell lung cancer cell line H446. The tested animals are SPF-class BALB/c nude mice; a male; each group of 5. The drug dosage settings are as in table 4.
Table 4 drug dosage configuration
| Group of | Test agent | Dosage (mg/kg) | Administration volume (mL/20 body weight) | Route of administration | Period of observation (days) |
| Model group 1 | Physiological saline | - | 0.2 | Administration by injection | 25 |
| Example 11 Low dose group | Example 11 | 20 | 0.2 | Administration by injection | 25 |
| EXAMPLE 11 high dose group | Example 11 | 30 | 0.2 | Administration by injection | 25 |
| Example 27 | Example 27 | 30 | 0.2 | Administration by injection | 25 |
| Model group 2 | Physiological saline | - | 0.2 | Gastric lavage administration | 25 |
| Example 40 Low dose group | Example 40 | 75 | 0.2 | Gastric lavage administration | 25 |
| EXAMPLE 40 high dose group | Example 40 | 150 | 0.2 | Gastric lavage administration | 25 |
The preparation method of the medicine comprises the following steps:
example 11 (20 mg/kg): the compound powder to be tested of 4 mg is weighed and dissolved in 2 mL normal saline to prepare the medicine with the concentration of 2 mg/mL, and the medicine is orally injected and administrated, and the administration volume is 0.2 mL/20 g.
Example 11 (30 mg/kg): the powder of the compound to be tested 6 mg is weighed and dissolved in 2 mL normal saline to prepare the drug with the concentration of 3 mg/mL, and the drug is orally injected and the drug administration volume is 0.2 mL/20 g.
Example 27 (30 mg/kg): the powder of the compound to be tested 6 mg is weighed and dissolved in 2 mL normal saline to prepare the drug with the concentration of 3 mg/mL, and the drug is orally injected and the drug administration volume is 0.2 mL/20 g.
Example 40 (75 mg/kg): 15 mg compound powder to be tested is weighed and dissolved in 2 mL normal saline to prepare a drug with the concentration of 7.5 mg/mL, and the drug is orally and parenterally administered, and the administration volume is 0.2 mL/20 g.
Example 40 (150 mg/kg): 30 mg of the compound powder to be tested is weighed and dissolved in 2 mL of physiological saline to prepare the drug with the concentration of 15 mg/mL, and the drug is orally and parenterally administrated, and the administration volume is 0.2 mL/20 g.
The experimental method comprises the following steps: the human lung cancer nude mice transplantation tumor model is established by inoculating a human small cell lung cancer cell strain H446 under the armpit skin of a nude mice. Taking H446 cells in logarithmic growth phase, inoculating under the right armpit of 50 nude mice under aseptic condition, and inoculating 5×10 cells 6 And/or just. The diameter of the transplanted tumor is measured by a vernier caliper until the tumor grows to 80 mm 3 Selecting 42 tumor-bearing nude mice with good growth state and uniform tumor size at left and right sides, and randomlyThe groups were divided into 7 groups of 6, i.e., model group 1, example 11 (20 mg/kg) low dose group, example 11 (30 mg/kg) high dose group, example 27 (30 mg/kg) group, model group 2, example 40 (75 mg/kg) low dose group, example 40 (150 mg/kg) high dose group. Test drug example 11 low and high dose groups, example 27 were given by injection, example 40 low and high dose groups were given by gavage, once every 2 days, model groups 1 and 2 were given an equal volume of vehicle control. The antitumor effect of the test object is dynamically observed by using a method for measuring tumor diameters. Tumor diameter was measured once every other day, and the weight of nude mice was weighed while measuring tumor diameter. Mice were sacrificed on day 27 and tumor pieces were surgically removed and fixed with 10% formaldehyde and stored in liquid nitrogen, respectively, for later use.
The experimental results show that: test agent example 11 showed potent antitumor activity at 20 mg/kg with a tumor growth inhibition TGI value of 25.7% and a relative tumor proliferation T/C value of 72.3% compared to the model group. The tumor growth inhibition was better (tgi=37.1%, T/c=60.2%) when the dose was increased to 30 mg/kg, much higher than in example 27 (tgi=30.2% and T/c=66.8%). Furthermore, example 40 exhibited more remarkable antitumor efficacy at an oral dose of 150 mg/kg. TGI value was 42.2% and T/C value was 52.1%. (FIGS. 1-3 are results of in vivo anti-tumor efficacy and toxicity studies of PI4KIIIβ inhibitors, respectively. FIGS. 1 and 2 contain a mouse tumor volume, a growth curve of body weight and a representative image of mouse tumor tissue. FIG. 3 shows pathological sections of the major tissue obtained from mice bearing lung tumors. Organs were stained with hematoxylin and eosin (H & E) and representative images were captured), and it can be seen in conjunction with the above figures that the test agents prepared in examples 11 and 40 have a significant inhibitory effect on human lung cancer H446 nude mice xenograft tumor growth.
The phenylthiazole amine PI4KIII beta inhibitor provided by the invention has high sensitivity to small cell lung cancer and colon cancer and anti-tumor curative effect by inhibiting proliferation of various solid tumors and hematological tumor cells through high efficiency on PI4KIII beta, and can be potentially used for clinical treatment.
Claims (9)
1. The phenylthiazole amine PI4KIII beta inhibitor is characterized by being a substituted phenylthiazole amine compound shown in a general formula V, or a stereoisomer or pharmaceutically acceptable salt thereof:wherein A isOr->；
R 1 Is a substituent on the benzene ring selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyC 1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxyC 1-C6 alkoxy or C1-C6 alkoxyC 1-C6 alkyl;
R 2 is that；
R 3 Or R is 4 Is C1-C6 alkyl, C1-C6 alkyl containing one or more substituents, C1-C6 alkoxy containing one or more substituents, C1-C6 alkanoyl, C1-C6 alkylsulfonyl, C3-C6 heterocyclyl containing one or more substituents;
x is sulfonyl or carbonyl.
2. The inhibitor according to claim 1, characterized in that it is a compound of formula i or ii:
wherein R is 1 、R 2 、R 4 And X is as defined in claim 1;
R 3 is that。
3. An inhibitor, wherein the inhibitor is one of the following:
(2- (5- (2-acetamido-4-methylthiazol-5-yl) -2-chlorophenyl sulfamide) ethyl) carbamic acid tert-butyl ester;
N- (2- (2-acetamido-4-methylthiazol-5-yl) -2-chlorophenyl sulfamide) ethyl propionamide;
(2- (2-acetamido-4-methylthiazol-5-yl) -2-chlorophenyl sulfamide) ethylcarbamate;
(2- ((5- (2-acetamido-4-methylthiazol-5-yl) -2-methoxyphenyl) sulfamide) ethyl) carbamic acid tert-butyl ester;
(5- (2-propionylamino-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamide) ethylcarbamic acid tert-butyl ester;
(5- (2-butyrylamino-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamide) ethylcarbamic acid tert-butyl ester;
(5- (2-pentanoylamino-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamide) ethylcarbamic acid tert-butyl ester;
(5- (2-hexanamido-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamido) ethylcarbamic acid tert-butyl ester;
(5- (2-heptanamido-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamido) ethylcarbamic acid tert-butyl ester;
(2- (2-methoxy-5- (4-methyl-2- (3-propylureido) thiazol-5-yl) phenyl) sulfamide) ethylcarbamic acid tert-butyl ester;
(2- (5- (2- (3-butylureido) -4-methylthiazol-5-yl) -2-methoxyphenylsulphonamido) ethyl) carbamic acid tert-butyl ester;
(2- (2-methoxy-5- (4-methyl-2- (3-methylbutanamide) thiazol-5-yl) phenyl) sulfamide) ethyl carbamic acid tert-butyl ester;
(5- (2-isobutyrylamino-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamide) ethylcarbamic acid tert-butyl ester;
(2- (2-methoxy-5- (4-methyl-2-pivaloylamide thiazol-5-yl) phenyl) sulphonamido) ethylcarbamic acid tert-butyl ester;
(5- (2- (3, 3-dimethylbutyramide) -4-methylthiazol-5-yl) -2-methoxyphenylsulphonamide) ethylcarbamic acid tert-butyl ester;
(2- (2-methoxy-5- (4-methyl-2- (4-methylpentanamide) thiazol-5-yl) phenyl) sulphonamido) ethylcarbamic acid tert-butyl ester;
(2- (2-methoxy-5- (4-methyl-2- (5-methylhexanamido) thiazol-5-yl) phenyl) sulphonamido) ethylcarbamic acid tert-butyl ester
(2- (5- (2- (cyclohexanecarboxamido) -4-methylthiazol-5-yl) -2-methoxyphenyl) sulfamide) ethylcarbamic acid tert-butyl ester;
(2- (2-chloro-5- (4-methyl-2- (3-methylbutanamidyl) thiazol-5-yl) phenyl) sulfamide) ethylcarbamic acid tert-butyl ester;
(2-chloro-5- (2- (3, 3-dimethylbutyramide) -4-methylthiazol-5-yl) phenylsulfonamide) ethylcarbamic acid tert-butyl ester;
(2-chloro-5- (4-methyl-2-pentanoylamino-5-yl) phenylsulfonamide) ethylcarbamic acid tert-butyl ester;
(2-chloro-5- (2-hexanamido-4-methylthiazol-5-yl) phenylsulfonamide) ethylcarbamic acid tert-butyl ester;
(2- (5- (2- (3-acetamidopropionamido) -4-methylthiazol-5-yl) -2-methoxyphenyl) sulfamide) ethylcarbamic acid tert-butyl ester;
(2- (2-methoxy-5- (4-methyl-2- (6-oxoheptanamido) thiazol-5-yl) phenyl) sulfamide) ethylcarbamic acid tert-butyl ester;
(2- (2-methoxy-5- (4-methyl-2- (6-oxohexanamide) thiazol-5-yl) phenyl) sulphonamide) ethylcarbamic acid tert-butyl ester;
(R) - (1- ((5- (2-hexanamido-4-methylthiazol-5-yl) -2-methoxyphenyl) sulfonyl) piperidin-3-yl) carbamic acid tert-butyl ester;
(S) - (1- ((5- (2-hexanamido-4-methylthiazol-5-yl) -2-methoxyphenyl) sulfonyl) pyrrolidin-3-yl) carbamic acid tert-butyl ester;
4- ((2-hexanamido-4-methylthiazol-5-yl) -2-methoxyphenylsulphonamido) piperidine-1-carboxylic acid tert-butyl ester;
n- (5- (3- (2- (3, 3-dimethylbutyramide) ethylaminosulfonyl) -4-methoxyphenyl) -4-methylthiazol-2-yl) hexanamide;
N- (5- (3- (2-hydroxy-2-methylpropyl) sulfamoyl) -4-methoxyphenyl) -4-methylthiazol-2-yl hexanamide;
n- (5- (3- (N- (2-inylethyl) sulfamoyl)) -4-methoxyphenyl) -4-methylthiazol-2-yl hexanamide;
n- (4- (3- (((2, 4-difluorobenzyl) -l 2-subunit) sulfonyl) -4-methoxyphenyl) -5-methylthiazol-2-yl) hexanamide;
(2- (2-hexanamido-4-methylthiazol-5-yl) -2-methoxybenzamide) ethylcarbamic acid tert-butyl ester.
4. A method for preparing an inhibitor according to claim 1, wherein 1- (4-chlorophenyl) -2-propanone or 1- (4-methoxyphenyl) -2-propanone is used as raw materials 1a and 1b, and the raw materials 1a and 1b and chlorosulfonic acid undergo substitution reaction at the 3 rd position of benzene ring to obtain intermediates 2a and 2b; r is introduced by Hinsberg reaction on the basis of intermediates 2a, 2b 2 The groups give intermediates 3a-3g; the intermediate 3a-3g and phenyl trimethyl ammonium tribromide undergo alpha-bromination reaction to obtain intermediate 4a-4g; the intermediate 4a-4g and N-acetylthiourea are condensed to obtain target compounds 5a-5g, and the synthetic route is as follows:
。
5. the method according to claim 4, wherein A process for preparing target compounds 5a-5g, which comprises starting from intermediates 4d, 4e as claimed in claim 4, simultaneously introducing R by substitution reaction of thiourea with various acid chlorides 3 The intermediate N-substituted thiourea obtained by the group is used as another raw material; the target compounds 7a-7r are obtained through condensation reaction of the two; or taking the intermediate 4e as a raw material, and performing condensation reaction with thiourea to obtain an intermediate 8; the intermediate 8 is respectively subjected to substitution reaction with 3-acetamidopropionyl chloride, 6-carbonyl heptanoyl chloride and 5-carbonyl hexanoyl chloride to obtain target compounds 9a-9c, and the synthetic route is as follows:
；
or according to the preparation method of the target compound 5a-5g, the obtained compound 4h-4x is taken as a raw material, and is subjected to condensation reaction with N-hexanyl thiourea to obtain the target compound 10a-10q, wherein the synthetic route is as follows:
。
6. the process according to claim 5, wherein the intermediate 12 is obtained by two-step reaction using the compound (11) as a raw material; the intermediate 12 is heated in acetic acid for reflux and is subjected to reduction reaction with iron powder to obtain an intermediate 13; the intermediate 13 undergoes hydrolysis reaction under acidic condition to obtain an intermediate 14; intermediate 14 reacts with tert-butyl (2-aminoethyl) carbamate to obtain intermediate 15, which is reacted in two steps to obtain target compound 17, the synthetic route is as follows:
；
Or 4' -methoxy propiophenone 18 is used as a raw material, and the target compound 22 is obtained through four steps of reactions, and the synthetic route is as follows:
。
7. a pharmaceutical composition comprising at least one pharmaceutically acceptable adjuvant, adjuvant or carrier, and the phenylthiazole amine PI4KIII β inhibitor of any of claims 1 to 3.
8. Use of a phenylthiazole amine PI4KIII beta inhibitor according to claim 1 or a pharmaceutical composition according to claim 7 for the preparation of a medicament for the prevention, treatment or adjuvant treatment of a proliferative disease, a metabolic disease, a neurological disease or tuberous sclerosis caused by excessive activation of PI4KIII beta kinase.
9. Use of the phenylthiazole amine PI4KIII beta inhibitor of claim 1 or the pharmaceutical composition of claim 7 in the manufacture of a medicament for inhibiting cancer cell growth.
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| CN102452998A (en) * | 2010-10-20 | 2012-05-16 | 天津药物研究院 | N-formyl hydroxylamine compound and its preparation method and use |
| CN114174275A (en) * | 2019-03-21 | 2022-03-11 | 小利兰·斯坦福大学托管委员会 | PI 4-kinase inhibitors and methods of use thereof |
| WO2022245977A2 (en) * | 2021-05-18 | 2022-11-24 | University Of Southern California | Methods for the expansion of human granulocytemacrophage progenitors and applications thereof |
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| GB201115665D0 (en) * | 2011-09-09 | 2011-10-26 | Univ Leuven Kath | Autoimmune and inflammatory disorder therapy |
| EP3419980A4 (en) * | 2016-02-26 | 2019-07-03 | The Board of Trustees of the Leland Stanford Junior University | Pi-kinase inhibitors with anti-infective activity |
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|---|---|---|---|---|
| CN102452998A (en) * | 2010-10-20 | 2012-05-16 | 天津药物研究院 | N-formyl hydroxylamine compound and its preparation method and use |
| CN114174275A (en) * | 2019-03-21 | 2022-03-11 | 小利兰·斯坦福大学托管委员会 | PI 4-kinase inhibitors and methods of use thereof |
| WO2022245977A2 (en) * | 2021-05-18 | 2022-11-24 | University Of Southern California | Methods for the expansion of human granulocytemacrophage progenitors and applications thereof |
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| Understanding the selectivity of inhibitors toward PI4KIIIaand PI4KIIIbbased molecular modeling†;Shuaizhen Tian 等;《Phys. Chem. Chem. Phys.》;20191231(第21期);22103-22112 * |
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