CN110759900B - Preparation method and application of thiophene compound - Google Patents

Preparation method and application of thiophene compound Download PDF

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CN110759900B
CN110759900B CN201911021259.3A CN201911021259A CN110759900B CN 110759900 B CN110759900 B CN 110759900B CN 201911021259 A CN201911021259 A CN 201911021259A CN 110759900 B CN110759900 B CN 110759900B
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cyano
morpholino
thiophen
triazol
hydrazine
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CN110759900A (en
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刘亚婧
赵燕芳
廖伟科
韩雨霏
齐银良
宫平
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Shenyang Pharmaceutical University
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and relates to a compound shown in a general formula IAnd pharmaceutically acceptable salts, solvates or prodrugs thereof, and a preparation method thereof. Wherein the substituents L, Ar and R have the meanings given in the specification. The invention also relates to a compound with a general formula I, which has a strong effect of inhibiting PI3K, and also relates to application of the compound and pharmaceutically acceptable salts, solvates or prodrugs thereof in preparing medicaments for treating and/or preventing diseases caused by abnormal high expression of PI3K, in particular to application in preparing medicaments for treating and/or preventing cancers.

Description

Preparation method and application of thiophene compound
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and relates to a novel thiophene compound, pharmaceutically acceptable salt, solvate or prodrug thereof, a preparation method thereof and a pharmaceutical composition containing the compound. The invention also relates to application of the compound and pharmaceutically acceptable salts, solvates or prodrugs thereof in preparing medicaments for treating and/or preventing diseases caused by abnormal high expression of PI3K, in particular to application in preparing medicaments for treating and/or preventing cancers.
Background
Malignant tumors are diseases caused by the malfunction of the mechanisms controlling cell growth and proliferation. With the increasing global population, the aging population and the external factors such as environmental pollution, the malignant tumor has become the second largest killer with the incidence rate second to the cardiovascular and cerebrovascular diseases and threatening the human health, and the death rate of the malignant tumor even exceeds the cardiovascular and cerebrovascular diseases and is the first of all the diseases.
Phosphoinositide 3-kinase (PI 3K) is a heterodimer consisting of a p85 regulatory subunit and a p110 catalytic subunit, and has serine/threonine (Ser/Thr) kinase activity and phosphatidylinositol kinase activity. The PI3K catalytic subunit p110 can be classified into three major groups according to its structural characteristics and substrate molecules: type I, type II, type III. PI3K is attractive as a target for tumor therapy because it is located at a critical signaling site for a number of important signaling pathways. When PI3K receives signals from tyrosine kinases and G protein-coupled receptors, the activated pl10 subunit can be converted to phosphatidylinositol-3, 4, 5-triphosphate (PIP3) by phosphorylating the hydroxyl group at position 3 of the substrate phosphatidylinositol-4, 5-diphosphate (PIP2), PIP3 being an important second messenger in cells that activates downstream multiple protein kinases such as Akt/PKB (protein kinase B), etc., thereby activating multiple downstream pathways.
The PTEN (Phosphatase and tensin homology deleted on chromosome ten) gene is a new tumor suppressor gene discovered in recent years, and the product PTEN protein can specifically catalyze the dephosphorylation at the 3-position of PIP3 to generate PIP2, negatively regulate a PI3K signal channel, block the transfer of Akt to a cell membrane, further influence the phosphorylation of Akt and inhibit a downstream channel mediated by Akt. The coordination of PTEN and PI3K can make the concentration of PIP3 in cells at a proper level and maintain the moderate activity of Akt. Loss of PTEN causes accumulation of PIP3 in the cell, imbalance in the PTEN-PI3K/Akt signaling pathway, and continuous activation of Akt, thereby rendering the cell anti-apoptotic. Over-expression of PTEN can inhibit Akt activation and thus promote apoptosis, so transfected PTEN can induce apoptosis.
The PI3K-Akt signaling pathway is widely involved in cell life activities including survival, proliferation, apoptosis, invasion, etc., and is overactivated in almost all human tumors. After the PI3K-Akt signal channel is activated, the apoptosis can be inhibited, the tolerance of cells to hypoxia and nutrition deficiency is enhanced, the survival and the proliferation of the cells are promoted, the cells participate in the formation of blood vessels, the growth of tumors is assisted, the metastasis of the tumors is promoted, and the occurrence and the development of the tumors are influenced by other carcinogenic factors. Therefore, in recent years, a plurality of small molecule inhibitors acting on the PI3K-Alt signal pathway have entered the clinical stage.
The inventor designs and synthesizes a series of thiophene derivatives on the basis of a reference document, and shows that the compound has good anti-tumor activity and obvious inhibitory activity to PI3K through pharmacological activity screening, and simultaneously has obvious inhibitory action to various human tumor cells.
Disclosure of Invention
The invention relates to compounds of general formula (I) and pharmaceutically acceptable salts, solvates or prodrugs thereof,
Figure BDA0002247296930000021
wherein:
r is selected from one or more of hydrogen, hydroxyl, halogen, nitro, amino and cyano;
l is
Figure BDA0002247296930000022
Ar is C6-C10Aryl or 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is optionally 1-3R, the same or different1Substitution;
R1is hydrogen, hydroxy, halogen, nitro, amino, cyano, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Alkylthio, C optionally substituted by hydroxy, amino or halogen1-C6Alkyl or C1-C6Alkoxy, mono-or di-C1-C6Alkyl-substituted amino, C1-C6Alkylamido, free, salified, esterified and amidated carboxyl, C1-C6Alkylsulfinyl radical, C1-C6Alkylsulfonyl radical, C1-C6Alkanoyl, carbamoyl, mono-or di-C1-C6Alkyl-substituted carbamoyl.
The present invention also preferably relates to compounds of formula I as defined below, and pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein,
r is hydrogen.
The present invention also preferably relates to compounds of formula I as defined below, and pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein,
r is hydrogen;
l is
Figure BDA0002247296930000031
Ar is phenyl, pyridyl, furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoquinolyl, indolyl, imidazolyl, triazolyl, naphthyl, 1, 3-benzodioxazole; and Ar is optionally 1 to 3 identical or different R1Substitution;
R1is hydrogen, hydroxy, halogen, nitro, amino, cyano, C1-C4Alkyl radical, C2-C3Alkenyl radical, C2-C3Alkynyl, C1-C3Alkoxy radical, C1-C3Alkylthio radical, C1-C3Alkylsulfonyl, C optionally substituted by hydroxy, amino or halogen1-C4Alkyl or C1-C3Alkoxy, mono-or di-C1-C3Alkyl-substituted amino groups.
The present invention also preferably relates to compounds of formula I as defined below, and pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein,
r is hydrogen;
l is
Figure BDA0002247296930000032
Ar is phenyl, pyridyl, furyl, thienyl, pyrrolyl, naphthyl, 1, 3-benzodioxazole, and Ar is optionally 1 to 3R, which may be the same or different1Substitution;
R1is hydrogen, hydroxy, fluorine, chlorine, bromine, cyano, methyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, methylsulfinyl, C1-C6An alkylsulfonyl group.
The compounds of formula I of the present invention and pharmaceutically acceptable salts, solvates or prodrugs thereof are preferably the following compounds, but these compounds are not meant to limit the present invention in any way,
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- [2, 5-bis (trifluoromethyl) phenyl ] urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (3-methoxyphenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2-fluoro-5-methylphenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2-chloro-5-trifluoromethylphenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (3, 5-difluorophenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (4-trifluoromethoxyphenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2, 5-dimethylphenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2-chloro-6-methylphenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (4-fluorophenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2-fluorophenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (3-chloro-4-fluorophenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2-bromo-4-fluorophenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (4-chlorophenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (4-methylphenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (3, 4-difluorophenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2, 6-dimethylphenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2-methoxyphenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (3-bromophenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2-chlorophenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (3-trifluoromethylphenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2-trifluoromethoxyphenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2, 4-dichlorophenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (3-trifluoromethyl-4-chlorophenyl) urea
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (4-hydroxy-3-methoxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (2, 4-dichlorobenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (2, 5-dimethoxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- [ (1, 3-benzodioxazol-5-yl) methylene) ] hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (4-hydroxy-3, 5-dibromobenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (4-hydroxy-3, 5-di-tert-butylbenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (4-methanesulfonylbenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (3, 5-dimethyl-4-hydroxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- [ (3-hydroxynaphthalen-2-yl) methylene ] hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- [ (thiophen-2-yl) methylene ] hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- [ (pyridin-3-yl) methylene ] hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (2-chloro-4-fluorobenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (2, 4-dihydroxybenzenemethylene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (3, 5-dimethoxy-4-hydroxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (3, 4-dihydroxybenzenemethylene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (4-cyanobenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (4-trifluoromethoxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (3-methoxy-4-hydroxy-5-bromobenzyl methylene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (4-trifluoromethylbenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (3-bromo-4-hydroxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- [ (1H-pyrrol-2-yl) methylene ] hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (3-fluoro-4-hydroxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- [ (furan-2-yl) methylene ] hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (2,4, 6-trimethylbenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (2-fluorobenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (3-bromobenzenemethylene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (4-methoxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (4-hydroxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (4-dimethylaminobenzenemy l) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (2, 6-dichlorobenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2-benzylidene hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (3,4, 5-trimethoxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (5-hydroxybenzylidene) hydrazine-1-carboxamide
Figure BDA0002247296930000071
Figure BDA0002247296930000081
Figure BDA0002247296930000091
Figure BDA0002247296930000101
Figure BDA0002247296930000111
Furthermore, the thiophene derivatives of formula I of the present invention may be reacted with an acid to form pharmaceutically acceptable salts thereof according to conventional methods in the art. The acid may include inorganic or organic acids, and salts with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, tartaric acid, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, and the like.
In addition, the present invention also includes prodrugs of the compounds of the present invention. Prodrugs, according to the present invention, are derivatives of compounds of formula i which may themselves have poor or even no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis or otherwise) to the corresponding biologically active form.
The term "halo" as used herein, unless otherwise indicated, refers to fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "alkenyl" means straight or branched chain alkenyl; "alkynyl" refers to straight or branched chain alkynyl groups; "aryl" refers to an organic group obtained by removing one hydrogen atom from an aromatic hydrocarbon, such as phenyl, naphthyl; 5-to 10-membered heteroaryl includes those containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic, the ring system is aromatic, and contains a total of 5 to 10 atoms, and examples thereof include imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzothiazolyl, indolyl, quinolyl and the like; 5-10 membered heterocyclic groups include those containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic but is non-aromatic, the ring system containing a total of 5 to 10 atoms and may optionally include 1 or 2 carbon-carbon double or triple bonds, and there may be mentioned, for example, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, thiazolinyl and the like.
The invention also relates to a compound with a general formula I, which has a strong effect of inhibiting PI3K, and also relates to application of the compound and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparing medicines for treating and/or preventing diseases caused by abnormal high expression of PI3K, in particular to application in preparing medicines for treating and/or preventing cancers.
The following synthetic schemes A-C describe the preparation of the compounds of formula I of this invention, all starting materials prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or commercially available. All of the final compounds of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All the variable factors applied in these routes are as defined below or in the claims.
The compounds of formula I, intermediates 1, according to the invention are prepared as in scheme A, the other substituents being as defined in the claims.
Figure BDA0002247296930000131
Route A Synthesis of intermediate 1
The compounds of formula I, compounds I-I (i.e. compounds I) according to the invention are prepared as in scheme B, the other substituents being as defined in the claims.
Figure BDA0002247296930000132
Route B Synthesis of Compounds I-I
The compounds of formula I, compounds I-ii according to the invention are prepared as in scheme C, the other substituents being as defined in the claims.
Figure BDA0002247296930000141
Route C Synthesis of Compounds I-ii
The specific implementation mode is as follows:
in the following examples, methods of preparing some of the compounds are depicted. It is to be understood that the following methods, as well as other methods known to those of ordinary skill in the art, can be applied to the preparation of all of the compounds described herein. The examples are intended to illustrate, but not to limit, the scope of the invention.
EXAMPLE 11 preparation of- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2-fluorophenyl) urea
1.13- (4-aminophenyl) -5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophene-4-carbonitrile preparation (intermediate 1)
1.1.12 preparation of- [ bis (methylthio) methylene ] malononitrile (1a)
7.5g (113.7mmol) of malononitrile and 17.3g (125.0mmol) of potassium carbonate are added to 75mL of DMSO at room temperature, cooled to 0 ℃ and 7.5mL (125mmol) of carbon disulfide are gradually added dropwise, and after the addition, stirring is carried out for 2h at 20 ℃. The reaction mixture was cooled to 0 ℃ and 14.1mL (227.3mmol) of methyl iodide was gradually added dropwise thereto, followed by reaction at 20 ℃ for 12 hours. After the reaction, the reaction solution was poured into 75mL of ice water, and a yellow solid was precipitated, filtered, washed with water, and dried to obtain 18.2g of a yellow solid with a yield of 93.9%.
1.1.1 preparation of ethyl-amino-4-cyano-5- (methylthio) thiophene-2-carboxylate (1b)
15.0g (88.2mmol) of intermediate 1a and 9.8mL (88.2mmol) of ethyl thioglycolate were added to 75mL of ethanol at room temperature, cooled to 0 ℃ and 12.2mL (88.2mmol) of triethylamine were gradually added dropwise and reacted at 20 ℃ for 12 hours. After the reaction, the reaction solution was filtered, and the filter cake was washed with a little ethanol and dried to obtain 15.5g of an off-white solid with a yield of 72.6%.
1.1.34 preparation of cyano-3-iodo-5- (methylthio) thiophene-2-carboxylic acid ethyl ester (1c)
6.0(62.0mmol) of iodine simple substance is added into acetonitrile (75mL) solution containing 7.5g (31.1mmol) of intermediate 1b at room temperature, the temperature is raised to 70 ℃, 6.3mL (62.0mmol) of isoamyl nitrite is gradually added dropwise, and the reaction is carried out for 12h at 20 ℃ after the dripping is finished. After the reaction, the mixture was cooled to 0 ℃, continuously stirred for 0.5h, filtered, and the filter cake was washed with a little cold acetonitrile and dried to obtain 6.9g of yellow solid with a yield of 63.0%.
1.1.44 preparation of cyano-3-iodo-5- [ methylsulfinyl (sulfinyl) ] thiophene-2-carboxylic acid ethyl ester (1d)
0.3g (1.1mmol) of sodium tungstate was added to a glacial acetic acid (75mL) solution containing 3.8g (10.7mmol) of intermediate 1c at room temperature, and 37.5mL of a 30% hydrogen peroxide solution was gradually added dropwise, and the reaction was carried out at 60 ℃ for 2 hours after completion of the dropwise addition. After the reaction, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with water and dried to obtain 3.9g of an off-white solid with a yield of 99.2%.
1.1.54 preparation of cyano-3-iodo-5-morpholinothiophene-2-carboxylic acid ethyl ester (1e)
3.9g (10.7mmol) of intermediate 1d and 60mL of tetrahydrofuran were added to a 100mL three-necked flask at room temperature, and 4.8mL (55.1mmol) of morpholine was gradually added dropwise under ice bath, and the reaction was carried out at 25 ℃ for 8 hours after completion of the dropwise addition at a temperature of <10 ℃. After the reaction, the reaction solution was poured into 30mL of ice water to precipitate a white solid, which was filtered, and the filter cake was washed with water and dried to obtain 3.2g of a white solid with a yield of 75.5%.
Preparation of 1.1.63- [4- [ (tert-butoxycarbonyl) amino ] phenyl ] -4-cyano-5-morpholinothiophene-2-carboxylic acid ethyl ester (1f)
2.6g (6.6mmol) of intermediate 1e, 3.0g (6.6mmol) of 4-aminoBoc-phenylboronic acid pinacol ester and 3.0g (19.8mmol) of cesium fluoride were added to a mixed solution of dioxane (25mL) and water (5mL) at room temperature, N2A solution of 0.2g (0.3mmol) of palladium bistriphenylphosphine dichloride in toluene (5mL) was added under protection and reacted at 95 ℃ for 15 h. After the reaction, the reaction solution was cooled to room temperature, and the reaction solution was concentrated, 10mL of water was added, followed by suction filtration, washing of the filter cake with water, and drying to obtain 2.4g of a white solid with a yield of 78.9%.
Preparation of 1.1.73- [4- [ (tert-butoxycarbonyl) amino ] phenyl ] -4-cyano-5-morpholinothiophene-2-carboxylic acid (1g)
6.0g (13.2mmol) of intermediate 1f, 60mL of tetrahydrofuran and 30mL of methanol were put into a 250mL round bottom flask at room temperature, 5.1g (212.6mmol) of a saturated aqueous solution of lithium hydroxide was added, and the mixture was reacted at 25 ℃ for 7 hours. After the reaction was completed, concentration was performed under reduced pressure, and the residue was added to 30mL of water, the pH was adjusted to 5 with a 2N hydrochloric acid solution, suction filtration was performed, the filter cake was washed with water, and drying was performed to obtain 4.4g of a white solid with a yield of 71.44%.
1.1.8 preparation of tert-butyl [4- (2-carboxamido-4-cyano-5-morpholinothiophen-3-yl) phenyl ] carbamate (1h)
5.4g (12.6mmol) of intermediate 1g and 2.4mL of triethylamine were added to 120mL of tetrahydrofuran at room temperature, and 1.8g (18.9mmol) of methyl chloroformate was gradually added dropwise under ice bath, followed by reaction at room temperature for 2 hours. Under ice bath, gradually dropwise adding 27mL of ammonia water, and reacting at room temperature for 2h after dropwise adding. After the reaction was completed, concentration was performed under reduced pressure, and the residue was added to 50mL of water, filtered with suction, washed with water, and dried to obtain 4.7g of a yellow solid with a yield of 86.1%.
1.1.9 preparation of tert-butyl (Z) - [4- [ 4-cyano-2- [ [ (dimethylamino) methylene ] carbamoyl ] -5-morpholinothiophen-3-yl ] phenyl ] carbamate (1i)
5.4g (12.6mmol) of intermediate 1h, 3.0g (25.2mmol) of DMF-DMA was added to 120mL of DMF at room temperature and reacted at 110 ℃ for 2 h. After the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was added to 30mL of water, filtered under suction, and the filter cake was washed with water and dried to obtain 4.4g of a pale yellow solid with a yield of 71.4%.
Preparation of 1.1.103- [4- [ (tert-butoxycarbonyl) amino ] phenyl ] ] -5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophene-4-carbonitrile (1j)
3.0g (6.2mmol) of intermediate 1i is added to 30mL of glacial acetic acid at room temperature, 15mL of 80% hydrazine hydrate is gradually added dropwise, and the reaction is carried out for 2h at 60 ℃ after the dropwise addition. After the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was added to 30mL of water, filtered, and the filter cake was washed with water and dried to obtain 2.4g of a color-like solid with a yield of 85.5%.
1.1.113- (4-aminophenyl) -5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophene-4-nitrile (1)
At room temperature, 3.0g (6.6mmol) of the intermediate 1j is added into 60mL of dichloromethane, the reaction system is brought to 0 ℃, 3.1mL (22.0mmol) of trifluoroacetic acid is gradually added dropwise, reaction is carried out for 3h at 25 ℃, reduced pressure concentration is carried out, the residue is added into 30mL of water, the pH value is adjusted to 8 by triethylamine, suction filtration is carried out, the filter cake is washed by water and dried, 1.7g of white solid is obtained, and the yield is 80.0%.
1.21 preparation of- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2-fluorophenyl) urea
Intermediate 1(9.3mmol), 2-fluorophenyl isocyanate (14.0mmol) were added to 40mL of dichloromethane at room temperature, reacted at 25 ℃ for 12h, filtered off with suction and dried to give a white solid.
The yield thereof was found to be 58.7%. 217.8-219.3 ℃ in m.p.; MS (ESI) M/z (%): 488.3[ M-H)]-。
1H NMR(400MHz,DMSO)δ14.04(s,1H),9.65(s,1H),8.80(s,1H),8.46(s,1H),8.16(t,J＝7.7Hz,1H),7.49(d,J＝8.0Hz,2H),7.30(d,J＝7.9Hz,2H),7.27–7.18(m,1H),7.14(t,J＝7.6Hz,1H),7.08–6.95(m,1H),3.79(s,4H),3.51(s,4H).
EXAMPLE 21 preparation of- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (4-fluorophenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophen-3-yl is prepared by using 4-fluorophenyl isocyanate as a raw material and adopting the synthetic method of 1.2 in example 1]Phenyl radical]-3- (4-fluorophenyl) urea in 65.9% yield. m.p. 231.4-232.3 ℃; MS (ESI) M/z (%): 488.3[ M-H)]-。
1H NMR(400MHz,DMSO)δ13.99(s,1H),9.17(s,1H),9.07(s,1H),8.46(s,1H),7.58(d,J＝8.9Hz,2H),7.48(d,J＝8.3Hz,2H),7.29(d,J＝8.4Hz,4H),3.84–3.76(m,4H),3.51(d,J＝4.3Hz,4H).
EXAMPLE 31 preparation of- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2-chlorophenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophene-3-yl is prepared by using 2-chlorophenyl isocyanate as a raw material and adopting the synthesis method of 1.2 in example 1]Phenyl radical]-3- (2-chlorophenyl) urea in 77.1% yield. m.p. 222.3-223.9 ℃; MS (ESI) M/z (%): 528.2[ M + Na [)]+。
1H NMR(400MHz,DMSO)δ14.03(s,1H),9.84(s,1H),8.49(s,1H),8.46(s,1H),8.17(d,J＝8.2Hz,1H),7.51(d,J＝8.3Hz,2H),7.46(d,J＝8.0Hz,1H),7.32(s,1H),7.29(d,J＝7.0Hz,2H),7.03(t,J＝7.6Hz,1H),3.79(s,4H),3.51(s,4H).
EXAMPLE 41 preparation of- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (3-bromophenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophen-3-yl is prepared by using 3-bromophenyl isocyanate as a raw material according to the synthesis method 1.2 in example 1]Phenyl radical]-3- (3-bromophenyl) urea, yield 72.5%. 198.7-200.3 ℃ in m.p.; MS (ESI) M/z (%): 548.2[ M-H]-。
1H NMR(400MHz,DMSO)δ13.99(s,1H),9.14(s,1H),9.06(s,1H),8.46(s,1H),7.87(s,1H),7.47(d,J＝8.4Hz,2H),7.33(d,J＝8.7Hz,1H),7.30(d,J＝8.3Hz,2H),7.24(t,J＝8.0Hz,1H),7.15(d,J＝7.9Hz,1H),3.79(s,4H),3.51(s,4H).
EXAMPLE 51 preparation of- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (4-methylphenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophen-3-yl is prepared by using 4-methylphenyl isocyanate as a raw material according to the synthesis method of 1.2 in example 1]Phenyl radical]-3- (4-methylphenyl) urea in 67.8% yield. m.p. 228.5-230.1 ℃; MS (ESI) M/z (%): 484.3[ M-H]-。
1H NMR(400MHz,DMSO)δ13.99(s,1H),8.95(s,1H),8.81(s,1H),8.46(s,1H),7.46(d,J＝8.3Hz,2H),7.35(d,J＝8.3Hz,2H),7.28(d,J＝8.3Hz,2H),7.09(d,J＝8.2Hz,2H),3.79(s,4H),3.51(s,4H),2.24(s,3H).
EXAMPLE 61 preparation of- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2-methoxyphenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophen-3-yl is prepared by using 2-methoxyphenyl isocyanate as a raw material according to the synthesis method of 1.2 in example 1]Phenyl radical]-3- (2-methoxyphenyl) urea, yield 66.2%. m.p. 208.8-210.1 ℃; MS (ESI) M/z (%): 500.3[ M-H]-。
1H NMR(400MHz,DMSO)δ13.98(s,1H,),9.46(s,1H),8.46(s,1H),8.29(s,1H),8.15(d,J＝7.8Hz,1H),7.47(d,J＝8.3Hz,2H),7.29(d,J＝8.1Hz,2H),7.03(d,J＝7.4Hz,1H),6.98–6.93(m,1H),6.90(t,J＝7.7Hz,1H),3.89(s,3H),3.79(s,4H),3.51(s,4H).
EXAMPLE 71 preparation of- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2, 6-dimethylphenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophen-3-yl is prepared by using 2, 6-dimethylphenyl isocyanate as a raw material according to the synthesis method of 1.2 in example 1]Phenyl radical]-3- (2, 6-dimethylphenyl) urea in 65.2% yield. m.p. 244.5-245.8 ℃; MS (ESI) M/z (%): 522.3[ M + Na%]+。
1H NMR(400MHz,DMSO)δ13.99(s,1H),9.25(s,1H),8.45(s,1H),8.08(s,1H),7.47(d,J＝8.4Hz,2H),7.25(d,J＝8.0Hz,2H),7.11–7.00(m,3H),3.79(s,4H),3.51(s,4H),2.22(s,6H).
EXAMPLE 81 preparation of- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (2-chloro-5-trifluoromethylphenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophene-3-yl is prepared by using 2-chloro-5-trifluoromethyl phenyl isocyanate as a raw material and adopting the synthesis method of 1.2 in the embodiment 1]Phenyl radical]-3- (2-chloro-5-trifluoromethylphenyl) urea in 59.4% yield. m.p. 244.5-245.7 ℃; MS (ESI) M/z (%): 572.3[ M-H]-。
1H NMR(400MHz,DMSO)δ13.99(s,1H),9.78(s,1H),8.46(s,3H),7.94(d,J＝8.3Hz,1H),7.62(d,J＝8.2Hz,1H),7.51(d,J＝8.4Hz,2H),7.32(d,J＝8.1Hz,2H),3.79(s,4H),3.51(s,4H).
EXAMPLE 91 preparation of- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (3, 5-difluorophenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophen-3-yl is prepared by using 3, 5-fluorophenyl isocyanate as a raw material according to the synthesis method of 1.2 in example 1]Phenyl radical]-3- (3, 5-difluorophenyl) urea, yield 81.2%. m.p. 223.2-225.0 ℃; MS (ESI) M/z (%): 506.3[ M-H]-。
1H NMR(400MHz,DMSO)δ14.00(s,1H),9.89(s,1H),8.76(s,1H),8.65(s,1H),8.46(s,1H),7.72(d,J＝8.4Hz,1H),7.51(d,J＝8.4Hz,2H),7.38(d,J＝8.2Hz,1H),7.32(d,J＝8.0Hz,2H),3.80(s,4H),3.51(s,4H).
EXAMPLE 101 preparation of- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -3- (3-chloro-4-fluorophenyl) urea
1- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophene-3-yl is prepared by using 3-chloro-4-fluorophenyl isocyanate as a raw material and adopting the synthesis method 1.2 in the embodiment 1]Phenyl radical]-3- (3-chloro-4-fluorophenyl) urea in a yield of 72.1%. m.p. 238.7-240.4 ℃; MS (ESI) M/z (%): 522.3[ M-H]-。
1H NMR(400MHz,DMSO)δ14.02(s,1H),9.57(s,1H),9.41(s,1H),8.46(s,1H),7.81(d,J＝7.5Hz,1H),7.47(d,J＝8.4Hz,2H),7.34(s,1H),7.31(d,J＝8.6Hz,2H),7.28(s,1H),3.79(s,4H),3.51(s,4H).
EXAMPLE 11 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2-benzylidenehydrazine-1-carboxamide
11.1 preparation of N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] hydrazinecarboxamide (intermediate 1l)
11.1.1 preparation of phenyl [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] carbamate (1k)
4.2g (12.0mmol) of the intermediate 1 was added to 80mL of acetone at room temperature, and 2.3mL (18.0mmol) of phenyl chloroformate was gradually added dropwise, and the reaction was carried out at room temperature for 3 hours after completion of the dropwise addition. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 50mL of water was added to the residue, and the mixture was extracted with dichloromethane (3X 10mL), the organic layers were combined, washed with water (2X 10mL) and saturated brine in this order (2X 10mL), dried, and dichloromethane was evaporated to dryness to obtain 4.1g of a white solid with a yield of 73.2%.
11.1.2 preparation of N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophen-3-yl ] phenyl ] hydrazine formamide (1l)
2.8g (6.0mmol) of intermediate 1l are added to 50mL1, 4-dioxane at room temperature, 1.0mL (12.0mmol) of 80% hydrazine hydrate are gradually added dropwise, and reaction is carried out for 2h at 100 ℃. After the reaction, 2.1g of white solid was obtained by suction filtration and drying, with a yield of 85.3%.
11.2 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2-benzylidene hydrazine-1-carboxamide
Intermediate 1l (5.0mmol), 1.0mL glacial acetic acid and benzaldehyde.6.0 mmol) were added to 10mL ethanol at room temperature and reacted at 80 ℃ for 5 h. After the reaction, filtering and drying to obtain white solid.
The yield thereof was found to be 64.5%. m.p. 241.8-243.6 ℃; MS (ESI) M/z (%): 521.3[ M + Na%]+。
1H NMR(400MHz,DMSO)δ14.00(s,1H),10.80(s,1H),9.03(s,1H),8.46(s,1H),7.97(s,1H),7.86(d,J＝6.9Hz,2H),7.68(d,J＝8.3Hz,2H),7.47–7.36(m,3H),7.32(d,J＝8.1Hz,2H),3.80(s,4H),3.52(s,4H).
EXAMPLE 12 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (4-fluorobenzylidene) hydrazine-1-carboxamide
Using 4-fluorobenzaldehyde as a raw material, preparing (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophen-3-yl by the synthetic method of 11.2 in example 11]Phenyl radical]-2- (4-fluorobenzylidene) hydrazine-1-carboxamide in 74.2% yield. m.p. 239.1-240.7 ℃; MS (ESI) M/z (%): 515.4[ M-H]-。
1H NMR(400MHz,DMSO)δ13.99(s,1H),10.90(s,1H),9.08(s,1H),8.47(s,1H),8.02(s,1H),7.99(s,2H),7.66(d,J＝8.3Hz,2H),7.41(d,J＝8.3Hz,2H),7.32(d,J＝8.3Hz,2H),3.80(s,4H),3.52(s,4H).
EXAMPLE 13 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (3-bromobenzylidene) hydrazine-1-carboxamide
3-bromobenzaldehyde is used as a raw material, and the (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophene-3-yl is prepared by the synthetic method of 11.2 in the example 11]Phenyl radical]-2- (3-bromobenzylidene) hydrazine-1-carboxamide in 75.2% yield. m.p. 240.1-241.5 ℃; MS (ESI) M/z (%): 575.3[ M-H]-。
1H NMR(400MHz,DMSO)δ13.99(s,1H),10.91(s,1H),9.14(s,1H),8.45(s,1H),8.18(s,1H),7.93(s,1H),7.78(d,J＝7.8Hz,1H),7.66(d,J＝8.5Hz,2H),7.56(d,J＝8.0Hz,1H),7.38(t,J＝7.8Hz,1H),7.31(d,J＝8.3Hz,2H),3.82–3.77(m,4H),3.54–3.49(m,4H).
EXAMPLE 14 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (3-hydroxybenzylidene) hydrazine-1-carboxamide
Using 3-hydroxybenzaldehyde as raw material, according to the synthesis method of 11.2 in example 11, (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophen-3-yl is prepared]Phenyl radical]-2- (3-hydroxybenzylidene) hydrazine-1-carboxamide in 61.5% yield. m.p. 241.7-242.5 ℃; MS (ESI) M/z (%): 513.3[ M-H]-。
1H NMR(400MHz,DMSO)δ13.99(s,1H),10.72(s,1H),9.54(s,1H),8.98(s,1H),8.46(s,1H),7.88(s,1H),7.66(d,J＝8.5Hz,2H),7.31(d,J＝8.4Hz,2H),7.27–7.19(m,3H),6.81(d,J＝7.4Hz,1H),3.80(s,4H),3.51(s,4H).
EXAMPLE 15 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (4-methoxybenzylidene) hydrazine-1-carboxamide
The (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophen-3-yl is prepared by the synthetic method of 11.2 in example 11 using 4-methoxybenzaldehyde as a raw material]Phenyl radical]-2- (4-methoxybenzylidene) hydrazine-1-carboxamide in 77.3% yield. m.p. 255.6-257.7 ℃; MS (ESI) M/z (%): 527.4[ M-H]-。
1H NMR(400MHz,DMSO)δ14.00(s,1H),10.67(s,1H),8.98(s,1H),8.47(s,1H),7.92(s,1H),7.80(d,J＝8.7Hz,2H),7.68(d,J＝8.5Hz,2H),7.32(d,J＝8.5Hz,2H),6.99(d,J＝8.8Hz,2H),3.81(s,4H),3.79(s,3H),3.52(s,4H).
EXAMPLE 16 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (3, 4-dihydroxybenzenemethylene) hydrazine-1-carboxamide
Using 3, 4-dihydroxybenzaldehyde as raw material, and preparing (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophene-3-yl by the synthetic method of 11.2 in example 11]Phenyl radical]-2- (3, 4-dihydroxybenzenemethylene) hydrazine-1-carboxamide, yield 77.2%. 246.8-248.5 ℃ in m.p.; MS (ESI) M/z (%): 529.3[ M-H]-。
1H NMR(400MHz,DMSO)δ13.96(s,1H),10.52(s,1H),8.90(s,1H),8.43(s,1H),7.79(s,1H),7.66(d,J＝8.5Hz,2H),7.30(d,J＝8.5Hz,2H),7.26(d,J＝1.6Hz,1H),7.05(dd,J＝8.2,1.7Hz,1H),6.77(d,J＝8.1Hz,1H),3.80(s,4H),3.51(s,4H).
EXAMPLE 17 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (3-methoxy-4-hydroxybenzylidene) hydrazine-1-carboxamide
Starting from 3-methoxy-4-hydroxybenzaldehyde, as in example 11, 11.2 in the presence of a catalyst to obtain (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophene-3-yl]Phenyl radical]-2- (3-methoxy-4-hydroxybenzylidene) hydrazine-1-carboxamide in a yield of 78.9%. 254.6-256.3 ℃ in m.p.; MS (ESI) M/z (%): 543.2[ M-H)]-。
1H NMR(400MHz,DMSO)δ14.01(s,1H),10.62(s,1H),9.43(s,1H),8.98(s,1H),8.47(s,1H),7.86(s,1H),7.67(d,J＝8.3Hz,2H),7.49(d,J＝1.3Hz,1H),7.31(d,J＝8.2Hz,2H),7.13(dd,J＝8.1,1.6Hz,1H),6.81(d,J＝8.1Hz,1H),3.86(s,3H),3.80(s,4H),3.51(s,4H).
EXAMPLE 18 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (4-trifluoromethoxybenzylidene) hydrazine-1-carboxamide
The (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophen-3-yl is prepared by the synthetic method of 11.2 in the example 11 by using 4-trifluoromethoxybenzaldehyde as a raw material]Phenyl radical]-2- (4-trifluoromethoxybenzylidene) hydrazine-1-carboxamide in 85.5% yield. 269.7-271.4 ℃ in m.p.; MS (ESI) M/z (%): 581.2[ M-H]-。
1H NMR(400MHz,DMSO)δ13.99(s,1H),10.90(s,1H),9.08(s,1H),8.46(s,1H),8.01(d,J＝8.8Hz,2H),7.99(s,1H),7.67(d,J＝8.5Hz,2H),7.41(d,J＝8.3Hz,2H),7.32(d,J＝8.3Hz,2H),3.83–3.76(m,4H),3.55–3.49(m,4H).
EXAMPLE 19 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (2, 6-dichlorobenzylidene) hydrazine-1-carboxamide
2, 6-dichlorobenzaldehyde is used as a raw material, and the (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophene-3-yl is prepared by the synthetic method of 11.2 in the example 11]Phenyl radical]-2- (2, 6-dichlorobenzylidene) hydrazine-1-carboxamide in a yield of 76.5%. m.p. 258.7-260.1 ℃; MS (ESI) M/z (%): 589.8[ M + Na [)]+。
1H NMR(400MHz,DMSO)δ13.98(s,1H),11.16(s,1H),8.79(s,1H),8.45(s,1H),8.19(s,1H),7.59(t,J＝8.1Hz,4H),7.43(t,J＝8.1Hz,1H),7.29(d,J＝8.2Hz,2H),3.79(s,4H),3.51(s,4H).
EXAMPLE 20 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (4-hydroxy-3, 5-di-tert-butylbenzylidene) hydrazine-1-carboxamide
The (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl is prepared by the synthetic method of 11.2 in example 11 using 4-hydroxy-3, 5-di-tert-butylbenzaldehyde as a raw material]Phenyl radical]-2- (4-hydroxy-3, 5-di-tert-butylbenzylidene) hydrazine-1-carboxamide, yield 90.2%. m.p. of 274.0 to 275.9 ℃; MS (ESI) M/z (%): 649.5[ M + Na [)]+。
1H NMR(400MHz,DMSO)δ13.98(s,1H),10.56(s,1H),8.93(s,1H),8.46(s,1H),7.89(s,1H),7.63(d,J＝8.4Hz,2H),7.49(s,2H),7.32(s,1H),7.30(s,2H),3.80(s,4H),3.51(s,4H),1.42(s,18H).
EXAMPLE 21 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (3, 5-dimethyl-4-hydroxybenzylidene) hydrazine-1-carboxamide
Using 3, 5-dimethyl-4-hydroxybenzaldehyde as raw material, and preparing (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophen-3-yl group by the method of 11.2 in example 11]Phenyl radical]-2- (3, 5-dimethyl-4-hydroxybenzylidene) hydrazine-1-carboxamide in 82.4% yield. m.p. 258.1-259.9 ℃; MS (ESI) M/z (%): 565.5[ M + Na [)]+。
1H NMR(400MHz,DMSO)δ13.99(s,1H),10.55(s,1H),8.90(s,0H),8.63(s,1H),8.47(s,1H),7.81(s,1H),7.68(d,J＝8.5Hz,2H),7.41(s,2H),7.31(d,J＝8.5Hz,2H),3.80(s,4H),3.51(s,4H),2.20(s,6H).
EXAMPLE 22 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- (3,4, 5-trimethoxybenzylidene) hydrazine-1-carboxamide
Using 3,4, 5-trimethoxybenzaldehyde as raw material, and preparing (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophen-3-yl by the method of 11.2 in example 11]Phenyl radical]-2- (3,4, 5-trimethoxybenzylidene) hydrazine-1-carboxamide in 77.9% yield. m.p. 247.4-249.1 deg.C; MS (ESI) M/z (%): 587.4[ M-H]-。
1H NMR(400MHz,DMSO)δ10.81(s,1H),9.04(s,1H),8.47(s,1H),7.89(s,1H),7.66(d,J＝8.5Hz,2H),7.32(d,J＝8.5Hz,2H),7.15(s,2H),3.86(s,6H),3.80(s,4H),3.70(s,3H),3.51(s,4H).
EXAMPLE 23 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- [ (1H-pyrrol-2-yl) methylene ] hydrazine-1-carboxamide
2-Pyrrolecarboxaldehyde is used as a raw material, and the (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophene-3-yl is prepared by the synthetic method of 11.2 in the example 11]Phenyl radical]-2- [ (1H-pyrrol-2-yl) methylene]Hydrazine-1-carboxamide, yield 59.2%. 245.8-247.2 ℃ in m.p.; MS (ESI) M/z (%): 486.3[ M-H]-。
1H NMR(400MHz,DMSO)δ14.00(s,1H),11.51(s,1H),10.56(s,1H),9.03(s,1H),8.47(s,1H),7.76(s,1H),7.63(d,J＝8.4Hz,2H),7.33(d,J＝8.4Hz,2H),7.01(s,1H),6.38(s,1H),6.12(dd,J＝5.4,2.4Hz,1H),3.80(s,4H),3.52(s,4H).
EXAMPLE 24 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- [ (furan-2-yl) methylene ] hydrazine-1-carboxamide
2-Furancarbaldehyde is used as a raw material, and the (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazole-3-yl) thiophene-3-yl is prepared according to the synthesis method of 11.2 in the example 11]Phenyl radical]-2- [ (furan-2-yl) methylene]Hydrazine-1-carboxamide, yield 66.8%. 246.7-248.3 ℃ in m.p.; MS (ESI) M/z (%): 511.2[ M + Na [)]+。
1H NMR(400MHz,DMSO)δ14.01(s,1H),10.76(s,1H),8.81(s,1H),8.46(s,1H),8.18(s,1H),7.63(d,J＝5.0Hz,1H),7.61(d,J＝8.2Hz,2H),7.44(d,J＝3.1Hz,1H),7.30(d,J＝7.7Hz,2H),7.12(dd,J＝4.9,3.7Hz,1H),3.83–3.76(m,4H),3.54–3.48(m,4H).
EXAMPLE 25 preparation of (E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1,2, 4-triazol-3-yl) thiophen-3-yl ] phenyl ] -2- [ (pyridin-2-yl) methylene ] hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1H-1, 2) was prepared from 2-pyridinecarboxaldehyde according to the synthesis method of 11.2 in example 114-Triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- [ (pyridin-2-yl) methylene]Hydrazine-1-carboxamide, yield 73.5%. m.p. 271.7-272.3 ℃; MS (ESI) M/z (%): 498.3[ M-H]-。
1H NMR(400MHz,DMSO)δ13.99(s,1H),10.97(s,1H),9.10(s,1H),9.01(s,1H),8.57(d,J＝3.8Hz,1H),8.47(s,1H),8.32(d,J＝7.9Hz,1H),7.99(s,1H),7.67(d,J＝8.4Hz,2H),7.45(dd,J＝7.8,4.8Hz,1H),7.32(d,J＝8.4Hz,2H),3.80(s,4H),3.52(s,4H).
In vitro antitumor cell Activity
The thiophene derivative of the formula I in the invention is subjected to in vitro screening for inhibiting the activity of human gastric cancer cells MKN-45, colon cancer cells HT-29 and lung cancer cells H460.
(1) After cells were thawed and passaged for 2-3 stabilities, they were digested from the bottom of the flask with trypsin solution (0.25%). After pouring the cell digest into the centrifuge tube, the culture medium is added to stop the digestion. Centrifuging the centrifuge tube at 800r/min for 10min, discarding supernatant, adding 5mL culture solution, blowing and beating the mixed cells, sucking 10 μ L cell suspension, adding into cell counting plate, counting, and adjusting cell concentration to 104Per well. 100. mu.L of the cell suspension was added to the 96-well plate except that the A1 well was a blank well and no cells were added. The 96-well plate was placed in an incubator for 24 h.
(2) The test sample was dissolved in 50. mu.L of dimethyl sulfoxide, and then an appropriate amount of culture solution was added to dissolve the sample to 2mg/mL of the liquid, and then the sample was diluted to 20,4,0.8,0.16, 0.032. mu.g/mL in a 24-well plate.
3 wells were added for each concentration, two columns of cells surrounding each, which were greatly affected by the environment, and only used as blank wells. The 96-well plate was placed in an incubator for 72 h.
(3) The drug-containing culture solution in the 96-well plate is discarded, the cells are washed twice by using Phosphate Buffer Solution (PBS), 100 mu L of MTT (tetrazole) (0.5mg/mL) is added into each well and put into an incubator for 4h, the MTT solution is discarded, and 100 mu L of dimethyl sulfoxide is added. And oscillating on a magnetic oscillator to fully dissolve the viable cells and the MTT reaction product formazan, and putting the formazan into an enzyme labeling instrument to measure the result. The drug can be determined by the Bliss methodThing IC50The value is obtained.
The results of the compound inhibiting the activity of human gastric cancer cell MKN-45, colon cancer cell HT-29 and lung cancer cell H460 take PF-4989216 as a positive control (see Table I).
Watch 1
Figure BDA0002247296930000251
Figure BDA0002247296930000261
PI3K alpha enzyme Activity assay
Since PI3K can phosphorylate PIP2 and convert it to PIP3, the inhibitory activity of PI3K is typically determined using a competitive fluorescence polarization kinase activity screening method. Specifically, PI3K was reacted at 50mM HEPES (pH 7.5),3mM MgCl21mM EGTA,100mM NaCl, 0.03% CHAPS and 25. mu.M ATP, PIP2 as substrate, and the final reaction volume was 10. mu.L. In the determination of the compounds of the examples, 2.5. mu.L of the corresponding PI3K enzyme and 50. mu.M of substrate were added to 10. mu.L of the reaction solution, as well as the compounds of the examples at a concentration between 0.16. mu.M and 10. mu.M. After 1 hour incubation at room temperature, the reaction was quenched with a chelator. Then the protein combined with phosphoinositide is added into the reaction system, and the phosphoinositide developing agent marked by the fluorophore is added after uniform mixing. The samples were placed in a 384 well blackboard and allowed to equilibrate for one hour. Finally, the polarization value is obtained by red fluorescence with a proper filter, and the obtained data is used for calculating IC50。
Inhibition data of example compounds and positive controls (PF-4989216 and PI103) on PI3K (see table two).
Table two:
Figure BDA0002247296930000271
from the above test results, it is clear that the compound of formula I to be protected by the present invention has good in vitro anti-tumor activity, comparable to or superior to that of the control drug PF-4989216.
While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims (9)

1. Compounds of the general formula I and pharmaceutically acceptable salts thereof,
Figure 441673DEST_PATH_IMAGE001
wherein:
r is selected from hydrogen
L is
Figure 15218DEST_PATH_IMAGE002
；
Ar is phenyl, pyridyl, furyl, thienyl, pyrrolyl, and Ar optionally 1-3 of the same or different R1Substitution;
R1is hydrogen, hydroxy, halogen, nitro, amino, cyano, methoxy, C1-C6Alkyl, halogenated C1-C6Alkyl or halogenated C1-C6An alkoxy group.
2. A compound of the general formula I according to claim 1, wherein,
R1is hydrogen, hydroxy, halogen, nitro, amino, cyano, methoxy, C1-C4Alkyl, halogenated C1-C4Alkyl or halogenated C1-C3An alkoxy group.
3. A compound of the general formula I according to claim 1 or 2, wherein,
R1is hydrogen, hydroxy, fluorine, chlorine, bromine, cyano, methyl, tert-butyl, methoxy, trifluoromethylA group consisting of trifluoromethoxy and trifluoromethoxy.
4. The following compounds and pharmaceutically acceptable salts:
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (4-hydroxy-3-methoxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (2, 4-dichlorobenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (2, 5-dimethoxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (4-hydroxy-3, 5-dibromobenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (4-hydroxy-3, 5-di-tert-butylbenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (3, 5-dimethyl-4-hydroxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (2-chloro-4-fluorobenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (2, 4-dihydroxybenzenemethylene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (3, 5-dimethoxy-4-hydroxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (3, 4-dihydroxybenzenemethylene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2-, (1H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (4-cyanobenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (4-trifluoromethoxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (3-methoxy-4-hydroxy-5-bromobenzyl methylene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (4-trifluoromethylbenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (3-bromo-4-hydroxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2-[（1H-pyrrol-2-yl) methylene]Hydrazine-1-carboxamides
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (3-fluoro-4-hydroxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- [ (furan-2-yl) methylene]Hydrazine-1-carboxamides
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (2,4, 6-trimethylbenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (2-fluorobenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (3-bromobenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (4-methoxybenzylidene) hydrazine-1-methylAmides of carboxylic acids
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (4-hydroxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (2, 6-dichlorobenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2-benzylidenehydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (3,4, 5-trimethoxybenzylidene) hydrazine-1-carboxamide
(E) -N- [4- [ 4-cyano-5-morpholino-2- (1)H-1,2, 4-triazol-3-yl) thiophen-3-yl]Phenyl radical]-2- (5-hydroxybenzylidene) hydrazine-1-carboxamide.
5. A pharmaceutical composition comprising a compound of any one of claims 1 to 4 and pharmaceutically acceptable salts thereof as an active ingredient together with pharmaceutically acceptable excipients.
6. The use of a compound according to any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 5, for the manufacture of a medicament for the treatment and/or prevention of proliferative diseases.
7. Use of a compound according to any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 5, for the preparation of a PI3K enzyme inhibitor.
8. Use of a compound according to any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 5, for the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
9. Use of a compound according to any one of claims 1 to 4 and pharmaceutically acceptable salts thereof or a pharmaceutical composition according to claim 5 for the manufacture of a medicament for the treatment and/or prophylaxis of ovarian, prostate, gastric, colon, lung cancer.
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