CN116023375A - Heterocyclic derivative, preparation method and application thereof - Google Patents
Heterocyclic derivative, preparation method and application thereof Download PDFInfo
- Publication number
- CN116023375A CN116023375A CN202211307952.9A CN202211307952A CN116023375A CN 116023375 A CN116023375 A CN 116023375A CN 202211307952 A CN202211307952 A CN 202211307952A CN 116023375 A CN116023375 A CN 116023375A
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- CN
- China
- Prior art keywords
- alkyl
- compound
- group
- cancer
- heteroaryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title claims abstract description 54
- 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims description 154
- -1 cyano, sulfonyl Chemical group 0.000 claims description 111
- 125000000217 alkyl group Chemical group 0.000 claims description 78
- 125000005843 halogen group Chemical group 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 6
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- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
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- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
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- 238000006722 reduction reaction Methods 0.000 claims description 4
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- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 2
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- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 2
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
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Landscapes
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Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to a heterocyclic derivative or pharmaceutically acceptable salt thereof serving as a glutaminase GLS1 inhibitor or pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a heterocyclic derivative serving as a glutaminase GLS1 inhibitor or pharmaceutically acceptable salt thereof, a preparation method and application thereof.
Background
In normal tissue cells, a common route for oxidative energy of three major organic substances (proteins, lipids and glucose) in the body is the tricarboxylic acid cycle, in which glucose is decomposed into adenosine triphosphate after a series of conversions to power the body; tumor cells grow rapidly and the energy supply requirement is higher than that of normal cells, so that hypoxia in the tumor microenvironment is caused to convert a main energy metabolism pathway into glycolysis, rapid but inefficient energy conversion is realized by converting glucose into lactose, and in some cases, the tumor cells still obtain energy mainly through substances metabolized by the glycolysis pathway even under the condition of sufficient oxygen, and the phenomenon is called the Warburg effect of tumor metabolism.
Glutamine is the most abundant free amino acid in body fluids, and is metabolized by Glutaminase (GLS) to produce glutamate, which is involved in substance synthesis, and can also be further metabolized to alpha-ketoglutarate (alpha-KG) to enter the tricarboxylic acid cycle to produce energy. Compared with normal tissues, the demand and consumption of GLS in most tumor cells are increased, so that the defect of insufficient metabolism of other substances caused by the deficiency of tricarboxylic acid circulation is overcome, the level of GLS is up-regulated by the tumor cells, and the conversion of glutamate into glutamate is increased to participate in the energy supply and the metabolism of the tricarboxylic acid circulation.
GLS can be classified into renal glutaminase (GLS 1) and hepatic glutaminase (GLS 2), and GLS1 is highly expressed and has a carcinomatous effect in most tumor cells, and GLS2 is low expressed and has a carcinomatous effect. GLS1 is a potential target for metabolic treatment of tumors, and specific inhibitors thereof have potential for treating diseases such as tumors.
Disclosure of Invention
The invention relates to a heterocyclic derivative serving as a GLS1 inhibitor, in particular to a heterocyclic derivative, a preparation method and medical application thereof, and particularly relates to a heterocyclic derivative shown in the following formula I and application thereof in preparing a medicament for GLS1 mediated diseases, and more particularly relates to application in preparing a medicament suitable for tumors.
An object of the present invention is to provide heterocyclic derivatives having the structure shown in formula I below, isomers thereof or pharmaceutically acceptable salts thereof:
wherein,,
a is selected from (C) 3 -C 8 ) Cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo groups;
l is selected from O and single bond;
X 1 、X 2 each independently selected from: s and ch=ch, and X 1 、X 2 S or ch=ch at different times;
R 1 selected from: (C) 1 -C 6 ) Alkyl, (C) 6 -C 10 ) Aryl (C) 1 -C 6 ) Alkyl, heteroaryl (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl (C) 1 -C 6 ) Alkyl or heterocycloalkyl (C) 1 -C 6 ) An alkyl group;
wherein said (C) 1 -C 6 ) Alkyl, (C) 6 -C 10 ) Aryl (C) 1 -C 6 ) Alkyl, heteroaryl (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl (C) 1 -C 6 ) Alkyl, heterocycloalkyl (C) 1 -C 6 ) Alkyl is unsubstituted or substituted with one or more substituents optionally selected from the group consisting of: halogen, hydroxy, cyano, sulfonyl, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy, (C) 1 -C 6 ) Alkoxy (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkoxy, halo (C) 1 -C 6 ) Alkoxy (C) 1 -C 6 ) Alkyl, (C) 6 -C 10 ) Aryl, (C) 6 -C 10 ) Aryl (C) 1 -C 6 ) Alkyl, (C) 6 -C 10 ) Aryloxy, (C) 6 -C 10 ) Aryloxy group (C) 1 -C 6 ) Alkyl, heteroaryl (C) 1 -C 6 ) Alkyl, heteroaryloxy (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, (C) 3 -C 8 ) Cycloalkyl (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyloxy, (C) 3 -C 8 ) Cycloalkyloxy (C) 1 -C 6 ) Alkyl, halo (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl (C) 1 -C 6 ) Alkyl, halo (C) 3 -C 8 ) Cycloalkyloxy, halo (C) 3 -C 8 ) Cycloalkyloxy (C) 1 -C 6 ) Alkyl, heterocycloalkyl (C) 1 -C 6 ) Alkyl, heterocycloalkyloxy (C) 1 -C 6 ) Alkyl, haloheterocycloalkyl (C) 1 -C 6 ) Alkyl, haloheterocycloalkyloxy and haloheterocycloalkyloxy (C) 1 -C 6 ) An alkyl group;
R 2 selected from heteroaryl, said heteroaryl being unsubstituted or substituted with one or more substituents optionally selected from: halogen, cyano, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy, halo (C) 1 -C 6 ) Alkyl or halo (C) 1 -C 6 ) An alkoxy group;
the heteroaryl is a 5-8 membered heteroaryl monocyclic ring having 1 or 2 groups selected from N, O, S;
the heterocycloalkyl group is a 3-8 membered ring having 1 or 2 rings selected from N, O, S.
Preferably, the compound of formula I, an isomer thereof or a pharmaceutically acceptable salt thereof, a is selected from cyclopropyl, cyclobutyl, wherein said cyclopropyl, cyclobutyl is unsubstituted or substituted by one or more fluoro.
Preferably, the compound of formula I, an isomer thereof or a pharmaceutically acceptable salt thereof,
R 1 selected from: (C) 1 -C 6 ) Alkyl, (C) 6 -C 10 ) Aryl (C) 1 -C 6 ) Alkyl, heteroaryl (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl (C) 1 -C 6 ) Alkyl or heterocycloalkyl (C) 1 -C 6 ) An alkyl group;
wherein said (C) 1 -C 6 ) Alkyl, (C) 6 -C 10 ) Aryl (C) 1 -C 6 ) Alkyl, heteroaryl (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl (C) 1 -C 6 ) Alkyl, heterocycloalkyl (C) 1 -C 6 ) Alkyl is unsubstituted or substituted with one or more substituents optionally selected from the group consisting of: halogen, cyano, sulfonyl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutoxy or
Preferably, the compound of formula I, an isomer thereof or a pharmaceutically acceptable salt thereof,
R 2 selected from pyridinyl, which pyridinyl is unsubstituted or substituted with one or more substituents optionally selected from: fluorine, chlorine, cyano, methyl, methoxy, trifluoromethyl or trifluoromethoxy.
Preferably, the compound of formula I, an isomer thereof or a pharmaceutically acceptable salt thereof,
the heteroaryl is selected from: pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl.
Preferably, the compound of formula I, an isomer thereof or a pharmaceutically acceptable salt thereof,
the heterocycloalkyl group is selected from: tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl or morpholinyl.
More preferably, a compound of formula I, an isomer thereof or a pharmaceutically acceptable salt thereof,
wherein,,
a is selected from cyclopropyl, cyclobutyl, wherein the cyclopropyl, cyclobutyl is unsubstituted or substituted by one or more fluoro;
l is selected from O or a single bond;
X 1 、X 2 each independently selected from: s and ch=ch, and X 1 、X 2 S or ch=ch at different times;
R 1 selected from: heteroaryl (C) 1 -C 6 ) An alkyl group; wherein the heteroaryl (C 1 -C 6 ) Alkyl is unsubstituted or optionally substituted with one or more substituents selected from the group consisting of: halogen, cyano, sulfonyl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutoxy or
R 2 Selected from: a pyridinyl group, said pyridinyl group being unsubstituted or substituted with one or more substituents optionally selected from: fluorine, chlorine, cyano, methyl, methoxy, trifluoromethyl or trifluoromethoxy.
The heteroaryl is selected from: pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl;
the heterocycloalkyl group is selected from: tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl or morpholinyl.
More preferably, the heterocyclic derivative with the structure shown in the formula I, an isomer thereof or a pharmaceutically acceptable salt thereof is selected from the following compounds:
the invention also provides a preparation method of the heterocyclic derivative with the structure shown in the formula I, which comprises the following steps:
the method comprises the following steps:
wherein LG represents a leaving group including, but not limited to, a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and the like. R is R 1 、R 2 、X 1 、X 2 A, L are defined above for heterocyclic derivatives of the structure shown in formula I;
(1) Reacting compound I-1 with compound I-2 to give I-3
The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, and any combination thereof, preferably N, N-dimethylformamide. The reaction is preferably carried out in the presence of a suitable condensing agent. The condensing agent may be selected from dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, 1-propylphosphoric anhydride, preferably 1-propylphosphoric anhydride. The reaction is preferably carried out in the presence of a suitable organic base. The organic base may be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, preferably diisopropylethylamine. The reaction is preferably carried out at a suitable temperature, preferably 20-50 ℃. The reaction is preferably carried out for a suitable time, for example 2 to 8 hours.
(2) The compound I-3 and the compound I-4 are subjected to coupling reaction to obtain I-5
The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, and any combination thereof, preferably tetrahydrofuran. The reaction is preferably carried out in the presence of a suitable catalyst. The catalyst may be selected from a variety of palladium catalysts, preferably bis triphenylphosphine palladium dichloride. The reaction is preferably carried out in the presence of a suitable base. The base may be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, preferably triethylamine. The reaction is preferably carried out at a suitable temperature, preferably 40-80 ℃. The reaction is preferably carried out for a suitable time, for example 8 to 12 hours.
(3) Subjecting the compound I-5 to reduction reaction to obtain I-6
The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, ethyl acetate, methanol, ethanol, and any combination thereof, preferably ethanol. The reaction is preferably carried out in the presence of a suitable catalyst. The catalyst may be selected from a variety of palladium catalysts, nickel catalysts, preferably palladium on carbon. The reaction is preferably carried out at a suitable temperature, preferably 20-40 ℃. The reaction is preferably carried out for a suitable time, for example 8 to 12 hours.
(4) The compound I-6 and the compound I-7 are subjected to ring closure reaction to obtain I-8
The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from trifluoroacetic acid, phosphorus oxychloride, preferably trifluoroacetic acid. The reaction is preferably carried out at a suitable temperature, preferably 40-80 ℃. The reaction is preferably carried out for a suitable time, for example 4-8 hours.
(5) Reacting the compound I-8 with the compound I-9 to obtain the heterocyclic derivative with the structure shown in the formula I
The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, and any combination thereof, preferably N, N-dimethylformamide. The reaction is preferably carried out in the presence of a suitable condensing agent. The condensing agent may be selected from dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, 1-propylphosphoric anhydride, preferably 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate. The reaction is preferably carried out in the presence of a suitable organic base. The organic base may be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, preferably diisopropylethylamine. The reaction is preferably carried out at a suitable temperature, preferably 20-50 ℃. The reaction is preferably carried out for a suitable time, for example 2 to 8 hours.
The second method is as follows:
wherein LG represents a leaving group including, but not limited to, a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and the like. R is R 1 、R 2 、X 1 、X 2 A, L are defined above for heterocyclic derivatives of the structure shown in formula I;
(1) The compound I-4 and the compound I-7 are subjected to ring closure reaction to obtain I-10
The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from trifluoroacetic acid, phosphorus oxychloride, preferably trifluoroacetic acid. The reaction is preferably carried out at a suitable temperature, preferably 40-80 ℃. The reaction is preferably carried out for a suitable time, for example 4-8 hours.
(2) Reacting compound I-10 with compound I-9 to give I-11
The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, and any combination thereof, preferably N, N-dimethylformamide. The reaction is preferably carried out in the presence of a suitable condensing agent. The condensing agent may be selected from dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, 1-propylphosphoric anhydride, preferably 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate. The reaction is preferably carried out in the presence of a suitable organic base. The organic base may be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, preferably diisopropylethylamine. The reaction is preferably carried out at a suitable temperature, preferably 20-50 ℃. The reaction is preferably carried out for a suitable time, for example 2 to 8 hours.
(3) Coupling the compound I-3 with the compound I-11 to obtain I-12
The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, 1, 4-dioxane, and any combination thereof, preferably tetrahydrofuran. The reaction is preferably carried out in the presence of a suitable catalyst. The catalyst may be selected from a variety of palladium catalysts, preferably bis triphenylphosphine palladium dichloride. The reaction is preferably carried out in the presence of a suitable base. The base may be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, preferably triethylamine. The reaction is preferably carried out at a suitable temperature, preferably 40-80 ℃. The reaction is preferably carried out for a suitable time, for example 8 to 12 hours.
(4) The heterocyclic derivative with the structure shown in the formula I is obtained by the reduction reaction of the compound I-12
The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, ethyl acetate, methanol, ethanol, and any combination thereof, preferably ethanol. The reaction is preferably carried out in the presence of a suitable catalyst. The catalyst may be selected from a variety of palladium catalysts, nickel catalysts, preferably palladium on carbon. The reaction is preferably carried out at a suitable temperature, preferably 20-40 ℃. The reaction is preferably carried out for a suitable time, for example 8 to 12 hours.
The specific conditions of each of the above reaction steps are well known in the art, and the present invention is not particularly limited thereto. The skilled artisan, in light of the teachings of the present invention in combination with the common general knowledge in the art, can choose to replace each substituent in the general formula to prepare different compounds, all of which are within the scope of the present invention.
The invention also relates to application of the compound shown in the formula I in preparing a medicament for preventing or treating diseases related to GLS 1.
In some embodiments, the GLS 1-associated disease or disorder is selected from a tumor or cancer, such as non-hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, oral cancer, brain cancer, gastric cancer, liver cancer, rectal cancer, pancreatic cancer, skin cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, fallopian tube tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma, mastoid malignancy, head and neck tumor, leukemia, or myeloma.
The invention discovers that a GLS1 inhibitor with a novel structure as shown in the formula I has better activity.
Detailed Description
In order to make the objects and technical solutions of the present invention more clear, the present invention is further described below with reference to specific examples. It is to be understood that these examples are for illustration of the invention only and are not intended to limit the scope of the invention. Moreover, the specific experimental methods not mentioned in the following examples were carried out according to conventional experimental methods.
In this application, when chemical names and structural formulas are not identical, the structural formulas should be taken as reference unless the context can infer that the chemical names, not the structural formulas, are correct.
Abbreviations herein have the following meanings:
| abbreviations (abbreviations) | Meaning of |
| DMSO-d 6 | Hexadeuterated dimethyl sulfoxide |
| TMS | Tetramethylsilane |
| 1 H NMR | Hydrogen spectrum |
| MS | Mass spectrometry |
| s | Singlet |
| d | Double peak |
| t | Triplet peak |
| q | Quadruple peak |
| dd | Double peak |
| m | Multiple peaks |
| br | Broad peak |
| J | Coupling constant |
| Hz | Hertz device |
The structure of the compound is characterized by Mass Spectrum (MS) or nuclear magnetic resonance 1 H NMR).
Nuclear magnetic resonance 1 H NMR) shift (delta) in parts per million (10) -6 Or ppm) is given in units of ppm); nuclear magnetic resonance 1 H NMR) was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) The internal standard is Tetramethylsilane (TMS).
The Mass Spectrum (MS) was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: therm, model: finnigan LCQ advantage MAX).
The thin silica gel layer is prepared from tobacco stage yellow sea HSGF254 or Qingdao GF254 silica gel plate.
Column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.
In the case where no specific explanation is given to the present invention, the reactions mentioned in the present invention are all carried out under a nitrogen atmosphere.
The term "nitrogen atmosphere" in the present invention means, for example, a 1L volume nitrogen balloon attached to a reaction flask.
The term "hydrogen atmosphere" in the present invention means, for example, a 1L volume hydrogen balloon connected to a reaction flask.
In the case where no specific explanation is given to the present invention, the solution mentioned in the reaction of the present invention is an aqueous solution.
The term "room temperature" in the present invention means that the temperature is between 10℃and 25 ℃.
Example 1 2 preparation of- (4-cyclopropylpyridin-2-yl) -N- (6- (4- (5- (2- (pyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (1)
The first step: preparation of N- (6-iodopyridazin-3-yl) -2- (4-cyclopropylpyridin-2-yl) acetamide (1 b)
2- (4-Cyclopropylpyridin-2-yl) acetic acid (0.53 g,3.0 mmol), 6-iodopyridazin-3-amine (0.64 g,2.9 mmol), N-diisopropylethylamine (0.7 mL,4.5 mmol) were dissolved in N, N-dimethylformamide (20 mL), and propylphosphonic anhydride solution (2 mL,50% N, N-dimethylformamide solution) was slowly added dropwise thereto and reacted at room temperature for 5 hours. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution, and the solid was precipitated, suction-filtered and the cake was dried to give the title compound 0.8g in a yield of 72.6%.
MS m/z(ES):381.0[M+1] +
And a second step of: preparation of 5- (but-3-yn-1-yl) -1,3, 4-thiadiazol-2-amine (1 d)
4-cyano-1-butyne (4.2 g,53.1 mmol), thiosemicarbazide (5.8 g,63.7 mmol) were dissolved in trifluoroacetic acid (50 mL) and the reaction mixture was heated to 65℃for 5 hours. The reaction solution was concentrated under reduced pressure, and 7.5% aqueous sodium hydrogencarbonate (100 mL) was added dropwise to the concentrate, followed by filtration and drying of the cake to give the title compound 5.3g, yield 65.2%
MS m/z(ES):154.0[M+1] +
And a third step of: preparation of N- (5- (but-3-yn-1-yl) -1,3, 4-thiadiazol-2-yl) -2- (pyridin-2-yl) acetamide (1 e)
5- (but-3-yn-1-yl) -1,3, 4-thiadiazol-2-amine (1.0 g,6.5 mmol) was dissolved in N, N-dimethylformamide (5 mL), 2- (pyridin-2-yl) acetic acid (0.89 g,6.5 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (2.97 g,7.8 mmol) and N, N-diisopropylethylamine (2.14 mL,13 mmol) were added in this order, and the reaction solution was stirred at 25℃for 3 hours. The reaction solution was poured into water, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the concentrate was purified by silica gel column chromatography (developing solvent: dichloromethane/methanol=10/1) to give the title compound 1.25g, yield 70.7%.
MS m/z(ES):273.1[M+1] +
Fourth step: preparation of 2- (4-cyclopropylpyridin-2-yl) -N- (6- (4- (5- (2- (pyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) but-1-yn-1-yl) pyridazin-3-yl) acetamide (1 f)
N- (6-iodopyridazin-3-yl) -2- (4-cyclopropylpyridin-2-yl) acetamide (700 mg,1.84 mmol), cuprous iodide (21 mg,0.11 mmol) and bis-triphenylphosphine palladium dichloride (40 mg,0.06 mmol) were dissolved in dry tetrahydrofuran (100 mL), and triethylamine (1 mL,7.37 mmol), N- (5- (but-3-yn-1-yl) -1,3, 4-thiadiazol-2-yl) -2- (pyridin-2-yl) acetamide (0.55 g,2.03 mmol) were added in this order under nitrogen protection, and the reaction mixture was heated to 80℃for 12 hours. The reaction solution was poured into water, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the concentrate was purified by silica gel column chromatography (developer: petroleum ether/ethyl acetate=2/1) to give the title compound in a yield of 65.2%.
MS m/z(ES):525.2[M+1] +
Fifth step: preparation of 2- (4-cyclopropylpyridin-2-yl) -N- (6- (4- (5- (2- (pyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (1)
2- (4-Cyclopropylpyridin-2-yl) -N- (6- (4- (5- (2- (pyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) but-1-yn-1-yl) pyridazin-3-yl) acetamide (200 mg,0.38 mmol) was dissolved in ethanol (100 mL), 10% palladium on carbon (0.04 g,0.38 mmol) was added thereto, and the mixture was allowed to react at room temperature under a hydrogen atmosphere for 12 hours. Filtration and concentration of the filtrate gave 50mg of the title compound in 24.9% yield by thin layer chromatography plate.
MS m/z(ES):529.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.68(s,1H),11.26(s,1H),8.51–8.46(m,1H),8.29(d,J＝5.2Hz,1H),8.20(d,J＝9.1Hz,1H),7.77(td,J＝7.7,1.9Hz,1H),7.55(d,J＝9.2Hz,1H),7.39(d,J＝7.8Hz,1H),7.30–7.26(m,1H),7.12(d,J＝1.8Hz,1H),6.95(dd,J＝5.2,1.8Hz,1H),4.00(s,2H),3.90(s,2H),3.03–2.99(m,2H),2.92–2.85(m,2H),1.95–1.88(m,1H),1.75–1.71(m,4H),1.10–0.97(m,2H),0.82–0.74(m,2H).
Example 2 2 preparation of- (4-Cyclobutoxypyridin-2-yl) -N- (6- (4- (5- (2- (pyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (2)
The first step: preparation of N- (6-iodopyridazin-3-yl) -2- (4-cyclobutoxy-pyridin-2-yl) acetamide (2 b)
2- (4-Cyclobutoxypyridin-2-yl) acetic acid (200 mg,0.97 mmol), 6-iodopyridazin-3-amine (213 mg,0.97 mmol), N-diisopropylethylamine (0.3 mL,1.94 mmol) were dissolved in N, N-dimethylformamide (10 mL), and a propylphosphonic anhydride solution (2 mL,50% N, N-dimethylformamide solution) was slowly added dropwise thereto and reacted at room temperature for 5 hours. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution, and the solid was separated out, suction-filtered and the cake was dried to give 50mg of the title compound in a yield of 12.6%.
MS m/z(ES):411.0[M+1] +
And a second step of: preparation of 2- (4-Cyclobutoxypyridin-2-yl) -N- (6- (4- (5- (2- (pyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) but-1-yn-1-yl) -pyridazin-3-yl) acetamide (2 c)
N- (6-iodopyridazin-3-yl) -2- (4-cyclobutoxy-pyridin-2-yl) acetamide (50 mg,0.12 mmol), cuprous iodide (1.37 mg, 0.0070 mmol) and bis triphenylphosphine palladium dichloride (2.6 mg, 0.04 mmol) were dissolved in dry tetrahydrofuran (5 mL), triethylamine (0.07 mL,0.48 mmol) and N- (5- (but-3-yn-1-yl) -1,3, 4-thiadiazol-2-yl) -2- (pyridin-2-yl) acetamide (36 g,0.13 mmol) were added in sequence under nitrogen protection, and the reaction mixture was heated to 80℃for 8 hours. The reaction solution was poured into water, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the concentrate was purified by silica gel column chromatography (developer: petroleum ether/ethyl acetate=2/1) to give the title compound 56.7mg, yield 85.2%.
MS m/z(ES):555.2[M+1] +
And a third step of: preparation of 2- (4-Cyclobutoxypyridin-2-yl) -N- (6- (4- (5- (2- (pyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) -pyridazin-3-yl) acetamide (2)
2- (4-Cyclobutoxypyridin-2-yl) -N- (6- (4- (5- (2- (pyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) but-1-yn-1-yl) -pyridazin-3-yl) acetamide (50 mg,0.09 mmol) was dissolved in ethanol (100 mL), 10% palladium on carbon (0.01 g,0.09 mmol) was added and the mixture was left to react at room temperature under a hydrogen atmosphere for 12 hours. Filtration and concentration of the filtrate gave the title compound in a yield of 19.9% by thin layer chromatography plate preparation.
MS m/z(ES):559.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.67(s,1H),11.26(s,1H),8.49(d,J＝4.8Hz,1H),8.28(d,J＝5.7Hz,1H),8.19(d,J＝9.2Hz,1H),7.77(td,J＝7.6,1.9Hz,1H),7.56(d,J＝9.2Hz,1H),7.39(d,J＝7.8Hz,1H),7.32–7.25(m,1H),6.90(d,J＝2.5Hz,1H),6.76(dd,J＝5.8,2.4Hz,1H),4.78(t,J＝7.1Hz,1H),4.00(s,2H),3.89(s,2H),3.01(s,2H),2.89(s,2H),2.44–2.41(m,2H),2.09–2.00(m,2H),1.81–1.77(m,4H),1.68–1.63(m,2H).
Example 3 2 preparation of- (4-cyclopropyl-6-methylpyridin-2-yl) -N- (6- (4- (5- (2- (pyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (3)
The first step: preparation of N- (6-iodopyridazin-3-yl) -2- (4-cyclopropyl-6-methylpyridin-2-yl) acetamide (3 b)
2- (4-cyclopropyl-6-methylpyridin-2-yl) acetic acid (0.5 g,2.6 mmol), 6-iodopyridazin-3-amine (0.58 g,2.6 mmol), N-diisopropylethylamine (0.7 mL,4.5 mmol) were dissolved in N, N-dimethylformamide (20 mL), and a propylphosphonic anhydride solution (2 mL,50% N, N-dimethylformamide solution) was slowly added dropwise thereto and reacted at room temperature for 5 hours. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution, and the solid was precipitated, suction-filtered and the cake was dried to give the title compound 0.75g in 73.2% yield.
MS m/z(ES):395.0[M+1] +
And a second step of: preparation of 2- (4-cyclopropyl-6-methylpyridin-2-yl) -N- (6- (4- (5- (2- (pyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) but-1-yn-1-yl) pyridazin-3-yl) acetamide (3 c)
N- (6-iodopyridazin-3-yl) -2- (4-cyclopropyl-6-methylpyridin-2-yl) acetamide (750 mg,1.9 mmol), cuprous iodide (21.7 mg,0.11 mmol) and bis-triphenylphosphine palladium dichloride (40 mg,0.06 mmol) were dissolved in dry tetrahydrofuran (100 mL), triethylamine (1 mL,7.37 mmol) and N- (5- (but-3-yn-1-yl) -1,3, 4-thiadiazol-2-yl) -2- (pyridin-2-yl) acetamide (0.55 g,2.03 mmol) were added in this order under nitrogen protection, and the reaction mixture was heated to 80℃for 12 hours. The reaction solution was poured into water, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the concentrate was purified by silica gel column chromatography (developer: petroleum ether/ethyl acetate=2/1) to give 640mg of the title compound in 62.5% yield.
MS m/z(ES):539.2[M+1] +
And a third step of: preparation of 2- (4-cyclopropyl-6-methylpyridin-2-yl) -N- (6- (4- (5- (2- (pyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (3)
2- (4-cyclopropyl-6-methylpyridin-2-yl) -N- (6- (4- (5- (2- (pyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) but-1-yn-1-yl) pyridazin-3-yl) acetamide (200 mg,0.37 mmol) was dissolved in ethanol (100 mL), 10% palladium on carbon (0.04 g,0.38 mmol) was added and the mixture was left to react at room temperature under a hydrogen atmosphere for 12 hours. Filtration and concentration of the filtrate gave the title compound 55mg, yield 27.4% by thin layer chromatography plate.
MS m/z(ES):543.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.66(s,1H),11.27(s,1H),8.48(dd,J＝5.1,1.8Hz,1H),8.19(d,J＝9.2Hz,1H),7.76(td,J＝7.7,1.9Hz,1H),7.55(d,J＝9.2Hz,1H),7.39(d,J＝7.8Hz,1H),7.28(dd,J＝7.6,4.8Hz,1H),6.91(d,J＝1.5Hz,1H),6.82(d,J＝1.6Hz,1H),4.00(s,2H),3.84(s,2H),3.00(s,2H),2.88(s,2H),2.36(s,3H),1.86(ddd,J＝13.2,8.5,4.9Hz,1H),1.73(p,J＝3.8Hz,4H),1.06–0.97(m,2H),0.86–0.71(m,2H).
Example 4 2 preparation of- (4-Cyclobutoxypyridin-2-yl) -N- (6- (4- (5- (2- (6-methylpyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (4)
The first step: preparation of N- (5- (but-3-yn-1-yl) -1,3, 4-thiadiazol-2-yl) -2- (6-methylpyridin-2-yl) acetamide (4 b)
5- (but-3-yn-1-yl) -1,3, 4-thiadiazol-2-amine (0.5 g,3.3 mmol) was dissolved in N, N-dimethylformamide (5 mL), 2- (6-methylpyridin-2-yl) acetic acid (0.49 g,3.3 mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.49 g,3.9 mmol) and N, N-diisopropylethylamine (1.1 mL,6 mmol) were sequentially added, and the reaction solution was stirred at 25℃for 5 hours. The reaction solution was poured into water, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the concentrate was purified by silica gel column chromatography (developing solvent: dichloromethane/methanol=10/1) to give the title compound in a yield of 0.67g, 70.7%.
MS m/z(ES):287.1[M+1] +
And a second step of: preparation of 2- (4-Cyclobutoxypyridin-2-yl) -N- (6- (4- (5- (2- (6-methylpyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) but-1-yn-1-yl) -pyridazin-3-yl) acetamide (4 c)
N- (6-iodopyridazin-3-yl) -2- (4-cyclobutoxy-pyridin-2-yl) acetamide (100 mg,0.24 mmol), cuprous iodide (2.74 mg,0.014 mmol) and bis triphenylphosphine palladium dichloride (5.2 mg,0.008 mmol) were dissolved in dry tetrahydrofuran (5 mL), triethylamine (0.14 mL,0.96 mmol) and N- (5- (but-3-yn-1-yl) -1,3, 4-thiadiazol-2-yl) -2- (6-methylpyridin-2-yl) acetamide (74.6 mg,0.26 mmol) were added in this order under nitrogen protection, and the reaction mixture was heated to 80℃for 8 hours. The reaction solution was poured into water, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the concentrate was purified by silica gel column chromatography (developer: petroleum ether/ethyl acetate=2/1) to give the title compound (103.4 mg, yield 75.7%).
MS m/z(ES):569.2[M+1] +
And a third step of: preparation of 2- (4-Cyclobutoxypyridin-2-yl) -N- (6- (4- (5- (2- (6-methylpyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) -pyridazin-3-yl) acetamide (4)
2- (4-Cyclobutoxypyridin-2-yl) -N- (6- (4- (5- (2- (6-methylpyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) but-1-yn-1-yl) -pyridazin-3-yl) acetamide (100 mg,0.18 mmol) was dissolved in ethanol (100 mL), 10% palladium on carbon (0.02 g,0.18 mmol) was added and the mixture was left to react at room temperature under a hydrogen atmosphere for 12 hours. Filtration and concentration of the filtrate gave 39mg of the title compound in 37.8% yield by thin layer chromatography plate.
MS m/z(ES):573.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.61(s,1H),11.26(s,1H),8.28(d,J＝5.7Hz,1H),8.19(d,J＝9.1Hz,2H),7.56(d,J＝9.2Hz,1H),7.16(dd,J＝15.3,7.7Hz,2H),6.89(s,1H),6.77–6.75(m,1H),4.77(t,J＝7.2Hz,1H),3.94(s,2H),3.89(s,2H),3.01(s,2H),2.89(s,2H),2.47–2.43(m,2H),2.42(s,3H),2.09–2.00(m,2H),1.84–1.60(m,6H).
Example 5 2 preparation of- (4-Cyclobutoxypyridin-2-yl) -N- (6- (4- (5- (2- (5-methoxypyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (5)
The title compound was prepared in the same manner as in example 4 using 2- (5-methoxypyridin-2-yl) acetic acid as a starting material.
MS m/z(ES):589.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.61(s,1H),11.26(s,1H),8.28(d,J＝5.7Hz,1H),8.19(dd,J＝6.0,3.1Hz,2H),7.56(d,J＝9.2Hz,1H),7.41–7.29(m,2H),6.89(d,J＝2.5Hz,1H),6.76(dd,J＝5.8,2.5Hz,1H),4.77(p,J＝7.2Hz,1H),3.91(d,J＝10.4Hz,4H),3.80(s,3H),3.01(s,2H),2.88(s,2H),2.47–2.41(m,2H),2.09–2.00(m,2H),1.84–1.60(m,6H).
Example 6 2 preparation of- (4-Cyclobutoxypyridin-2-yl) -N- (5- (4- (6- (2- (pyridin-2-yl) acetamido) pyridazin-3-yl) butyl) -1,3, 4-thiadiazol-2-yl) acetamide (6)
The first step: preparation of N- (6-iodopyridazin-3-yl) -2- (pyridin-2-yl) acetamide (6 b)
Pyridine-2-acetic acid (3.1 g,22.71 mmol), 6-iodopyridazin-3-amine (5 g,22.71 mmol), N-diisopropylethylamine (7.5 mL,45.42 mmol) were dissolved in N, N-dimethylformamide (100 mL), and a propylphosphonic anhydride solution (20 mL,50% N, N-dimethylformamide solution) was slowly added dropwise thereto and reacted at room temperature for 8 hours. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution, and the solid was separated out, suction-filtered and the cake was dried to give 6.8g of the title compound in 88.6% yield.
MS m/z(ES):341.0[M+1] +
And a second step of: preparation of N- (6- (4-cyanobut-1-yn-1-yl) pyridazin-3-yl) -2- (pyridin-2-yl) acetamide (6 c)
N- (6-iodopyridazin-3-yl) -2- (pyridin-2-yl) acetamide (6.3 g,18.43 mmol), cuprous iodide (0.21 g,1.11 mmol) and bis triphenylphosphine palladium dichloride (0.39 g,0.56 mmol) were dissolved in dry tetrahydrofuran (100 mL), triethylamine (10 mL,73.72 mmol) and 4-cyano-1-butyne (1.6 g,20.27 mmol) were added in this order under nitrogen protection, and the reaction mixture was heated to 80℃to react for 12 hours. The reaction solution was poured into water, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the concentrate was purified by silica gel column chromatography (developer: petroleum ether/ethyl acetate=1/1) to give the title compound 3.8g, yield 70.1%.
MS m/z(ES):292.1[M+1] +
And a third step of: preparation of N- (6- (4-cyanobutyl) pyridazin-3-yl) -2- (pyridin-2-yl) acetamide (6 d)
N- (6- (4-Cyanobut-1-yn-1-yl) pyridazin-3-yl) -2- (pyridin-2-yl) acetamide (3.5 g,12.03 mmol) was dissolved in ethanol (100 mL), 10% palladium on carbon (1.0 g,12.03 mmol) was added, and the mixture was allowed to react at room temperature under a hydrogen atmosphere for 12 hours. Filtration and concentration of the filtrate gave 3.4g of the title compound in 95.8% yield.
MS m/z(ES):296.1[M+1] +
Fourth step: preparation of N- (6- (4- (5-amino-1, 3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) -2- (pyridin-2-yl) acetamide (6 e)
N- (6- (4-Cyanobutyl) pyridazin-3-yl) -2- (pyridin-2-yl) acetamide (3.3 g,11.1 mmol) and thiosemicarbazide (1.2 g,13.32 mmol) were dissolved in trifluoroacetic acid (50 mL) and the reaction mixture was heated to 65℃for 5 hours. The reaction solution was concentrated under reduced pressure, and 7.5% aqueous sodium hydrogencarbonate (100 mL) was added dropwise to the concentrate, followed by filtration and drying of the cake to give 3.1g of the title compound in 75.6% yield
MS m/z(ES):370.1[M+1] +
Fifth step: preparation of 2- (4-Cyclobutoxypyridin-2-yl) -N- (5- (4- (6- (2- (pyridin-2-yl) acetamido) pyridazin-3-yl) butyl) -1,3, 4-thiadiazol-2-yl) acetamide (6)
N- (6- (4- (5-amino-1, 3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) -2- (pyridin-2-yl) acetamide (100 mg,0.27 mmol) was dissolved in N, N-dimethylformamide (5 mL), 2- (4-cyclobutoxy-pyridin-2-yl) acetic acid (55.95 mg,0.27 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (123 mg,0.32 mmol) and N, N-diisopropylethylamine (0.15 mL,0.88 mmol) were sequentially added, and the reaction solution was stirred at 25℃for 5 hours. The reaction solution was poured into water, extracted 3 times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 12.8mg, yield 8.5% by thin layer chromatography.
MS m/z(ES):559.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.63(s,1H),11.29(s,1H),8.50(dt,J＝4.9,1.3Hz,1H),8.26(d,J＝5.7Hz,1H),8.20(d,J＝9.1Hz,1H),7.76(td,J＝7.7,1.9Hz,1H),7.56(d,J＝9.2Hz,1H),7.43–7.37(m,1H),7.27(ddd,J＝7.6,4.9,1.2Hz,1H),6.89(d,J＝2.4Hz,1H),6.77(dd,J＝5.7,2.5Hz,1H),4.78(p,J＝7.2Hz,1H),3.98(s,2H),3.92(s,2H),3.31(s,2H),3.01(s,2H),2.88(s,2H),2.47–2.41(m,2H),2.09–1.98(m,2H),1.76–1.72(m,4H).
Example 72 preparation of- (4-Cyclobutoxypyridin-2-yl) -N- (5- (4- (6- (2- (3-trifluoromethoxyphenyl) acetamido) pyridazin-3-yl) butyl) -1,3, 4-thiadiazol-2-yl) acetamide (7)
The first step: preparation of N- (6-iodopyridazin-3-yl) -2- (3-trifluoromethoxyphenyl) acetamide (3 b)
3-trifluoromethoxybenzeneacetic acid (5 g,22.71 mmol), 6-iodopyridazin-3-amine (5 g,22.71 mmol) and N, N-diisopropylethylamine (7.5 mL,45.42 mmol) were dissolved in N, N-dimethylformamide (100 mL), and a propylphosphonic anhydride solution (20 mL,50% N, N-dimethylformamide solution) was slowly added dropwise thereto and reacted at room temperature for 5 hours. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution, and the solid was precipitated, suction-filtered and the cake was dried to give 7.8g of the title compound in a yield of 81.2%.
MS m/z(ES):424.0[M+1] +
And a second step of: preparation of N- (6- (4-cyanobut-1-yn-1-yl) pyridazin-3-yl) -2- (3-trifluoromethoxyphenyl) acetamide (3 c)
N- (6-iodopyridazin-3-yl) -2- (3-trifluoromethoxyphenyl) acetamide (7.8 g,18.43 mmol), cuprous iodide (0.21 g,1.11 mmol) and bis triphenylphosphine palladium dichloride (0.39 g,0.56 mmol) were dissolved in dry tetrahydrofuran (100 mL), triethylamine (10 mL,73.72 mmol) and 4-cyano-1-butyne (1.6 g,20.27 mmol) were added in this order under nitrogen protection, and the reaction mixture was heated to 80℃to react for 12 hours. The reaction solution was poured into water, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the concentrate was purified by silica gel column chromatography (developer: petroleum ether/ethyl acetate=2/1) to give the title compound (4.5 g, yield 65.2%).
MS m/z(ES):375.1[M+1] +
And a third step of: preparation of N- (6- (4-cyanobutyl) pyridazin-3-yl) -2- (3-trifluoromethoxyphenyl) acetamide (3 d)
N- (6- (4-Cyanobut-1-yn-1-yl) pyridazin-3-yl) -2- (3-trifluoromethoxyphenyl) acetamide (4.5 g,12.03 mmol) was dissolved in ethanol (100 mL), 10% palladium on carbon (1.0 g,12.03 mmol) was added, and the mixture was allowed to react at room temperature under a hydrogen atmosphere for 12 hours. Filtration and concentration of the filtrate gave 4.2g of the title compound in 93.3% yield.
MS m/z(ES):379.1[M+1] +
Fourth step: preparation of N- (6- (4- (5-amino-1, 3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) -2- (3-trifluoromethoxyphenyl) acetamide (3 e)
N- (6- (4-Cyanobutyl) pyridazin-3-yl) -2- (3-trifluoromethoxyphenyl) acetamide (4.2 g,11.1 mmol) and thiosemicarbazide (1.2 g,13.32 mmol) were dissolved in trifluoroacetic acid (50 mL), and the reaction mixture was heated to 65℃for 5 hours. The reaction solution was concentrated under reduced pressure, and 7.5% aqueous sodium hydrogencarbonate (100 mL) was added dropwise to the concentrate, followed by filtration and drying of the cake to give 3.5g of the title compound in 69.8% yield
MS m/z(ES):453.1[M+1] +
Fifth step: preparation of 2- (4-Cyclobutoxypyridin-2-yl) -N- (5- (4- (6- (2- (3-trifluoromethoxyphenyl) acetamido) pyridazin-3-yl) butyl) -1,3, 4-thiadiazol-2-yl) acetamide (3)
N- (6- (4- (5-amino-1, 3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) -2- (3-trifluoromethoxyphenyl) acetamide (100 mg,0.22 mmol) was dissolved in N, N-dimethylformamide (5 mL), 2- (4-cyclobutoxy-pyridin-2-yl) acetic acid (45.59 mg,0.22 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (100 mg,0.26 mmol) and N, N-diisopropylethylamine (0.15 mL,0.88 mmol) were sequentially added, and the reaction solution was stirred at 25℃for 5 hours. The reaction solution was poured into water, extracted 3 times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound 20mg, yield 14.2% by thin layer chromatography.
MS m/z(ES):642.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.59(s,1H),11.31(s,1H),8.26(d,J＝5.7Hz,1H),8.18(d,J＝9.2Hz,1H),7.55(d,J＝9.2Hz,1H),7.46(t,J＝8.1Hz,1H),7.37(dd,J＝7.5,1.5Hz,2H),7.29–7.22(m,1H),6.88(d,J＝2.5Hz,1H),6.77(dd,J＝5.8,2.5Hz,1H),4.77(p,J＝7.2Hz,1H),3.91(s,2H),3.85(s,2H),3.01(q,J＝5.1,3.9Hz,2H),2.87(d,J＝7.0Hz,2H),2.46–2.39(m,2H),2.09–2.01(m,2H),1.84–1.60(m,6H).
Example 8 2 preparation of- (4-Cyclobutoxypyridin-2-yl) -N- (5- (4- (6- (2- (3-methylsulfonylphenyl) acetamido) pyridazin-3-yl) butyl) -1,3, 4-thiadiazol-2-yl) acetamide (8)
The title compound was prepared in the same manner as in example 7 using 2- (3-methylsulfonylphenyl) acetic acid as a starting material.
MS m/z(ES):589.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.61(s,1H),11.33(s,1H),8.28(d,J＝5.7Hz,1H),8.20(d,J＝9.2Hz,1H),7.57(d,J＝9.2Hz,1H),7.48(t,J＝8.1Hz,1H),7.39(dd,J＝7.5,1.5Hz,2H),7.30–7.24(m,1H),6.90(d,J＝2.5Hz,1H),6.79(dd,J＝5.8,2.5Hz,1H),4.79(p,J＝7.2Hz,1H),3.93(s,2H),3.87(s,2H),3.35(s,3H),3.03(q,J＝5.1,3.9Hz,2H),2.89(d,J＝7.0Hz,2H),2.48–2.41(m,2H),2.11–2.05(m,2H),1.86–1.64(m,6H).
Example 9 2 preparation of- (5-cyclopropylpyridin-2-yl) -N- (6- (4- (5- (2- (pyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (9)
The title compound was prepared in the same manner as in example 1 using 2- (5-cyclopropylpyridin-2-yl) acetic acid as a starting material.
MS m/z(ES):529.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.68(s,1H),11.28(s,1H),8.50(dd,J＝5.0,1.7Hz,1H),8.36(d,J＝2.4Hz,1H),8.18(d,J＝9.1Hz,1H),7.79(td,J＝7.7,1.9Hz,1H),7.56(d,J＝9.2Hz,1H),7.46(dd,J＝7.9,2.4Hz,1H),7.41(d,J＝7.8Hz,1H),7.35–7.28(m,2H),4.01(s,2H),3.95(s,2H),3.03–3.00(m,2H),2.89–2.87(m,2H),1.99–1.92(m,1H),1.76–1.71(m,4H),1.04–0.95(m,2H),0.77–0.69(m,2H).
Example 10 preparation of 2- (4-Cyclobutoxypyridin-2-yl) -N- (6- (4- (5- (2- (pyridin-3-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (10)
The title compound was prepared in the same manner as in example 4 using 2- (pyridin-3-yl) acetic acid as a starting material.
MS m/z(ES):559.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.79(s,1H),11.54(s,1H),8.73–8.68(m,3H),8.20–8.11(m,2H),7.74(dd,J＝8.0,5.3Hz,1H),7.61(d,J＝9.2Hz,1H),7.48(d,J＝2.7Hz,1H),7.37(dd,J＝6.8,2.7Hz,1H),5.04(p,J＝7.2Hz,1H),4.28(s,2H),4.03(s,2H),3.03(s,2H),2.90(s,2H),2.54–2.51(m,2H),2.17–2.12(m,2H),1.88–1.64(m,6H).
Example 11 preparation of 2- (4-Cyclobutoxypyridin-2-yl) -N- (6- (4- (5- (2- (4-fluoropyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (11)
The title compound was prepared in the same manner as in example 4 using 2- (4-fluoropyridin-2-yl) acetic acid as a starting material.
MS m/z(ES):577.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.64(s,1H),11.26(s,1H),8.53(dd,J＝9.0,5.7Hz,1H),8.28(d,J＝5.7Hz,1H),8.19(d,J＝9.2Hz,1H),7.56(d,J＝9.2Hz,1H),7.35(dd,J＝10.2,2.6Hz,1H),7.25(ddd,J＝8.6,5.7,2.5Hz,1H),6.90(d,J＝2.4Hz,1H),6.76(dd,J＝5.8,2.5Hz,1H),4.77(p,J＝7.2Hz,1H),4.04(s,2H),3.90(s,2H),3.02(s,2H),2.88(s,2H),2.47–2.38(m,2H),2.09–1.99(m,2H),1.84–1.59(m,6H).
Example 12 preparation of N- (6- (4- (5-acetamido-1, 3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) -2- (4-cyclobutoxy-pyridin-2-yl) -acetamide (12)
The title compound was obtained in the same manner as in example 4 using acetic anhydride as a starting material.
MS m/z(ES):482.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.37(s,1H),11.27(s,1H),8.28(d,J＝5.7Hz,1H),8.20(d,J＝9.1Hz,1H),7.56(d,J＝9.2Hz,1H),6.90(d,J＝2.5Hz,1H),6.76(dd,J＝5.8,2.5Hz,1H),4.77(p,J＝7.1Hz,1H),3.90(s,2H),3.01(s,2H),2.88(s,2H),2.46–2.41(m,2H),2.15(s,3H),2.09–1.99(m,2H),1.81–1.60(m,6H).
Example 13 preparation of 2- (4-cyclopropylpyridin-2-yl) -N- (6- (4- (5- (2- (5-methoxypyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (13)
The first step: preparation of 2- (4-cyclopropylpyridin-2-yl) -N- (6- (4- (5- (2- (5-methoxypyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) but-1-yn-1-yl) -pyridazin-3-yl) acetamide (13 a)
Intermediate 5b (72.6 mg,0.24 mmol), cuprous iodide (2.74 mg,0.014 mmol) and bis-triphenylphosphine palladium dichloride (5.2 mg,0.008 mmol) were dissolved in dry tetrahydrofuran (5 mL), triethylamine (0.14 mL,0.96 mmol) and intermediate 1b (98.9 mg,0.26 mmol) were added in sequence under nitrogen protection, and the reaction mixture was heated to 80℃for 8 hours. The reaction solution was poured into water, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the concentrate was purified by silica gel column chromatography (developer: petroleum ether/ethyl acetate=2/1) to give the title compound (100.8 mg, yield 75.7%).
MS m/z(ES):555.2[M+1] +
And a second step of: preparation of 2- (4-cyclopropylpyridin-2-yl) -N- (6- (4- (5- (2- (5-methoxypyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (13)
2- (4-Cyclopropylpyridin-2-yl) -N- (6- (4- (5- (2- (5-methoxypyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) but-1-yn-1-yl) -pyridazin-3-yl) acetamide (100 mg,0.18 mmol) was dissolved in ethanol (100 mL), 10% palladium on carbon (0.02 g,0.18 mmol) was added, and the mixture was left to react at room temperature under a hydrogen atmosphere for 12 hours. Filtration and concentration of the filtrate gave 38.8mg of the title compound in 38.5% yield by thin layer chromatography plate.
MS m/z(ES):559.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.61(s,1H),11.25(s,1H),8.29(d,J＝5.3Hz,1H),8.19(dd,J＝6.1,3.2Hz,2H),7.55(d,J＝9.2Hz,1H),7.38–7.29(m,2H),7.12(s,1H),6.95(d,J＝5.2Hz,1H),3.91(d,J＝9.0Hz,4H),3.80(s,3H),3.02(s,2H),2.88(s,2H),1.95–1.88(m,1H),1.76–1.71(m,4H),1.05(dq,J＝6.7,4.3Hz,2H),0.81–0.76(m,2H).
Example 14 preparation of 2- (4-Cyclobutoxypyridin-2-yl) -N- (6- (4- (5- (2- (thiazol-2-yl) acetami-yl) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (14)
The title compound was prepared in the same manner as in example 4 using 2- (thiazol-2-yl) acetic acid as a starting material.
MS m/z(ES):565.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.65(s,1H),11.26(s,1H),8.28(d,J＝5.7Hz,1H),8.19(d,J＝9.1Hz,1H),7.75(d,J＝3.3Hz,1H),7.68(d,J＝3.3Hz,1H),7.56(d,J＝9.2Hz,1H),6.90(d,J＝2.4Hz,1H),6.76(dd,J＝5.7,2.4Hz,1H),4.78(p,J＝7.3Hz,1H),4.31(s,2H),3.89(s,2H),3.02(s,2H),2.89(s,2H),2.47–2.40(m,2H),2.09–2.00(m,2H),1.85–1.60(m,6H).
Example 15 preparation of 2- (4-Cyclobutoxypyridin-2-yl) -N- (6- (4- (5- (2- (6-methoxypyridin-3-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (15)
The title compound was prepared in the same manner as in example 4 using 2- (6-methoxy-3-yl) acetic acid as a starting material.
MS m/z(ES):589.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.65(s,1H),11.26(s,1H),8.28(d,J＝5.7Hz,1H),8.19(d,J＝9.2Hz,1H),8.08(d,J＝2.4Hz,1H),7.64(dd,J＝8.5,2.5Hz,1H),7.55(d,J＝9.1Hz,1H),6.90(d,J＝2.5Hz,1H),6.82–6.73(m,2H),4.77(p,J＝7.1Hz,1H),3.90(s,2H),3.82(s,3H),3.76(s,2H),3.01(s,2H),2.89(s,2H),2.47–2.41(m,2H),2.09–1.99(m,2H),1.84–1.61(m,6H).
EXAMPLE 16 preparation of 2- (4-cyclopropylpyridin-2-yl) -N- (6- (4- (5- (2- (pyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (16)
The title compound was prepared in the same manner as in example 2 using 2- (4-cyclopropoxy pyridin-2-yl) acetic acid as a starting material.
MS m/z(ES):545.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.67(s,1H),11.26(s,1H),8.49(d,J＝4.8Hz,1H),8.28(d,J＝5.7Hz,1H),8.19(d,J＝9.2Hz,1H),7.77(td,J＝7.6,1.9Hz,1H),7.56(d,J＝9.2Hz,1H),7.39(d,J＝7.8Hz,1H),7.32–7.25(m,1H),6.90(d,J＝2.5Hz,1H),6.76(dd,J＝5.8,2.4Hz,1H),4.78(t,J＝7.1Hz,1H),4.00(s,2H),3.89(s,2H),3.01(s,2H),2.89(s,2H),2.44–2.41(m,2H),2.09–2.00(m,2H),1.81–1.77(m,4H).
EXAMPLE 17 preparation of 2- (4-Cyclobutoxypyridin-2-yl) -N- (6- (4- (5- (2- (4-methoxypyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (17)
The title compound was prepared in the same manner as in example 4 using 2- (4-methoxypyridin-2-yl) acetic acid as a starting material.
MS m/z(ES):589.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.65(s,1H),11.28(s,1H),8.30(dd,J＝5.8,2.1Hz,2H),8.19(d,J＝9.2Hz,1H),7.56(d,J＝9.2Hz,1H),7.00(d,J＝2.5Hz,1H),6.95–6.86(m,2H),6.79(dd,J＝5.8,2.5Hz,1H),4.77(p,J＝7.2Hz,1H),3.91(d,J＝10.4Hz,4H),3.80(s,3H),3.01(s,2H),2.88(s,2H),2.47–2.41(m,2H),2.09–2.00(m,2H),1.84–1.60(m,6H).
Example 18 preparation of 2- (4-Cyclobutoxypyridin-2-yl) -N- (6- (4- (5- (2- (5-fluoropyridin-2-yl) acetamido) -1,3, 4-thiadiazol-2-yl) butyl) pyridazin-3-yl) acetamide (18)
The title compound was prepared in the same manner as in example 4 using 2- (5-fluoropyridin-2-yl) acetic acid as a starting material.
MS m/z(ES):577.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.67(s,1H),11.28(s,1H),8.49(d,J＝3.0Hz,1H),8.31(d,J＝5.8Hz,1H),8.19(d,J＝9.1Hz,1H),7.71(td,J＝8.7,3.0Hz,1H),7.56(d,J＝9.2Hz,1H),7.48(dd,J＝8.7,4.6Hz,1H),6.94(d,J＝2.4Hz,1H),6.81(dd,J＝5.8,2.5Hz,1H),4.79(p,J＝7.1Hz,1H),4.01(s,2H),3.92(s,2H),3.04–2.99(m,2H),2.88(d,J＝7.4Hz,2H),2.47–2.41(m,2H),2.10–1.98(m,2H),1.85–1.59(m,6H).
Example 19 preparation of 2- (4-Cyclobutoxypyridin-2-yl) -N- (5- (4- (6- (2- (5-methoxypyridin-2-yl) acetamido) pyridazin-3-yl) butyl) -1,3, 4-thiadiazol-2-yl) acetamide (19)
The title compound was prepared in the same manner as in example 6 using 2- (5-methoxypyridin-2-yl) acetic acid as a starting material.
MS m/z(ES):589.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.62(s,1H),11.27(s,1H),8.29(d,J＝5.7Hz,1H),8.20(dd,J＝6.0,3.1Hz,2H),7.57(d,J＝9.2Hz,1H),7.42–7.29(m,2H),6.90(d,J＝2.5Hz,1H),6.77(dd,J＝5.8,2.5Hz,1H),4.78(p,J＝7.2Hz,1H),3.92(d,J＝10.4Hz,4H),3.81(s,3H),3.01(s,2H),2.89(s,2H),2.47–2.41(m,2H),2.10–2.00(m,2H),1.85–1.59(m,6H).
Biological evaluation
Test example 1: a549 cell proliferation inhibition test
1. Purpose of test
IC of different compounds on A549 cells is determined by using A549 cell line and GLS1 high-expression human non-small cell lung cancer cell line through cell proliferation inhibition test 50 Values. The inhibition of proliferation of cells by the compounds of the present invention was studied and the efficacy of the test compounds was evaluated.
2. Test materials
2.1, medicine:
positive drug: CB-839, purchased to Chengdu Ding Dang Zhi Ji Zhi Shi Ji Co., ltd., powder, lot number DDEL0824-23;
test agent: the compound of example 1, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210420;
test agent: the compound of example 2, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210413;
test agent: example 3 compound, lot number supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210706;
test agent: the compound of example 4, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210720;
test agent: the compound of example 5, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210720;
test agent: the compound of example 6, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210510;
test agent: the compound of example 7, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210401;
Test agent: the compound of example 8, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210520;
test agent: the compound of example 9, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210817;
test agent: the compound of example 10, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210817;
test agent: the compound of example 11, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210810;
test agent: the compound of example 12, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210819;
test agent: the compound of example 13, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210825;
test agent: the compound of example 14, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210824;
test agent: the compound of example 15, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210824;
test agent: the compound of example 16, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210914;
Test agent: the compound of example 17, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210907;
test agent: the compound of example 18, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210907;
test agent: the compound of example 19, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210914.
2.2, test instrument:
multifunctional enzyme-labeled instrument SpectraMaxM2e, molecular Devices;
a cytometer, countStar;
inverted microscope, olympus;
12-lane 10uL manual pipette, 12-lane 300uL manual pipette, 12-lane 10uL electric pipette, 12-lane 300uL electric pipette, sidoris;
centrifuge tubes, flat bottom 96 well plates, and the like.
2.3, test cells:
a549 cells purchased from chenopodium and biotechnology limited.
3. Test method
3.1 cell culture
At 37℃with 5% CO 2 Under the conditions, A549 cells were maintained in complete medium (RPMI-1640, 10% FBS,100 units/mL penicillin and 100ug/mL streptomycin) and subcultured when the cells reached 85% or more confluence.
3.2 cell plating
Treating cells when the cells can be subcultured, measuring the concentration and the activity rate of the cells by adopting a cell counter, and preparing 2 x 10 4 Per mL of cell suspension, e.g., 2000 cells/well, 100uL of cell suspension was seeded in 96-well plates, supplemented with 50uL of complete medium, 37℃C,5％CO 2 Overnight in the environment.
3.3 drug treatment
The next day, compound concentrations of 10mM were prepared separately using DMSO as solvent as stock concentration of compound; diluting the stock concentration by 10 times with DMSO, namely, 1mM mother solution, and then carrying out 3-time gradient dilution, wherein the total concentration is 9 gradient concentrations; then 9 gradient concentrations of 2.4uL are sucked to a constant volume of 200uL of complete culture medium, and the microporous vibrating plate is incubated for about 20min; finally, 50uL of the mixture was pipetted into the corresponding 96-well plate, so that the final concentration of DMSO was 0.3%. Placing at 37deg.C 5% CO 2 Incubation was carried out for 72h.
3.4, result detection
After 72h incubation, the original medium was removed and a medium containing 10% CCK-8, 37℃and 5% CO was added 2 Incubating for 60min, and measuring OD value at 450nM of the multifunctional enzyme labeling instrument.
4. Test results
4-parameter curve fitting was performed on the results of the proliferation inhibition of a549 cells by different compounds, and IC of different compounds was calculated using GraphPad software 50 Values. The inhibitory activity of the compounds of the present invention on a549 cells is shown in table 1.
TABLE 1 inhibitory Activity of the inventive Compounds against A549 cells
From the test data of the compounds in table 1 on the inhibition activity of a549 cells, the compounds in the invention have obvious inhibition activity of a549 cells.
Test example 2: GLS1 enzyme Activity assay
1. Test purpose glutamate was produced by the action of glutamine and human recombinant GAC enzyme and NAD was measured by the action of glutamate dehydrogenase + The change in fluorescence intensity of reduced NADPH, the IC of the test compound for human recombinant GAC enzyme was calculated 50 The test compounds were evaluated for inhibition of enzymatic activity of recombinant forms of glutaminase 1.
2. Test materials
2.1, medicine:
positive drug: CB-839, purchased to Chengdu Ding Dang Zhi Ji Zhi Shi Ji Co., ltd., powder, lot number DDEL0824-23;
test agent: the compound of example 1, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210420;
test agent: the compound of example 2, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210413;
test agent: example 3 compound, lot number supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210706;
test agent: the compound of example 4, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210720;
test agent: the compound of example 5, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210720;
Test agent: the compound of example 6, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210510;
test agent: the compound of example 7, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210401;
test agent: the compound of example 8, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210520;
test agent: the compound of example 9, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210817;
test agent: the compound of example 13, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210825;
test agent: the compound of example 15, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210824;
test agent: the compound of example 16, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210914;
test agent: the compound of example 17, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210907.
2.2, test instruments, materials
Multifunctional enzyme-labeled instrument Envision 2104,Perkin Elmer;
Centrifuge 5810r, eppendorf;
96-well plate 249944;
GLS1InhibitorScreeningAssayKit，BPSBioscience；
DTT(DL-Dithiothreitol)，Sigma；
3. test method
(1) Preparing a 10mM stock solution of the compound, and pipetting 50uL of the compound into 384 well dilution plates;
(2) Compounds were diluted with DMSO gradient according to 1:3.33 and transferred to 0.2uL of diluted compounds to corresponding 384 well assay plates, each compound being replicated 2 times;
(3) Adding 10uL of enzyme working solution to a 384-hole experimental plate, centrifuging at 1000RPM for 1min;
(4) After incubation at 25 ℃ for 60min, 10uL of substrate working solution is added and the reaction is started;
(5) After incubation at 25 ℃ for 60min, the fluorescence intensity is measured by a multifunctional enzyme-labeled instrument at 340Ex/450 Em;
4. test results
4-parameter curve fitting was performed on the results of the action of different compounds on GLS1 recombinase inhibitory activity, and the IC of the different compounds was calculated using XLfit software 50 Values. The GLS1 recombinase inhibitory activity of the compound of the invention is shown in Table 2.
TABLE 2 inhibition of GLS1 recombinase by the inventive Compounds
| Numbering of compounds | IC 50 (nM) | Numbering of compounds | IC 50 (nM) |
| 1 | 178.82 | 2 | 142.30 |
| 3 | 82.07 | 4 | 63.9 |
| 5 | 68.22 | 6 | 112.31 |
| 7 | 110.07 | 8 | 93.02 |
| 9 | 241.81 | 13 | 91.64 |
| 15 | 33.32 | 16 | 224.81 |
| 17 | 73.65 | CB-839 | 229.82 |
From the experimental data of the compounds in table 2 on GLS1 recombinase inhibition activity, the compounds of the present invention have remarkable GLS1 inhibition activity.
Test example 3: study of rat pharmacokinetics
1. Purpose of test
SD rats are taken as test animals, and the blood concentration in plasma at different times after the respective intragastric administration of the compounds of the present invention is determined by using an LC-MS/MS method. The pharmacokinetic behavior of the compound of the invention in rats was studied and its pharmacokinetic profile was evaluated.
2. Test materials
2.1, medicine:
positive drug: CB-839, purchased to Chengdu Ding Dang Zhi Ji Zhi Shi Ji Co., ltd., powder, lot number DDEL0824-23;
test agent: the compound of example 1, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210420;
test agent: the compound of example 2, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210413;
test agent: the compound of example 5, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210720;
test agent: the compound of example 13, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210825;
test agent: the compound of example 16, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210914;
test agent: the compound of example 17, lot number, supplied by the research and development center of the division of bio-pharmaceuticals, inc. On the barton: 20210907.
2.2, test instrument:
shimadzu LC-30A AB API4500 tandem mass spectrometer, vacuum blood collection tube, blood collection needle, filter paper, injector, etc.
2.3 test animals
SD rats, females, weighing 180-220g, 4 in each group, offered by Chengdu Envy Biotech Co., ltd., production facility license: SYXK (Chuan) 2017-205. Animals were kept in the animal house after being purchased back, and the indication was observed for at least 3 days, and used for the test after quarantine was passed.
3. Test method
3.1, grouping: according to the random groupings of table 3, there was no statistical difference between groups.
Table 3 test groups and dosing regimen
3.2, blood sample collection and measurement:
the corresponding test agents were administered to each group of lavage according to Table 3, 15min, 30min, 60min, 1.5h, 2h, 4h, 6h, 8h, 24h, 0.2mL of jugular vein blood was taken before administration, after administration, placed in EDTA-K2 anticoagulant tube, 4500r/min, centrifuged for 10min, and 50uL of separated plasma was frozen in a centrifuge tube at-80℃in a refrigerator.
3.3 analytical methods
Taking out 50uL of blood plasma at each time point preserved at-80 ℃, adding 150uL of acetonitrile, swirling for 2min, centrifuging for 15min (3500 r/min), and taking 10uL of solution supernatant for LC-MS/MS analysis.
4. Pharmacokinetic parameter calculation:
the pharmacokinetic behavior of the test compounds was subjected to an atrioventricular model fit and the principal pharmacokinetic parameters (T) were calculated using DAS2.0 software 1/2 、T max 、C max 、AUC last Etc.).
5. Test results:
table 4 pharmacokinetic parameters of the example compounds
As can be seen from the test results in Table 4, the compounds of example 1, example 2, example 5, example 13, example 16 and example 17 are significantly better than CB-839 in terms of maximum blood concentration and area under the curve, compared with the positive group, which means that the compounds prepared in examples 1, 2, 5, 13, 16 and 17 have significantly improved pharmacokinetic properties compared with CB-839.
It is to be understood that the foregoing detailed description and accompanying examples are merely exemplary and are not to be considered limiting the scope of the invention, which is defined solely by the appended claims and their equivalents. Various alterations and modifications to the disclosed embodiments will be readily apparent to those skilled in the art. Such variations and modifications may be made without departing from the spirit and scope thereof, including but not limited to those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.
Claims (10)
1. A compound as shown in formula I, an isomer thereof or a pharmaceutically acceptable salt thereof,
wherein,,
a is selected from (C) 3 -C 8 ) Cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or more halo groups;
l is selected from O or a single bond;
X 1 、X 2 each independently selected from: s and ch=CH, and X 1 、X 2 S or ch=ch at different times;
R 1 selected from: (C) 1 -C 6 ) Alkyl, (C) 6 -C 10 ) Aryl (C) 1 -C 6 ) Alkyl, heteroaryl (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl (C) 1 -C 6 ) Alkyl or heterocycloalkyl (C) 1 -C 6 ) An alkyl group;
wherein said (C) 1 -C 6 ) Alkyl, (C) 6 -C 10 ) Aryl (C) 1 -C 6 ) Alkyl, heteroaryl (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl (C) 1 -C 6 ) Alkyl, heterocycloalkyl (C) 1 -C 6 ) Alkyl is unsubstituted or substituted with one or more substituents optionally selected from the group consisting of: halogen, hydroxy, cyano, sulfonyl, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy, (C) 1 -C 6 ) Alkoxy (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkyl, halo (C) 1 -C 6 ) Alkoxy, halo (C) 1 -C 6 ) Alkoxy (C) 1 -C 6 ) Alkyl, (C) 6 -C 10 ) Aryl, (C) 6 -C 10 ) Aryl (C) 1 -C 6 ) Alkyl, (C) 6 -C 10 ) Aryloxy, (C) 6 -C 10 ) Aryloxy group (C) 1 -C 6 ) Alkyl, heteroaryl (C) 1 -C 6 ) Alkyl, heteroaryloxy (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl, (C) 3 -C 8 ) Cycloalkyl (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyloxy, (C) 3 -C 8 ) Cycloalkyloxy (C) 1 -C 6 ) Alkyl, halo (C) 3 -C 8 ) Cycloalkyl, halo (C) 3 -C 8 ) Cycloalkyl (C) 1 -C 6 ) Alkyl, halo (C) 3 -C 8 ) Cycloalkyloxy, halo (C) 3 -C 8 ) Cycloalkyloxy (C) 1 -C 6 ) Alkyl, heterocycloalkyl (C) 1 -C 6 ) Alkyl, heterocycloalkyloxy (C) 1 -C 6 ) Alkyl, haloheterocycloalkyl (C) 1 -C 6 ) Alkyl, haloheterocycloalkyloxy or haloheterocycloalkyloxy (C) 1 -C 6 ) An alkyl group;
R 2 selected from heteroaryl, said heteroaryl being unsubstituted or substituted with one or more substituents optionally selected from: halogen, cyano, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy, halo (C) 1 -C 6 ) Alkyl or halo (C) 1 -C 6 ) An alkoxy group;
the heteroaryl is a 5-8 membered heteroaryl monocyclic ring having 1 or 2 groups selected from N, O, S;
the heterocycloalkyl group is a 3-8 membered ring having 1 or 2 rings selected from N, O, S.
2. The compound of formula I, an isomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 1,
a is selected from cyclopropyl or cyclobutyl, wherein the cyclopropyl, cyclobutyl is unsubstituted or substituted by one or more fluoro.
3. The compound of formula I, an isomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 1,
R 1 selected from: (C) 1 -C 6 ) Alkyl, (C) 6 -C 10 ) Aryl (C) 1 -C 6 ) Alkyl, heteroaryl (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl (C) 1 -C 6 ) Alkyl or heterocycloalkyl (C) 1 -C 6 ) An alkyl group;
wherein said (C) 1 -C 6 ) Alkyl, (C) 6 -C 10 ) Aryl (C) 1 -C 6 ) Alkyl, heteroaryl (C) 1 -C 6 ) Alkyl, (C) 3 -C 8 ) Cycloalkyl (C) 1 -C 6 ) Alkyl, heterocycloalkyl (C) 1 -C 6 ) Alkyl being unsubstituted or substitutedOne or more substituents selected from the group consisting of: halogen, cyano, sulfonyl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutoxy or
4. The compound of formula I, an isomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 1,
R 2 Selected from pyridinyl, which pyridinyl is unsubstituted or substituted with one or more substituents optionally selected from: fluorine, chlorine, cyano, methyl, methoxy, trifluoromethyl or trifluoromethoxy.
5. The compound of formula I, an isomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claim 1 to 3,
the heteroaryl is selected from: pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl.
6. The compound of formula I, an isomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claim 1 to 3,
the heterocycloalkyl group is selected from: tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl or morpholinyl.
7. The compound of formula I, an isomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 1,
wherein,,
a is selected from cyclopropyl, cyclobutyl, wherein the cyclopropyl, cyclobutyl is unsubstituted or substituted by one or more fluoro;
l is selected from O and single bond;
X 1 、X 2 each independently selected from: s and ch=ch, and X 1 、X 2 At different timesS or ch=ch;
R 1 selected from: heteroaryl (C) 1 -C 6 ) An alkyl group; wherein the heteroaryl (C 1 -C 6 ) Alkyl is unsubstituted or substituted with one or more substituents optionally selected from the group consisting of: halogen, cyano, sulfonyl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutoxy or 
R 2 Selected from: a pyridinyl group, said pyridinyl group being unsubstituted or substituted with one or more substituents optionally selected from: fluorine, chlorine, cyano, methyl, methoxy, trifluoromethyl or trifluoromethoxy;
the heteroaryl is selected from: pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl;
the heterocycloalkyl group is selected from: tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl or morpholinyl.
8. A compound of formula I as defined in any one of claims 1-4, 7, an isomer thereof or a pharmaceutically acceptable salt thereof, said compound being selected from the group consisting of:
9. the use of a heterocyclic derivative of the structure shown in any one of claims 1-4, 7, an isomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of GLS 1-related diseases; preferably, the GLS 1-associated disease refers to non-hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, oral cancer, brain cancer, stomach cancer, liver cancer, rectal cancer, pancreatic cancer, skin cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, fallopian tube tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma, mastoid malignancy, head and neck tumor, leukemia or myeloma.
10. A process for the preparation of heterocyclic derivatives of the structure according to any one of claims 1-4, 7, comprising the steps of:
route one:
wherein LG represents a leaving group;
preferably, the leaving group is a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group;
(1) Reacting compound I-1 with compound I-2 to obtain I-3;
(2) Coupling the compound I-3 with the compound I-4 to obtain I-5;
(3) The compound I-5 is subjected to reduction reaction to obtain I-6;
(4) The compound I-6 and the compound I-7 are subjected to ring closure reaction to obtain I-8;
(5) Reacting the compound I-8 with the compound I-9 to obtain a heterocyclic derivative with a structure shown in a formula I; or route two:
wherein LG represents a leaving group;
preferably, the leaving group is a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group;
(1) The compound I-4 and the compound I-7 are subjected to ring closure reaction to obtain I-10;
(2) Reacting compound I-10 with compound I-9 to give I-11;
(3) Coupling the compound I-3 with the compound I-11 to obtain I-12;
(4) The heterocyclic derivative with the structure shown in the formula I is obtained by the reduction reaction of the compound I-12.
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