CN111303135A - 4- (4-pyrazolyloxy) quinoline compound, preparation method, pharmaceutical composition and application thereof - Google Patents
4- (4-pyrazolyloxy) quinoline compound, preparation method, pharmaceutical composition and application thereof Download PDFInfo
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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Abstract
The invention relates to a 4- (4-pyrazolyloxy) quinoline compound, a preparation method, a pharmaceutical composition and application thereof. In particular to 4- (4-pyrazolyloxy) quinoline compounds with the structural general formula shown in the specification or compounds thereofThe compounds can be used as therapeutic agents, particularly as TGF- β signal pathway inhibitors, and have good application prospects in preparation of medicaments for preventing, relieving and treating diseases mediated by TGF- β signal pathway disorder.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a 4- (4-pyrazolyloxy) quinoline compound, a preparation method, a pharmaceutical composition and application thereof.
Background
In recent years, there have been many important advances in the field of cancer treatment, and cancer-targeted therapies, immunotherapy, cell transplantation therapies, and the like have made it hope that patients will survive and live at high quality. However, the current cancer therapies still have many disadvantages, such as the effective response rate of the PD-1/PD-L1 drug in cancer immunotherapy is very low, and the drug is only effective for 10-20% of patients. Thus, there is a need for improvements to existing therapies, particularly cancer treatment regimens, that increase patient remission and survival.
Under pressure, the tissue microenvironment changes, and a great deal of experimental evidence also indicates that disorder of the tissue microenvironment is closely related to disorder of the signal pathway of transforming growth factor- β (transforming growth factor- β - β) and cancer immunotherapy (such as PD-1/PD-L1 monoclonal antibody drug) is closely related to the occurrence and metastasis of cancer, and the intervention of important factors/signal pathways in the tissue microenvironment, such as TGF- β signal pathways, is an important direction in the field of medical research and development in recent years.
TGF- β/SMAD signaling pathway is characterized by three subtypes (β, β, β) free ligand through binding to cell surface TGF- β transmembrane serine/threonine kinase receptors to form a complex activating receptor specific SMAD protein (R-SAMD), R-SAMD enters into nuclei and further interacts with other cytokines to regulate transcription of genes after binding to the common SMAD receptor (co-SMAD), TGF- β signaling pathway abnormalities can lead to many diseases, such as cancer, tissue fibrosis, arterial metastasis, and so on, and thus, the tumor metastasis inhibition is often shown to be effective in the field of tumor treatment, especially in early stage tumor development, the tumor metastasis inhibition is shown to be effective in clinical tests for early stage tumor development, especially in response to early stage tumor growth, migration, differentiation, apoptosis, and so on, and plays an important role in the balance of embryonic development and tissue organogenesis, repair, immune inspection, adult homeostasis in the organism.
Based on the characteristics of a TGF- β signal pathway, a TGF- β protein type I receptor (TGF β receptor I, also called active-like kinase 5, ALK5) on the cell surface is an ideal target in the field of small molecule targeted drug development, the phosphorylation of downstream signal transduction protein Smad2/3 by ALK5 protein is selectively targeted and inhibited through small molecules, the transmission of TGF- β signals into a cell nucleus is weakened or blocked, and the TGF- β signal pathway is adjusted to be normal, so that various TGF- β signal pathway mediated diseases are treated.
Disclosure of Invention
Based on the above, the invention provides a novel 4- (4-pyrazolyloxy) quinoline compound which can be used as a therapeutic agent, particularly as a TGF- β signal pathway inhibitor, and has a good application prospect in the preparation of medicaments for preventing, relieving and treating diseases mediated by TGF- β signal pathway disorder.
4- (4-pyrazolyloxy) quinoline compounds with the following general structural formula, or tautomers, or racemes, or racemates, or enantiomers, or diastereomers, or pharmaceutically acceptable salts thereof:
wherein R is1Selected from H, C1-C10 straight chain or C3-C10 branched chain alkyl, C1-C10 straight chain or C3-C10 branched chain alkoxy, C2-C10 cycloalkoxy, C5-C10 aryl, C2-C10 heteroaryl;
R2selected from H, C1-C10 straight chain or C3-C10 branched chain alkyl, C1-C10 straight chain or C3-C10 branched chain alkoxy, C3-C10 naphthenic base, C2-C10 cycloalkoxy, C5-C10 aryl and C2-C10 heteroaryl;
R3selected from H, C1-C10 straight chain or C3-C10 branched chain alkyl, C1-C10 straight chain or C3-C10 branched chain alkoxy, C3-C10 naphthenic base, C2-C10 cycloalkoxy, C5-C10 aryl and C2-C10 heteroaryl;
R4selected from H, halogen, C1-C10 linear or C3-C10 branched alkyl, C1-C10 linear or C3-C10 branched alkoxy, C3-C10 cycloalkyl, C2-C10 cycloalkoxy, ester group, carboxyl group, amine group, amide group, C5-C10 aryl, C2-C10 heteroaryl, C2-C5 heteroaryl ether, C1-C5 heterocyclyl or a combination thereof;
R5selected from H, halogen, C1-C10 linear or C3-C5 branched alkyl, C1-C10 linear or C3-C5 branched alkoxy or combinations thereof.
In one embodiment, R4Selected from: H. halogen, ester group, carboxyl group or group having the structural formula shown below:
wherein A is1Selected from the group consisting of C1-C3 alkyl carboxamides, amine groups or absent;
A2selected from C2-C6 cycloalkoxy, C4-C10 azaaryl;
A3selected from amine, ester, C2-C5 azaheterocyclyl, C2-C5 azaaryl ether or absent;
A4the compound is selected from C4-C6 cycloalkoxy, C3-C5 cycloalkyl, C1-C3 straight chain or C3 branched chain alkyl, and n is 0-3.
In one embodiment, R4Selected from the group having the general structural formula shown below:
wherein A is1Selected from amine groups or absent;
A2is selected from
Wherein, X1Each independently is C or N, and at least one X1Is N;
A3selected from amino, carbomethoxy, carboxyl, amino,
Wherein, X2Each independently is C or N, and at least one X2Is N;
A4is selected from C4-C6 cycloalkoxy, cyclopropyl, methyl and ethyl, and n is 0-2.
In one embodiment, R5Selected from: H. halogen, C1-C2 linear alkoxy, halogenated C1-C2 linear alkyl.
In one embodiment, R1-3Each independently selected from H, C3-C5 cycloalkyl, C3-C6 cycloalkoxy.
In one embodiment, the 4- (4-pyrazolyloxy) quinoline compound has the following structural general formula:
in one embodiment, the 4- (4-pyrazolyloxy) quinoline compound is selected from the following compounds:
the invention also provides a preparation method of the 4- (4-pyrazolyloxy) quinoline compound, which comprises the following steps:
(1) reacting the compound 1 with a bromization reagent to obtain a compound 2;
(2) carrying out substitution reaction on the compound 2 and the compound 3 to obtain a compound 4;
(3) carrying out substitution reaction on the compound 4 and the compound 5 to obtain a compound 6;
(4) reacting the compound 6 with hydrazine hydrate to obtain a compound 7;
(5) the compound 7 and the compound 8 are subjected to substitution reaction.
The invention also provides a preparation method of the 4- (4-pyrazolyloxy) quinoline compound, which comprises the following steps:
(1) reacting the compound 1 with a bromization reagent to obtain a compound 2;
(2) carrying out substitution reaction on the compound 2 and the compound a to obtain a compound b;
(3) carrying out substitution reaction on the compound b and a compound 5 to obtain a compound c;
(4) reacting the compound c with hydrazine hydrate to obtain a compound d;
(5) carrying out substitution reaction on the compound d and a compound 8 to obtain a compound e;
(6) and (3) carrying out substitution reaction on the compound e and the compound f.
The invention also provides a pharmaceutical composition, which comprises an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the 4- (4-pyrazolyloxy) quinoline compound, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
The invention also provides the application of the 4- (4-pyrazolyloxy) quinoline compound, or the tautomer thereof, or the racemate thereof, or the enantiomer thereof, or the diastereoisomer thereof, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparing TGF- β signal pathway inhibitors.
The invention also provides the application of the 4- (4-pyrazolyloxy) quinoline compound, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the application of the pharmaceutical composition in preparing medicines with the effects of preventing and treating cancers, infectious diseases, autoimmune diseases, tissue fibrosis, abnormal cartilage development or pulmonary hypertension.
Compared with the prior art, the invention has the following beneficial effects:
the invention discovers a novel molecular framework structure with the function of restoring a TGF- β signal path to normal through research, wherein the molecular framework structure is 4- (4-pyrazolyloxy) quinoline, the action mechanism of the molecular framework structure is that the molecular framework structure is used as an ALK5 inhibitor to regulate and control ALK5, so that the TGF- β signal path is restored to normal, the effect of intervening (preventing, alleviating or treating) related various diseases is achieved, and the diseases can be specifically cancer, infectious diseases, autoimmune diseases, tissue fibrosis, abnormal cartilage development or pulmonary hypertension, and the application prospect is good.
Detailed Description
The 4- (4-pyrazolyloxy) quinoline compounds, the preparation method, the pharmaceutical compositions and the applications thereof according to the present invention will be described in further detail with reference to the following specific examples.
Aryl refers to a hydrocarbon group containing at least one aromatic ring, including monocyclic groups and polycyclic ring systems. Heteroaryl refers to a hydrocarbon group (containing heteroatoms) containing at least one heteroaromatic ring, including monocyclic groups and polycyclic ring systems. These polycyclic rings may have two or more rings in which two carbon atoms are shared by two adjacent rings, i.e., fused rings. At least one of these rings of the polycyclic ring system is aromatic or heteroaromatic. For the purposes of the present invention, aromatic or heteroaromatic ring systems include not only aromatic or heteroaromatic systems, but also systems in which a plurality of aryl or heteroaryl groups may also be interrupted by short nonaromatic units, for example C, N or O atoms. Thus, for example, systems such as 9,9' -spirobifluorene, 9, 9-diarylfluorene, triarylamines, diaryl ethers, etc., are likewise considered aryl for the purposes of this invention.
The embodiment of the invention provides a 4- (4-pyrazolyloxy) quinoline compound with the following structural general formula, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein R is1Selected from H, C1-C10 straight chain or C3-C10 branched chain alkyl, C1-C10 straight chain or C3-C10 branched chain alkoxy, C2-C10 cycloalkoxy, C5-C10 aryl, C2-C10 heteroaryl;
R2selected from H, C1-C10 straight chain or C3-C10 branched chain alkyl, C1-C10 straight chain or C3-C10 branched chain alkoxy, C3-C10 naphthenic base, C2-C10 cycloalkoxy, C5-C10 aryl and C2-C10 heteroaryl;
R3selected from H, C1-C10 straight chain or C3-C10 branched chain alkyl, C1-C10 straight chain or C3-C10 branched chain alkoxy, C3-C10 naphthenic base, C2-C10 cycloalkoxy, C5-C10 aryl and C2-C10 heteroaryl;
R4selected from H, halogen, C1-C10 linear or C3-C10 branched alkyl, C1-C10 linear or C3-C10 branched alkoxy, C3-C10 cycloalkyl, C2-C10 cycloalkoxy, ester group, carboxyl group, amine group, amide group, C5-C10 aryl, C2-C10 heteroaryl, C2-C5 heteroaryl ether, C1-C5 heterocyclyl or a combination thereof;
R5selected from H, halogen, C1-C10 linear or C3-C5 branched alkyl, C1-C10 linear or C3-C5 branched alkoxy or combinations thereof.
The general formula uses 4- (4-pyrazolyloxy) quinoline as a molecular skeleton, and performs appropriate R at a specific site in cooperation1-5The compound can achieve excellent ALK5 inhibition effect, and further regulate ALK5, so that a TGF- β signal channel is recovered to be normal, and the effect of intervening (preventing, alleviating or treating) related various diseases is achieved.
The "pharmaceutically acceptable salt" may be an inorganic acid or an organic acid salt, such as hydrochloride, sulfate, phosphate, organic sulfonate, citrate, maleate, oxalate, and the like.
In one particular embodiment, the 4- (4-pyrazolyloxy) quinoline is not 7-chloro-4-pyrazoloquinoline.
In one particular embodiment, the 4- (4-pyrazolyloxy) quinoline is not:
in one specific embodiment, R4Selected from: H. halogen, ester group, carboxyl group or group having the structural formula shown below:
wherein A is1Selected from the group consisting of C1-C3 alkyl carboxamides, amine groups or absent;
A2selected from C2-C6 cycloalkoxy, C4-C10 azaaryl;
A3selected from amine, ester, C2-C5 azaheterocyclyl, C2-C5 azaaryl ether or absent;
A4the compound is selected from C4-C6 cycloalkoxy, C3-C5 cycloalkyl, C1-C3 straight chain or C3 branched chain alkyl, and n is 0-3.
More preferably, R4Selected from the group consisting ofA group of the general structural formula:
wherein A is1Selected from amine groups or absent;
A2is selected from
Wherein, X1Each independently is C or N, and at least one X1Is N;
A3selected from amino, carbomethoxy, carboxyl, amino,
Wherein, X2Each independently is C or N, and at least one X2Is N;
A4is selected from C4-C6 cycloalkoxy, cyclopropyl, methyl and ethyl, and n is 0-2.
In one specific embodiment, R5Selected from: H. halogen, C1-C2 linear alkoxy, halogenated C1-C2 linear alkyl.
In one specific embodiment, R1-3Each independently selected from H, C3-C5 cycloalkyl, C3-C6 cycloalkoxy.
In one specific embodiment, the 4- (4-pyrazolyloxy) quinoline compound has the following structural general formula:
in one specific embodiment, the 4- (4-pyrazolyloxy) quinoline compound is selected from the following compounds:
the embodiment of the invention also provides a preparation method of the 4- (4-pyrazolyloxy) quinoline compound, which has the advantages of easily obtained raw materials and simple steps, and specifically comprises the following steps:
(1) reacting the compound 1 with a bromization reagent to obtain a compound 2;
(2) carrying out substitution reaction on the compound 2 and the compound 3 to obtain a compound 4;
(3) carrying out substitution reaction on the compound 4 and the compound 5 to obtain a compound 6;
(4) reacting the compound 6 with hydrazine hydrate to obtain a compound 7;
(5) the compound 7 and the compound 8 are subjected to substitution reaction.
The embodiment of the invention also provides a preparation method of the 4- (4-pyrazolyloxy) quinoline compound, which has the advantages of easily obtained raw materials and simple steps, and specifically comprises the following steps:
(1) reacting the compound 1 with a bromization reagent to obtain a compound 2;
(2) carrying out substitution reaction on the compound 2 and the compound a to obtain a compound b;
(3) carrying out substitution reaction on the compound b and a compound 5 to obtain a compound c;
(4) reacting the compound c with hydrazine hydrate to obtain a compound d;
(5) carrying out substitution reaction on the compound d and a compound 8 to obtain a compound e;
(6) and (3) carrying out substitution reaction on the compound e and the compound f.
The embodiment of the invention also provides a pharmaceutical composition, which comprises an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the 4- (4-pyrazolyloxy) quinoline compound, or the tautomer thereof, or the racemate thereof, or the enantiomer thereof, or the diastereomer thereof, or the pharmaceutically acceptable salt thereof.
The embodiment of the invention also provides the application of the 4- (4-pyrazolyloxy) quinoline compound, or the tautomer thereof, or the racemate thereof, or the enantiomer thereof, or the diastereomer thereof, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of TGF- β signal pathway inhibitors.
The embodiment of the invention also provides application of the 4- (4-pyrazolyloxy) quinoline compound, or a tautomer, a racemate, an enantiomer, a diastereomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparing a medicine for preventing and treating cancer, tissue fibrosis, dysplasia cartilaginosa or pulmonary hypertension.
The following specific examples are provided, and the starting materials, reaction reagents and the like used in the following examples are all commercially available products unless otherwise specified. Reagents and solvents used in the experiment are all processed according to the specific conditions of the reaction.
In the following examples, analytical data of samples were determined by the following instruments: the nuclear magnetic resonance is measured by a Bruker AMX-400 nuclear magnetic resonance instrument and a Bruker AMX-500 nuclear magnetic resonance instrument, TMS (tetramethylsilane) is an internal standard, the unit of chemical shift is ppm, and the unit of coupling constant is Hz; mass spectra were determined by an Agilent1200/MSD mass spectrometer.
Silica gel 200-300 mesh for column chromatography is produced by Qingdao ocean factory; the TLC silica gel plate is an HSGF-254 thin-layer chromatography prefabricated plate produced by a cigarette bench chemical plant; the boiling range of petroleum ether is 60-90 ℃; the color is developed by adopting an ultraviolet lamp, an iodine cylinder, phosphomolybdic acid and the like.
The abbreviations used in the present invention are the same as those commonly used in the art, and some of the meanings are as follows:
PE: petroleum ether, DCM: dichloromethane, EA: ethyl acetate, THF: tetrahydrofuran, MeOH: methanol, DMF: n, N-dimethylformamide, DME: ethylene glycol dimethyl ether, DMA: n, N-dimethylacetamide, DIEA: n, N-diisopropylethylamine, TEA: triethylamine, DCC: dicyclohexylcarbodiimide, DMAP: 4-N, N-dimethylaminopyridine, HOBt: 1-hydroxybenzotriazole, edc.hcl: 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride, Boc anhydride: di-tert-butyl dicarbonate.
Example 1(LEC002-77)
Synthetic route for Compound 1(LEC 002-77):
synthesis procedure of Compound 1:
intermediate 1-a synthesis:
to the flask were added 1- (tetrahydro-2H-pyran-4-yl) ethanone (5.05g,39mmol), bromosuccinimide (NBS, 6.90g, 39mmol) and methanol (100 mL). After the addition, the reaction was stirred at 50 ℃ for 3 hours in an oil bath. Then, it was cooled to room temperature, concentrated to remove the solvent, and the residue was purified by silica gel column chromatography to give the product (6.05g, 75%) as a brown liquid 1-a. LC-MS (ESI) M/z 207.0[ M-H ═]-。
Intermediate 1-b Synthesis:
the flask was charged with intermediate 1-a (6.01g,29mmol), 6-bromo-4-hydroxyquinoline (6.72g, 30mmol), potassium carbonate (8.01g, 58mmol) and acetonitrile (150 mL). After the addition, the reaction was stirred at 60 ℃ for 5 hours in an oil bath. Then cooled to room temperature, concentrated to remove the solvent, and the residue was purified by silica gel column chromatography to give the product (6.40g, 63%) as a brown oil 1-b. LC-MS (ESI) 349.0[ M-H ]]-。
Synthesis of intermediates 1-c:
to the flask was added intermediate 1-b (6.40g,18.3mmol), N, N-dimethylformamide dimethyl acetal (15 mL). After the addition, the reaction was stirred for 2 hours at 105 ℃ in an oil bath. Then cooled to room temperature, concentrated to remove the solvent and the residue was purified by washing with petroleum ether to give the product (6.30g, 85%) as a brown paste 1-c. LC-MS (ESI) m/z ═ m/z404.2[M-H]-。
Synthesis of intermediates 1-d:
to the flask were added intermediate 1-c (6.30g,15.5mmol), hydrazine hydrate solution (0.93g, 19mmol) and ethanol (150 mL). After the addition, the reaction was stirred at 50 ℃ for 6 hours in an oil bath. Then cooled to room temperature, concentrated to remove the solvent, and the residue was purified by silica gel column chromatography to give the product (4.19g, 72%) as a pale yellow paste of product 1-d. LC-MS (ESI) M/z 374.0[ M-H ═]-。
Synthesis of Compound 1:
to the flask were added copper acetate (2.43g,13.4mmol), 2,2' -bipyridine (2.09g, 13.4mmol) and dichloroethane (150 mL). After the addition was complete, the reaction was stirred for 25 minutes at 75 ℃ in an oil bath, then cooled to room temperature, intermediate 1-d (4.19g, 11.2mmol), cyclopropylboronic acid (0.96g,22.4mmol), sodium carbonate (3.56g, 33.6mmol) were added and air was bubbled through the bottom of the flask and stirred for 6 hours at 50 ℃ in an oil bath. Then cooled to room temperature, concentrated to remove the solvent, and the residue was purified by silica gel column chromatography to give the product (3.25g, 70%) as an oily product, compound 1.
LC-MS(ESI):m/z＝414.1[M-H]-。
1H NMR(500MHz,CDCl3)δ8.60(s,1H),7.63(s,2H),7.48(d,J＝7.7Hz,1H),6.92(d,J＝9.0Hz,1H),6.37(d,J＝7.6Hz,1H),3.93(d,J＝11.6Hz,2H),3.71-3.66(m,1H),3.33(dd,J＝21.6,11.4Hz,2H),2.62(t,J＝11.4Hz,1H),1.91–1.70(m,2H),1.61–1.50(m,2H),1.24-1.21(m,2H),1.13(d,J＝7.0Hz,2H)。
The compounds 2 to 6 of examples 2 to 6 can be prepared by referring to the preparation procedure of example 1.
Example 2(LEC002-078)
LC-MS(ESI):m/z＝503.18[M-H]+。
1H NMR(500MHz,Chloroform-d)δ8.38(d,J＝9.0Hz,1H),7.58(s,1H),7.38(d,J＝7.7Hz,1H),6.97(dd,J＝9.0,2.4Hz,1H),6.35(s,1H),6.26(d,J＝7.7Hz,1H),3.94–3.88(m,2H),3.78(s,3H),3.66(tt,J＝7.3,3.8Hz,1H),3.31(qd,J＝11.9,2.1Hz,2H),2.64(tt,J＝11.7,3.8Hz,1H),1.79(dqd,J＝24.0,12.0,4.4Hz,2H),1.62–1.54(m,2H),1.19(t,J＝4.8Hz,2H),1.10(d,J＝6.7Hz,2H)。
Example 3(LEC002-109)
LC-MS(ESI):m/z＝402.18[M-H]-。
1H NMR(500MHz,Chloroform-d)δ8.56(d,J＝8.4Hz,1H),7.64(s,1H),7.59(d,J＝8.4Hz,1H),7.53(d,J＝7.8Hz,1H),7.26(s,1H),6.42(d,J＝7.8Hz,1H),3.98–3.89(m,2H),3.70(tt,J＝7.4,3.8Hz,1H),3.29(qd,J＝12.1,2.1Hz,2H),2.59(tt,J＝11.8,3.8Hz,1H),1.88-1.73(m,2H),1.64–1.50(m,2H),1.28–1.20(m,2H),1.13(d,J＝7.3Hz,2H)。
Example 4(LEC002-173)
LC-MS(ESI):m/z＝461.20[M-H]-
1H NMR(500MHz,Chloroform-d)δ8.79(s,1H),8.19(d,J＝10.6Hz,1H),7.64(s,1H),7.52(d,J＝7.7Hz,1H),7.15(s,1H),7.10(d,J＝8.9Hz,1H),6.38(d,J＝7.7Hz,1H),3.98–3.83(m,4H),3.76(q,J＝7.8Hz,1H),3.71–3.61(m,1H),3.52(td,J＝10.9,10.5,5.8Hz,2H),3.28(q,J＝10.0Hz,2H),2.70–2.46(m,2H),2.16–2.05(m,1H),1.78(d,J＝13.1Hz,2H),1.71-1.68(m,1H),1.56(d,J＝13.2Hz,2H),1.26(d,J＝15.5Hz,1H),1.24-1.20(m,2H),1.11(d,J＝6.8Hz,2H)。
Example 5(LEC001-145)
LC-MS(ESI):m/z＝392.1[M-H]-。
1H NMR(500MHz,Chloroform-d)δ9.08(d,J＝2.0Hz,1H),8.15(dd,J＝8.9,2.1Hz,1H),7.65(s,1H),7.47(d,J＝7.8Hz,1H),7.04(d,J＝8.9Hz,1H),6.36(d,J＝7.8Hz,1H),3.94(s,3H),3.88(dq,J＝11.2,2.1Hz,2H),3.68(q,J＝11.3,5.7Hz,1H),3.35-3.25(m,2H),2.59(tt,J＝11.8,3.8Hz,1H),1.80-1.70(m,2H),1.56(d,J＝13.4Hz,2H),1.24–1.19(m,2H),1.11(d,J＝7.0Hz,2H)。
Example 6(LEC002-172)
LC-MS(ESI):m/z＝378.22[M-H]-。
1H NMR(500MHz,CDCl3)δ9.21(s,1H),8.21(d,J＝8.9Hz,1H),7.71(s,1H),7.51(t,J＝16.8Hz,1H),7.07(dd,J＝18.0,8.7Hz,1H),6.47(t,J＝10.0Hz,1H),4.40(s,1H),3.90(d,J＝11.6Hz,2H),3.69(d,J＝3.5Hz,1H),3.30(q,J＝11.7Hz,2H),2.61(t,J＝11.7Hz,1H),1.78(dt,J＝37.7,11.6Hz,2H),1.58(d,J＝13.2Hz,2H),1.21(d,J＝21.7Hz,2H),1.12(d,J＝6.9Hz,2H)。
Example 7(LEC002-186)
The synthetic route is as follows:
the synthesis steps are as follows:
add the product of example 1 (0.10g,0.24mmol), 4, 6-diaminopyrimidine (0.053g,0.48mmol), cesium carbonate (0.20g,0.60mmol), palladium acetate (0.007g,0.03mmol), Xantphos ligand (0.035g,0.06mmol) and 1, 4-dioxane (18mL) to the microwave tube. After the addition, the reaction was stirred at 150 ℃ for 30 minutes under microwave conditions. Cooled to room temperature, concentrated to remove the solvent, and the residue was purified by silica gel column chromatography to give the product (0.045g, 42%) as a white solid.
LC-MS(ESI):m/z＝442.13[M-H]-。
1H NMR(500MHz,DMSO-d6)δ9.16(s,1H),8.34(s,1H),8.21(s,1H),8.06(s,1H),7.82(dd,J＝14.0,8.4Hz,2H),7.38(d,J＝7.5Hz,1H),6.98(d,J＝9.2Hz,1H),6.39(s,2H),6.07(d,J＝7.6Hz,1H),3.89(d,J＝11.0Hz,2H),3.76(d,J＝11.1Hz,1H),3.38-3.29(m,2H),2.60(t,J＝13.3Hz,2H),1.62-1.48(m,3H),1.13-1.09(m,2H),1.00(t,J＝6.6Hz,2H)。
The compounds of examples 8 to 10 were prepared according to the preparation scheme of example 7.
Example 8(LEC015-008)
LC-MS(ESI):m/z＝525.24[M-H]-。
1H NMR(500MHz,Chloroform-d)δ8.27(s,1H),8.25(s,1H),7.74(d,J＝9.2Hz,1H),7.61(s,1H),7.45(d,J＝7.6Hz,1H),7.02(d,J＝8.9Hz,2H),6.31(d,J＝7.7Hz,1H),5.99(s,1H),3.90(d,J＝12.8Hz,2H),3.73-3.66(m,1H),3.65-3.58(m,4H),3.31(q,J＝11.0Hz,2H),2.70-2.62(m,2H),2.49-2.45(m,4H),2.33(s,3H),1.61-1.48(m,3H),1.12-1.07(m,2H),0.98-0.95(m,2H)。
Example 9(LEC015-013)
LC-MS(ESI):m/z＝484.20[M-H]-。
1H NMR(500MHz,Chloroform-d)δ8.41(d,J＝5.6Hz,1H),8.27(d,J＝2.6Hz,1H),7.70(d,J＝2.3Hz,1H),7.64(s,1H),7.55–7.48(m,2H),7.11–7.00(m,3H),6.37(d,J＝7.7Hz,1H),3.98(s,3H),3.92(d,J＝9.8Hz,2H),3.74–3.62(m,1H),3.40–3.25(m,2H),2.75–2.60(m,1H),1.88–1.72(m,2H),1.66–1.61(m,2H),1.21(d,J＝2.7Hz,2H),1.12(d,J＝7.2Hz,2H)。
Example 10(LEC002-183)
LC-MS(ESI):m/z＝667.20[M-H]-。
1H NMR(500MHz,Chloroform-d)δ8.69(s,2H),7.97(t,J＝7.2Hz,2H),7.66(s,2H),7.49(d,J＝7.7Hz,2H),7.11(d,J＝8.8Hz,2H),6.37(d,J＝7.7Hz,2H),3.91(d,J＝11.0Hz,4H),3.70-3.68(m,2H),3.31(q,J＝11.5Hz,4H),2.65(t,J＝11.7Hz,2H),1.91–1.71(m,4H),1.63(d,J＝15.0Hz,4H),1.24-1.22(m,4H),1.13(t,J＝7.0Hz,4H)。
Biological evaluation test:
the compounds of examples 1-10 were tested for their inhibitory effect on TGF- β R1(ALK5) kinase activity.
The inhibitory effect of compounds on TGF- β R1(ALK5) kinase activity was determined using the following assay:
by LanthaScreenTMThe Eu Kinase Binding Assay method detects the inhibitory activity of a series of compounds on ALK5 Kinase, and the specific test flow is as follows: the compounds were prepared in 10mM stock solution in DMSO, diluted 1:3 gradient, and loaded in 384-PP (from LABCYTE, P-05525) for use; preparing 1X Kinase Buffer A to dilute the following reaction reagents; 15nL of compound was added to a reaction plate (from Perkin Elmer, model ProxiPlate-384 Plus) using a micropipette system (from LABCYTE, model Echo 520); add 5. mu.L of ALK5 solution (available from Thermoscientific form, PV5837) per well; adding 5 μ L Eu-Anti-GST Antibody solution (from Thermo Scientific Forma, PV5594) into each well, and shaking for 15 min; mu.L of Kinase Tracer178solution (available from Thermo Scientific Forma, PV5593) was added to each well and mixed by shaking. The total reaction system contained 50mM Tris (pH 7.5), 150mM NaCl, 0.5mM EDTA, 0.02%
X-100, 2mM DTT, 50% Glycerol, 50mM HEPES (pH 7.5), 10mM MgCl2, 1mM EGTA, 0.01% Brij-35, 5nM ALK5, 2nM Eu-Anti-GSTANTIBody, 20nM Kinase Tracer178, 0.1% DMSO. The reaction plate was incubated at 30 ℃ for 60 min. The test was performed using a multi-label microplate tester (available from PE corporation, model Envision multilabel reader). Data analysis was performed using GraphPadPrism 5Demo software. Using a non-linear regression modelComputationally related compound IC50Values, repeated three times, averaged.
IC of the Compounds of examples 1 to 10 on TGF- β R1(ALK5) kinase Activity measured according to the above-described method50The values are given in table 1 below.
TABLE 1 IC inhibition of ALK5 kinase activity by compounds50Value of
| Example numbering | Batch number | ALK5 Activity IC50 |
| 1 | LEC002-77 | 30μM |
| 2 | LEC002-078 | 30μM |
| 3 | LEC002-109 | 30μM |
| 4 | LEC002-173 | 10μM |
| 5 | LEC001-145 | 30μM |
| 6 | LEC002-172 | 10μM |
| 7 | LEC002-186 | 1000nM |
| 8 | LEC015-008 | 108nM |
| 9 | LEC015-013 | 1140nM |
| 10 | LEC002-183 | 3000nM |
As is clear from Table 1, the compounds of the present invention have significant inhibitory effects on TGF- β R1(ALK5) kinase activity, and among them, the compounds of examples 7 to 9 are more preferable.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (12)
1. 4- (4-pyrazolyloxy) quinoline compounds with the following general structural formula, or tautomers, or racemes, or racemates, or enantiomers, or diastereomers, or pharmaceutically acceptable salts thereof:
wherein R is1Selected from H, C1-C10 straight chain or C3-C10 branched chain alkyl, C1-C10 straight chain or C3-C10 branched chain alkoxy, C2-C10 cycloalkoxy, C5-C10 aryl, C2-C10 heteroaryl;
R2selected from H, C1-C10 straight chain or C3-C10 branched chain alkyl, C1-C10 straight chain or C3-C10 branched chain alkoxy, C3-C10 naphthenic base, C2-C10 cycloalkoxy, C5-C10 aryl and C2-C10 heteroaryl;
R3selected from H, C1-C10 straight chain or C3-C10 branched chain alkyl, C1-C10 straight chain or C3-C10 branched chain alkoxy, C3-C10 naphthenic base, C2-C10 cycloalkoxy, C5-C10 aryl and C2-C10 heteroaryl;
R4selected from H, halogen, C1-C10 linear or C3-C10 branched alkyl, C1-C10 linear or C3-C10 branched alkoxy, C3-C10 cycloalkyl, C2-C10 cycloalkoxy, ester group, carboxyl group, amine group, amide group, C5-C10 aryl, C2-C10 heteroaryl, C2-C5 heteroaryl ether, C1-C5 heterocyclyl or a combination thereof;
R5selected from H, halogen, C1-C10 linear or C3-C5 branched alkyl, C1-C10 linear or C3-C5 branched alkoxy or combinations thereof.
2. The 4- (4-pyrazolyloxy) quinoline compound according to claim 1, wherein R is selected from the group consisting of a tautomer, a racemate, an enantiomer, a diastereomer, and a pharmaceutically acceptable salt thereof4Selected from: H. halogen, ester group, carboxyl group or group having the structural formula shown below:
wherein A is1Selected from the group consisting of C1-C3 alkyl carboxamides, amine groups or absent;
A2selected from C2-C6 cycloalkoxy, C4-C10 azaaryl;
A3selected from amine, ester, C2-C5 azaheterocyclyl, C2-C5 azaaryl ether or absent;
A4the compound is selected from C4-C6 cycloalkoxy, C3-C5 cycloalkyl, C1-C3 straight chain or C3 branched chain alkyl, and n is 0-3.
3. The 4- (4-pyrazolyloxy) quinoline compound according to claim 2, wherein R is selected from the group consisting of a tautomer, a racemate, an enantiomer, a diastereomer, and a pharmaceutically acceptable salt thereof4Selected from the group having the general structural formula shown below:
wherein A is1Selected from amine groups or absent;
A2is selected from
Wherein, X1Each independently is C or N, and at least one X1Is N;
A3selected from amino, carbomethoxy, carboxyl, amino,
Wherein, X2Each independently is C or N, and at least one X2Is N;
A4is selected from C4-C6 cycloalkoxy, cyclopropyl, methyl and ethyl, and n is 0-2.
4. 4- (4-pyrazolyloxy) quinolines according to claim 1, or tautomers thereof, or racemates thereofA compound represented by formula (I), wherein R represents a group represented by formula (I), or a racemate thereof, or an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof5Selected from: H. halogen, C1-C2 linear alkoxy, halogenated C1-C2 linear alkyl.
5. The 4- (4-pyrazolyloxy) quinoline compound according to any one of claims 1 to 4, wherein R is R, a tautomer thereof, a racemate thereof, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof1-3Each independently selected from H, C3-C5 cycloalkyl, C3-C6 cycloalkoxy.
6. The 4- (4-pyrazolyloxy) quinoline compound according to claim 5, wherein the compound has the following general structural formula:
7. the 4- (4-pyrazolyloxy) quinoline compound according to claim 1, wherein the 4- (4-pyrazolyloxy) quinoline compound is selected from the group consisting of:
8. the method for preparing 4- (4-pyrazolyloxy) quinolines as claimed in any of claims 1 to 7, comprising the steps of:
(1) reacting the compound 1 with a bromization reagent to obtain a compound 2;
(2) carrying out substitution reaction on the compound 2 and the compound 3 to obtain a compound 4;
(3) carrying out substitution reaction on the compound 4 and the compound 5 to obtain a compound 6;
(4) reacting the compound 6 with hydrazine hydrate to obtain a compound 7;
(5) the compound 7 and the compound 8 are subjected to substitution reaction.
9. The method for preparing 4- (4-pyrazolyloxy) quinolines as claimed in any of claims 1 to 7, comprising the steps of:
(1) reacting the compound 1 with a bromization reagent to obtain a compound 2;
(2) carrying out substitution reaction on the compound 2 and the compound a to obtain a compound b;
(3) carrying out substitution reaction on the compound b and a compound 5 to obtain a compound c;
(4) reacting the compound c with hydrazine hydrate to obtain a compound d;
(5) carrying out substitution reaction on the compound d and a compound 8 to obtain a compound e;
(6) and (3) carrying out substitution reaction on the compound e and the compound f.
10. A pharmaceutical composition, comprising an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient comprises the 4- (4-pyrazolyloxy) quinoline compound according to any one of claims 1 to 7, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
11. Use of the 4- (4-pyrazolyloxy) quinoline compound according to any one of claims 1 to 7, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for preparing a TGF- β signaling pathway inhibitor.
12. Use of the 4- (4-pyrazolyloxy) quinoline compound according to any one of claims 1 to 7, or a tautomer thereof, or a racemate thereof, or an enantiomer thereof, or a diastereomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 in the preparation of a medicament for preventing or treating cancer, infectious diseases, autoimmune diseases, tissue fibrosis, dysplasia cartilaginosa, or pulmonary hypertension.
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