CN111116565B - 2-aryl-4- (4-pyrazolyloxy) pyridine compound, preparation method thereof, pharmaceutical composition and application thereof - Google Patents

2-aryl-4- (4-pyrazolyloxy) pyridine compound, preparation method thereof, pharmaceutical composition and application thereof Download PDF

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CN111116565B
CN111116565B CN202010247992.3A CN202010247992A CN111116565B CN 111116565 B CN111116565 B CN 111116565B CN 202010247992 A CN202010247992 A CN 202010247992A CN 111116565 B CN111116565 B CN 111116565B
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compound
aryl
pyrazolyloxy
reacting
pharmaceutically acceptable
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CN111116565A (en
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吴晓焜
马洪艳
李孟心
雷桥仕
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Zhongkelijian Pharmaceutical Guangzhou Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/14—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 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

The invention relates to a 2-aryl-4- (4-pyrazolyloxy) pyridine compound, a preparation method thereof, a pharmaceutical composition and application thereof, in particular to a 2-aryl-4- (4-pyrazolyloxy) pyridine compound with a structural general formula shown in the specification, or a pharmaceutically acceptable salt thereof, which can be used as a therapeutic preparation, particularly as a TGF- β signal pathway inhibitor, and has good application prospect in preparation of drugs for preventing, relieving and treating diseases mediated by TGF- β signal pathway disorder.

Description

2-aryl-4- (4-pyrazolyloxy) pyridine compound, preparation method thereof, pharmaceutical composition and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to 2-aryl-4- (4-pyrazolyloxy) pyridine compounds, a preparation method, a pharmaceutical composition and application thereof.
Background
However, various current cancer therapies still have a plurality of defects, such as very low effective response rate of patients with PD-1/PD-L1 drugs in the cancer immunotherapy and effectiveness on only 10-20% of patients, so that improvement on the existing therapies, particularly cancer treatment schemes, is urgently needed to increase the remission rate and survival rate of patients.
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 composed of three subtypes (β, β, β) free ligand, which bind to cell surface TGF- β transmembrane serine/threonine kinase receptors to form a complex activating receptor-specific SMAD protein (R-SAMD), which binds to common SMAD (co-SMAD) and then enters into the nucleus and further interacts with other cytokines to regulate transcription of genes, TGF- β signaling pathway abnormalities can lead to many diseases, such as cancer, tissue fibrosis, arterial metastasis, metastatic metastasis, and the like, and is often tested against early stage cancers, especially cancer metastasis, and tumor metastasis, and the like, and thus has been shown to be effective in clinical tests for enhancing the survival of various cancers, especially in early stage cancers, especially in clinical tests for enhancing the survival of tumors, especially in early stage cancers, especially in clinical tests for enhancing the survival of animals, especially in response to early stage cancers, especially in clinical tests for anti-tumor cancers, especially in early stage cancers, especially in clinical tests for enhancing the survival of tumors by administering TGF- β/SMAD signaling.
Based on the characteristics of a TGF- β signal path, a TGF- β protein type I receptor (TGF β receptor I, also called active-like kinase 5, A β K5) 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 the A β K5 protein is inhibited through small molecule selective targeting, the transmission of TGF- β signals into a cell nucleus is weakened or blocked, and the TGF- β signal path is adjusted to be normal, so that various diseases mediated by the TGF- β signal path are treated.
Disclosure of Invention
Based on the above, there is a need for 2-aryl-4- (4-pyrazolyloxy) pyridines which can be used as therapeutic agents, particularly as TGF- β signaling pathway inhibitors, and have a promising application prospect in the preparation of drugs for preventing, alleviating and treating diseases mediated by TGF- β signaling pathway disorders.
2-aryl-4- (4-pyrazolyloxy) pyridines having the structural formula shown below, or a pharmaceutically acceptable salt thereof:
Figure 100002_DEST_PATH_IMAGE001
wherein R is2Selected from H, C1-C10 linear chain or C3-C10 branched chain alkyl, C1-C10 linear chain or C3-C10 branched chain alkoxy, C3-C10 naphthenic baseC2-C10 cycloalkoxy, C5-C10 aryl, C2-C10 heteroaryl;
R3one or more of halogen, C1-C5 straight chain or C3-C5 branched chain alkoxy, C2-C10 cycloalkoxy, C5-C10 aryl and C2-C10 heteroaryl;
ar is at least one R0A substituted C5-C15 aryl or C2-C10 heteroaryl; wherein R is0Each independently selected from H, halogen, C1-C5 linear or C3-C5 branched alkyl, C1-C5 linear or C3-C5 branched alkoxy, C2-C10 nitrogen heterocyclic group, C2-C5 heteroaryl, amido, -NH2、-NH-、
Figure 976237DEST_PATH_IMAGE002
、
Figure 100002_DEST_PATH_IMAGE003
、
Figure 259320DEST_PATH_IMAGE004
One or more of cyano, hydroxy and alkenyl, and R on adjacent C atoms0The groups may be linked to form a ring.
In one embodiment, Ar is selected from the group having the general structural formula shown below:
Figure 100002_DEST_PATH_IMAGE005
n =1, 2 or 3;
Ar0selected from the group consisting of C5-C10 aryl, C2-C5 heteroaryl;
R0each independently selected from H, halogen, C1-C5 linear or C3-C5 branched alkyl, C1-C5 linear or C3-C5 branched alkoxy, C2-C10 nitrogen heterocyclic group, C2-C5 heteroaryl, amido, -NH2、-NH-、
Figure 643028DEST_PATH_IMAGE002
、
Figure 960745DEST_PATH_IMAGE003
、
Figure 302865DEST_PATH_IMAGE004
One or more of cyano, hydroxy and alkenyl, and R on adjacent C atoms0The groups may be linked to form a ring.
In one embodiment, Ar is selected from the group consisting of:
Figure 355135DEST_PATH_IMAGE006
、
Figure 100002_DEST_PATH_IMAGE007
wherein X is independently C or N, and at least one X is N.
In one embodiment, R0Each independently selected from the group consisting of:
-F、-Cl、-（C=O）NH2、-（C=O）NHCH3、-NHCH2C（CH3）OH、-OCH3、
-NH（C=O）CH3、-（C=O）N（CH3）2、-CN、-（C=O）OCH3、-CF3、
Figure 729484DEST_PATH_IMAGE008
、
Figure 100002_DEST_PATH_IMAGE009
or two R on adjacent C atoms0Radical formation
Figure 104971DEST_PATH_IMAGE010
。
In one embodiment, R3Selected from C3-C7 cycloalkoxy, C5-C7 aryl and halogen combined group, and C5-C7 aryl and C1-C2 alkoxy combined group.
In one embodiment, R3Selected from the group consisting of:
Figure 100002_DEST_PATH_IMAGE011
、
Figure 867259DEST_PATH_IMAGE012
、
Figure 100002_DEST_PATH_IMAGE013
。
in one embodiment, R2Selected from H, C3-C5 cycloalkyl.
In one embodiment, the 2-aryl-4- (4-pyrazolyloxy) pyridine compound is selected from the following compounds:
Figure 875666DEST_PATH_IMAGE014
、
Figure 100002_DEST_PATH_IMAGE015
、
Figure 116024DEST_PATH_IMAGE016
、
Figure 100002_DEST_PATH_IMAGE017
、
Figure 159066DEST_PATH_IMAGE018
、
Figure 100002_DEST_PATH_IMAGE019
、
Figure 842988DEST_PATH_IMAGE020
、
Figure 100002_DEST_PATH_IMAGE021
、
Figure 322380DEST_PATH_IMAGE022
、
Figure 100002_DEST_PATH_IMAGE023
、
Figure 117161DEST_PATH_IMAGE024
、
Figure 100002_DEST_PATH_IMAGE025
、
Figure 263977DEST_PATH_IMAGE026
、
Figure 100002_DEST_PATH_IMAGE027
、
Figure 853222DEST_PATH_IMAGE028
、
Figure 100002_DEST_PATH_IMAGE029
、
Figure 351068DEST_PATH_IMAGE030
、
Figure 100002_DEST_PATH_IMAGE031
、
Figure 683960DEST_PATH_IMAGE032
、
Figure 100002_DEST_PATH_IMAGE033
、
Figure 436016DEST_PATH_IMAGE034
、
Figure 100002_DEST_PATH_IMAGE035
。
the invention also provides a preparation method of the 2-aryl-4- (4-pyrazolyloxy) pyridine compound, which comprises the following steps:
Figure 711008DEST_PATH_IMAGE036
(1) reacting the compound 1 with a halogenating reagent to obtain a compound 2, wherein X represents halogen;
(2) carrying out substitution reaction on the compound 2 and 2-bromo-4-hydroxypyridine to obtain a compound 3;
(3) reacting the compound 3 with N, N-dimethylformamide dimethyl acetal to obtain a compound 4;
(4) reacting the compound 4 with hydrazine hydrate to obtain a compound 5;
(5) compound 5 and R2-B（OH）2Carrying out coupling or substitution reaction to obtain a compound 6;
(6) compound 6 with Ar-B (OH)2Carrying out Suzuki coupling reaction;
wherein R is2、R3And Ar is as defined above.
The invention also provides a preparation method of the 2-aryl-4- (4-pyrazolyloxy) pyridine compound, which comprises the following steps:
Figure DEST_PATH_IMAGE037
(1) reacting the compound 1 with a halogenating reagent to obtain a compound 2, wherein X represents halogen;
(2) carrying out substitution reaction on the compound 2 and 2-bromo-4-hydroxypyridine to obtain a compound 3;
(3) reacting the compound 3 with N, N-dimethylformamide dimethyl acetal to obtain a compound 4;
(4) reacting the compound 4 with hydrazine hydrate to obtain a compound 5;
(5) compound 5 and R2-B（OH）2Reacting to obtain a compound 6;
(6) compound 6 with Cl-Ar0-B（OH）2Carrying out Suzuki coupling reaction to obtain a compound 7;
(7) carrying out a coupling reaction with a compound 7 to react the group-Ar0-ClReacting to form-Ar;
wherein R is2、R3Ar and Ar0The definition of (A) is as described above.
The invention also provides a pharmaceutical composition, which comprises an active ingredient and a pharmaceutically acceptable auxiliary material, wherein the active ingredient comprises the 2-aryl-4- (4-pyrazolyloxy) pyridine compound or the pharmaceutically acceptable salt thereof.
The invention also provides the application of the 2-aryl-4- (4-pyrazolyloxy) pyridine compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing TGF- β signaling pathway inhibitors.
The invention also provides an application of the 2-aryl-4- (4-pyrazolyloxy) pyridine compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing a medicament for preventing and treating cancer, infectious diseases, autoimmune diseases, tissue fibrosis, abnormal cartilage development or pulmonary hypertension mediated by TGF- β signal channel disorder.
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) pyridine, 2-Ar substitution is carried out on a pyridine ring, the action mechanism is that the molecular framework structure is used as an A L K5 inhibitor to regulate and control A L K5, so that the TGF- β signal path is restored to normal, and the effect of intervening (preventing, relieving or treating) related diseases is achieved, and the diseases can be specifically cancer, infectious diseases, autoimmune diseases, tissue fibrosis, abnormal cartilage development or pulmonary hypertension, and have good application prospect.
Detailed Description
The 2-aryl-4- (4-pyrazolyloxy) pyridines, the preparation method, the pharmaceutical composition and the use of the present invention will be described in 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.
Embodiments of the present invention provide 2-aryl-4- (4-pyrazolyloxy) pyridines having the general structural formula shown below, or a pharmaceutically acceptable salt thereof:
Figure 181304DEST_PATH_IMAGE001
wherein R is2Selected 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;
R3one or more of halogen, C1-C5 straight chain or C3-C5 branched chain alkoxy, C2-C10 cycloalkoxy, C5-C10 aryl and C2-C10 heteroaryl;
ar is at least one R0A substituted C5-C15 aryl or C2-C10 heteroaryl; wherein R is0Each independently selected from H, halogen, C1-C5 linear or C3-C5 branched alkyl, C1-C5 linear or C3-C5 branched alkoxy, C2-C10 nitrogen heterocyclic group, C2-C5 heteroaryl, amido, -NH2、-NH-、
Figure 98313DEST_PATH_IMAGE002
、
Figure 970454DEST_PATH_IMAGE003
、
Figure 963818DEST_PATH_IMAGE004
One or more of cyano, hydroxy and alkenyl, and R on adjacent C atoms0The groups may be linked to form a ring.
The general formula of the structure has 4- (4-pyrazolyloxy) pyridine and a molecular skeleton with 2-Ar substitution on the pyridine ring, and proper R is performed at a specific position1-3The substitution can achieve excellent A L K5 inhibition effect, and further regulate and control A L K5, 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, Ar is selected from the group having the general structural formula shown below:
Figure 186989DEST_PATH_IMAGE005
n =1, 2 or 3;
Ar0selected from the group consisting of C5-C10 aryl, C2-C5 heteroaryl;
R0each independently selected from H, halogen, C1-C5 linear or C3-C5 branched alkyl, C1-C5 linear or C3-C5 branched alkoxy, C2-C10 nitrogen heterocyclic group, C2-C5 heteroaryl, amido, -NH2、-NH-、
Figure 392842DEST_PATH_IMAGE002
、
Figure 899916DEST_PATH_IMAGE003
、
Figure 798602DEST_PATH_IMAGE004
One or more of cyano, hydroxy and alkenyl, and R on adjacent C atoms0The groups may be linked to form a ring.
In one particular embodiment, Ar is selected from the following groups (.' represents a substitution site):
Figure 977910DEST_PATH_IMAGE038
、
Figure DEST_PATH_IMAGE039
wherein X is independently C or N, and at least one X is N.
In one specific embodiment, R0Each independently selected from the group consisting of:
-F、-Cl、-（C=O）NH2、-（C=O）NHCH3、-NHCH2C（CH3）OH、-OCH3、
-NH（C=O）CH3、-（C=O）N（CH3）2、-CN、-（C=O）OCH3、-CF3、
Figure 971143DEST_PATH_IMAGE008
、
Figure 83455DEST_PATH_IMAGE009
or two R on adjacent C atoms0Radical formation
Figure 153042DEST_PATH_IMAGE010
。
In one specific embodiment, R3Selected from C3-C7 cycloalkoxy, C5-C7 aryl and halogen combined group, and C5-C7 aryl and C1-C2 alkoxy combined group. More specifically, R3Selected from halogen substituted or C1-C2 alkoxy substituted C5-C7 aryl.
In one specific embodiment, R3Selected from the group consisting of:
Figure 350806DEST_PATH_IMAGE011
、
Figure 898462DEST_PATH_IMAGE012
、
Figure 114548DEST_PATH_IMAGE013
。
in one specific embodiment, R2Selected from H, C3-C5 cycloalkyl. More specifically, R2Is cyclopropyl.
In one specific embodiment, the 2-aryl-4- (4-pyrazolyloxy) pyridine compound is selected from the following compounds:
Figure 355037DEST_PATH_IMAGE014
、
Figure 40096DEST_PATH_IMAGE015
、
Figure 391443DEST_PATH_IMAGE016
、
Figure 478347DEST_PATH_IMAGE040
、
Figure 139005DEST_PATH_IMAGE018
、
Figure 45781DEST_PATH_IMAGE019
、
Figure DEST_PATH_IMAGE041
、
Figure 669660DEST_PATH_IMAGE021
、
Figure 860339DEST_PATH_IMAGE022
、
Figure 177051DEST_PATH_IMAGE023
、
Figure 571123DEST_PATH_IMAGE024
、
Figure 264273DEST_PATH_IMAGE025
、
Figure 309458DEST_PATH_IMAGE042
、
Figure DEST_PATH_IMAGE043
、
Figure 797071DEST_PATH_IMAGE028
、
Figure 678439DEST_PATH_IMAGE029
、
Figure 909701DEST_PATH_IMAGE030
、
Figure 809392DEST_PATH_IMAGE031
、
Figure 733486DEST_PATH_IMAGE044
、
Figure 102150DEST_PATH_IMAGE033
、
Figure 137103DEST_PATH_IMAGE034
、
Figure DEST_PATH_IMAGE045
。
the embodiment of the invention also provides a preparation method of the 2-aryl-4- (4-pyrazolyloxy) pyridine compound, which has the advantages of easily obtained raw materials and simple steps, and specifically comprises the following steps:
Figure 649159DEST_PATH_IMAGE036
(1) reacting the compound 1 with a halogenating reagent to obtain a compound 2, wherein X represents halogen;
(2) carrying out substitution reaction on the compound 2 and 2-bromo-4-hydroxypyridine to obtain a compound 3;
(3) reacting the compound 3 with N, N-dimethylformamide dimethyl acetal to obtain a compound 4;
(4) reacting the compound 4 with hydrazine hydrate to obtain a compound 5;
(5) compound 5 and R2-B（OH）2Carrying out coupling or substitution reaction to obtain a compound 6;
(6) compound 6 with Ar-B (OH)2Suzuki coupling reaction was performed.
Wherein R is2、R3And Ar is as defined above.
The embodiment of the invention also provides a preparation method of the 2-aryl-4- (4-pyrazolyloxy) pyridine compound, which has the advantages of easily obtained raw materials and simple steps, and specifically comprises the following steps:
Figure 744154DEST_PATH_IMAGE037
(1) reacting the compound 1 with a halogenating reagent to obtain a compound 2, wherein X represents halogen;
(2) carrying out substitution reaction on the compound 2 and 2-bromo-4-hydroxypyridine to obtain a compound 3;
(3) reacting the compound 3 with N, N-dimethylformamide dimethyl acetal to obtain a compound 4;
(4) reacting the compound 4 with hydrazine hydrate to obtain a compound 5;
(5) compound 5 and R2-B（OH）2Reacting to obtain a compound 6;
(6) compound 6 with Cl-Ar0-B（OH）2Carrying out Suzuki coupling reaction to obtain a compound 7;
(7) carrying out a coupling reaction with a compound 7 to react the group-Ar0-Cl reactionforming-Ar.
Wherein R is2、R3Ar and Ar0The definition of (A) is as described above.
The embodiment of the invention also provides a pharmaceutical composition, which comprises an active ingredient and a pharmaceutically acceptable auxiliary material, wherein the active ingredient comprises the 2-aryl-4- (4-pyrazolyloxy) pyridine compound or the pharmaceutically acceptable salt thereof.
Embodiments of the present invention also provide the use of a 2-aryl-4- (4-pyrazolyloxy) pyridine compound, or a pharmaceutically acceptable salt thereof, as described above, or a pharmaceutical composition, as described above, in the preparation of an inhibitor of the TGF- β signaling pathway.
The embodiment of the invention also provides an application of the 2-aryl-4- (4-pyrazolyloxy) pyridine compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preparing a medicine with the effect of preventing and treating cancers, infectious diseases, autoimmune diseases, tissue fibrosis, dysplasia cartilaginis or pulmonary hypertension mediated by TGF- β signaling pathway disorder.
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 (produced by Qingdao ocean chemical plant) is used for column chromatography, a T L C silica gel plate is an HSGF-254 thin layer chromatography prefabricated plate produced by a tobacco stage chemical plant, the boiling range of petroleum ether is 60-90 ℃, and an ultraviolet lamp, an iodine cylinder, phosphomolybdic acid and the like are used for color development.
The abbreviations used in the present invention are the same as those commonly used in the art and have the following meanings:
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 (L EC 002-079)
Figure 600115DEST_PATH_IMAGE014
Synthetic route to compound 1:
Figure 438758DEST_PATH_IMAGE046
step A:
1- (tetrahydro-2H-pyran-4-yl) ethanone (5.00g, 39.01mmol) was added to the flask, dissolved in methanol (50m L), and while stirring at room temperature, bromosuccinimide (6.90g, 39.01mmol) was additionally weighed, dissolved in methanol (50m L), slowly added to the reaction solution, then transferred under oil bath conditions, stirred at 50 ℃ for 3H, then cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 4/1) to obtain the objective product 1-a (7.80g, yield: 97.50%) as a white solid.
MS(m/z):208.01[M+H]。
And B:
to a flask were added 2-bromo-4-hydroxypyridine (3.00g, 17.24mmol), intermediate 1-a (7.10g,34.48mmol), potassium carbonate (4.70g, 34.48mmol) and acetonitrile (30m L.) after addition, the reaction was stirred under oil bath conditions at 60 ℃ for 5h, then cooled to room temperature, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 1/1) to give the desired product 1-b (4.61g, yield: 89.20%) as a brown oil.
MS(m/z):301.01[M+H]。
And C:
the flask was charged with intermediate 1-b (4.50g, 14.99mmol), N, N-dimethylformamide dimethyl acetal (8.93g, 74.94 mmol). After the addition, the reaction was stirred at 105 ℃ for 3h in an oil bath. Then, it was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was eluted with petroleum ether to give the objective product 1-c (5.07g, yield: 95.32%) as a brown solid.
MS(m/z):356.01[M+H]。
Step D:
to a flask was added intermediate 1-c (5.07g, 14.28mmol), hydrazine hydrate solution (1.43g, 28.57mmol) and ethanol (30m L), acetic acid (10m L.) after addition, the reaction was stirred under oil bath conditions at 50 ℃ for 6h then cooled to room temperature, the solvent was removed by concentration, and the residue was added saturated NaHCO3Extracting the solution with ethyl acetate for three times to obtain organic phase, and adding anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate ═ 100%) to give the objective product 1-d (4.15g, yield: 90.06%) as a colorless oil.
MS(m/z):324.01[M+H]。
Step E:
to the flask was added copper acetate (2.79g, 15.36mmol), 2,2' -bipyridine (2.40g, 15.36mmol) and dichloroethane (50m L.) after the addition was completed, the reaction was stirred at 75 ℃ for 25min under an oil bath, then cooled to room temperature, and intermediate 1-d (4.15g, 12.80mmol), cyclopropylboronic acid (2.20g, 25.60mmol) and NaCO were added3(2.71g,25.60mmol) and air was bubbled through the bottom of the flask and the reaction was stirred for an additional 6h at 75 ℃ under an oil bath. Then, it was cooled to room temperature, ethyl acetate was added and the organic phase was filtered, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate 1/2) to give the objective product 1-e (3.78g, yield: 81.25%) as a colorless solid.
1H NMR (500 MHz, CDCl3) 8.20 (d, J = 5.6 Hz, 1H), 7.30 (s, 1H),7.02 (s, 1H), 6.85 (d, J = 5.6 Hz, 1H), 3.97 (d, J = 11.2 Hz, 2H), 3.57 –3.55 (m, 1H), 3.41 (t, J = 11.7 Hz, 2H), 2.78 – 2.73 (m, 1H), 1.89 – 1.80 (m,2H), 1.71 (d, J = 14.8 Hz, 2H), 1.11 (s, 2H), 1.02 (d, J = 6.8 Hz, 2H)。
MS(m/z):364.10[M+H]。HPLC:90.22%。
Step F:
into the flask were added intermediate 1-e (0.20g, 0.54mmol), 3-acetamidophenylboronic acid (0.14g,0.82mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (0.44g, 0.05mmol), potassium carbonate (0.22g, 1.62mmol) and 1, 4-dioxane (12m L), water (3m L.) after addition, the reaction was stirred under microwave conditions at 150 ℃ for 30min, then cooled to room temperature, NH was added4Extracting with Cl solution and ethyl acetate for three times to obtain organic phase, and adding anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate ═ 100%) to give compound 1(0.14g, yield: 65.40%) as a colorless oil.
1H NMR (500 MHz, CDCl3) 8.48 (d, J = 5.6 Hz, 1H), 7.81 (s, 1H),7.68 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H),7.32 (s, 1H), 7.29 (d, J = 1.8 Hz, 1H), 6.78 (d, J = 5.6 Hz, 1H), 3.96 (d, J= 13.8 Hz, 1H), 3.58 – 3.53 (m, 1H), 3.41 (t, J = 11.6 Hz, 2H), 2.84 – 2.78(m, 1H), 2.15 (s, 3H), 1.92 – 1.84 (m, 2H), 1.74 (d, J = 13.0 Hz, 2H), 1.13 –1.09 (m, 2H), 1.03 – 0.99 (m, 2H)。
MS(m/z):419.2[M+H]。HPLC:99.62%。
Example 2 (L EC 002-084)
Figure 313042DEST_PATH_IMAGE015
The compound of example 2 was obtained as a colorless oil according to the preparation procedure of example 1.
1H NMR (500 MHz, CDCl3) 8.48 (d, J = 5.6 Hz, 1H), 7.72 (d, J = 14.0Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.32 (s, 1H), 7.21 (s, 1H), 7.02 (t, J =8.5 Hz, 1H), 6.75 (d, J = 5.6 Hz, 1H), 3.99 – 3.94 (m, 2H), 3.93 (s, 3H),3.66 – 3.51 (m, 1H), 3.41 (t, J = 11.8 Hz, 2H), 2.84 – 2.78 (m, 1H), 1.93 –1.85 (m, 2H), 1.74 (d, J = 11.7 Hz, 2H), 1.15 – 1.09 (m, 2H), 1.04 – 1.00 (m,2H)。
MS(m/z):410.2[M+H]。HPLC:98.92%。
Example 3 (L EC 002-085)
Figure 578938DEST_PATH_IMAGE016
The compound of example 3 was obtained as a colorless oil according to the preparation procedure of example 1.
1H NMR (500 MHz, CDCl3) 8.49 (d, J = 5.6 Hz, 1H), 8.41 (d, J = 5.1Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.54 – 7.44 (m,1H), 7.35 (d, J = 2.2 Hz, 1H), 7.32 (s, 1H), 6.79 (dd, J = 5.6, 2.2 Hz, 1H),6.70 (s, 1H), 6.26 (s, 1H), 4.00 – 3.89 (m, 2H), 3.57 – 3.53 (m, 1H), 3.44 –3.34 (m, 2H), 2.83 – 2.76 (m, 1H), 1.93 – 1.79 (m, 2H), 1.77 – 1.64 (m, 2H),1.14 – 1.06 (m, 2H), 1.02 – 0.98 (m, 2H)。
MS(m/z):427.19[M+Na]。HPLC:99.22%。
Example 4 (L EC 002-086)
Figure DEST_PATH_IMAGE047
The compound of example 4 was obtained as a colorless oil according to the preparation procedure of example 1.
1H NMR (500 MHz, CDCl3) 8.53 (s, 1H), 8.00 (d, J = 7.1 Hz, 2H),7.90 (d, J = 5.2 Hz, 2H), 7.33 (s, 2H), 6.83 (d, J = 14.2 Hz, 1H), 6.32 (s,1H), 6.09 (s, 1H), 3.95 (d, J = 11.1 Hz, 2H), 3.52 (d, J = 38.5 Hz, 1H), 3.40(t, J = 11.8 Hz, 2H), 2.81 (t, J = 10.1 Hz, 1H), 1.92 – 1.84 (m, 2H), 1.75 –1.66 (m, 2H), 1.24 (s, 2H), 1.11 (s, 2H)。
MS(m/z):405.2[M+H]。HPLC:99.35%。
Example 5 (L EC 002-088)
Figure 125457DEST_PATH_IMAGE018
Example 5 was obtained as a colorless oil according to the preparation procedure of example 1.
1H NMR (500 MHz, CDCl3) 8.53 (d, J = 5.7 Hz, 1H), 7.99 – 7.90 (m,2H), 7.49 (t, J = 7.5 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.31 (s, 1H), 7.28(d, J = 2.2 Hz, 1H), 6.80 (dd, J = 5.6, 2.2 Hz, 1H), 3.95 (d, J = 11.3 Hz,2H), 3.58 – 3.54 (m, 1H), 3.40 (t, J = 11.7 Hz, 2H), 3.12 (s, 3H), 3.00 (s,3H), 2.83 – 2.78 (m, 1H), 1.90 – 1.83 (m, 2H), 1.73 (d, J = 13.0 Hz, 2H),1.14 – 1.06 (m, 2H), 1.02 – 0.98 (m, 2H)。
MS(m/z):433.3[M+H]。HPLC:96.71%。
Example 6 (L EC 002-089)
Figure 17058DEST_PATH_IMAGE048
The compound of example 6 was obtained as a colorless oil according to the preparation procedure of example 1.
1H NMR (500 MHz, CDCl3) 8.57 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H),8.16 (d, J = 7.2 Hz, 1H), 8.08 (d, J = 7.2 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H),7.36 (s, 1H), 7.33 (s, 1H), 6.80 (d, J = 5.6 Hz, 1H), 3.97 (d, J = 1.9 Hz,2H), 3.94 (s, 3H), 3.59 – 3.55 (m, 1H), 3.41 (t, J = 11.7 Hz, 2H), 2.84 –2.97 (m, 1H), 1.91 – 1.84 (m, 2H), 1.75 (d, J = 13.0 Hz, 2H), 1.14 – 1.10 (m,2H), 1.04 – 1.00 (m, 2H)。
MS(m/z):442.2[M+Na]。HPLC:95.46%。
Example 7 (L EC 002-092)
Figure 762160DEST_PATH_IMAGE020
The compound of example 7 was obtained as a white solid according to the procedure of example 1.
MS(m/z):388.2[M+H]。HPLC:98.03%。
Example 8 (L EC 002-106)
Figure 198958DEST_PATH_IMAGE021
The compound of example 8 was obtained as a colorless oil according to the preparation procedure of example 1.
MS(m/z):406.24[M+H]。HPLC:98.41%。
Example 9 (L EC 002-114)
Figure 763932DEST_PATH_IMAGE022
The compound of example 9 was obtained as a colorless oil according to the preparation procedure of example 1.
1H NMR (500 MHz, CDCl3) 8.55 (d, J = 5.7 Hz, 1H), 8.05 (d, J = 8.2Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.33 (s, 2H), 6.84 (dd, J = 5.7, 2.3 Hz,1H), 3.98 – 3.96 (m, 2H), 3.60 – 3.55 (m, 1H), 3.41 (t, J = 10.8 Hz, 2H),2.89 – 2.76 (m, 1H), 1.94 – 1.85 (m, 2H), 1.75 (d, J = 13.1 Hz, 2H), 1.16 –1.08 (m, 2H), 1.07 – 0.98 (m, 2H)。
MS(m/z):430.20[M+H]。HPLC:96.94%。
Example 10 (L EC 002-115)
Figure 928066DEST_PATH_IMAGE023
The compound of example 10 was obtained as a colorless oil according to the preparation procedure of example 1.
MS(m/z):431.22[M+H]。HPLC:96.33%。
Example 11 (L EC 002-117)
Figure 527674DEST_PATH_IMAGE024
The compound of example 11 was obtained as a colorless oil according to the preparation procedure of example 1.
MS(m/z):381.21[M+H]。HPLC:94.48%。
Example 12 (L EC 002-122)
Figure 400952DEST_PATH_IMAGE025
The compound of example 12 was obtained as a white solid according to the preparation procedure of example 1.
1H NMR (500 MHz, CDCl3) 8.57 (d, J = 5.6 Hz, 1H), 8.32 (d, J = 5.3Hz, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.51 (s, 1H), 7.37 (d, J = 2.3 Hz, 1H),7.34 (s, 1H), 6.90 (dd, J = 5.6, 2.4 Hz, 1H), 3.97 (d, J = 14.0 Hz, 2H), 3.60– 3.56 (m, 1H), 3.41 (t, J = 10.7 Hz, 2H), 2.84 – 2.78 (m, 1H), 1.95 – 1.82(m, 2H), 1.79 – 1.68 (m, 2H), 1.19 – 1.10 (m, 2H), 1.06 – 1.02 (m, 2H)。
MS(m/z):381.17[M+H]。HPLC:98.00%。
Example 13 (L EC 002-146)
Figure DEST_PATH_IMAGE049
The compound of example 13 was obtained as a colorless oil according to the preparation procedure of example 1.
MS(m/z):442.2[M+Na]。HPLC:94.04%。
Example 14 (L EC 002-150)
Figure 922063DEST_PATH_IMAGE043
The compound of example 14 was obtained as a colorless oil according to the preparation procedure of example 1.
MS(m/z):397.2[M+H]。HPLC:93.32%。
Example 15 (L EC 002-155)
Figure 889888DEST_PATH_IMAGE050
Into the flask were charged example 14(0.10g, 0.25mmol), 1-amino-2-methyl-2-propanol (0.05g,0.55mmol), palladium acetate (0.03g, 0.012mmol), 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene (0.014g,0.025mmol), cesium carbonate (0.24g, 0.75mmol) and 1.4-dioxane (15m L.) after addition, the reaction was stirred under microwave conditions at 150 ℃ for 30min, then cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel chromatography (eluent: ethanol/dichloromethane 1/10) to give the desired product, example 15(0.05g, yield: 44.63%) as a colorless oil.
MS(m/z):450.24[M+H]。HPLC:93.50%。
Example 16 (L EC 002-160-2)
Figure 609583DEST_PATH_IMAGE029
The compound of example 16 was obtained as a colorless oil according to the preparation procedure of example 1.
1H NMR (500 MHz, CDCl3) 8.49 (d, J = 5.5 Hz, 1H), 8.35 (s, 1H),8.03 (d, J = 7.7 Hz, 1H), 7.92 (d, J = 7.5 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H),7.56 (d, J = 7.7 Hz, 1H), 7.54 (s, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 7.16 (t,J = 7.5 Hz, 1H), 7.08 – 7.02 (m, 1H), 6.88 (d, J = 5.6 Hz, 1H), 6.33 (s, 1H),5.74 (s, 1H), 3.76 – 3.68 (m, 1H), 1.31 – 1.26 (m, 2H), 1.14 – 1.10 (m, 2H)。
MS(m/z):437.12[M+Na]。HPLC:98.84%。
Example 17 (L EC 002-161)
Figure 388183DEST_PATH_IMAGE030
The compound of example 17 was obtained as a white solid according to the preparation procedure of example 1.
1H NMR (500 MHz, CDCl3) 8.42 (d, J = 5.5 Hz, 1H), 7.66 (d, J = 12.6Hz, 1H), 7.60 (dd, J = 13.5, 7.8 Hz, 2H), 7.50 (s, 1H), 7.26 (s, 1H), 7.21(s, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.05 – 6.99 (m, 2H), 6.79 (d, J = 5.4 Hz,1H), 3.93 (s, 3H), 3.72 – 3.68 (m, 1H), 1.26 – 1.21 (m, 2H), 1.11 – 1.07 (m,2H)。
MS(m/z):420.14[M+H]。HPLC:99.62%。
Example 18 (L EC 002-187)
Figure DEST_PATH_IMAGE051
The compound of example 18 was obtained as a white solid according to the procedure of example 1.
1H NMR (500 MHz, CDCl3) 8.51 (d, J = 5.7 Hz, 1H), 7.97 (d, J = 8.3Hz, 2H), 7.89 (d, J = 8.3 Hz, 2H), 7.46 (s, 1H), 7.36 (dd, J = 10.1, 2.1 Hz,2H), 7.30 (dd, J = 8.4, 1.9 Hz, 1H), 6.87 (dd, J = 5.7, 2.3 Hz, 1H), 6.80 (d,J = 8.4 Hz, 1H), 6.21 (s, 1H), 5.86 (s, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.68– 3.64 (m, 1H), 1.22 – 1.21 (m, 2H), 1.11 – 1.06 (m, 2H)。
MS(m/z):479.22[M+Na]。HPLC:98.83%。
Example 19 (L EC 002-195)
Figure 849120DEST_PATH_IMAGE052
The compound of example 19 was obtained as a white solid according to the preparation procedure of example 1.
MS(m/z):437.15[M+Na]。HPLC:93.20%。
Example 20 (L EC 002-196)
Figure DEST_PATH_IMAGE053
The compound of example 20 was obtained as a colorless oil according to the preparation procedure of example 1.
MS(m/z):407.09[M+H]。HPLC:94.95%。
Example 21 (L EC 015-004)
Figure 105789DEST_PATH_IMAGE054
The compound of example 21 was obtained according to the preparation procedure of example 15 as a white solid.
1H NMR (500 MHz, CDCl3) 8.49 (d, J = 5.6 Hz, 1H), 8.37 (d, J = 5.3Hz, 1H), 8.33 (s, 1H), 7.70 (s, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.52 (s, 1H),7.35 (s, 1H), 7.33 (d, J = 5.3 Hz, 1H), 7.29 (d, J = 3.9 Hz, 1H), 7.23 (s,1H), 7.14 (t, J = 7.5 Hz, 1H), 7.07 – 6.99 (m, 1H), 6.91 (d, J = 5.2 Hz, 1H),3.83 – 3.57 (m, 5H), 2.56 – 2.47 (m, 4H), 2.35 (s, 3H), 1.27 – 1.21 (m, 2H),1.15 – 1.04 (m, 2H)。
MS(m/z):564.23[M+H]。HPLC:98.93%。
Example 22 (L EC 015-014)
Figure 663678DEST_PATH_IMAGE035
The compound of example 22 was obtained as a colorless oil according to the preparation procedure of example 15.
1H NMR (500 MHz, CDCl3) 8.83 (s, 2H), 8.51 (d, J = 5.7 Hz, 1H),8.36 (d, J = 5.3 Hz, 1H), 7.68 (dd, J = 5.3, 1.5 Hz, 1H), 7.63 (td, J = 7.5,1.7 Hz, 1H), 7.55 (s, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.30 – 7.27 (m, 1H),7.16 (t, J = 7.6 Hz, 1H), 7.08 – 7.01 (m, 1H), 6.90 (dd, J = 5.7, 2.4 Hz,1H), 6.56 – 6.48 (m, 1H), 6.34 (dd, J = 16.9, 10.2 Hz, 1H), 5.84 (d, J = 11.1Hz, 1H), 3.75 – 3.71 (m, 1H), 1.29 – 1.27 (m, 2H), 1.14 – 1.07 (m, 2H)。
MS(m/z):442.18[M+H]。HPLC:97.44%。
Biological evaluation test:
the compounds of examples 1-22 were tested for their inhibitory effect on TGF- β R1(A L K5) kinase activity.
The inhibitory effect of compounds on TGF- β R1(A L K5) kinase activity was determined using the following assay:
a series of compounds were tested for their A L K5 Kinase inhibitory activity by L antiscreen (Eu Kinase Binding Assay) method, which comprises preparing 10mM stock solution of the compounds with DMSO, diluting the stock solution in a 1:3 gradient, loading the diluted stock solution in 384-PP (L ABCYTE, P-05525) for use, preparing 1X Kinase Buffer A to dilute the following reagents, and loading the diluted reagents in a microplate (L ABCYTE, model: Echo 520) using a micropipette system (Pro) on a reaction plate (Perkin Elmer, model: Pro)xiPlate-384 Plus) 15n L compound, 5 μ L A L K5 solution per well (available from Thermoscientific Forma, PV 5837), 5 μ L Eu-Anti-GST Antibody solution per well (available from Thermo Scientific Forma, PV 5594), shaking and mixing for 15min, 5 μ L Kinase Tracer178 solution per well (available from Thermo Scientific Forma, PV 5593), shaking and mixing, the total reaction system comprising 50mM Tris (pH7.5), 150mM NaCl, 0.5mM EDTA, 0.02% Triton X-100, 2mM DTT, 50% Glycerol, 50mM EPES (pH7.5), 10mM MgCl2, 1mM TA, 0.01% Triton j-35, 5 Brij 25K 8678, 2mM DTT, 50% Glycerol, 50mM EDTA (pH7.5), 10mM DMSO 2, 1mM TA, 0.01% assay, 5% assay, 10mM DMSO, 10K 8678, 0% assay using a linear regression model of PCR assay using a 10mM assay on a microplate 30 mM Biocide, 10mM DMSO, 0.178, 0.20 ℃ assay50Values, repeated three times, averaged.
IC of the TGF- β R1(A L K5) kinase Activity of the Compounds of examples 1 to 22 measured as described above50The values are given in table 1 below.
TABLE 1 IC inhibition of A L K5 kinase Activity by Compounds50Value of
Figure DEST_PATH_IMAGE055
As is clear from Table 1, the compounds of the present invention have significant inhibitory effects on TGF- β R1(A L K5) kinase activity, and among them, the compounds of examples 1, 2, 4, 13, 14, 16, 17, 19, 20 and 21 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. 2-aryl-4- (4-pyrazolyloxy) pyridines having the structural formula shown below, or a pharmaceutically acceptable salt thereof:
Figure DEST_PATH_IMAGE001
wherein R is2Selected from C3-C5 cycloalkyl;
R3is selected from
Figure 773280DEST_PATH_IMAGE002
、
Figure DEST_PATH_IMAGE003
、
Figure 205136DEST_PATH_IMAGE004
；
Ar is selected from the following groups:
Figure DEST_PATH_IMAGE005
n =1, 2 or 3;
Ar0selected from:
Figure 546118DEST_PATH_IMAGE006
、
Figure DEST_PATH_IMAGE007
wherein X is independently C or N, and at least one X is N;
R0each independently selected from the group consisting of: halogen, - (C = O) NH2、-（C=O）NHCH3、-NHCH2C（CH3）2OH、-OCH3、-NH（C=O）CH3、-（C=O）N（CH3）2、-CN、-（C=O）OCH3、-CF3、
Figure 477165DEST_PATH_IMAGE008
Or two R on adjacent C atoms0Radical formation
Figure DEST_PATH_IMAGE009
。
2. 2-aryl-4- (4-pyrazolyloxy) pyridines, or pharmaceutically acceptable salts thereof, according to claim 1, characterized in that Ar is selected from the following groups:
Figure 363254DEST_PATH_IMAGE010
。
3. the 2-aryl-4- (4-pyrazolyloxy) pyridines according to claim 1, wherein R is0Each independently selected from the group consisting of:
-F、-Cl、-OCH3、-（C=O）NH2、-（C=O）NHCH3、
Figure 365845DEST_PATH_IMAGE008
。
4. the 2-aryl-4- (4-pyrazolyloxy) pyridines according to any one of claims 1 to 3, wherein R is2Selected from C3 cycloalkyl.
5. The 2-aryl-4- (4-pyrazolyloxy) pyridines according to any one of claims 1 to 3, wherein R is3Is selected from
Figure 295755DEST_PATH_IMAGE002
。
6. The 2-aryl-4- (4-pyrazolyloxy) pyridines according to any one of claims 1 to 3, wherein R is3Is selected from
Figure DEST_PATH_IMAGE011
。
7. A2-aryl-4- (4-pyrazolyloxy) pyridine compound or a pharmaceutically acceptable salt thereof, wherein the 2-aryl-4- (4-pyrazolyloxy) pyridine compound is selected from the following compounds:
Figure 663283DEST_PATH_IMAGE012
、
Figure DEST_PATH_IMAGE013
、
Figure 639329DEST_PATH_IMAGE014
、
Figure DEST_PATH_IMAGE015
、
Figure 85092DEST_PATH_IMAGE016
、
Figure DEST_PATH_IMAGE017
、
Figure 338350DEST_PATH_IMAGE018
、
Figure DEST_PATH_IMAGE019
、
Figure 611199DEST_PATH_IMAGE020
、
Figure DEST_PATH_IMAGE021
、
Figure 510760DEST_PATH_IMAGE022
、
Figure DEST_PATH_IMAGE023
、
Figure 323995DEST_PATH_IMAGE024
、
Figure DEST_PATH_IMAGE025
、
Figure 759655DEST_PATH_IMAGE026
、
Figure DEST_PATH_IMAGE027
、
Figure 203406DEST_PATH_IMAGE028
、
Figure DEST_PATH_IMAGE029
、
Figure 262367DEST_PATH_IMAGE030
、
Figure DEST_PATH_IMAGE031
、
Figure 82555DEST_PATH_IMAGE032
、
Figure DEST_PATH_IMAGE033
。
8. a process for the preparation of 2-aryl-4- (4-pyrazolyloxy) pyridines according to any of claims 1 to 7, comprising the steps of:
Figure 107143DEST_PATH_IMAGE034
(1) reacting the compound 1 with a halogenating reagent to obtain a compound 2, wherein X represents halogen;
(2) carrying out substitution reaction on the compound 2 and 2-bromo-4-hydroxypyridine to obtain a compound 3;
(3) reacting the compound 3 with N, N-dimethylformamide dimethyl acetal to obtain a compound 4;
(4) reacting the compound 4 with hydrazine hydrate to obtain a compound 5;
(5) compound 5 and R2-B（OH）2Carrying out coupling or substitution reaction to obtain a compound 6;
(6) compound 6 with Ar-B (OH)2Carrying out Suzuki coupling reaction;
wherein R is2、R3And Ar is as defined in any one of claims 1 to 7.
9. A process for the preparation of 2-aryl-4- (4-pyrazolyloxy) pyridines according to any of claims 1 to 7, comprising the steps of:
Figure DEST_PATH_IMAGE035
(1) reacting the compound 1 with a halogenating reagent to obtain a compound 2, wherein X represents halogen;
(2) carrying out substitution reaction on the compound 2 and 2-bromo-4-hydroxypyridine to obtain a compound 3;
(3) reacting the compound 3 with N, N-dimethylformamide dimethyl acetal to obtain a compound 4;
(4) reacting the compound 4 with hydrazine hydrate to obtain a compound 5;
(5) compound 5 and R2-B（OH）2Reacting to obtain a compound 6;
(6) compound 6 with Cl-Ar0-B（OH）2Carrying out Suzuki coupling reaction to obtain a compound 7;
(7) carrying out a coupling reaction with a compound 7 to react the group-Ar0-Cl to form-Ar;
wherein R is2、R3Ar and Ar0The definition of (A) is as defined in any one of claims 1 to 7.
10. A pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient comprises the 2-aryl-4- (4-pyrazolyloxy) pyridine compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.
11. Use of a 2-aryl-4- (4-pyrazolyloxy) pyridine compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for the preparation of a TGF- β signaling pathway inhibitor.
12. Use of the 2-aryl-4- (4-pyrazolyloxy) pyridine compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 10 for preparing a medicament for preventing and treating cancer, infectious diseases, autoimmune diseases, tissue fibrosis, dysplasia cartilaginous bone, or pulmonary hypertension mediated by TGF- β signaling pathway disorder.
CN202010247992.3A 2020-04-01 2020-04-01 2-aryl-4- (4-pyrazolyloxy) pyridine compound, preparation method thereof, pharmaceutical composition and application thereof Expired - Fee Related CN111116565B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1175578A (en) * 1996-08-07 1998-03-11 美国氰胺公司 Herbicidal 2, 6 -disubstituted pyridines and 2, 4 -disubstituted pyrimidines
CN106132950A (en) * 2014-01-01 2016-11-16 麦迪韦逊技术股份有限公司 Compound and using method
CN106795139A (en) * 2014-10-07 2017-05-31 伊莱利利公司 Aminopyridine base epoxide pyrazole compound

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1175578A (en) * 1996-08-07 1998-03-11 美国氰胺公司 Herbicidal 2, 6 -disubstituted pyridines and 2, 4 -disubstituted pyrimidines
CN106132950A (en) * 2014-01-01 2016-11-16 麦迪韦逊技术股份有限公司 Compound and using method
CN106795139A (en) * 2014-10-07 2017-05-31 伊莱利利公司 Aminopyridine base epoxide pyrazole compound

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