CN117510470A - Pyridazinone compounds and application thereof - Google Patents

Pyridazinone compounds and application thereof Download PDF

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CN117510470A
CN117510470A CN202210891299.9A CN202210891299A CN117510470A CN 117510470 A CN117510470 A CN 117510470A CN 202210891299 A CN202210891299 A CN 202210891299A CN 117510470 A CN117510470 A CN 117510470A
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unsubstituted
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陆小云
张章
王超凡
涂正超
周洋
宋晓娟
李捷
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Jinan University
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    • 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
    • A—HUMAN NECESSITIES
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    • A61P35/00—Antineoplastic agents
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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Abstract

The invention provides a pyridazinone compound with a structure shown in a formula (I), or pharmaceutically acceptable salt or stereoisomer thereof and application thereof. The inventionThe pyridazinone compounds can effectively inhibit the activities of kinases such as c-Met, TRK, AXL and the like, inhibit the proliferation, migration and invasion of various tumor cells and drug-resistant cells thereof, and can be used for preparing medicines for preventing and/or treating various malignant tumors.

Description

Pyridazinone compounds and application thereof
Technical Field
The invention relates to the technical field of chemical medicines, in particular to a pyridazinone compound and application thereof.
Background
Malignant tumors pose serious risks to human health, and pose serious challenges for treatment of malignant tumors. A variety of antitumor targets have been found, among which protein tyrosine kinases are a very promising target for treatment, and a variety of protein tyrosine kinase inhibitors have been approved for the treatment of various malignant tumors.
The receptor type protein tyrosine kinase c-Met is the Hepatocyte Growth Factor Receptor (HGFR), the only known high affinity ligand for Hepatocyte Growth Factor (HGF). It is expressed predominantly in epithelial cells, and its mature form consists of an extracellular alpha chain and a transmembrane beta chain. After HGF binds to C-Met, tyr1234 and Tyr1235 located in the kinase domain phosphorylate themselves, and subsequently Tyr1349 and Tyr1356 located at the tail of the C-terminus phosphorylate and recruit downstream signaling factors, activating RAS/MAPK, PI3K/AKT, STAT3/JNK and other signaling pathways, thus regulating a series of biological effects such as cell growth, survival, movement, proliferation and the like. A large amount of clinical data show that the c-Met gene amplification, the protein overexpression, the 14 exon skipping mutation, the gene fusion and the like are closely related to the occurrence of various types of tumors, such as lung cancer, gastric cancer, liver cancer, breast cancer, skin cancer, colorectal cancer and the like, and have abnormal regulation. Because of the important role of c-Met signaling in human tumor formation, invasion and metastasis, it has become an important target for anti-tumor development.
The c-Met inhibitors can be mainly classified into two types, i.e., type I and type II, and type I can be further classified into type Ia and type Ib according to the binding mode. Currently, the highly selective Ib inhibitors capmatiib, teponinib and savoliinib have been approved for the treatment of non-small cell lung cancer patients with 14 exon skipping mutations, and several Ib inhibitors such as bozitinib, gluretinib are also in clinical trial phase. Other multi-target inhibitors, such as type Ia crizotinib, type II cabozantinib, merestinib and glesatinib, also showed good c-Met inhibitory activity and clinical trials for c-Met abnormalities were also conducted.
Acquired resistance inevitably occurs with long-term use of c-Met inhibitors, and mutations in certain amino acids of the kinase domain have been found in the clinic to lead to resistance phenomena, such as Asp1228 and Tyr1230 site mutations, which occur with the use of type I inhibitors, and Leu1195 and Phe1200 site mutations, which occur with the use of type II inhibitors. Currently, the main way to overcome mutations is the mutual use of type I and type II inhibitors, i.e. the use of type II inhibitors when drug resistance of type I inhibitors occurs, and vice versa.
Disclosure of Invention
Based on the above, the invention provides a pyridazinone compound or pharmaceutically acceptable salt or stereoisomer thereof, which can be used as a protein kinase inhibitor, can effectively inhibit the activity of protein kinase such as c-Met, TRK, AXL and the like, and can inhibit proliferation, migration and invasion of various tumor cells and drug-resistant cells thereof.
The invention comprises the following technical scheme.
A pyridazinone compound having a structure represented by formula (I):
wherein: l (L) 1 Selected from: c (C) 2 -C 10 Alkylene, halogen substituted C 2 -C 10 Alkylene, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 10 Cycloalkyl group,
M is selected from: -O-, -NH-, -S-, -C (O) -, -S (O) 2 -、-C(O)O-、-OC(O)-、-C(O)NH-、-NHC(O)-、-S(O) 2 NH-、-NHS(O) 2 -, -HNC (O) NH-or absent;
R 1 selected from: H. halogen, -NR 7 R 8 、R 9 Substituted or unsubstituted 5-10 membered heterocyclyl, R 9 Substituted or unsubstituted 5-10 membered heteroaryl; r is R 7 、R 8 Each independently selected from: H. c (C) 1 -C 10 Alkyl, - (CH) 2 ) m NR 10 R 11 The method comprises the steps of carrying out a first treatment on the surface of the Each R is 9 Each independently selected from: H. halogen, amino, hydroxy, cyano, R 12 Substituted or unsubstituted C 1 ～C 10 Alkyl, R 12 Substituted or unsubstituted C 1 -C 10 Alkoxy, R 12 Substituted or unsubstituted C 3 ～C 10 Cycloalkyl, R 12 Substituted or unsubstituted C 3 -C 10 Epoxy group, R 12 A substituted or unsubstituted 3-10 membered heterocyclyl; r is R 10 、R 11 Each independently selected from: H. c (C) 1 -C 10 Alkyl, or R 10 、R 11 Together with the nitrogen atom to which they are attached form R 9 A substituted or unsubstituted 3-10 membered heterocyclyl; each R is 12 Each independently selected from: H. halogen, hydroxy, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy substituted C 1 ～C 6 Alkyl, C 1 ～C 6 Alkyl acyl, C 1 ～C 6 Alkoxy, 3-10 membered heterocyclyl, C 1 ～C 6 Alkyl substituted 3-10 membered heterocyclyl; m is selected from: an integer of 0 to 10;
R 2 、R 6 each independently selected from: H. halogen;
R 3 、R 5 each independently selected from: H. halogen, nitro, amino, cyano, R 12 Substituted or unsubstituted C 1 ～C 20 Alkyl, R 12 Substituted or unsubstituted C 1 -C 20 An alkoxy group;
R 4 selected from: H.halogen, halogen,-NR 7 R 8 、R 12 Substituted or unsubstituted C 1 ～C 20 Alkyl, R 12 Substituted or unsubstituted C 1 -C 20 Alkoxy, R 9 Substituted or unsubstituted 5-10 membered heterocyclyl, R 9 Substituted or unsubstituted 5-10 membered heteroaryl; each R is 13 Each independently selected from: H. c (C) 1 ～C 6 An alkyl group;
when R is 1 Selected from R 9 Substituted or unsubstituted 5-10 membered heterocyclyl, R 9 Substituted or unsubstituted 5-10 membered heteroaryl, R 4 Selected from:when R is 9 And R is 13 Can be connected to form C 2 -C 10 An alkylene group.
In some of these embodiments, L 1 Selected from: c (C) 2 -C 6 Alkylene, halogen substituted C 2 -C 6 Alkylene, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl groups.
In some of these embodiments, L 1 Selected from: c (C) 2 -C 3 Alkylene, halogen substituted C 2 -C 3 Alkylene, vinyl.
In some of these embodiments, L 1 Selected from:
in some of these embodiments, M is-O-, or is absent.
In some of these embodiments, R 1 Selected from: H. halogen, -NR 7 R 8 、R 9 Substituted or unsubstituted 5-8 membered heterocyclyl, R 9 Substituted or unsubstituted 5-6 membered heteroaryl; r is R 7 、R 8 Each independently selected from: H. c (C) 1 -C 6 Alkyl, - (CH) 2 ) m NR 10 R 11 The method comprises the steps of carrying out a first treatment on the surface of the Each R is 9 Each independently selected from: H. halogen, amino, hydroxy, cyano, R 12 Substituted or unsubstituted C 1 ～C 6 Alkyl, R 12 Substituted or unsubstituted C 1 -C 6 Alkoxy, R 12 Substituted or unsubstituted C 3 ～C 8 Cycloalkyl, R 12 A substituted or unsubstituted 3-8 membered heterocyclic group; r is R 10 、R 11 Each independently selected from: H. c (C) 1 -C 6 Alkyl, or R 10 、R 11 Together with the nitrogen atom to which they are attached form R 9 A substituted or unsubstituted 4-8 membered heterocyclic group; each R is 12 Each independently selected from: H. halogen, C 1 ～C 3 Alkyl, C 1 ～C 3 Alkoxy substituted C 1 ～C 3 Alkyl, C 1 ～C 3 Alkanoyl, hydroxy, C 1 ～C 3 Alkoxy, 4-6 membered heterocyclyl, C 1 ～C 3 Alkyl substituted 4-6 membered heterocyclyl; m is selected from: 1. 2, 3 and 4.
In some of these embodiments, R 1 Selected from: H. halogen, -NR 7 R 8 、R 9 Substituted or unsubstituted 5-8 membered nitrogen-containing heterocyclic group, R 9 A substituted or unsubstituted 5-6 membered nitrogen containing heteroaryl; r is R 7 、R 8 Each independently selected from: H. c (C) 1 -C 3 Alkyl, - (CH) 2 ) m NR 10 R 11 The method comprises the steps of carrying out a first treatment on the surface of the Each R is 9 Each independently selected from: H. r is R 12 Substituted or unsubstituted C 1 ～C 3 Alkyl, R 12 A substituted or unsubstituted 5-8 membered heterocyclic group; r is R 10 、R 11 Each independently selected from: H. c (C) 1 -C 3 Alkyl, or R 10 、R 11 Together with the nitrogen atom to which they are attached form R 9 A substituted or unsubstituted 5-8 membered nitrogen-containing heterocyclic group; each R is 12 Each independently selected from: H. c (C) 1 ～C 3 Alkyl group,Hydroxy, C 1 ～C 3 Alkoxy, 5-6 membered heterocyclyl; m is selected from: 1. 2.
In some of these embodiments, R 1 Selected from: -NR 7 R 8 、R 9 Substituted or unsubstituted morpholinyl, R 9 Substituted or unsubstituted pyrazolyl, R 9 Substituted or unsubstituted piperazinyl, R 9 Substituted or unsubstituted piperidinyl, R 9 Substituted or unsubstituted pyrrolopyrrolyl; r is R 7 、R 8 Each independently selected from: H. - (CH) 2 ) m NR 10 R 11 The method comprises the steps of carrying out a first treatment on the surface of the Each R is 9 Each independently selected from: H. r is R 12 Substituted or unsubstituted C 1 ～C 3 Alkyl, R 12 Substituted or unsubstituted piperidinyl, R 12 Substituted or unsubstituted tetrahydropyranyl; r is R 10 、R 11 Together with the nitrogen atom to which they are attached form R 9 Substituted or unsubstituted morpholinyl or piperidinyl; each R is 12 Each independently selected from: H. c (C) 1 ～C 3 Alkyl, hydroxy, C 1 ～C 3 Alkoxy, morpholinyl; m is selected from: 1. 2.
In some of these embodiments, each R 9 Each independently selected from: H. hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH 2 OH、-CH 2 CH 2 OH、-CH 2 CH 2 OCH 3 、-CH 2 CN、
In some of these embodiments, R 1 A group selected from any one of the following:
in some of these embodiments, R 2 And R is 6 Are all hydrogen.
In some of these embodiments, R 3 、R 5 Each independently selected from: H. halogen, nitro, amino, cyano, C 1 ～C 6 Alkyl, halogen substituted C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, halogen substituted C 1 ～C 6 An alkoxy group.
In some of these embodiments, R 3 、R 5 Each independently selected from: H. f, cl, br, nitro, amino, cyano, trifluoromethyl, trifluoroethyl, C 1 ～C 3 Alkyl, C 1 ～C 3 Methoxy, trifluoromethoxy, trifluoroethoxy.
In some of these embodiments, R 4 Selected from: H. halogen, halogen,-NR 7 R 8 、R 12 Substituted or unsubstituted C 1 ～C 6 Alkyl, R 12 Substituted or unsubstituted C 1 -C 6 Alkoxy, R 9 Substituted or unsubstituted 5-6 membered heterocyclyl, R 9 Substituted or unsubstituted 5-6 membered heteroaryl; each R is 13 Each independently selected from: H. c (C) 1 ～C 3 An alkyl group; when R is 3 And R is 5 When both are H, R 4 Not be->
In some of these embodiments, R 4 Selected from: H. halogen, morpholinyl,C 1 ～C 3 Alkyl, R 9 Substituted or unsubstituted pyrazolyl; each R is 13 Each independently selected from: H. c (C) 1 ～C 3 An alkyl group.
In some of these embodiments, R 2 And R is 6 Are all hydrogen;
R 3 and R is 5 One of which is H and the other is selected from: H. f, cl, br, nitro, amino, cyano, trifluoromethyl, trifluoroethyl, methyl, ethyl; or R is 3 And R is 5 And F is the same time;
R 4 selected from: H. f, methyl group,And when R is 3 And R is 5 When both are H, R 4 Not be->
The invention also provides application of the pyridazinone compound or pharmaceutically acceptable salt or stereoisomer thereof, which comprises the following technical scheme.
Application of the pyridazinone compound or pharmaceutically acceptable salt or stereoisomer thereof in preparing c-Met kinase inhibitor, TRK kinase inhibitor and/or AXL kinase inhibitor.
The application of the pyridazinone compound or the pharmaceutically acceptable salt or the stereoisomer thereof in preparing medicaments for preventing and/or treating diseases mediated by c-Met kinase, TRK kinase and/or AXL kinase.
In some of these embodiments, the disease mediated by c-Met kinase, TRK kinase and/or AXL kinase is a tumor, preferably non-small cell lung cancer, gastric cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, ovarian cancer, glioma.
The invention also provides a medicinal composition for preventing and/or treating tumors, which comprises the following technical scheme.
A pharmaceutical composition for preventing and/or treating tumors comprises an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the pyridazinone compound or pharmaceutically acceptable salts or stereoisomers thereof.
The inventor of the invention researches and develops a pyridazinone compound with a novel structure, which can effectively inhibit the activities of c-Met, TRK, AXL and other kinases, inhibit the proliferation, migration and invasion of various tumor cells and drug-resistant cells thereof, and can be used for preparing drugs for preventing and/or treating various malignant tumors.
Detailed Description
In the compounds of the invention, when any variable (e.g., R 9 Etc.) occur more than once in any component, the definition of each occurrence is independent of the definition of each other occurrence. Also, combinations of substituents and variables are permissible provided that such combinations stabilize the compounds. The lines drawn from the substituents into the ring system indicate that the bond referred to may be attached to any substitutable ring atom. If the ring system is polycyclic, it means that such bonds are only attached to any suitable carbon atom adjacent to the ring. It is to be understood that substituents and substitution patterns of the compounds of this invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that may be readily synthesized from readily available starting materials by techniques in the art and methods set forth below. If the substituent itself is substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, as long as the structure is stabilized.
The phrase "R" as used herein f Substitution "," R substitution "is considered to correspond to the phrase" substituted with at least one substituent ", and in this case the preferred embodiment will have from 1 to 4 substituents.
The term "alkyl" as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. For example, "C 1 -C 6 Alkyl "medium" C 1 -C 6 The definition of "includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched chain. For example, "C 1 -C 6 The alkyl group includes, in particular, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl.
The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "alkaneOxy "refers to a group having an-O-alkyl structure, e.g., -OCH 3 、-OCH 2 CH 3 、-OCH 2 CH 2 CH 3 、-O-CH 2 CH(CH 3 ) 2 、-OCH 2 CH 2 CH 2 CH 3 、-O-CH(CH 3 ) 2 Etc.
The term "heterocyclyl" is a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent (including monocyclic, spiro, parallel, bridged, etc.), wherein one or more ring atoms are selected from heteroatoms of N, O or S (O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon, wherein a nitrogen-containing heterocyclyl means that at least one ring atom is N. For example: Etc.
The term "heteroaryl" refers to an aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N or S, heteroaryl groups within the scope of the invention include, but are not limited to: quinazolines, quinolinyl, pyrazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, and the like.
As understood by those skilled in the art, "halo" or "halogen" as used herein means chlorine, fluorine, bromine and iodine.
The present invention includes the free forms of the compounds of formula (I), as well as pharmaceutically acceptable salts and stereoisomers thereof. Stereoisomers according to the invention, i.e.as enantiomers, diastereomers, cis/trans (syn-/anti-isomer), cis/trans (cis-/trans-isomer) isomers, epimers and (E) -/(Z) -isomers, depending on the structure. The compounds of formula (I) may be used in the context of the present invention in the form of pure stereoisomers or in the form of any mixture of stereoisomers, in which case the racemate is preferred.
The term "free form" refers to an amine compound in a non-salt form. Included are pharmaceutically acceptable salts including not only the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the compounds of formula (I) in free form. The free form of the particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention such acid and base salts are otherwise pharmaceutically comparable to their respective free forms.
Pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Typically, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess of an inorganic or organic acid in the form of the desired salt in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.
Thus, pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention formed by the reaction of a basic compound of the invention with an inorganic or organic acid. For example, conventional nontoxic salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, and also salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.
If the compounds of the present invention are acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic and organic bases, salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, and the like. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, guava, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Berg et al, "Pharmaceutical Salts" j.pharm.sci.'1977:66:1-19 describe in more detail the preparation of pharmaceutically acceptable salts as described above and other typical pharmaceutically acceptable salts.
Since under physiological conditions the deprotonated acidic moiety, e.g. carboxyl, in the compound may be anionic, and this charge may then be balanced out by the protonated or alkylated basic moiety, e.g. tetravalent nitrogen atom, which is internally cationic, it should be noted that the compounds of the present invention are potentially internal salts or zwitterions.
In one embodiment, the present invention provides a method of treating hyperproliferative diseases or conditions, such as human or other mammalian tumors, using compounds having the structure of formula (I) and pharmaceutically acceptable salts thereof.
In one embodiment, the compounds contemplated by the present invention and pharmaceutically acceptable salts thereof may be used to treat or control non-small cell lung cancer, gastric cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, ovarian cancer, glioma, and the like.
The invention also provides a pharmaceutical composition comprising an active ingredient in a safe and effective amount, and a pharmaceutically acceptable carrier.
The "active ingredient" described herein includes the compound of formula (I) described herein.
The active ingredients and the pharmaceutical compositions of the invention can be used as kinase inhibitors such as c-Met, TRK, AXL and the like. In another preferred embodiment, the composition is used for preparing a medicament for preventing and/or treating tumors.
"safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity.
"compatible" as used herein means that the components of the composition are capable of blending with and between the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients.
Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g. ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
In another preferred embodiment, the compounds of the invention (I) may form complexes with macromolecular compounds or macromolecules by non-bonding. In another preferred embodiment, the compounds of the invention (I) as small molecules may also be linked to macromolecular compounds or macromolecules via chemical bonds. The macromolecular compounds may be biological macromolecules such as polysaccharides, proteins, nucleic acids, polypeptides and the like.
The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and the like.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
In these solid dosage forms, the active ingredient is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients:
(a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;
(b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia;
(c) Humectants, for example, glycerin;
(d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
(e) Slow solvents, such as paraffin;
(f) Absorption accelerators, for example quaternary amine compounds;
(g) Wetting agents, for example cetyl alcohol and glycerol monostearate;
(h) Adsorbents, such as kaolin; and
(i) Lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
The solid dosage forms may also be prepared using coatings and shells, such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such a composition may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like. In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredient, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
The above-mentioned features of the invention, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions such as Sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
The following are specific examples:
example 1.2 preparation of- ((3- (1-pyrazol-4-yl) quinolin-6-yl) methyl) -6-phenylpyridazin-3 (2H) -one (Compound 1)
Preparation of (3-bromoquinolin-6-yl) methanol (Compound 1 a)
1g of 3-bromoquinoline-6-carboxylic acid is dissolved in ultra-dry tetrahydrofuran solution, argon is replaced, the solution is placed at 0 ℃, 20mL of borane tetrahydrofuran solution (1.0 mol/L) is slowly added dropwise, stirring is carried out for 30min at 0 ℃, the reaction is carried out at normal temperature, TLC shows that the raw materials disappear after 1h, and the reaction is stopped. Methanol was slowly added in an ice bath, and then the mixture was quenched by heating to 60℃for 30min, followed by column chromatography to give 534mg (yield 57%). 1 H NMR(400MHz,DMSO)δ8.90(d,J＝2.1Hz,1H),8.71(d,J＝2.4Hz,1H),7.99(d,J＝8.6Hz,1H),7.89(s,1H),7.75(d,J＝8.7Hz,1H),5.50(t,J＝5.8Hz,1H),4.71(d,J＝4.9Hz,2H).
Step 2.3 preparation of bromo-6- (bromomethyl) quinoline (Compound 1 b)
500mg (2.11 mmol) of compound 1a was taken in a 100ml round bottom flask, 50ml of chloroform was added to dissolve it, and it was placed under ice bath, 0.25ml (2.74 mmol) of phosphorus tribromide was slowly added dropwise, after stirring for 5min, it was transferred to 60 ℃ to react for 2h, after TLC showed the disappearance of the starting material, the reaction was stopped, the solvent was spun-dried, slowly added dropwise with saturated sodium bicarbonate solution under ice bath to quench it, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and after spinning-drying, the next step was directly thrown.
Step 3.6 preparation of phenylpyridazin-3 (2H) -one (Compound 1 c)
5g (41.6 mmol) of acetophenone and 4.5g (48.8 mmol) of glyoxylic acid monohydrate are dissolved in 50ml of acetic acid and reacted at 95℃for 18h, after the system has cooled to room temperature, 4ml (83.2 mmol) of hydrazine hydrate are slowly added and the reaction is continued at 95℃for 4h. The system was cooled to room temperature, slowly precipitated solid, suction filtered, and the solid was washed with a large amount of water and dried to give 1.3g of a white solid (yield 40%). 1 H NMR(400MHz,DMSO)δ13.19(s,1H),8.04(d,J＝9.9Hz,1H),7.89-7.83(m,2H),7.52–7.42(m,3H),7.00(d,J＝9.8Hz,1H).
Step 4.2 preparation of- ((3-bromoquinolin-6-yl) methyl) -6-phenylpyridazin-3 (2H) -one (Compound 1 d)
100mg (0.30 mmol) of Compound 1b and 63mg (0.37 mmol) of Compound 1c were dissolved in 20ml of DMSO, 11mg (0.034 mmol) of tetrabutylammonium bromide and 27mg (0.48 mmol) of potassium hydroxide were added, stirred overnight at normal temperature, water was added to the system, extraction was performed three times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and after spin-drying, 49mg of a white powdery solid was obtained by column chromatography (yield 38%). 1 H NMR(400MHz,DMSO)δ8.91(d,J＝2.3Hz,1H),8.74(d,J＝2.3Hz,1H),8.12(d,J＝9.7Hz,1H),8.02(d,J＝8.4Hz,1H),7.92-7.86(m,3H),7.82(d,J＝8.7Hz,1H),7.52-7.44(m,3H),7.13(d,J＝9.7Hz,1H),5.54(s,2H).
Step 5.2 preparation of- ((3- (1-pyrazol-4-yl) quinolin-6-yl) methyl) -6-phenylpyridazin-3 (2H) -one (Compound 1)
50mg (0.13 mmol) of compound 1d and 32mg (0.15 mmol) of 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole were dissolved in a mixed solvent of 1, 4-dioxane and water 10mg (0.014 mmol) Pd (dppf) Cl was added 2 And 35mg (0.25 mmol) K 2 CO 3 After the reaction was completed, the solvent was dried by spin-drying under the protection of argon at 100℃for 4 hours, and then purified by flash chromatography on silica gel column to give 46mg of Compound 1 (yield 92%). 1 H NMR(400MHz,DMSO)δ9.16(d,J＝2.2Hz,1H),8.48(s,1H),8.38(s,1H),8.11(d,J＝9.9Hz,1H),8.09(s,1H),7.97(d,J＝8.7Hz,1H),7.91(d,J＝7.4Hz,2H),7.81(s,1H),7.71(d,J＝8.6Hz,1H),7.52–7.44(m,3H),7.14(d,J＝9.7Hz,1H),5.53(s,2H),3.90(s,3H).
Example 2.preparation of 2- (2- (3-morpholinoquinolin-6-yl) methyl) -6-phenylpyridazin-3 (2H) -one (Compound 2)
50mg (0.13 mmol) of Compound 1d and 17mg (0.20 mmol) of morpholine were dissolved in toluene, 12mg (0.013 mmol) of Pd were added 2 (dba) 3 15mg (0.026 mmol) XantPhos and 25mg (0.26 mmol) NaOBu-t were reacted overnight at 100℃under argon, after which the solvent was dried by flash chromatography on silica gel to give 34mg of compound 2 (67% yield). 1 H NMR(600MHz,DMSO)δ8.84(d,J＝2.9Hz,1H),8.11(d,J＝9.8Hz,1H),7.90(d,J＝7.0Hz,2H),7.86(d,J＝8.6Hz,1H),7.69(d,J＝1.9Hz,1H),7.54–7.44(m,5H),7.13(d,J＝9.7Hz,1H),5.49(s,2H),3.81–3.75(m,4H),3.27–3.24(m,4H).
Example 3.preparation of 6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -2- (quinolin-6-ylmethyl) pyridazin-3 (2H) -one (Compound 3)
Step 1.6 preparation of (bromomethyl) quinoline (Compound 2 a)
The compound 1a of step 2 of example 1 was replaced with 6-hydroxymethylquinoline, and the remaining reagents and preparation methods were the same as those of example 1 to prepare compound 2a, which was directly used in the next step.
Step 2.6 preparation of (4-bromophenyl) pyridazin-3 (2H) -one (Compound 2 b)
The acetophenone in step 3 of example 1 was replaced with 4-bromoacetophenone, and the remaining reagents and preparation methods were the same as in example 1 to prepare compound 2b. 1 H NMR(400MHz,DMSO):δ13.29(s,1H),8.02(d,J＝9.7Hz,1H),7.99(s,1H),7.83(d,J＝7.9Hz,1H),7.58(d,J＝8.0Hz,1H),7.40(t,J＝7.9Hz,1H),6.99(d,J＝10.0Hz,1H).
Step 3.preparation of 6- (4-bromophenyl) -2- (quinolin-6-ylmethyl) pyridazin-3 (2H) -one (Compound 2 c)
Compound 2c was obtained by replacing compounds 1b and 1c in step 4 of example 1 with compounds 2a and 2b, and the remaining reagents and preparation methods were the same as those of example 1. 1 HNMR(400MHz,DMSO)δ8.88(dd,J＝4.3,1.7Hz,1H),8.37(d,J＝8.3Hz,1H),8.11(d,J＝9.8Hz,1H),8.01(d,J＝8.7Hz,1H),7.91(s,1H),7.86(d,J＝8.4Hz,2H),7.77(dd,J＝8.7,2.0Hz,1H),7.69(m,2H),7.52(dd,J＝8.3,4.2Hz,1H),7.14(d,J＝9.8Hz,1H),5.54(s,2H).
Step 4.preparation of 6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -2- (quinolin-6-ylmethyl) pyridazin-3 (2H) -one (Compound 3)
Compound 3 was prepared by replacing compound 1d in step 5 of example 1 with compound 2c, and the remaining reagents and preparation methods were the same as in example 1. 1 HNMR(600MHz,DMSO)δ8.88(dd,J＝4.2,1.7Hz,1H),8.37(d,J＝7.6Hz,1H),8.21(s,1H),8.11(d,J＝9.8Hz,1H),8.02(d,J＝8.7Hz,1H),7.93(m,2H),7.88(d,J＝8.3Hz,2H),7.79(dd,J＝8.8,2.0Hz,1H),7.67(d,J＝8.3Hz,2H),7.52(dd,J＝8.3,4.2Hz,1H),7.12(d,J＝9.7Hz,1H),5.54(s,2H),3.87(s,3H).
Example 4.6 preparation of 6- (morpholinophenyl) -2- (quinolin-6-ylmethyl) pyridazin-3 (2H) -one (Compound 4)
Compound 4 was obtained by replacing compound 1d in example 2 with compound 2c, and the other reagents and preparation methods were the same as those in example 2. 1 HNMR(400MHz,DMSO)δ8.88(d,J＝2.6Hz,1H),8.38(d,J＝8.2Hz,1H),8.05(d,J＝9.8Hz,1H),8.01(d,J＝8.7Hz,1H),7.91(s,1H),7.81–7.74(m,3H),7.52(dd,J＝8.4,4.2Hz,1H),7.07(d,J＝9.8Hz,1H),7.02(d,J＝8.7Hz,2H),5.51(s,2H),3.74(t,J＝4.8Hz,4H),3.19(t,J＝4.8Hz,4H).
Example 5.preparation of 2- (2- (3- (1-methyl-1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6-phenylpyridazin-3 (2H) -one (Compound 5)
Step 1.2 preparation of 2- (3-bromoquinolin-6-yl) acetic acid (Compound 3 a)
3g (10.2 mmol) of 2- (3-bromoquinolin-6-yl) acetic acid are dissolved in 150ml of THF in a volume ratio of: meOH: h 2 O=10: 1:5 to which 2.1g (50.7 mmol) of lithium hydroxide monohydrate was added and stirred at room temperature for 4 hours. After the reaction was completed by TLC, the solvent was dried by spin-drying, and then acidified to ph=1 with 10% hcl, and suction filtration, to obtain 2.6g of a white solid (yield 96%). 1 HNMR(400MHz,DMSO)δ8.92(d,J＝2.3Hz,1H),8.69(d,J＝2.4Hz,1H),7.99(d,J＝8.6Hz,1H),7.83(d,J＝1.9Hz,1H),7.73(dd,J＝8.7,1.9Hz,1H),3.82(s,2H).
Step 2.preparation of 2- (3-bromoquinolin-6-yl) -1-ethanol (Compound 3 b)
Compound 3b was obtained by replacing the compound 3-bromoquinoline-6-carboxylic acid in step 1 of example 1 with compound 3a, and the other reagents and preparation methods were the same as in example 1. 1 H NMR(400MHz,DMSO)δ8.87(d,J＝2.3Hz,1H),8.62(d,J＝2.2Hz,1H),7.94(d,J＝8.6Hz,1H),7.76(d,J＝1.9Hz,1H),7.70(dd,J＝8.6,2.0Hz,1H),4.74(t,J＝5.2Hz,1H),3.72(td,J＝6.7,5.1Hz,2H),2.92(t,J＝6.7Hz,2H).
Step 3.preparation of 3-bromo-6- (2-bromoethyl) quinoline (Compound 3 c)
The compound 1a in step 2 of example 1 was changed to the compound 3b, and the other reagents and preparation methods were the same as those of example 1 to prepare the compound 3c, which was directly used in the next step.
Step 4.preparation of 2- (2- (3-bromoquinolin-6-yl) ethyl) -6-phenylpyridazin-3 (2H) -one (Compound 3 d)
Compound 3d was obtained by replacing compound 1b in step 4 of example 1 with compound 3c, and the other reagents and preparation methods were the same as those of example 1. 1 H NMR(400MHz,DMSO)δ8.86(d,J＝2.4Hz,1H),8.58(d,J＝2.7Hz,1H),7.99–7.92(m,2H),7.77–7.68(m,2H),7.68–7.62(m,2H),7.41–7.34(m,3H),7.01(d,J＝9.7Hz,1H),4.49(t,J＝7.1Hz,2H),3.30(t,J＝7.2Hz,2H).
Step 5.preparation of 2- (2- (3- (1-methyl-1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6-phenylpyridazin-3 (2H) -one (Compound 5)
The procedure of example 1, step 5, and the reagents used and the preparation method are repeated except that compound 1d is replaced by compound 3d1, to prepare compound 5. 1 H NMR(400MHz,DMSO)δ9.12(d,J＝2.2Hz,1H),8.37(s,1H),8.07(s,1H),8.00(d,J＝9.7Hz,1H),7.91(d,J＝8.5Hz,1H),7.81–7.66(m,3H),7.59(dd,J＝8.6,2.0Hz,1H),7.42–7.38(m,3H),7.03(d,J＝9.7Hz,1H),4.52(t,J＝7.1Hz,2H),3.30(t,J＝7.0Hz,2H).
Example 6.preparation of 2- (2- (3-morpholinoquinolin-6-yl) ethyl) -6-phenylpyridazin-3 (2H) -one (Compound 6)
Compound 6 was obtained by replacing compound 1d in example 2 with compound 3d, and the other reagents and preparation methods were the same as those in example 2. 1 H NMR(600MHz,DMSO)δ8.80(d,J＝2.9Hz,1H),7.99(d,J＝9.7Hz,1H),7.80(d,J＝8.5Hz,1H),7.74–7.70(m,2H),7.61(d,J＝1.9Hz,1H),7.44–7.37(m,5H),7.03(d,J＝9.7Hz,1H),4.48(t,J＝7.2Hz,2H),3.79(t,J＝4.8Hz,4H),3.26–3.22(m,6H).
Example 7.6 preparation of 6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -2- (2- (quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 7)
Step 1.2- (quinolin-6-yl) -1-ethanol (Compound 4 a) preparation
The 3-bromoquinoline-6-carboxylic acid in step 1 of example 1 was changed to 2- (quinolin-6-yl) acetic acid, and the remaining reagents and preparation methods were the same as in example 1 to prepare compound 4a. 1 HNMR(400MHz,DMSO)δ8.84(dd,J＝4.2,1.7Hz,1H),8.27(dd,J＝8.4,1.7Hz,1H),7.94(d,J＝8.6Hz,1H),7.77(d,J＝2.0Hz,1H),7.65(dd,J＝8.6,2.0Hz,1H),7.48(dd,J＝8.3,4.2Hz,1H),3.74(t,J＝6.8Hz,2H),2.93(t,J＝6.8Hz,2H).
Step 2.6 preparation of (2-bromoethyl) quinoline (Compound 4 b)
Compound 1a in step 2 of example 1 was replaced with compound 4a, and the remaining reagents and preparation methods were the same as in example 1 to obtain compound 4b.
Step 3.preparation of 6- (4-bromophenyl) -2- (2- (quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 4 c)
Compound 4c was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 4b and compound 2b, and the remaining reagents and preparation methods were the same as in example 1. 1 HNMR(400MHz,DMSO)δ8.84(dd,J＝4.3,1.7Hz,1H),8.26(d,J＝8.4Hz,1H),8.00(d,J＝9.7Hz,1H),7.95(d,J＝8.6Hz,1H),7.78(d,J＝2.0Hz,1H),7.70–7.63(m,3H),7.60–7.57(m,2H),7.48(dd,J＝8.3,4.2Hz,1H),7.03(d,J＝9.7Hz,1H),4.51(t,J＝7.1Hz,2H),3.30(t,J＝7.2Hz,2H).
Step 4.6 preparation of 6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -2- (2- (quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 7)
Compound 7 was prepared by replacing compound 1d in step 5 of example 1 with compound 4c, and the remaining reagents and preparation methods were the same as in example 1. 1 HNMR(600MHz,DMSO)δ8.84(dd,J＝4.1,1.7Hz,1H),8.26(d,J＝7.9Hz,1H),8.20(s,1H),8.01(d,J＝9.7Hz,1H),7.96(d,J＝8.6Hz,1H),7.92(d,J＝0.9Hz,1H),7.79(d,J＝2.0Hz,1H),7.71(d,J＝8.4Hz,2H),7.69(dd,J＝8.6,2.1Hz,1H),7.59(d,J＝8.4Hz,2H),7.48(dd,J＝8.3,4.2Hz,1H),7.02(d,J＝9.7Hz,1H),4.51(t,J＝7.2Hz,2H),3.88(s,3H),3.31(t,J＝7.2Hz,2H).
Example 8.6 preparation of 6- (4-morpholinophenyl) -2- (2- (quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 8)
Compound 8 was obtained by replacing compound 1d in example 2 with compound 4c, and the other reagents and preparation methods were the same as those in example 2. 1 H NMR(600MHz,DMSO)δ8.84(dd,J＝4.2,1.7Hz,1H),8.26(d,J＝7.9Hz,1H),7.94(m,2H),7.78(d,J＝2.0Hz,1H),7.67(dd,J＝8.6,2.0Hz,1H),7.61(d,J＝8.9Hz,2H),7.48(dd,J＝8.2,4.1Hz,1H),6.96(d,J＝9.7Hz,1H),6.94(d,J＝9.0Hz,2H),4.47(t,J＝7.3Hz,2H),3.74(t,J＝4.9Hz,4H),3.29(t,J＝7.2Hz,2H),3.16(t,J＝4.9Hz,4H).
Example 9.preparation of 6- (2-fluorophenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 9)
Step 1.preparation of ethyl 2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) acetate (Compound 5 a)
Compound 5a was prepared by replacing compound 1d of step 5 of example 1 with ethyl 2- (3-bromoquinolin-6-yl) acetate, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(400MHz,DMSO)δ9.16(d,J＝2.2Hz,1H),8.43(d,J＝2.2Hz,1H),8.39(s,1H),8.10(s,1H),7.94(d,J＝8.6Hz,1H),7.79(d,J＝1.9Hz,1H),7.58(dd,J＝8.7,2.0Hz,1H),4.11(q,J＝7.1Hz,2H),3.92(s,3H),3.88(s,2H),1.20(t,J＝7.1Hz,3H).
Step 2.preparation of 2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethan-1-ol (Compound 5 b)
4.6g (15.6 mmol) of compound 5a were dissolved in an ultra-dry tetrahydrofuran solution, argon was replaced, and the solution was placed at 0℃and 47mL (46.6 mmol) of lithium aluminum hydride in tetrahydrofuran (1.0 mol/L) was slowly added dropwise,stirring was carried out at 0deg.C for 30min, and after TLC showed disappearance of starting material, the reaction was stopped. Slowly adding 15% sodium hydroxide solution in ice bath for quenching, suction filtering, spinning the filtrate, and obtaining 2.5g white solid (yield 64%) through column chromatography. 1 H NMR(400MHz,DMSO)δ9.11(d,J＝2.2Hz,1H),8.42–8.35(m,2H),8.09(s,1H),7.89(d,J＝8.6Hz,1H),7.72(s,1H),7.57(d,J＝8.4Hz,1H),4.73(t,J＝5.2Hz,1H),3.92(s,3H),3.72(q,J＝6.4Hz,2H),2.92(t,J＝6.8Hz,2H).
Step 3.preparation of 6- (2-bromoethyl) -3- (1-methyl-1H-pyrazol-4-yl) quinoline (Compound 5 c)
The compound 1a in step 2 of example 1 was replaced with the compound 5b, and the remaining reagents and preparation methods were the same as those of example 1, to prepare the compound 5c, which was directly used in the next step.
Step 4.6- (2-fluorophenyl) pyridazin-3 (2H) -one preparation (Compound 5 d)
The acetophenone in step 3 of example 1 was replaced with 2' -fluoro acetophenone, and the remaining reagents and preparation methods were the same as in example 1 to prepare compound 5d. 1 H NMR(400MHz,DMSO)δ13.26(s,1H),7.99(d,J＝9.9Hz,1H),7.78(d,J＝8.6Hz,2H),7.63(d,J＝8.6Hz,2H),6.99(d,J＝9.9Hz,1H).
Step 5.preparation of 6- (2-fluorophenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 9)
Compound 9 was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 5c and compound 5d, and the remaining reagents and preparation methods were the same as in example 1. 1 HNMR(400MHz,DMSO)δ9.13(d,J＝2.3Hz,1H),8.38–8.36(m,2H),8.08(s,1H),7.91(d,J＝8.6Hz,1H),7.75–7.69(m,2H),7.58(dd,J＝8.6,2.0Hz,1H),7.51–7.43(m,1H),7.35–7.28(m,2H),7.15(td,J＝7.5,1.1Hz,1H),7.03(d,J＝9.7Hz,1H),4.51(t,J＝7.1Hz,2H),3.91(s,3H),3.29(t,J＝7.1Hz,2H).
EXAMPLE 10 preparation of 6- (3-fluorophenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 10)
Step 1.6 preparation of 6- (3-fluorophenyl) pyridazin-3 (2H) -one (Compound 6 a)
The acetophenone in step 3 of example 1 was changed to 3' -fluoro acetophenone, and the remaining reagents and preparation methods were the same as in example 1 to obtain compound 6a. 1 H NMR(400MHz,DMSO)δ13.35(s,1H),7.75(dd,J＝9.9,2.5Hz,1H),7.71–7.65(m,1H),7.55–7.48(m,1H),7.39–7.29(m,2H),6.99(d,J＝9.9Hz,1H).
Step 5.preparation of 6- (3-fluorophenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 10)
Compound 10 was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 5c and compound 6a, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(400MHz,DMSO)δ9.11(d,J＝2.3Hz,1H),8.36(s,2H),8.07(s,1H),8.03(d,J＝9.7Hz,1H),7.90(d,J＝8.6Hz,1H),7.72(d,J＝1.9Hz,1H),7.61–7.54(m,2H),7.52–7.40(m,2H),7.23(td,J＝8.5,2.6Hz,1H),7.05(d,J＝9.7Hz,1H),4.52(t,J＝7.1Hz,2H),3.91(s,3H),3.30(t,J＝7.6Hz,2H).
EXAMPLE 11 preparation of 6- (4-fluorophenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 11)
Step 1.6 preparation of (4-fluorophenyl) pyridazin-3 (2H) -one (Compound 7 a)
The acetophenone in step 3 of example 1 was replaced with 4' -fluoro acetophenone, and the remaining reagents and preparation methods were the same as in example 1 to prepare compound 7a. 1 H NMR(400MHz,DMSO)δ13.20(s,1H),8.02(d,J＝9.9Hz,1H),7.94–7.86(m,2H),7.35–7.25(m,2H),6.99(d,J＝9.8Hz,1H).
Step 2.preparation of 6- (4-fluorophenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 11)
Compound 11 was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 5c and compound 7a, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(400MHz,DMSO)δ9.11(d,J＝2.2Hz,1H),8.36(s,2H),8.07(s,1H),7.99(d,J＝9.7Hz,1H),7.90(d,J＝8.6Hz,1H),7.75–7.81(m,2H),7.71(s,1H),7.59(dd,J＝8.6,2.0Hz,1H),7.23(t,J＝8.7Hz,2H),7.03(d,J＝9.7Hz,1H),4.50(t,J＝7.1Hz,2H),3.91(s,3H),3.29(d,J＝7.2Hz,2H).
EXAMPLE 12 preparation of 6- (3-bromophenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 12)
Step 1.6 preparation of (3-bromophenyl) pyridazin-3 (2H) -one (Compound 8 a)
The acetophenone in step 3 of example 1 was replaced with 3' -bromoacetophenone, and the remaining reagents and preparation methods were the same as in example 1 to prepare compound 8a. 1 H NMR(400MHz,DMSO)δ13.29(s,1H),8.05(d,J＝9.9Hz,1H),8.01(s,1H),7.85(d,J＝7.9Hz,1H),7.62(d,J＝8.0Hz,1H),7.43(t,J＝8.0Hz,1H),6.99(d,J＝9.9Hz,1H).
Step 2.preparation of 6- (3-bromophenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 12)
Compound 12 was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 5c and compound 8a, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(400MHz,DMSO)δ9.11(d,J＝2.2Hz,1H),8.36(s,2H),8.06(s,1H),8.02(d,J＝9.8Hz,1H),7.90(d,J＝8.6Hz,1H),7.79(s,1H),7.73–7.69(m,2H),7.58(d,J＝6.4Hz,2H),7.35(t,J＝7.8Hz,1H),7.04(d,J＝9.7Hz,1H),4.52(t,J＝7.1Hz,2H),3.91(s,3H),3.29(t,J＝7.1Hz,2H).
EXAMPLE 13 preparation of 6- (3-chlorophenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 13)
Step 1.6 preparation of (3-chlorophenyl) pyridazin-3 (2H) -one (Compound 9 a)
The acetophenone in step 3 of example 1 was changed to 3' -chloroacetophenone, and the remaining reagents and preparation methods were the same as those of example 1 to prepare compound 9a. 1 H NMR(400MHz,DMSO)δ13.30(s,1H),8.06(d,J＝10.0Hz,1H),7.89–7.87(m,1H),7.84–7.95(m,1H),7.51–7.47(m,2H),7.00(d,J＝9.9Hz,1H).
Step 2.preparation of 6- (3-chlorophenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 13)
Compound 13 was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 5c and compound 9a, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(600MHz,DMSO)δ9.11(d,J＝1.9Hz,1H),8.40–8.32(m,2H),8.06(s,1H),8.02(d,J＝9.7Hz,1H),7.89(d,J＝8.6Hz,1H),7.71(s,1H),7.68–7.61(m,2H),7.57(d,J＝7.0Hz,1H),7.46–7.38(m,2H),7.04(d,J＝9.7Hz,1H),4.52(t,J＝7.0Hz,2H),3.91(s,3H),3.29(t,J＝7.0Hz,2H).
EXAMPLE 14 preparation of 3- (1- (2- (3- (1-methyl-1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) benzonitrile (Compound 14)
Step 1.preparation of 3- (6-oxo-1, 6-dihydropyridazin) -3-yl) benzonitrile (Compound 10 a)
The acetophenone in step 3 of example 1 was changed to 3-acetophenone, and the remaining reagents and preparation methods were the same as those of example 1 to obtain compound 10a. 1 H NMR(400MHz,DMSO)δ13.35(s,1H),8.28(d,J＝2.1Hz,1H),8.18(d,J＝8.1Hz,1H),8.11(d,J＝9.9Hz,1H),7.90(d,J＝7.7Hz,1H),7.68(t,J＝7.9Hz,1H),7.03(d,J＝9.8Hz,1H).
Step 2.preparation of 3- (1- (2- (3- (1-methyl-1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) benzonitrile (Compound 14)
Compound 14 was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 5c and compound 10a, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(400MHz,DMSO)δ9.11(d,J＝2.2Hz,1H),8.35(m,2H),8.20(t,J＝1.7Hz,1H),8.09(d,J＝9.8Hz,1H),8.06(s,1H),8.04–8.01(m,1H),7.90(d,J＝8.6Hz,1H),7.87(dt,J＝7.8,1.3Hz,1H),7.71(d,J＝1.9Hz,1H),7.62–7.56(m,2H),7.08(d,J＝9.7Hz,1H),4.53(t,J＝7.1Hz,2H),3.91(s,3H),3.30(t,J＝7.1Hz,2H).
EXAMPLE 15 preparation of 2- (2- (3- (1-methyl-1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6- (3-nitrophenyl) pyridazin-3 (2H) -one (Compound 15)
Step 1.6 preparation of (3-nitrophenyl) pyridazin-3 (2H) -one (Compound 11 a)
The acetophenone in step 3 of example 1 was replaced with m-nitroacetophenone, and the remaining reagents and preparation methods were the same as those of example 1 to prepare compound 11a. 1 HNMR(400MHz,DMSO)δ13.38(s,1H),8.60(t,J＝2.1Hz,1H),8.28(d,J＝8.0Hz,1H),8.24(dd,J＝7.8,1.9Hz,1H),8.15(d,J＝9.9Hz,1H),7.75(t,J＝8.0Hz,1H),7.03(d,J＝9.9Hz,1H).
Step 2.preparation of 2- (2- (3- (1-methyl-1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6- (3-nitrophenyl) pyridazin-3 (2H) -one (Compound 15)
Compound 15 was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 5c and compound 11a, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(600MHz,DMSO)δ9.07(d,J＝2.2Hz,1H),8.45(t,J＝2.1Hz,1H),8.33(s,1H),8.31(d,J＝2.3Hz,1H),8.21((dd,J＝8.2,1.4Hz,1H)1H),8.13–8.10(m,2H),8.04(s,1H),7.89(d,J＝8.5Hz,1H),7.68–7.64(m,2H),7.58(dd,J＝8.6,2.0Hz,1H),7.08(d,J＝9.7Hz,1H),4.53(t,J＝7.1Hz,2H),3.90(s,3H),3.29(t,J＝7.1Hz,2H).
EXAMPLE 16 preparation of 2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6- (3- (trifluoromethyl) phenyl) pyridazin-3 (2H) -one (Compound 16)
Step 1.6 preparation of 6- (3- (trifluoromethyl) phenyl) pyridazin-3 (2H) -one (Compound 12 a)
The acetophenone in step 3 of example 1 was replaced with m-trifluoromethyl acetophenone, and the remaining reagents and preparation methods were the same as in example 1 to prepare compound 12a. 1 H NMR(400MHz,DMSO)δ13.34(s,1H),8.18–8.10(m,3H),7.80–7.74(m,1H),7.74–7.67(m,1H),7.02(d,J＝9.8Hz,1H).
Step 2.preparation of 2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6- (3- (trifluoromethyl) phenyl) pyridazin-3 (2H) -one (Compound 16)
Compound 16 was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 5c and compound 12a, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(400MHz,DMSO)δ9.10(d,J＝2.3Hz,1H),8.35(m,2H),8.12(d,J＝9.7Hz,1H),8.06(s,1H),8.01(d,J＝7.9Hz,1H),7.96(s,1H),7.89(d,J＝8.6Hz,1H),7.76(d,J＝7.8Hz,1H),7.70(d,J＝1.9Hz,1H),7.63(t,J＝7.8Hz,1H),7.59(dd,J＝8.5,1.9Hz,1H),7.08(d,J＝9.7Hz,1H),4.55(t,J＝7.0Hz,2H),3.91(s,3H),3.30(t,J＝7.1Hz,2H).
EXAMPLE 17 preparation of 6- (3-aminophenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 17)
50mg of compound 16 was dissolved in 10mL of methanol, 10mg of palladium on carbon (10%) was added, and reacted under a hydrogen atmosphere for 3 hours, after the reaction was completed, suction filtration was performed, and the filtrate was dried by spin-drying through a column to obtain 47mg of a white solid, the yield was 50%. 1 H NMR(600MHz,DMSO)δ9.12(d,J＝2.3Hz,1H),8.38(d,J＝2.6Hz,1H),8.37(s,1H),8.08(s,1H),7.92(d,J＝8.5Hz,1H),7.84(d,J＝9.7Hz,1H),7.72(d,J＝1.9Hz,1H),7.58(dd,J＝8.6,2.0Hz,1H),7.07(t,J＝7.8Hz,1H),7.00(t,J＝2.0Hz,1H),6.98(d,J＝9.7Hz,1H),6.89-6.86(m,1H),6.62(dd,J＝8.0,1.3Hz,1H),5.21(s,2H),4.49(t,J＝7.3Hz,2H),3.91(s,3H),3.30(d,J＝7.2Hz,2H).
EXAMPLE 18 preparation of 2- (2- (3- (1-methyl-1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6- (m-tolyl) pyridazin-3 (2H) -one (Compound 18)
Step 1.6- (m-tolyl) pyridazin-3 (2H) -one preparation (Compound 13 a)
The acetophenone in step 3 of example 1 was replaced by m-methylacetophenone, and the remaining reagents and preparation methods were the same as those of example 1 to prepare compound 13a. 1 H NMR(400MHz,DMSO)δ13.19(s,1H),8.00(d,J＝9.9Hz,1H),7.67(s,1H),7.63(d,J＝8.0Hz,1H),7.35(t,J＝7.6Hz,1H),7.24(d,J＝7.0Hz,1H),6.98(d,J＝9.9Hz,1H),2.35(s,3H).
Step 2.preparation of 2- (2- (3- (1-methyl-1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6- (m-tolyl) pyridazin-3 (2H) -one (Compound 18)
Compound 18 was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 5c and compound 13a, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(400MHz,DMSO)δ9.11(d,J＝2.2Hz,1H),8.36(s,2H),8.07(s,1H),7.98–7.87(m,2H),7.70(s,1H),7.57(d,J＝8.6Hz,1H),7.48(d,J＝7.7Hz,1H),7.34(s,1H),7.26(t,J＝7.6Hz,1H),7.18(d,J＝7.6Hz,1H),7.02(d,J＝9.7Hz,1H),4.51(t,J＝7.0Hz,2H),3.91(s,3H),3.28(t,J＝7.0Hz,2H),2.22(s,3H).
EXAMPLE 19 preparation of 6- (3-methoxyphenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 19)
Step 1.6 preparation of (3-methoxyphenyl) pyridazin-3 (2H) -one (Compound 14 a)
The acetophenone in step 3 of example 1 was replaced with 3-methoxyacetophenone, and the remaining reagents and preparation methods were the same as those of example 1 to prepare compound 14a. 1 H NMR(400MHz,DMSO)δ13.20(s,1H),8.03(d,J＝9.9Hz,1H),7.45–7.35(m,3H),7.03–6.95(m,2H),3.81(s,3H).
Step 2.preparation of 6- (3-methoxyphenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 19)
Compound 19 was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 5c and compound 14a, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(400MHz,DMSO)δ9.11(d,J＝2.2Hz,1H),8.36(s,2H),8.07(s,1H),8.00(d,J＝9.7Hz,1H),7.90(d,J＝8.6Hz,1H),7.71(s,1H),7.58(d,J＝8.6Hz,1H),7.34-7.26(m,2H),7.20(s,1H),7.02(d,J＝9.7Hz,1H),6.97(d,J＝7.1Hz,1H),4.52(t,J＝7.0Hz,2H),3.91(s,3H),3.72(s,3H),3.29(d,J＝7.1Hz,2H).
EXAMPLE 20 preparation of 2- (2- (3- (1-methyl-1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6- (3- (trifluoromethoxy)) phenyl) pyridazin-3 (2H) -one (Compound 20)
Step 1.6 preparation of 6- (3- (trifluoromethoxy) phenyl) pyridazin-3 (2H) -one (Compound 15 a)
The acetophenone in step 3 of example 1 was changed to 3- (trifluoromethoxy) acetophenone, and the remaining reagents and preparation methods were the same as in example 1 to obtain compound 15a. 1 H NMR(400MHz,DMSO)δ13.28(s,1H),8.07(d,J＝9.9Hz,1H),7.88(d,J＝7.8Hz,1H),7.79(s,1H),7.60(t,J＝8.0Hz,1H),7.40(d,J＝7.2Hz,1H),7.01(d,J＝9.9Hz,1H).
Step 2.preparation of 2- (2- (3- (1-methyl-1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6- (3- (trifluoromethoxy)) phenyl) pyridazin-3 (2H) -one (Compound 20)
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Compound 20 was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 5c and compound 15a, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(400MHz,DMSO)δ9.10(d,J＝2.2Hz,1H),8.35(s,2H),8.09–8.02(m,2H),7.89(d,J＝8.5Hz,1H),7.76(d,J＝7.8Hz,1H),7.70(s,1H),7.62–7.49(m,3H),7.40(d,J＝8.2Hz,1H),7.06(d,J＝9.7Hz,1H),4.53(t,J＝7.0Hz,2H),3.91(s,3H),3.29(d,J＝7.0Hz,3H).
EXAMPLE 21 preparation of 2- (2- (3- (1-methyl-1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6- (p-tolyl) pyridazin-3 (2H) -one (Compound 21)
Step 1.6- (p-tolyl) pyridazin-3 (2H) -one preparation (Compound 16 a)
The acetophenone in step 3 of example 1 was converted to p-methylacetophenone, and the remaining reagents and preparation methods were the same as in example 1 to prepare compound 16a. 1 H NMR(400MHz,DMSO)δ13.15(s,1H),8.00(d,J＝9.9Hz,1H),7.75(d,J＝8.3Hz,2H),7.28(d,J＝8.0Hz,2H),6.97(d,J＝9.9Hz,1H),2.34(s,3H).
Step 2.preparation of 2- (2- (3- (1-methyl-1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6- (p-tolyl) pyridazin-3 (2H) -one (Compound 21)
Compound 21 was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 5c and compound 16a, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(400MHz,DMSO)δ9.11(d,J＝2.2Hz,1H),8.36(s,2H),8.07(s,1H),7.96(d,J＝9.7Hz,1H),7.90(d,J＝8.6Hz,1H),7.71(d,J＝2.0Hz,1H),7.65–7.60(m,2H),7.58(dd,J＝8.6,2.0Hz,1H),7.21(d,J＝7.9Hz,2H),7.01(d,J＝9.7Hz,1H),4.50(t,J＝7.1Hz,2H),3.91(s,3H),3.29(t,J＝7.1Hz,2H),2.32(s,3H).
EXAMPLE 22 preparation of 6- (3, 4-difluorophenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 22)
Step 1.6 preparation of 6- (3, 4-difluorophenyl) pyridazin-3 (2H) -one (Compound 17 a)
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The acetophenone in step 3 of example 1 was changed to 3',4' -difluoroacetophenone, and the remaining reagents and preparation methods were the same as in example 1 to obtain compound 17a. 1 H NMR(400MHz,DMSO)δ13.03(s,1H),7.99(d,J＝9.9Hz,1H),7.85–7.77(m,1H),7.70–7.61(m,1H),7.52–7.40(m,1H),6.97(d,J＝9.9Hz,1H).
Step 2.preparation of 6- (3, 4-difluorophenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 22)
Compound 22 was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 5c and compound 17a, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(400MHz,DMSO)δ9.11(d,J＝2.3Hz,1H),8.38–8.34(m,2H),8.07(s,1H),8.02(d,J＝9.7Hz,1H),7.90(d,J＝8.6Hz,1H),7.75–7.67(m,2H),7.59(td,J＝8.8,2.4Hz,2H),7.47(q,J＝9.2Hz,1H),7.05(d,J＝9.7Hz,1H),4.51(t,J＝7.1Hz,2H),3.91(s,3H),3.29(d,J＝7.1Hz,2H).
EXAMPLE 23 preparation of 6- (3, 5-difluorophenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (compound 23)
Step 1.6 preparation of 6- (3, 5-difluorophenyl) pyridazin-3 (2H) -one (Compound 18 a)
The acetophenone in step 3 of example 1 was changed to 3',5' -difluoroacetophenone, and the remaining reagents and preparation methods were the same as in example 1 to obtain compound 18a. 1 H NMR(400MHz,DMSO)δ13.36(s,1H),8.10(d,J＝10.0Hz,1H),7.61-7.56(m,2H),7.37–7.29(m,1H),7.02(d,J＝9.9Hz,1H).
Step 2.preparation of 6- (3, 5-difluorophenyl) -2- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 23)
Compound 23 was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 5c and compound 18a, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(400MHz,DMSO)δ9.10(d,J＝2.2Hz,1H),8.35(s,2H),8.06(s,1H),8.04(d,J＝9.7Hz,2H),7.89(d,J＝8.6Hz,1H),7.71(s,1H),7.57(dd,J＝8.6,2.0Hz,1H),7.41–7.35(m,2H),7.29–7.23(m,1H),7.06(d,J＝9.7Hz,1H),4.52(t,J＝7.0Hz,2H),3.91(s,3H),3.29(t,J＝7.0Hz,2H).
EXAMPLE 24 preparation of 2- (2- (3- (1-methyl-1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6- (3, 4, 5-trifluorophenyl) pyridazin-3 (2H) -one (Compound 24)
Step 1.6 preparation of 6- (3, 4, 5-trifluorophenyl) pyridazin-3 (2H) -one (Compound 19 a)
The acetophenone in step 3 of example 1 was changed to 3',4',5' -trifluoroacetophenone, and the remaining reagents and preparation methods were the same as in example 1 to obtain compound 19a. 1 H NMR(400MHz,DMSO)δ13.36(s,1H),8.08(d,J＝10.0Hz,1H),7.85–7.65(m,2H),7.03(d,J＝9.9Hz,1H).
Step 2.preparation of 2- (2- (3- (1-methyl-1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6- (3, 4, 5-trifluorophenyl) pyridazin-3 (2H) -one (Compound 24)
Compound 24 was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 5c and compound 19a, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(400MHz,DMSO)δ9.11(d,J＝2.3Hz,1H),8.37–8.33(m,2H),8.06(s,1H),8.03(d,J＝9.8Hz,1H),7.89(d,J＝8.6Hz,1H),7.71(d,J＝1.9Hz,1H),7.64–7.55(m,3H),7.07(d,J＝9.7Hz,1H),4.51(t,J＝7.0Hz,2H),3.91(s,3H),3.29(t,J＝7.0Hz,2H).
EXAMPLE 25 preparation of methyl 4- (1- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) benzoate (Compound 25)
Step 1.6 preparation of chloro-2- (2- (3- (1-methyl-1H) -pyrazol-4-yl) quinolin-6-yl) ethyl) pyridazin-3 (2H) -one (Compound 20 a)
Compound 20a was obtained by replacing Compound 1b and Compound 1c in step 4 of example 1 with Compound 5c and 3-hydroxy-6-chloropyridazine, and the other reagents and preparation methods were the same as those of example 1. 1 HNMR(400MHz,DMSO)δ9.13(d,J＝2.2Hz,1H),8.39(m,2H),8.09(s,1H),7.90(d,J＝8.6Hz,1H),7.69(s,1H),7.59–7.50(m,2H),7.03(d,J＝9.7Hz,1H),4.36(t,J＝7.3Hz,2H),3.92(s,3H),3.21(t,J＝7.3Hz,2H).
Step 2 preparation of methyl 4- (1- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) benzoate (Compound 25)
60mg (0.16 mmol) of the compound 20a and 74mg (0.41 mmol) of 4-methoxycarbonylphenylboronic acid are dissolved in a mixed solvent of ethylene glycol dimethyl ether and water, and 11mg (0.016 mmol) of Pd (dppf) Cl is added 2 And 53mg (0.50 mmol) NaCO 3 The reaction was carried out overnight at 100℃under the protection of argon, and after the completion of the reaction, the solvent was dried by spin-drying, and purified by flash chromatography on silica gel column to give 70mg of Compound 25 (yield 94%). 1 H NMR(400MHz,DMSO)δ9.11(d,J＝2.1Hz,1H),8.35(s,2H),8.04(m,2H),7.92(m,3H),7.83(m,2H),7.70(s,1H),7.59(d,J＝8.6Hz,1H),7.06(d,J＝9.7Hz,1H),4.53(t,J＝7.1Hz,2H),3.91(s,3H),3.86(s,3H),3.30(t,J＝7.1Hz,2H).
EXAMPLE 26 preparation of 4- (1- (2- (3- (1-methyl-1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) benzoic acid (Compound 26)
2- (3-bromoquinolin-6-yl) acetic acid in step 1 of example 5 was changed to compound 25, and the remaining reagents and preparation methods were the same as in example 5 to obtain compound 26. 1 H NMR(600MHz,DMSO)δ9.35(d,J＝2.1Hz,1H),8.83(s,1H),8.45(s,1H),8.15(s,1H),8.12(d,J＝8.7Hz,1H),8.06(d,J＝9.8Hz,1H),7.95(d,J＝8.5Hz,2H),7.89(s,1H),7.84(d,J＝8.4Hz,2H),7.82(d,J＝7.1Hz,1H),7.06(d,J＝9.7Hz,1H),4.55(t,J＝7.0Hz,2H),3.93(s,3H),3.37(t,J＝7.1Hz,2H).
EXAMPLE 27 preparation of N-methyl-4- (1- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) benzamide (Compound 27)
100mg (0.22 mmol) of compound 26 are dissolved in 10mLN, N-Dimethylformamide (DMF), 421mg (1.11 mmol) of HATU and 0.36ml (2.21 mmol) of N, N-Diisopropylethylamine (DIPEA) are added in sequence, after stirring at room temperature for 15 minutes 34mg (1.09 mmol) of methylamine hydrochloride are added to the mixture and stirring is continued for a further 15 minutes. Pouring the mixture into H 2 O was extracted with ethyl acetate, and the organic phase was washed with brine, anhydrous Na 2 SO 4 Drying, spin drying and column passing gave 84mg of white solid in 82% yield. 1 HNMR(600MHz,DMSO)δ9.11(d,J＝2.3Hz,1H),8.52(q,J＝4.5Hz,1H),8.35(s,2H),8.07(s,1H),8.05(d,J＝10.0Hz,1H),7.91(d,J＝8.5Hz,1H),7.86(d,J＝8.4Hz,2H),7.81(d,J＝8.4Hz,2H),7.71(s,1H),7.60(dd,J＝8.6,1.9Hz,1H),7.05(d,J＝9.7Hz,1H),4.53(t,J＝7.2Hz,2H),3.91(s,3H),3.31(t,J＝7.2Hz,2H),2.80(d,J＝4.4Hz,3H).
EXAMPLE 28 preparation of methyl 4- (1- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoate (Compound 28)
The compound 28 was prepared by substituting 4-methoxycarbonylphenylboronic acid in step 2 of example 25 with methyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) benzoate, and then using the same reagents and preparation methods as in example 25. 1 H NMR(600MHz,DMSO)δ9.09(d,J＝2.2Hz,1H),8.35(s,1H),8.34(d,J＝2.3Hz,1H),8.16(d,J＝9.8Hz,1H),8.13(dd,J＝8.1,1.8Hz,1H),8.07–8.04(m,2H),7.89(d,J＝8.5Hz,1H),7.87(d,J＝8.1Hz,1H),7.69(d,J＝2.0Hz,1H),7.58(dd,J＝8.6,2.0Hz,1H),7.10(d,J＝9.7Hz,1H),4.55(t,J＝7.0Hz,2H),3.91(s,3H),3.88(s,3H),3.31(t,J＝7.0Hz,2H).
EXAMPLE 29 preparation of 4- (1- (2- (3- (1-methyl-1H-pyrazol) -4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoic acid (Compound 29)
2- (3-bromoquinolin-6-yl) acetic acid in step 1 of example 5 was changed to compound 28, and compound 29 was prepared by the same procedure as in example 5 except that the reagent was used. 1 H NMR(600MHz,DMSO)δ9.18(d,J＝2.2Hz,1H),8.51(s,1H),8.38(s,1H),8.15(d,J＝9.8Hz,1H),8.10(dd,J＝8.1,1.8Hz,1H),8.08(s,1H),8.00(d,J＝1.8Hz,1H),7.95(d,J＝8.6Hz,1H),7.84(d,J＝8.1Hz,1H),7.75(d,J＝1.9Hz,1H),7.66(dd,J＝8.6,1.9Hz,1H),7.09(d,J＝9.7Hz,1H),4.56(t,J＝7.0Hz,2H),3.92(s,3H),3.32(d,J＝7.0Hz,2H).
EXAMPLE 30 preparation of N-methyl-4- (1- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 30)
Compound 30 was prepared by replacing compound 26 in example 27 with compound 29, and the remaining reagents and preparation methods were the same as in example 27. 1 H NMR(400MHz,DMSO)δ9.10(d,J＝2.2Hz,1H),8.37–8.34(m,2H),8.35(d,J＝3.0Hz,2H),8.15(s,1H),8.08–8.03(m,2H),7.98(d,J＝1.7Hz,1H),7.89(d,J＝8.6Hz,1H),7.70(d,J＝2.0Hz,1H),7.58(dd,J＝8.5,1.9Hz,1H),7.55(d,J＝8.0Hz,1H),7.09(d,J＝9.7Hz,1H),4.55(t,J＝7.0Hz,2H),3.91(s,3H),3.30(t,J＝7.0Hz,2H),2.76(d,J＝4.6Hz,3H).
EXAMPLE 31 preparation of N-methyl-4- (1- (2- (3- (4-methylpiperazin-1-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 31)
Step 1.preparation of methyl 4- (6-methoxypyridazin-3-yl) -2- (trifluoromethyl) benzoate (Compound 21 a)
378mg (2.6 mmol) of 6-methoxy-3-chloropyridazine and 950mg (2.9 mmol) of methyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) benzoate were dissolved in a mixed solvent of 1, 4-dioxan and water, and 302mg (0.3 mmol) of Pd (PPh 3 ) 4 And 832mg (7.8 mmol) of Na 2 CO 3 The reaction was carried out overnight at 80℃under the protection of argon, the solvent was dried by spin-drying after the completion of the reaction, and the resultant was purified by flash chromatography on silica gel column to give 790mg (yield 97%). 1 H NMR(400MHz,CDCl3)δ8.47(s,1H),8.27(dd,J＝8.1,1.8Hz,1H),7.95(d,J＝8.1Hz,1H),7.87(d,J＝9.2Hz,1H),7.14(d,J＝9.2Hz,1H),4.24(s,3H),3.99(s,3H).
Step 2 preparation of methyl 4- (6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoate (Compound 21 b)
730mg (2.3 mmol) of compound 21a were dissolved in 1, 4-dioxane and 2N HCl (v/v, 1/1), after stirring at 80℃for 4h, the organic solvent was dried by spin-drying and water was added thereto, the solid product was filtered, washed with water and dried to give 680mg of white solid in 98% yield. 1 HNMR(400MHz,DMSO)δ13.43(s,1H),8.31–8.24(m,2H),8.20(d,J＝9.9Hz,1H),7.96(d,J＝8.2Hz,1H),7.05(d,J＝9.8Hz,1H),3.89(s,3H).
Step 3 preparation of methyl 4- (1- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoate (Compound 21 c)
Compound 21c was prepared by replacing compound 1b and compound 1c in step 4 of example 1 with compound 3c and compound 21b, and the remaining reagents and preparation methods were the same as in example 1. 1 H NMR(400MHz,DMSO)δ8.85(d,J＝2.3Hz,1H),8.59(d,J＝2.3Hz,1H),8.16(d,J＝9.7Hz,1H),8.11(d,J＝8.3Hz,1H),7.98(s,1H),7.93(s,1H),7.87(d,J＝8.1Hz,1H),7.77–7.70(m,2H),7.10(d,J＝10.2Hz,1H),4.55(t,J＝6.9Hz,2H),3.89(d,J＝1.6Hz,3H),3.30(t,J＝6.9Hz,2H).
Step 4.preparation of 4- (1- (2- (3-bromoquinolin) -6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoic acid (Compound 21 d)
2- (3-bromoquinolin-6-yl) acetic acid in step 1 of example 5 was changed to compound 21c, and the remaining reagents and preparation methods were the same as in example 5 to obtain compound 21d.
Step 5.preparation of 4- (1- (2- (3-bromoquinolin) -6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -N-methyl-2- (trifluoromethyl) benzamide (Compound 21 e)
Compound 21e was obtained by replacing compound 26 in example 27 with compound 21d, and the remaining reagents and preparation methods were the same as those in example 27. 1 H NMR(400MHz,DMSO)δ8.86(d,J＝2.3Hz,1H),8.60(d,J＝2.3Hz,1H),8.43(q,J＝4.6Hz,1H),8.13(d,J＝9.8Hz,1H),8.04(d,J＝8.0Hz,1H),7.94(d,J＝8.6Hz,1H),7.90(s,1H),7.76(s,1H),7.71(dd,J＝8.6,2.0Hz,1H),7.55(d,J＝8.0Hz,1H),7.08(d,J＝9.7Hz,1H),4.54(t,J＝6.9Hz,2H),3.31(t,J＝6.9Hz,2H),2.76(d,J＝4.5Hz,3H).
Preparation of N-methyl-4- (1- (2- (3- (4-methylpiperazin-1-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 31)
The compound 1d and morpholine from example 2 were exchanged for the compound 21e and N-methylPiperazine, the rest of the reagents and the preparation method are the same as in example 2, obtaining compound 31. 1 H NMR(400MHz,DMSO)δ8.78(d,J＝2.9Hz,1H),8.44(q,J＝4.5Hz,1H),8.14(d,J＝9.8Hz,1H),8.05(dd,J＝8.0,1.8Hz,1H),7.99(d,J＝1.7Hz,1H),7.76(d,J＝8.5Hz,1H),7.59(d,J＝1.9Hz,1H),7.54(d,J＝8.0Hz,1H),7.42(d,J＝2.8Hz,1H),7.36(dd,J＝8.5,1.9Hz,1H),7.08(d,J＝9.7Hz,1H),4.52(t,J＝7.0Hz,2H),3.30–3.22(m,6H),2.76(d,J＝4.4Hz,3H),2.53–2.50(m,4H).
EXAMPLE 32 preparation of N-methyl-4- (1- (2- (3- (4-morpholinopiperidin) -1-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 32)
Compound 32 was prepared by replacing compound 1d and morpholine in example 2 with compound 21e and 4- (4-piperidinyl) morpholine, and the remaining reagents and preparation methods were the same as in example 2. 1 H NMR(400MHz,DMSO)δ8.77(d,J＝2.7Hz,1H),8.45(q,J＝4.6Hz,1H),8.14(d,J＝9.8Hz,1H),8.05(d,J＝8.1Hz,1H),8.01(s,1H),7.75(d,J＝8.5Hz,1H),7.58(s,1H),7.55(d,J＝8.0Hz,1H),7.41(d,J＝2.8Hz,1H),7.34(dd,J＝8.5,1.8Hz,1H),7.08(d,J＝9.7Hz,1H),4.51(t,J＝7.1Hz,2H),3.84(d,J＝12.8Hz,2H),3.58(t,J＝4.5Hz,4H),3.24(t,J＝7.1Hz,2H),2.81–2.68(m,5H),2.51–2.45(m,4H),2.37–2.27(m,1H),1.89(d,J＝12.4Hz,2H),1.61–1.44(m,2H).
EXAMPLE 33 preparation of N-methyl-4- (1- (2- (3- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 33)
The procedure of example 2 was repeated except that compound 1d and morpholine in example 2 were replaced with compound 21e and 1-methyl-4- (4-piperidinyl) piperazine, and the remaining reagents and preparation methods were the same as those of example 2To compound 33. 1 H NMR(400MHz,DMSO)δ8.76(d,J＝2.8Hz,1H),8.44(q,J＝4.5Hz,1H),8.13(d,J＝9.8Hz,1H),8.04(dd,J＝8.0,1.8Hz,1H),8.00(s,1H),7.74(d,J＝8.5Hz,1H),7.58(d,J＝1.9Hz,1H),7.54(d,J＝8.0Hz,1H),7.40(d,J＝2.8Hz,1H),7.34(dd,J＝8.5,1.9Hz,1H),7.08(d,J＝9.7Hz,1H),4.51(t,J＝7.1Hz,2H),3.85(d,J＝11.9Hz,2H),3.24(t,J＝7.1Hz,2H),2.79–2.70(m,5H),2.53–2.46(m,5H),2.38–2.26(m,4H),2.13(s,3H),1.86(d,J＝12.4Hz,2H),1.59–1.47(m,2H).
EXAMPLE 34 preparation of N-methyl-4- (6-oxo-1- (2- (3- (4- (pyrrolidin) -1-yl) piperidin-1-yl) quinolin-6-yl) ethyl) -1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 34)
Compound 34 was prepared by substituting compound 1d and morpholine from example 2 with compound 21e and 4-pyrrolidin-1-yl-piperidine, using the same reagents and preparation method as in example 2. 1 H NMR(400MHz,DMSO)δ8.76(d,J＝2.8Hz,1H),8.45(q,J＝4.6Hz,1H),8.13(d,J＝9.7Hz,1H),8.05(d,J＝8.0Hz,1H),8.01(s,1H),7.75(d,J＝8.5Hz,1H),7.58(s,1H),7.55(d,J＝8.0Hz,1H),7.40(d,J＝2.8Hz,1H),7.34(dd,J＝8.6,1.8Hz,1H),7.08(d,J＝9.7Hz,1H),4.51(t,J＝7.1Hz,2H),3.80–3.67(m,2H),3.24(t,J＝7.1Hz,2H),2.87–2.72(m,5H),2.21–2.11(m,1H),2.01–1.89(m,2H),1.72–1.64(m,4H),1.61–1.47(m,2H),1.26–1.10(m,4H).
EXAMPLE 35 preparation of 4- (1- (2- (3- (hexahydropyrrolidin [3,4-c ] pyrrol-2 (1H) -yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -N-methyl-2- (trifluoromethyl) benzamide (Compound 35)
Step 1. Preparation of tert-butyl 5- (6- (2- (3- (4- (methylcarbamoyl) -3- (trifluoromethyl) phenyl) -6-oxopyridazin-1 (6H) -yl) ethyl) quinolin-3-yl) hexahydropyrrolidine [3,4-c ] pyrrole-2 (1H) -carboxylate (Compound 22 a)
The compound 1d and morpholine from example 2 were exchanged for the compound 21e and 2-BOC-octahydropyrrolo [3,4-C ]]Pyrrole, the remaining reagents used and the preparation method were the same as in example 2 to prepare compound 22a. 1 H NMR(400MHz,DMSO)δ8.46(d,J＝2.8Hz,1H),8.44(q,J＝4.5Hz,1H),8.14(d,J＝9.8Hz,1H),8.07(dd,J＝8.0,1.8Hz,1H),8.02(s,1H),7.72(d,J＝8.5Hz,1H),7.55(d,J＝8.0Hz,1H),7.51(d,J＝1.9Hz,1H),7.25(dd,J＝8.5,1.9Hz,1H),7.08(d,J＝9.7Hz,1H),7.00(d,J＝2.8Hz,1H),4.51(t,J＝7.1Hz,2H),3.62–3.50(m,4H),3.32–3.16(m,6H),3.08–2.98(m,2H),2.76(d,J＝4.5Hz,3H),1.39(s,9H).
Step 2.4 preparation of 1- (2- (3- (hexahydropyrrolidin [3,4-c ] pyrrol-2 (1H) -yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -N-methyl-2- (trifluoromethyl) benzamide (Compound 35)
30mg of 22a was dissolved in 10mL of methylene chloride, 5mL of trifluoroacetic acid was added, and after stirring at room temperature for 0.5 hours, the solvent was concentrated in vacuo and purified by silica gel column to give 25mg of a white solid in 95% yield. 1 HNMR(400MHz,DMSO)δ8.52(d,J＝2.8Hz,1H),8.46(q,J＝4.5Hz,1H),8.13(d,J＝9.7Hz,1H),8.05(d,J＝8.0Hz,1H),8.03(s,1H),7.73(d,J＝8.5Hz,1H),7.55(d,J＝8.0Hz,1H),7.52(d,J＝1.8Hz,1H),7.28(dd,J＝8.5,1.9Hz,1H),7.11–7.02(m,2H),4.51(t,J＝7.1Hz,2H),3.54–3.48(m,2H),3.23(t,J＝7.0Hz,2H),3.21–3.16(m,2H),3.04–2.98(m,2H),2.92–2.85(m,2H),2.77(d,J＝4.5Hz,3H),2.72–2.66(m,2H).
EXAMPLE 36 preparation of N-methyl-4- (1- (2- (3- ((2-morpholinoethyl) amino) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 36)
Compound 36 was prepared by substituting compound 1d and morpholine in example 2 with compound 21e and N- (2-aminoethyl) morpholine, using the same reagents and preparation methods as in example 2. 1 H NMR(400MHz,DMSO)δ8.44(t,J＝4.7Hz,1H),8.42(d,J＝2.7Hz,1H),8.13(d,J＝9.8Hz,1H),8.06(dd,J＝7.9,1.8Hz,1H),8.03(d,J＝1.8Hz,1H),7.67(d,J＝8.5Hz,1H),7.55(d,J＝8.0Hz,1H),7.46(d,J＝2.0Hz,1H),7.20(dd,J＝8.5,1.9Hz,1H),7.08(d,J＝9.8Hz,1H),6.95(d,J＝2.9Hz,1H),6.09(t,J＝5.4Hz,1H),4.50(t,J＝7.1Hz,2H),3.60(t,J＝4.6Hz,4H),3.24–3.16(m,4H),2.77(d,J＝4.6Hz,3H),2.55(t,J＝6.6Hz,2H),2.44(t,J＝4.7Hz,4H).
EXAMPLE 37 preparation of N-methyl-4- (6-oxo-1- (2- (3- ((2- (piperidin-1-yl) ethyl) amino) quinolin-6-yl) ethyl) -1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 37)
Compound 37 is prepared by replacing compound 1d and morpholine in example 2 with compound 21e and 1- (2-aminoethyl) piperidine, and the remaining reagents and preparation methods are the same as in example 2. 1 H NMR(400MHz,DMSO)δ8.44(q,J＝4.3Hz,1H),8.42(d,J＝2.8Hz,1H),8.14(d,J＝9.8Hz,1H),8.06(dd,J＝7.9,1.8Hz,1H),8.04(d,J＝1.7Hz,1H),7.67(d,J＝8.5Hz,1H),7.55(d,J＝8.0Hz,1H),7.46(d,J＝1.9Hz,1H),7.20(dd,J＝8.5,1.9Hz,1H),7.08(d,J＝9.7Hz,1H),6.94(d,J＝2.7Hz,1H),6.05(t,J＝5.4Hz,1H),4.50(t,J＝7.1Hz,2H),3.25–3.14(m,4H),2.76(d,J＝4.6Hz,3H),2.53(t,J＝6.7Hz,2H),2.45–5.37(m,4H),1.55–1.48(m,4H),1.43–1.36(m,2H).
EXAMPLE 38 preparation of 4- (1- (2- (3- (1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -N-methyl-2- (trifluoromethyl) benzamide (Compound 38)
Will be implementedCompound 38 was prepared by the same procedure as in example 1 except that compound 1d and 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole in step 5 were replaced with compound 21e and 4-pyrazole boronic acid pinacol ester. 1 H NMR(400MHz,DMSO)δ13.11(s,1H),9.16(d,J＝2.2Hz,1H),8.43(q,J＝4.3Hz,1H),8.40(d,J＝2.2Hz,1H),8.14(d,J＝9.8Hz,1H),8.05(d,J＝7.9Hz,1H),7.99(s,1H),7.89(d,J＝8.6Hz,1H),7.70(d,J＝1.9Hz,1H),7.61–7.51(m,2H),7.09(d,J＝9.7Hz,1H),4.55(t,J＝7.0Hz,2H),3.30(t,J＝7.0Hz,2H),2.76(d,J＝4.4Hz,3H).
EXAMPLE 39 preparation of N-methyl-4- (6-oxo-1- (2- (3- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 39)
Step 1. Preparation of tert-butyl 4- (4- (6- (2- (3- (4- (methylcarbamoyl) -3- (trifluoromethyl) phenyl) -6-oxopyridazin-1 (6H) -yl) ethyl) quinolin-3-yl)) -1H-pyrazol-1-yl) piperidine-1-carboxylate (preparation of compound 23 a)
The compounds 1d and 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole of step 5 of example 1 were exchanged for the compounds 21e and 4- [4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazol-1-yl]The piperidine-1-carboxylic acid tert-butyl ester was prepared as compound 23a in the same manner as in example 1. 1 H NMR(400MHz,DMSO)δ9.13(d,J＝2.2Hz,1H),8.51(s,1H),8.43(q,J＝4.5Hz,1H),8.37(d,J＝2.3Hz,1H),8.14(d,J＝9.8Hz,1H),8.10(s,1H),8.05(dd,J＝7.9,1.8Hz,1H),7.98(d,J＝1.8Hz,1H),7.89(d,J＝8.6Hz,1H),7.69(d,J＝1.9Hz,1H),7.59(dd,J＝8.6,1.9Hz,1H),7.54(d,J＝8.0Hz,1H),7.09(d,J＝9.8Hz,1H),4.55(t,J＝7.0Hz,2H),4.46–4.36(m,1H),4.07(d,J＝13.2Hz,2H),3.30(t,J＝7.0Hz,2H),2.95(s,2H),2.76(d,J＝4.6Hz,3H),2.11–2.02(m,2H),1.83(qd,J＝12.4,4.4Hz,2H),1.43(s,9H).
Preparation of N-methyl-4- (6-oxo-1- (2- (3- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 39)
Compound 39 was prepared by the same procedure as in example 35 except that compound 22a in step 2 of example 35 was replaced with compound 23 a. 1 H NMR(400MHz,DMSO)δ9.13(d,J＝2.2Hz,1H),8.46(s,1H),8.43(q,J＝4.7Hz,1H),8.37(d,J＝2.2Hz,1H),8.14(d,J＝9.8Hz,1H),8.09(s,1H),8.05(dd,J＝8.0,1.8Hz,1H),7.98(d,J＝1.8Hz,1H),7.89(d,J＝8.5Hz,1H),7.69(d,J＝1.9Hz,1H),7.58(dd,J＝8.6,1.9Hz,1H),7.54(d,J＝8.0Hz,1H),7.09(d,J＝9.7Hz,1H),4.55(t,J＝7.0Hz,2H),4.31–4.21(m,1H),3.30(t,J＝7.0Hz,2H),3.13–3.06(m,2H),2.76(d,J＝4.6Hz,3H),2.66(td,J＝12.4,2.5Hz,2H),2.08–1.98(m,2H),1.91–1.80(m,2H).
EXAMPLE 40 preparation of N-methyl-4- (6-oxo-1- (2- (3- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 40)
Compound 40 was prepared by replacing compound 1d and 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole in step 5 of example 1 with compound 21e and 1- (tetrahydropyran-4-yl) -1H-pyrazole-4-boronic acid pinacol ester, the remaining reagents and preparation methods being the same as in example 1. 1 H NMR(600MHz,DMSO)δ9.14(d,J＝2.2Hz,1H),8.51(s,1H),8.43(q,J＝4.6Hz,1H),8.38(d,J＝2.3Hz,1H),8.14(d,J＝9.7Hz,1H),8.11(s,1H),8.05(dd,J＝8.0,1.8Hz,1H),7.98(d,J＝1.8Hz,1H),7.89(d,J＝8.5Hz,1H),7.69(d,J＝1.9Hz,1H),7.59(dd,J＝8.6,1.9Hz,1H),7.55(d,J＝8.0Hz,1H),7.09(d,J＝9.7Hz,1H),4.55(t,J＝7.0Hz,2H),4.49–4.25(m,1H),4.02–3.96(m,2H),3.50(td,J＝11.7,2.3Hz,2H),3.31(t,J＝7.0Hz,2H),2.76(d,J＝4.7Hz,3H),2.06–1.96(m,4H).
EXAMPLE 41.preparation of 4- (1- (2- (3- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -N-methyl-2- (trifluoromethyl) benzamide (Compound 41)
Compound 41 was prepared by replacing compound 1d and 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole in step 5 of example 1 with compound 21e and 1- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -1H-4-pyrazole-boronic acid pinacol ester, the remaining reagents and preparation methods being the same as in example 1. 1 H NMR(600MHz,DMSO)δ9.12(d,J＝2.2Hz,1H),8.44(q,J＝4.6Hz,1H),8.38(s,1H),8.37(d,J＝2.3Hz,1H),8.13(d,J＝9.7Hz,1H),8.09(s,1H),8.05(dd,J＝8.0,1.8Hz,1H),7.98(d,J＝1.8Hz,1H),7.89(d,J＝8.5Hz,1H),7.70(d,J＝2.0Hz,1H),7.58(dd,J＝8.6,1.9Hz,1H),7.55(d,J＝8.0Hz,1H),7.09(d,J＝9.7Hz,1H),4.99(t,J＝5.3Hz,1H),4.55(t,J＝7.1Hz,2H),4.21(t,J＝5.6Hz,2H),3.80(q,J＝5.5Hz,2H),3.31(t,J＝7.0Hz,2H),2.76(d,J＝4.6Hz,3H).
EXAMPLE 42 preparation of 4- (1- (2- (3- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -N-methyl-2- (trifluoromethyl) benzamide (Compound 42)
Compound 42 was prepared by the same procedure as in example 1, except that compound 1d and 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole in example 1 step 5 were replaced with compound 21e and 1- (2-methoxyethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole. 1 H NMR(400MHz,DMSO)δ9.12(d,J＝2.2Hz,1H),8.43(q,J＝4.5Hz,1H),8.40–8.34(m,2H),8.13(d,J＝9.7Hz,1H),8.09(s,1H),8.05(d,J＝8.1Hz,1H),7.99(s,1H),7.89(d,J＝8.6Hz,1H),7.70(d,J＝1.9Hz,1H),7.58(dd,J＝8.8,2.0Hz,2H),7.55(d,J＝8.1Hz,1H),7.09(d,J＝9.7Hz,1H),4.55(t,J＝7.0Hz,2H),4.32(t,J＝5.2Hz,2H),3.74(t,J＝5.2Hz,2H),3.32(t,J＝7.0Hz,2H),3.26(s,3H),2.76(d,J＝4.4Hz,3H).
EXAMPLE 43 preparation of N-methyl-4- (1- (2- (3- (1- (2-morpholinoethyl)) -1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 43)
Compound 43 is prepared by replacing compound 1d and 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole in step 5 of example 1 with compound 21e and 1- (2-morpholinoethyl) -1H-pyrazole-4-boronic acid pinacol ester, the remaining reagents and preparation methods being the same as in example 1. 1 H NMR(600MHz,DMSO)δ9.11(d,J＝2.2Hz,1H),8.45(q,J＝4.6Hz,1H),8.41(s,1H),8.35(d,J＝2.2Hz,1H),8.13(d,J＝9.7Hz,1H),8.08(s,1H),8.05(dd,J＝8.0,1.8Hz,1H),7.97(d,J＝1.7Hz,1H),7.89(d,J＝8.6Hz,1H),7.71(d,J＝1.9Hz,1H),7.58(dd,J＝8.6,2.0Hz,1H),7.55(d,J＝8.0Hz,1H),7.08(d,J＝9.7Hz,1H),4.55(t,J＝7.1Hz,2H),4.29(t,J＝6.6Hz,2H),3.56(t,J＝4.6Hz,4H),3.31(t,J＝7.1Hz,2H),2.76(m,5H),2.43(t,J＝4.5Hz,4H).
EXAMPLE 44 preparation of N-methyl-4- (1- (2- ((3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) oxy) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 44)
Step 1.2 preparation of- ((3-bromoquinolin-6-yl) oxy) ethyl acetate (Compound 24 a)
250mg (1.1 mmol) of 3-bromo-6-hydroxyquinoline, 204mg (1.2 mmol) of ethyl bromoacetate and 463mg (3.3 mmol) of K 2 CO 3 Dissolving in DMF, and concentrating the system inStirred at 80℃for 2 hours. After TLC showed the reaction was completed, the system was cooled to room temperature, poured into water and extracted with ethyl acetate, and the organic phase was spin-dried over column to give 310mg of a white solid in 90% yield. 1 H NMR(400MHz,CDCl 3 )δ8.76(d,J＝2.2Hz,1H),8.16(d,J＝2.3Hz,1H),7.99(d,J＝9.2Hz,1H),7.44(dd,J＝9.2,2.8Hz,1H),6.92(d,J＝2.8Hz,1H),4.73(s,2H),4.30(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,4H).
Step 2.2 preparation of ethyl- ((3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) oxy) acetate (Compound 24 b)
Compound 24b was prepared by replacing compound 1d in step 5 of example 1 with compound 24a, and the remaining reagents and preparation methods were the same as those of example 1. 1 HNMR(400MHz,CDCl3)δ8.92(d,J＝2.2Hz,1H),8.03(d,J＝2.4Hz,1H),7.99(d,J＝9.2Hz,1H),7.89(s,1H),7.76(s,1H),7.39(dd,J＝9.2,2.6Hz,1H),7.01(d,J＝2.7Hz,1H),4.75(s,2H),4.30(q,J＝7.2Hz,2H),3.99(s,3H),1.31(t,J＝7.1Hz,3H).
Step 3.2 preparation of- ((3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) oxy) ethan-1-ol (Compound 24 c)
Compound 24c was prepared by replacing compound 5a in step 2 of example 9 with compound 24b, and the remaining reagents and preparation methods were the same as those of example 9. 1 H NMR(400MHz,DMSO)δ9.00(d,J＝2.2Hz,1H),8.36(s,1H),8.34(d,J＝2.2Hz,1H),8.06(s,1H),7.88(d,J＝9.1Hz,1H),7.33(dd,J＝9.1,2.7Hz,1H),7.29(d,J＝2.8Hz,1H),4.95(t,J＝5.5Hz,1H),4.13(t,J＝5.0Hz,2H),3.92(s,3H),3.84-3.76(m,2H).
Step 4.2 preparation of Ethyl- ((3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) oxy) methanesulfonate (Compound 24 d)
120mg (0.45 mmol) of compound 24c was dissolved in 15ml of LDCM, placed at 0deg.C, 0.12ml (0.88 mmol) of triethylamine and 0.04ml (0.53 mmol) of methylsulfonyl chloride were slowly added, after slowly warming to room temperature and stirring for 1 hour, water was added and extracted with DCM, and the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 150mg of an oily liquid in 97% yield.
Step 5 preparation of methyl 4- (1- (2- ((3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) oxy) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoate (Compound 24 e)
150mg (0.43 mmol) of compound 24d and 154mg (0.52 mmol) of compound 21b were dissolved in 15 mM DMF, and 281mg (0.86 mmol) of cesium carbonate was added and stirred at 50 ℃. After the completion of the reaction by TLC, it was poured into water and extracted with ethyl acetate, and the organic phase was spin-dried over the column to give 90mg of a white solid in 40% yield. 1 H NMR(400MHz,DMSO)δ9.00(d,J＝2.2Hz,1H),8.33(s,1H),8.30–8.24(m,3H),8.21(d,J＝9.8Hz,1H),8.03(s,1H),7.94(d,J＝8.3Hz,1H),7.83(d,J＝9.1Hz,1H),7.36(d,J＝2.8Hz,1H),7.25(dd,J＝9.1,2.8Hz,1H),7.15(d,J＝9.7Hz,1H),4.68-4.59(m,4H),3.92(s,3H),3.89(s,3H).
Step 6.preparation of 4- (1- (2- ((3- (1-methyl-1H-pyrazol-4-yl) quinolin) -6-yl) oxy) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoic acid (compound 24 f)
2- (3-bromoquinolin-6-yl) acetic acid in step 1 of example 5 was changed to compound 24e, and the remaining reagents and preparation methods were the same as in example 5 to prepare compound 24f.
Preparation of N-methyl-4- (1- (2- ((3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) oxy) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 44)
Compound 44 was obtained by replacing compound 26 in example 27 with compound 24f, and the remaining reagents and preparation methods were the same as those in example 27. 1 HNMR(600MHz,DMSO)δ9.00(d,J＝2.2Hz,1H),8.6(q,J＝4.6Hz,1H),8.33(s,1H),8.29(d,J＝2.3Hz,1H),8.22–8.15(m,3H),8.04(s,1H),7.84(d,J＝9.1Hz,1H),7.61(d,J＝8.5Hz,1H),7.36(d,J＝2.8Hz,1H),7.24(dd,J＝9.1,2.8Hz,1H),7.13(d,J＝9.7Hz,1H),4.63(m,4H),3.92(s,3H),2.77(d,J＝4.5Hz,3H).
EXAMPLE 45 preparation of 3- (1-methyl-1H-pyrazol-4-yl) -N- (3- (4- (methylcarbamoyl) -3- (trifluoromethyl) phenyl) -6-oxopyridazin-1 (6H) -yl) quinoline-6-carboxamide (Compound 45)
Preparation of N-hydroxy-P, P-diphenylphosphinic acid amide (Compound 25 a)
2.4g (34.5 mmol) of hydroxylamine hydrochloride was dissolved in a mixed solvent of 25mL of water and 25mL of 1, 4-dioxane, and a 1.33g (33.3 mmol) NaOH solution dissolved in 25mL of water was slowly added dropwise. The system was cooled to-5℃and 3.3g (13.9 mmol) of diphenylphosphinoyl chloride solution dissolved in 20ml of 1, 4-dioxane, pre-cooled to below 10℃was added rapidly with vigorous stirring. After stirring for 5 minutes, the reaction mixture was poured into ice water and filtered, and the filter cake was washed with ice water. The filter cake was transferred to a flask, 278mg (6.95 mmol) of NaOH in 50mL of water was added at 0deg.C, stirring was continued for 30 min, suction filtration and the resulting filter cake was dried in vacuo to give 1.6g of a white solid in 48% yield.
Step 2.preparation of methyl 4- (1-amino-6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoate (Compound 25 b)
1g (3.4 mmol) of compound 21b was dissolved in 30ml of THF, 752mg (6.7 mmol) of t-BuOK was added and stirred for 30 minutes, then 1.25g (5.4 mmol) of compound 25a was added and stirred overnight, the system was diluted with ethyl acetate, saturated NaHCO 3 And brine, dried over anhydrous sodium sulfate, and concentrated to give 664mg of a white solid in 64% yield. 1 H NMR(400MHz,DMSO)δ8.34-8.25(m,2H),8.19(d,J＝9.6Hz,1H),7.97(d,J＝8.0Hz,1H),7.18-7.11(m,3H),3.90(s,3H).
Step 3 preparation of methyl 4- (1- (3-bromoquinoline-6-carboxamide) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoate (Compound 25 c)
535mg (2.1 mmol) of 3-bromoquinoline-6-carboxylic acid, 664mg (2.1 mmol) of compound 25b,573mg (4.2 mmol) of HOBT,813mg (4.2 mmol) of EDC and 415mg (3.4 mmol) of 4-DMAP are dissolved in 40mL of pyridine, after stirring at room temperature for 12 hours, the mixture is concentrated to dryness, the residue is diluted with ethyl acetate and taken up in saturated NaHCO 3 Washing, spin drying of the organic phase and passing through the column gave 800mg of white solid in 69% yield. 1 HNMR(400MHz,DMSO)δ12.56(s,1H),9.07(s,1H),8.92(s,1H),8.67(s,1H),8.38(d,J＝9.8Hz,1H),8.34-8.26(m,3H),8.20(d,J＝8.9Hz,1H),7.97(d,J＝8.1Hz,1H),7.40(d,J＝9.7Hz,1H),3.89(s,3H).
Step 4.preparation of 4- (1- (3-bromoquinoline-6-carboxamide) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoic acid (Compound 25 d)
2- (3-bromoquinolin-6-yl) acetic acid in step 1 of example 5 was changed to compound 25c, and the remaining reagents and preparation methods were the same as in example 5 to obtain compound 25d.
Step 5.preparation of 3-bromo-N- (3- (4- (methylcarbamoyl) -3- (trifluoromethyl) phenyl) -6-oxopyridazin-1 (6H) -yl) quinoline-6-carboxamide (Compound 25 e)
Compound 25e was prepared by replacing compound 26 in example 27 with compound 25d, and the remaining reagents and preparation methods were the same as in example 27. 1 H NMR(400MHz,DMSO)δ12.55(s,1H),9.10(d,J＝2.4Hz,1H),8.95(d,J＝2.3Hz,1H),8.68(d,J＝2.0Hz,1H),8.51(q,J＝4.6Hz,1H),8.37(d,J＝9.8Hz,1H),8.31(d,J＝8.7Hz,1H),8.28–8.19(m,3H),7.68(d,J＝8.0Hz,1H),7.39(d,J＝9.8Hz,1H),2.78(d,J＝4.5Hz,3H).
Step 6.preparation of 3- (1-methyl-1H-pyrazol-4-yl) -N- (3- (4- (methylcarbamoyl) -3- (trifluoromethyl) phenyl) -6-oxopyridazin-1 (6H) -yl) quinoline-6-carboxamide (Compound 45)
Compound 45 was prepared by replacing compound 1d in step 5 of example 1 with compound 25e, and the remaining reagents and preparation methods were the same as in example 1. 1 HNMR(600MHz,DMSO)δ12.49(s,1H),9.34(d,J＝2.3Hz,1H),8.68(d,J＝2.3Hz,1H),8.63(d,J＝2.1Hz,1H),8.52(q,J＝4.7Hz,1H),8.46(s,1H),8.38(d,J＝9.9Hz,1H),8.26(d,J＝8.0Hz,1H),8.24(s,1H),8.21-8.14(m,3H),7.68(d,J＝8.1Hz,1H),7.39(d,J＝9.8Hz,1H),3.94(s,3H),2.78(d,J＝4.5Hz,3H).
EXAMPLE 46 preparation of (E) -N-methyl-4- (1- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) vinyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 46)
Step 1.3 preparation of methyl-3-bromoquinoline-6-carboxylate (Compound 26 a)
10g (39.6 mmol) of 3-bromoquinoline-6-carboxylic acid, 6.75g (47.6 mmol) of iodomethane and 11.0g (79.5 mmol) of K 2 CO 3 Dissolved in 250ml of LDMF and stirred overnight at room temperature. It was poured into water and extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous Na 2 SO 4 Drying and concentration gave 9.9g of a yellow solid in 95% yield. 1 HNMR(400MHz,CDCl 3 ):δ8.92(d,J＝2.0Hz,1H),8.44(s,1H),8.34(d,J＝1.6Hz,1H),8.24(dd,J＝8.8,1.2Hz,1H),8.05(d,J＝8.8Hz,1H),3.94(s,3H).
Step 2.preparation of 3- (1-methyl-1H-pyrazol-4-yl) quinoline-6-carboxylic acid methyl ester (Compound 26 b)
Compound 26b was prepared by replacing compound 1d in step 5 of example 1 with compound 26a, and the other reagents and preparation methods were the same as those of example 1. 1 HNMR(400MHz,DMSO)δ9.31(d,J＝2.3Hz,1H),8.69(d,J＝2.3Hz,1H),8.62(d,J＝1.9Hz,1H),8.41(s,1H),8.15–8.05(m,3H),3.94(s,3H),3.93(s,3H).
Preparation of (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) methanol (Compound 26 c)
Compound 26c was prepared by replacing compound 5a in step 2 of example 9 with compound 26b, and the remaining reagents and preparation methods were the same as those of example 9. 1 HNMR(400MHz,DMSO)δ9.14(d,J＝2.3Hz,1H),8.44(d,J＝2.3Hz,1H),8.37(s,1H),8.11(s,1H),7.94(d,J＝8.6Hz,1H),7.83(s,1H),7.62(dd,J＝8.6,1.8Hz,1H),5.46(t,J＝5.7Hz,1H),4.71(d,J＝5.6Hz,2H),3.92(s,3H).
Step 4.3 preparation of- (1-methyl-1H-pyrazol-4-yl) quinoline-6-carbaldehyde (Compound 26 d)
300mg (1.25 mmol) of compound 26c was dissolved in 20mL DCM, 544mg (6.26 mmol) of manganese dioxide was added, the system was stirred at room temperature overnight, suction filtered and the organic phase was chromatographed on a column to give 250mg of a white solid in 84% yield. 1 H NMR(400MHz,DMSO)δ10.20(s,1H),9.34(d,J＝2.3Hz,1H),8.70(d,J＝2.2Hz,1H),8.56(s,1H),8.45(s,1H),8.15(s,1H),8.14–8.04(m,2H),3.94(s,3H).
Step 5.preparation of methyl 4- (1- (hydroxymethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoate (Compound 26 e)
500mg of Compound 21b was added to 10mL of 37% formaldehyde solution and 10mLH 2 O, reflux at 100deg.C for 10 hr, cooling to room temperature, suction filtering, collecting crystalline solid, and mixing with small amount of H 2 O washing gave 450mg of a white crystalline solid in 82% yield. 1 H NMR(400MHz,DMSO)δ8.36(d,J＝1.7Hz,1H),8.31(dd,J＝8.1,1.8Hz,1H),8.21(d,J＝9.8Hz,1H),7.97(d,J＝8.1Hz,1H),7.12(d,J＝9.8Hz,1H),6.91(t,J＝7.7Hz,1H),5.44(d,J＝7.6Hz,2H),3.90(s,3H).
Step 6.preparation of methyl 4- (1- (chloromethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoate (Compound 26 f)
Compound 26e was dissolved in a mixed solvent of 5mL of DCM and 5mL of MF, 0.10mL (1.37 mmol) of thionyl chloride dissolved in 2mL of DCM was slowly added to the system at 0deg.C, after stirring for 2 hours at room temperature, it was cooled to 0deg.C, 20mL of water was slowly added, the pH of the system was adjusted to 6.7-7.4 with saturated sodium bicarbonate solution, the system was extracted with DCM, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give compound 26f, which was used directly in the next step.
Preparation of ((3- (4- (methoxycarbonyl) -3- (trifluoromethyl) phenyl) -6-oxopyridazin-1 (6H) -yl) methyl) triphenylphosphine (Compound 26 g)
330mg (0.95 mmol) of compound 26f and 190mg (1.27 mmol) of sodium iodide are dissolved in 20ml of acetonitrile, after refluxing for 2 hours, the system is cooled to 30-40℃and 303mg (1.16 mmol) of triphenylphosphine are added, after further refluxing for 6 hours, the reaction medium is cooled to room temperature, filtered off with suction, and the filtrate is concentrated to give 350mg of a yellow foamy solid in 52% yield. The product was used in the next step without further purification.
Step 8 preparation of methyl (E) -4- (1- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) vinyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoate (Compound 26H)
188mg (0.79 mmol) of compound 26d and 350mg (0.67 mmol) of compound 26g are dissolved in 15mL of acetonitrile, after stirring at 0℃for 30 minutes 82mg (0.73 mmol) of potassium tert-butoxide are added to the system, stirring is continued at room temperature for 2 hours, suction filtration is carried out, and the obtained crude product is purified by preparative HPLC after concentration of the filtrate to give 180mg of a yellow solid in 55% yield. 1 H NMR(600MHz,DMSO)δ9.10(d,J＝2.5Hz,1H),8.46-8.42(m,1H),8.42-8.38(m,2H),8.37-8.29(m,2H),8.26(d,J＝10.0Hz,1H),8.07(s,1H),8.03-7.96(m,2H),7.95-7.91(m,2H),7.48(d,J＝14.0Hz,1H),7.21(d,J＝7.7Hz,1H),3.91(s,6H).
Preparation of (E) -4- (1- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin) -6-yl) vinyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoic acid (Compound 26 i)
2- (3-bromoquinolin-6-yl) acetic acid in step 1 of example 5 was changed to compound 26h, and the remaining reagents and preparation methods were the same as in example 5 to prepare compound 26i.
Preparation of (E) -N-methyl-4- (1- (2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) vinyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzamide (Compound 46)
Compound 46 was obtained by substituting compound 26 in example 27 with compound 26i, and the other reagents and preparation methods were the same as those in example 27. 1 H NMR(600MHz,DMSO)δ9.13(d,J＝2.2Hz,1H),8.53(q,J＝4.6Hz,1H),8.45(d,J＝2.1Hz,1H),8.41(dd,J＝8.1,1.8Hz,1H),8.39–8.34(m,3H),8.28(d,J＝9.8Hz,1H),8.10–8.05(m,2H),8.01–7.93(m,2H),7.70(d,J＝8.0Hz,1H),7.54(d,J＝14.4Hz,1H),7.23(d,J＝9.8Hz,1H),3.92(s,3H),2.81(d,J＝4.6Hz,3H).
EXAMPLE 47.preparation of 4- (1- (2, 2-difluoro-2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -N-methyl-2- (trifluoromethyl) benzamide (Compound 47)
Step 1.preparation of methyl 2- (quinolin-6-yl) acetate (Compound 27 a)
The 3-bromoquinoline-6-carboxylic acid in step 1 of example 46 was changed to 6-quinolineacetic acid, and the remaining reagents and preparation methods were the same as in example 46 to obtain compound 27a. 1 HNMR(400MHz,DMSO)δ8.86(dd,J＝4.3,1.8Hz,1H),8.34-8.30(m,1H),7.95(d,J＝8.6Hz,1H),7.84(m,1H),7.67(dd,J＝8.8,2.0Hz,1H),7.52(dd,J＝8.2,4.2Hz,1H),3.80(s,2H)3.63(s,3H).
Preparation of methyl step 2.2,2-difluoro-2- (quinolin-6-yl) acetate (Compound 27 b)
8.5g (40.5 mmol) of compound 27a and 28g (168.1 mmol) of N-fluorobenzenesulfonimide (NFSI) are dissolved in 200mL of anhydrous THF and the atmosphere is closed off with argon, the system is cooled to-78℃and 167mL (167.3 mmol) of lithium bis (trimethylsilyl) amide (LiHMDS, 1mol/LTHF solution) are slowly added. After slowly heating the reaction system to 0 ℃ within 1 hour, the system was suction-filtered, the filtrate was concentrated, and the residue was diluted with ethyl acetate and extracted with saturated ammonium chloride solution. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 6.7g of a pale yellow solid in 67% yield. 1 H NMR(400MHz,CDCl 3 )δ9.01(d,J＝2.4Hz,1H),8.28-8.17(m,2H),8.13(s,1H),7.90(dd,J＝8.9,2.2Hz,1H),7.49(dd,J＝8.3,4.2Hz,1H),3.88(s,3H).
Preparation of methyl step 3.2,2-difluoro-2- (3-iodoquinolin-6-yl) acetate (Compound 27 c)
3g (12.7 mmol) of compound 27b was dissolved in 50ml of acetic acid, 3.98g (17.7 mmol) of N-iodosuccinimide (NIS) was added, the system was stirred at 100℃for 2 hours, after cooling, the reaction mixture was poured into an aqueous solution, a saturated solution of sodium thiosulfate was added, extraction was performed with ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate, and 1.9g of a white solid was obtained by column chromatography in 42% yield. 1 H NMR(400MHz,CDCl 3 )δ9.14(d,J＝2.1Hz,1H),8.64(d,J＝2.0Hz,1H),8.17(d,J＝8.8Hz,1H),8.03(s,1H),7.92(dd,J＝8.9,2.0Hz,1H),3.89(s,3H).
Preparation of step 4.2,2-difluoro-2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) acetic acid methyl ester (Compound 27 d)
2g (5.5 mmol) of compound 27c and 1.7g (8.2 mmol) of 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole were dissolved in a mixed solvent of 1, 4-dioxane and water, and 200mg (0.27 mmol) of Pd (dppf) Cl was added 2 And 988mg (7.1 mmol) K 2 CO 3 After the reaction was completed, the solvent was dried by spin-drying under the protection of argon at 60℃for 2 hours, and then the compound (830 mg, yield 49%) was obtained by flash chromatography on silica gel column. 1 H NMR(400MHz,DMSO)δ9.32(d,J＝2.2Hz,1H),8.69(d,J＝2.2Hz,1H),8.42(s,1H),8.24(d,J＝2.1Hz,1H),8.15(d,J＝8.8Hz,1H),8.11(s,1H),7.81(dd,J＝8.8,2.1Hz,1H),3.93(s,3H),3.89(s,3H).
Preparation of step 5.2,2-difluoro-2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethan-1-ol (Compound 27 e)
Compound 800mg (2.5 mmol) of 27d was dissolved in 50ml MeOH, 143mg (3.8 mmol) of sodium borohydride was slowly added at-10℃and after TLC monitoring the reaction was complete, the mixture was quenched with dilute hydrochloric acid slowly, the ethyl acetate was used for extraction, the organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give 120mg of a white solid in 18% yield. 1 H NMR(400MHz,DMSO)δ9.27(d,J＝2.3Hz,1H),8.62(d,J＝2.3Hz,1H),8.41(s,1H),8.14-8.10(m,2H),8.08(d,J＝8.7Hz,1H),7.78(dd,J＝8.8,2.0Hz,1H),5.70(t,J＝6.4Hz,1H),4.03-3.93(m,2H),3.93(s,3H).
Preparation of step 6.2,2-difluoro-2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) 4-methylbenzenesulfonic acid ethyl ester (Compound 27 f)
120mg (0.42 mmol) of compound 27e was dissolved in dry DCM, 63mg (0.62 mmol) of triethylamine was added, and the mixture was cooled at-78℃for 10min and 176mg (0.62 mmol) of trifluoromethanesulfonic anhydride was slowly added dropwise. After the completion of the dropwise addition, the reaction mixture was slowly warmed to room temperature over 1 hour, then diluted with water, extracted with DCM, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 100mg of a brown oily liquid in 55% yield. The crude product was used in the next step without further purification.
Step 7 preparation of methyl 4- (1- (2, 2-difluoro-2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoate (Compound 27 g)
100mg (0.24 mmol) of compound 27f and 85mg (0.29 mmol) of compound 21b were dissolved in 20mL of MF, and after addition of 85mg (0.3 mmol) of cesium carbonate, the mixture was stirred at room temperature for 10h. The system was poured into water and extracted with ethyl acetate and the organic phase was spin-dried over the column to give 20mg of a white solid in 15% yield. 1 H NMR(400MHz,DMSO)δ9.25(d,J＝2.2Hz,1H),8.56(d,J＝2.4Hz,1H),8.37(s,1H),8.19(d,J＝9.8Hz,1H),8.12–8.01(m,4H),7.98(s,1H),7.83(d,J＝8.1Hz,1H),7.79(dd,J＝8.8,2.0Hz,1H),7.14(d,J＝9.8Hz,1H),5.11(t,J＝13.0Hz,2H),3.92(s,3H),3.87(s,3H).
Step 8.preparation of 4- (1- (2, 2-difluoro-2- (3- (1-methyl-1H-) pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoic acid (Compound 27H)
2- (3-bromoquinolin-6-yl) acetic acid in step 1 of example 5 was changed to 27g, and the remaining reagents and preparation methods were the same as those of example 5 to obtain compound 27h.
Step 9.preparation of 4- (1- (2, 2-difluoro-2- (3- (1-methyl-1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -N-methyl-2- (trifluoromethyl) benzamide (Compound 47)
Compound 47 was prepared by substituting compound 26 in example 27 with compound 27h, and the other reagents and preparation methods were the same as in example 27. 1 H NMR(600MHz,DMSO)δ9.27(d,J＝2.2Hz,1H),8.59(d,J＝2.3Hz,1H),8.43(q,J＝4.5Hz,1H),8.39(s,1H),8.18(d,J＝9.8Hz,1H),8.13(d,J＝2.1Hz,1H),8.10-8.06(m,2H),7.99(dd,J＝8.0,1.8Hz,1H),7.90(d,J＝1.8Hz,1H),7.79(dd,J＝8.8,2.1Hz,1H),7.52(d,J＝8.0Hz,1H),7.13(d,J＝9.8Hz,1H),5.11(t,J＝13.1Hz,2H),3.92(s,3H),2.75(d,J＝4.5Hz,3H).
Example 48.6 3 - (trifluoromethyl) -5 1 ,5 6 -dihydro-1 1 H-8-aza-2 (3, 6) -quinoline-5 (1, 3) -pyridazinone-1 (4, 1) -pyrazoline-6 (1, 4) -benzocyclododecane-5 6 Preparation of 7-diketone (Compound 48)
Step 1 preparation of methyl 4- (1- (2- (3- (1H-pyrazol-4-yl)) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoate (Compound 28 a)
Compound 28a was prepared by replacing compound 1d and 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole in step 5 of example 1 with compound 21c and 4-pyrazole boronic acid pinacol ester, the remaining reagents and preparation methods being the same as in example 1. 1 HNMR(400MHz,DMSO)δ13.12(s,1H),9.15(d,J＝2.2Hz,1H),8.37(d,J＝2.3Hz,1H),8.15(d,J＝9.8Hz,1H),8.11(dd,J＝8.2,1.8Hz,1H),8.06(s,1H),7.91–7.83(m,2H),7.69(d,J＝2.0Hz,1H),7.57(dd,J＝8.5,1.9Hz,2H),7.09(d,J＝9.7Hz,1H),4.55(t,J＝7.0Hz,2H),3.87(s,3H),3.30(t,J＝7.0Hz,2H).
Step 2.4 preparation of- ((tert-Butoxycarbonyl) amino) butylmethanesulfonate (Compound 28 b)
200mg (1.1 mmol) of tert-butyl (4-hydroxybutyl) carbamate are dissolved in dry dichloromethane, 0.098mL (1.3 mmol) of methylsulfonyl chloride and 0.22mL (1.6 mmol) of triethylamine are added at 0℃and after 10min they are transferred to room temperature and stirred for 1 hour, after TLC monitoring the reaction is complete they are poured into water and extracted with dichloromethane and the organic phase is washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo to give 254mg of a colourless oil as a liquid in 90% yield. The product was used in the next step without further purification.
Step 3 preparation of methyl 4- (1- (2- (3- (1- (4- ((tert-butoxycarbonyl) amino) butyl) -1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoate (Compound 28 c)
160mg (0.3 mmol) of compound 28a was dissolved in 15mL of dry DMF, 16mg (0.4 mmol) of sodium hydride (60% dispersed in kerosene) was added at 0deg.C, and after stirring for 30 minutes, 100mg (0.4 mmol) of compound 28b dissolved in 5mL of LDMF was slowly added dropwise to the system, and after 10 minutes the system was transferred to room temperature for stirring for 2 hours. After the completion of the reaction by TLC, the system was quenched with methanol and extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 200mg of a pale yellow solid by column chromatography in 94% yield. 1 HNMR(400MHz,DMSO)δ9.10(d,J＝2.2Hz,1H),8.38(s,1H),8.33(d,J＝2.3Hz,1H),8.14(d,J＝9.7Hz,1H),8.10(d,J＝8.1Hz,1H),8.06(s,2H),7.91–7.83(m,2H),7.67(d,J＝1.9Hz,1H),7.57(dd,J＝8.6,1.9Hz,1H),7.09(d,J＝9.7Hz,1H),6.83(t,J＝5.8Hz,1H),4.54(t,J＝7.0Hz,2H),4.15(t,J＝6.9Hz,2H),3.87(s,3H),3.30(t,J＝7.0Hz,2H),2.99–2.92(m,2H),1,85–1.76(m,2H),1.41–1.33(m,11H).
Step 4.preparation of 4- (1- (2- (3- (1- (4- ((tert-butoxycarbonyl) amino) butyl) -1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoic acid (Compound 28 d)
2- (3-bromoquinolin-6-yl) acetic acid in step 1 of example 5 was changed to compound 28c, and the remaining reagents and preparation methods were the same as in example 5 to obtain compound 28d.
Step 5.6 3 - (trifluoromethyl) -5 1 ,5 6 -dihydro-1 1 H-8-aza-2 (3, 6) -quinoline-5 (1, 3) -pyridazinone-1 (4, 1) -pyrazoline-6 (1, 4) -benzocyclododecane-5 6 Preparation of 7-diketone (Compound 48)
To 193mg (0.29 mmol) of compound 28d was dissolved in 10mL of methylene chloride, 5mL of trifluoroacetic acid was added, and the system was stirred at room temperature for 1 hour, followed by spin-drying of the solvent. The crude product was dissolved in 40mL of dichloromethane and 2mL of LDMF, then 0.48mL (2.8 mmol) of DIPEA and 142mg (0.37 mmol) of FDPP were added and the reaction mixture was stirred at room temperature for 48 hours. After the reaction was completed, the system was diluted with water and extracted with dichloromethane, the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 45mg of a white solid by column chromatography in 28% yield. 1 HNMR(400MHz,DMSO)δ9.15(d,J＝2.2Hz,1H),8.66–8.60(m,2H),8.36(t,J＝6.1Hz,1H),8.27(d,J＝1.9Hz,1H),8.13(s,1H),8.07(d,J＝9.8Hz,1H),8.01(s,1H),7.89(dd,J＝8.2,2.0Hz,1H),7.79(d,J＝8.6Hz,1H),7.40(dd,J＝8.6,1.9Hz,1H),7.28(d,J＝8.1Hz,1H),7.00(d,J＝9.7Hz,1H),4.76(t,J＝5.6Hz,2H),4.26(t,J＝5.5Hz,2H),3.44(t,J＝5.6Hz,2H),3.22–3.16(m,2H),1.98–1.88(m,2H),1.37–1.29(m,2H).
Example 49.6 3 - (trifluoromethyl) -5 1 ,5 6 -dihydro-1 1 H-8-aza-2 (3, 6) -quinoline-5 (1, 3) -pyridazinone-1 (4, 1) -pyrazoline-6 (1, 4) -phencyclitridecane-5 6 7-diketone (Compound 49) Is prepared from
Step 1.5 preparation of- ((tert-Butoxycarbonyl) amino) pentylmethanesulfonate (Compound 29 a)
The compound 29a was prepared by replacing tert-butyl (4-hydroxybutyl) carbamate in step 2 of example 48 with tert-butyl (5-hydroxypentyl) carbamate, and the remaining reagents and preparation methods were the same as in example 48.
Step 2 preparation of methyl 4- (1- (2- (3- (1- (5- ((tert-butoxycarbonyl) amino) pentyl) -1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoate (Compound 29 b)
Compound 29b was prepared by substituting compound 28b from step 3 of example 48 with compound 29a, and the remaining reagents and preparation methods were the same as those of example 48. 1 HNMR(400MHz,DMSO)δ9.10(d,J＝2.2Hz,1H),8.38(s,1H),8.36–8.33(m,1H),8.16(dd,J＝9.8,1.7Hz,1H),8.12(d,J＝8.1Hz,1H),8.07–8.04(m,2H),7.91–7.82(m,2H),7.68(d,J＝2.0Hz,1H),7.58(dd,J＝8.5,2.0Hz,1H),7.10(d,J＝9.7Hz,1H),6.77(t,J＝5.8Hz,1H),4.55(t,J＝6.9Hz,2H),4.14(t,J＝7.0Hz,2H),3.88(s,3H),3.30(t,J＝7.0Hz,2H),2.92–2.87(m,2H),1.87–1.77(m,2H),1.46–1.36(m,2H),1.34(s,9H),1.27–1.19(m,2H).
Step 3.preparation of 4- (1- (2- (3- (1- (5- ((tert-butoxycarbonyl) amino) pentyl) -1H-pyrazol-4-yl) quinolin-6-yl) ethyl) -6-oxo-1, 6-dihydropyridazin-3-yl) -2- (trifluoromethyl) benzoic acid (Compound 29 c)
2- (3-bromoquinolin-6-yl) acetic acid in step 1 of example 5 was changed to compound 29b, and the remaining reagents and preparation methods were the same as in example 5 to obtain compound 29c.
Step 4.6 3 - (trifluoromethyl) -5 1 ,5 6 -dihydro-1 1 H-8-aza-2 (3, 6) -quinoline-5 (1, 3) -pyridazinone-1 (4, 1) -pyrazoline-6 (1, 4) -phencyclitridecane-5 6 Preparation of 7-diketone (Compound 49)
Compound 49 was prepared by replacing compound 28d in step 5 of example 48 with compound 29c, and the remaining reagents and preparation methods were the same as those of example 48. 1 HNMR(600MHz,DMSO)δ9.06(d,J＝2.2Hz,1H),8.53(d,J＝2.2Hz,1H),8.43(s,1H),8.22(t,J＝5.6Hz,1H),8.18–8.15(m,1H),8.10–8.07(m,1H),7.97(d,J＝9.8Hz,1H),7.85(d,J＝1.8Hz,1H),7.72(d,J＝8.5Hz,1H),7.28(dd,J＝8.5,1.9Hz,1H),7.08(dd,J＝7.9,1.8Hz,1H),7.01(d,J＝9.6Hz,1H),6.80(d,J＝8.0Hz,1H),4.64(t,J＝5.8Hz,2H),4.24(t,J＝5.7Hz,2H),3.39–3.36(m,2H),3.18–3.16(m,2H),1.85–1.80(m,2H),1.49–1.43(m,2H),1.12–1.05(m,2H).
Experimental example 1: inhibition activity test of pyridazinone compounds on c-Met kinase
Kinase activity assay: application of Z' -LYTE TM Techniques (detection by fluorescence, enzyme-coupled format, based on differential susceptibility of phosphorylated and non-phosphorylated polypeptides to proteolytic cleavage), employing Fluorescence Resonance Energy Transfer (FRET) principles, using Z' -LYTE TM FRET peptide substrates, secondary reactions test compounds for their inhibitory activity on c-Met kinase (american life technologies, PV3144, PV3616, PV 3617).
Enzymatic reaction: into 384-well plates, 5. Mu.L of enzyme-substrate system [50mM 4-hydroxyethylpiperazine ethanesulfonic acid (HEPES) pH 7.5,0.01% BRIJ-35,10mM magnesium chloride (MgCl) was added 2 ) 1mM ethylene glycol bis (2-aminoethyl ether) tetraacetic acid (EGTA), 2. Mu.M Tyr 01 peptide substrate]Transferring into 5nL of compound to be detected (concentration gradient) by using an echo520 ultra-trace liquid pipetting system, oscillating at room temperature for 10-20min, and then using echo520The ultra-micro liquid pipetting system is respectively transferred into 200nL,12.5nL and 25nLATP (the final concentration is 400uM,25uM and 50uM respectively), and after shaking and mixing, the mixture is centrifuged and reacted for 1.5 hours at 30 ℃ in a dark place.
Detection reaction: 2.5. Mu.L of reaction solution (Development Solution) (1:128 dilution) was added to each well and incubated at 37℃for 1h in the absence of light, followed by 5. Mu.L of Stop Reagent.
Reading a plate: the multi-label microplate detector (Perkin Elmer EnVision Multimode Plate Reader) detects fluorescent signals (excitation light wavelength 400nm, emission light wavelength 460nm, 535 nm).
And (3) calculating: the inhibition rate of each well was calculated from the total active well and the control signal well, and the data analysis method was as follows:
phosphorylation ratio = 1- { (emission ratio xf100% -c100%)/[ c0% -c100% + emission ratio× (f100% -f0%) ] } ×100;
inhibition = 100× (1-compound phosphorylation ratio/negative control phosphorylation ratio).
IC50 values were calculated using medical mapping software (GraphPad prism 5.0).
The kinase activity test results are shown in table 1.
TABLE 1
Numbering of compounds c-Met(IC 50 /nM) Numbering of compounds c-Met(IC 50 /nM)
1 *** 26 **
2 *** 27 *
3 **** 28 *
4 **** 29 *
5 ** 30 *
6 ** 31 **
7 *** 32 **
8 *** 33 **
9 ** 34 **
10 ** 35 **
11 ** 36 **
12 * 37 **
13 * 38 *
14 ** 39 *
15 ** 40 *
16 * 41 *
17 * 42 *
18 * 43 *
19 ** 44 **
20 ** 45 ****
21 * 46 **
22 ** 47 *
23 ** 48 *
24 * 49 *
25 *
IC 50 :<10nM＝*；10-100nM＝**；100-1000nM＝***；>1μM＝****
As can be seen from the data in Table 1, the pyridazinone compounds of the present invention have a strong inhibitory activity against c-Met kinase.
Experimental example 2: cell proliferation inhibition Activity Studies based on tumor cells
In vitro inhibition of cell proliferation was detected using the CCK8 assay. Commercial cells of Hs746T used in this experiment were purchased directly from American Type Culture Collection (ATCC) and cultured according to the recommended experimental conditions for ATCC, with the addition of 10% FBS and 1%100X penicillin-streptomycin diabody. Hs746T cells were stored in the corresponding growth medium and passed on for at least two generations prior to resuscitating use. The experimental procedure was as follows, a suitable amount of cells in logarithmic growth phase was inoculated in 96-well plates, each with a volume of 100. Mu.L, and then in the presence of 5% CO 2 Is incubated overnight at 37 ℃. The test compound was dissolved in DMSO to prepare a 10mM/L stock solution, and then 10 gradients were diluted, each concentration gradient was prepared by mixing 2. Mu.L of the compound solution with 998. Mu.L of the culture solution. 100. Mu.L of the mixed culture solution was added to the corresponding 96-well plate. 2 μL of MSO solution was used as the corresponding blank. After 120 hours incubation, CCK8 reagent was added. CCK8 was mixed with medium at 1:2, for example, 1ml of CCK8 is added into 2ml of culture medium, 30 mu l of diluted CCK8 is added into each well of a 96-well plate after mixing, beating and mixing are carried out, and the mixture is left for about 1 to 4 hours. Measuring an OD value by a super enzyme-labeled instrument; according to the data of OD450 and OD650, the actual absorbance value A of each hole is obtained (A=OD 450-OD 650), and then according to the actual absorbance value A of each hole, the cell survival rate of each treatment hole is obtained:
cell viability (%) = [ (As-Ac)/(Ab-Ac) ] ×100% ]
As: experimental hole (treatment holes containing cells and different concentrations)
Ab: solvent control well (solvent treatment well with cell and drug concentration of 0)
Ac: blank hole (hole without cell and medicine)
The cell viability data and the concentrations of the corresponding test and control compounds were then input into GraphPad Prism 8 software and IC50 values were calculated using a non-linear regression model.
The test results are shown in Table 2.
TABLE 2
IC 50 :<10nM＝*；10-100nM＝**；100-1000nM＝***；>1μM＝****。
From the data in Table 2, it can be seen that the novel pyridazinone compounds of the present invention have a strong inhibitory activity on the proliferation of Hs746T cancer cells.
Experimental example 3: inhibition activity test of pyridazinone compounds on TRKs and AXL kinase
Kinase activity assay: application of Z' -LYTE TM Techniques (detection by fluorescence, enzyme-coupled format, based on differential susceptibility of phosphorylated and non-phosphorylated polypeptides to proteolytic cleavage), employing Fluorescence Resonance Energy Transfer (FRET) principles, using Z' -LYTE TM FRET peptide substrates, secondary reactions test compounds for their inhibitory activity against TRKs (TRKA, TRKB, TRKC), AXL kinase (american life technologies, inc. PV3144, PV3616, PV 3617).
Enzymatic reaction: into 384-well plates, 5. Mu.L of enzyme-substrate system [50mM 4-hydroxyethylpiperazine ethanesulfonic acid (HEPES) pH 7.5,0.01% BRIJ-35,10mM magnesium chloride (MgCl) was added 2 ) 1mM ethylene glycol bis (2-aminoethyl ether) tetraacetic acid (EGTA), 2. Mu.M Tyr 01 peptide substrate]Transferring into 5nL of compound to be detected (concentration gradient) by using an echo520 ultra-trace liquid pipetting system, oscillating at room temperature for 10-20min, and using eThe cho520 ultra-trace liquid pipetting system is respectively transferred into 200nL,12.5nL and 25nLATP (the final concentration is 400uM,25uM and 50uM respectively), and after shaking and mixing, the solution is centrifuged and reacted for 1.5 hours at 30 ℃ in a dark place.
Detection reaction: 2.5. Mu.L of reaction solution (Development Solution) (1:128 dilution) was added to each well and incubated at 37℃for 1h in the absence of light, followed by 5. Mu.L of Stop Reagent.
Reading a plate: the multi-label microplate detector (Perkin Elmer EnVision Multimode Plate Reader) detects fluorescent signals (excitation light wavelength 400nm, emission light wavelength 460nm, 535 nm).
And (3) calculating: the inhibition rate of each well was calculated from the total active well and the control signal well, and the data analysis method was as follows:
phosphorylation ratio = 1- { (emission ratio xf100% -c100%)/[ c0% -c100% + emission ratio× (f100% -f0%) ] } ×100;
inhibition = 100× (1-compound phosphorylation ratio/negative control phosphorylation ratio).
IC50 values were calculated using medical mapping software (GraphPad prism 5.0).
The kinase activity test results are shown in Table 3.
TABLE 3 Table 3
Compound (IC) 50 /nM) AXL TRKA TRKB TRKC
40 *** ** ** **
IC 50 :<10nM＝*；10-100nM＝**；100-1000nM＝***；>1μM＝****。
Experimental example 4: drug-resistant cell proliferation inhibition activity research based on Ba/F3-MET and other stable strains
In vitro inhibition of cell proliferation was detected using the CCK8 assay. Ba/F3 cells (pre-mouse B cells) used in this experiment were purchased from Japanese cell banks, and Ba/F3-Tpr-Met, ba/F3-Tpr-Met-F1200L, ba/F3-Tpr-Met-F1200I, ba/F3-Tpr-Met-M1250T, ba/F3-Tpr-Met-L1195V, ba/F3-Tpr-Met-H1094Y, ba/F3-Tpr-Met-Y1230H, ba/F3-Tpr-Met-D1228N monoclonal stable strains were constructed by the present laboratory and were identified as completely correct by experiments on positive drug activity, protein expression, gene sequencing, and the like.
The brief steps for the construction of the stable strain are as follows: constructing pCDNA3.1 (+) plasmid vectors carrying genes of Tpr-Met, tpr-Met-F1200L, tpr-Met-F1200I and the like; usingCell Line/>The Kit V Kit electrotransfers the plasmid into Ba/F3 cells; after 48 hours of electrotransformation, adding geneticin (G418) with a final concentration of 1000 mug/ml for screening for two weeks, and removing interleukin 3 (IL 3) for further screening to obtain a polyclonal stable strain; then selecting monoclonal by limiting dilution method; further, identifying the stable strain by using positive drugs, western Blot (WB) and gene sequencing; identification of the exact monoclonal can be used in studies of the cytostatic activity of the inhibitor.
Cells such as Ba/F3-TPR-MET are stored in corresponding growth media and transferred for at least two generations before resuscitating. The experimental procedure was as follows, a suitable amount of cells in logarithmic growth phase was inoculated in 96-well plates, each with a volume of 100. Mu.LThen in the presence of 5% CO 2 Is incubated overnight at 37 ℃. The test compound was dissolved in DMSO to prepare a 10mM/L stock solution, and then 10 gradients were diluted, each concentration gradient was prepared by mixing 2. Mu.L of the compound solution with 998. Mu.L of the culture solution. 100. Mu.L of the mixed culture solution was added to the corresponding 96-well plate. 2 μL of MSO solution was used as the corresponding blank. After incubation for 72 hours of co-cultivation, CCK8 reagent was added. CCK8 was mixed with medium at 1:2, for example, 1ml of CCK8 is added into 2ml of culture medium, 30 mu l of diluted CCK8 is added into each well of a 96-well plate after mixing, beating and mixing are carried out, and the mixture is left for about 1 to 4 hours. Measuring an OD value by a super enzyme-labeled instrument; according to the data of OD450 and OD650, the actual absorbance value A of each hole is obtained (A=OD 450-OD 650), and then according to the actual absorbance value A of each hole, the cell survival rate of each treatment hole is obtained:
Cell viability (%) = [ (As-Ac)/(Ab-Ac) ] ×100% ]
As: experimental hole (treatment holes containing cells and different concentrations)
Ab: solvent control well (solvent treatment well with cell and drug concentration of 0)
Ac: blank hole (hole without cell and medicine)
The cell viability data and the concentrations of the corresponding test and control compounds were then input into GraphPad Prism 8 software and IC50 values were calculated using a non-linear regression model.
The test results are shown in Table 4.
TABLE 4 Table 4
IC 50 (nM) Compound 40 Compound 48
Ba/F3-Tpr-Met * *
Ba/F3-Tpr-Met-F1200L * *
Ba/F3-Tpr-Met-M1250T * *
Ba/F3-Tpr-Met-F1200I ** **
Ba/F3-Tpr-Met-L1195V ** **
Ba/F3-Tpr-Met-H1094Y * *
Ba/F3-Tpr-Met-D1228N **** ****
Ba/F3-Tpr-Met-Y1230H **** ****
IC 50 ：＜10nM＝*；10-100nM＝**；100-1000nM＝***；＞1μM＝****。
As can be seen from the data in Table 4, the novel pyridazinone compounds of the present invention have a strong inhibitory activity against cell proliferation of stable strains such as Ba/F3-MET.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the following embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (21)

1. A pyridazinone compound having a structure represented by formula (I):
wherein: l (L) 1 Selected from: c (C) 2 -C 10 Alkylene, halogen substituted C 2 -C 10 Alkylene, C 2 -C 10 Alkenyl, C 2 -C 10 Alkynyl, C 3 -C 10 Cycloalkyl group,
M is selected from: -O-, -NH-, -S-, -C (O) -, -S (O) 2 -、-C(O)O-、-OC(O)-、-C(O)NH-、-NHC(O)-、-S(O) 2 NH-、-NHS(O) 2 -, -HNC (O) NH-or absent;
R 1 selected from: H. halogen, -NR 7 R 8 、R 9 Substituted or unsubstituted 5-10 membered heterocyclyl, R 9 Substituted or unsubstituted5-10 membered heteroaryl; r is R 7 、R 8 Each independently selected from: H. c (C) 1 -C 10 Alkyl, - (CH) 2 ) m NR 10 R 11 The method comprises the steps of carrying out a first treatment on the surface of the Each R is 9 Each independently selected from: H. halogen, amino, hydroxy, cyano, R 12 Substituted or unsubstituted C 1 ～C 10 Alkyl, R 12 Substituted or unsubstituted C 1 -C 10 Alkoxy, R 12 Substituted or unsubstituted C 3 ～C 10 Cycloalkyl, R 12 Substituted or unsubstituted C 3 -C 10 Epoxy group, R 12 A substituted or unsubstituted 3-10 membered heterocyclyl; r is R 10 、R 11 Each independently selected from: H. c (C) 1 -C 10 Alkyl, or R 10 、R 11 Together with the nitrogen atom to which they are attached form R 9 A substituted or unsubstituted 3-10 membered heterocyclyl; each R is 12 Each independently selected from: H. halogen, hydroxy, C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy substituted C 1 ～C 6 Alkyl, C 1 ～C 6 Alkyl acyl, C 1 ～C 6 Alkoxy, 3-10 membered heterocyclyl, C 1 ～C 6 Alkyl substituted 3-10 membered heterocyclyl; m is selected from: an integer of 0 to 10;
R 2 、R 6 Each independently selected from: H. halogen;
R 3 、R 5 each independently selected from: H. halogen, nitro, amino, cyano, R 12 Substituted or unsubstituted C 1 ～C 20 Alkyl, R 12 Substituted or unsubstituted C 1 -C 20 An alkoxy group;
R 4 selected from: H. halogen, halogen,-NR 7 R 8 、R 12 Substituted or unsubstituted C 1 ～C 20 Alkyl, R 12 Substituted or unsubstituted C 1 -C 20 Alkoxy, R 9 Substituted or unsubstituted 5-10 membered heterocyclyl, R 9 Substituted or unsubstituted 5-10 membered heteroaryl; each R is 13 Each independently selected from: H. c (C) 1 ～C 6 An alkyl group;
when R is 1 Selected from R 9 Substituted or unsubstituted 5-10 membered heterocyclyl, R 9 Substituted or unsubstituted 5-10 membered heteroaryl, R 4 Selected from:when R is 9 And R is 13 Can be connected to form C 2 -C 10 An alkylene group.
2. The pyridazinone compound according to claim 1, wherein L is 1 Selected from: c (C) 2 -C 6 Alkylene, halogen substituted C 2 -C 6 Alkylene, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl groups.
3. The pyridazinone compound according to claim 2, wherein L is 1 Selected from: c (C) 2 -C 3 Alkylene, halogen substituted C 2 -C 3 Alkylene, vinyl.
4. The pyridazinone compound according to claim 1, wherein L is 1 Selected from:
5. the pyridazinone compound according to claim 1, wherein M is-O-, or is absent, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.
6. The pyridazinone compound according to claim 1, wherein R 1 Selected from: H. halogen, -NR 7 R 8 、R 9 Substituted or unsubstituted 5-8 membered heterocyclyl, R 9 Substituted or unsubstituted 5-6 membered heteroaryl; r is R 7 、R 8 Each independently selected from: H. c (C) 1 -C 6 Alkyl, - (CH) 2 ) m NR 10 R 11 The method comprises the steps of carrying out a first treatment on the surface of the Each R is 9 Each independently selected from: H. halogen, amino, hydroxy, cyano, R 12 Substituted or unsubstituted C 1 ～C 6 Alkyl, R 12 Substituted or unsubstituted C 1 -C 6 Alkoxy, R 12 Substituted or unsubstituted C 3 ～C 8 Cycloalkyl, R 12 A substituted or unsubstituted 3-8 membered heterocyclic group; r is R 10 、R 11 Each independently selected from: H. c (C) 1 -C 6 Alkyl, or R 10 、R 11 Together with the nitrogen atom to which they are attached form R 9 A substituted or unsubstituted 4-8 membered heterocyclic group; each R is 12 Each independently selected from: H. halogen, C 1 ～C 3 Alkyl, C 1 ～C 3 Alkoxy substituted C 1 ～C 3 Alkyl, C 1 ～C 3 Alkanoyl, hydroxy, C 1 ～C 3 Alkoxy, 4-6 membered heterocyclyl, C 1 ～C 3 Alkyl substituted 4-6 membered heterocyclyl; m is selected from: 1. 2, 3 and 4.
7. The pyridazinone compound according to claim 6, wherein R 1 Selected from: H. halogen, -NR 7 R 8 、R 9 Substituted or unsubstituted 5-8 membered nitrogen-containing heterocyclic group, R 9 A substituted or unsubstituted 5-6 membered nitrogen containing heteroaryl; r is R 7 、R 8 Each independently selected from: H. c (C) 1 -C 3 Alkyl group、-(CH 2 ) m NR 10 R 11 The method comprises the steps of carrying out a first treatment on the surface of the Each R is 9 Each independently selected from: H. r is R 12 Substituted or unsubstituted C 1 ～C 3 Alkyl, R 12 A substituted or unsubstituted 5-8 membered heterocyclic group; r is R 10 、R 11 Each independently selected from: H. c (C) 1 -C 3 Alkyl, or R 10 、R 11 Together with the nitrogen atom to which they are attached form R 9 A substituted or unsubstituted 5-8 membered nitrogen-containing heterocyclic group; each R is 12 Each independently selected from: H. c (C) 1 ～C 3 Alkyl, hydroxy, C 1 ～C 3 Alkoxy, 5-6 membered heterocyclyl; m is selected from: 1. 2.
8. The pyridazinone compound according to claim 7, wherein R 1 Selected from: -NR 7 R 8 、R 9 Substituted or unsubstituted morpholinyl, R 9 Substituted or unsubstituted pyrazolyl, R 9 Substituted or unsubstituted piperazinyl, R 9 Substituted or unsubstituted piperidinyl, R 9 Substituted or unsubstituted pyrrolopyrrolyl; r is R 7 、R 8 Each independently selected from: H. - (CH) 2 ) m NR 10 R 11 The method comprises the steps of carrying out a first treatment on the surface of the Each R is 9 Each independently selected from: H. r is R 12 Substituted or unsubstituted C 1 ～C 3 Alkyl, R 12 Substituted or unsubstituted piperidinyl, R 12 Substituted or unsubstituted tetrahydropyranyl; r is R 10 、R 11 Together with the nitrogen atom to which they are attached form R 9 Substituted or unsubstituted morpholinyl or piperidinyl; each R is 12 Each independently selected from: H. c (C) 1 ～C 3 Alkyl, hydroxy, C 1 ～C 3 Alkoxy, morpholinyl; m is selected from: 1. 2.
9. The pyridazinone compound according to claim 1, wherein each R is 9 Each independently selected from: H. hydroxy group,Amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH 2 OH、-CH 2 CH 2 OH、-CH 2 CH 2 OCH 3 、-CH 2 CN、
10. The pyridazinone compound according to claim 1, wherein R 1 A group selected from any one of the following:
11. the pyridazinone compound according to any one of claims 1 to 10, wherein R 2 And R is 6 Are all hydrogen.
12. The pyridazinone compound according to any one of claims 1 to 10, wherein R 3 、R 5 Each independently selected from: H. halogen, nitro, amino, cyano, C 1 ～C 6 Alkyl, halogen substituted C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, halogen substituted C 1 ～C 6 An alkoxy group.
13. The pyridazinone compound according to claim 12, wherein R 3 、R 5 Each independently selected from: H. f, cl, br, nitro, amino, cyano, trifluoromethylRadical, trifluoroethyl, C 1 ～C 3 Alkyl, C 1 ～C 3 Methoxy, trifluoromethoxy, trifluoroethoxy.
14. The pyridazinone compound according to any one of claims 1 to 10, wherein R 4 Selected from: H. halogen, halogen,-NR 7 R 8 、R 12 Substituted or unsubstituted C 1 ～C 6 Alkyl, R 12 Substituted or unsubstituted C 1 -C 6 Alkoxy, R 9 Substituted or unsubstituted 5-6 membered heterocyclyl, R 9 Substituted or unsubstituted 5-6 membered heteroaryl; each R is 13 Each independently selected from: H. c (C) 1 ～C 3 An alkyl group; when R is 3 And R is 5 When both are H, R 4 Not be->
15. The pyridazinone compound according to claim 14, wherein R 4 Selected from: H. halogen, morpholinyl,C 1 ～C 3 Alkyl, R 9 Substituted or unsubstituted pyrazolyl; each R is 13 Each independently selected from: H. c (C) 1 ～C 3 An alkyl group.
16. The pyridazinone compound according to claim 1, wherein R 2 And R is 6 Are all hydrogen;
R 3 and R is 5 One of which is H and the other is selected from: H. f, cl, br, nitro, amino, cyano, trifluoromethyl, trifluoroethyl, methyl, ethyl; or R is 3 And R is 5 And F is the same time;
R 4 selected from: H. f, methyl group,And when R is 3 And R is 5 When both are H, R 4 Not be->
17. The pyridazinone compound according to claim 1, wherein the pyridazinone compound is selected from the group consisting of:
18. use of a pyridazinone compound according to any one of claims 1-17 or a pharmaceutically acceptable salt or stereoisomer thereof for the preparation of a c-Met kinase inhibitor, a TRK kinase inhibitor and/or an AXL kinase inhibitor.
19. Use of a pyridazinone compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt or stereoisomer thereof for the manufacture of a medicament for the prevention and/or treatment of a disease mediated by c-Met kinase, TRK kinase and/or AXL kinase.
20. Use according to claim 19, wherein the disease mediated by c-Met kinase, TRK kinase and/or AXL kinase is a tumour, preferably non-small cell lung cancer, gastric cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, ovarian cancer, glioma.
21. A pharmaceutical composition for the prevention and/or treatment of tumors, characterized by comprising an active ingredient and a pharmaceutically acceptable adjuvant, wherein the active ingredient comprises a pyridazinone compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt or stereoisomer thereof.
CN202210891299.9A 2022-07-27 2022-07-27 Pyridazinone compounds and application thereof Pending CN117510470A (en)

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