CN112409332B - Triazole derivative and application thereof in medicines - Google Patents

Triazole derivative and application thereof in medicines Download PDF

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CN112409332B
CN112409332B CN201910783496.7A CN201910783496A CN112409332B CN 112409332 B CN112409332 B CN 112409332B CN 201910783496 A CN201910783496 A CN 201910783496A CN 112409332 B CN112409332 B CN 112409332B
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isopropyl
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triazol
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CN112409332A (en
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习宁
张涛
李敏雄
陈鹏
白长林
陈武宏
陈疏影
王元泽
王茜
彭菊
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Sunshine Lake Pharma Co Ltd
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    • 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
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    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

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Abstract

The invention discloses amide derivatives and application thereof, in particular to novel triazole derivatives and a pharmaceutical composition containing the compounds. The invention also relates to a method for preparing the compound and a pharmaceutical composition, and application of the compound and the pharmaceutical composition in preparing medicines for treating ASK 1-mediated diseases and/or symptoms, in particular application in preparing medicines for treating nonalcoholic steatohepatitis.

Description

Triazole derivative and application thereof in medicines
Technical Field
The invention belongs to the field of medicines, and in particular relates to a triazole derivative with enzyme inhibition activity and a pharmaceutical composition thereof, wherein the compound and the composition can be used for preparing medicines for treating ASK 1-regulated diseases.
Background
The data indicate that liver disease has now become one of the leading causes of human death. Liver diseases are generally classified into acute liver diseases and chronic liver diseases according to the duration of the disease. Liver disease may be caused by infection, injury, medication, poisoning, drinking, abnormal accumulation of normal components in blood, autoimmunity, gene defects, or other unknown factors. Common liver diseases include chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver ischemia-reperfusion injury, primary biliary cirrhosis, etc.
Apoptosis signal-regulating kinase 1 (Apoptosis signal-regulating kinase 1, ask 1) is one of the family members of mitogen-activated protein kinase kinases (mitogen-activated protein kinase kinase kinase, MAP3 Ks), MAP3Ks being capable of activating c-Jun N-terminal protein kinase (N-terminal protein kinase, JNK) and p38MAP (mitogen-activated protein) kinase (Ichijo, h., nishida, e., irie, k., dijke, p.t., saitoh, moriguchi, t., matsumoto, k., miyazono, k., and Gotoh, y. (1997) Science,275,90-94).
ASK1, also known as cytomitogen-activated protein kinase 5 (mitogen-activated protein kinase kinase kinase, MAPKKK5, MAP3K 5), comprises 1375 amino acid residues, constitutes 11 kinase subdomains and a serine/threonine kinase region located in the molecular middle flanking the N-terminal and C-terminal coiled-coil regions (Wang et al J.biol. Chem.1996,271,31607-31611,Ichijo etal.Science.1997,275,90-94;Tobiume et al.Biochem.Biophys.Res.Commun.1997,239,905-910). ASK1 can be activated by a variety of stimuli, such as: oxidative stress, active oxygen, endotoxin, tumor necrosis factor-alpha, endoplasmic reticulum stress, intracellular calcium ion concentration, and the like.
Studies have shown that ASK1 not only regulates cell death, but also plays an important role in cellular activities such as cytokine responses, cell differentiation, innate immune responses, and the like. Modulation of ASK1 activity can treat or prevent a variety of diseases including neurodegenerative diseases, cardiovascular diseases, inflammation, autoimmune diseases, metabolic disorders, and the like. ASK1 modulators have great potential in the treatment of, inter alia, heart kidney disease (including kidney disease, diabetic nephropathy and chronic kidney disease), fibrotic disease (including pulmonary fibrosis and kidney fibrosis), respiratory disease (including chronic embolic pulmonary obstruction and acute lung injury), and liver disease.
Currently, researchers have conducted some studies in an effort to find therapeutic agents capable of effectively inhibiting ASK1 expression or activity. PCT applications WO 2009027483, WO2009123986, WO2010008843, WO2011008709, WO2011041293, WO2011097079, WO2012003387, WO2013112741, WO2014100541 and WO2015095059 disclose a number of small molecule compounds as ASK1 modulators for the prevention or treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases and neurodegenerative diseases. PCT applications WO2015187499 and WO2016049070 disclose the use of ASK1 modulators for the treatment of liver disease. However, there remains a need for more and better ASK1 modulators in the clinic.
Disclosure of Invention
The present invention provides a compound, or a pharmaceutical composition thereof, which is useful as a modulator of ASK 1. The invention further relates to the use of said compounds or pharmaceutical compositions thereof for the preparation of a medicament for the treatment of diseases and/or disorders by modulating ASK1 activity by said compounds. The invention further describes a synthesis method of the compound. The compounds of the present invention exhibit excellent biological activity and pharmacokinetic properties.
Specifically:
in one aspect, the present invention relates to a compound which is a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I),
wherein:
w is CH or N;
R 1 is hydrogen, deuterium, C 1-6 Alkoxy, -N (R) 3 )C(＝O)R 4 、-N(R 3 )S(＝O) n R 4 、-S(＝O) n R 4 or-S (=o) n NR 3 R 4 Wherein, C 1-6 Alkoxy is substituted with 1, 2 or 3 groups selected from deuterium, oxo (=o), amino, nitro, cyano and C 1-3 The group of the alkoxy group is substituted;
R 2 is hydrogen, deuterium, fluorine, chlorine or C 1-6 Alkyl, wherein, C 1-6 Alkyl is optionally substituted with 1, 2, 3 or 4 groups selected from deuterium, halogen atom, hydroxy, oxo (=o), amino, nitro, cyano and C 1-3 The group of the alkoxy group is substituted;
R 3 and R is 4 Each independently is hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy, wherein said C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 Alkoxy is independently optionally substituted with 1, 2, 3 or 4 groups selected from deuterium, halogen atom, hydroxy, oxo (=o), amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 The group of the alkoxy group is substituted;
ring A isWherein the method comprises the steps of
The saidIndependently optionally covered with 1
Or 2 are selected from deuterium, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 The group of the alkoxy group is substituted;
n is 0, 1 or 2.
In some embodiments, R 1 Is hydrogen, deuterium, C 1-4 Alkoxy, -N (R) 3 )C(＝O)R 4 、-N(R 3 )S(＝O) n R 4 、-S(＝O) n R 4 or-S (=o) n NR 3 R 4 Wherein, C 1-4 Alkoxy is substituted with 1, 2 or 3 groups selected from deuterium, oxo (=o), amino, nitro, cyano and C 1-3 The groups of the alkoxy groups are substituted.
In other embodiments, R 1 Is hydrogen, deuterium, methoxy, ethoxy, isopropoxy, -N (R) 3 )C(＝O)R 4 、-N(R 3 )S(＝O) n R 4 、-S(＝O) n R 4 or-S (=o) n NR 3 R 4 Wherein the methoxy, ethoxy and isopropoxy groups are substituted with 1, 2 or 3 groups selected from deuterium, oxo (=o), amino, nitro, cyano, methoxy, ethoxy and isopropoxy groups.
In some embodiments, R 2 Is hydrogen, deuterium, fluorine, chlorine or C 1-4 Alkyl, wherein, C 1-4 Alkyl is optionally substituted with 1, 2, 3 or 4 groups selected from deuterium, halogen atom, hydroxy, oxo (=o), amino, nitro, cyano and C 1-3 The groups of the alkoxy groups are substituted.
In other embodiments, R 2 Is hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl are independently optionally substituted with 1, 2, 3 or 4 groups selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl,Oxo (=o), amino, nitro, cyano, methyl, ethyl, methoxy, ethoxy, and isopropoxy groups.
In some embodiments, R 3 And R is 4 Each independently is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are independently optionally substituted with 1, 2, 3 or 4 groups selected from deuterium, fluoro, chloro, bromo, iodo, hydroxy, oxo (=o), amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
In some embodiments, ring a is Wherein said->Independently optionally substituted with 1 or 2 groups selected from deuterium, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy and isopropoxy.
In another aspect, the invention relates to stereoisomers, geometric isomers, tautomers, nitroxides, solvates, hydrates, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof of one of the following compounds or of one of the following compounds, but in no way limited to:
in one aspect, the present invention relates to a pharmaceutical composition comprising a compound according to formula (I) of the present invention, or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combination thereof.
In one aspect, the present invention relates to the use of a compound as described above or a pharmaceutical composition thereof for the manufacture of a medicament for preventing, treating or alleviating ASK 1-mediated disorders in a patient.
In some embodiments, ASK 1-mediated diseases according to the invention are autoimmune diseases, inflammatory diseases, cardiovascular diseases, heart and kidney diseases, fibrotic diseases, respiratory diseases, liver diseases or neurodegenerative diseases.
In other embodiments, the cardiovascular disease of the present application is diabetes, diabetic nephropathy, or other diabetic complications; the fibrotic disease is pulmonary fibrosis or renal fibrosis; the respiratory disease is chronic embolic pulmonary resistance, idiopathic pulmonary fibrosis or acute lung injury; the liver disease is chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver ischemia-reperfusion injury or primary biliary cirrhosis.
In another aspect, the present application relates to methods for the preparation, isolation and purification of compounds comprised by formula (I).
The foregoing merely outlines certain aspects of the application and is not limited in this regard. These and other aspects are described more fully below.
Detailed description of the drawings
Definitions and general terms
Reference will now be made in detail to certain embodiments of the application, examples of which are illustrated in the accompanying structural and chemical formulas. The application is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the application. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The present application is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.
It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
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 to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato:1999, and "March's Advanced Organic Chemistry" by Michael b.smith and Jerry March, john Wiley & Sons, new york:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.
The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.
"stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.
"chiral" is a molecule that has properties that do not overlap with its mirror image; and "achiral" refers to a molecule that may overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.
"diastereoisomers" refers to stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may be present in the form of one of the possible isomers or mixtures thereof, for example racemates and non-corresponding isomer mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis, for example, reference may be made to Jacques, et al, encomers, racemates and Resolutions (Wiley Interscience, new York, 1981); principles of Asymmetric Synthesis (2) nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers (prototropic tautomer)) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valance tautomers) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optional bond" means that the bond may or may not be present, and that the description includes single, double, or triple bonds.
The term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. The compounds of the invention may be optionally substituted with one or more substituents, as described in the present invention, such as the compounds of the general formula above, or as specific examples within the examples, subclasses, and classes of compounds encompassed by the invention. The term "optionally substituted with … …" may be used interchangeably with the term "unsubstituted or substituted with …," i.e., the structure is unsubstituted or substituted with one or more substituents described herein.
An optional substituent group may be substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position. Wherein the substituents may be, but are not limited to, hydrogen, deuterium, oxo (=o), halogen, cyano, nitro, hydroxy, mercapto, amino, alkylamino, arylamino, aminoalkyl, alkyl, alkenyl, alkynyl, alkylthio, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkanoyl, aryl acyl, heteroaryl acyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, alkylacyloxy, carboxyl, alkoxyacyl, aryloxyacyl, heteroaryloxyacyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkoxysulfonyl, aminoacyl, alkylaminoacyl, aminosulfonyl, alkylaminosulfonyl, and the like.
The term "unsubstituted" means that the specified group carries no substituent.
In addition, unless explicitly indicated otherwise, the descriptions used in this disclosure of the manner in which each … is independently "and" … is independently "and" … is independently "are to be construed broadly as meaning that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1 -C 6 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 An alkyl group.
In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.
The term "alkyl" or "alkyl group" as used herein means a saturated, straight or branched, monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1 to 20 carbon atoms. In some embodiments, the alkyl group contains 1 to 12 carbon atoms; in other embodiments, the alkyl group contains 1 to 6 carbon atoms; in still other embodiments, the alkyl group contains 1 to 4 carbon atoms; in some embodiments, the alkyl group contains 1 to 3 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ) Ethyl (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like.
The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1 to 12 carbon atoms. In some embodiments, the alkoxy group contains 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH) 3 ) Ethoxy (EtO, -OCH) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH) 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentoxy (n-pentoxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentoxy (-OCH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentoxy (-OCH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) And so on.
The term "haloalkyl", "haloalkenyl" or "haloalkoxy" means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.
The term "unsaturated" as used in the present invention means that the group contains one or more unsaturations.
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state forms of P; primary, secondary, tertiary and quaternary ammonium salt forms; or a form in which the hydrogen on the nitrogen atom of the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl, R is a substituent according to the invention).
The term "halogen" or "halogen atom" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not generally produce allergies or similar inappropriate reactions, such as gastrointestinal discomfort, dizziness, etc., when administered to humans. Preferably, the term "pharmaceutically acceptable" as used herein refers to use in animals, more particularly in humans, approved by the federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia.
The term "carrier" refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water and aqueous solutions saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly injectable solutions. Suitable drug carriers are described in "Remington's Pharmaceutical Sciences" of e.w. martin.
The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be ester, and in the prior invention, the ester can be phenyl ester, aliphatic (C 1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, one compound contains a hydroxyl group, i.e., it can be acylated to give the compound in a prodrug form. Other prodrug forms include phosphates, e.g. the phosphate compounds are the per-parentAnd (3) phosphorylating the hydroxyl group on the polymer. For a complete discussion of prodrugs, reference may be made to the following documents: higuchi and V.stilla, pro-drugs as Novel Delivery Systems, vol.14of the A.C.S. symposium Series, edward B.Roche, ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al, prodrug: design and Clinical Applications, nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al, prodrugs of Phosphates and Phosphonates, journal of Medicinal Chemistry,2008,51,2328-2345.
"metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.
As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: S.M. Berge et al describe pharmaceutically acceptable salts in detail in J.pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, and the like, or by other methods described in the literature such as ion exchange. Pharmaceutically acceptable base addition salts include, but are not limited to, inorganic base salts, such as ammonium salts and metal salts of groups I to XII of the periodic table, and organic base salts, such as salts with primary, secondary and tertiary amines.
"solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.
The term "treating" as used herein refers in some embodiments to ameliorating a disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.
The term "therapeutically effective amount" means that the amount of the compound, when administered to a subject to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" may vary with the compound, the disease and severity, as well as the condition, age, weight, sex, etc., of the subject to be treated.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound, basic or acidic moiety using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "manual of pharmaceutically acceptable salts: a list of further suitable salts can be found in Properties, selection and application (Handbook of Pharmaceutical Salts: properties, selection, and Use) ", stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002).
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) containing them, for their crystallization. The disclosed compounds may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); accordingly, the present invention is intended to include solvated and unsolvated forms.
Any formulae given herein are also intended to represent non-isotopically enriched forms as well as isotopically enriched forms of such compounds. Isotopically enriched compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H， 3 H， 11 C， 13 C， 14 C， 15 N， 17 O， 18 O， 18 F， 31 P， 32 P， 35 S， 36 Cl and Cl 125 I. Isotopically enriched compounds of the present invention can be prepared by conventional techniques familiar to those skilled in the art or by describing the examples and processes of preparation herein as using a suitable isotopically-labeled reagent in place of the originally used unlabeled reagent.
All tautomeric forms of the compounds of the invention are included within the scope of the invention unless otherwise indicated. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.
The term "heart and kidney disease" as used herein refers to a disease associated with renal function that may be caused or exacerbated by cardiovascular problems such as hypertension. Hypertension is widely recognized as a major cause of kidney disease.
The term "respiratory disease" as used herein refers to a disease comprising chronic embolic pulmonary obstruction and idiopathic pulmonary fibrosis.
The term "non-alcoholic fatty liver disease (NAFLD)" as used herein is a metabolic disease associated with insulin resistance, including Simple Fatty Liver (SFL), non-alcoholic steatohepatitis (NASH), fatty liver fibrosis and cirrhosis.
The term "liver fibrosis" as used herein includes liver fibrosis due to any cause including, but not limited to, virus-induced liver fibrosis such as liver fibrosis caused by hepatitis b and hepatitis c; liver fibrosis due to contact with alcohol (alcoholic liver disease), pharmaceutical compounds, oxidative stress, cancer radiotherapy or industrial chemicals; and liver fibrosis caused by diseases such as primary biliary cirrhosis, fatty liver, obesity, nonalcoholic steatohepatitis, cystic fibrosis, hemochromatosis and autoimmune hepatitis.
The term "ASK1 modulator" as used herein refers to a substance that binds to ASK1 and modulates its activity.
The terms "a," "an," "the," and similar terms used in the context of the present invention (especially in the context of the claims) may be construed to include both the singular and the plural unless the context clearly dictates otherwise.
Pharmaceutical compositions, formulations, administration and uses of the compounds of the invention
According to another aspect, the pharmaceutical composition of the invention is characterized by comprising a compound of formula (I), a compound listed herein, or a compound of the examples, and a pharmaceutically acceptable carrier. The amount of the compound in the compositions of the invention is effective to treat or ameliorate ASK 1-mediated diseases in a patient.
The compounds of the invention exist in free form or as suitable, pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be administered directly or indirectly according to the needs of the patient, the compounds described in other aspects of the present invention, metabolites thereof, or residues thereof.
As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, including any solvents, diluents, or other liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, and the like, suitable for the particular target dosage form. As described in the following documents: in Remington, the Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York, in combination with the teachings of the literature herein, shows that different carriers can be used In the formulation of pharmaceutically acceptable compositions and their well-known methods of preparation. In addition to the extent to which any conventional carrier vehicle is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions with any other component of the pharmaceutically acceptable composition in a deleterious manner, their use is also contemplated by the present invention.
Materials that may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins, such as human serum proteins, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; a gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol, phosphate buffer, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating materials, sweetening, flavoring and perfuming agents, preserving and antioxidant agents.
Preferably, the compound is administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier selected with regard to the form of administration and conventional pharmaceutical practice (referred to herein as a pharmaceutical carrier), which may be in the form of oral tablets, capsules, elixirs, syrups and the like.
For example, for oral administration in tablet or capsule form, the active pharmaceutical ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral pharmaceutical component may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, and the like. Furthermore, suitable binders, lubricants, disintegrating agents, and coloring agents can also be added to the mixture, as desired or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrating agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
The compounds of the present invention may be administered in the form of oral dosage forms such as tablets, capsules (each of which includes sustained or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular form, all dosage forms used being well known to those of ordinary skill in the pharmaceutical arts. They may be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the mode of administration selected and standard pharmaceutical practice.
The compounds of the invention may be administered in intranasal form via topical use of suitable intranasal vehicles or by transdermal routes using transdermal patches. When administered in the form of a transdermal delivery system, the dosage administered is continuous rather than intermittent throughout the administration period.
The compounds of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
The compounds of the present invention are also coupled to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl amine methacrylate-phenol, polyhydroxyethyl asparaginol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers for achieving controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.
The dosage regimen of the compounds of the invention will vary with various factors known, such as the pharmacokinetic profile of the particular agent and its mode and route of administration; the race, age, sex, health condition, medical condition and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the desired effect. A physician or veterinarian can make the decision and prescribe an effective amount of the drug to prevent, counter or arrest the progress of the thromboembolic disorder.
In accordance with general guidelines, the daily oral dosage of each active ingredient employed is in the range of from about 0.001 to 1000mg/kg body weight, preferably from about 0.01 to 100mg/kg body weight, in order to achieve the indicated effect. And, most preferably, between about 1.0 and 20mg/kg body weight/day. For intravenous administration, the most preferred dosage range during conventional rate infusion is about 1 to about 10mg/kg body weight/minute. The compounds of the present invention may be administered once daily or may be administered in two, three or four times daily administrations.
Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain from about 1mg to about 100mg of the active ingredient. In these pharmaceutical compositions, the weight of the active ingredient will generally be about 0.5-95% of the total weight of the composition.
When the compounds of the present invention are administered with other therapeutic agents, generally, the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage when administered alone, given the additional or synergistic effect of the therapeutic agents when administered in combination.
The compound of the present invention or a pharmaceutically acceptable salt thereof or a hydrate thereof is useful for preventing, treating or alleviating a disease mediated by ASK1 in a patient, and particularly is useful for treating diabetes, diabetic nephropathy, other diabetic complications, chronic kidney disease, pulmonary and renal fibrosis, chronic embolic pulmonary obstruction, idiopathic pulmonary fibrosis, acute lung injury, chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver ischemia-reperfusion injury, primary biliary cirrhosis, and other hepatitis, and the like.
General synthetic procedure
For the purpose of illustrating the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method of practicing the invention.
In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined herein, unless otherwise indicated. The following reaction schemes and examples are provided to further illustrate the present invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare other compounds of the present invention, and other methods for preparing compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known reagents in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.
The examples described below are given unless otherwise indicated that all temperatures are given in degrees celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, arco Chemical Company and Alfa Chemical Company and used without further purification. Unless otherwise indicated, the reagents in general are commercially available from Shandong chemical plant, guangdong Guanghua chemical plant, guangzhou chemical plant, tianjin good, chemical Co., ltd., tianjin Fuchen chemical plant, wuhan Xinhua Yuan technology development Co., qingdao Teng chemical Co., ltd., and Qingdao sea chemical plant
Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by reflux drying of metallic sodium. The anhydrous methylene chloride and chloroform are obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide were dried over anhydrous sodium sulfate in advance for use.
The following reaction is typically carried out under nitrogen or argon pressure or with a dry tube (unless otherwise indicated) over anhydrous solvent, the reaction flask is capped with a suitable rubber stopper and the substrate is injected through a syringe. The glassware was dried.
The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao ocean chemical plant.
1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer. 1 H NMR Spectroscopy with CDC1 3 、DMSO-d 6 、CD 3 OD or acetone-d 6 TMS (0 ppm) or chloroform (7.26 ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (single, singlet), d (doublet ), t (triplet), q (quartet), m (multiplet), br (broadened, broad), br (broadened singlet, broad singlet), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet). Coupling constant J, expressed in hertz (Hz).
The measurement conditions for low resolution Mass Spectrometry (MS) data are: agilent 6120 four-stage HPLC-MS (column type: zorbax SB-C18, 2.1X30 mm,3.5 μm, 6min, flow rate 0.6mL/min. Mobile phase: 5% -95% (CH containing 0.1% formic acid) 3 CN) in (H containing 0.1% formic acid) 2 O) was detected by UV at 210nm/254nm using electrospray ionization (ESI).
The pure compounds were detected by UV at 210nm/254nm using Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (column model: NOVASEP 50/80mm DAC).
The following abbreviations are used throughout the present invention:
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
DMSO-d 6 Deuterated dimethyl sulfoxide
DCM dichloromethane
THF tetrahydrofuran
MeOH methanol
EtOH ethanol
(CH 2 OH) 2 Ethylene glycol
EA or EtOAc ethyl acetate
PE Petroleum ether
SOCl 2 Thionyl chloride
n-BuOH n-butanol
HOAc, acOH or CH 3 COOH acetic acid
Ac 2 O acetic anhydride
HCOOH formic acid
HCl hydrogen chloride
H 2 SO 4 Sulfuric acid
NH 3 Ammonia gas
CH 2 I 2 Diiodomethane
ACN acetonitrile
DMAP 4-dimethylaminopyridine
AIBN azo-bis-isobutyronitrile
NBS N-bromosuccinimide
TFA trifluoroacetic acid
TFE trifluoroethanol
TEA or Et 3 N-triethylamine
NH 4 Cl ammonium chloride
NH 4 OAc ammonium acetate
NaCl sodium chloride
KI potassium iodide
CsF cesium fluoride
LiOH lithium hydroxide
NaOH sodium hydroxide
Cs 2 CO 3 Cesium carbonate
Ag 2 CO 3 Silver carbonate
K 3 PO 4 Potassium phosphate
K 2 CO 3 Potassium carbonate
NaHCO 3 Sodium bicarbonate
KNO 3 Potassium nitrate
CH 3 COOK potassium acetate
Co(OAc) 2 -4H 2 O cobalt acetate tetrahydrate
CuI cuprous iodide
Cu 2 Cuprous oxide O
Fe iron
g
mg
M mol per liter
N moles per liter
mol
mmol millimoles
mL/mL
Mu L microliters
MPa megapascals
Pd 2 (dba) 3 Tris (dibenzylideneacetone) dipalladium
Pd 2 (OAc) 2 Palladium acetate
Xantphos or Xphos 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene
Pd(dppf) 2 Cl 2 [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride
DIBAL/DIBAL-H diisobutylaluminum hydride
DMF-DMA N, N-dimethylformamide dimethyl acetal
HATU 2- (7-oxybenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate
BINAP (. + -.) -2,2' -bis- (di)Phenylphosphine compoundsRadical) -11' -binaphthyl
m-CPBA m-chloroperoxybenzoic acid
PIA iodobenzene diacetic acid
The following schemes describe the steps for preparing the disclosed compounds. Wherein each A, R, R3, R4 and W has the definition set forth herein, unless otherwise indicated.
Reaction scheme 1
The [ (x) ray ]8) The compounds shown can be prepared by the method described in scheme 1: the [ (x) ray ]1) The compounds shown react under the action of nitric acid to obtain the formula2) The compounds shown. The [ (x) ray ]2) The compound shown reacts with methanol to obtain the formula3) The compounds shown. The [ (x) ray ]3) The compound shown reacts with methyl hydrazine to obtain the formula4) The compounds shown. The [ (x) ray ]4) The compound shown in the formula5) The compounds shown react to obtain the formula6) The compounds shown. The [ (x) ray ]6) The compound shown reacts with hydrogen to obtain the formula7) The compounds shown. The [ (x) ray ]7) The compounds shown react under the action of formic acid to obtain the formula 8) The compounds shown.
Reaction scheme 2
The [ (x) ray ]10) The compounds shown can be prepared by the method described in scheme 2: the [ (x) ray ]7) The compound shown reacts under the action of isoamyl nitrite and cuprous iodide to obtain the compound shown in the formula [ ]9) The compounds shown. The [ (x) ray ]9) The compound shown reacts with 4-cyclopropyl-1H-imidazole to obtain the formula [ (]10) The compounds shown.
Reaction scheme 3
The [ (x) ray ]16) The compounds shown can be prepared by the method described in scheme 3: the [ (x) ray ]11) The compounds and the formula are12) The compounds shown react to obtain the formula13) The compounds shown. The [ (x) ray ]13) The compounds shown react under the action of sodium borohydride to obtain the compounds with the formula [ ]14) The compounds shown. The [ (x) ray ]14) The compounds shown react under the action of triethylsilane to obtain the formula [ (]15) The compounds shown. The [ (x) ray ]15) The compounds shown react under the action of potassium nitrate to obtain the formula16) The compounds shown.
Reaction scheme 4
The [ (x) ray ]22) The compounds shown can be prepared by the method described in scheme 4: the [ (x) ray ]17) The compound shown in the specification reacts with 2-picolinic acid to obtain the formula18) The compounds shown. The [ (x) ray ]18) The shown compound reacts under the action of diethyl azodicarboxylate to obtain the compound with the formula of [ (]19) The compounds shown. The [ (x) ray ] 19) The compound shown in the formula5) The compounds shown react to obtain the formula20) The compounds shown. The [ (x) ray ]20) The compounds shown react under the action of sodium methyl mercaptide to obtain the formula [ ]21) The compounds shown. The [ (x) ray ]21) The compounds are reacted under the action of m-chloroperoxybenzoic acid to obtain the formula [ ]22) The compounds shown.
Reaction scheme 5
The [ (x) ray ]29) The compounds shown can be prepared by the method described in scheme 5: the [ (x) ray ]5) The shown compound reacts with N-carbamic acid tert-butyl ester to obtain the formula [ ]23) The compounds shown. The [ (x) ray ]23) The compounds shown react under the action of hydrochloric acid to obtain the formula24) The compounds shown. The [ (x) ray ]25) The compound shown reacts with N-isopropyl-2-amine to obtain the formula26) The compounds shown. The [ (x) ray ]26) The shown compound reacts under the action of n-butyllithium and DMF to obtain the formula [ ]27) The compounds shown. The [ (x) ray ]27) The compounds shown react under the action of potassium nitrate to obtain the formula28) The compounds shown. The [ (x) ray ]24) The compounds and the formula are28) The compounds shown react to obtain the formula29) The compounds shown.
Reaction scheme 6
The [ (x) ray ]34) The compounds shown can be prepared by the method described in scheme 6: the [ (x) ray ]30) The compounds shown react under the action of oxalyl chloride to obtain the compounds with the formula [ (] 31) The compounds shown. The [ (x) ray ]31) The compounds and the formula are12) The compounds shown react to obtain the formula32) The compounds shown. The [ (x) ray ]32) The compounds shown react under the action of ammonia water to obtain the formula33) The compounds shown. The [ (x) ray ]33) The compounds shown react under the action of trimethyl orthoformate and ammonium chloride to obtain the compound with the formula of [ (]34) The compounds shown.
Reaction scheme 7
The [ (x) ray ]42) The compounds shown can be prepared by the method described in scheme 7: the [ (x) ray ]35) The compound shown reacts with methanol to obtain the formula36) The compounds shown. The [ (x) ray ]36) The compound shown reacts with 1-bromo-2-methoxyethane to obtain the formula37) The compounds shown. The [ (x) ray ]37) The compounds are reacted under the action of lithium hydroxide to obtain the formula38) The compounds shown. The [ (x) ray ]38) The compounds shown react under the action of oxalyl chloride to obtain the compounds with the formula [ (]39) The compounds shown. The [ (x) ray ]39) The compounds and the formula are12) The compounds shown react to obtain the formula40) The compounds shown. The [ (x) ray ]40) The shown compound reacts with hydrogen to obtain the formula41) The compounds shown. The [ (x) ray ]41) The compounds shown react under the action of trimethyl orthoformate and ammonium chloride to obtain the compound with the formula of [ (]42) The compounds shown.
Reaction scheme 8
The [ (x) ray ]50) The compounds shown can be prepared by the method described in scheme 8: the [ (x) ray ] 43) The compound shown reacts with (E) -3- (dimethylamino) ethyl acrylate in oxalyl chloride to obtain the compound shown in the formula44) The compounds shown. The [ (x) ray ]44) The compounds shown react under the action of the propyl-2-amine to obtain the compound with the formula of [ (]45) The compounds shown. The [ (x) ray ]45) The compounds shown react under the action of hydrochloric acid to obtain the formula46) The compounds shown. The [ (x) ray ]46) The compounds shown react under the action of hydrochloric acid to obtain the formula47) The compounds shown. The [ (x) ray ]47) The compounds shown react under the action of bromine to obtain the formula48) The compounds shown. The [ (x) ray ]48) The compounds and the formula are49) The compounds shown react to obtain the formula50) The compounds shown. Reaction scheme 9
The [ (x) ray ]55) The compounds shown can be prepared by the method described in scheme 9: the [ (x) ray ]51) The compounds shown react under the action of iron and ammonium chloride to obtain the compounds with the formula [ ]52) The compounds shown. The [ (x) ray ]52) The compound shown reacts under the action of sodium nitrite and sulfuric acid to obtain the compound shown in the formula53) The compounds shown. The [ (x) ray ]53) The compound shown reacts with 1-bromo-2-methoxyethane to obtain the formula54) The compounds shown. The [ (x) ray ]54) The compounds and the formula are49) The compounds shown react to obtain the formula55) The compounds shown.
Reaction scheme 10
The [ (x) ray ]57) The compounds shown can be prepared by the method described in scheme 10: the [ (x) ray ] 56) The compounds are reacted under the action of potassium nitrate and sulfuric acid to obtain the formula [ ]57) The compounds shown.
Reaction scheme 11
The [ (x) ray ]60) The compounds shown can be prepared by the method described in scheme 11: the [ (x) ray ]57) The compounds shown react under the action of formic acid to obtain the formula58) The compounds shown. The [ (x) ray ]58) The compounds are reacted under the action of 2-bromo-1-cyclopropyl-ethanone to obtain the formula [ (]59) The compounds shown. The [ (x) ray ]59) The compounds shown react under the action of ammonium acetate to obtain the formula60) The compounds shown.
Reaction scheme 12
The [ (x) ray ]62) The compounds shown can be prepared by the method described in scheme 12: the [ (x) ray ]57) The compounds and the formula are61) The compounds shown react to obtain the formula62) The compounds shown.
Reaction scheme 13
The [ (x) ray ]63) The compounds shown can be prepared by the method described in scheme 13: the [ (x) ray ]57) The shown compound reacts with acetic anhydride to obtain the formula63) The compounds shown.
Reaction scheme 14
The [ (x) ray ]65) The compounds shown can be prepared by the method described in scheme 14: the [ (x) ray ]57) The shown compound reacts under the action of thionyl chloride, hydrochloric acid, sodium nitrite and cuprous chloride to obtain the formula [ ]64) The compounds shown. The [ (x) ray ] 64) The compounds shown react under the action of ammonia water to obtain the formula65) The compounds shown.
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further described below in conjunction with the examples.
Examples
Example 1N- (2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-3-oxo-2, 3-dihydro-1H-indazol-5-yl) carboxamide
First step Synthesis of 2-fluoro-4-methyl-5-nitrobenzoic acid
Sulfuric acid (5.45 g,54.5mmol, 98%) and nitric acid (5.09 g,72.7mmol, 90%) were added sequentially to a solution of 2-fluoro-4-methylbenzoic acid (7.00 g,45.4 mmol) in sulfuric acid (100 mL, 98%) at 0deg.C, stirred at 0deg.C for 3 hours, water (500 mL) was added, filtered and the filter cake was collected to give the title compound as a white solid (8.75 g, 96.5%).
MS(ESI,pos.ion)m/z:200.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.45(d,J＝6.8Hz,1H),7.55(d,J＝11.3Hz,1H),2.59(s,3H)。
Second step Synthesis of methyl 2-fluoro-4-methyl-5-nitrobenzoate
SOCl is put into 2 (10.76 g,90.4 mmol) and DMF (0.33 g,4.52 mmol) were added sequentially to 2-fluoro-4-methyl-5-nitrobenzoic acid (2.60 g,10.3 mmol) in MeOH (100 mL), stirring at reflux, and concentrating the reaction to dryness, and then purifying by column chromatography (EA/PE (v/v) =1/10) to give the title compound as a yellow solid (8.52 g, 89.9%).
MS(ESI,pos.ion)m/z:214.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.48(d,J＝6.8Hz,1H),7.61(d,J＝11.4Hz,1H),3.90(s,3H),2.61(s,3H)。
Third step Synthesis of 1, 6-dimethyl-5-nitro-1H-indazol-3 (2H) -one
Methyl hydrazine (8.65 g,75.1mmol, 40%) was added to a solution of methyl 2-fluoro-4-methyl-5-nitrobenzoate (4.00 g,18.8 mmol) in n-BuOH (40 mL), the reaction was stirred at 120 ℃ overnight, the reaction concentrated to dryness, and then purified by column chromatography (EA/PE (v/v) =1/1) to give the title compound as a yellow solid (2.91 g, 74.8%).
MS(ESI,pos.ion)m/z:208.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)11.26(s,1H),8.47(s,1H),7.47(s,1H),3.81(s,3H),2.62(s,3H)。
Fourth step Synthesis of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-5-nitro-1H-indazol-3 (2H) -one
2-bromo-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine (0.72 g,2.70 mmol), BINAP (0.48 g,0.77 mmol), pd (OAc) 2 (0.17 g,0.77 mmol) and Cs 2 CO 3 (2.51 g,7.72 mmol) was added sequentially to a solution of 1, 6-dimethyl-5-nitro-1H-indazol-3 (2H) -one (0.80 g,3.86 mmol) in 1, 4-dioxane (150 mL), the reaction was stirred at reflux for 11H, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (0.41 g, 26.4%).
MS(ESI,pos.ion)m/z:394.1[M+H] + 。
Fifth step Synthesis of 5-amino-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-1H-indazol-3 (2H) -one
Palladium on carbon (0.60 g,1.53mmol, 10%) was added to a solution of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-5-nitro-1H-indazol-3 (2H) -one (0.60 g,1.53 mmol) in MeOH (20 mL), hydrogen protected, stirred at room temperature, reacted for 4 hours, filtered, the filtrate concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/20) to give the title compound as a yellow solid (0.15 g, 28.0%).
MS(ESI,pos.ion)m/z:364.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.67(s,1H),8.08(t,J＝7.9Hz,1H),7.89(d,J＝7.4Hz,1H),7.33(d,J＝8.1Hz,1H),7.29(s,1H),6.45(s,1H),4.63(s,2H),4.64–4.51(m,1H),3.85(s,3H),2.24(s,3H),0.79(d,J＝6.7Hz,6H)。
Sixth step Synthesis of N-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-3-oxo-2, 3-dihydro-1H-indazol-5-yl) carboxamide
A solution of HCOOH (0.10 ml,2.75 mmol) in HOAc (0.20 ml,2.20 mmol) was added to the flask and the reaction was stirred at 70℃for 1 hour. The reaction was added to a solution of 5-amino-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-1H-indazol-3 (2H) -one (0.10 g,0.27 mmol) in THF (10 mL) at 0 ℃ and stirred at room temperature overnight, the reaction was concentrated to dryness, DCM (50 mL) was added, then the pH was adjusted to 7 with saturated aqueous sodium bicarbonate, the solution was separated, the aqueous phase was extracted with DCM (50 ml×2), the organic phase was collected, the organic phase brine (100 ml×2) was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/20) to give the title compound as a yellow solid (0.08 g, 68.1%).
MS(ESI,pos.ion)m/z:392.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)9.76–9.50(m,1H),8.67(s,1H),8.25(s,1H),8.11(s,1H),7.93(s,1H),7.75(s,1H),7.57(s,1H),7.45–7.27(m,1H),4.48(s,1H),3.95(s,3H),2.39(s,3H),0.76(d,J＝3.9Hz,6H)； 13 C NMR(151MHz,DMSO-d 6 )δ(ppm)162.4(s),160.4(s),149.6(s),149.3(s),145.6(s),143.6(s),142.3(s),139.7(s),131.7(s),130.2(s),119.0(s),112.8(s),112.3(s),111.6(s),111.1(s),48.2(s),35.7(s),22.8(s),19.4(s)。
Example 2 5- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-1H-indazol-3 (2H) -one
First step Synthesis of 6-bromopyridine hydrazide
Hydrazine hydrate (6.89 mL,138.9mmol, 98%) was added to a solution of methyl 6-bromopyridine carboxylate (15.0 g,69.4 mmol) in EtOH (150 mL), stirred at reflux for 1 hour, filtered and the filter cake collected to give the title compound as a white solid (12.10 g, 80.7%).
MS(ESI,pos.ion)m/z:216.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)9.86(s,1H),8.04–7.79(m,3H),4.61(s,2H)。
Second step Synthesis of (Z) -N' - (6-bromopyridine formyl) -N, N-dimethylformamide
DMF-DMA (29.0 mL,222.1 mmol) was added to a solution of 6-bromopyridine formylhydrazine (12.0 g,55.5 mmol) in ACN (200 mL) and the reaction was stirred at reflux for 7 h and the reaction concentrated to dryness to give the title compound as a yellow solid (15.0 g, 100%).
MS(ESI,pos.ion)m/z:271.1[M+H] + 。
Third step Synthesis of 2-bromo-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine
HOAc (4.74 mL,83.0 mmol) and propan-2-amine (19.0 mL,221.3 mmol) were added sequentially to a solution of (Z) -N' - (6-bromopyridyl) -N, N-dimethylformamide (15.0 g,55.3 mmol) in ACN (200 mL), the reaction was stirred at reflux overnight, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/50) to give the title compound as a yellow liquid (5.80 g, 39.2%).
MS(ESI,pos.ion)m/z:267.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.92(s,1H),8.16(d,J＝7.7Hz,1H),7.94(t,J＝7.8Hz,1H),7.77(d,J＝7.9Hz,1H),5.39–5.24(m,1H),1.49(d,J＝6.7Hz,6H)。
Fourth step Synthesis of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-5-nitro-1H-indazol-3 (2H) -one
2-bromo-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine (0.72 g,2.70 mmol), BINAP (0.48 g,0.77 mmol), pd (OAc) 2 (0.17 g,0.77 mmol) and Cs 2 CO 3 (2.51 g,7.72 mmol) was added sequentially to a solution of 1, 6-dimethyl-5-nitro-1H-indazol-3 (2H) -one (0.80 g,3.86 mmol) in 1, 4-dioxane (150 mL), the reaction was stirred at reflux for 11H, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (0.41 g, 26.4%).
MS(ESI,pos.ion)m/z:394.1[M+H] + 。
Fifth step Synthesis of 5-amino-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-1H-indazol-3 (2H) -one
Palladium on carbon (0.60 g,1.53mmol, 10%) was added to a solution of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-5-nitro-1H-indazol-3 (2H) -one (0.60 g,1.53 mmol) in MeOH (20 mL), hydrogen protected, stirred at room temperature, reacted for 4 hours, filtered, the filtrate concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/20) to give the title compound as a yellow solid (0.15 g, 28.0%).
MS(ESI,pos.ion)m/z:364.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.67(s,1H),8.08(t,J＝7.9Hz,1H),7.89(d,J＝7.4Hz,1H),7.33(d,J＝8.1Hz,1H),7.29(s,1H),6.45(s,1H),4.63(s,2H),4.64–4.51(m,1H),3.85(s,3H),2.24(s,3H),0.79(d,J＝6.7Hz,6H)。
Sixth step Synthesis of 5-iodo-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-1H-indazol-3 (2H) -one
Isoamyl nitrite (0.39 g,3.30 mmol), cuI (0.19 g,0.99 mmol) and CH 2 I 2 (1.11 g,4.13 mmol) was added sequentially to a solution of 5-amino-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-1H-indazol-3 (2H) -one (0.30 g,0.83 mmol) in THF (10 mL), and the mixture was stirred under reflux for 1 hour, and the reaction mixture was concentrated toDried and then purified by column chromatography (MeOH/DCM (v/v) =1/20) to give the title compound as a yellow solid (0.28 g, 76.0%).
MS(ESI,pos.ion)m/z:475.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.85(s,1H),8.12(t,J＝7.4Hz,1H),7.94(d,J＝9.7Hz,2H),7.75(s,1H),7.39(d,J＝8.0Hz,1H),4.51(s,1H),3.95(s,3H),2.53(s,3H),0.77(d,J＝6.5Hz,6H)。
Seventh step Synthesis of 4-cyclopropyl-1H-imidazole
Formamidine acetate (9.58 g,92.0 mmol) was added to 2-bromo-1-cyclopropylethanone (3.00 g,18.4 mmol) (CH 2 OH) 2 To a solution of (50 mL), the reaction was stirred at reflux for 11 h, water (50 mL) was added, then EA (200 mL. Times.3) was extracted, the organic phase was washed with brine (100 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness, then purified by column chromatography (MeOH/DCM (v/v) =1/20) to give the title compound as a yellow liquid (1.72 g, 83.6%).
MS(ESI,pos.ion)m/z:109.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)7.44(s,1H),6.74(s,1H),3.41(s,1H),1.77(s,1H),0.79–0.72(m,2H),0.59(dd,J＝5.0,2.2Hz,2H)；
Eighth step Synthesis of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-1H-indazol-3 (2H) -one
4-cyclopropyl-1H-imidazole (0.21 g,1.94 mmol), quinolin-8-ol (0.21 g,1.45 mmol), cu 2 O (0.21 g,1.45 mmol) and K 3 PO 4 (0.51 g,2.43 mmol) was added sequentially to a solution of 5-iodo-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-1H-indazol-3 (2H) -one (0.23 g,0.48 mmol) in DMSO (90 mL), stirred at 100deg.C for 24 hours, water (200 mL) was added, then EA (200 mL. Times.3) extracted, the organic phase was washed with brine (100 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness, then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (0.035 g, 16.1%).
MS(ESI,pos.ion)m/z:455.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.71(s,1H),8.09(s,1H),7.93(s,1H),7.74(s,1H),7.53(s,1H),7.39(d,J＝19.1Hz,2H),7.03(s,1H),4.49(s,1H),4.02(s,3H),2.26(s,3H),1.81(s,1H),0.76(dd,J＝44.1,23.5Hz,10H)；
13 C NMR(101MHz,DMSO-d 6 ):δ(ppm)162.4(s),149.7(s),145.6(s),142.2(s),141.3(s),133.9(s),131.5(s),118.9(s),117.0(s),113.0(s),111.7(d,J＝19.2Hz),48.1(s),35.9(s),22.8(s),18.9(s),9.3(s),7.5(s)。
Example 3 5- (4-cyclopropyl-1H-imidazol-1-yl) -2- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -1, 6-dimethyl-1H-indazol-3 (2H) -one
First step Synthesis of N- (3-bromophenyl) -2-fluoro-4-methyl-5-nitrobenzamide
3-Bromoaniline (3.10 g,18.1 mmol), HATU (11.4 g,30.1 mmol) and Et 3 N (4.56 g,45.2 mmol) was added sequentially to a solution of 2-fluoro-4-methyl-5-nitrobenzoic acid (3.00 g,15.1 mmol) in DMF (50 mL), stirred at room temperature for 2 hours, water (1000 mL) was added, the filter cake was collected, and then purified by column chromatography (EA/PE (v/v) =1/5) to give the title compound as a yellow solid (4.27 g, 79.0%). MS (ESI, pos.ion) m/z 353.2[ M+H ]] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)10.72(s,1H),8.38(d,J＝6.5Hz,1H),8.04(s,1H),7.63(t,J＝7.8Hz,2H),7.42–7.25(m,2H),2.61(s,3H)。
Second step Synthesis of N- (3-bromophenyl) -4-methyl-2- (methylamino) -5-nitrobenzamide
Methylamine hydrate (0.40 g,5.10mmol, 40%) was added to a solution of N- (3-bromophenyl) -2-fluoro-4-methyl-5-nitrobenzamide (1.50 g,4.25 mmol) in N-BuOH (40 mL) and the reaction stirred at 120℃for 5 hours and concentrated to dryness to give the title compound as a yellow solid (1.49 g, 96.3%).
MS(ESI,pos.ion)m/z:364.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)10.53(s,1H),8.59(s,1H),8.23(d,J＝4.5Hz,1H),8.06(s,1H),7.72–7.61(m,1H),7.38–7.24(m,2H),6.67(s,1H),2.92(d,J＝4.6Hz,3H),2.62(s,3H)。
Third step Synthesis of 2- (3-bromophenyl) -1, 6-dimethyl-5-nitro-1H-indazol-3 (2H) -one
CF at 0 DEG C 3 COOH (4.6 mL,61.8 mmol) and PIA (7.96 g,24.7 mmol) were added sequentially to a solution of N- (3-bromophenyl) -4-methyl-2- (methylamino) -5-nitrobenzamide (4.5 g,12.4 mmol) in DCM (100 mL), the reaction was stirred at 0deg.C for 2 hours, the reaction concentrated to dryness, and then purified by column chromatography (EA/PE (v/v) =1/5) to give the title compound as a yellow solid (1.60 g, 35.8%).
MS(ESI,pos.ion)m/z:362.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.41(s,1H),7.79(s,1H),7.75(s,1H),7.61(d,J＝7.2Hz,1H),7.54(d,J＝7.4Hz,2H),3.31(s,4H),2.69(s,4H)。
Fourth step Synthesis of 1, 6-dimethyl-5-nitro-2- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-yl) phenyl) -1H-indazol-3 (2H) -one
Bis (pinacolato) diboron (1.58 g,6.21 mmol), pd (dppf) Cl 2 (0.68 g,0.83 mmol) and CH 3 COOK (1.62 g,16.6 mmol) was added sequentially to a solution of 2- (3-bromophenyl) -1, 6-dimethyl-5-nitro-1H-indazol-3 (2H) -one (1.50 g,4.14 mmol) in 1, 4-dioxane (50 mL), the reaction was stirred at reflux for 2 hours, the reaction concentrated to dryness, and then purified by column chromatography (EA/PE (v/v) =4/1) to give the title compound as a yellow solid (0.96 g, 57.0%).
MS(ESI,pos.ion)m/z:410.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.41(d,J＝4.9Hz,1H),7.77(s,2H),7.69(d,J＝3.8Hz,1H),7.61(d,J＝5.5Hz,2H),3.29(s,3H),2.69(s,3H),1.32(s,12H)。
Fifth step of synthesis of formylhydrazine
Hydrazine hydrate (13.8 g,270.0mmol, 98%) was added to a solution of ethyl formate (20.0 g,270.0 mmol) in EtOH (40 mL) at 0deg.C and the reaction stirred at room temperature overnight and the reaction concentrated to dryness to give the title compound as a white solid (16.2 g, 100%).
MS(ESI,pos.ion)m/z:61.1[M+H] + 。
Sixth step Synthesis of 4-isopropyl-4H-1, 2, 4-triazole
Trimethyl orthoformate (27.0 g,254.8 mmol) was added to a solution of formylhydrazine (10.2 g,169.8 mmol) in MeOH (100 mL), stirred at reflux for 3 hours, then isopropylamine (10.0 g,169.8 mmol) was added, stirred at reflux overnight, the reaction was concentrated to dryness, and then purified by column chromatography (MeOH/DCM) =1/30) to give the title compound as a red liquid (2.52 g, 13.3%).
MS(ESI,pos.ion)m/z:112.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.59(s,2H),4.58–4.44(m,1H),1.42(d,J＝6.7Hz,6H)。
Seventh step Synthesis of 3-bromo-4-isopropyl-4H-1, 2, 4-triazole
NBS (2.16 g,12.1 mmol) and AIBN (2.21 g,13.5 mmol) were added to a solution of 4-isopropyl-4H-1, 2, 4-triazole (1.50 g,13.5 mmol) in DCM (30 mL), stirred at room temperature for 10 hours, water (100 mL) was added, then pH was adjusted to 7 with saturated aqueous sodium bicarbonate, the separated liquid, the aqueous phase was extracted with DCM (50 mL. Times.2), the organic phase was collected, washed with brine (100 mL. Times.2), dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a red solid (1.50 g, 58.5%).
MS(ESI,pos.ion)m/z:190.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.85(s,1H),4.40-4.50(m,,1H),1.43(d,J＝6.7Hz,6H)。
Eighth step Synthesis of 2- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -1, 6-dimethyl-5-nitro-1H-indazol-3 (2H) -one
Pd (dppf) Cl 2 (0.40 g,0.49 mmol) and K 2 CO 3 (1.35 g,9.78 mmol) was added sequentially to 1, 6-dimethyl-5-nitro-2- (3- (4, 5-tetramethyl-1, 3, 2-di-methyl)In a solution of oxyboropentan-yl) phenyl) -1H-indazol-3 (2H) -one (1.00 g,2.44 mmol) in 1, 4-dioxane (120 mL) and water (30 mL), the reaction was stirred at reflux overnight, the reaction was concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (0.55 g, 57.0%).
MS(ESI,pos.ion)m/z:393.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.90(s,1H),8.43(s,1H),7.83–7.73(m,3H),7.66(dd,J＝21.9,7.8Hz,2H),4.64–4.45(m,1H),3.37(s,3H),2.69(s,3H),1.46(d,J＝6.7Hz,6H)。
Synthesis of 5-amino-2- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -1, 6-dimethyl-1H-indazol-3 (2H) -one
Palladium on carbon (1.49 g,1.40 mmol) was added to a solution of 2- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -1, 6-dimethyl-5-nitro-1H-indazol-3 (2H) -one (0.55 g,1.40 mmol) in MeOH (20 mL), hydrogen protected, stirred at room temperature, reacted for 4 hours, filtered, the filtrate concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/20) to give the title compound as a yellow solid (0.27 g, 53.7%).
MS(ESI,pos.ion)m/z:363.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.89(s,1H),7.81(s,1H),7.71(s,1H),7.60–7.53(m,1H),7.50(d,J＝6.2Hz,1H),7.30(s,1H),6.93(s,1H),4.99(s,2H),4.52(dd,J＝13.2,6.5Hz,1H),3.03(s,3H),2.24(s,3H),1.46(d,J＝6.6Hz,6H)。
Tenth step Synthesis of 5-iodo-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-1H-indazol-3 (2H) -one
Isoamyl nitrite (0.35 g,2.98 mmol), cuI (0.17 g,0.89 mmol) and CH 2 I 2 (0.99 g,3.73 mmol) was added sequentially to a solution of 5-amino-2- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -1, 6-dimethyl-1H-indazol-3 (2H) -one (0.27 g,0.75 mmol) in THF (20 mL), the reaction was stirred at reflux for 0.5H, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/50) to give the title compound as a yellow solid (0.27 g, 76.6%).
MS(ESI,pos.ion)m/z:474.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.16(s,1H),7.76(d,J＝25.2Hz,4H),7.53(d,J＝34.1Hz,2H),4.70(s,1H),3.19(s,3H),2.53(s,3H),1.46(s,6H)。
Synthesis of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -1, 6-dimethyl-1H-indazol-3 (2H) -one in an eleventh step
4-cyclopropyl-1H-imidazole (0.12 g,1.10 mmol), quinolin-8-ol (0.12 g,0.82 mmol), cu 2 O (0.12 g,0.82 mmol) and K 3 PO 4 (0.29 g,1.37 mmol) was added sequentially to a solution of 5-iodo-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-1H-indazol-3 (2H) -one (0.13 g,0.27 mmol) in DMSO (10 mL), stirred at 100℃for 12H, water (200 mL) was added, then EA (200 mL. Times.3) extracted, the organic phase was washed with brine (100 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness, then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (0.023 g, 18.5%).
MS(ESI,pos.ion)m/z:454.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.93(s,1H),7.83–7.56(m,7H),7.18(s,1H),4.60–4.48(m,1H),3.26(s,3H),2.27(s,3H),1.85(s,1H),1.46(d,J＝6.4Hz,6H),0.80(d,J＝6.3Hz,2H),0.71(s,2H)；
13 C NMR(151MHz,DMSO-d 6 ):δ(ppm)161.4(s),152.3(s),151.7(s),143.9(s),142.9(s),140.8(s),137.7(s),135.7(s),133.2(s),130.5(s),128.8(s),126.8(s),124.5(s),123.6(s),121.5(s),116.6(d,J＝18.6Hz),115.8(s),48.1(s),23.7(s),19.1(s),9.4(s),7.6(s)。
Example 4 2- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -1, 6-dimethyl-1H-indazol-3 (2H) -one
4-cyclopropyl-1H-imidazole (0.12 g,1.10 mmol),Quinolin-8-ol (0.12 g,0.82 mmol), cu 2 O (0.12 g,0.82 mmol) and K 3 PO 4 (0.29 g,1.37 mmol) was added sequentially to a solution of 5-iodo-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 6-dimethyl-1H-indazol-3 (2H) -one (0.13 g,0.27 mmol) in DMSO (10 mL), stirred at 100℃for 12H, water (200 mL) was added, then EA (200 mL. Times.3) extracted, the organic phase was washed with brine (100 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness, then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (0.035 g, 36.8%).
MS(ESI,pos.ion)m/z:348.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.92(s,1H),7.80(s,1H),7.70(t,J＝10.9Hz,3H),7.56(d,J＝6.6Hz,1H),7.51(s,1H),7.14(d,J＝7.8Hz,1H),4.60–4.50(m,1H),3.20(s,3H),2.48(s,3H),1.46(d,J＝6.3Hz,6H)；
13 C NMR(151MHz,DMSO-d 6 ):δ(ppm)162.1(s),153.1(s),152.4(s),144.8(s),142.9(s),136.1(s),130.4(s),128.7(s),126.4(s),125.3(s),124.1(s),123.9(s),123.3(s),115.9(s),113.8(s),48.1(s),23.7(s),22.3(s)。
Example 5N- (2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methyl-3-oxoisoindol-5-yl) ethylsulfonamide
First step Synthesis of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methylisoindole-1, 3-dione
6- (4-isopropyl-1, 2, 4-triazol-3-yl) pyridin-2-amine (5.877 g,28.92 mmol), 5-methyl isobenzofuran-1, 3-dione (3.074 g,18.96 mmol) and AcOH (15 mL) were added to a reaction flask, reacted at 110 ℃ for 8 hours with stirring, concentrated to dryness, water (100 mL) was added, then pH was adjusted to 8 using saturated aqueous sodium bicarbonate solution, DCM (100 ml×5) was extracted, the organic phase concentrated to dryness, and then column chromatography was purified (MeOH/DCM (v/v) =1/36) to give the title compound as a yellow solid (2.874 g, 43.64%).
MS(ESI,pos.ion)m/z:348.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.37(s,1H),8.35(d,J＝7.8Hz,1H),8.02(t,J＝7.9Hz,1H),7.88(d,J＝7.7Hz,1H),7.80(s,1H),7.63(d,J＝7.6Hz,1H),7.54(d,J＝8.0Hz,1H),5.83–5.68(m,1H),2.57(s,3H),1.53(d,J＝6.7Hz,6H)。
Second step Synthesis of 3-hydroxy-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methylisoindol-1-one
Sodium borohydride (1.542 g,40.76 mmol) was added to a solution of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methylisoindole-1, 3-dione (2.8 g,8.1 mmol) in MeOH (50 mL) at 0deg.C, stirred at room temperature for 1 hour, water (100 mL) was added, then DCM (100 mL. Times.4) was extracted, the organic phase dried over anhydrous sodium sulfate, filtered, and the organic phase concentrated to dryness to afford the title compound as a pale yellow solid that was used directly in the next reaction.
MS(ESI,pos.ion)m/z:350.6[M+H] + 。
Step three Synthesis of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methylisoindol-1-one
Triethylsilane (19 mL,119 mmol) was added to a solution of 3-hydroxy-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methylisoindol-1-one (2.8 g,8.0 mmol) in TFA (30 mL), stirred at room temperature for 2 hours, concentrated to dryness, then adjusted to basic with saturated aqueous sodium bicarbonate (100 mL), DCM (100 ml×3) extracted, the organic phase concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a white solid (1.31 g, 49%).
MS(ESI,pos.ion)m/z:334.5[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.76–8.69(m,1.5H),8.38(s,1.5H),8.04(dd,J＝7.4,3.2Hz,1.5H),7.90(t,J＝8.0Hz,1.5H),7.82(d,J＝7.8Hz,1H),7.74(s,0.5H),7.47–7.41(m,1H),7.36(s,1H),7.33(d,J＝7.8Hz,1H),5.68–5.55(m,1.5H),4.99(s,3H),2.50(s,3H),2.47(s,1.5H),1.63(d,J＝6.8Hz,9H)。
Fourth step Synthesis of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methyl-6-nitroisoindol-1-one
KNO at 0 DEG C 3 (456.6 mg,4.516 mmol) was added to a solution of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methylisoindol-1-one (1.2 g,3.6 mmol) in sulfuric acid (10 mL, 98%) and reacted overnight at 0℃with stirring, the reaction mixture was then added to ice water (200 mL), naHCO 3 Ph=8, DCM/MeOH (10/1, 200ml×4) extraction, concentration of the organic phase to dryness, and purification by column chromatography (MeOH/DCM (v/v) =1/50) afforded the title compound as a white solid (1.21 g, 89%).
MS(ESI,pos.ion)m/z:379.2[M+H] + 。
Fifth step Synthesis of 6-amino-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methylisoindol-1-one
Palladium on carbon (1 g,10 mass%) was added to a solution of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methyl-6-nitroisoindol-1-one (1.21 g,3.20 mmol) in MeOH (60 mL), hydrogen was allowed to stir at room temperature overnight, filtered, the filter cake rinsed with DCM/MeOH (10/1, 100 mL. Times.2), the filtrate concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/34) to give the title compound as a white solid (720 mg, 64.86%).
MS(ESI,pos.ion)m/z:349.3[M+H] + 。
Sixth step Synthesis of N- (ethylsulfonyl) -N- (2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methyl-3-oxoisoindol-5-yl) ethylsulfonamide
Ethylsulfonyl chloride (0.85 mL,9.0 mmol) was added to a solution of 6-amino-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methylisoindol-1-one (618 mg,1.774 mmol) and triethylamine (1.5 mL,11 mmol) in DCM (40 mL) at 0deg.C, stirred at room temperature overnight, then water (1 mL) was added, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/35) to give the title compound as a yellow solid (950 mg, 100%).
MS(ESI,pos.ion)m/z:533.3[M+H] + 。
Seventh step Synthesis of N- (2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methyl-3-oxoisoindol-5-yl) ethanesulfonamide
Sodium hydroxide (1.696 g,42.40 mmol) in water (25 mL) was added to a solution of N- (ethylsulfonyl) -N- (2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methyl-3-oxoisoindol-5-yl) ethylsulfonamide (950 mg,1.784 mmol) in THF (25 mL), reacted for 1 hour at room temperature with stirring, water (50 mL) was added, then extracted with DCM (50 mL x 6), the organic phase was collected, washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, the organic phase concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/32) to give the title compound as a white solid (79 mg, 10.05%).
MS(ESI,pos.ion)m/z:441.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)9.31(s,1H),8.93(s,1H),8.60(d,J＝8.3Hz,1H),8.06(t,J＝8.0Hz,1H),7.90(d,J＝7.5Hz,1H),7.69(s,1H),7.62(s,1H),5.51(dt,J＝13.3,6.6Hz,1H),5.09(s,2H),3.15(q,J＝7.3Hz,2H),2.46(s,3H),1.56(d,J＝6.7Hz,6H),1.27(t,J＝7.3Hz,3H)；
13 C NMR(151MHz,DMSO-d 6 ):δ(ppm)167.3,151.5,150.5,146.4,143.7,140.0,139.9,139.3,136.7,131.1,126.4,120.1,119.4,113.9,49.6,48.8,47.1,23.8,19.4,8.5。
Example 6N- (2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methyl-1-oxoisoindol-4-yl) ethylsulfonamide
First step Synthesis of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methyl-4-nitroisoindol-1-one
KNO at 0 DEG C 3 (456.6 mg,4.516 mmol) was added to a solution of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methylisoindol-1-one (1.2 g,3.6 mmol) in sulfuric acid (10 mL, 98%) and reacted overnight at 0℃with stirring, the reaction mixture was then added to ice water (200 mL), naHCO 3 pH=8, DCM/MeOH (10/1, 200 mL. Times.4) extraction, organic phase concentration After drying, column chromatography purification (MeOH/DCM (v/v) =1/50) afforded the title compound as a white solid (1.21 g, 89%).
MS(ESI,pos.ion)m/z:379.2[M+H] + 。
Second step Synthesis of 4-amino-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methylisoindol-1-one
Palladium on carbon (1 g,10 mass%) was added to a solution of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methyl-6-nitroisoindol-1-one (1.21 g,3.20 mmol) in MeOH (60 mL), hydrogen was allowed to stir at room temperature overnight, filtered, the filter cake rinsed with DCM/MeOH (10/1, 100 mL. Times.2), the filtrate concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/34) to give the title compound as a white solid (720 mg, 64.86%).
MS(ESI,pos.ion)m/z:349.3[M+H] + 。
Step three Synthesis of N- (ethylsulfonyl) -N- (2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methyl-1-oxoisoindol-4-yl) ethylsulfonamide
Ethylsulfonyl chloride (0.85 mL,9.0 mmol) was added to a solution of 6-amino-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methylisoindol-1-one (618 mg,1.774 mmol) and triethylamine (1.5 mL,11 mmol) in DCM (40 mL) at 0deg.C, stirred at room temperature overnight, then water (1 mL) was added, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/35) to give the title compound as a yellow solid (950 mg, 100%).
MS(ESI,pos.ion)m/z:533.3[M+H] + 。
Fourth step Synthesis of N- (2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-methyl-1-oxoisoindol-4-yl) ethylsulfonamide
Sodium hydroxide (1.696 g,42.40 mmol) in water (25 mL) was added to a solution of N- (ethylsulfonyl) -N- (2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methyl-3-oxoisoindol-5-yl) ethylsulfonamide (950 mg,1.784 mmol) in THF (25 mL), reacted for 1 hour at room temperature with stirring, water (50 mL) was added, then extracted with DCM (50 mL x 6), the organic phase was collected, washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, the organic phase concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/32) to give the title compound as a white solid (14.5 mg, 1.85%).
MS(ESI,pos.ion)m/z:441.1[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 ):δ(ppm)9.45(s,1H),8.92(s,1H),8.60(d,J＝8.4Hz,1H),8.08(t,J＝8.0Hz,1H),7.98(d,J＝7.6Hz,1H),7.71(d,J＝7.7Hz,1H),7.51(d,J＝7.7Hz,1H),5.71(dt,J＝13.3,6.6Hz,1H),5.27(s,2H),3.24(q,J＝7.1Hz,2H),2.50(s,3H),1.60(d,J＝6.6Hz,6H),1.34(t,J＝7.2Hz,3H)；
13 C NMR(151MHz,DMSO-d 6 ):δ(ppm)167.1,151.3,150.2,146.4,143.8,142.4,141.8,140.1,132.1,131.9,131.3,122.9,119.1,113.8,49.6,49.0,48.7,23.7,18.7,8.6。
Example 7N- (2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3-oxoisoindol-5-yl) ethylsulfonamide
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First step Synthesis of methyl 6- (6-nitro-1-oxoisoindol-2-yl) picolinate
Xantphos (655.3 mg,1.133 mmol), pd 2 (dba) 3 (516.2 mg,0.5637 mmol) and Cs 2 CO 3 (7.338 g,22.52 mmol) was added sequentially to a solution of 6-nitroisoindol-1-one (2.018 g,11.33 mmol) and methyl 6-bromopyridine-2-carboxylate (2.457 g,11.35 mmol) in 1, 4-dioxane (100 mL), reacted at 80℃for 9 hours with stirring, the reaction concentrated to dryness, and then purified by column chromatography (EtOAc/PE (v/v) =1/2) to give the title compound as a yellow solid (760 mg, 21.41%).
MS(ESI,pos.ion)m/z:314.2[M+H] + 。
Second step Synthesis of methyl 6- (6-amino-1-oxoisoindol-2-yl) picolinate
Methyl 6- (6-nitro-1-oxo-isoindol-2-yl) pyridine-2-carboxylate (760 mg,2.426 mmol), palladium on carbon (500 mg,10 mass%) and MeOH (50 mL), hydrogen were reacted for 12 hours with stirring at room temperature, filtered, the filter cake rinsed with DCM (100 ml×2), the filtrate concentrated to dryness and then purified by column chromatography (EtOAc/PE (v) =1/1) to give the title compound as a white solid (258 mg, 37.54%).
MS(ESI,pos.ion)m/z:284.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.88–8.80(m,1H),7.90–7.83(m,2H),7.33(d,J＝8.1Hz,1H),7.18(d,J＝2.0Hz,1H),6.95(dd,J＝8.1,2.1Hz,1H),5.10(s,2H),4.00(s,3H),3.88(s,2H)。
Third step Synthesis of 6- (6-amino-1-oxoisoindol-2-yl) pyridine formylhydrazine
Hydrazine hydrate (0.4 mL,8mmol,98 mass%) was added to a solution of methyl 6- (6-amino-1-oxoisoindol-2-yl) picolinate (258 mg,0.9107 mmol) in EtOH (25 mL) and the reaction was stirred at 80℃for 4 h and the reaction solution was concentrated to dryness to give the title compound as a white solid which was used directly in the next reaction.
MS(ESI,pos.ion)m/z:284.2[M+H] + 。
Synthesis of fourth step (E) -N' - (2- (6- ((E) -2- ((dimethylamino) methylene) hydrazinocarbonyl) pyridin-2-yl) -3-oxoisoindol-5-yl) -N, N-dimethylformamide
A solution of 6- (6-amino-1-oxoisoindol-2-yl) pyridine formylhydrazine (570 mg,2.012 mmol) and DMF-DMA (2 mL,15.06 mmol) in ACN (25 mL) was added to the reaction flask and the reaction was stirred at 90℃for 4 hours, and the reaction solution was concentrated to dryness to give the title compound as a brown oil which was used directly in the next reaction.
MS(ESI,pos.ion)m/z:394.3[M+H] + 。
Fifth step Synthesis of 6-amino-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) isoindol-1-one
Propan-2-amine (1 mL,12 mmol) was added to a solution of (E) -N' - (2- (6- ((E) -2- ((dimethylamino) methylene) hydrazinocarbonyl) pyridin-2-yl) -3-oxoisoindol-5-yl) -N, N-dimethylformamide (79mg, 2.008 mmol) and acetic acid (0.15 mL,2.6 mmol) in ACN (50 mL) and the reaction was stirred overnight at 90℃in a sealed bottle, the reaction concentrated to dryness and then purified by column chromatography (MeOH/DCM (v/v) =1/34) to give the title compound as a pale yellow solid (242 mg, 36.04%).
MS(ESI,pos.ion)m/z:335.2[M+H] + 。
Sixth step Synthesis of N- (ethylsulfonyl) -N- (2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3-oxoisoindol-5-yl) ethanesulfonamide
To a solution of 6-amino-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) isoindol-1-one (200 mg,0.5981 mmol) and TEA (0.4 mL,3 mmol) in DCM (20 mL) at 0 ℃ was added ethanesulfonyl chloride (0.2 mL,2 mmol), stirred at room temperature, reacted overnight, meOH (2 mL) was added, concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/35) to give the title compound as a yellow solid (81 mg, 26.11%).
MS(ESI,pos.ion)m/z:519.1[M+H] + 。
Seventh step Synthesis of N- (2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3-oxoisoindol-5-yl) ethylsulfonamide
NaOH (167 mg,4.1753 mmol) in water (2.5 mL) was added to a solution of N- (ethylsulfonyl) -N- (2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3-oxoisoindol-5-yl) ethanesulfonamide (81 mg,0.1562 mmol) in THF (2.5 mL), stirred at room temperature for 1 hour, pH=7.0 with 0.1M HCl, then water (30 mL) was added, DCM (50 mL. Times.6) was added and the organic phase concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as an off-white solid (30 mg, 45.03%).
MS(ESI,pos.ion)m/z:427.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)10.14(s,1H),8.92(s,1H),8.61(d,J＝8.4Hz,1H),8.07(t,J＝8.0Hz,1H),7.91(d,J＝7.5Hz,1H),7.70(d,J＝8.2Hz,1H),7.65(d,J＝1.4Hz,1H),7.54(dd,J＝8.2,1.7Hz,1H),5.57–5.44(m,1H),5.11(s,2H),3.18–3.11(m,2H),1.56(d,J＝6.7Hz,6H),1.21(t,J＝7.2Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 ):δ(ppm)167.3,151.4,150.6,146.4,143.7,140.0,139.3,137.0,133.5,125.4,124.8,119.6,114.0,113.8,49.7,48.8,45.8,23.8,8.5。
Example 8 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (methylsulfonyl) isoindolin-1-one
First step Synthesis of N- (4-fluorophenyl) pyridine carboxamide
Picolinic acid (5.90 g,47.94 mmol), HATU (22.77 g,59.93 mmol) and Et 3 N (6.05 g,59.93 mmol) was added sequentially to a solution of (4-fluorophenyl) methylamine (5.00 g,39.95 mmol) in DCM (300 mL), the reaction was stirred at room temperature overnight, water (200 mL) was added, then DCM (500 mL. Times.3) was extracted, the organic phase was washed with brine (100 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, then purified by column chromatography (EtOAc/PE (v/v) =1/5) to give the title compound as a colorless liquid (9.30 g, 100.0%).
MS(ESI,pos.ion)m/z:231.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)9.37(t,J＝5.9Hz,1H),8.64(d,J＝4.6Hz,1H),8.06(d,J＝7.7Hz,1H),7.99(t,J＝7.6Hz,1H),7.63–7.56(m,1H),7.38(dd,J＝8.2,5.8Hz,2H),7.13(t,J＝8.8Hz,2H),4.49(d,J＝6.4Hz,2H)。
Second step Synthesis of 6-fluoroisoindolin-1-one
Diethyl azodicarboxylate (3.03 g,17.40 mmol), pivalic acid (1.77 g,17.40 mmol), ag 2 CO 3 (4.78 g,17.40 mmol) and Co (OAc) 2 -4H 2 O (0.43 g,1.74 mmol) was added sequentially to a solution of N- (4-fluorophenyl) pyridine carboxamide (2.00 g,8.69 mmol) in TFE (20 mL), reacted at 120℃for 25 hours under stirring in an autoclave, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/50) to give the title compound as a white solid (0.50 g, 38.0%).
MS(ESI,pos.ion)m/z:152.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.71(s,1H),7.62(dd,J＝8.0,4.7Hz,1H),7.45(dd,J＝14.8,5.2Hz,2H),4.36(s,2H)。
Third step Synthesis of 6-fluoro-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) isoindolin-1-one
2-bromo-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine (1.15 g,4.30 mmol), BINAP (0.62 g,0.99 mmol), cs 2 CO 3 (2.15 g,6.62 mmol) and Pd (OAc) 2 (0.22 g,0.99 mmol) was added sequentially to a solution of 6-fluoroisoindolin-1-one (0.50 g,3.31 mmol) in 1, 4-dioxane (20 mL), the reaction was stirred at reflux for 5 h, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a grey solid (1.05 g, 94.1%).
MS(ESI,pos.ion)m/z:338.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.94(s,1H),8.62(d,J＝8.3Hz,1H),8.09(t,J＝7.9Hz,1H),7.93(d,J＝7.4Hz,1H),7.81(dd,J＝8.2,4.6Hz,1H),7.67–7.57(m,2H),5.61–5.52(m,1H),5.15(s,2H),1.57(d,J＝6.7Hz,6H)。
Fourth step Synthesis of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (methylthio) isoindolin-1-one
Sodium methyl mercaptide (0.25 g,3.63 mmol) was added to a solution of 6-fluoro-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) isoindolin-1-one (1.02 g,3.02 mmol) in DMF (20 mL), stirred at 80 ℃ for overnight, water (50 mL) was added, then EA (200 mL x 3) was extracted, the organic phase was washed with brine (100 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate concentrated to dryness, and then column chromatography was performed (MeOH/DCM (v/v) =1/30) to give the title compound as a grey solid (0.31 g, 28.0%).
MS(ESI,pos.ion)m/z:366.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.93(s,1H),8.63(d,J＝8.3Hz,1H),8.08(t,J＝8.0Hz,1H),7.92(d,J＝7.5Hz,1H),7.69–7.60(m,3H),5.62–5.52(m,1H),5.12(s,2H),2.58(s,3H),1.57(d,J＝6.7Hz,6H)。
Fifth step Synthesis of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl-6- (methylsulfonyl) isoindolin-1-one
m-CPBA (0.33 g,1.92 mmol) was added to a solution of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (methylthio) isoindolin-1-one (0.28 g,0.77 mmol) in DCM (30 mL), stirred at room temperature for 10 hours, saturated aqueous sodium thiosulfate (50 mL) was added, DCM (200 ml×3) was extracted, the organic phase brine (100 ml×2) was washed, the organic phase dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness, then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a white solid (0.18 g, 59.0%).
MS(ESI,pos.ion)m/z:398.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.94(s,1H),8.64(d,J＝8.3Hz,1H),8.32(s,1H),8.27(dd,J＝8.0,1.6Hz,1H),8.11(t,J＝8.0Hz,1H),8.05(d,J＝8.0Hz,1H),7.95(d,J＝7.6Hz,1H),5.62–5.52(m,1H),5.29(s,2H),3.35(s,3H),1.58(d,J＝6.7Hz,6H)；
13 C NMR(151MHz,DMSO-d 6 ):δ(ppm)166.3,151.1,150.5,147.1,146.4,143.8,141.8,140.2,133.5,131.6,125.9,122.9,119.9,114.2,50.4,48.9,43.9,23.8。
Example 9 7- (4-cyclopropyl-1H-imidazol-1-yl) -2- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylphthalazin-1 (2H) -one
First step Synthesis of tert-butyl 1- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) hydrazinecarboxylate
Cs is processed by 2 CO 3 (14.13 g,43.37 mmol), BINAP (851.6 mg, 1.365 mmol) and Pd (OAc) 2 (316.6 mg,1.410 mmol) was added sequentially to a solution of 3- (3-bromophenyl) -4-isopropyl-1, 2, 4-triazole (3.9 g,15 mmol) and tert-butyl N-carbamate (3.31 g,25.0 mmol) in 1, 4-dioxane (100 mL), the reaction was stirred at 100deg.C for 4 hours, the reaction was concentrated to dryness, DCM/MeOH (10:1, 200 mL), filtered, the filter cake rinsed with DCM/MeOH (10:1, 200 mL. Times.4), the filtrate concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a yellowish-brown solid (1.5 g, 32.0%).
MS(ESI,pos.ion)m/z:318.1[M+H] + 。
Second step Synthesis of 3- (3-hydrazinophenyl) -4-isopropyl-4H-1, 2, 4-triazole
A solution of HCl in 1, 4-dioxane (30 mL,120mmol,4 mol/L) was added to a solution of tert-butyl 1- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) hydrazinocarboxylate (1.5 g,4.7 mmol) in DCM (6 mL), the reaction was stirred at RT overnight, the reaction was concentrated to dryness, etOAc (50 mL) was added, hydrochloric acid (0.5M, 50 mL. Times.3) was washed, and the organic phase was concentrated to dryness to give the title compound which was used directly in the next reaction.
MS(ESI,pos.ion)m/z:218.1[M+H] + 。
Third step of synthesis of N, N-diisopropyl-4-methylbenzamide
N-isopropyl-2-amine (8.8 mL,63 mmol) and TEA (14 mL,101 mmol) were added sequentially to a solution of 4-methylbenzoyl chloride (8.11 g,52.5 mmol) in DCM (100 mL) at 0deg.C, the reaction was stirred at room temperature overnight, meOH (4 mL) was added, the reaction was concentrated to dryness, and then purified by column chromatography (EtOAc/PE (v/v) =1/20) to give the title compound as a white solid (10.54 g, 91.6%).
MS(ESI,pos.ion)m/z:220.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 )δ(ppm)7.22–7.14(m,4H),4.08–3.22(m,2H),2.35(s,3H),1.67–0.91(m,12H)。
Fourth step Synthesis of 2-formyl-N, N-diisopropyl-4-methylbenzamide
A solution of N-butyllithium in N-hexane (23 mL,58mmol,2.5 mol/L) was added to a solution of N, N-diisopropyl-4-methylbenzamide (10.54 g,48.06 mmol) in THF (200 mL) at-78deg.C, stirred for 1.5 hours, DMF (4.264 g,58.34 mmol) in THF (15 mL) was added, and the mixture was heated to-50deg.C and stirred for 2 hours, saturated NH was added 4 Aqueous Cl (4 mL), the reaction was concentrated to dryness, and then purified by column chromatography (EtOAc/PE (v/v) =1/10) to give the title compound as a pale yellow solid (8.67 g, 72.9%).
MS(ESI,pos.ion)m/z:248.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 ):δ(ppm)10.06(s,1H),7.73(s,1H),7.42(d,J＝7.7Hz,1H),7.18(d,J＝7.7Hz,1H),3.65–3.48(m,2H),2.43(s,3H),1.59(d,J＝6.8Hz,6H),1.08(d,J＝6.7Hz,6H)。
Fifth step Synthesis of 2-formyl-N, N-diisopropyl-4-methyl-5-nitrobenzamide
To KNO 3 (1.540 g,15.29 mmol) was added to a solution of 2-formyl-N, N-diisopropyl-4-methylbenzamide (3.03 g,12.3 mmol) in sulfuric acid (12 mL,98 mass%) and reacted at 0℃for 9 hours with stirring, then the reaction solution was added to ice water (200 mL), naHCO 3 The pH was adjusted to 8, then DCM (150 ml×4) extracted, the organic phase concentrated to dryness, and then purified by column chromatography (EtOAc/PE (v/v) =1/6) to give the title compound as a yellow solid (2.566 g, 71.6%).
MS(ESI,pos.ion)m/z:293.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 ):δ(ppm)10.11(s,1H),7.91(s,1H),7.82(s,1H),3.65–3.51(m,2H),2.66(s,3H),1.59(d,J＝6.8Hz,6H),1.14(d,J＝6.6Hz,6H)；
13 C NMR(151MHz,CDCl 3 ):δ(ppm)189.0,165.8,151.8,139.6,134.7,134.1,133.9,122.4,51.6,46.6,20.6,20.3,20.0。
Sixth step Synthesis of 2- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-7-nitrophthalazin-1 (2H) -one
A solution of 2-formyl-N, N-diisopropyl-4-methyl-5-nitrobenzamide (1.51 g,5.17 mmol), 3- (3-hydrazinophenyl) -4-isopropyl-4H-1, 2, 4-triazole (1.93 g,8.88 mmol) and HCl (8 mL,36 mass%) in 1, 4-dioxane (10 mL) was added to a 50mL autoclave, the reaction was stirred at 100deg.C overnight, the reaction concentrated to dryness, and the mixture was added to DCM (200 mL), saturated NaHCO 3 The aqueous solution was adjusted to pH 7-8, extracted with DCM (50 ml×4), the organic phase concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/37) to give the title compound as a brown solid (431 mg, 21.4%).
MS(ESI,pos.ion)m/z:391.2[M+H] + 。
Seventh step Synthesis of 7-amino-2- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylparaben-diazin-1 (2H) -one
A suspension of 2- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-7-nitrophthalazin-1 (2H) -one (431 mg,1.104 mmol) and palladium on carbon (400 mg,10 mass%) in MeOH was added to the reaction flask, protected by hydrogen, stirred at room temperature for 5 hours, filtered, the filter cake washed with DCM/MeOH (10:1, 50 mL. Times.4) and the filtrate concentrated to dryness to give the title compound as a brown solid (340 mg, 85.45%).
MS(ESI,pos.ion)m/z:361.1[M+H] + 。
Eighth step Synthesis of N- (3- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -7-methyl-4-oxo-3, 4-dihydro-phthalazin-6-yl) carboxamide
Formic acid (2 mL,53.0 mmol) and Ac 2 O (4 mL,42.3 mmol) was added to the flask, reacted at 65℃for 1 hour with stirring and then allowed to stand at room temperature to give the mixed anhydride for use.
The mixed anhydride (1 mL) was added to a suspension of 7-amino-2- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylphthalazin-1 (2H) -one (340 mg,0.9434 mmol) in THF (12 mL) at 0deg.C, the reaction was stirred at room temperature overnight, the reaction concentrated to dryness, saturated NaHCO 3 The aqueous solution was adjusted to pH 7-8, the reaction was concentrated to dryness, then DCM/MeOH (10:1, 80 mL) was added, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give the title compound as a brown solid which was used directly in the next reaction.
MS(ESI,pos.ion)m/z:389.1[M+H] + 。
Synthesis of N- (2-cyclopropyl-2-oxoethyl) -N- (3- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -7-methyl-4-oxo-3, 4-dihydro-phthalazin-6-yl) carboxamide in the ninth step
Will K 2 CO 3 (413.3 mg, 2.99mmol) and KI (174.7 mg,1.052 mmol) were added sequentially to a mixture of N- (3- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -7-methyl-4-oxo-3, 4-dihydro-phthalazin-6-yl) carboxamide (366 mg,0.9423 mmol) and 2-bromo-1-cyclopropyl-ethanone (482.6 mg,2.961 mmol) in DMF (8 mL), the reaction was stirred at room temperature and concentrated to dryness, and then purified by column chromatography (MeOH/DCM) =1/30) to give the title compound as a brown solid (153 mg, 34.51%).
MS(ESI,pos.ion)m/z:471.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.35(d,J＝2.5Hz,2H),8.29(s,1H),8.26(s,1H),7.95(s,1H),7.88–7.82(m,1H),7.71(s,1H),7.65–7.59(m,2H),4.80(s,2H),4.68–4.57(m,1H),2.59(s,3H),2.01–1.91(m,1H),1.53(d,J＝6.7Hz,6H),1.11–1.07(m,2H),1.00–0.93(m,2H)。
Tenth step Synthesis of 7- (4-cyclopropyl-1H-imidazol-1-yl) -2- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylphthalazin-1 (2H) -one
Will be Acetic acid Ammonium (342.7 mg, 4.4476 mmol) to a solution of N- (2-cyclopropyl-2-oxoethyl) -N- (3- (3- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) phenyl) -7-methyl-4-oxo-3, 4-dihydro-phthalazin-6-yl) carboxamide (143 mg,0.3039 mmol) in acetic acid (6 mL) was added, the reaction was stirred overnight at 115℃and concentrated to dryness, water (30 mL) was added, saturated NaHCO 3 The aqueous solution was adjusted to pH 7-8, then extracted with DCM (50 ml×5) and the organic phase concentrated to dryness, then purified by column chromatography (MeOH/DCM (v/v) =1/26) to give the title compound as a white solid (33.4 mg, 24.3%).
MS(ESI,pos.ion)m/z:452.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.36(s,1H),8.30(s,2H),7.97(s,1H),7.92–7.83(m,1H),7.73(s,1H),7.67–7.60(m,2H),7.58(s,1H),6.88(s,1H),4.73–4.52(m,1H),2.45(s,3H),1.96–1.87(m,1H),1.52(d,J＝6.7Hz,6H),0.94–0.79(m,4H)；
13 C NMR(101MHz,CDCl 3 ):δ(ppm)158.3,152.8,145.6,142.0,141.3,140.4,140.3,137.8,136.6,129.4,129.1,129.0,128.2,127.7,127.6,126.8,126.0,124.7,115.5,47.9,24.0,18.7,8.8,7.2。
Example 10N- (3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-3, 4-dihydro-phthalazin-6-yl) ethylsulphonamide
First step Synthesis of tert-butyl 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) hydrazinecarboxylate
Tert-butyl N-carbamate (1.23 g,9.31 mmol), pd (OAc) 2 (174.2 mg,0.7759 mmol), BINAP (472.0 mg,0.7580 mmol) and Cs 2 CO 3 (3.81 g,11.7 mmol) was added sequentially to a solution of 2-bromo-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine (2.01 g,0.8042 mmol) in 1, 4-dioxane (35 mL), under nitrogen, stirred at 100deg.C for 4 hours, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/50) to give the title compound as a brown oil (2.10 g, 87.7%).
MS(ESI,pos.ion)m/z:319.3[M+H] + 。
Second step Synthesis of 2-hydrazino-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine
Aqueous HCl (6.5 mL,78 mmol) was added to a solution of tert-butyl 1- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) carbazate (2.10 g,6.60 mmol) in DCM (25 mL) and the reaction was stirred at RT for 1H, concentrated to dryness and saturated NaHCO 3 The aqueous solution was adjusted to pH 8, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/10) to give the title compound as a brown oil (1.14 g, 79.2%).
MS(ESI,pos.ion)m/z:219.2[M+H] + 。
Third step Synthesis of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methyl-7-nitrophthalazin-1 (2H) -one
2-formyl-N, N-diisopropyll-4-methyl-5-nitrobenzamide (1.83 g,6.26 mmol) and HCl solution (4.5 mL,54 mmol) were added sequentially to a solution of 2-hydrazino-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine (1.14 g,5.22 mmol) in 1, 4-dioxane (20 mL) at 0deg.C, the reaction was stirred overnight in a sealed tube and concentrated to dryness, then column chromatography was performed to purify (MeOH/DCM (v/v) =1/20) to give the title compound as a pale yellow solid (1.21 g, 59.2%).
MS(ESI,pos.ion)m/z:392.2[M+H] + 。
Fourth step Synthesis of 7-amino-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methylphthalazin-1 (2H) -one
Palladium on carbon (400 mg,10 mass%) was added to a solution of 2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methyl-7-nitrophthalazin-1 (2H) -one (1.21 g,3.09 mmol) in MeOH, hydrogen protected, stirred at room temperature overnight, filtered, the filtrate concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/15) to give the title compound as a pale yellow solid (1.08 g, 96.7%).
MS(ESI,pos.ion)m/z:362.2[M+H] + 。
Fifth step Synthesis of N- (3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-3, 4-dihydro-phthalazin-6-yl) ethylsulfonamide
Ethanesulfonyl chloride (360.2 mg,2.80 mmol) and TEA (280.2 mg,2.769 mmol) were added to a solution of 7-amino-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methylphthalazin-1 (2H) -one (200.2 mg,0.5540 mmol) in DCM (25 mL) at 0deg.C, the reaction stirred at room temperature overnight, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/10) to give the title compound as a pale yellow solid (23.8 mg, 9.5%).
MS(ESI,pos.ion)m/z:454.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)9.67(s,1H),8.96(s,1H),8.49(s,1H),8.27(s,1H),8.25–8.17(m,2H),7.90(s,1H),7.82(d,J＝6.6Hz,1H),5.44-5.34(m,1H),3.25(q,J＝7.1Hz,2H),2.53(s,3H),1.44(d,J＝6.4Hz,6H),1.27(t,J＝7.1Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 ):δ(ppm)158.6,153.4,150.3,147.1,143.9,140.8,140.4,139.3,138.8,129.8,127.1,126.7,123.5,122.4,119.2,49.0,47.4,23.5,19.2,8.5。
Example 11N- (2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1-oxo-1, 2-dihydroisoquinolin-7-yl) ethylsulfonamide
Ethanesulfonyl chloride (15.2 mg,0.12 mmol) and Et 3 N (0.1 mL,0.7 mmol) was added sequentially to DC of 7-amino-2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) isoquinolin-1 (2H) -one (41.2 mg,0.12 mmol)M (8 mL, 98%) and the reaction stirred at room temperature for 48 hours and the reaction concentrated to dryness to give the title compound as a white solid (32 mg, 61.4%).
MS(ESI,pos.ion)m/z:439.3[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.92(s,1H),8.19(dd,J＝14.2,7.3Hz,3H),7.98(dd,J＝6.8,2.0Hz,1H),7.74(dd,J＝8.1,3.3Hz,2H),7.65(dd,J＝8.6,2.1Hz,1H),6.78(d,J＝7.6Hz,1H),5.36–5.26(m,1H),3.15(d,J＝7.3Hz,2H),1.48(d,J＝6.7Hz,6H),1.21(t,J＝7.3Hz,3H)；
13 C NMR(101MHz,DMSO-d 6 ):δ(ppm)161.0,151.9,150.3,147.4,143.9,139.9,138.3,133.3,129.9,128.3,127.1,125.8,123.1,122.7,116.9,106.3,48.9,45.9,23.6,8.5。
Example 12N- (3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-3, 4-dihydro-quinazolin-6-yl) acetamide
6-amino-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methylquinazolin-4 (3H) -one (80.3 mg,0.22 mmol) and acetic anhydride (5 mL,53.2 mmol) were added to a reaction flask, and the reaction was stirred at 80℃for 1 hour, and the reaction mixture was added to saturated NaHCO 3 Ethyl acetate (200 mL) was extracted from aqueous (100 mL), the organic phase dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated to dryness, followed by column chromatography purification (MeOH/DCM (v/v) =1/20) to give the title compound as a white solid (80 mg, 89.3%).
MS(ESI,pos.ion)m/z:404.3[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)9.61(s,1H),8.93(s,1H),8.60(s,1H),8.42(s,1H),8.25(d,J＝4.4Hz,2H),7.96(s,1H),7.64(s,1H),5.38–5.27(m,1H),2.43(s,3H),2.14(s,3H),1.47(d,J＝6.7Hz,6H)；
13 C NMR(151MHz,DMSO-d 6 ):δ(ppm)169.3,159.8,150.1,149.5,147.6,145.3,144.6,144.0,140.4,140.1,136.9,129.1,123.9,123.1,121.2,120.1,49.0,26.0,24.0,23.6,18.9。
Example 13N- (3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-3, 4-dihydro-quinazolin-6-yl) methylsulfonamide
Methanesulfonyl chloride (54.3 mg,0.47 mmol) and Et 3 N (0.2 mL,1.4 mmol) was added sequentially to a solution of 6-amino-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methylquinazolin-4 (3H) -one (100.2 mg,0.28 mmol) in DCM (8 mL, 98%) and the reaction stirred at room temperature for 1H and concentrated to dryness to give the title compound as a white solid (60 mg, 49.2%).
MS(ESI,pos.ion)m/z:440.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)9.46(s,1H),8.94(s,1H),8.65(s,1H),8.26(d,J＝4.1Hz,2H),8.14(s,1H),7.99–7.94(m,1H),7.69(s,1H),5.40–5.29(m,1H),3.07(s,3H),2.51(s,3H),1.48(d,J＝6.7Hz,6H)；
13 C NMR(151MHz,DMSO-d 6 ):δ(ppm)159.7,150.1,149.4,147.6,145.9,145.6,144.0,142.5,140.4,136.0,129.8,123.9,123.1,122.3,120.6,49.0,40.5,23.6,19.2。
Example 14N- (3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-3, 4-dihydro-quinazolin-6-yl) ethylsulfonamide
Ethanesulfonyl chloride (54.3 mg,0.47 mmol) and Et 3 N (0.2 mL,1.4 mmol) was added sequentially to a solution of 6-amino-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methylquinazolin-4 (3H) -one (100.2 mg,0.28 mmol) in DCM (8 mL, 98%) and the reaction stirred at room temperature for 1H and concentrated to dryness to give the title compound as a white solid (41 mg, 32.6%).
MS(ESI,pos.ion)m/z:454.3[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)9.46(s,1H),8.95(s,1H),8.64(s,1H),8.26(d,J＝4.1Hz,2H),8.14(s,1H),8.01–7.93(m,1H),7.68(s,1H),5.37–5.27(m,1H),3.17(d,J＝7.3Hz,2H),1.48(d,J＝6.6Hz,6H),1.26(dd,J＝16.6,9.3Hz,6H)；
13 C NMR(101MHz,DMSO-d 6 ):δ(ppm)159.7,150.1,149.4,147.5,145.8,145.4,144.0,142.1,140.4,136.1,129.7,123.9,123.1,121.9,120.5,49.0,47.1,23.5,19.2,8.5。
Example 15 3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-3, 4-dihydroquinazoline-6-sulfonamide
First step Synthesis of 3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-3, 4-dihydroquinazolin-6-sulfonyl chloride
Thionyl chloride (1.0 mL,13.8 mmol) was added dropwise to water (5 mL) at 0℃and the reaction mixture was warmed to room temperature, and cuprous chloride (18.5 mg,0.187 mmol) was added thereto, followed by stirring at 5℃for 15 minutes to give a solution A.
A solution of sodium nitrite (84.5 mg,1.22 mmol) in water (1 mL) was added dropwise to a solution of 6-amino-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methylquinazolin-4 (3H) -one (400.1 mg,1.107 mmol) in hydrochloric acid (1.0 mL,12mmol, 12M) at 0deg.C and reacted for 10 minutes with stirring at-5deg.C to give solution B.
Solution a was added dropwise to solution B at-5 ℃, the reaction was stirred at 0 ℃ for 1 hour, the reaction solution was added to water (10 mL), then DCM (100 ml×5) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give the title compound as a yellow solid (75.3 mg, 15.3%). MS (ESI, pos.ion) m/z 445.1[ M+H ]] + 。
Second step Synthesis of 3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-3, 4-dihydroquinazoline-6-sulfonamide
NH at 0 DEG C 4 OH (0.5 mL,3mmol,25 mass%) was added to a solution of 3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-3, 4-dihydroquinazolin-6-sulfonyl chloride (75.3 mg,0.169 mmol) in acetonitrile (5 mL) and the reaction was stirred overnight at 0deg.C, concentrated to dryness, then EtOH (10 mL) was added and stirred for 1 hour and filtered to give the title compound as a red solid (45.2 mg, 62.8%). MS (ESI, pos.ion) m/z 426.1[ M+H ]] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.94(s,1H),8.78(s,1H),8.70(s,1H),8.27(d,J＝4.4Hz,2H),7.97(dd,J＝8.6,4.2Hz,1H),7.77(s,1H),7.70(s,2H),5.38–5.28(m,1H),2.77(s,3H),1.47(d,J＝6.7Hz,6H)；
13 C NMR(151MHz,DMSO-d 6 ):δ(ppm)159.1,149.6,149.2,148.6,147.8,147.2,143.5,143.2,141.6,140.0,130.5,126.0,123.6,122.4,119.2,48.4,23.1,20.1。
Example 16 3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (2-methoxyethoxy) quinazolin-4 (3H) -one
First step Synthesis of methyl 5-hydroxy-2-nitrobenzoate
Will H 2 SO 4 (1 mL, 98%) was added to a solution of 5-hydroxy-2-nitrobenzoic acid (3.01 g,20.2 mmol) in MeOH (20 mL), the reaction was stirred at 80℃overnight, the reaction was added to ice water (300 mL), extracted with ethyl acetate (200 mL) and the organic phase was concentrated to dryness to give the title compound as a brown oil (2.20 g, 67.9%).
MS(ESI,pos.ion)m/z:198.05[M+H] + 。
Second step Synthesis of methyl 5- (2-methoxyethoxy) -2-nitrobenzoate
Cs is processed by 2 CO 3 (6.7 g,21mmol,100 mass%) and 1-bromo-2-methoxy-ethane (2.5 g,18mmol,100 mass%) were added sequentially to a solution of methyl 5-hydroxy-2-nitrobenzoate (2.1 g,11.0 mmol) in DMF (20 mL) and stirred at room temperature The reaction was stirred for 24 hours, the reaction was added to water (300 mL), extracted with ethyl acetate (200 mL) and the organic phase was concentrated to dryness to give the title compound as a yellow solid (2.20 g, 81.0%).
MS(ESI,pos.ion)m/z:219.2[M+H] + 。
Third step Synthesis of 5- (2-methoxyethoxy) -2-nitrobenzoic acid
Water (2 mL,110 mmol) and LiOH (1.92 g,80.2 mmol) were added sequentially to a solution of methyl 5- (2-methoxyethoxy) -2-nitrobenzoate (2.0 g,7.8 mmol) in MeOH (10 mL) at 0deg.C, the reaction was stirred at room temperature for 0.5 h, HCl (10 mmol/L) was adjusted to pH 7, then the reaction was added to ice water (300 mL) and ethyl acetate (200 mL) was extracted to give the title compound as a pale yellow solid (1.72 g, 91.0%).
MS(ESI,pos.ion)m/z:240.1[M-H] - ；
Fourth step Synthesis of 5- (2-methoxyethoxy) -2-nitrobenzoyl chloride
DMF (0.1 mL) and oxalyl chloride (3.6 mL,41mmol,100 mass%) were added to a solution of 5- (2-methoxyethoxy) -2-nitrobenzoic acid (1.6 g,6.6 mmol) in DCM (20 mL) and the reaction stirred at RT for 1 h and the reaction concentrated to dryness to give the title compound as a yellow solid (1.65 g, 96.0%).
Fifth step Synthesis of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (2-methoxyethoxy) -2-nitrobenzamide
5- (2-methoxyethoxy) -2-nitrobenzoyl chloride (1.6 g,6.4mmol,100 mass%) and pyridine (0.97 g,14.0mmol,100 mass%) were added to a solution of 6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine (1.3 g,6.4 mmol) in DCM (25 mL), the reaction was stirred at room temperature for 1H, the reaction concentrated to dryness and then purified by column chromatography (MeOH/DCM (v/v) =1/20) to give the title compound as a white solid (1.3 g, 49.0%).
MS(ESI,pos.ion)m/z:427.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)11.14(s,1H),8.86(s,1H),8.22(d,J＝9.1Hz,2H),8.04(t,J＝8.0Hz,1H),7.91(d,J＝7.6Hz,1H),7.33(d,J＝2.4Hz,1H),7.28(dd,J＝9.2,2.6Hz,1H),5.71–5.59(m,1H),4.36–4.29(m,2H),3.77–3.66(m,2H),3.32(s,3H),1.41(d,J＝6.7Hz,6H)。
Sixth step Synthesis of 2-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (2-methoxyethoxy) benzamide
Palladium on carbon (220.5 mg,1.37mmol,10 mass%) was added to a solution of N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (2-methoxyethoxy) -2-nitrobenzamide (1.1 g,2.6 mmol) in methanol (25 mL), hydrogen was allowed to stir at room temperature, the reaction was filtered, the filtrate concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/20) to give the title compound as a yellow solid (600 mg, 60.0%).
MS(ESI,pos.ion)m/z:397.2[M+H] + 。
Seventh step Synthesis of 3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (2-methoxyethoxy) quinazolin-4 (3H) -one
NH is added to 4 Cl (50.0 mg,0.9mmol,100 mass%) was added to a solution of 2-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5- (2-methoxyethoxy) benzamide (0.60 g,1.32 mmol) in trimethyl orthoformate (25 mL) and the reaction was stirred at 100deg.C overnight, the reaction concentrated to dryness and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a red solid (500.0 mg, 80.0%).
MS(ESI,pos.ion)m/z:407.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm):8.94(s,1H),8.58(s,1H),8.27(s,2H),8.00–7.92(m,1H),7.73(d,J＝8.8Hz,1H),7.64(s,1H),7.58–7.49(m,1H),5.41–5.28(m,1H),4.26(s,2H),3.72(s,2H),3.34(s,3H),1.48(d,J＝6.6Hz,6H)；
13 C NMR(101MHz,DMSO-d 6 ):δ(ppm):159.9,158.2,150.1,149.5,147.6,144.0,143.9,142.2,140.4,129.7,125.1,123.8,123.1,123.0,108.1,70.7,68.2,58.7,49.0,23.6。
Example 17 6- (4-cyclopropyl-1H-imidazol-1-yl) -7-fluoro-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinazolin-4 (3H) -one
First step Synthesis of methyl 4-fluoro-2-nitrobenzoate
Will H 2 SO 4 (8 mL,147mmol,98 mass%) was added dropwise to a solution of 4-fluoro-2-nitro-benzoic acid (5.03 g,27.2 mmol) in methanol (30 mL, 741mmol), the reaction was stirred at reflux for 6 h, the reaction concentrated to dryness, etOAc (400 mL) was added, followed by water (100 mL) wash, saturated NaHCO 3 Aqueous (100 mL) and saturated aqueous NaCl (100 mL) were washed, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give the title compound as a yellow liquid (4.78 g, 88.3%).
MS(ESI,pos.ion)m/z:200.0[M+H] + ；
1 H NMR(400MHz,CDCl 3 ):δ(ppm)7.82(dd,J＝8.6,5.4Hz,1H),7.57(dd,J＝7.8,2.2Hz,1H),7.41–7.33(m,1H),3.91(s,3H)。
Second step Synthesis of 4-fluoro-2-nitrobenzamide
Methyl 4-fluoro-2-nitrobenzoate (4.78 g,24.0 mmol) and ammonia in methanol (50 mL,350mmol,7 mol/L) were added to a 250mL autoclave, the reaction was stirred at 70℃overnight, the reaction concentrated to dryness, and then purified by column chromatography (EtOAc/PE (v) =1/1) to give the title compound as a white solid (3.16 g, 71.5%).
MS(ESI,pos.ion)m/z:185.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 ):δ(ppm)7.78(dd,J＝8.1,2.4Hz,1H),7.62(dd,J＝8.5,5.3Hz,1H),7.40(td,J＝8.3,2.4Hz,1H),5.87(s,2H)。
Third step Synthesis of 4-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -2-nitrobenzamide
At 0 ℃, cs is treated 2 CO 3 (8.306 g,25.49 mmol), BINAP (1.015 g,1.630 mmol) and Pd (OAc) 2 (390.5 mg,1.739 mmol) was added sequentially to a solution of 4-fluoro-2-nitro-benzamide (3.16 g,17.2 mmol) and 2-bromo-6- (4-isopropyl-1, 2, 4-triazol-3-yl) pyridine (4.502 g,16.85 mmol) in 1, 4-dioxane (60 mL), and the mixture was stirred at 100deg.C for 7 hours Concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/35) to give the title compound as a brown solid (2.57 g, 40.4%).
MS(ESI,pos.ion)m/z:371.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.35(d,J＝7.5Hz,2H),8.11(s,1H),8.07(d,J＝7.7Hz,1H),7.95(t,J＝8.0Hz,1H),7.88(dd,J＝8.1,2.4Hz,1H),7.74(dd,J＝8.5,5.2Hz,1H),7.53–7.47(m,1H),5.49–5.41(m,1H),1.51(d,J＝6.7Hz,6H)。
Fourth step Synthesis of 2-amino-4-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) benzamide
Palladium on carbon (1 g,10 mass%) was added to a solution of 4-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -2-nitrobenzamide (2.57 g,6.94 mmol) in methanol (50 mL), hydrogen protected, stirred at room temperature overnight, filtered, the filter cake rinsed with DCM (200 mL), the filtrate concentrated to dryness, then EtOH (12 mL) was added, heated to reflux and then at room temperature filtered and the filter cake collected to give the title compound as a white solid (1.41 g, 59.7%).
MS(ESI,pos.ion)m/z:341.3[M+H] + ；
1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.36(s,1H),8.30(d,J＝8.2Hz,1H),8.21(s,1H),8.00(d,J＝7.5Hz,1H),7.90(t,J＝8.0Hz,1H),7.51(dd,J＝8.7,6.1Hz,1H),6.44(ddd,J＝12.9,9.4,2.4Hz,2H),5.83(s,2H),5.49(hept,J＝6.5Hz,1H),1.55(d,J＝6.7Hz,6H)。
Fifth step Synthesis of 2-acetamido-4-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) benzamide
Acetic anhydride (2 mL,21.29 mmol) was added to a solution of 2-amino-4-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) benzamide (1.41 g,4.14 mmol) in AcOH (10 mL), reacted at 70℃for 4 hours with stirring, and the reaction concentrated to dryness to give the title compound as a brown solid which was used directly in the next reaction.
MS(ESI,pos.ion)m/z:383.2[M+H] + 。
Sixth step Synthesis of 2-acetamido-4-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-nitrobenzamide
KNO at 0 DEG C 3 (742.9 mg,7.348 mmol) was added to a solution of 2-acetamido-4-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) benzamide (1.35 g,3.53 mmol) in sulfuric acid (20 mL,98 mass%) and reacted overnight at 0deg.C under stirring, then the reaction mixture was added to ice water (200 mL), naHCO 3 The pH was adjusted to 8, extracted with DCM/MeOH (10:1, 100 mL. Times.10), the organic phase dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness to afford the title compound as a brown solid that was used directly in the next reaction.
MS(ESI,pos.ion)m/z:428.1[M+H] + 。
Seventh step Synthesis of 2-amino-4-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-nitrobenzamide
A suspension of 2-acetamido-4-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-nitrobenzamide (1.5 g,3.5 mmol) and hydrochloric acid (20 mL,240mmol,12 mol/L) in MeOH (15 mL) was added to a reaction flask, stirred at room temperature and reacted for 7 hours, the reaction concentrated to dryness, water (150 mL) was added, naHCO 3 The pH was adjusted to 8 and then extracted with DCM/MeOH (10:1, 100 mL. Times.10), the organic phase concentrated to dryness and then purified by column chromatography (MeOH/DCM (v/v) =1/34) to give the title compound as a yellow solid (442 mg, 33.0%). MS (ESI, pos.ion) m/z 386.1[ M+H ]] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm)10.94(s,1H),8.86(s,1H),8.56(d,J＝8.6Hz,1H),8.05–7.98(m,2H),7.89–7.83(m,1H),7.73(s,2H),6.68(d,J＝14.5Hz,1H),5.69–5.57(m,1H),1.44(d,J＝6.7Hz,6H)。
Eighth step Synthesis of 2, 5-diamino-4-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) benzamide
Palladium on carbon (300 mg,10 mass%) was added to a suspension of 2-amino-4-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -5-nitrobenzamide (390 mg,1.012 mmol) in MeOH (15 mL), the reaction was stirred at room temperature for 8 hours under hydrogen protection, filtered, the filter cake rinsed with DCM/MeOH (10:1, 40 mL. Times.4) and the filtrate concentrated to dryness to afford the title compound as a brown solid for the next reaction.
MS(ESI,pos.ion)m/z:356.1[M+H] + 。
Synthesis of 6-amino-7-fluoro-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinazolin-4 (3H) -one in the ninth step
A mixture of trimethyl orthoformate (15 mL,140 mmol) of 2, 5-diamino-4-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) benzamide (360 mg,1.013 mmol) was added to the reaction flask and the reaction stirred at 100deg.C for 5 days, the reaction concentrated to dryness and then purified by column chromatography (MeOH/DCM (v/v) =1/35) to give the title compound as a yellowish brown solid (235 mg, 63.5%).
MS(ESI,pos.ion)m/z:366.2[M+H] + 。
Tenth step Synthesis of N- (7-fluoro-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-oxo-3, 4-dihydro-quinazolin-6-yl) carboxamide
Formic acid (2 mL,53.0 mmol) and Ac 2 O (4 mL,42.3 mmol) was added to the flask and reacted at 65℃for 1 hour with stirring, and then at room temperature to give the mixed anhydride for use.
The resulting mixed anhydride was added to a suspension of 6-amino-7-fluoro-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinazolin-4 (3H) -one (210 mg,0.5747 mmol) in THF (8 mL) at 0deg.C, stirred at room temperature overnight, the reaction concentrated to dryness and saturated NaHCO was added 3 The aqueous solution was adjusted to pH 8, filtered, and the filter cake was washed with water (40 mL) and the filter cake was collected to give the title compound as a white solid (115 mg, 50.86%).
MS(ESI,pos.ion)m/z:394.1[M+H] + 。
Synthesis of N- (2-cyclopropyl-2-oxoethyl) -N- (7-fluoro-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-oxo-3, 4-dihydro-quinazolin-6-yl) carboxamide in the eleventh step
Will K 2 CO 3 (86.6 mg,0.627 mmol) and KI (58.6 mg,0.353 mmol) were added to a mixture of N- (7-fluoro-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-oxo-3, 4-dihydroquinazolin-6-yl) carboxamide (115 mg,0.2923 mmol) and 2-bromo-1-cyclopropyl-ethanone (103.5 mg,0.6349 mmol) in DMF (5 mL), and the mixture was stirred at room temperature for 2 days, the reaction mixture was concentratedTo dryness, then column chromatography purification (MeOH/DCM (v/v) =1/35) gave the title compound as a yellow solid (86 mg, 61.87%).
MS(ESI,pos.ion)m/z:476.2[M+H] + 。
Twelfth step Synthesis of 6- (4-cyclopropyl-1H-imidazol-1-yl) -7-fluoro-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinazolin-4 (3H) -one
Ammonium acetate (137.9 mg,1.789 mmol) was added to a solution of N- (2-cyclopropyl-2-oxoethyl) -N- (7-fluoro-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-oxo-3, 4-dihydroquinazolin-6-yl) carboxamide (86 mg,0.1809 mmol) in acetic acid (4 mL), the reaction was stirred at 110℃overnight, the reaction concentrated to dryness, water (30 mL) was added, naHCO 3 The pH was adjusted to 8, then extracted with DCM/MeOH (10:1, 30 mL. Times.5), the organic phase concentrated to dryness under reduced pressure, and then purified by column chromatography (MeOH/DCM (v/v) =1/26) to give the title compound as a pale yellow solid (30.4 mg, 36.8%).
MS(ESI,pos.ion)m/z:457.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.94(s,1H),8.77(s,1H),8.34(d,J＝8.2Hz,1H),8.28(d,J＝3.9Hz,2H),8.01(s,1H),7.99–7.93(m,1H),7.89(d,J＝11.6Hz,1H),7.47(s,1H),5.39–5.25(m,1H),1.93–1.84(m,1H),1.48(d,J＝6.7Hz,6H),0.85–0.79(m,2H),0.75–0.67(m,2H)；
13 C NMR(151MHz,DMSO-d 6 ):δ(ppm)159.5,159.0,157.7,150.1,149.1,148.1(d,J＝12.9Hz),147.7(d,J＝10.7Hz),144.8,144.1,140.5,137.3(d,J＝4.5Hz),125.8(d,J＝13.2Hz),124.1,123.4(d,J＝2.1Hz),123.0,119.8,115.4(d,J＝1.5Hz),115.4(d,J＝21.3Hz),49.0,23.6,9.3,7.5。
Example 18N- (3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-3, 4-dihydro-quinazolin-6-yl) -2-methoxyethylsulfonamide
First step Synthesis of 2-fluoro-4-methyl-5-nitrobenzoyl chloride
Oxalyl chloride (4.20 mL,50.2 mmol) was added to a solution of 2-fluoro-4-methyl-5-nitrobenzoic acid (2.00 g,10.0 mmol) and DMF (0.15 mL,2.00 mmol) in THF (50 mL) at 0deg.C and the reaction stirred at reflux for 1 h and the reaction concentrated to dryness to give the title compound as a yellow solid (2.19 g, 100.0%).
Second step Synthesis of 2-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-methyl-5-nitrobenzamide
2-fluoro-4-methyl-5-nitrobenzoyl chloride (2.14 g,9.84 mmol) was added to a solution of 6- (4-isopropyl-1, 2, 4-triazol-3-yl) pyridin-2-amine (2.00 g,9.84 mmol) and pyridine (20 mL) in DCM (40 mL) at 0℃and stirred at room temperature for 5 hours, the pH was adjusted to 1 with HCl (3 mol/L), the separated liquid was taken up, the aqueous phase was extracted with DCM (50 mL. Times.2), the organic phase was collected, washed with brine (100 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate concentrated to dryness and then purified by column chromatography (MeOH/DCM (v) =1/30) to give the title compound as a yellow solid (3.0 g, 79.0%).
MS(ESI,pos.ion)m/z:385.1[M+H] + 。
Third step Synthesis of 2-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-methyl-5-nitrobenzamide
NH is added to 3 To a solution of 2-fluoro-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-methyl-5-nitrobenzamide (2.00 g,5.20 mmol) in DMSO (30 mL), was added water (100 mL) and the filter cake was collected to give the title compound as a yellow solid (1.90 g, 95.7%) and stirred at 100℃overnight.
MS(ESI,pos.ion)m/z:382.2[M+H] + 。
Fourth step Synthesis of 3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-6-nitroquinazolin-4 (3H) -one
NH is added to 4 Cl (0.13 g,2.49 mmol) was added to a solution of trimethyl orthoformate (50 mL) in 2-amino-N- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-methyl-5-nitrobenzamide (1.90 g,4.98 mmol), stirred at 100deg.C and reacted overnight, and the reaction concentrated to dryness to give the title compound as yellow Solid (1.90 g, 97.4%).
MS(ESI,pos.ion)m/z:392.2[M+H] + 。
Fifth step Synthesis of 6-amino-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methylquinazolin-4 (3H) -one
Fe (1.09 g,19.4 mmol) and NH 4 Cl (2.08 g,38.8 mmol) was added 3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-6-nitroquinazolin-4 (3H) -one (1.90 g,4.85 mmol) EtOH (60 mL) and H 2 In a mixed solution of O (20 ml), the reaction was stirred at 80 ℃ for 1 hour, the reaction solution was filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (1.25 g, 71.3%).
MS(ESI,pos.ion)m/z:362.2[M+H] + 。
Sixth step Synthesis of N- (3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-3, 4-dihydroquinazolin-6-yl) -2-methoxy-N- ((2-methoxyethyl) sulfonyl) ethyl sulfonamide
Et is added to 3 N (1.50 mL,11.1 mmol) and DMAP (0.054 g,0.44 mmol) were added to a solution of 6-amino-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methylquinazolin-4 (3H) -one (0.80 g,2.21 mmol) in DCM (50 mL), stirred at 0deg.C, then 2-methoxyethylsulfonyl chloride (3.51 g,22.1 mmol) was added, stirred at room temperature and reacted overnight, water (50 mL) was added, then DCM (200 mL. Times.3) was extracted, the organic phase brine (100 mL. Times.2) was washed, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (MeOH/DCM) =1/30) to give the title compound as a white solid (1.25 g, 93.2%).
MS(ESI,pos.ion)m/z:606.2[M+H] + 。
Seventh step Synthesis of N- (3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-3, 4-dihydro-quinazolin-6-yl) -2-methoxyethyl sulfonamide
NaOH (0.92 g,23.1 mmol) was added to a solution of N- (3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-3, 4-dihydroquinazolin-6-yl) -2-methoxy-N- ((2-methoxyethyl) sulfonyl) ethyl sulfonamide (0.70 g,1.16 mmol) in EtOH (15 mL) and water (12 mL), stirred at room temperature for 1 hour, the pH was adjusted to 1 with concentrated hydrochloric acid, then DCM (50 mL. Times.2) was extracted, the organic phase was washed with brine (100 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (MeOH/DCM) =1/30) to give the title compound as a white solid (0.10 g, 18.0%).
MS(ESI,pos.ion)m/z:484.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.94(s,1H),8.64(s,1H),8.26(d,J＝3.7Hz,2H),8.19(s,1H),8.00–7.95(m,1H),7.67(s,1H),5.43–5.23(m,1H),3.73(t,J＝5.8Hz,2H),3.44(d,J＝5.9Hz,2H),3.38(s,3H),3.22(s,3H),1.48(d,J＝6.6Hz,6H)；
13 C NMR(151MHz,DMSO-d 6 ):δ(ppm)159.7,150.1,149.4,147.6,145.7,145.4,140.0,142.2,140.4,136.0,129.6,123.9,123.0,121.7,120.5,66.3,58.5,52.3,49.0,23.5,19.2。
Example 19N- (1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-oxo-1, 4-dihydro-quinolin-6-yl) ethanesulfonamide
First step Synthesis of ethyl (E) -3- (dimethylamino) -2- (2-fluoro-5-nitrobenzoyl) acrylate
A solution of 2-chloro-5-nitrobenzoic acid (45.16 g,236.6 mmol) in thionyl chloride (250 mL,3.41 mol) was added to the reaction flask, the reaction was stirred under reflux for 3 hours, the thionyl chloride was removed by concentration under reduced pressure, then anhydrous toluene (300 mL) was added, and then (E) -3- (dimethylamino) acrylic acid ethyl ester (38.02 g,260.2 mmol) and Et were added 3 N (26.27, 257.0 mmol), stirred at 110deg.C for 2 hours, the reaction concentrated to dryness, and then purified by column chromatography (EtOAc/PE (v/v) =1/1) to give the title compound as a brown oil (66.51 g, 90.1%).
MS(ESI,pos.ion)m/z:311.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.35(dd,J＝5.6,2.6Hz,1H),8.23–8.15(m,1H),7.82(s,1H),7.12(t,J＝8.9Hz,1H),3.90(q,J＝7.1Hz,2H),3.32(s,3H),2.86(s,3H),0.89(t,J＝7.1Hz,3H)。
Second step Synthesis of 1-isopropyl-6-nitro-4-oxo-1, 4-dihydroquinoline-3-acrylic acid ethyl ester
Propan-2-amine (19.21 g,325.0 mmol) was added dropwise to a solution of ethyl (E) -3- (dimethylamino) -2- (2-fluoro-5-nitrobenzoyl) acrylate (66.00 g,212.7 mmol) in EtOH (300 mL), reacted at room temperature for 1 hour with stirring, the reaction solution concentrated to dryness, anhydrous DMSO (300 mL) was added, followed by K 2 CO 3 (59.31 g,429.1 mmol) was stirred at 100deg.C for 3 hours, cooled to room temperature, then the reaction mixture was added to water (300 mL), filtered, and the filter cake was rinsed with EtOAc (50 mL. Times.3) and the filter cake was collected to give the title compound as a yellow solid (44.0 g, 68.0%).
MS(ESI,pos.ion)m/z:305.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 ) Delta (ppm) 9.33 (d, j=2.7 hz, 1H), 8.67 (s, 1H), 8.47 (dd, j=9.4, 2.7hz, 1H), 7.72 (d, j=9.4 hz, 1H), 4.99-4.87 (m, 1H), 4.42 (q, j=7.1 hz, 2H), 1.66 (d, j=6.6 hz, 6H), 1.42 (t, j=7.1 hz, 3H). Third step Synthesis of 1-isopropyl-6-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid
HCl (27.4 mL,329mmol,12 mol/L) was added dropwise to a solution of ethyl 1-isopropyl-6-nitro-4-oxo-1, 4-dihydroquinoline-3-acrylate (5.01 g,16.5 mmol) in THF (25 mL), the reaction was stirred at reflux for 2h, cooled to room temperature, filtered, the filter cake rinsed with THF (5X 3 mL) and the filter cake collected to give the title compound as a yellow solid (3.41 g, 75.0%).
MS(ESI,pos.ion)m/z:277.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):9.05(d,J＝2.7Hz,1H),8.96(s,1H),8.66(dd,J＝9.5,2.8Hz,1H),8.44(d,J＝9.6Hz,1H),5.40–5.24(m,1H),1.61(d,J＝6.5Hz,6H)。
Fourth step Synthesis of 1-isopropyl-6-nitroquinolin-4 (1H) -one
A solution of 1-isopropyl-6-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (457 mg,1.640 mmol) in HCl (2 ml,20mmol, 10M) was added to the reaction flask and reacted overnight at 130℃with stirringSaturated NaHCO 3 The aqueous solution was adjusted to pH 10, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/35) to give the title compound as a yellow solid (190 mg, 49.9%).
MS(ESI,pos.ion)m/z:233.1[M+H] + ；
1 H NMR(400MHz,CDCl 3 ):δ(ppm)9.32(d,J＝2.7Hz,1H),8.46(dd,J＝9.5,2.8Hz,1H),7.76(d,J＝8.1Hz,1H),7.67(d,J＝9.5Hz,1H),6.42(d,J＝8.1Hz,1H),4.91(dt,J＝13.3,6.6Hz,1H),1.60(s,6H)。
Fifth step Synthesis of 3-bromo-1-isopropyl-6-nitroquinolin-4 (1H) -one
HCl (4 mL,10 mol/L) was added to a solution of 1-isopropyl-6-nitroquinolin-4 (1H) -one (2.01 g,8.65 mmol) in DCM (30 mL), the reaction solution was cooled to 0℃and then bromine (1.26 g,7.88 mmol) was added, the reaction was stirred at 0℃for 15 min, then stirred at room temperature overnight, water (50 mL), saturated NaHCO was added 3 The aqueous solution was adjusted to pH 8, extracted with DCM (200 mL. Times.3), the organic phase dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to dryness to give the title compound as a yellow solid (2.50 g, 93.0%).
MS(ESI,pos.ion)m/z:311.0[M+H] + 。
Sixth step Synthesis of 1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-nitroquinolin-4 (1H) -one
CsF (1.51 g,9.94 mmol), XPhos (436 mg,0.9146 mmol) and Pd 2 (dba) 3 (826.2 mg,0.9023 mmol) was added to a solution of 3-bromo-1-isopropyl-6-nitroquinolin-4 (1H) -one (1.41 g,4.53 mmol) and 2- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -6- (trimethyltin) pyridine (2.46 g,7.01 mmol) in toluene (70 mL) and the reaction was stirred at 100deg.C overnight, concentrated to dryness and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (688 mg, 36.3%).
MS(ESI,pos.ion)m/z:419.2[M+H] + 。
Seventh step Synthesis of 6-amino-1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinolin-4 (1H) -one
Palladium on carbon (107 mg,10 mass%) was added to a solution of 1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-nitroquinolin-4 (1H) -one (688.1 mg, 1.640 mmol) in EtOH (30 mL), the reaction was stirred at room temperature under hydrogen pressure in an autoclave for 4 hours at 2MPa, filtered, the filtrate concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/15) to give the title compound as a yellow solid (280 mg, 43.82%).
MS(ESI,pos.ion)m/z:389.3[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.92(s,1H),8.80(dd,J＝5.9,3.2Hz,1H),8.75(s,1H),7.97(dd,J＝8.1,5.5Hz,2H),7.73(d,J＝9.2Hz,1H),7.54(d,J＝2.6Hz,1H),7.10(dd,J＝9.1,2.6Hz,1H),5.70(dt,J＝13.5,6.7Hz,1H),5.50(s,2H),5.08(dt,J＝12.9,6.5Hz,1H),1.52(dd,J＝6.5,3.4Hz,12H)。
Eighth step Synthesis of N- (ethylsulfonyl) -N- (1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-oxo-1, 4-dihydroquinolin-6-yl) ethanesulfonamide
Et is added to 3 N (1.5 mL,11.0 mmol) was added to a solution of 6-amino-1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinolin-4 (1H) -one (100 mg,0.2574 mmol) in DCM (5 mL), then cooled to 0deg.C, ethanesulfonyl chloride (0.7 mL,7 mmol) was added, the reaction was stirred at room temperature overnight, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (120 mg, 81.4%).
MS(ESI,pos.ion)m/z:573.2[M+H] + 。
Synthesis of N- (1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-oxo-1, 4-dihydroquinolin-6-yl) ethanesulfonamide in the ninth step
NaOH (160.1 mg, 4.003mmol) was added to N- (ethylsulfonyl) -N- (1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-oxo-1, 4-dihydroquinolin-6-yl) ethanesulfonamide (120.1 g,0.2097 mmol) in THF/H 2 O (2.5 mL/2.5 mL), stirred at room temperature for 0.5 h, the reaction concentrated to dryness, and purified by column chromatography (MeOH/DCM (v/v) =1/25) to give the title compound as a white solid (70 mg, 69.5%).
MS(ESI,pos.ion)m/z:481.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)10.11(s,1H),8.93(s,1H),8.88(s,1H),8.76–8.70(m,1H),8.26(d,J＝2.5Hz,1H),8.02(t,J＝7.4Hz,3H),7.67(dd,J＝9.2,2.5Hz,1H),5.70(dt,J＝13.4,6.7Hz,1H),5.15(dt,J＝13.1,6.5Hz,1H),3.13(q,J＝7.3Hz,2H),1.54(t,J＝6.8Hz,12H),1.22(t,J＝7.3Hz,3H)；
13 C NMR(151MHz,DMSO-d 6 ):δ(ppm)173.9,153.6,150.9,147.6,143.6,139.7,138.0,135.9,135.5,129.0,125.3,123.9,121.8,118.4,117.0,116.1,51.3,48.5,45.7,23.8,22.1,8.5。
Example 20 1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-oxo-1, 4-dihydroquinoline-6-sulfonamide
First step Synthesis of 1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-oxo-1, 4-dihydroquinoline-6-sulfonyl chloride
Thionyl chloride (14.0 mmol) was added dropwise to water (5 mL) at 0deg.C, the reaction mixture was warmed to room temperature, cuprous chloride (25.1 mg,0.254 mmol) was added, and the reaction was stirred at 5deg.C for 15 minutes to give solution A.
A solution of sodium nitrite (40.1 mg,0.581 mmol) in water (1 mL) was added dropwise to a solution of 6-amino-1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinolin-4 (1H) -one (200 mg,0.515 mmol) in hydrochloric acid (1.0 mL,10mmol, 10M) at 0deg.C and reacted at-5deg.C for 10 minutes under stirring to give solution B.
Solution a was added dropwise to solution B at-5 ℃, the reaction was stirred at 0 ℃ for 4 hours, the reaction solution was added to water (10 mL), then DCM (100 ml×5) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give the title compound as a yellow solid (120 mg, 49.4%). MS (ESI, pos.ion) m/z 472.2[ M+H ]] + 。
Second step Synthesis of 1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-oxo-1, 4-dihydroquinoline-6-sulfonamide
NH at 0 DEG C 4 OH (1 mL,14mmol,25 mass%) was added to a solution of 1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4-oxo-1, 4-dihydroquinoline-6-sulfonyl chloride (120 mg,0.254 mmol) in acetonitrile (8 mL), the reaction was stirred overnight at 0deg.C, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/15) to give the title compound as a white solid (13 mg, 11.3%). MS (ESI, pos.ion) m/z 453.2[ M+H ]] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.95(d,J＝9.1Hz,2H),8.85(d,J＝2.1Hz,1H),8.72–8.67(m,1H),8.22(d,J＝9.3Hz,1H),8.15(dd,J＝9.1,2.1Hz,1H),8.08–8.01(m,2H),7.54(s,2H),5.70(dt,J＝13.5,6.8Hz,1H),5.23(dt,J＝13.2,6.5Hz,1H),1.57(d,J＝6.5Hz,7H),1.53(d,J＝6.7Hz,6H)；
13 C NMR(101MHz,DMSO-d 6 ):δ(ppm)173.7,152.5,150.4,147.3,143.2,140.6,140.5,139.5,137.7,129.0,126.9,124.7,123.6,121.8,118.2,117.7,51.3,48.0,23.3,21.5。
Example 21N- (1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-1, 4-dihydroquinolin-6-yl) ethylsulfonamide
First step Synthesis of 2-fluoro-4-methyl-5-nitrobenzoyl chloride
DMF (1.2 mL,15.76 mmol) and oxalyl chloride (20.0 mL,236.5 mmol) were added sequentially to a solution of 2-fluoro-4-methyl-5-nitrobenzoic acid (15.70 g,78.83 mmol) in DCM (300 mL) at 0deg.C and the reaction stirred at room temperature for 1 h and concentrated to dryness to give the title compound as a yellow liquid (17.15 g, 100.0%).
Second step Synthesis of (E) -3- (dimethylamino) -2- (2-fluoro-4-methyl-5-nitrobenzoyl) acrylic acid ethyl ester
2-fluoro-4-methyl-5-nitrobenzoyl chloride (17.20 g,79.05 mmol) and Et at 0deg.C 3 N (22 ml,158.1 mmol) was added sequentially to (E) -3- (dimethylamino) propeneA solution of ethyl acetate (13.58 g,94.86 mmol) in toluene (200 mL) was stirred at reflux and the reaction was concentrated to dryness, then purified by column chromatography (EA/PE (v/v) =1/5) to give the title compound as a yellow liquid (12.40 g, 48.4%).
MS(ESI,pos.ion)m/z:325.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.06(d,J＝6.5Hz,1H),7.85(s,1H),7.40(d,J＝10.6Hz,1H),3.91(q,J＝7.1Hz,2H),3.36(s,3H),2.81(s,3H),2.57(s,3H),0.94(t,J＝7.1Hz,3H)。
Third step Synthesis of 1-isopropyl-7-methyl-6-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ethyl ester
Propan-2-amine (2.26 g,38.24 mmol) and K 2 CO 3 (11.61 g,84.12 mmol) was added sequentially to a solution of ethyl (E) -3- (dimethylamino) -2- (2-fluoro-4-methyl-5-nitrobenzoyl) acrylate (12.40 g,38.24 mmol) in DMSO (200 mL), reacted overnight at 100deg.C with the addition of water (500 mL), filtered and the filter cake collected to give the title compound as a yellow solid (7.60 g, 62.4%).
MS(ESI,pos.ion)m/z:319.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.77(s,1H),8.64(s,1H),8.10(s,1H),5.27–5.02(m,1H),4.26(q,J＝7.1Hz,2H),2.72(s,3H),1.53(d,J＝6.5Hz,6H),1.30(t,J＝7.1Hz,3H)。
Fourth step Synthesis of 1-isopropyl-7-methyl-6-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid
LiOH (5.73 g,238.8 mmol) was added to a solution of ethyl 1-isopropyl-7-methyl-6-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylate (7.60 g,23.88 mmol) in MeOH (100 mL), the reaction was stirred at room temperature for 5 hours, then pH was adjusted to 7 with saturated aqueous citric acid, suction filtered and the filter cake collected to give the title compound as a yellow solid (6.60 g, 95.2%).
MS(ESI,pos.ion)m/z:291.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)14.54(s,1H),8.92(s,1H),8.87(s,1H),8.33(s,1H),5.53–5.33(m,1H),2.77(s,3H),1.59(d,J＝6.5Hz,6H)。
Fifth step Synthesis of 3-bromo-1-isopropyl-7-methyl-6-nitroquinolin-4 (1H) -one
At 0 ℃, naHCO is added 3 (13.37 g,159.1 mmol) was added to a solution of 1-isopropyl-7-methyl-6-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (6.60 g,22.74 mmol) in DMF (150 mL), stirred at 0deg.C for 1 hour, NBS (4.45 g,25.01 mmol) was added, stirred at RT overnight, water (200 mL) was added, DCM (200 mL. Times.3) was extracted, the organic phase brine (100 mL. Times.2) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness, then purified by column chromatography (MeOH/DCM (v/v) =1/100) to give the title compound as a yellow solid (5.10 g, 69.0%).
MS(ESI,pos.ion)m/z:325.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.79(s,1H),8.65(s,1H),8.10(s,1H),5.21–5.16(m,1H),2.72(s,3H),1.53(s,3H),1.51(s,3H)。
Sixth step Synthesis of 1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-6-nitroquinolin-4 (1H) -one
2- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -6- (trimethyltin) pyridine (2.14 g,6.09 mmol), X-PHOS (0.97 g,2.03 mmol), csF (1.54 g,10.15 mmol) and Pd 2 (dba) 3 (1.86 g,2.03 mmol) was added sequentially to a solution of 3-bromo-1-isopropyl-7-methyl-6-nitroquinolin-4 (1H) -one (2.20 g,6.76 mmol) in DMF (40 mL), nitrogen-protected, stirred at 100deg.C for 4 hours, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (1.50 g, 51.3%).
MS(ESI,pos.ion)m/z:433.1[M+H] + 。
Seventh step Synthesis of 6-amino-1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methylquinolin-4 (1H) -one
Palladium on carbon (0.95 g,0.90mmol, 10%) was added to a solution of 1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-6-nitroquinolin-4 (1H) -one (1.30 g,3.00 mmol) in MeOH (50 mL), protected with hydrogen, stirred at room temperature, reacted for 7 hours, filtered, the filtrate concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (0.69 g, 57.0%).
MS(ESI,pos.ion)m/z:403.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ) Delta (ppm) 8.93 (s, 1H), 8.84-8.80 (m, 1H), 8.74 (s, 1H), 7.98-7.95 (m, 2H), 7.66 (s, 1H), 7.59 (s, 1H), 5.75-5.67 (m, 1H), 5.28 (s, 2H), 5.17-5.09 (m, 1H), 2.30 (s, 3H), 1.55-1.50 (m, 12H); eighth step Synthesis of N- (1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-1, 4-dihydroquinolin-6-yl) ethylsulfonamide
To a solution of 6-amino-1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methylquinolin-4 (1H) -one (0.10 g,0.25 mmol) in DCM (10 mL) and pyridine (20 mL) was added ethanesulfonyl chloride (0.48 g,3.73 mmol), stirred at room temperature for 10 hours, hydrochloric acid (20 mL,1 n) was added, DCM (50 ml×3) was extracted, the organic phase brine (100 ml×2) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness, followed by column chromatography purification (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (0.060 g, 48.8%).
MS(ESI,pos.ion)m/z:495.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)9.31(s,1H),8.94(s,1H),8.88(s,1H),8.74(dd,J＝5.8,3.2Hz,1H),8.28(s,1H),8.03–7.99(m,2H),7.94(s,1H),5.70–5.60(m,1H),5.20–5.10(m,1H),3.15(q,J＝7.3Hz,2H),2.54(s,3H),1.56–1.52(m,12H),1.30(t,J＝7.3Hz,3H)；
13 C NMR(151MHz,DMSO-d 6 ):δ(ppm)173.9,153.6,150.9,147.6,143.7,140.2,139.9,138.0,137.4,133.2,126.9,123.9,122.9,121.8,118.5,117.2,51.0,48.5,46.6,23.8,22.2,19.5,8.5。
Example 22N- (1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-1, 4-dihydroquinolin-6-yl) acetamide
HOAc (0.030 g,0.50 mm)ol), HATU (0.28 g,0.75 mmol) and Et 3 N (0.075 g,0.75 mmol) was added sequentially to a solution of 6-amino-1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methylquinolin-4 (1H) -one (0.10 g,0.25 mmol) in DCM (30 mL), stirred at room temperature overnight, water (20 mL) was added, DCM (50 mL. Times.3) was extracted, the organic phase brine (100 mL. Times.2) was washed, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated to dryness, and then column chromatography (MeOH/DCM (v/v) =1/30) gave the title compound as a yellow solid (0.066 g, 59.8%).
MS(ESI,pos.ion)m/z:445.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)9.51(s,1H),8.94(s,1H),8.87(s,1H),8.77–8.73(m,1H),8.45(s,1H),8.02–7.99(m,2H),7.89(s,1H),5.81–5.74(m,1H),5.25–5.13(m,1H),2.43(s,3H),2.13(s,3H),1.55(dd,J＝6.3,4.4Hz,12H)；
13 C NMR(151MHz,DMSO-d 6 ):δ(ppm)174.1,169.1,153.8,151.0,147.6,143.6,139.6,138.2,137.9,136.7,134.1,126.7,123.9,122.1,121.7,117.7,116.9,50.9,48.5,23.8,22.2,19.1。
Example 23 6- (4-cyclopropyl-1H-imidazol-1-yl) -1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinolin-4 (1H) -one
First step Synthesis of N- (3-bromo-1-isopropyl-4-oxo-1, 4-dihydroquinolin-6-yl) carboxamide
Ac of HCOOH (1.5 mL,40.0 mmol) 2 A solution of O (3.0 mL,31.9 mmol) was added to the flask and stirred at 65deg.C for 1 hour, cooled to 0deg.C, a solution of 6-amino-3-bromo-1-isopropylquinolin-4 (1H) -one (800 mg,2.85 mmol) in DCM (20 mL) was added, stirred at RT for 3 hours, then saturated NaHCO 3 The aqueous solution was adjusted to pH 8, extracted with DCM (3X 100 mL), the organic phase dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to dryness to give the title compound as a white solid (879 mg, 99.9%).
MS(ESI,pos.ion)m/z:309.0[M+H] + 。
Second step Synthesis of N- (3-bromo-1-isopropyl-4-oxo-1, 4-dihydroquinolin-6-yl) -N- (2-cyclopropyl-2-oxoethyl) carboxamide
N- (3-bromo-1-isopropyl-4-oxo-1, 4-dihydroquinolin-6-yl) carboxamide (879 mg,2.84 mmol), 2-bromo-1-cyclopropylethanone (1.40 g,8.59 mmol), K 2 CO 3 (1.20 g,8.68 mmol) and KI (470 mg,2.84 mmol) were added sequentially to DMF (12 mL), stirred at room temperature and reacted overnight, filtered, the filter cake rinsed with DCM (50 mL), the filtrate concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/20) to give the title compound as a yellow oil (900 mg, 80.9%).
MS(ESI,pos.ion)m/z:391.1[M+H] + 。
Third step Synthesis of 3-bromo-6- (4-cyclopropyl-1H-imidazol-1-yl) -1-isopropylquinolin-4 (1H) -one
NH is added to 4 OAc (886 mg,11.5 mmol) is added to a solution of N- (3-bromo-1-isopropyl-4-oxo-1, 4-dihydroquinolin-6-yl) -N- (2-cyclopropyl-2-oxoethyl) carboxamide (900 mg,2.30 mmol) in AcOH (20 mL), reacted at 110℃overnight with stirring, then saturated NaHCO is added 3 The aqueous solution was adjusted to pH 8, extracted with DCM (100 ml×3), the organic phase dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness, followed by column chromatography purification (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (730 mg, 85.2%).
MS(ESI,pos.ion)m/z:372.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.57(s,1H),8.28(d,J＝2.6Hz,1H),8.21(s,1H),8.11(d,J＝9.5Hz,1H),8.04(dd,J＝9.3,2.6Hz,1H),5.15(dt,J＝13.1,6.5Hz,1H),1.90–1.82(m,1H),1.51(d,J＝6.5Hz,6H),0.84–0.78(m,2H),0.74–0.69(m,2H)。
Fourth step Synthesis of 6- (4-cyclopropyl-1H-imidazol-1-yl) -1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) quinolin-4 (1H) -one
CsF (284 mg,1.88 mmol), XPhos (89.8 mg,0.188 mmol) and Pd 2 (dba) 3 (175 mg,0.191 mmol) was added sequentially 3-bromo-6- (4-cyclopropyl-1H-imidazol-1-yl) -1-isopropylquinolin-4 (1H) -one (350 mg,0.940 mmol)In a solution of 2- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -6- (trimethyltin) pyridine (500 mg,1.43 mmol) in toluene (20 mL), the reaction was stirred at 100 ℃ overnight, the reaction was concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/20) to give the title compound as a white solid (100 mg, 22.2%).
MS(ESI,pos.ion)m/z:480.2[M+H] + ；
1 H NMR(600MHz,DMSO-d 6 ):δ(ppm)8.95(s,2H),8.75(dd,J＝6.4,2.1Hz,1H),8.46(d,J＝2.2Hz,1H),8.27(s,1H),8.18(d,J＝9.3Hz,1H),8.09(dd,J＝9.2,2.3Hz,1H),8.06–8.01(m,2H),7.66(s,1H),5.72(dt,J＝13.4,6.7Hz,1H),5.27(dt,J＝13.1,6.5Hz,1H),1.93–1.87(m,1H),1.58(d,J＝6.5Hz,6H),1.55(d,J＝6.7Hz,6H),0.85-0.81(m,2H),0.77-0.72(m,2H)；
13 C NMR(101MHz,DMSO-d 6 ):δ(ppm)173.4,152.9,150.4,147.2,145.0,143.1,139.7,137.5,137.1,134.8,133.2,128.5,124.5,123.4,121.5,118.5,117.0,116.1,112.8,51.0,48.0,23.28,2.60,8.9,7.0。
Example 24 6- (4-cyclopropyl-1H-imidazol-1-yl) -1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methylquinolin-4 (1H) -one
First step Synthesis of N- (1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-1, 4-dihydroquinolin-6-yl) carboxamide
HCOOH (0.42 ml,11.18 mmol) (Ac) 2 O (0.85 mL,8.94 mmol) was added to a reaction flask, the reaction was stirred at 70℃for 1 hour, then 6-amino-1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methylquinolin-4 (1H) -one (0.45 g,1.12 mmol) in DCM (50 mL) was added, the reaction was stirred at room temperature for 8 hours, the reaction solution was concentrated to dryness, and DCM (50 mL) was added as saturated NaHCO 3 The pH of the aqueous solution was adjusted to 7, the solution was separated, the aqueous phase was extracted with DCM (50 mL. Times.2), the organic phase was washed with brine (100 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated toThe title compound was obtained as a yellow solid (0.48 g, 100.0%).
MS(ESI,pos.ion)m/z:431.2[M+H] + 。
Second step Synthesis of N- (2-cyclopropyl-2-oxoethyl) -N- (1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-1, 4-dihydroquinolin-6-yl) carboxamide
2-bromo-1-cyclopropylethanone (1.04 g,6.39 mmol), KI (0.42 g,2.56 mmol) and Cs 2 CO 3 (1.25 g,3.83 mmol) was added sequentially to a solution of N- (1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-1, 4-dihydroquinolin-6-yl) carboxamide (0.55 g,1.28 mmol) in DMF (50 mL), stirred at 70℃overnight, the reaction concentrated to dryness and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (0.25 g, 38.0%).
MS(ESI,pos.ion)m/z:513.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.94(s,1H),8.90(d,J＝5.9Hz,1H),8.73–8.70(m,1H),8.27(d,J＝4.6Hz,2H),8.05–8.00(m,3H),5.71(dd,J＝13.4,6.8Hz,1H),5.23(dd,J＝12.9,6.5Hz,1H),3.27(s,2H),2.48(s,3H),2.12(d,J＝6.0Hz,1H),1.54(t,J＝6.7Hz,12H),1.00–0.93(m,4H)。
Third step Synthesis of 6- (4-cyclopropyl-1H-imidazol-1-yl) -1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methylquinolin-4 (1H) -one
NH is added to 4 OAc (0.19 g,2.44 mmol) was added to a solution of N- (2-cyclopropyl-2-oxoethyl) -N- (1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4-oxo-1, 4-dihydroquinolin-6-yl) carboxamide (0.25 g,0.49 mmol) in HOAc (20 mL), stirred at 150℃overnight, the reaction concentrated to dryness and DCM (50 mL) was added, saturated NaHCO 3 The aqueous solution was adjusted to pH 7, the solution was separated, the aqueous phase was extracted with DCM (50 ml×2), the organic phase was washed with brine (100 ml×2), the organic phase was dried over anhydrous sodium sulfate, and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (0.046 g, 19.0%).
MS(ESI,pos.ion)m/z:494.2[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.95(d,J＝11.0Hz,2H),8.71(dd,J＝6.0,3.1Hz,1H),8.14(d,J＝10.4Hz,2H),8.05–8.00(m,2H),7.75(s,1H),7.24(s,1H),5.75–5.66(m,1H),5.33–5.24(m,1H),2.38(s,3H),1.87(d,J＝4.6Hz,1H),1.56(dd,J＝11.4,6.6Hz,12H),0.84–0.80(m,2H),0.73(d,J＝2.7Hz,2H)；
13 C NMR(151MHz,DMSO-d 6 ):δ(ppm)173.9,153.3,150.9,147.7,144.2,143.7,140.4,139.0,138.8,138.1,137.5,134.0,126.7,123.9,123.8,122.0,119.1,117.7,116.5,48.5,23.8,22.2,18.8,9.4,7.6。
Example 25 1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (2-methoxyethoxy) quinolin-4 (1H) -one
First step Synthesis of 6-amino-3-bromo-1-isopropylquinolin-4 (1H) -one
NH is added to 4 Cl (1.08 g,20.2 mmol) and Fe (1.10 g,19.7 mmol) were added sequentially to 3-bromo-1-isopropyl-6-nitroquinolin-4 (1H) -one (1.04 g,3.34 mmol) in EtOH/H 2 O (30 mL/3 mL), the reaction was stirred at room temperature overnight, the reaction was filtered, the filtrate was concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/40) to give the title compound as a yellow solid (800 mg, 85.1%).
MS(ESI,pos.ion)m/z:281.0[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm):8.28(s,1H),7.68(d,J＝9.3Hz,1H),7.36(d,J＝2.7Hz,1H),7.08(dd,J＝9.2,2.7Hz,1H),5.48(s,2H),4.97(dt,J＝13.2,6.6Hz,1H),1.46(d,J＝6.5Hz,6H)。
Second step Synthesis of 3-bromo-6-hydroxy-1-isopropylquinolin-4 (1H) -one
Ice-cold 6-amino-3-bromo-1-isopropylquinolin-4 (1H) -one (1.07 g,3.81 mmol) sulfuric acid (2.00 mL,36.58 mol) was added to a solution of sodium nitrite (461.2 g,6.685 mmol) in water (4 mL) at 15℃with stirringStirring for 15 min, stirring at 90 deg.C for 30 min, cooling to room temperature, and adding saturated NaHCO 3 The aqueous solution was adjusted to pH 8, filtered, extracted with DCM (100 ml×3), the organic phase dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to dryness, then purified by column chromatography (MeOH/DCM (v/v) =1/35) to give the title compound as a red solid (390.1 mg, 36.3%).
MS(ESI,pos.ion)m/z:282.0[M+H] + 。
Third step Synthesis of 3-bromo-1-isopropyl-6- (2-methoxyethoxy) quinolin-4 (1H) -one
Cesium carbonate (116.3 g,0.3569 mmol) was added to a solution of 3-bromo-6-hydroxy-1-isopropylquinolin-4 (1H) -one (390.1 mg,1.383 mmol) and 1-bromo-2-methoxyethane (293.2 mg,2.110 mmol) in DMF (2 mL), stirred at 100 ℃ overnight, filtered, the filtrate concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/40) to give the title compound as a yellow solid (260 mg, 55.3%).
MS(ESI,pos.ion)m/z:340.0[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.47(s,1H),7.93(d,J＝9.6Hz,1H),7.66(d,J＝2.9Hz,1H),7.42(dd,J＝9.4,2.9Hz,1H),5.07(dt,J＝13.1,6.6Hz,1H),4.22–4.16(m,2H),3.75–3.67(m,2H),3.32(s,3H),1.49(d,J＝6.5Hz,6H)。
Fourth step Synthesis of 1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6- (2-methoxyethoxy) quinolin-4 (1H) -one
CsF (217.1 mg,1.429 mmol), XPhos (67.3 mg,0.141 mmol) and Pd 2 (dba) 3 (131.2 mg,0.1433 mmol) of 3-bromo-1-isopropyl-6- (2-methoxyethoxy) quinolin-4 (1H) -one (240.1 mg,0.7058 mmol) and a solution of 2- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -6- (trimethyltin) pyridine (385.2 mg,1.097 mmol) in toluene (15 mL) were added sequentially, the reaction was stirred at 100℃overnight, the reaction concentrated to dryness, and then the column chromatography was purified (MeOH/DCM (v/v) =1/25) to give the title compound as a white solid (60.5 mg, 19.2%). MS (ESI, pos.ion) m/z 448.2[ M+H ] ] + ；
1 H NMR(600MHz,DMSO-d 6 ):δ(ppm)8.93(s,1H),8.88(s,1H),8.79–8.75(m,1H),8.01–7.96(m,3H),7.84(d,J＝3.0Hz,1H),7.44(dd,J＝9.3,3.0Hz,1H),5.71(dt,J＝13.4,6.7Hz,1H),5.18(dt,J＝13.1,6.5Hz,1H),4.26–4.22(m,2H),3.74–3.71(m,2H),1.54(t,J＝6.6Hz,12H)；
13 C NMR(101MHz,DMSO-d 6 ):δ(ppm)173.2,155.3,153.3,150.4,147.1,143.1,138.6,137.4,133.5,129.0,123.3,122.2,121.2,118.2,115.9,107.3,70.3,67.4,58.2,50.8,48.0,23.3,21.7。
Example 26 6- (4-cyclopropyl-1H-imidazol-1-yl) -1-isopropyl-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 7-dimethylquinolin-4 (1H) -one
First step Synthesis of 2-fluoro-4-methyl-5-nitrobenzoic acid
KNO at 0 DEG C 3 (3.985 g,39.42 mmol) H was added to 2-fluoro-4-methyl-benzoic acid (5.046 g,32.74 mmol) 2 SO 4 (20 mL, 98%) and then stirred at 0deg.C for 2 hours, then the reaction mixture was added to ice water (200 mL), filtered, the filter cake rinsed with water (30 mL. Times.2), and the filter cake was collected to give the title compound as a white solid (6.43 g, 98.6%).
MS(ESI,pos.ion)m/z:200.1[M+H] + 。
Second step Synthesis of 2-fluoro-4-methyl-5-nitrobenzoyl chloride
Oxalyl chloride (8 mL,95 mmol) was added to a solution of 2-fluoro-4-methyl-5-nitrobenzoic acid (6.43 g,32.3 mmol) and DMF (0.3 mL,4 mmol) in DCM (100 mL) at 0deg.C and the reaction stirred at room temperature for 1h and the reaction concentrated to dryness to give the title compound for the next reaction.
Third step Synthesis of (E) -3- (dimethylamino) -2- (2-fluoro-4-methyl-5-nitrobenzoyl) acrylic acid ethyl ester
TEA (13.5 mL,97.1 mmol) and (E) -3- (dimethylamino) prop-2-enoic acid ethyl ester (4.724 g,32.99 mmol) were added sequentially to a suspension of 2-fluoro-4-methyl-5-nitro-benzoyl chloride (7.03 g,32.3 mmol) in toluene (100 mL) at 0deg.C, and the reaction stirred at 105deg.C The reaction was concentrated to dryness overnight, and then purified by column chromatography (EA/PE (v/v) =1/2) to give the title compound as a brown oil (4.49 g, 42.9%). MS (ESI, pos.ion) m/z 325.1[ M+H ]] + 。
Fourth step Synthesis of 1, 7-dimethyl-6-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid ethyl ester
Ethyl (E) -3- (dimethylamino) -2- (2-fluoro-4-methyl-5-nitrobenzoyl) acrylate (4.49 g,13.8 mmol), methylamine in methanol (1.748 g,16.89mmol,30 mass%), K 2 CO 3 (3.841 g,27.79 mmol) and DMSO (20 mL) were added to a 100mL autoclave and reacted at 100℃for 8 hours with stirring, then the reaction solution was added to water (200 mL), filtered, and the filter cake was rinsed with water (10 mL. Times.2) and the filter cake was collected to give the title compound as a brown solid (4.01 g, 99.8%).
MS(ESI,pos.ion)m/z:291.1[M+H] + 。
Fifth step Synthesis of 1, 7-dimethyl-6-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid
LiOH (2.4476 g,102.1 mmol) was added to ethyl 1, 7-dimethyl-6-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylate (4.01 g,13.8 mmol) EtOH/H 2 O (30/15 mL) solution, stirring at room temperature, then adjusting pH to 5-6 with aqueous hydrochloric acid, adding water (50 mL), stirring for 0.5 hr, filtering, rinsing the filter cake with water (20 mL. Times.2), and collecting the filter cake to give the title compound as a yellow solid (3.62 g, 99.9%).
MS(ESI,pos.ion)m/z:263.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)14.57(s,1H),9.11(s,1H),8.85(s,1H),8.09(s,1H),4.11(s,3H),2.75(s,3H)。
Sixth step Synthesis of 3-bromo-1, 7-dimethyl-6-nitroquinolin-4 (1H) -one
At 0 ℃, naHCO is added 3 (8.36 g,99.5 mmol) was added to a solution of 1, 7-dimethyl-6-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (3.62 g,13.8 mmol) in DMF (60 mL), stirred at 0deg.C for 1 hour, NBS (2.764 g,15.53 mmol) was added, stirred at 0deg.C for 4 hours, water (200 mL) was added, filtered, the filter cake was rinsed with water (20 mL. Times.2), and the filter cake was collected to give the title compound as a yellow solidBody (3.244 g, 79.1%).
MS(ESI,pos.ion)m/z:297.0[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.75(s,1H),8.70(s,1H),7.82(s,1H),3.90(s,3H),2.71(s,3H)。
Seventh step Synthesis of 6-amino-3-bromo-1, 7-dimethylquinolin-4 (1H) -one
NH is added to 4 Cl (2.864 g,53.54 mmol) and Fe (2.41 g,43.2 mmol) were added sequentially to 3-bromo-1, 7-dimethyl-6-nitroquinolin-4 (1H) -one (3.01 g,10.1 mmol) in EtOH/H 2 O (60/20 mL) solution, reflux stirred for 6 hours, the reaction concentrated to dryness, then DCM/MeOH (10:1, 300 mL) was added, stirred for 0.5 hours, filtered, rinsed with DCM/MeOH (10:1, 100 mL), the filtrate was collected, concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/30) to give the title compound as a yellow solid (2.513 g, 92.9%).
MS(ESI,pos.ion)m/z:267.1[M+H] + 。
Eighth step Synthesis of 3-bromo-6- ((2-cyclopropyl-2-oxoethyl) amino) -1, 7-dimethylquinolin-4 (1H) -one
Will K 2 CO 3 (2.608 g,18.87 mmol) and KI (1.254 g,9.181 mmol) were added sequentially to a solution of 6-amino-3-bromo-1, 7-dimethylquinolin-4 (1H) -one (2.41 g,9.02 mmol) and 2-bromo-1-cyclopropyl-ethanone (2.925 g,17.94 mmol) in DMF (5 mL), the reaction was stirred at room temperature for 24 hours, then water (150 mL) was added, the mixture was filtered, the filter cake was rinsed with water (30 mL. Times.2) and the filter cake was collected to give the title compound as a yellow solid (2.78 g, 88.2%).
MS(ESI,pos.ion)m/z:349.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.37(s,1H),7.46(s,1H),6.99(s,1H),5.63(s,1H),4.24(d,J＝3.8Hz,2H),3.82(s,3H),2.33(s,3H),2.31–2.23(m,1H),0.97–0.85(m,4H)。
Synthesis of N- (3-bromo-1, 7-dimethyl-4-oxo-1, 4-dihydroquinolin-6-yl) -N- (2-cyclopropyl-2-oxoethyl) carboxamide in the ninth step
Formic acid (4 mL,106 mmol) and Ac 2 O (8 mL,84.6 mmol) was added to the reaction flask, 6Stirring and reacting for 1 hour at 5 ℃, and cooling to room temperature to obtain mixed anhydride for standby.
The prepared mixed anhydride (8 mL) was added to a suspension of 3-bromo-6- ((2-cyclopropyl-2-oxoethyl) amino) -1, 7-dimethylquinolin-4 (1H) -one (1.068 g,3.058 mmol) in THF (40 mL) at 0deg.C and the reaction stirred at room temperature for 4H, the reaction filtered and the filter cake rinsed with PE (20 mL) to give the title compound as a white solid (1.013 g, 87.81%).
MS(ESI,pos.ion)m/z:377.0[M+H] + 。
Tenth step Synthesis of 3-bromo-6- (4-cyclopropyl-1H-imidazol-1-yl) -1, 7-dimethylquinolin-4 (1H) -one
Ammonium acetate (2.379 g,30.86 mmol) was added to a solution of N- (3-bromo-1, 7-dimethyl-4-oxo-1, 4-dihydroquinolin-6-yl) -N- (2-cyclopropyl-2-oxoethyl) carboxamide (1.013 g,2.686 mmol) in acetic acid (25 mL), reacted overnight at 110℃with stirring, water (100 mL) was added, then saturated NaHCO 3 The aqueous solution was adjusted to pH 8, then extracted with DCM/MeOH (10:1, 100ml×4) and the organic phase concentrated to dryness, then purified by column chromatography (MeOH/DCM (v/v) =1/35) to give the title compound as a yellow solid (768 mg, 79.84%).
MS(ESI,pos.ion)m/z:358.1[M+H] + ；
1 H NMR(400MHz,DMSO-d 6 ):δ(ppm)8.31(s,1H),7.94(s,1H),7.46(d,J＝1.0Hz,1H),7.34(s,1H),6.81(d,J＝0.9Hz,1H),3.86(s,3H),2.37(s,3H),1.94–1.88(m,1H),0.91–0.86(m,2H),0.86–0.81(m,2H)。
Synthesis of eleventh step 6- (4-cyclopropyl-1H-imidazol-1-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -1, 7-dimethylquinolin-4 (1H) -one
X-phos (160.8 mg,0.3373 mmol), pd 2 (dba) 3 (304.7 mg,0.3327 mmol) and CsF (524.5 mg, 3.457 mmol) were added sequentially to a solution of 3-bromo-6- (4-cyclopropyl-1H-imidazol-1-yl) -1, 7-dimethylquinolin-4 (1H) -one (605.4 mg,1.690 mmol) and 2- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -6- (trimethyltin) pyridine (786 mg, 2.235 mmol) in toluene (25 mL), the reaction was stirred at 100deg.C for 10 hours, the reaction concentrated to dryness, and then purified by column chromatography (MeOH/DCM (v/v) =1/20) to give the title compound as whiteColor solid (243 mg, 30.88%).
MS(ESI,pos.ion)m/z:466.2[M+H] + ；
1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.79(d,J＝8.0Hz,1H),8.64(s,1H),8.40(d,J＝14.3Hz,2H),8.04(d,J＝7.7Hz,1H),7.90(t,J＝7.9Hz,1H),7.50(s,1H),7.39(s,1H),6.85(s,1H),5.57–5.40(m,1H),3.95(s,3H),2.40(s,3H),1.92(ddd,J＝13.2,8.3,5.1Hz,1H),1.59(d,J＝6.8Hz,6H),0.94–0.87(m,2H),0.86–0.79(m,2H)；
13 C NMR(151MHz,CDCl 3 ):δ(ppm)175.1,152.5,151.8,146.9,145.2,145.2,141.6,139.2,138.9,137.7,136.8,134.1,126.8,125.1,124.2,122.7,118.6,117.7,115.8,48.3,41.4,23.9,18.9,8.9,7.2。
Biological assay
The LC/MS/MS system for analysis comprises an Agilent 1200 series vacuum degasser, a binary pump, an orifice plate automatic sampler, a column oven, and an Agilent G6430 triple quadrupole mass spectrometer with an Electric Spray Ionization (ESI) source. Quantitative analysis was performed in MRM mode and mass spectrometry conditions are shown in table a:
table A
Multiple reaction detection scan 490.2→383.1
Fracture voltage 230V
Capillary voltage 55V
Dryer temperature 350℃
Atomizer 40psi
Dryer flow rate 10L/min
Analysis using a Waters XBridge C18,2.1 x 50mm,3.5 μm column, 5 μl sample was injected. Analysis conditions: the mobile phases were water (0.1% formic acid and 2m ammonium formate) (a) and 0 methanol (0.1% formic acid and 2m ammonium formate) (B). The flow rate was 0.4mL/min. The mobile phase gradient is shown in table B:
Table B
Time Gradient of mobile phase B
0.5min 5％
1.0min 95％
2.2min 95％
2.3min 5％
5.0min Termination of
Also for analysis was an Agilent 6330 series LC/MS mass spectrometer equipped with a G1312A binary pump, a G1367A autosampler and a G1314C UV detector; LC/MS mass spectrometers employ ESI ion sources. The MS conditions were optimized for each analyte using standard solutions. Waters XBiridge C18 column was used during the analysis and the specification was: 50X 2.1mm I.D., 3.5. Mu.M. The mobile phase is water (containing 5mM ammonium acetate and 0.1% formic acid) (A): acetonitrile (containing 5mM ammonium acetate and 0.1% formic acid) solution (B) (70:30, v/v); the flow rate is 0.6mL/min; the column temperature is kept at room temperature; 20. Mu.L of sample was injected.
Example A Stability in human and rat liver microsomes
Human or rat liver microsomes were placed in polypropylene tubes, double Kong Fuyo. Typical incubation mixtures include human or rat liver microsomes (0.5 mg protein/mL), target compound (1 μm) and NADPH (2.0 mM) potassium phosphate buffer (PBS, 100mM, ph 7.4) in a total volume of 15 μl, test compounds were dissolved in DMSO and diluted with PBS to give a final DMSO solution concentration of 0.05%. And incubated in a water bath at 37℃in air, after 3 minutes of pre-incubation, protein was added to the mixture and the reaction was started. At various time points (0, 5, 10, 15, 30 and 60 minutes) the reaction was terminated by adding the same volume of ice-cold acetonitrile. The samples were stored at-80℃until LC/MS/MS analysis was performed.
The concentration of the compound in the human or rat liver microsome incubation mixture was determined by LC/MS method.
Parallel incubation experiments were performed using denatured microsomes as negative control, incubated at 37℃and the reactions stopped at various time points (0, 15 and 60 minutes).
Verapamil (1 μm) served as a positive control, incubated at 37 ℃, and the reactions were terminated at different time points (0, 5, 10, 15, 30 and 60 minutes).
Data analysis
For each reaction, the concentration of the compound (expressed as a percentage) in human or rat liver microsome incubation was plotted as a percentage of the relative time point of zero to infer in vivo liver intrinsic clearance CLint (ref.: naritomi Y, tershita S, kimura S, suzuki a, kagayama a, sugiyama y.prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metabolism and Disposition 2001, 29:1316-1324.). Results referring to table 1, table 1 shows the results of experiments on the stability of the compounds provided in some examples of the present invention in human and rat liver microparticles.
TABLE 1 Experimental results of the stability of the compounds provided in some examples of the invention in human and rat liver particles
As can be seen from table 1, the compounds of the present invention exhibited suitable stability when incubated in human and rat liver microsomes.Example B After oral or intravenous administration of the compounds of the invention to mice, rats, dogs and cynomolgus monkeys Pharmacokinetic assessment of (2)
Pharmacokinetic studies of the compounds of the invention in mice, rats, dogs or cynomolgus monkeys were evaluated. The compounds of the present invention are administered in 5% -10% DMSO, 5% -10% Kolliphor HS15, and 80% -90% saline solution, or 5% -10% DMSO, 60% peg400, and 35% saline solution. For intravenous administration, animals are given a dose of 0.5 or 1 mg/kg. For oral doses (p.o.), rats, mice, dogs and cynomolgus monkeys were 2.5mg/kg or 5mg/kg. Blood was taken at time points 0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0, 12 and 24 hours (venous group added 0.083 hours) (mouse 0.05mL, rat 0.05mL, canine and cynomolgus 0.3 mL) and centrifuged at 3,000 or 4,000rpm for 10 minutes. The plasma solutions were collected and stored at-20℃or-70℃until LC/MS/MS analysis as described above was performed. The results are shown in Table 2, and Table 2 shows the results of experiments on the drug substitution characteristics of the compounds provided in some examples of the present invention in rats.
TABLE 2 experimental results of the pharmacokinetic profile of the compounds provided in some examples of the invention in rats
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As can be seen from Table 2, the compounds of the present invention exhibit good pharmacokinetic properties, are absorbed well and have an ideal half-life (T 1/2 ) And higher oral bioavailability (F).
EXAMPLE C kinase Activity assay
The utility of the disclosed compounds as protein kinase inhibitors can be evaluated by the following experiments.
General description of kinase assays
Kinase assay by detection of incorporation of gamma- 33 P-ATP Myelin Basic Protein (MBP). A buffer salt solution (TBS; 50mM Tris pH 8.0,138mM NaCl,2.7mM KCl) of MBP (Sigma #M-1891) tris was prepared at 20. Mu.g/ml, and a highly binding white 384-well plate (Greiner) was coated at 60. Mu.L per well. Incubation was carried out at 4℃for 24 hours. The plate was then washed 3 times with 100. Mu.L TBS. Kinase reaction in a total volume of 34. Mu.L kinase buffer (formulated as needed, e.g., 5mM Hepes pH 7.6,15mM NaCl,0.01% bovine serum albumin (Sigma #I-5506), 10mM MgCl 2 1mM DTT,0.02%TritonX-100). Compounds were dissolved in DMSO and added to each well with a final concentration of 1% compound in DMSO solution. The assay for each compound was performed at least twice. For example, the final concentration of enzyme is 10nM or 20nM. Addition of unlabeled ATP (10. Mu.M) and gamma-) 33 P-labeled ATP (2X 10 per well) 6 cpm,3000 Ci/mmol) was started. The reaction was run with shaking at room temperature for 1 hour. 384-well plates were washed with 7 XPBS and 50. Mu.L of scintillation fluid per well was added. The results were checked with a Wallac Trilux counter. To one skilled in the art, this is merelyOne of the detection methods may be other methods.
IC with suppressed test method 50 And/or inhibition constant K i 。IC 50 Defined as the concentration of the compound that inhibited 50% of the enzyme activity under the assay conditions. IC was estimated by making a curve containing 10 concentration points using a dilution factor of 1/2log 50 Values (e.g., a typical curve is made with compound concentrations of 3. Mu.M, 1. Mu.M, 0.3. Mu.M, 0.1. Mu.M, 0.03. Mu.M, 0.01. Mu.M, 0.003. Mu.M, 0.001. Mu.M, 0.0003. Mu.M, 0. Mu.M).
ASK1(h)
ASK1 (h) was incubated with 8mM MOPS pH 7.0,0.2mM EDTA,0.33mg/mL myelin basic protein, 10mM magnesium acetate and [ gamma-33P-ATP ] (specific activity about 500cpm/pmol, concentration as desired). The reaction was initiated by addition of MgATP mixture. After incubation for 40 minutes at room temperature, the reaction was stopped by adding 3% phosphoric acid solution. mu.L of the reaction was then spotted on a P30 filter pad, washed 3 times in 75mM phosphoric acid for 5 minutes each, washed once in methanol, then dried and flash counted.
The kinase assay of the present invention was carried out by Eurofins, UK. The results of the kinase activity assay are shown in Table 3.
In addition, the kinase activity of the compounds may be determined by Kinomescan TM Detection is based on the quantitative detection of compounds using an active site directed competitive binding assay. The assay is performed by combining three compounds, namely a DNA-tagged enzyme, an immobilized ligand and a test compound, and qPCR is performed by DNA-tagging to test the ability of the compound to compete with the immobilized ligand.
Most experiments were performed by culturing kinase-labeled T7 phage strains from E.coli hosts derived from BL21 strains, infecting E.coli in the logarithmic growth phase with T7 phage, incubating to lyse with shaking at 32℃and centrifuging the lysates to remove cell debris, and transferring the remaining kinases to HEK-293 cells for qPCR detection using DNA markers. After the streptavidin coated particles were treated with biotinylated small molecule ligands for 30min at room temperature, affinity resins were generated for kinase experiments. Superfluous ligand particle channelAfter biotin blocking, by blocking solution (SEABLOCK TM (Pierce), 1% bovine serum albumin, 0.05% Tween 20,1mM DTT) to wash unbound ligand, reducing non-specific binding. By mixing in 1X binding buffer (20% SEABLOCK TM Binding of kinase to ligand affinity particles and test compound in 0.17 Xphosphate buffer, 0.05% Tween 20,6mM DTT), all in 96 well plates, final volume of reaction 0.135mL, incubation at room temperature for 1 hour with shaking, washing of affinity particles with washing buffer (1 Xphosphate buffer, 0.05% Tween 20), re-suspension with elution buffer (1 Xphosphate buffer, 0.05% Tween 20, 0.5. Mu.M non-biotinylated affinity ligand), incubation at room temperature for 30min with shaking, and detection of kinase concentration in the eluate by qPCR.
TABLE 3 ASK1 kinase assay results for compounds provided in some examples of this invention
Example number IC50(nM)
Example 5 28
Example 6 46
Example 8 28
Example 9 73
Example 11 45
Example 19 43
Example 20 54
Example 23 21
Example 24 49
Example 25 61
As can be seen from Table 3, the compounds of the present invention showed a good ASK1 kinase inhibitory activity in the kinase assay.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (5)

1. A compound having the structure of one of:
or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a compound of claim 1; and the pharmaceutical composition optionally further comprises a pharmaceutically acceptable carrier.
3. Use of a compound of claim 1 or a pharmaceutical composition of claim 2 in the manufacture of a medicament for treating or alleviating ASK 1-mediated disorders in a patient.
4. The use according to claim 3, wherein said ASK 1-mediated disease is an autoimmune disease, an inflammatory disease, a cardiovascular disease, a heart kidney disease, a fibrotic disease, a respiratory disease, a liver disease or a neurodegenerative disease.
5. The use according to claim 4, wherein the cardiovascular disease is diabetes or other diabetic complications;
the fibrotic disease is pulmonary fibrosis or renal fibrosis;
The respiratory disease is chronic embolic pulmonary resistance, idiopathic pulmonary fibrosis or acute lung injury;
the liver disease is chronic liver disease, metabolic liver disease, liver fibrosis, primary sclerosing cholangitis, non-alcoholic fatty liver disease, liver ischemia-reperfusion injury or primary biliary cirrhosis.
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