CN109956928B - Pyridine compound, preparation method and application thereof - Google Patents

Pyridine compound, preparation method and application thereof Download PDF

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CN109956928B
CN109956928B CN201811471642.4A CN201811471642A CN109956928B CN 109956928 B CN109956928 B CN 109956928B CN 201811471642 A CN201811471642 A CN 201811471642A CN 109956928 B CN109956928 B CN 109956928B
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compound
pharmaceutically acceptable
acceptable salt
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alkyl
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CN109956928A (en
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刘金明
蔡家强
唐建川
王坤建
王利春
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Abstract

The present invention relates to a pyridine compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof. The invention also relates to a pharmaceutical composition containing the compound, a preparation method and application of the compound.

Description

Pyridine compound, preparation method and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a pyridine compound, a pharmaceutical composition containing the pyridine compound, a preparation method and application of the pyridine compound.
Background
Mitogen-activated protein kinase (MAPK) signaling cascades combine different extracellular and intracellular sequences (queue) with appropriate cellular stress responses including Cell growth, differentiation, inflammation, and apoptosis (Kumar S., Boehm J., and Lee.J.C. (2003) Nat.Rev.drug Dis.2: 717. 726; Pimieta G., and Pascal J. (2007) Cell Cycle, 6: 2826. sup. 2632). MAPK exists as three groups, MAP3K, MAP2K, and MAPK, and is activated sequentially. MAP3K reacts directly to environmental signals and phosphorylated MAP2K, which in turn specifically phosphorylates MAPK. MAPK then mediates the appropriate cellular response by phosphorylating cellular substrates that include transcription factors that regulate gene expression.
Apoptosis signal-regulating kinase 1(ASK1) is a member of the mitogen-activated protein kinase (MAP3K) family that activates c-Jun N-terminal protein kinase (JNK) and p38 MAPK (Ichijo h., Nishida e., Irie k., Dijke p.t., Saitoh m., Moriguchi t., Matsumoto k., Miyazono k., and Gotoh Y (1997) Science, 275, 90-94). Activation of ASK1 can be achieved by a variety of stimuli including oxidative stress, Reactive Oxygen Species (ROS), LPS, TNF-a, FasL, ER stress, and increasing intracellular calcium concentration (Hattori k., Naguro I., Runchel c., and Ichijo H. (2009) Cell com.signal.7: 1-10; Takeda k., Noguchi t., Naguro I., and Ichijo, H. (2008) annu.rev.rmacol.toxicol.48: 199-225; Nagai H., Noguchi t., Takeda k., and Ichijo I. (2007) j.biochem.mol.biol.biol.40: 1-6). In response to these stimulation signals, ASK1 is activated via autophosphorylation at Thr838 and in turn phosphorylates MAP2K (e.g., MKK3/6 and MKK4/7), which then phosphorylates and activates JNK and p38 MAPK, respectively.
Phosphorylation of ASK1 may lead to apoptosis or other cellular responses. There have been reports showing that ASK1 activation and signaling play an important role in disorders and diseases including chronic fatty and fibrotic induced disorders and diseases (nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)), neurodegenerative diseases, cardiovascular diseases, diabetes (including diabetic nephropathy and other complications of diabetes), inflammatory diseases, autoimmune diseases, respiratory diseases (including Chronic Obstructive Pulmonary Disease (COPD), Idiopathic Pulmonary Fibrosis (IPF) and acute lung injury) and metabolic-related diseases. In addition, ASK1 has also been implicated in mediating organ damage following cardiac, cerebral and renal ischemia and reperfusion (Watanabe et al, (2005) BBRC 333, 562-567; Zhang et al, (2003) Life Sci.74, 37-43; Terada et al, (2007) BBRC 364, 1043-49). Thus, ASK1 signaling inhibitors (e.g., ASK1 inhibitors) have the potential to remedy or improve the life of patients suffering from such conditions.
US2011/0009410 discloses an apoptosis signal-regulating kinase 1(ASK1) inhibitor. There is also a need in the art to develop ASK1 inhibitors with superior activity and potency.
Disclosure of Invention
In some aspects, the invention relates to a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein:
Figure BDA0001890952750000021
Figure BDA0001890952750000022
represents a single or double bond, wherein
Figure BDA0001890952750000023
At mostContains only one double bond;
R1is a 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: c1-6Alkyl radical, C1-6Haloalkyl and C3-6A cycloalkyl group;
R2selected from halogen, N (R)4)(R5)、C1-6Alkyl radical, C1-6Haloalkyl and C3-10A cycloalkyl group;
R3is selected from C1-6Alkyl and C3-6Cycloalkyl, wherein said alkyl or cycloalkyl is each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxy and-O-C1-6An alkyl group;
q is selected from C and N;
y is selected from C (R)4)、C(R4)(R5)、N(R4) And O;
z is selected from C (R)4) And C (R)4)(R5) (ii) a And is
R4And R5Each independently selected from hydrogen and C1-6Alkyl and C3-6A cycloalkyl group.
In other aspects, the invention relates to pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and optionally, one or more pharmaceutically acceptable carriers or excipients.
In other aspects, the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for use as an inhibitor of apoptosis signal-regulating kinase 1(ASK 1).
In other aspects, the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the treatment of an ASK 1-mediated disease or condition.
In other aspects, the invention relates to methods of preparing the compounds of the invention.
In some embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein:
Figure BDA0001890952750000024
Figure BDA0001890952750000031
represents a single or double bond, wherein
Figure BDA0001890952750000032
At most one double bond;
R1is a 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: c1-6Alkyl radical, C1-6Haloalkyl and C3-6A cycloalkyl group;
R2selected from halogen, N (R)4)(R5)、C1-6Alkyl radical, C1-6Haloalkyl and C3-10A cycloalkyl group;
R3is selected from C1-6Alkyl and C3-6Cycloalkyl, wherein said alkyl or cycloalkyl is each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxy and-O-C1-6An alkyl group;
q is selected from C and N;
y is selected from C (R)4)、C(R4)(R5)、N(R4) And O;
z is selected from C (R)4) And C (R)4)(R5) (ii) a And is
R4And R5Each is independentSelected from hydrogen and C1-6Alkyl and C3-6A cycloalkyl group.
In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, having the structure of formula (II), formula (III), formula (IV) or formula (V), wherein:
Figure BDA0001890952750000033
R1、R2、R3and R4As defined in formula I.
In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, wherein: r1Is a 5-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: c1-4Alkyl radical, C1-4Haloalkyl and C3-6A cycloalkyl group; preferably, R1Independently is an imidazolyl group optionally substituted with one or two methyl, ethyl, isopropyl, cyclopropyl or trifluoromethyl groups; more preferably, R1Independently 4-cyclopropyl-1H-imidazol-1-yl.
In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, wherein: r2Selected from halogen, N (R)4)(R5)、C1-4Alkyl radical, C1-4Haloalkyl and C3-6Cycloalkyl radical, R4And R5As defined in formula I; preferably, R2Selected from fluorine, chlorine, bromine, iodine, dimethylamino, C1-4Alkyl radical, C1-4Fluoroalkyl and C3-6A cycloalkyl group; more preferably, R2Selected from fluorine, chlorine, dimethylamino, methyl, ethyl, isopropyl, cyclopropyl, trifluoroMethyl and difluoromethyl.
In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, wherein: r3Is selected from C1-4Alkyl radical, C1-4Haloalkyl, C1-4alkyl-O-C1-4Alkyl or C3-6A cycloalkyl group; preferably, R3Selected from methyl, ethyl, isopropyl or cyclopropyl; more preferably, R3Is isopropyl.
In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, wherein: when Q is C, it is attached to one double bond; when Q is N, it is not linked to a double bond.
In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, wherein: when Y is C (R)4) When it is attached to a double bond; when Y is C (R)4)(R5)、N(R4) Or O, which is not attached to a double bond.
In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, wherein Y is selected from CH, CH2、NCH3And O.
In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, wherein: when Z is C (R)4) When it is attached to a double bond; when Z is C (R)4)(R5) When it is not attached to a double bond.
In some embodiments, the invention provides compounds, or pharmaceutically acceptable salts, stereoisomers, polymorphs, pharmaceutically acceptable salts, stereoisomers, polymorphs, pharmaceutically acceptable salts, solvates, and solvates thereof,A solvate, N-oxide, isotopically-labelled compound, metabolite or prodrug, wherein Z is selected from CH and CH2。
In some embodiments, the present invention provides compounds, or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, wherein: r4And R5Each independently selected from hydrogen and C1-4Alkyl and C3-6A cycloalkyl group; preferably, R4And R5Each independently selected from hydrogen, methyl, ethyl, isopropyl or cyclopropyl.
In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein said compound is selected from the group consisting of:
Figure BDA0001890952750000041
Figure BDA0001890952750000051
atoms in the compounds of the present invention may be replaced by their isotopes. For example12C can be substituted by its isotopes13C or14C, replacing;1h can be covered2H (D, deuterium) or3H (T, tritium) substitution, and the like. The invention includes compounds of formula I and isotopically-labelled compounds obtained by substituting any atom in the compounds of formula I with its isotope.
The invention also relates to a method for preparing said compounds, comprising the following synthetic route:
the first synthetic route is as follows: process for the preparation of compounds of formula (II)
Figure BDA0001890952750000052
Wherein:
x is halogen, such as F, Cl, Br or I, preferably Cl and Br;
R1、R2and R3As described above.
(1) Carrying out ring expansion reaction on the compound II-1 and azide to obtain a compound II-2;
the reaction is preferably carried out in a suitable organic solvent which may be selected from chloroform, dichloromethane, tetrahydrofuran, ethers (e.g. diethyl ether etc.), 1, 4-dioxane and any combination thereof, preferably dichloromethane or chloroform. The reaction is carried out in the presence of a suitable azide, such as sodium azide. The reaction is preferably carried out at a suitable temperature, preferably 0 ℃ or room temperature (20-30 ℃). The reaction is preferably carried out for a suitable time, for example 1 to 2 hours or 4 to 12 hours, for example 2 hours, 6 hours, 8 hours or overnight.
(2) Carrying out coupling reaction on the compound II-2 to obtain a compound II-3;
the coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a palladium metal catalyst, such as tris (dibenzylideneacetone) dipalladium, [1, 1 '-bis (diphenylphosphino) ferrocene ] dichloropalladium, palladium triphenylphosphine, palladium acetate, preferably [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium. The base is an inorganic base such as potassium phosphate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, preferably potassium carbonate. Preferably, the coupling reaction is carried out in a suitable organic solvent which may be selected from 1, 4-dioxane, benzene, toluene and xylene, for example 1, 4-dioxane. Preferably, the coupling reaction is carried out under a suitable protective atmosphere (e.g. nitrogen atmosphere). Preferably, the coupling reaction is carried out at a suitable temperature, which may be, for example, 80 to 120 ℃, preferably 110 ℃. Preferably, the coupling reaction is carried out for a suitable time, for example 1 to 3 hours, for example 2 hours.
(3) Carrying out coupling reaction on the compound II-3 to obtain a compound shown in a formula II;
the coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a copper metal catalyst, such as cuprous iodide, cuprous chloride, cuprous oxide, cupric chloride, cupric acetate, cupric oxide, preferably cuprous iodide. The base is an inorganic base such as potassium phosphate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, preferably potassium phosphate. Preferably, the coupling reaction is carried out in a suitable organic solvent which may be selected from 1, 4-dioxane, benzene, toluene and xylene, for example 1, 4-dioxane. Preferably, the coupling reaction is carried out in the presence of a suitable ligand, which may be selected from N, N ' -dimethylethylenediamine, trans-N, N ' -dimethyl-1, 2-cyclohexanediamine, preferably trans-N, N ' -dimethyl-1, 2-cyclohexanediamine. Preferably, the coupling reaction is carried out at a suitable temperature, which may be, for example, 80 to 120 ℃, preferably 99 ℃, 101 ℃ or 110 ℃. Preferably, the coupling reaction is carried out for a suitable time, for example 8 to 24 hours, for example 12 hours.
The second synthetic route is as follows: process for the preparation of compounds of formula (IV)
Figure BDA0001890952750000061
Wherein:
PG is a protecting group for hydroxyl;
R1、R2and R3As described above.
(1) Carrying out coupling reaction on the compound IV-1 to obtain a compound IV-2;
the coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a palladium metal catalyst, such as tris (dibenzylideneacetone) dipalladium, [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium, palladium triphenylphosphine, palladium acetate, preferably tris (dibenzylideneacetone) dipalladium. The base is an inorganic or organic base, such as sodium tert-butoxide, potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, preferably sodium tert-butoxide. Preferably, the coupling reaction is carried out in the presence of an organophosphorus compound (e.g., derived from biphenyl) selected from BINAP, Xantphos, and XPhos, preferably Xantphos. Preferably, the coupling reaction is carried out in a suitable organic solvent which may be selected from 1, 4-dioxane, benzene, toluene and xylene, for example 1, 4-dioxane. Preferably, the coupling reaction is carried out under a suitable protective atmosphere (e.g. nitrogen atmosphere). Preferably, the coupling reaction is carried out at a suitable temperature, which may be, for example, 80 to 120 ℃, preferably 90 ℃ or 100 ℃. Preferably, the coupling reaction is carried out for a suitable time, for example 8 to 24 hours, for example 12 hours.
(2) Removing the protecting group of the hydroxyl from the compound IV-2 to obtain a compound IV-3;
the deprotection reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from chloroform, dichloromethane, tetrahydrofuran, ethers (e.g., diethyl ether, etc.), 1, 4-dioxane, and any combination thereof, preferably dichloromethane. The reaction is preferably carried out in the presence of an acid. The acid may be, for example, hydrobromic acid, boron tribromide. The reaction is preferably carried out at a suitable temperature. The temperature may be, for example, room temperature to 60 ℃, such as 20-30 ℃. The reaction is preferably carried out for a suitable time, for example 1 to 2 hours or 8 to 24 hours, for example 2 hours or 12 hours.
(3) Carrying out a ring closing reaction on the compound IV-3 to obtain a compound shown in the formula IV;
the ring closure reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethers (e.g., diethyl ether, etc.), 1, 4-dioxane, and any combination thereof, preferably N, N-dimethylformamide. The ring closing reagent for the reaction is preferably DMF-DMA. The reaction is preferably carried out at a suitable temperature. The temperature may be, for example, room temperature to 60 ℃, such as 30-40 ℃. The reaction is preferably carried out for a suitable time, for example 8 to 24 hours, for example 12 hours.
The specific conditions of the above-mentioned reaction steps are known in the art, and the present invention is not particularly limited thereto. According to the teaching of the present invention and the common knowledge in the field, the skilled person can make selective substitutions on each substituent in the general formula to prepare different compounds, and the alternatives and substitutions are all within the protection scope of the present invention.
The invention also relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and optionally, one or more pharmaceutically acceptable carriers or excipients.
The invention also relates to application of the compound shown in the formula I or pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof or a pharmaceutical composition thereof in preparing a medicament serving as an apoptosis signal-regulated kinase 1(ASK1) inhibitor.
The invention also relates to application of the compound shown in the formula I or pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof or a pharmaceutical composition thereof in preparing a medicament for treating ASK 1-mediated diseases or symptoms.
The present invention also relates to a method of treating ASK1 mediated diseases or disorders, comprising administering to a subject in need thereof an effective amount of a compound of formula I of the present invention or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition thereof.
The invention also relates to a compound shown in the formula I or pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof or a pharmaceutical composition thereof, which is used for treating ASK1 mediated diseases or symptoms.
The invention also relates to a compound shown in the formula I or a pharmaceutically acceptable salt, a stereoisomer, a polymorph, a solvate, an N-oxide, an isotopically labeled compound, a metabolite or a prodrug thereof or a pharmaceutical composition thereof, which is used for inhibiting apoptosis signal regulating kinase 1(ASK 1).
In some embodiments, the ASK 1-mediated disease or disorder is selected from disorders and diseases caused by chronic fatty or fibrotic conditions, such as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, extrahepatic cholestatic conditions; liver fibrosis; obstructive or chronic inflammatory disorders of the liver; cirrhosis of the liver; cholestatic lesions and fibrotic effects (fibrotic lesions) associated with alcohol-induced cirrhosis or with viral infectious forms of hepatitis; (ii) an autoimmune disease; respiratory diseases (including COPD, Idiopathic Pulmonary Fibrosis (IPF) and acute lung injury); inflammatory diseases; chronic kidney disease; cardiovascular diseases; diabetes (including diabetic nephropathy, and other complications of diabetes) and neurodegenerative diseases.
In the present invention, the purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of an active ingredient, and exert biological activity. Wherein the vectors include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, 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 silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin.
The excipient refers to an additive in the medicinal preparation except the main medicament. The composition has stable properties, no incompatibility with main drug, no side effect, no influence on curative effect, no deformation at room temperature, no crack, mildew, moth-eaten feeling, no harm to human body, no physiological effect, no chemical or physical effect with main drug, no influence on content determination of main drug, etc. Such as binders, fillers, disintegrants, lubricants in tablets; wine, vinegar, medicinal juice, etc. in the Chinese medicinal pill; base portion in semisolid formulations ointments, creams; preservatives, antioxidants, flavoring agents, fragrances, solubilizers, emulsifiers, solubilizers, tonicity adjusting agents, colorants and the like in liquid preparations can all be referred to as excipients.
The compounds of the present invention, or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, can be administered by the following routes: parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular routes, or as inhalants. The pharmaceutical compositions may optionally be administered in combination with other agents that have at least some effect in the treatment of various diseases.
The compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof can be formulated into various suitable dosage forms depending on the route of administration.
The pharmaceutical composition or suitable dosage form according to the invention may contain from 0.01mg to 1000mg of a compound according to the invention, suitably from 0.1mg to 800mg, preferably from 0.5 to 500mg, more preferably from 1 to 350mg, particularly preferably from 5 to 250 mg.
When administered orally, the compounds of the present invention, or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, can be formulated into any orally acceptable dosage form including, but not limited to, tablets, capsules, aqueous solutions or suspensions. Among these, carriers for tablets generally include lactose and corn starch, and additionally, lubricating agents such as magnesium stearate may be added. Diluents used in capsule formulations generally include lactose and dried corn starch. Aqueous suspension formulations are generally prepared by mixing the active ingredient with suitable emulsifying and suspending agents. Optionally, some sweetener, aromatic or colorant may be added into the above oral preparation.
When topically applied to the skin, the compounds of the present invention, or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, can be formulated into suitable ointment, lotion or cream formulations wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers that may be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil, sorbitan monostearate tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds of the present invention, or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs thereof, can also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oily suspensions or sterile injectable solutions. Among the carriers and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oil may also be employed as a solvent or suspending medium, such as a monoglyceride or diglyceride.
In embodiments of the invention, suitable in vitro or in vivo assays are performed to determine the efficacy of the pharmaceutical compositions of the invention and whether administration is suitable for treating a disease or medical condition in an individual. Examples of such assays are described below in the non-limiting examples in connection with specific diseases or medical treatments. Generally, an effective amount of a composition of the invention sufficient to achieve a prophylactic or therapeutic effect is from about 0.001 mg/kg body weight/day to about 10,000 mg/kg body weight/day. Suitably, the dose is from about 0.01 mg/kg body weight/day to about 1000mg/kg body weight/day. The dosage range may be about 0.01 to 1000mg/kg of subject body weight per day, every second day, or every third day, more usually 0.1 to 500mg/kg of subject body weight. Exemplary treatment regimens are once every two days or once a week or once a month. The formulation is typically administered multiple times, and the interval between single doses may be daily, weekly, monthly or yearly. Alternatively, the formulation may be administered as a sustained release formulation, in which case less frequency of administration is required. The dose and frequency will vary depending on the half-life of the formulation in the subject. It may also vary depending on whether prophylactic or therapeutic treatment is carried out. In prophylactic applications, relatively low doses are administered chronically at relatively infrequent intervals. In therapeutic applications, it is sometimes desirable to administer relatively high doses at relatively short intervals until the progression of the disease is delayed or halted, and preferably until the individual exhibits a partial or complete improvement in the symptoms of the disease, after which a prophylactic regimen can be administered to the patient.
The terms of the present invention are explained below, and for specific terms, if the meaning of the present invention is inconsistent with the meaning commonly understood by those skilled in the art, the meaning of the present invention shall prevail; if not defined in the present invention, it has a meaning generally understood by those skilled in the art. Unless stated to the contrary, the terms used in the present invention have the following meanings:
the terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are used herein by the term inclusive or open-ended and do not exclude additional unrecited elements or method steps.
The term "hydrogen" as used herein and in each of the groups described, refers to protium (H), deuterium (D) or tritium (T). In certain preferred embodiments, the hydrogen is H. In certain preferred embodiments, the hydrogen is D.
The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.
The term "C" as used in the present invention1-6Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms, e.g. C1-4Alkyl radical, C1-2Alkyl radical, C1Alkyl radical, C2Alkyl radical, C3Alkyl radical, C4Alkyl radical, C5Alkyl or C6Alkyl, preferably C1-4An alkyl group. Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
The term "C" as used in the present invention1-6Haloalkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms, e.g. C, substituted by one or more halogen atoms1-4Haloalkyl, C1-2Haloalkyl, C1Haloalkyl, C2Haloalkyl, C3HalogenatedAlkyl radical, C4Haloalkyl, C5Haloalkyl or C6Haloalkyl, preferably C1-6A fluoroalkyl group. Specific examples include, but are not limited to, trifluoromethyl, difluoromethyl, trifluoroethyl, monofluoromethyl, and the like.
The term "C" as used in the present invention3-10Cycloalkyl "means a saturated or partially saturated monocycloalkyl group containing from 3 to 10 carbon atoms. Preference is given to 3-to 6-membered cycloalkyl radicals, for example 3-, 4-, 5-or 6-membered cycloalkyl radicals. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "5-6 membered heteroaryl" as used herein refers to a monocyclic aromatic group containing 5-6 ring members, and at least 1 up to 4 (e.g., 1, 2, 3, or 4) of said ring members are heteroatoms selected from N, O and S, e.g., 5 membered heteroaryl, 6 membered heteroaryl, and the like. Specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, pyridazinyl, pyrazinyl, 1, 2, 3-triazinyl, 1, 3, 5-triazinyl, 1, 2, 4, 5-tetrazinyl, and the like.
If a substituent is described as "optionally substituted", the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced individually and/or together with an independently selected optional substituent. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogen is present) may each be replaced with an independently selected optional substituent.
The term "one or more" as used herein means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
Unless indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.
The term "stereoisomer" as used herein denotes an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, they can result in racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures of two or more structurally different forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is understood that the scope of this application encompasses all such isomers or mixtures thereof in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerization and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.
The compounds of the invention may exist in the form of solvates, such as hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.
The compounds of the present invention or pharmaceutically acceptable salts thereof may also form solvates, such as, for example, alcoholates and the like.
The compounds of the invention may also be prodrugs or in a form which releases the active ingredient upon metabolic changes in the body. The selection and preparation of suitable prodrug derivatives is well known to those skilled in the art.
The compounds of the invention may also be in chemically protected form, the protecting group being protected on an active group (e.g. an amino group) of the compound, which protecting group is metabolised in vivo to release the active ingredient. The selection and preparation of suitable chemically protected forms is well known to those skilled in the art.
The term "pharmaceutically acceptable" as used herein means that the substance or composition must be chemically and/or toxicologically compatible with the other components comprising the formulation and/or the mammal being treated therewith.
The term "pharmaceutically acceptable salt" as used herein includes conventional salts with pharmaceutically acceptable inorganic or organic acids or bases. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
The term "pharmaceutical composition" as used herein includes products comprising a therapeutically effective amount of a compound of formula I of the present invention, as well as any product which results, directly or indirectly, from combination of compounds of formula I of the present invention.
The term "effective amount" as used herein refers to an amount sufficient to achieve a desired therapeutic effect, e.g., to achieve alleviation of symptoms associated with the disease being treated.
The term "treatment" as used herein is intended to reduce or eliminate the disease state or condition for which it is directed. A subject is successfully "treated" if the subject receives a therapeutic amount of a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof according to the methods described herein, and the subject exhibits an observable and/or detectable decrease or improvement in one or more of the indications and symptoms of the subject. It is also understood that treatment of the disease state or condition described includes not only complete treatment, but also less than complete treatment, but achieves some biologically or medically relevant result.
Advantageous effects of the invention
The present invention provides compounds useful as ASK1 inhibitors, which have excellent properties such as good inhibitory activity against ASK1, good physicochemical properties (e.g., solubility, physical and/or chemical stability), good pharmacokinetic properties (e.g., good bioavailability, suitable blood drug concentration, half-life and duration of action), good safety (less toxicity and/or fewer side effects, wider therapeutic window), and the like.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
The structure of the compound is determined by nuclear magnetic resonance1H-NMR) or Mass Spectrometry (MS).1H-NMR was measured using a JEOL Eclipse 400 NMR spectrometer using deuterated methanol (CD) as the solvent3OD), deuterated chloroform (CDCl)3) Or hexadeutero dimethyl sulfoxide (DMSO-d)6) Internal standard is Tetramethylsilane (TMS), and chemical shift (delta) is 10-6(ppm) is given as a unit.
Determination of MS was performed using an agilent (esi) mass spectrometer, manufacturer: agilent, model: agilent 6120B.
Preparative high performance liquid chromatograph (YMC, ODS, 250X 20mm column) was prepared using Shimadzu LC-8A.
Thin layer chromatography silica gel plate (TLC) an aluminum plate (20X 20cm) from Merck was used, and the specification for separation and purification by thin layer chromatography was GF 254 (0.4-0.5 mm) from a cigarette bench.
The reaction was monitored by Thin Layer Chromatography (TLC) or LC-MS using a developing system of: a dichloromethane and methanol system, a normal hexane and ethyl acetate system, a petroleum ether and ethyl acetate system, and the volume ratio of the solvent is adjusted according to the different polarities of the compounds, or triethylamine and the like are added for adjustment.
The microwave reaction used a BiotageInitiator + (400W, RT-300 ℃ C.) microwave reactor.
The column chromatography generally uses 200-300 mesh silica gel as a carrier. The system of eluents comprises: the volume ratio of the solvent is adjusted according to the different polarities of the compound in a dichloromethane and methanol system and a normal hexane and ethyl acetate system, and a small amount of triethylamine can also be added for adjustment.
In the examples, the reaction temperature is, unless otherwise specified, room temperature (20 ℃ C. to 35 ℃ C.).
The reagents used in the present invention were purchased from Acros Organics, Aldrich Chemical Company, Texas Chemical, and the like.
In the conventional synthesis methods, examples and intermediate synthesis examples, the meanings of the abbreviations are as follows.
Figure BDA0001890952750000101
Figure BDA0001890952750000111
Preparation of intermediates
Intermediate preparation example 1: preparation of 2-bromo-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine
Figure BDA0001890952750000112
The first step is as follows: preparation of 6-aminopyridine formylhydrazine
Methyl 6-aminopyridinecarboxylate (50g, 329mmol) and hydrazine hydrate (32.9g, 658mmol) were added to methanol (500mL) and stirred under reflux for 3 h. The reaction solution was then cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate to give a solid which was the title compound of this step (42g, yield: 83.0%).
The second step is that: (E) preparation of (E) -N' - (6- ((E) -2- ((dimethylamino) methylene) hydrazinecarbonyl) pyridin-2-yl) -N, N-dimethylformamidine
The compound obtained in the first step (42g, 275mmol) was dissolved in DMF-DMA (500mL) and heated under reflux for 18 h. The reaction was then cooled and concentrated. Ethyl acetate was added and the reaction was heated to 50 ℃ and stirred for 20 minutes, cooled and filtered to obtain the title compound of this step as a solid (60g, yield: 72%).
The third step: preparation of 6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-amine
The compound (10g, 38.2mmol) obtained in the second step was dissolved in a mixed solvent of acetonitrile and acetic acid (4: 1, 100mL), isopropylamine (11.3g, 191mmol) was added, and the mixture was refluxed for 24 hours. Then, the reaction solution was cooled, concentrated, to which water was added, the reaction solution was made weakly alkaline with a 1N aqueous solution of sodium hydroxide, and a solid was precipitated, filtered and dried to obtain the title compound of this step (3.0g, yield: 39%).
The fourth step: preparation of 2-bromo-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine
The compound (3.0g, 14.8mmol) obtained in the third step was dissolved in an aqueous solution of hydrobromic acid (30mL), and after cooling to 0 deg.C, an aqueous solution of sodium nitrite (1.0g, 14.8mmol) was added dropwise, stirring was continued at that temperature for 0.5 hour, followed by dropwise addition of bromine (2.37g, 14.8mmol), and stirring was continued at room temperature for 2 hours. The reaction solution was made weakly basic with a 2N aqueous solution of sodium hydroxide, extracted with ethyl acetate, the ethyl acetate layer was washed with an aqueous solution of sodium thiosulfate, dried, filtered, concentrated and the residue was purified by silica gel column chromatography to give the title compound (2.8g, yield: 72%).
Examples
Example 1: preparation of 7- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (Compound 1)
Figure BDA0001890952750000121
The first step is as follows: preparation of 5-bromo-6-nitro-2, 3-dihydro-1H-inden-1-one
5-bromo-2, 3-dihydro-1H-inden-1-one (30.0g, 142mmol) was added in portions to fuming nitric acid (200mL) cooled in an ice bath, stirred at-10 ℃ to-15 ℃ for 4.5 hours, the reaction solution was poured into ice water, stirred for 30 minutes, filtered, the filter cake was dissolved with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by silica gel column chromatography after concentration to obtain the title compound of this step (19.0g, yield: 52.2%).
The second step is that: preparation of 6-amino-5-bromo-2, 3-dihydro-1H-inden-1-one
Dissolving the compound (19.0g, 74.2mmol) obtained in the first step in ethanol (180mL) and water (60mL), adding reduced iron powder (20.8g, 371.0mmol) and ammonium chloride (2.0g, 37.1mmol), heating to reflux and stirring for 4 hours, filtering the reaction solution while the reaction solution is hot, washing the filter cake twice with hot absolute ethanol, combining the filtrates, evaporating to dryness under reduced pressure, dissolving the crude product in dichloromethane (500mL), washing twice with saturated aqueous sodium chloride solution, drying with anhydrous sodium sulfate, filtering, evaporating the filtrate to dryness under reduced pressure to obtain the title compound (11.2g, yield: 66.8%) in the step.
The third step: preparation of 5-bromo-6- ((2-cyclopropyl-2-oxoethyl) amino) -2, 3-dihydro-1H-inden-1-one
The compound (7.0g, 31.0mmol) obtained in the second step, potassium iodide (4.7g, 28.2mmol) and potassium carbonate (5.1g, 37.2mmol) were dissolved in DMF (100mL), stirred for 10 minutes under nitrogen protection, then 2-bromo-1-cyclopropylethanone (10.1g, 62.0mmol) was added, after the addition was completed, the temperature was raised to 60 ℃ and stirred overnight, the reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (7.3g, yield: 76.8%) of this step.
The fourth step: preparation of 5-bromo-6- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -2, 3-dihydro-1H-inden-1-one
Dissolving the compound (6.6g, 21.4mmol) obtained in the third step in acetic acid (80mL), adding potassium thiocyanate (4.2g, 42.8mmol), heating to 110 ℃, stirring for 8 hours, evaporating the reaction liquid under reduced pressure to remove acetic acid, adding water (100mL) to the residue, extracting with ethyl acetate, washing twice with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, filtering, evaporating the filtrate under reduced pressure to dryness to obtain a solid, namely the crude product of the title compound (6.8g, directly used for the next reaction) in the step.
The fifth step: preparation of 5-bromo-6- (4-cyclopropyl-1H-imidazol-1-yl) -2, 3-dihydro-1H-inden-1-one
Hydrogen peroxide (9mL), acetic acid (80mL) and water (16mL) were placed in a three-necked flask, the temperature was raised to 45 ℃ and the compound obtained in the fourth step (6.8g, 19.5mmol) was added in portions, after stirring for 2 hours, 20% aqueous sodium sulfide (30mL) was added, after stirring for 1 hour, the pH was adjusted to 10 with ammonia, dichloromethane was extracted, the organic phase was concentrated, and then purified by silica gel column chromatography to obtain the title compound of this step (4.0g, yield: 64.7%).
And a sixth step: preparation of 6-bromo-7- (4-cyclopropyl-1H-imidazol-1-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
Dissolving the compound (4.0g, 12.6mmol) obtained in the fifth step in chloroform (80mL), adding methanesulfonic acid (12.1g, 126mmol), cooling to 0 ℃ in an ice bath, adding sodium azide (2.5g, 37.8mmol) in portions, slowly returning to room temperature after addition, stirring overnight, quenching the reaction solution with 1N aqueous sodium hydroxide solution under cooling in an ice bath, extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, and evaporating to dryness under reduced pressure to obtain a solid, namely the title compound (3.6g, yield: 85.9%) in the present step.
The seventh step: preparation of 7- (4-cyclopropyl-1H-imidazol-1-yl) -6-methyl-3, 4-dihydroisoquinolin-1 (2H) -one
The compound (125mg, 0.38mmol) obtained in the sixth step, trimethylcyclotriboroxane (143mg, 1.14mmol) and potassium carbonate (158mg, 1.14mmol) were dissolved in 1, 4-dioxane (10mL), and Pd (dppf) Cl was added under nitrogen protection2(20mg), reaction at 110 ℃ for 2 hours in the microwave, filtration of the reaction solution, evaporation of the filtrate under reduced pressure and purification of the residue by preparative thin layer chromatography to give the title compound (56 m)g, yield: 56.0%).
Eighth step: preparation of 7- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -6-methyl-3, 4-dihydroisoquinolin-1 (2H) -one
The compound (56mg, 0.21mmol) obtained in the seventh step, 2-bromo-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine (85mg, 0.32mmol), trans-N, N' -dimethyl-1, 2-cyclohexanediamine (33mg, 0.23mmol) and anhydrous potassium phosphate (62mg, 0.29mmol) were dissolved in 1, 4-dioxane (30mL), cuprous iodide (40mg, 0.21mmol) was added under nitrogen protection, after completion of the heating to reflux and stirring overnight, the reaction solution was filtered, the filtrate was evaporated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give the title compound (39mg, yield: 41.1%).
MS m/z(ESI)：454[M+H]+
1H-NMR(400MHz，DMSO-d6)δ：8.91(s，1H)，8.06-8.02(m，1H)，7.97-7.94(m，2H)，7.79(s，1H)，7.69(d，J＝1.2Hz，1H)，7.47(s，1H)，7.17(d，J＝0.8Hz，1H)，5.38(m，1H)，4.25(t，J＝6.4Hz，2H)，3.18(t，J＝6.0Hz，2H)，2.24(s，3H)，1.89-1.82(m，1H)，1.51(s，3H)，1.49(s，3H)，0.83-0.78(m，2H)，0.73-0.69(m，2H)。
Example 2: preparation of 6- (4-cyclopropyl-1H-imidazol-1-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4H-chromen-4-one (Compound 2)
Figure BDA0001890952750000131
The first step is as follows: preparation of 1- (2-methoxy-4-methylphenyl) ethanone
1- (2-hydroxy-4-methylphenyl) ethanone (5.0g, 33.3mmol) was added to tetrahydrofuran (50mL), potassium hydroxide (2.8g, 49.9mmol) was added, methyl iodide (11.8g, 83.3mmol) was added dropwise, and after the addition was completed, the mixture was stirred at room temperature for 48 hours. The reaction mixture was slowly added dropwise to ice water, extracted with ethyl acetate (50 mL. multidot.3), dried, filtered and concentrated to give the title compound of this step (5.4g, yield: 99%).
The second step is that: preparation of 1- (2-methoxy-4-methyl-5-nitrophenyl) ethanone
The compound (5.4g, 32.9mmol) obtained in the first step was added to concentrated sulfuric acid (50mL), cooled to-10 ℃ and concentrated nitric acid (3.47g, 34.3mmol) was added dropwise, followed by stirring at room temperature for 0.5 hour. The reaction was slowly added dropwise to ice water to precipitate a solid, which was filtered and dried to give the crude title compound (7.12g) of this step, which was used directly in the next reaction.
The third step: preparation of 1- (5-amino-2-methoxy-4-methylphenyl) ethanone
The compound (7.12g, 34.1mmol) obtained in the second step was dissolved in a mixed solvent of ethanol and tetrahydrofuran (2: 1, 80mL), palladium on carbon (800mg) was added, hydrogen gas was substituted, and the mixture was stirred at room temperature overnight. The reaction solution was then filtered, and concentrated to give the title compound of this step (2.43g, yield: 40%).
The fourth step: preparation of 2- ((5-acetyl-4-methoxy-2-methylphenyl) amino) -1-cyclopropylethanone
The compound (2.43g, 13.6mmol) obtained in the third step was dissolved in DMF (30mL), potassium carbonate (2.24g, 16.3mmol) and potassium iodide (2.46g, 15.0mmol) were added, stirring was carried out at room temperature for 5 minutes, 2-bromo-1-cyclopropylethanone (2.64g, 16.3mmol) was added, and heating was carried out at 60 ℃ for 4 hours. The reaction solution was then cooled, water was added, and extraction with ethyl acetate, dried, filtered, concentrated, and purified by silica gel column chromatography to give the title compound of this step (2.17g, yield: 62%).
The fifth step: preparation of 1- (5- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -2-methoxy-4-methylphenyl) ethanone
The compound (2.17g, 8.3mmol) obtained in the fourth step was dissolved in acetic acid (25mL), potassium thiocyanate (1.62g, 16.6mmol) was added and heated to 110 ℃ and stirred for 4 hours. The reaction solution was then cooled, water was added, extraction was performed with ethyl acetate, dried, filtered and concentrated, and the residue was purified by silica gel column chromatography to give the title compound of this step (2.13g, yield: 85%).
And a sixth step: preparation of 1- (5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxy-4-methylphenyl) ethanone
Hydrogen peroxide (2.39g, 21.3mmol) was dissolved in acetic acid (20mL) and water (5mL) and heated to 45 deg.C, then the compound obtained in the fifth step (2.13g, 7.1mmol) was added in portions and, after completion, stirred for 0.5 h. The reaction solution was then cooled, pH-adjusted to 10 with aqueous ammonia, water was added, extraction was conducted with ethyl acetate, drying, filtration and concentration were conducted, and the residue was purified by silica gel column chromatography to give the title compound of this step (0.97g, yield: 51%).
The seventh step: preparation of 1- (5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxy-4-methylphenyl) -2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) ethanone
The compound (972mg, 3.6mmol) obtained in the sixth step was dissolved in 1, 4-dioxane (10mL), 2-bromo-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine (1.92g, 7.2mmol) and sodium tert-butoxide (865mg, 9.0mmol) were added, nitrogen gas was replaced, and Pd was added2(dba)3(329mg, 0.36mmol) and Xantphos (416mg, 0.72mmol) and heated to 90 ℃ with stirring overnight. The reaction solution was then cooled, water was added, extracted with ethyl acetate, dried, filtered, concentrated, and the residue was purified by silica gel column chromatography to give the title compound of this step (604mg, yield: 36%).
Eighth step: preparation of 1- (5- (4-cyclopropyl-1H-imidazol-1-yl) -2-hydroxy-4-methylphenyl) -2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) ethanone
The compound (604mg, 1.3mmol) obtained in the seventh step was dissolved in methylene chloride (10mL), cooled to 0 ℃ and boron tribromide (2.55mL, 2.6mmol) was added dropwise, followed by stirring at room temperature for 2 hours. Water was then added dropwise at 0 deg.C, pH adjusted to 8 with sodium bicarbonate solution, extracted with ethyl acetate, dried, filtered and concentrated to give the crude title compound of this step (700mg) which was used directly in the next reaction.
The ninth step: preparation of 6- (4-cyclopropyl-1H-imidazol-1-yl) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -7-methyl-4H-chromen-4-one
The compound (700mg, 1.58mmol) obtained in the eighth step was dissolved in DMF-DMA (5mL) and DMF (1mL) and stirred at 40 ℃ overnight. The reaction solution was concentrated, and the residue was purified by preparative high performance liquid chromatography to give the title compound (240 mg).
MS m/z(ESI)：452[M+H]+
1H-NMR(400MHz，DMSO-d6)6：8.99(s，1H)，8.94(s，1H)，8.35-8.32(m，1H)，8.13-8.09(m，2H)，7.96(s，1H)，7.86(s，1H)，7.77(d，J＝1.2Hz，1H)，7.26(d，J＝1.6Hz，1H)，5.49-5.46(m，1H)，2.34(s，3H)，1.90-1.84(m，1H)，1.54-1.52(m，6H)，0.84-0.81(m，2H)，0.74-0.71(m，2H)。
Example 3: preparation of 6-cyclopropyl-7- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (Compound 3)
Figure BDA0001890952750000141
The first step is as follows: preparation of 6-cyclopropyl-7- (4-cyclopropyl-1H-imidazol-1-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
Placing 6-bromo-7- (4-cyclopropyl-1H-imidazol-1-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (350mg, 1.05mmol), cyclopropylboronic acid (1.8g, 21.00mmol) and potassium carbonate (290mg, 2.10mmol) in a single-neck flask, adding 1, 4-dioxane (20.0mL) and water (0.5mL), replacing with nitrogen for 3 times, adding Pd (dppf) Cl2(40mg), after the addition, the temperature was raised to 100 ℃ and the mixture was stirred for 10 hours, the reaction mixture was filtered, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give the objective compound of this step (136mg, yield: 44.2%).
The second step is that: preparation of 6-cyclopropyl-7- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
The compound (100mg, 0.34mmol) obtained in the first step, 2-bromo-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine (136mg, 0.51mmol), potassium phosphate anhydrous (102mg, 0.48mmol) and trans-N, N' -dimethyl-1, 2-cyclohexanediamine (53mg, 0.37mmol) were dissolved in 1, 4-dioxane (8mL), cuprous iodide (65mg, 0.34mmol) was added, after addition, the reaction mixture was stirred overnight with warming to 95 ℃, the filtrate was filtered and evaporated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give the objective compound (70mg, yield: 42.9%).
MS m/z(ESI)：480[M+H]+
1H-NMR(400MHz，DMSO-d6)δ：8.91(s，1H)，8.05-7.80(m，1H)，7.98-7.94(m，2H)，7.77(s，1H)，7.71(d，J＝1.2Hz，1H)，7.19(d，J＝1.2Hz，1H)，7.11(s，1H)，5.41-5.34(m，1H)，4.23(t，J＝6.0Hz，2H)，3.16(t，J＝6.0Hz，2H)，1.89-1.83(m，1H)，1.69-1.63(m，1H)，1.50(s，3H)，1.49(s，3H)，1.02-0.98(m，2H)，0.85-0.78(m，4H)，0.74-0.70(m，2H)。
Example 4: preparation of 6-chloro-7- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (Compound 4)
Figure BDA0001890952750000151
The first step is as follows: preparation of 5-chloro-6-nitro-2, 3-dihydro-1H-inden-1-one
5-chloro-2, 3-dihydro-1H-inden-1-one (5.0g, 30.1mmol) was added slowly in portions to fuming nitric acid (40mL) at-10 ℃ and the reaction was maintained at low temperature for 2 hours. The reaction mixture was poured into ice water to precipitate a solid, which was then filtered, and the filter cake was washed with water and dried to obtain the title compound (6.0g, yield: 94.3%) of this step.
The second step is that: preparation of 6-amino-5-chloro-2, 3-dihydro-1H-inden-1-one
The compound (4.0g, 19.0mmol) obtained in the first step, iron powder (5.3g, 94.6mmol) and ammonium chloride (5.2g, 97.2mmol) were added to a mixed solvent of ethanol (50mL) and water (10mL) and reacted at 90 ℃ overnight under nitrogen. Then, the mixture was filtered through celite while it was hot, and the filter cake was sufficiently washed with methanol, and the filtrate was collected, dried, and concentrated to obtain the title compound of this step (3.0g, yield: 87.3%).
The third step: preparation of 5-chloro-6- ((2-cyclopropyl-2-oxoethyl) amino) -2, 3-dihydro-1H-inden-1-one
The compound obtained in the second step (600mg, 3.3mmol), potassium carbonate (915mg, 6.6mmol), potassium iodide (116mg, 0.7mmol) and 2-bromo-1-cyclopropylethanone (806mg, 5.0mmol) were dissolved in DMF (10mL) and reacted at 60 ℃ under nitrogen overnight. The reaction solution was then filtered, and the filtrate was collected, concentrated and purified by preparative high performance liquid chromatography to give the title compound of this step (300mg, yield: 34.4%).
The fourth step: preparation of 5-chloro-6- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -2, 3-dihydro-1H-inden-1-one
The compound (300mg, 1.2mmol) obtained in the third step was dissolved in acetic acid (10mL), and potassium thiocyanate (233mg, 2.4mmol) was added and reacted at 110 ℃ for 4 hours. Then, extraction was performed with methylene chloride, and the organic phase was concentrated to obtain the title compound (300mg, yield: 86.4%) of this step.
The fifth step: preparation of 5-chloro-6- (4-cyclopropyl-1H-imidazol-1-yl) -2, 3-dihydro-1H-inden-1-one
The compound (300mg, 1.0mmol) obtained in the fourth step was dissolved in acetic acid (10mL) and water (1mL), hydrogen peroxide (0.5mL, 3.0mmol) was added and reacted at 50 ℃ for 1 hour. The reaction was then quenched with aqueous sodium sulfite solution, extracted with dichloromethane, and the organic phase was concentrated to give the title compound of this step (250mg, yield: 93.4%).
And a sixth step: preparation of 6-chloro-7- (4-cyclopropyl-1H-imidazol-1-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
The compound (300mg, 1.1mmol) obtained in the fifth step was dissolved in dichloromethane (3mL) and methanesulfonic acid (3mL), and sodium azide (143mg, 2.2mmol) was added in portions under ice bath and reacted at 0 ℃ for 2 hours. The reaction was then quenched with 2N aqueous sodium hydroxide solution, extracted with dichloromethane, and the organic phase was concentrated to give the title compound of this step (200mg, yield: 63.4%).
The seventh step: preparation of 6-chloro-7- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
The compound (100mg, 0.4mmol) obtained in the sixth step and 2-bromo-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine (100mg, 0.4mmol) were dissolved in 1, 4-dioxane (10mL), and potassium phosphate (149mg, 0.8mmol), trans-N, N' -dimethyl-1, 2-cyclohexanediamine (30mg) and cuprous iodide (20mg) were added and reacted at 99 ℃ overnight. Extraction with dichloromethane and concentration of the organic phase followed by purification by preparative high performance liquid chromatography gave the title compound (20mg, yield: 12.4%).
MS m/z(ESI)：474.0[M+H]+
1H-NMR(400MHz，DMSO-d6)δ：8.92(s，1H)，8.07-7.96(m，4H)，7.84(s，1H)，7.78(s，1H)，7.24(s，1H)，5.41-5.34(m，1H)，4.27(t，J＝6.4Hz，2H)，3.23(t，J＝6.0Hz，2H)，1.88-1.86(m，1H)，1.51(s，3H)，1.49(s，3H)，0.83-0.70(m，4H)。
Example 5: preparation of 6- (4-cyclopropyl-1H-imidazol-1-yl) -7-fluoro-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4H-chromen-4-one (Compound 5)
Figure BDA0001890952750000161
The first step is as follows: preparation of 1- (4-fluoro-2-methoxy-5-nitrophenyl) ethanone
1- (4-fluoro-2-methoxyphenyl) ethanone (5.5g, 32.7mmol) was added to concentrated sulfuric acid (36mL), cooled to-10 ℃, and potassium nitrate (3.47g, 34.3mmol) was added in portions, followed by stirring at room temperature for 3 hours. The reaction mixture was slowly added dropwise to ice water to precipitate a solid, which was then filtered and dried to obtain the title compound (6.654g, yield: 99%) of this step.
The second step is that: preparation of 1- (5-amino-4-fluoro-2-methoxyphenyl) ethanone
The compound (6.654g, 31.2mmol) obtained in the first step was dissolved in a mixed solvent of ethanol and tetrahydrofuran (2: 1, 70mL), palladium on carbon (600mg) was added, hydrogen gas was substituted, and the mixture was stirred at room temperature overnight. The reaction solution was then filtered, and concentrated to give the title compound of this step (5.571g, yield: 100%).
The third step: preparation of 2- ((5-acetyl-2-fluoro-4-methoxyphenyl) amino) -1-cyclopropylethanone
The compound obtained in the second step (5.571g, 30.4mmol) was dissolved in DMF (60mL), potassium carbonate (5.05g, 36.5mmol) and potassium iodide (5.5g, 33.4mmol) were added, and stirring was carried out at room temperature for 5 minutes, followed by addition of 2-bromo-1-cyclopropylethanone (9.8g, 60.1mmol), and heating to 60 ℃ for 4 hours. The reaction solution was then cooled, water was added thereto, extracted with ethyl acetate, dried, filtered, concentrated and purified by preparative high performance liquid chromatography to give the title compound of this step (3.94g, yield: 48%).
The fourth step: preparation of 1- (5- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -4-fluoro-2-methoxyphenyl) ethanone
The compound (3.94g, 15mmol) obtained in the third step was dissolved in acetic acid (40mL), potassium thiocyanate (2.89g, 30mmol) was added, and the mixture was heated to 110 ℃ and stirred for 4 hours. The reaction was then cooled, water was added, extracted with ethyl acetate, dried, filtered and concentrated to give the crude title compound of this step (4.96 g).
The fifth step: preparation of 1- (5- (4-cyclopropyl-1H-imidazol-1-yl) -4-fluoro-2-methoxyphenyl) ethanone
Hydrogen peroxide (5.51g, 48.6mmol) was dissolved in acetic acid (50mL) and water (13mL) and heated to 45 ℃ and then the compound obtained in the fourth step (4.96g, 16.2mmol) was added in portions and, after the addition was complete, stirred for 0.5 h. The reaction solution was then cooled, pH-adjusted to 10 with aqueous ammonia, water was added, extraction was performed with ethyl acetate, drying, filtration, concentration and purification by preparative high performance liquid chromatography gave the title compound of this step (1.8g, yield: 40%).
And a sixth step: preparation of 1- (5- (4-cyclopropyl-1H-imidazol-1-yl) -4-fluoro-2-methoxyphenyl) -2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) ethanone
The compound (700mg, 2.5mmol) obtained in the fifth step was dissolved in 1, 4-dioxane (10mL), 2-bromo-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine (819mg, 3.0mmol) and sodium tert-butoxide (490mg, 5.0mmol) were added, nitrogen gas was substituted, and Pd was added2(dba)3(49mg, 0.5mmol) and Xantphos (60mg, 1.0mmol) and heated to 90 ℃ and stirred overnight. Then cooling the reaction solution, adding water, extracting with ethyl acetate, drying, filtering, concentrating, and purifying by preparative high performance liquid chromatography to obtain the final productThe title compound of step (60mg, yield: 5.1%).
The seventh step: preparation of 1- (5- (4-cyclopropyl-1H-imidazol-1-yl) -4-fluoro-2-hydroxyphenyl) -2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) ethanone
The compound (60mg, 0.13mmol) obtained in the sixth step was dissolved in methylene chloride (5mL), cooled to 0 ℃ and boron tribromide (650mg, 2.6mmol) was added dropwise, followed by stirring at room temperature for 2 hours after the addition. Water was then added dropwise at 0 deg.C, pH adjusted to 8 with sodium bicarbonate solution, extracted with ethyl acetate, dried, filtered and concentrated to give the crude title compound of this step (60 mg).
Eighth step: preparation of 6- (4-cyclopropyl-1H-imidazol-1-yl) -7-fluoro-3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4H-chromen-4-one
The compound (60mg, 0.12mmol) obtained in the seventh step was dissolved in DMF-DMA (5mL) and DMF (1mL) and stirred at 40 ℃ overnight. The reaction solution was concentrated and purified by preparative high performance liquid chromatography to give the title compound (22 mg).
MS m/z(ESI)：457[M+H]+
1H-NMR(400MHz，DMSO-d6)δ：9.08(s，1H)，8.93(s，1H)，8.30-8.13(m，2H)，8.10-8.00(m，3H)，7.97-7.95(m，1H)，7.68(s，1H)，5.46-5.35(m，1H)，1.90-1.87(m，1H)，1.65-1.60(m，6H)，0.84-0.80(m，2H)，0.75-0.72(m，2H)。
Example 6: preparation of 6- (4-cyclopropyl-1H-imidazol-1-yl) -7- (dimethylamino) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4H-chromen-4-one (Compound 6)
Figure BDA0001890952750000171
The first step is as follows: preparation of 1- (5- (4-cyclopropyl-1H-imidazol-1-yl) -4- (dimethylamino) -2-methoxyphenyl) ethanone
1- (5- (4-cyclopropyl-1H-imidazol-1-yl) -4-fluoro-2-methoxyphenyl) ethanone (200mg, 0.73mmol) was added to DMSO (5mL), potassium carbonate (605mg, 4.4mmol) was added, finally dimethylamine hydrochloride (179mg, 2.2mmol) was added, after addition warmed to 80 ℃ and stirred overnight. The reaction mixture was slowly added dropwise to water to precipitate a solid, which was then filtered and dried to obtain the title compound (218mg, yield: 99%) of this step.
The second step is that: preparation of 1- (5- (4-cyclopropyl-1H-imidazol-1-yl) -4- (dimethylamino) -2-methoxyphenyl) -2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) ethanone
The compound (218mg, 0.73mmol) obtained in the first step was dissolved in 1, 4-dioxane (5mL), 2-bromo-6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridine (194mg, 1.1mmol) and sodium tert-butoxide (175mg, 1.8mmol) were added, nitrogen was substituted, and Pd was added2(dba)3(13mg, 0.01mmol) and Xantphos (17mg, 0.02mmol) and heated to 90 ℃ with stirring overnight. The reaction solution was then cooled, water was added, extracted with ethyl acetate, dried, filtered, concentrated and purified by preparative high performance liquid chromatography to give the title compound of this step (145mg, yield: 41%).
The third step: preparation of 1- (5- (4-cyclopropyl-1H-imidazol-1-yl) -4- (dimethylamino) -2-hydroxyphenyl) -2- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) ethanone
The compound (145mg, 0.30mmol) obtained in the second step was dissolved in methylene chloride (5mL), cooled to 0 ℃ and boron tribromide (716mg, 3.0mmol) was added dropwise, followed by stirring at room temperature for 2 hours after the addition. Water was then added dropwise at 0 deg.C, pH adjusted to 8 with sodium bicarbonate solution, extracted with ethyl acetate, dried, filtered and concentrated to give the crude title compound of this step (110 mg).
The fourth step: preparation of 6- (4-cyclopropyl-1H-imidazol-1-yl) -7- (dimethylamino) -3- (6- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) pyridin-2-yl) -4H-chromen-4-one
The compound (110mg, 0.23mmol) obtained in the third step was dissolved in DMF-DMA (5mL) and DMF (1mL) and stirred at 40 ℃ overnight. The reaction solution was concentrated and purified by preparative high performance liquid chromatography to give the title compound (10 mg).
MS m/z(ESI)：482[M+H]+
1H-NMR(400MHz，DMSO-d6)δ：8.93(s，1H)，8.88(s，1H)，8.34-8.32(m，1H)，8.09-8.07(m，2H)，7.83-7.80(m，2H)，7.23(s，1H)，7.17(s，1H)，5.46(s，1H)，2.6(s，6H)，1.87-1.83(m，1H)，1.53-1.51(m，6H)，0.83-0.80(m，2H)，0.75-0.70(m，2H)。
Using synthetic procedures analogous to those described above for examples 1-6 and known to those skilled in the art, the following compounds in Table 1 were prepared:
TABLE 1
Figure BDA0001890952750000181
Figure BDA0001890952750000191
Drug efficacy screening method and data
Experimental example 1: ASK1 enzyme activity inhibition test
1.1 test methods
The inhibition of ASK1 enzyme by compounds was determined using the KinEASE-STK (Cisbio) kit. The reaction was initiated by pre-incubating ASK1 enzyme with different concentrations of test compound for 30 minutes at room temperature and adding substrate and Adenosine Triphosphate (ATP). After incubation for 120 min at room temperature, detection was carried out after addition of TK antibody-cryptate and streptavidin-XL 665. The relative percent inhibitory activity of the test compounds at different concentrations was calculated by the following formula, using the vehicle group (DMSO) as a negative control and the buffer group (without ASK1 enzyme) as a blank control:
the percentage of relative inhibitory activity was 1- (test compound group-buffer group)/(vehicle group-buffer group) at various concentrations 100%
The percent relative inhibitory activity of the compound groups at different concentrations was plotted against compound concentration, and the IC was calculated according to the following equation, fitting a curve to a four parameter model50The value:
y＝min+(max-min)/(1+(x/IC50)^(-Hillslope))
where y is the relative percent inhibitory activity, max and min are the maximum and minimum values of the fitted curve, respectively, x is the log concentration of the compound, and Hillslope is the slope of the curve.
1.2 test results
The inhibitory effect of the compounds on ASK1 activity was determined according to the above method, and the results are shown in table 2:
TABLE 2
Compound numbering IC50(nM)
1 5.1
2 1.3
3 0.7
4 1.6
5 0.7
6 0.4
1.3 conclusion of the test
As shown in Table 2, the compounds of the present invention all have strong inhibitory activity against ASK1 enzyme.
Experimental example 2: rat Pharmacokinetic (PK) study
Respectively administered by vein (IV) and intragastric (PO)The compounds of the invention were administered to male SD rats and pharmacokinetic characteristics were examined. The dosages of IV and PO were 1mg/kg and 5mg/kg, respectively, with IV vehicle being 5% DMSO: 5% Solutol: 90% saline, and PO vehicle being 0.5% MC. Blood was collected at various time points after IV and PO dosing, blood was edta.k2Anticoagulated, centrifuged to obtain plasma samples, stored at-80 ℃. Plasma samples were processed for precipitated protein and analyzed by LC-MS/MS. Pharmacokinetic parameters were calculated using the winnonlin6.3 software using a non-compartmental model, and the results are shown in tables 3 and 4.
Table 3: pharmacokinetic parameters of IV administered Compounds in rats
Figure BDA0001890952750000201
As shown in Table 3, the in vivo exposure (AUC) of Compound 2 and Compound 6 of the present invention to rats administered at a dose IV of 1mg/kglast) 2727h ANG/mL and 3218h ANG/mL respectively, corresponding to maximum blood concentration (C)max) 860ng/mL and 989ng/mL, respectively, indicate that Compound 2 and Compound 6 of the present invention have excellent drug exposure in rats by IV administration.
Table 4: pharmacokinetic parameters of PO-dosed Compounds in rats
Figure BDA0001890952750000211
As shown in Table 4, AUC in rat blood of Compound 2 and Compound 6 of the present invention administered by PO at a dose of 5mg/kglast13381h ng/mL and 8580h ng/mL respectively, and bioavailability of 98.1% and 53.1% respectively, indicating that Compound 2 and Compound 6 of the present invention have excellent drug exposure and bioavailability in rats by PO administration.
Other compounds of the invention also have AUC's similar to those described abovelastValue, CmaxValue and bioavailability of a drug similar to those described above in ratsPharmacokinetic properties.
While specific embodiments of the invention have been described in detail, it will be appreciated by those skilled in the art that various modifications and alternatives to those details could be developed in light of the overall teachings of the disclosure, and that such modifications are intended to be within the scope of the disclosure. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (20)

1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein:
Figure FDA0003072576960000011
Figure FDA0003072576960000012
represents a single or double bond, wherein
Figure FDA0003072576960000013
At most one double bond;
R1is a 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: c1-6Alkyl radical, C1-6Haloalkyl and C3-6A cycloalkyl group;
R2selected from halogen, N (R)4)(R5)、C1-6Alkyl radical, C1-6Haloalkyl and C3-10A cycloalkyl group;
R3is selected from C1-6Alkyl and C3-6Cycloalkyl, wherein said alkyl or cycloalkyl is each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxy and-O-C1-6An alkyl group;
q is selected from C and N;
y is selected from N (R)4) And O;
z is selected from C (R)4) And C (R)4)(R5) (ii) a And is
R4And R5Each independently selected from hydrogen and C1-6Alkyl and C3-6A cycloalkyl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of formula (IV) or formula (V), wherein:
Figure FDA0003072576960000014
R1、R2、R3and R4As defined in claim 1.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: r1Is a 5-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: c1-4Alkyl radical, C1-4Haloalkyl and C3-6A cycloalkyl group.
4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein: r1Independently an imidazolyl group, which is optionally substituted with one or two methyl, ethyl, isopropyl, cyclopropyl or trifluoromethyl groups.
5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein: r1Independently 4-cyclopropyl-1H-imidazol-1-yl.
6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: r2Selected from halogen, N (R)4)(R5)、C1-4Alkyl radical, C1-4Haloalkyl and C3-6Cycloalkyl radical, R4And R5As defined in claim 1.
7. The compound of claim 6 or a pharmaceutically acceptable salt thereofA salt of (i) wherein: r2Selected from fluorine, chlorine, bromine, iodine, dimethylamino, C1-4Alkyl radical, C1-4Fluoroalkyl and C3-6A cycloalkyl group.
8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein: r2Selected from the group consisting of fluoro, chloro, dimethylamino, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl and difluoromethyl.
9. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: r3Is selected from C1-4Alkyl radical, C1-4Haloalkyl, C1-4alkyl-O-C1-4Alkyl or C3-6A cycloalkyl group.
10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein: r3Selected from methyl, ethyl, isopropyl or cyclopropyl.
11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein: r3Is isopropyl.
12. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: r4And R5Each independently selected from hydrogen and C1-4Alkyl and C3-6A cycloalkyl group.
13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein: r4And R5Each independently selected from hydrogen, methyl, ethyl, isopropyl or cyclopropyl.
14. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure FDA0003072576960000021
Figure FDA0003072576960000031
15. a pharmaceutical composition comprising a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, and optionally, one or more pharmaceutically acceptable carriers or excipients.
16. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, in the manufacture of a medicament for use as an inhibitor of apoptosis signal-regulating kinase 1(ASK 1).
17. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, in the manufacture of a medicament for the treatment of an ASK1 mediated disease or condition.
18. The use of claim 17, wherein the ASK1 mediated disease or condition is selected from the group consisting of conditions and diseases caused by chronic fatty or fibrotic degeneration; (ii) an autoimmune disease; respiratory diseases; inflammatory diseases; chronic kidney disease; cardiovascular diseases; diabetes and neurodegenerative diseases.
19. The use of claim 17, wherein the ASK1 mediated disease or condition is selected from the group consisting of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, extrahepatic cholestatic conditions; liver fibrosis; obstructive or chronic inflammatory disorders of the liver; cirrhosis of the liver; COPD, Idiopathic Pulmonary Fibrosis (IPF) and acute lung injury; diabetic nephropathy and other complications of diabetes.
20. The use of claim 17, wherein the ASK1 mediated disease or condition is selected from the group consisting of cholestatic and fibrotic effects associated with alcohol-induced cirrhosis or with viral infectious forms of hepatitis.
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