WO2020143385A1 - Inhibiteur d'arylamide, son procédé de préparation et son application - Google Patents

Inhibiteur d'arylamide, son procédé de préparation et son application Download PDF

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WO2020143385A1
WO2020143385A1 PCT/CN2019/124633 CN2019124633W WO2020143385A1 WO 2020143385 A1 WO2020143385 A1 WO 2020143385A1 CN 2019124633 W CN2019124633 W CN 2019124633W WO 2020143385 A1 WO2020143385 A1 WO 2020143385A1
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吕彬华
崔大为
王润卿
庞旭东
刘连军
汪祝兵
盛泽林
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Suzhou Zelgen Biopharmaceutical Co Ltd
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    • 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
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Definitions

  • the mitotic activated protein kinase signaling (MAPK) pathway is a key signaling pathway for cell mitosis and apoptosis.
  • MAPK mitotic activated protein kinase kinase kinase
  • MAP3K mitotic activated protein kinase kinase kinase
  • MAP2K mitotic activated protein kinase kinase
  • MAPK mitotic activated protein kinase kinase kinase
  • MAP3K mitotic activated protein kinase kinase
  • MAPK mitotic activated protein kinase kinase kinase
  • Apoptosis signal kinase 1 (ASK1) is one of the members of the mitogen-activated protein kinase kinase family and plays a key role in cytokine and stress-induced apoptosis (Paul Yosuke Kawarazaki, Hidenori Ichijo, Isao Naguro, Expert Opin. Ther. Targets 2014 18(6):651-664). Numerous animal and human experiments have shown that the ASK1 pathway is overexpressed in hepatocytes of obese and non-alcoholic fatty liver patients, and is closely related to steatosis, insulin resistance and inflammation.
  • apoptosis signal kinase 1 is expected to become a new generation of drugs for the treatment of inflammatory and metabolic diseases (such as non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver fibrosis and cirrhosis). Therefore, ASK1 inhibitors have very good development and application prospects as pharmaceuticals in the pharmaceutical industry.
  • the object of the present invention is to provide a class of compounds with novel structures, which can be used as selective ASK1 inhibitors, have selective inhibitory effects on apoptosis signal kinase 1, excellent pharmacodynamic properties and the like.
  • an arylamide compound having the structure of general formula (I), or a stereoisomer, tautomer, racemate, or polymorph thereof, or Pharmaceutically acceptable salts, hydrates, solvates, or prodrugs;
  • M 1 and M 2 are each independently selected from: N or CR 7 ;
  • Ring A is selected from the group consisting of substituted or unsubstituted C3-C20 carbocycles (preferably, C3-C10 carbocycles), substituted or unsubstituted 3-20 membered heterocycles (preferably, 3-12 membered heterocycles) Ring), substituted or unsubstituted C6-C20 aromatic ring (preferably, C6-C12 aromatic ring) or substituted or unsubstituted 5-20 membered heteroaromatic ring (preferably, 5 to 12 membered heteroaromatic ring) ;
  • the substitution means that ring A is substituted by oxo, thio, or -(CH 2 ) n- (that is, two hydrogen atoms connected to the same carbon atom on the group are replaced by the group), Or H on ring A is substituted with one or more (preferably 1 to 3) substituents selected from the group consisting of deuterium atoms, substituted or unsubstituted alkyl groups, substituted or un
  • Each R 1 is the same or different, and each independently is a group selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, amino, nitro, hydroxyl, cyanide Group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH 2 ) n R 10 , -(CH 2 ) n OR 10 , -(CH 2 ) n CH(R 10 )(CH 2 ) o NR 11 R 12 (including: -(CH 2 ) n CH(OH)(CH 2 ) o NHR 11 ), -(CH 2 ) n O(CH 2 ) o R 10 , -(CH 2 ) n SR 10 , -(CH 2 ) n COR 10
  • R 2 , each of R 3 and R 5 are independently selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyanide Group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH 2 ) n OR 10 , -(CH 2 ) n SR 10 , -(CH 2 ) n COR 10 , -(CH 2 ) n C(O)OR 10 , -(CH 2 ) n S(O) m R 10 , -(CH 2 ) n NR 11 R 12 , -(CH 2 ) n C(O)NR 11 R 12 (preferably -(CH
  • R 4 is selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, hydroxyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; alternatively, R 4 and M 3 together with the N atom connected to them form a ring selected from the group consisting of substituted or unsubstituted heterocycle, substituted or unsubstituted Substituted heteroaromatic ring;
  • M 3 and M 4 are each independently selected from N or CR 7 ; or M 3 and M 4 and their adjacent chemical bonds together constitute a group selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group;
  • M 5 is selected from the group: N or CR 7 ;
  • X and Y are independently selected from: bond, -NR 8 -, CR 8 R 9 -, -S(O) m -,
  • X and/or Y and M 1 , M 2 or M 5 and the chemical bonds to which they are connected together form a ring selected from the group consisting of substituted or unsubstituted carbocycles, substituted or unsubstituted heterocycles, substituted or unsubstituted Aromatic ring, substituted or unsubstituted heteroaromatic ring;
  • R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, amino, nitro, hydroxyl, cyano , Substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH 2 ) n OR 10 , -(CH 2 ) n SR 10 , -(CH 2 ) n COR 10 , -(CH 2 ) n C(O)OR 10 , -(CH 2 ) n S(O) m R 10 , -(CH 2 ) n NR 11 R 12 , -(CH 2 ) n C(O)NR 11 R 12 (including -(CH 2 )
  • substitution refers to the substitution of one or more (preferably 1-3) hydrogen atoms on the group with substituents selected from the group consisting of deuterium atoms, alkyl groups, deuterated alkyl groups, Haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R 10 , -(CH 2 ) n OR 10 , -(CH 2 ) n SR 10 , -(CH 2 ) n COR 10 , -(CH 2 ) n C(O)OR 10 , -(CH 2 ) n S(O) m R 10 , -(CH 2 ) n NR 11 R 12 , -(CH 2 ) n C(O)NR 11 R 12 (including -(CH 2 ) n C(O)
  • R 10 is independently selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, amino group, hydroxyl group, cyano group, substituted or unsubstituted cycloalkyl group, substitution Or unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group;
  • R 13 and R 14 are each independently selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, amino group, hydroxyl group, ester group, substituted or unsubstituted cycloalkane Group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; wherein, in R 13 and R 14 , the substitution refers to one or more groups on the group (Preferably 1-3) hydrogen atoms are substituted with substituents selected from the group consisting of deuterium atoms, alkyl groups, alkoxy groups, halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, ester groups;
  • R 5 is a hydrogen atom or a deuterium atom.
  • each R 1 is independently a substituted or unsubstituted group selected from the group consisting of:
  • substitution means that one or more (preferably 1-3) hydrogens on the group are replaced by a substituent selected from the group consisting of deuterium atom, halogen, C1-C6 alkyl, C1-C6 haloalkyl , C1-C6 deuterated alkyl.
  • each R 1 is independently a corresponding group in a specific compound.
  • R 8 is selected from a hydrogen atom or a deuterium atom; or, (ii) X, Y, and M 5 and the chemical bonds connected thereto form a group selected from the group consisting of Ring: substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl.
  • M 3 is CR 7 .
  • GR-MD-02 CC chemokine receptor type 2 and type 5 (CCR2 and CCR5) dual antagonists (e.g. Cenicriviroc), hexanokinase (KHK) inhibitors (PF -06835919), glucagon-like peptide-1 (GLP-1) receptor agonist (such as liraglutide, semaglutide), anti-lysyl oxidase-like protein-2 (LOXL2) monoclonal antibody (such as seuzumab) , Cholic acid and arachidonic acid complex Aramchol, or a combination thereof.
  • Cenicriviroc Cenicriviroc
  • KHK hexanokinase
  • GLP-1 glucagon-like peptide-1
  • LXL2 anti-lysyl oxidase-like protein-2
  • ASK1-mediated diseases include: inflammation, cardiovascular disease, infection, immune disease, metabolic disease, or a combination thereof.
  • (C 1 -C 6 )alkyl refers to a linear or branched alkyl group, including from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, Tert-butyl, isobutyl.
  • Substituted alkyl means that one or more positions in the alkyl are substituted, especially 1-4 substituents, which can be substituted at any position.
  • alkenyl refers to a straight or branched chain hydrocarbon group containing 2-18 carbon atoms, at least one carbon-carbon double bond substituent. Typical groups include vinyl or allyl.
  • (C 2 -C 6 )alkenyl refers to a linear or branched group containing 2-6 carbon atoms and having at least one carbon-carbon double bond, such as vinyl, propenyl, 2-propenyl , (E)-2-butenyl, (Z)-2-butenyl, (E)-2-methyl-2-butenyl, (Z)-2-methyl-2-butenyl , 2,3-dimethyl-2-butenyl, (Z)-2-pentenyl, (E)-1-pentenyl, (Z)-1-hexenyl, (E)-2 -Pentenyl, (Z)-2-hexenyl, (E)-1-hexenyl, (Z)-1-hexenyl, (E)-2 -Penten
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include spiro, bridged or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spirocyclic heterocycles (excluding heteroaromatic rings), bridged cycloalkyl, bridged cycloalkenyl, Bridged-ring heterocycles (excluding heteroaromatic rings), fused cycloalkyl groups, fused cycloalkenyl groups, fused ring heterocyclic groups or fused ring aromatic ring groups, the above-mentioned cycloalkyl groups, cycloalkenyl groups, heterocyclic groups and heterocyclic aromatic groups The group may be optionally substituted.
  • heterocyclyl refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, for example, 4-7 membered monocyclic, 7-11 membered bicyclic, or 8-16 membered Tricyclic system), in which at least one heteroatom exists in a ring with at least one carbon atom.
  • Each heterocycle containing a heteroatom may carry 1, 2, 3, or 4 heteroatoms. These heteroatoms are selected from nitrogen, oxygen, or sulfur atoms.
  • the nitrogen or sulfur atoms can be oxidized, and the nitrogen atoms can also be It is quaternized.
  • the heterocyclic group can be attached to any heteroatom or carbon atom residue of the ring or ring system molecule.
  • aryl refers to an aromatic cyclic hydrocarbon compound group having 1 to 5 rings, especially to monocyclic and bicyclic groups such as phenyl, biphenyl, or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic ring of the aryl group can be connected by a single bond (such as biphenyl), or fused (such as naphthalene, anthracene, etc.). "Substituted aryl” means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include fused ring substituents, especially fused ring alkyl groups, fused ring alkenyl groups, fused ring heterocyclic groups or fused ring aromatic ring groups, the above mentioned cycloalkyl groups, cycloalkenyl groups, heterocyclic groups and heterocyclic aromatic groups
  • the group may be optionally substituted.
  • salts of the compounds of the present invention are also within the scope of the present invention. Unless otherwise stated, the compounds in the present invention are understood to include salts thereof.
  • the term “salt” as used herein refers to an acidic or basic salt formed with inorganic or organic acids and bases.
  • the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and when it contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions (“internal salts”) that may be formed are included in Within the scope of the term "salt”.
  • compositions of the present invention may form salts.
  • Compound I reacts with a certain amount, such as an equivalent amount of acid or base, to be salted out in a medium, or lyophilized in an aqueous solution.
  • Certain compounds of the present invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and organic base-forming salts (such as organic amines) such as benzathine and dicyclohexyl Amine, Hepamine (salt with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl Amines, and salts with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (Eg dimethyl sulfate, diethyl sulfate, dibutyl ester and dipentyl ester), long-chain halides (eg decyl, dodecyl, tetradecyl and tetradecyl chloride, bromide And iodide), aralkyl halides (such as benzyl and phenyl bromide) and so on.
  • alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates Eg dimethyl sulfate, diethyl sulfate, dibut
  • prodrugs and solvates of the compounds of the present invention are also covered.
  • prodrug here refers to a compound that produces a compound, salt, or solvate of the present invention through chemical transformations of metabolism or chemical processes when treating related diseases.
  • the compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates in the present invention may exist in tautomeric forms (eg amides and imine ethers). All these tautomers are part of the present invention.
  • the stereoisomers of all compounds are within the scope of the present invention.
  • the independent stereoisomers of the compounds in the present invention may not co-exist with other isomers (for example, as a pure or substantially pure optical isomer has a special activity), or may be a mixture, such as Racemate, or a mixture with all other stereoisomers or a part thereof.
  • the chiral center of the present invention has two configurations of S or R, which were defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974.
  • racemic form can be solved by physical methods, such as fractional crystallization, or separation and crystallization by derivatization to diastereomers, or separation by chiral column chromatography.
  • Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to traditional methods, such as salt formation with optically active acids and recrystallization.
  • the compound of the present invention the compound obtained by preparation, separation and purification in sequence has a weight content equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure” compound), described in the text Listed.
  • very pure compounds of the invention also form part of the invention.
  • the ratio of isomer mixtures containing isomers can be varied.
  • a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios easily understood by those of ordinary skill in the art, as well as ratios of mixtures of more complex isomers, are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in practice, one or more atoms are usually replaced by atoms with different atomic weight or mass number.
  • Examples of compound isotopes that can be listed as the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Isotope-labeled compounds can be prepared by a general method by replacing easily-available isotope-labeled reagents with non-isotopic reagents using the schemes disclosed in the examples.
  • a specific enantiomer synthesis of the compound of the present invention can be prepared by asymmetric synthesis, or derivatized with chiral adjuvants, the resulting diastereomeric mixture is separated, and the chiral adjuvant is removed The pure enantiomer.
  • a suitable optically active acid or base can be used to form a diastereomeric salt with it, which can then be separated by crystallization or chromatography. Separation by conventional means, and then the pure enantiomer is obtained.
  • the compounds of the present invention can be substituted with any number of substituents or functional groups to expand their scope of inclusion.
  • substitution occurs before or after the term “optional”
  • the general formula including substituents in the formulation of the present invention refers to the replacement of hydrogen radicals with a specified structural substituent.
  • each position of the substituent may be the same or different.
  • substitution includes all permissible substitutions of organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • nitrogen such as a heteroatom may have a hydrogen substituent or any allowable organic compound described above to supplement its valence state.
  • the present invention is not intended to limit the substitution of organic compounds in any way.
  • the present invention believes that the combination of substituents and variable groups is good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases.
  • stable here refers to a compound with stability, which is tested for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, and is used herein for the above purpose.
  • Metabolites of the compounds and pharmaceutically acceptable salts involved in this application, as well as prodrugs that can be converted into the structure of the compounds and pharmaceutically acceptable salts involved in this application, are also included in the claims of this application in.
  • the compound of the present invention has excellent selective inhibitory activity of apoptosis signal-regulated kinase 1 (ASK1), the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and
  • the pharmaceutical composition containing the compound of the present invention as the main active ingredient can be used for the treatment, prevention and alleviation of diseases mediated by apoptotic signal-regulated kinase 1 (ASK1).
  • ASK1 apoptotic signal-regulated kinase 1
  • the compounds of the present invention can be used to treat the following diseases: inflammation, cardiovascular disease, infection, immune disease or metabolic disease.
  • the pharmaceutical composition of the present invention contains a compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier in a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound/dose of the present invention, and more preferably, 10-500 mg of the compound/dose of the present invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components of the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarding solvents, such as paraffin; (f) Absorption accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain an opaque agent, and the release of the active compound or compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compound can also be formed into a microcapsule form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils,
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and flavors.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and flavors.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the original drug administration mode and dosage can be kept unchanged, while the compound of formula I is taken at the same time or subsequently.
  • a pharmaceutical composition containing one or more known drugs and the compound of formula I at the same time may be preferably used.
  • Drug combination also includes taking the compound of formula I with one or more other known drugs during overlapping time periods.
  • the dose of the compound of formula I or the known drugs may be lower than the dose of them alone.
  • Drugs or active ingredients that can be used in combination with the compounds of the present invention include, but are not limited to: bile acid receptor (FXR) agonists (eg, Obeticholic acid, Tropifexor, GS-9674), peroxisome proliferator activation Receptor (PPAR) agonist (eg Elafibranor, Saroglitazar, Remogliflozin Etabonate), thyroid hormone receptor ⁇ (THR ⁇ ) agonist (eg MGL-3196), diacylglycerol-O-acyltransferase (DGAT) inhibitor ( Such as Pradigastat, PF-06865571), acetyl-CoA carboxylase (ACC) inhibitors (such as GS-0976, PF-05221304), caspase inhibitors (such as Emricasan), smooth receptor (SMO) inhibitors (E.g.
  • FXR bile acid receptor
  • PPAR peroxisome proliferator activation Receptor
  • galectin inhibitors e.g. GR-MD-02
  • CCR2 and CCR5 dual antagonists e.g. Cenicriviroc
  • hexanokinase KHK
  • PF-06835919 hexanokinase inhibitor
  • GLP-1 glucagon-like peptide-1 receptor agonist
  • LXL2 anti-lysyl oxidase-like protein-2
  • Aramchol a complex of monoclonal antibodies (such as semaglutide), cholic acid, and arachidonic acid.
  • the inflammation, cardiovascular disease, infection, immune disease, metabolic disease or cancer involved in this application include (but are not limited to): primary cholestatic cirrhosis (PBC), primary sclerosing cholecystitis ( PSC), cholestasis, autoimmune hepatitis, viral hepatitis (such as hepatitis B), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver disease (NASH), or liver fibrosis; arteriosclerosis, blood lipids Disorders, hypercholesterolemia or hypertriglyceridemia; type I diabetes, type II diabetes or obesity; lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, blood cancer, bone cancer, kidney cancer, stomach cancer, liver cancer Or colorectal cancer.
  • PBC primary cholestatic cirrhosis
  • PSC primary sclerosing cholecystitis
  • cholestasis autoimmune hepatitis
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as humans) in need of treatment, wherein the dose when administered is a pharmaceutically effective dose, for a person of 60 kg body weight, daily
  • the dose to be administered is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skills of skilled physicians.
  • the object of the present invention is to provide a new class of compounds that have selective inhibitory effect on apoptosis signal-regulated kinase 1 (ASK1) or better pharmacodynamic properties and uses thereof.
  • ASK1 apoptosis signal-regulated kinase 1
  • the compound of the present invention has a structure represented by formula (I)
  • each group or ring is as described above.
  • the compound of the present invention has excellent selective inhibitory activity against apoptosis signal-regulated kinase 1 (ASK1).
  • the compounds of the present invention have low inhibitory activity against CYP3A4 and other CYP enzymes, thereby avoiding possible drug-drug interactions and increasing drug safety.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and liquid-mass spectrometry (LC-MS).
  • LC-MS Liquid chromatography-mass spectrometry
  • the thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, TLC uses 0.15-0.20mm, and the preparation thin layer chromatography uses 0.4mm-0.5mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be used or synthesized according to the literature reported in the art.
  • the resulting reaction liquid was separated with ethyl acetate (150 mL) and water (150 mL).
  • the aqueous phase was separated and extracted with ethyl acetate (2x50 mL).
  • the organic phases were combined, washed with water (2x100 mL) and saturated brine (2x100 mL), dried over anhydrous sodium sulfate, and filtered.
  • the filtrate was concentrated and dried at 40°C under reduced pressure to obtain the target product (crude product 4.2g), which was directly used in the next reaction without purification.
  • Step 4 Preparation of 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester
  • Step 5 Preparation of 7-fluoro-4-(2-methoxyethyl) 3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid
  • Step 6 7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(2-methoxyethyl Radical)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide
  • Oxalyl chloride (200 mg, 1.6 mmol) was added dropwise to 7-fluoro-4-(2-methoxyethyl)3,4-dihydro-2H-benzo[b][1,4]oxo at room temperature
  • Azine-6-carboxylic acid (200 mg, 0.78 mmol) in dichloromethane (5 mL). The reaction solution was reacted at room temperature for 1 hour, and then concentrated under reduced pressure at 40°C.
  • Step 5 Preparation of 7-fluoro-3-(hydroxymethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylic acid methyl ester
  • Step 6 Preparation of 7-fluoro-3-(methylsulfonyloxymethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylic acid methyl ester
  • Methanesulfonyl chloride (445mg, 3.87mmol) was added dropwise to 7-fluoro-3-(hydroxymethyl)-2-3-dihydrobenzo[b][1,4]dioxin-6- at room temperature
  • Methyl carboxylate (780 mg, 3.2 mmol) and diisopropylethylamine (623 mg, 4.8 mmol) in THF (5 mL).
  • the resulting mixed solution was stirred at room temperature for 2 to 3 hours, and then dichloromethane (50 mL) and water (50 mL) were added for liquid separation.
  • Step 7 Preparation of 7-fluoro-3-(methoxymethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylic acid
  • the aqueous phase was separated and extracted with dichloromethane (2x50 mL).
  • the organic phases were combined and washed with saturated brine (2x50 mL), then dried over anhydrous sodium sulfate and filtered.
  • the filtrate was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain the target product (400 mg).
  • Step 8 7-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-(methoxymethyl )
  • Step 1 Preparation of 7-fluoro-3(S)-hydroxymethyl-2,3-dihydrobenzo[b][1,4]diox-6-carboxylic acid methyl ester
  • Step 2 Preparation of 7-fluoro-3(S)-methylsulfonylhydroxymethyl-2,3-dihydrobenzo[b][1,4]diox-6-carboxylic acid methyl ester
  • Step 3 Preparation of 7-fluoro-3(S)-methoxymethyl-2,3-dihydrobenzo[b][1,4]dioxo-6-carboxylic acid
  • the aqueous phase was separated and extracted with dichloromethane (2x50 mL). All organic phases were combined and washed with saturated brine (2x50 mL), then dried over anhydrous sodium sulfate and filtered.
  • the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to obtain the target product (450 mg, yield 66%).
  • Step 1 Preparation of 1-(2-methoxyethyl)-1H-pyrrole[3,2-c]pyridine-6-carboxylic acid-(2-methoxyethyl) ester
  • N,N-dimethylmethyl 5-fluoro-6-bromo-1H-indazole 750 mg, 3.5 mmol
  • Pd(dppf)Cl 2 150 mg, 0.02 mmol
  • potassium carbonate 1.0 g, 7.2 mmol
  • a mixed solution of amide (15 mL) and methanol (30 mL) was reacted at 90-100° C. for 8-12 h under a carbon monoxide atmosphere (2 MPa). The resulting mixture was cooled to room temperature and then concentrated under reduced pressure below 40°C. The residue was separated with ethyl acetate (100 mL) and water (100 mL).
  • Step 2 Preparation of 5-fluoro-1-(methoxyethyl)-indazole-6-carboxylic acid and 5-fluoro-2-(methoxyethyl)-indazole-6-carboxylic acid
  • the third step 5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-(2-methoxy (Ethyl) 1H-indazole-6-carboxamide and 5-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl) Preparation of -2-(2-methoxyethyl) 1H-indazole-6-carboxamide
  • Example 5 Using Example 5 as a general method, the following compounds were synthesized using different starting materials.
  • the fourth step 6-fluoro-3-(2-methoxyethyl)-1-methyl-2-oxo-2-3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid preparation
  • Step 5 6-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-(2-methoxy Preparation of ethyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazole-5-carboxamide
  • hASK1 enzyme GST-ASK1 (654-971)
  • Kit ADP-Glo TM Kinase Assay 10,000 tests;
  • ATP Ultra Pure ATP, 100mM. Included in kit.
  • Glycerol Sigma-Aldrich
  • Buffer 10 mM MOPS pH 7.0; 10 mM Mg-Acetate; 1 mM DTT (added before use); 0.025% NP-40; 0.05% BSA; 1.5% glycerol.
  • Pre-prepared ASK1+MKK6 solution (2x) dilute hASK1 enzyme and MKK6 with buffer to a final concentration of 0.25nM hASK1, 300nM MKK6;
  • Pre-prepared ATP solution (2x) dilute ATP with buffer to a final concentration of 100uM;
  • step 5 Add the ASK1-MKK6 mixture (2x) to the 384-well plate to which the corresponding compound has been added in step 4, 2.5 ⁇ L/well, mix by shaking, and incubate at room temperature for 15 min.
  • Example 1 Compound number ASK1IC 50 (nM) Example 1 11.5 Example 2 5
  • Example 2A 4.1
  • Example 2B 7.3
  • Example 3A 6.0
  • Example 3B 12.4
  • Example 4B 27.4
  • Example 6 7.9
  • Example 8 15.4
  • Example 9 1.2
  • Example 18 6
  • Example 20A 42.6
  • Example 20B 55.3
  • Example 22A 74.5 Example 22B 22.7
  • Example 23A 61.0 Example 23B 26.2
  • Example 24A 24.0 Example 24B 26.3
  • Example 25 8.1
  • Example 26 70
  • Example 27 114 Example 28 64.5
  • Example 29 202 Example 30 27.7
  • Example 31 3.3
  • Example 32 19.9
  • Example 33 75.4
  • Example 34 10.2
  • Example 35A 9.3
  • Example 35B 0.9
  • Example 36 0.8
  • the compounds of the present invention exhibit better metabolic properties in rats, including higher plasma exposure AUC, maximum plasma concentration C max and half-life t 1/2 .
  • mice were adapted to feed for 3-7 days in a SPF barrier and then switched to HFD feed for 8 weeks.
  • the mice were randomly divided into groups according to body weight.
  • the grouped mice were given oral CCl 4 twice a week for four weeks.
  • the oral administration was started once a day on the day of CCl 4 modeling and continued for 28 days.
  • the vehicle control group was given a vehicle corresponding to the test article, and the administration volume was 10 mL/Kg. 48 hours after the last CCl 4 administration, the mice were euthanized with CO 2 .
  • the non-coagulated venous blood was collected from the heart of the mouse, and the whole blood was placed at room temperature for more than 30 minutes, and then centrifuged under the centrifugal condition of 5000 rpm for 5 minutes at 4 degrees Celsius. After separation, the obtained serum was divided into two portions, filled into 1.5mL EP tubes, and stored at -80 degrees Celsius for later use.
  • the alanine aminotransferase kit and aspartate aminotransferase kit were used to detect the ALT and AST levels in the serum of mice, and to score liver cell degeneration, necrosis, balloon-like degeneration, and inflammatory cell infiltration.
  • the compound of the present invention has an excellent therapeutic effect on high-fat feed (HFD) and CCl 4 induced liver vascularization.
  • test compound was mixed with human liver microsomes (0.1 mg/mL) and NADPH (1 mM) at 7 concentrations (0.14, 0.41, 1.23, 3.70, 11.11, 33.33, 100 uM in DMSO) on the probe substrate midazolam Incubate at 37°C for 5 minutes in the presence of (2.5uM).
  • a selective CYP3A4 inhibitor (ketoconazole, Ketoconazole) was used as a positive reference to conduct experiments with the test compound.
  • CYP3A4 inhibitory test testosterone, testosterone
  • Test compounds were tested at 7 concentrations (0.14, 0.41, 1.23, 3.70, 11.11, 33.33, 100 uM in DMSO) with human liver microsomes (0.1 mg/mL) and NADPH (1 mM) on the probe substrate testosterone (50 uM) Incubate for 5 minutes at 37°C in the presence of.
  • a selective CYP3A4 inhibitor (ketoconazole, Ketoconazole) was used as a positive reference to conduct experiments with the test compound.
  • control compound GS-4997 The structure of the control compound GS-4997 is as follows:

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Abstract

La présente invention concerne un inhibiteur de kinase 1 régulant le signal d'apoptose (ASK1). L'invention concerne un composé arylamide ayant la structure représentée par la formule (I), et un stéréoisomère, un tautomère ou un sel, hydrate, solvate et promédicament pharmaceutiquement acceptables de celui-ci ; et concerne également une composition pharmaceutique du sel pharmaceutiquement acceptable dudit composé. Le présent composé arylamide peut être utilisé pour traiter et prévenir une stéatohépatite non alcoolique et des maladies associées.
PCT/CN2019/124633 2019-01-09 2019-12-11 Inhibiteur d'arylamide, son procédé de préparation et son application Ceased WO2020143385A1 (fr)

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