WO2020219808A1 - Inhibiteurs dicarbamate de ns5a pour le traitement d'infections par le virus de l'hépatite c et de maladies associées - Google Patents

Inhibiteurs dicarbamate de ns5a pour le traitement d'infections par le virus de l'hépatite c et de maladies associées Download PDF

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Publication number
WO2020219808A1
WO2020219808A1 PCT/US2020/029717 US2020029717W WO2020219808A1 WO 2020219808 A1 WO2020219808 A1 WO 2020219808A1 US 2020029717 W US2020029717 W US 2020029717W WO 2020219808 A1 WO2020219808 A1 WO 2020219808A1
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bis
optionally substituted
diyl
compound
pharmaceutically acceptable
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PCT/US2020/029717
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English (en)
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Michael John COSTANZO
Michael Alan GREEN
Jirong Peng
Don Zhang
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Beta Pharma, Inc.
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Publication of WO2020219808A1 publication Critical patent/WO2020219808A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N

Definitions

  • the present invention relates to novel dicarbamate compounds, compositions and methods for the treatment or prevention of a disease, disorder, or medical condition caused by the hepatitis C virus in humans, including cirrhosis and liver cancer.
  • Hepatitis C is a liver disease that is caused by the hepatitis C virus (HCV). HCV can cause both acute and chronic hepatitis, ranging in severity from a mild infection lasting only a few weeks to a serious, lifelong illness. In 2018, it was estimated by the WHO that 71 million people globally were living with chronic hepatitis C. A significant number of these chronically infected individuals will eventually develop cirrhosis and/or liver cancer, resulting in approximately 399,000 deaths worldwide each year.
  • HCV hepatitis C virus
  • HCV hepatitis C virus
  • IFN interferon
  • the HCV genome consists of a single strand of RNA of about 9,600 nucleotides encoding a polypeptide precursor of about 3,000 amino acids. Co- and posttranslational proteolytic cleavage of this precursor by cellular and viral enzymes yields the nonstructural (NS) proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B, which are required for membrane-associated RNA replication (Kim, C. W., Chang, K.-M., Clin. Mol. Hepatol. 2013, 19, 17-25).
  • NS nonstructural
  • the nonstructural protein NS5A has been identified as a promising drug target for antiviral therapeutic intervention because it exerts functionally essential effects in regulation of HCV replication, assembly and egress (Pawlotsky, J.-M., J. Hepatol. 2013, 59, 375-382). It is a proline-rich and hydrophilic phosphoprotein of 447 residues with three domains. While no clear enzymatic functions have been assigned to NS5A, it appears to function through interactions with other HCV proteins and host cell factors. Inhibition of NS5A at picomolar concentrations has been associated with significant reductions in HCV RNA levels in cell culture-based models. In the clinic, small molecule inhibitors of NS5A have been shown to be effective when administered in combination therapy (Schinazi, R. F., Infect. Drug Resist. 2014, 7, 41-56).
  • Daclatasvir (W02008021927A2) and ledipasvir (W02010132601A1) are representative examples of dicarbamate-based NS5A inhibitors that are currently in the clinic as approved drugs.
  • Other clinically successful examples include elbasvir
  • NS5A inhibitors have certain limitations. Although many of the marketed NS5A inhibitors display potent activity against the HCV genotypes la and lb, their relative antiviral effectiveness against HCV genotypes 2-6 can vary dramatically from one structural motif to another (Gao, M., Curr. Opin. Virol. 2013, 3, 514-520). In addition, the emergence of antiviral resistance in the form of resistance-associated variants (RAVs) continues to be a problem and can render existing clinical NS5A inhibitors ineffective (Chayama, K., Biochem. Biophys. Res. Commun. 2018, 500, 152-157). Clearly a need still exists to develop new small molecule NS5A inhibitors that have pan-genotypic activity and/or are potent against RAVs.
  • RAVs resistance-associated variants
  • the present invention relates to dicarbamate compounds of the following general formula I, wherein the dash represents a covalent bond.
  • the present invention provides a compound of formula I:
  • M is selected from the formulas II, III, and IV, where R 1 at each occurrence is independently C1-C6 alkyl:
  • P 1 and P 2 are the same or different and are independently absent (a direct bond) or selected from the formulas:
  • L 1 is a direct bond to A 1 or A 2
  • L 2 is a direct bond to P 1 or P 2 ; provided, however, that P 1 and Q 1 are not both absent, and P 2 and Q 2 are not both absent; and that P 1
  • a 1 and A 2 are the same or different and are independently selected from formulas:
  • L 3 at each occurrence is independently a direct bond to B 1 or B 2 ;
  • L 4 at each occurrence is independently a direct bond to Q 1 or Q 2 ;
  • R 2 and R 3 at each occurrence are the same or different and are independently selected from H and C1-C6 alkyl optionally substituted, or taken together along with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl optionally substituted;
  • B 1 and B 2 are the same or different and are independently selected from formula: wherein R 4 is C 1 -C 6 alkyl or aryl-(Ci-C 3 ) alkyl, each optionally substituted; and R 5 is C 1 -C 6 alkyl, aryl, heteroaryl, substituted C 1 -C 6 alkyl, aryl-(Ci-C 3 ) alkyl, substituted aryl-(Ci-C 3 ) alkyl, heteroaryl-(Ci-C 3 ) alkyl, substituted heteroaryl-(Ci-C 3 ) alkyl, substituted aryl, or substituted heteroaryl; and L 5 is a direct bond to A 1 or A 2 .
  • Another aspect of the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or prodrug thereof, and one or more pharmaceutically acceptable excipients, such as adjuvants, diluents, and/or carriers.
  • Another aspect of the invention is directed to a method of inhibiting the function of an HCV NS5A protein comprising contacting a biological sample containing the HCV NS5A protein with a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, prodrug,.
  • Another aspect of the invention is directed to a method for the treatment or prevention of a disease, disorder or medical condition caused by HCV in a patient, comprising administering to the patient a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof.
  • the diseases, disorders or medical conditions caused by HCV may include cirrhosis, liver cancer or hepatitis C infection.
  • the present invention provides use of a compound of formula (I) according to any embodiments described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, prodrug, or composition thereof, in the manufacture of a medicament for treatment of a disease or disorder associated caused by HCV.
  • the compounds according to this invention can generally be prepared by a series of steps according to the synthetic methods described herein, in combination with the knowledge known to a person skilled in synthetic organic chemistry.
  • Other aspects or advantages of the present invention will be apparent to those skilled in the art in view of the following detailed description and claims in combination with the knowledge and skills generally known in the field.
  • the present invention provides novel dicarbamate compounds useful as inhibitors of
  • NS5A for the treatment of hepatitis C virus (HCV) infections and diseases or conditions associated with HCV infections.
  • HCV hepatitis C virus
  • the present invention provides a compound of formula I:
  • M is selected from the formulas II, III, and IV, where R 1 at each occurrence is independently C1-C6 alkyl:
  • P 1 and P 2 are the same or different and are independently absent (a direct bond) or selected from the formulas:
  • Q 1 and Q 2 are independently absent (a direct bond), , or L- H wherein L 1 is a direct bond to A 1 or A 2 , and L 2 is a direct bond to P 1 or P 2 ; provided, however, that P 1 and Q 1 are not both absent, and P 2 and Q 2 are not both absent; and that P 1
  • a 1 and A 2 are the same or different and are independently selected from formulas:
  • L 3 at each occurrence is independently a direct bond to B 1 or B 2 ;
  • L 4 at each occurrence is independently a direct bond to Q 1 or Q 2 ;
  • R 2 and R 3 at each occurrence are the same or different and are independently selected from H and Ci-G, alkyl optionally substituted, or taken together along with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl optionally substituted;
  • B 1 and B 2 are the same or different and are independently selected from formula:
  • R 4 is C 1 -C 6 alkyl or aryl-(Ci-C 3 ) alkyl, each optionally substituted; and R 5 is C 1 -C 6 alkyl, aryl, heteroaryl, substituted C1-C6 alkyl, aryl-(Ci-C3) alkyl, substituted aryl-(Ci-C3) alkyl, heteroaryl-(Ci-C3) alkyl, substituted heteroaryl-(Ci-C3) alkyl, substituted aryl, or substituted heteroaryl; and L 5 is a direct bond to A 1 or A 2 .
  • M is II;
  • P 1 and P 2 are each ; Q 1 and Q 2 are absent; A 1 and A 2 are each
  • R 4 is C 1 -C 6 alkyl optionally substituted; and R 5 is C 1 -C 6 alkyl optionally substituted.
  • each X is CH; R 2 and R 3 are independently hydrogen, methyl, ethyl, or taken together along with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl optionally substituted.
  • R 2 and R 3 are independently hydrogen or methyl; R 4 is methyl or ethyl; and R 5 is isopropyl.
  • R 5 is C1-C6 alkyl optionally substituted.
  • R 5 is C1-C6 alkyl optionally substituted.
  • each X is CH; R 2 and R 3 are independently hydrogen, methyl, ethyl, or taken together along with the carbon atom to which they are attached form a C3-C6 cycloalkyl optionally substituted.
  • R 2 and R 3 are independently hydrogen or methyl; R 4 is methyl or ethyl, each optionally substituted; and R 5 is isopropyl optionally substituted.
  • IV; P and P are each , wherein X is CH; Q 1 and Q 2 are absent; A 1 and A
  • R 5 is Ci-G, alkyl or Ce- Cio aryl, each optionally substituted.
  • P 1 and P 2 are each , wherein X is N; Q 1 and Q ,2 2 are absen ft; A D ⁇ 1 and A i 2 2 are
  • R 5 is Ci-G, alkyl or aryl, each optionally substituted.
  • R 5 is isopropyl or phenyl, each optionally substituted.
  • M is IV; P 1 and P 2 are each , wherein X is CH or N; Q 1 and Q 2 are absent; A 1 and A 2 are each optionally substituted; and R 5 is C 6 -C 10 aryl, each optionally substituted.
  • M is optionally substituted; and R 5 is C 6 -C 10 aryl optionally substituted.
  • R 5 is phenyl optionally substituted.
  • R 2 and R 3 are independently hydrogen, methyl, ethyl, or taken together along with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl optionally substituted; and R 4 is C 1 -C 4 alkyl optionally substituted.
  • R 2 and R 3 are independently hydrogen or methyl; R 4 is methyl or ethyl.
  • the present invention encompasses any and all possible combinations of the embodiments disclosed herein.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or prodrug thereof, selected from the group consisting of:
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or prodrug thereof, selected from the group consisting of:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) according to any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or prodrug thereof, and one or more pharmaceutically acceptable excipients, such as adjuvants, diluents, and/or carriers.
  • the pharmaceutical composition further comprises a second agent having anti-HCV activity.
  • the second agent having anti-HCV activity is selected from the group consisting of a recombinant Human Interferon Alfa, a nucleoside analog, a direct acting antiviral, a NS3/4A protease inhibitor, a nucleotide NS5B polymerase inhibitor, a NS5A inhibitors, a non-nucleoside NS5B polymerase inhibitors, and combinations thereof.
  • the second agent is selected from the group consisting of peginterferon, ribavirin, daclatasvir, boceprevir, telapravir, simeprevir, sofosbuvir, dasabuvir, ombitasvir, velpatasvir, ledipasvir, paritaprevir, ritonavir, elbasvir, grazoprevir, asunaprevir, beclabuvir, and combinations thereof.
  • the present invention provides a method of inhibiting the function of the HCV NS5A protein, comprising contacting a biological sample containing the HCV NS5A protein with a compound according to any embodiment disclosed herein, or a salt, stereoisomer, tautomer, solvate, or prodrug thereof.
  • the present invention provides use of a compound of formula (I) according to any embodiments described herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, prodrug, or composition thereof, in the manufacture of a medicament for treatment of a disease or disorder associated caused by HCV.
  • the present invention provides a method of treating or preventing a disease, disorder, or medical condition associated with an HCV activity in a subject, comprising administering to the subject a therapeutically effective amount of the compound of according to any embodiment disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or prodrug thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the method is further in conjunction with administration of a second agent having anti-HCV activity to the subject.
  • the second agent is selected from the group consisting of a recombinant Human Interferon Alfa, a nucleoside analog, a direct acting antiviral, a NS3/4A protease inhibitor, a nucleotide NS5B polymerase inhibitor, a NS5A inhibitors, a non-nucleoside NS5B polymerase inhibitors, including, but limited to, peginterferon, ribavirin, daclatasvir, boceprevir, telapravir, simeprevir, sofosbuvir, dasabuvir, ombitasvir, velpatasvir, ledipasvir, paritaprevir, ritonavir, elbasvir, grazoprevir, asunaprevir, beclabuvir, and combinations thereof.
  • a recombinant Human Interferon Alfa a nucleoside analog, a direct acting antiviral, a NS3/4A protease inhibitor, a nu
  • the method for the treatment or prevention of a disease, disorder, or medical condition associated with HCV activity in a subject comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition according to any embodiment disclosed herein.
  • the disease, disorder, or medical condition associated with HCV activity includes, but is not limited to, hepatitis C infection, chronic hepatitis, cirrhosis, hepatocellular carcinoma (HCC), liver cancer, mixed cryoglobulinemia, porphyria cutanea tarda, leukocytoclastic vasculitis, lichen planus (LP), sicca syndrome, urticaria, pruritus, thrombocytopenic purpura, and psoriasis.
  • the diseases, disorders or medical conditions caused by HCV may include cirrhosis, liver cancer and hepatitis C infection.
  • the disease is cirrhosis.
  • the disease is liver cancer.
  • the disease is hepatitis C infection.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups containing 1 to 8 carbons, preferably 1 to 6, more preferably 1 to 4, carbons.
  • the term encompasses, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, or the like.
  • alkylene refers to a bivalent saturated aliphatic radical derived from an alkane by removal of two hydrogen atoms. Examples include, but are not limited to, methylene (— Ctk— ), ethylene (— CH 2 CH 2 — ), propylene (— CH 2 CH 2 CH 2 — ), or the like.
  • cycloalkyl as used herein alone or as a part of another group, includes saturated cyclic hydrocarbon radical having 3 to 8 carbons forming the ring. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • aryl refers to monocyclic or bicyclic aromatic radical containing 6 to 10 carbons in the ring portion (such as phenyl and naphthyl, including 1 -naphthyl and 2-naphthyl).
  • heteroaryl refers to 5- to 14-membered monocyclic, bicyclic, or tricyclic, sometimes preferably 5- to 10-membered monocyclic or bicyclic, aromatic radical comprising one or more, preferably one to four, sometimes preferably one to three, heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S) in the aromatic ring(s).
  • heteroaryl rings have less aromatic character than their all-carbon counterparts.
  • a heteroaryl group need only have some degree of aromatic character.
  • Halo or“halogen” as used herein, refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I).
  • any group for example, alkyl, alkenyl,“cycloalkyl,”“aryl,”“heterocyclyl,” or “heteroaryl”, is said to be“optionally substituted,” unless specifically defined, it means that the group is or is not substituted by from one to five, sometimes preferably one to three, substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Ci-Ce haloalkyl, C 1 -C 6 haloalkoxy, hydroxy, oxo, C 1 -C 6 acyl, cyano, nitro, and NR a R b (R a and R b are each independently H or C 1 -C 4 alkyl), or the like, provided that such substitution would not violate the conventional bonding principles known to a person of skill in the art.
  • the phrase“optionally substituted” is used before a list of groups, it means that each one of the groups listed may be optionally substituted.
  • aryl when an aryl, heteroaryl, cycloalkyl, heterocyclyl, or the like, is between two or more groups, it should be interpreted as a divalent group with a proper name“arylene,”“heteroarylene,”“cycloalkylene,”“heterocycylene,” or the like. Although sometimes no such distinction is made, for example,“aryl” should be interpreted as“arylene”, as a person of skill in the art would understand.
  • substitution means the substitution may or may not occur and includes instances where said substitution occurs and instances in which it does not.
  • substituents only sterically practical and/or synthetically feasible compounds are meant to be included. Unless otherwise specified in this specification, when a variable is said to optionally substituted or substituted with a substituent(s), this is to be understood that this substitution occurs by replacing a hydrogen that is covalently bound to the variable with one these substituent(s).
  • the term“pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. See, e.g., S. M. Berge et a , J. Pharm. Sci, 1977, 66, 1-19, which is incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, lumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory and (+) or d, meaning the compound, is dextrorotatory.
  • these compounds called stereoisomers, are identical except that they are mirror images of one another.
  • a specific stereoisomer of a mirror image pair may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • ( R ) or (S) it is to designate the absolute configuration of a substituent in context to the whole compound and not in context to the substituent alone.
  • tautomer refers to a molecule in which a proton may shift from one atom to another atom in the same molecule, for example, in amide and carbamide bonds or heterocycles such as imidazole.
  • the compounds presented herein may exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist, and the exact ratio of the tautomers may depend on several factors, including physical state, temperature, solvent, and pH, etc. For illustration purpose, some examples of tautomeric equilibrium (not exhaustive) may include:
  • racemic mixture and“racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • Enantiopure or “enantomerically pure” means a pure stereoisomer uncontaminated by its enantiomer.“Enantiomerically enriched” means a compound in which one of two (or more) enantiomers is found in greater concentrations in a given sample than another enantiomer.
  • the term“substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • solvate means a physical association of a compound of this invention with a stoichiometric or non- stoichiometric amount of solvent molecules.
  • one molecule of the compound associates with one or more, preferably one to three, solvent molecules. It is also possible that multiple (e.g., 1.5 or 2) molecules of the compound share one solvent molecule.
  • This physical association may include hydrogen bonding.
  • the solvates will be capable of isolation as crystalline solid.
  • the solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement.
  • Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isoprop anolates. Methods of solvation are generally known in the art.
  • prodrug means derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become, by solvolysis or under physiological conditions, the compounds of the invention which are pharmaceutically active in vivo.
  • a prodrug of a compound may be formed in a conventional manner with a functional group of the compounds such as with an amino, hydroxy or carboxy group when present.
  • the prodrug derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine.
  • compositions which include any compounds of the present invention, or pharmaceutically acceptable salts or solvates thereof, and one or more, preferably one to three, pharmaceutically acceptable carriers, diluents, or other excipients.
  • the carrier(s), diluent(s), or other excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the subject being treated.
  • compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • pharmaceutically acceptable refers to the property of those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitable comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or and absorption agent such as betonite, kaolin, or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt and/or
  • absorption agent such as betonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present disclosure can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac,
  • Oral fluids such as solution, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release, for example, by coating or embedding particulate material in polymers, wax, or the like.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • subject or“patient” includes both humans and other mammalian animals, including but not limited to horses, cats, dogs, monkeys, and cows, and preferably humans.
  • treatment includes partial or total inhibition of a disease, disorder, or medical condition caused by the heptatitis C virus in humans, including cirrhosis and liver cancer.
  • prevention includes either preventing the onset of hepatitis C infection altogether or preventing the onset of hepatitis C infection in individuals at risk.
  • the compounds described herein, and/or the pharmaceutically acceptable salts and solvates thereof, can be synthesized from commercially available starting materials by methods well known to those skilled in the art.
  • the following general synthetic schemes illustrate methods for most of compound preparation.
  • G 1 and G 2 are leaving groups that are the same or different and are exemplified but not limited to halogen, mesylate, tosylate or triflate.
  • the reagents, solvents, temperatures, catalysts and ligands are not limited to what is depicted for illustrative purposes. Certain abbreviations and acronyms well known to those trained in the art that are used in the schemes are listed below for clarity.
  • /7-BU3P tri-n-butylphosphine
  • dppf l,r-bis(diphenylphosphino)ferrocene
  • FCC flash column chromatography using silica
  • HATU 1 -
  • IBCF isobutylchloroformate
  • LDA lithium diisopropylamide
  • LiHMDS lithium bis(trimethylsilyl)amide [LiN(SiMe3)2];
  • NMM N- methyl morpho line
  • Pd2(dba)3 tris(dibenzylideneaeetone)dipalladium(0)
  • Pd(PPh3)2Cl2 bis(triphenylphosphine)palladium(II) dichloride
  • Pd(dppf)Cl2 [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II);
  • T3P 2,4,6-tripropyl- 1 ,3 ,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide;
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
  • XtalFluor-E (diethylamino)difluorosulfonium tetrafluoroborate.
  • Scheme 1 shows a general synthesis of the compounds of the formula I of the invention when the compounds have a symmetric structure of formula 5, wherein a transition metal-mediated cross-coupling reaction is used to construct the P'-M and M-P 2 bonds.
  • a transition metal-mediated cross-coupling reaction is used to construct the P'-M and M-P 2 bonds.
  • the Suzuki reaction is employed to couple an intermediate G'-M-G 2 1, where G 1 and G 2 are the same or different, with boronic acids or esters 2 using a palladium catalyst such as Pd(dppf)2Cl2.
  • boronic acids or esters 3 can be coupled under similar conditions with 4 to furnish compound 5 of the formula I.
  • Other transition metal- mediated cross-coupling reactions that enable P*-M and M-P 2 bond formation but employ alternative coupling partners and reagents include but are not limited to the Negishi, Kumada, Sonagasira and Stille reactions.
  • Scheme 2 shows a synthesis of the compounds of the formula I of the invention that contain a carboxamide linkage. Coupling of carboxylic acids 6 with amines 7 using peptide coupling reagents such as HATU affords carboxamides 8 of the formula I. Alternatively, the reaction of amines 7 with the corresponding carboxylic acid halide, activated ester or mixed anhydride derivatives of 6 can also provide carboxamides 8 of the formula I.
  • any of the X, X 1 , X 2 , X 3 , Y, Y 1 , Y 2 , Y 3 , G, G 1 , G 2 , and G 3 may be selected, as needed, from various coupling, leaving, or protecting groups, preferably with good selectivities. Where needed, protection and deprotection of certain functional groups, for example, hydroxyl (-OH), amino (-NFb), and carboxyl group (-CO2H) may be implemented.
  • the compounds thus obtained can be further modified at their peripheral positions to provide the desired compounds.
  • Synthetic chemistry transformations are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
  • the compounds of the formula I and/or their pharmaceutically acceptable salts and solvates described herein can be purified by column chromatography, high performance liquid chromatography, crystallization, or other suitable methods.
  • (+)-4,12-Dibromo[2.2]- paracyclophane (10) (100 mg, 0.2732 mmol; CAS#23927-40-4), 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzenamine (11) (239 mg, 1.09 mmol; CAS#210907-84-9) and K3PO4 (476 mg, 2.24 mmol) were combined with 10.6 mL of 10:1 mixture of 1,4-dioxane and water (v/v) in a microwave reaction tube.
  • the resulting white slurry was degassed via N2 bubbling for 30 min., treated with Pd(dppf)Cl2 ⁇ CH2CI2 (22 mg, 0.0273 mmol) and heated on a microwave reactor at 80 °C with vigorous stirring for 2 h.
  • the reaction mixture was cooled to room temperature and partitioned between water and CPhCk/MeOH (19:1).
  • the aqueous layer was extracted 2 more times with CPhCb/MeOH (19:1) and the combined organic extracts were washed twice with brine, dried (Na2SC>4), filtered and concentrated in vacuo.
  • N-Uert-Bu to x y c ar b o n y 1 ) - L - p ro line (13) (27 mg, 0.126 mmol) and DIEA (30 pL, 0.1713 mmol) were dissolved in DMF (1.0 mL) and treated with HATU (65 mg, 0.1713 mmol).
  • the reaction mixture was placed under a nitrogen atmosphere, stirred at r.t. for 30 min. and then treated with a solution of ( ⁇ )-4,12-bis-(3-aminophenyl)-[2.2]paracyclophane (12) (22 mg, 0.0571 mmol) in DMF (1.5 mL).
  • N-( methoxycarbonyl )- - valine (16) 29 mg, 0.1630 mmol
  • DIEA 76 pL, 0.4348 mmol
  • HATU 62 mg, 0.1630 mmol
  • reaction mixture was degassed again and then heated to reflux while stirring, under N2 for 17 h.
  • the cooled reaction mixture was concentrated in vacuo, triturated several times with ethyl acetate and filtered.
  • the filtrate was washed with brine, dried (CaSCL), filtered and concentrated in vacuo. The residue was recrystallized from boiling heptane to yield 9.3 g of
  • % Pd on carbon (311 mg dry basis; 50 wt. % H2O; Degussa type E101) was added under N2 at r.t. to a rapidly stirred suspension of 4,4'-(3,3"-dinitro-[l,r:4',l"-terphenyl]-2',5'-diyl)bis(2- methylbut-3-yn-2-ol) (29) (1.09 g, 2.25 mmol) in EtOAc (200 mL). The suspension was subsequently sparged with hydrogen gas for 5 min. and then stirred under a hydrogen atmosphere for 7 h. The reaction was vented, flushed with N2, filtered through Celite, and the filtrate was concentrated in vacuo.
  • reaction mixture was cooled to r.t. and concentrated in vacuo and triturated with hot EtOAc.
  • the combined triturations were filtered through Celite and the filtrate was washed with 0.1 N aq. HC1, brine, dried (CaSC ), heated to boiling and then diluted with heptane to precipitate crude product.
  • a suspension of (/?)-2-((methoxycarbonyl)amino)-2-phenylacetic acid (35) (2.5 g, 12.1 mmol) and benzyl L-prolinate hydrochloride (47) (2.9 g, 12.1 mmol) in EtOAc (120 mL) was treated with a 50 wt. % solution of T3P in EtOAc (7.2 mL, 12.2 mmol) at r.t under a N2 followed by DIEA (6.3 mL, 36.2 mmol).
  • Example 7 Dimethyl (( 1 /?, 1 'R)-((2S,2'S)-((( 1 , 1 ,5,5-tetramethyl- 1 ,2,3,5,6,7-hexahydro-s-indacene-4,8- diyl)bis(4, 1 -phenylene))bis( 17/-imidazole-5,2-diyl ))his( pyrrolidine-2, 1 -diyl))bis(2-oxo- 1 - phenylethane-2, l-diyl))dicarbamate (54).
  • the title compound (59) was prepared in an analogous manner described for Example 6 (46) from 4,8-dibromo-l,l,5,5-tetramethyl-l,2,3,5,6,7-hexahydro-s-indacene (41) (437 mg, 1.2 mmol), ieri-butyl (5)-2-(5-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-l//-imidazol-2-yl)pyrrolidine-l-carboxylate (58) (2.2 g, 5.1 mmol), sodium carbonate (3.1 g, 29 mmol), Pd(dppf)Cl2 ⁇ CH2CI2 (192 mg, 0.2 mmol), and tetrabutylammonium chloride hydrate (66 mg, 0.2 mmol) in 1 :1 mixture (v/v) of THF and water (47 mL).
  • control compounds Daclatasvir and Sofosbuvir against selected HCV genotypes. Both control compounds are FDA approved direct-acting antiviral agents against Hepatitis C Virus (HCV) used for the treatment of chronic HCV infection and have published HCV genotype selectivity and potency values from which the reliability of the assay can be inferred and compared with the test compound assayed profile.
  • HCV Hepatitis C Virus
  • the HCV GTlb-Luc (Con-1) Replicon Assay (luciferase endpoint) was conducted in Huh Luc/Neo cells by Southern Research, Frederick, Maryland, USA.
  • the HCV GTlb (Con-1) replicon assay evaluated the antiviral activity of compounds at six serial dilutions in triplicate. Sofosbuvir was included in each run as a reference standard.
  • the Huh Luc/Neo replicon cells were plated at 5,000 cells/well into separate 96- well plates for analysis of cell viability or antiviral activity. On the following day, diluted test samples were added to the appropriate wells. Cells were processed 72 hours later when they were still sub-confluent.
  • the HCV replicon levels were quantified by replicon-derived luciferase activity. Curve fitting software was used to generate EC50 values (the concentration inhibiting HCV replicon by 50%).
  • GTla WT Replicon GTlb/3a NS5a and GTlb/6a NS5a Chimeric Replicons and Cytotoxicity (CCso) Assays. These assays were conducted in Huh7 cells by WuXi Apptec Co. Ltd. (Shanghai, China) and daclatasvir was used as a reference standard.
  • the chimeric replicons GTlb/3a and GTlb/6a were constructed using the GTlb replicon as a backbone.
  • Huh7 cells were transiently transfected with the replicon RNAs by electroporation and seeded at a density of 10,000 cells/well in 96-well plates. The cells were cultured and treated with the compounds at 37 °C and 5% CO2 for 3 days.
  • the cell viability was determined with the CellTiter- Fluor kit in cells of GTla replicon assay in accordance with the protocol provided by the supplier.
  • the supernatants were removed from the wells.
  • the antiviral activity was determined by monitoring replicon reporter firefly luciferase using Bright-Glo in accordance with the protocol provided by the supplier.
  • the raw data (RLU) were used for calculating the antiviral activity (% inhibition) of the compounds.
  • Inhibition% (CPD-ZPE)/(HPE-ZPE)*100%
  • ZPE Average of signals from DMSO control wells.
  • HPE Average of signals from medium control wells.
  • STD reference standard
  • WT wild type
  • GTlb-Luc (Con 1) assay was conducted in Huh Luc/Neo cells
  • Gtla-wt, Gtlb/3a NS5a and Gtlb/6a NS5a are transient transfected replicon assays and were conducted in Huh7 cells
  • NT not tested
  • * Literature values from the Solvaldi package insert (rev. 03/2015) and Gao, M. in Curr. Opin.in Virology 2013, 3, 514-520.
  • the structures claimed in this application were designed in an effort to develop a selectivity and potency profile improvement over currently approved agents.
  • Favorable comparison of the genotypic selectivity, potency, and cytotoxicity of the claimed structures against that of daclatasvir and dofosbuvir provides a rationale for further development of these compounds.

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Abstract

L'invention concerne des composés dicarbamate utilisés en tant qu'inhibiteurs de NS5A, ainsi que leurs utilisations thérapeutiques et leurs procédés de préparation. Ces composés, et leurs sels, stéréoisomères, tautomères, solvates et promédicaments pharmaceutiquement acceptables, et des compositions pharmaceutiques de ceux-ci, sont utiles dans le traitement de maladies et de troubles provoqués par le virus de l'hépatite C chez l'homme, notamment la cirrhose et le cancer du foie.
PCT/US2020/029717 2019-04-25 2020-04-24 Inhibiteurs dicarbamate de ns5a pour le traitement d'infections par le virus de l'hépatite c et de maladies associées WO2020219808A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008021927A2 (fr) * 2006-08-11 2008-02-21 Bristol-Myers Squibb Company Inhibiteurs du virus de l'hépatite c
US20140249074A1 (en) * 2009-05-13 2014-09-04 Gilead Pharmasset Llc Antiviral compounds
WO2017076187A1 (fr) * 2015-11-06 2017-05-11 江苏豪森药业集团有限公司 Dérivé 1,4(1,4)-diphénylhexacyclophane-12,43-diyle, procédé de préparation et application de celui-ci
US9717712B2 (en) * 2013-07-02 2017-08-01 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus
US9833440B2 (en) * 2011-05-27 2017-12-05 Achillion Pharmaceuticals, Inc. Substituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenes useful for treating HCV infections

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008021927A2 (fr) * 2006-08-11 2008-02-21 Bristol-Myers Squibb Company Inhibiteurs du virus de l'hépatite c
US20140249074A1 (en) * 2009-05-13 2014-09-04 Gilead Pharmasset Llc Antiviral compounds
US9833440B2 (en) * 2011-05-27 2017-12-05 Achillion Pharmaceuticals, Inc. Substituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenes useful for treating HCV infections
US9717712B2 (en) * 2013-07-02 2017-08-01 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus
WO2017076187A1 (fr) * 2015-11-06 2017-05-11 江苏豪森药业集团有限公司 Dérivé 1,4(1,4)-diphénylhexacyclophane-12,43-diyle, procédé de préparation et application de celui-ci

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