WO2024089159A1 - Inhibiteurs de protéase principale - Google Patents

Inhibiteurs de protéase principale Download PDF

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Publication number
WO2024089159A1
WO2024089159A1 PCT/EP2023/079898 EP2023079898W WO2024089159A1 WO 2024089159 A1 WO2024089159 A1 WO 2024089159A1 EP 2023079898 W EP2023079898 W EP 2023079898W WO 2024089159 A1 WO2024089159 A1 WO 2024089159A1
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group
alkyl
independently selected
compound
alkoxy
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PCT/EP2023/079898
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English (en)
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Farid El Oualid
Alfred Nijkerk
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Ubiq Holding B.V.
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Publication of WO2024089159A1 publication Critical patent/WO2024089159A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • the invention relates to compounds, pharmaceutical compositions and methods capable of inhibiting or preventing replication of a virus expressing Main Protease (M pro ).
  • the invention also relates to the use of these compounds and pharmaceutical compositions in the treatment or prevention of a disease or condition caused by infection with a virus expressing Main Protease (M pro ).
  • the invention further relates to the use of these compounds and pharmaceutical compositions in the manufacture of a medicament for treating infection by a virus expressing Main Protease (M pro ) and/or treating or preventing a disease or condition caused by infection by a virus expressing Main Protease (M pro ), in a subject in need thereof.
  • Coronaviruses belong to the Nidovirales order of enveloped positivesense single-stranded RNA viruses (Anirudhan et al. J Med Virol. 2021 , 93, 2722).
  • HCoV-229E and HCoV- OC43, with infections exhibiting symptoms similar to those of the common cold caused by rhinovirus.
  • These two coronaviruses were identified in 1965 and have been extensively studied for the following 20 years.
  • HCoVs human CoVs
  • HCoV-229E HCoV-OC43
  • HCoV-NL63 HCoV-HKU1
  • MERS- CoV SARS-CoV
  • SARS-CoV SARS-CoV
  • SARS-CoV-2 belonging to alpha- and beta-coronaviruses about 30% of mild upper respiratory diseases are caused by HCoV-229E, HCoV- OC43, HCoV-NL63, and HCoV-HKU1.
  • SARS-CoV and MERS-CoV which first appeared in China in 2002 and in Saudi Arabia in 2012, respectively, caused severe health and economic crisis at the global level. Even though its infection rate is slow, MERS-CoV infections are still ongoing.
  • SARS-CoV-2 coronavirus
  • COVID-19 coronavirus disease 2019
  • SARS-CoV-2 is a close cousin of SARS-CoV, sharing an overall amino-acid sequence identity of 82%. Based on this similarity it is reasonable to assume that knowledge of the molecular pathogenesis of SARS-CoV and SARS-CoV-2 could result in treatment strategies for coronavirus diseases.
  • Coronavirus replication and transcription function is encoded by the so-called “replicase” gene (Ziebuhr et al., J. Gen. Virol. 2000, 81 , 853), which consists of two overlapping polyproteins that are extensively processed by viral proteases.
  • the C- proximal region is processed at eleven conserved interdomain junctions by the coronavirus “3C-like” or main protease (M Pro ).
  • M Pro main protease
  • the name “3C-like” protease derives from certain similarities between the coronavirus enzyme and the well-known picornavirus 3C proteases.
  • MP ro is a 33.8-kDa cysteine protease which mediates the maturation of functional polypeptides involved in the assembly of replicationtranscription machinery.
  • SARS-CoV-2 M Pro digests the polyprotein at no less than 11 conserved sites, starting with the autolytic cleavage of this enzyme itself.
  • the structure of SARS- CoV-2 M Pro was established using high resolution X-ray (Zhang et al. Science. 2020, 368, 409). This study revealed that the SARS-CoV M Pro and SARS-CoV-2 M Pro have a high degree of similarity and identified a couple of differences between both SARS- CoV M Pro and SARS-CoV-2 M Pro .
  • M Pro since M Pro has no human homolog and is highly conserved among all coronaviruses (Yang et al. Curr. Pharm. Des. 2006, 12, 4573), it represents an attractive drug target against coronaviruses.
  • the present invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein:
  • Z is either a oxygen or a sulphur atom
  • R 1 is selected from the group consisting of hydrogen, methyl optionally substituted with one to three halo, phenyl optionally substituted with one to five halo.
  • R 2 is selected from the group consisting of: wherein each R 2a is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl; wherein each R 2b is independently selected from the group consisting of hydrogen, halo, hydroxy, trifluoromethyl, Ci-Ce alkyl-C(O)-, Ci-Ce alkyl-OC(O)- and Ci-Ce alkoxy Wherein each R 2c is independently selected from the group consisting of hydrogen, halo, hydroxy, oxo, trifluoromethyl, Ci-Ce alkyl ; Ci-Ce alkoxy wherein n, a, b and c are at each occurrence independently selected from 0, 1 and 2; wherein q is at each occurrence independently selected from 0, 1 , 2, 3 and 4; wherein p is at each occurrence independently selected from 0, 1 , 2 and 3; wherein m is at each occurrence independently selected from 0 to 5;
  • R 3 is selected from the group consisting of hydrogen and methyl
  • R 4 is selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12- membered heterocycloalkyl, C6-C10 aryl and 5- to 10-membered heteroaryl; wherein each R4 group is optionally substituted with one to two R 4a ; or R 3 and R 4 , taken together with the nitrogen and carbon atoms to which they are attached, form a 4- to 12-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, which can be optionally substituted with one to two R 4a ;
  • R 4a is at each occurrence independently selected from the group consisting of R 4b , R 4b -O-, R 4b -NH-, (R 4b ) 2 -N-, R 4b -C(O)NH- and R 4b -OC(O)NH-;
  • each R 4b is at each occurrence independently selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12-membered heterocycloalkyl, Ce- C10 aryl and 5- to 10-membered heteroaryl; wherein each R 4b group is optionally substituted with one to two R 4c ;
  • R 4c is at each occurrence independently selected from the group consisting of R 4d , R 4d -O-, R 4d -NH-, (R 4d ) 2 -N-, R 4d -C(O)NH- and R 4d -OC(O)NH-;
  • each R 4d is at each occurrence is independently selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12-membered heterocycloalkyl, Ce- C10 aryl and 5- to 10-membered heteroaryl; wherein each R 4 , R 4b and R 4d is optionally substituted with one to five substituents at each occurrence independently selected from the group consisting of methyl, halo, hydroxy, oxo, imino and sulfanylidene.
  • compounds of the invention are potent inhibitors of SARS-CoV2 and MERS-CoV.
  • the alkyne group of the compounds according to the invention covalently interacts with the catalytic cysteine residue of M Pro thereby preventing viral replication.
  • the inventors believe that this is a proximity-driven activity-based reaction and that the present compounds are non-reactive against other thiols. This is indicative of reduced off- target effects, compared to the M Pro known from the prior art discussed herein elsewhere.
  • Z is either an oxygen or a sulphur atom
  • X is either a nitrogen or a carbon atom
  • Y is hydrogen or, when X is a nitrogen atom, Y and R 5 or R 6 , taken together with the nitrogen and carbon atoms to which they are attached, form a 4- to 12-membered heterocycloalkyl or a 5- to 10-membered heteroaryl;
  • R 5 is selected from the group consisting of Ci-Ce alkyl, (C3-C6 cycloalkyl)-Ci-C3 alkyl and (phenyl)-Ci-C3 alkyl; wherein each R 5 group is optionally substituted with one to five substituents at each occurrence independently selected from the group consisting of C1-C3 alkyl, halo, - CF 3 ;
  • R 6 is selected from the group consisting of Ci-Cs alkyl, Ci-Cs alkoxy, (Ci-Cs alkoxy)- Ci-Cs alkyl, C3-C12 cycloalkyl, (C3-C12 cycloalkyl)-Ci-C8 alkyl, (C3-C12 cycloalkyl)-Ci- Cs alkoxy, C3-C12 cycloalkoxy, (C3-C12 cycloalkoxy)-Ci-C8 alkyl, (C3-C12 cycloalkoxy)- Ci-Cs alkoxy, 4- to 12-membered heterocycloalkyl, (4- to 12-membered heterocycloalkyl)-Ci-C8 alkyl, (4- to 12-membered heterocycloalkyl)-Ci-C8 alkoxy, 4- to 12-membered heterocycloalkoxy, (4- to 12-membered heterocycloalkoxy)-Ci-C8
  • R 6a at each occurrence is independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, halo, hydroxy, oxo, phenyl, benzyl, Ci-Ce alkyl-C(O)NH-, Ci-Ce cycloalkyl-C(O)NH-, 5- to 6-membered heterocycloalkyl-C(O)NH, phenyl-C(O)NH- 5- to 6-membered heteroaryl-C(O)NH-, Ci-Ce alkyl-OC(O)NH-; wherein each R 6a group is optionally substituted with one to five fluoro or one substituent selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, chloro, hydroxy, oxo, trifluoromethyl.
  • a compound as defined herein is provided, selected from the group consisting of and pharmaceutically acceptable salts, solvates and hydrates thereof
  • the invention provides a method for preparing a compound as defined herein, or a pharmaceutically acceptable salt thereof, said method comprising the steps of: a) providing a first compound according to formula (X) wherein R 1 is selected from the group consisting of hydrogen, methyl optionally substituted with one to three halo, phenyl optionally substituted with one to five halo. R 2 is selected from the group consisting of:
  • each R 2a is independently selected from the group consisting of hydrogen and Ci-Ce alkyl; wherein each R 2b is independently selected from the group consisting of hydrogen, halo, hydroxy, trifluoromethyl, Ci-Ce alkyl-C(O)-, Ci-Ce alkyl-OC(O)- and Ci-Ce alkoxy Wherein each R 2c is independently selected from the group consisting of hydrogen, halo, hydroxy, oxo, trifluoromethyl, Ci-Ce alkyl ; Ci-Ce alkoxy wherein n, a, b and c are at each occurrence independently selected from 0, 1 and 2; wherein q is at each occurrence independently selected from 0, 1 , 2, 3 and 4; wherein p is at each occurrence independently selected from 0, 1 , 2 and 3; wherein m is at each occurrence independently selected from 0 to 5;
  • R 3 is selected from the group consisting of hydrogen and methyl; b) providing a second compound according to formula (Y) wherein Z is either an oxygen or a sulphur atom;
  • R 7 is selected from the group consisting of hydroxy, halo and carboxylate
  • R 4 is selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12- membered heterocycloalkyl, C6-C10 aryl and 5- to 10-membered heteroaryl; wherein each R4 group is optionally substituted with one to two R 4a ; or R 3 and R 4 , taken together with the nitrogen and carbon atoms to which they are attached, form a 4- to 12-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, which can be optionally substituted with one to two R 4a ;
  • R 4a is at each occurrence independently selected from the group consisting of R 4b , R 4b -O-, R 4b -NH-, (R 4b ) 2 -N-, R 4b -C(O)NH- and R 4b -OC(O)NH-;
  • each R 4b is at each occurrence independently selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12-membered heterocycloalkyl, Ce- C10 aryl and 5- to 10-membered heteroaryl; wherein each R 4b group is optionally substituted with one to two R 4c ;
  • R 4c is at each occurrence independently selected from the group consisting of R 4d , R 4d -O-, R 4d -NH-, (R 4d ) 2 -N-, R 4d -C(O)NH- and R 4d -OC(O)NH-;
  • each R 4d is at each occurrence is independently selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12-membered heterocycloalkyl, Ce- C10 aryl and 5- to 10-membered heteroaryl; wherein each R 4 , R 4b and R 4d is optionally substituted with one to five substituents at each occurrence independently selected from the group consisting of methyl, halo, hydroxy, oxo, imino and sulfanylidene. c) reacting said first compound with said second compound under conditions that result in the formation of a compound of any one of the embodiments of the first aspect.
  • a third aspect of the present invention provides pharmaceutical compositions comprising a compound as defined herein or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • said pharmaceutical composition is provided in a unit dosage form suitable for oral administration, preferably in the form of a tablet or capsule.
  • a fourth aspect of the present invention provides a method for treating a viral infection and/or treating or preventing a disease or condition caused by infection with a virus expressing Main Protease (MP ro ), in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound as defined herein.
  • MP ro Main Protease
  • a fifth aspect of the present invention provides a method for inhibiting or preventing replication of a virus expressing Main Protease (MP ro ), the method comprising contacting the viruses with an inhibitory amount of a compound as defined herein.
  • a use is provided of a compound as defined herein in a method of treating infection by a virus expressing Main Protease (M pro ) and/or treating or preventing a disease or condition caused by infection by a virus expressing Main Protease (M pro ).
  • a use is provided of a compound as defined herein, in the manufacture of a medicament for treating infection by a virus expressing Main Protease (M pro ) and/or treating or preventing a disease or condition caused by infection by a virus expressing Main Protease (M pro ).
  • the first aspect of the invention concerns a compound of formula I: or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein:
  • Z is either a oxygen or a sulphur atom
  • R 1 is selected from the group consisting of hydrogen, methyl optionally substituted with one to three halo, phenyl optionally substituted with one to five halo.
  • R 2 is selected from the group consisting of: wherein each R 2a is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl; wherein each R 2b is independently selected from the group consisting of hydrogen, halo, hydroxy, trifluoromethyl, Ci-Ce alkyl-C(O)-, Ci-Ce alkyl-OC(O)- and Ci-Ce alkoxy Wherein each R 2c is independently selected from the group consisting of hydrogen, halo, hydroxy, oxo, trifluoromethyl, Ci-Ce alkyl ; Ci-Ce alkoxy wherein n, a, b and c are at each occurrence independently selected from 0, 1 and 2; wherein q is at each occurrence independently selected from 0, 1 , 2, 3 and 4; wherein p is at each occurrence independently selected from 0, 1 , 2 and 3; wherein m is at each occurrence independently selected from 0 to 5;
  • R 3 is selected from the group consisting of hydrogen and methyl
  • R 4 is selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12- membered heterocycloalkyl, C6-C10 aryl and 5- to 10-membered heteroaryl; wherein each R4 group is optionally substituted with one to two R 4a ; or R 3 and R 4 , taken together with the nitrogen and carbon atoms to which they are attached, form a 4- to 12-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, which can be optionally substituted with one to two R 4a ;
  • R 4a is at each occurrence independently selected from the group consisting of R 4b , R 4b -O-, R 4b -NH-, (R 4b ) 2 -N-, R 4b -C(O)NH- and R 4b -OC(O)NH-;
  • each R 4b is at each occurrence independently selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12-membered heterocycloalkyl, Ce- C10 aryl and 5- to 10-membered heteroaryl; wherein each R 4b group is optionally substituted with one to two R 4c ;
  • R 4c is at each occurrence independently selected from the group consisting of R 4d , R 4d -O-, R 4d -NH-, (R 4d ) 2 -N-, R 4d -C(O)NH- and R 4d -OC(O)NH-;
  • each R 4d is at each occurrence is independently selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12-membered heterocycloalkyl, Ce- C10 aryl and 5- to 10-membered heteroaryl; wherein each R 4 , R 4b and R 4d is optionally substituted with one to five substituents at each occurrence independently selected from the group consisting of methyl, halo, hydroxy, oxo, imino and sulfanylidene.
  • the compound of the invention is a compound according to formula I, with the proviso that R 4 comprises not more than one moiety selected from the group consisting of heterocycloalkyl and heteroaryl, where the term heterocycloalkyl includes mono- as well as polycyclic heterocycloalkyl and the term heteroaryl includes mono- as well as polycyclic heteroary.
  • the compound of the invention is a compound according to formula I with the proviso that said compound according to formula (I) is not (1 S,3aR,6aS)-2-(4,7-dichloro-1 H-indole-2-carbonyl)-N-[(2S)-1-[(3S)- 2-oxopyrrolidin-3-yl]but-3-yn-2-yl]-hexahydro-1 H-cyclopenta[c]pyrrole-1 - carboxamide.
  • the compound of the invention is a compound according to formula I with the proviso that said compound according to formula (I) is not any of the following compounds:
  • the compound of the invention is a compound according to formula 1(a), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof.
  • the compound of the invention is a compound according to formula 1(a), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein R 2a is selected from the group comprising hydrogen.
  • the compound of invention is a compound according to formula 1(b), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof. In certain embodiments, the compound of the invention is a compound according to formula 1(c), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof.
  • the compound of the invention is a compound according to formula 1(c), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein m is selected from 0 and 1 .
  • the compound the invention is a compound according to formula l(d), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof.
  • the compound of the invention is a compound according to formula I (d), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein q is 1 .
  • the compound of the invention is a compound according to formula 1(e), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof.
  • the compound of the invention is a compound according to formula 1(e), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein R 2b is hydrogen, b is 0, c is 1 and p is 0.
  • the compound of the invention is a compound according to formula l(f), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof. 1(f)
  • the compound the invention is a compound according to formula 1(f), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein R 2b is hydrogen.
  • the compound of the invention is a compound according to formula 1(g), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof.
  • the compound of the invention is compound according to formula 1(g), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein R 2b is hydrogen.
  • the compound of the invention is a compound according to formula 1(h), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof.
  • the compound of the invention is a compound according to formula 1(h), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein R 2b is hydrogen, a is 1 and p is 0.
  • the compound of the invention is a compound of any one of formulae I and 1(a) to 1(h), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein R 4 is: wherein:
  • Z is at each occurrence independently selected from either an oxygen or a sulphur atom
  • X is either a nitrogen or a carbon atom
  • Y is hydrogen or, when X is a nitrogen atom, Y and R 5 or R 6 , taken together with the nitrogen and carbon atoms to which they are attached, form a 4- to 12-membered heterocycloalkyl or a 5- to 10-membered heteroaryl; preferably a 4- to 7-membered or 9-12 membered heterocycloalkyl or a 5- to 10-membered heteroaryl;
  • R 5 is selected from the group consisting of Ci-Ce alkyl, (C3-C6 cycloalkyl)-Ci-C3 alkyl and (phenyl)-Ci-C3 alkyl; wherein each R 5 group is optionally substituted with one to five substituents at each occurrence independently selected from the group consisting of C1-C3 alkyl, halo, - CF 3 ;
  • R 6 is selected from the group consisting of Ci-Cs alkyl, Ci-Cs alkoxy, (Ci-Cs alkoxy)- Ci-Cs alkyl, C3-C12 cycloalkyl, (C3-C12 cycloalkyl)-Ci-C8 alkyl, (C3-C12 cycloalkyl)-Ci- Cs alkoxy, C3-C12 cycloalkoxy, (C3-C12 cycloalkoxy)-Ci-C8 alkyl, (C3-C12 cycloalkoxy)- Ci-Cs alkoxy, 4- to 12-membered heterocycloalkyl, (4- to 12-membered heterocycloalkyl)-Ci-C8 alkyl, (4- to 12-membered heterocycloalkyl)-Ci-C8 alkoxy, 4- to 12-membered heterocycloalkoxy, (4- to 12-membered heterocycloalkoxy)-Ci-C8
  • R 6a at each occurrence is independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, halo, hydroxy, oxo, phenyl, benzyl, Ci-Ce alkyl-C(O)NH-, Ci-Ce cycloalkyl-C(O)NH-, 5- to 6-membered heterocycloalkyl-C(O)NH, phenyl-C(O)NH-, 5- to 6-membered heteroaryl-C(O)NH-, Ci-Ce alkyl-OC(O)NH-, preferably selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, fluoro, hydroxy, oxo, phenyl, benzyl, C1-C6 alkyl-C(O)NH- Ci-Ce cycloalkyl-C(O)NH- 5- to 6-membered heterocycloalkyl- C(O)NH, phen
  • the compound of the invention is a compound according to general formula (II), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof.
  • the compound of the invention is a compound according to formula 11(a), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof.
  • the compound of the invention is a compound according to formula 11(a), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein R 2a is selected from the group comprising hydrogen.
  • the compound of the invention is a compound according to formula 11(b), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof.
  • the compound of the invention is a compound according to formula 11(c), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof.
  • the compound of the invention is a compound according to formula 11(c), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein m is selected from 0 and 1 .
  • the compound of the invention is a compound according to formula 11(d), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof.
  • the compound of the invention is a compound according to formula 11(d), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein q is 1 .
  • the compound of the invention is a compound according to formula ll(e), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof.
  • the compound of the invention is a compound according to formula ll(e), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein R 2b is hydrogen, b is 0, c is 1 and p is 0.
  • the compound of the invention is a compound according to formula ll(f), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof.
  • the compound of the invention is a compound according to formula 11(f), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein R 2b is hydrogen.
  • the compound of the invention is a compound according to formula 11(g), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof. H(g)
  • the compound of the invention is a compound according to formula 11(g), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein R 2b is hydrogen.
  • the compound of the invention is a compound according to formula 11(h), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof.
  • the compound of the invention is a compound according to formula 11(h), or a pharmaceutically acceptable salt, solvate and/or hydrate thereof, wherein R 2b is hydrogen, a is 1 and p is 0.
  • R 3 preferably represents hydrogen.
  • R 1 preferably represents hydrogen, fluoro or trimethylfluoro, most preferably hydrogen.
  • R 5 is preferably selected from the group consisting of:
  • R 5 is preferably selected from the group consisting of:
  • R 6 is preferably is selected from the group consisting of:
  • R 6 is preferably is selected from the group consisting of: In the above formulae (II) and (lla-llh) when X is nitrogen, Y and R 6 , taken together with the nitrogen and carbon atoms to which they are attached, form
  • Compounds of the invention contain at least one chiral centre and, therefore, exist as stereoisomers, such as enantiomers and diastereomers. According to the invention, the chemical structures depicted herein, and therefore the compounds of the invention, encompass all of the corresponding compound's stereoisomers.
  • the chemical structures depicted herein by structural formula not indicating a specific stereochemistry encompass both a stereochemical ly pure form and mixtures of different stereoisomers, such as enantiomers and/or diastereomers.
  • the invention encompasses compounds of formulae (I), (la-lh), (II) and (lla-llh), in enantiomerically pure form, enantiomerically-enriched form, diastereomerically pure form, diastereomerically enriched form, as racemic mixture or as diastereomeric mixture.
  • compounds of formulae (I), (la-lh), (II) and (lla-llh), wherein one of the stereoisomers makes up more than 60 mol%, more than 80 mol%, more than 90 mol%, more than 95 mol%, more than 97 mol%, more than 98.5 mol%, more than 99 mol% of the compound.
  • a compound is considered stereochemical ly pure when one of the stereoisomers makes up more than more than 90 mol%, more than 95 mol%, more than 97 mol%, more than 98.5 mol%, more than 99 mol% of the compound.
  • Enantiomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, or crystallizing the compound in a chiral solvent.
  • Diastereomeric mixtures can be resolved into their component diastereomers by well-known methods for separating two chemical compounds, for example based on their different melting points, boiling points etc.
  • Stereochemically pure compounds can also be obtained from stereochemically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • the compound of the invention has the absolute configuration as represented by formula (lx).
  • the compound of the invention is compound selected from the group consisting of: and pharmaceutically acceptable salts, solvates and hydrates thereof,
  • each R 3b is independently selected from the group consisting of hydrogen, halo, hydroxy, trifluoromethyl, -C(O)Ci-Ce alkyl, -C(O)OCi-Ce alkyl and Ci-Ce alkoxy; wherein a is at each occurrence independently selected from 0, 1 and 2.
  • the compound of the invention is compound selected from the group consisting of: (1 R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-/ ⁇ /- ((S)-1 -((S)-2-oxopyrrolidin-3-yl)but-3-yn-2-yl)-3-azabicyclo[3.1 ,0]hexane-2- carboxamide, benzyl ((S)-4-methyl-1 -oxo-1 -(((S)-1 -((S)-2-oxopyrrolidin-3-yl)but-3-yn-2- yl)amino)pentan-2-yl)carbamate, 4-methoxy-/V-((S)-4-methyl-1 -oxo-1 -(((S)-1 -((S)-2-oxopyrrolidin-3-yl)
  • IIIPAC names proposed herein for the compounds (and intermediates) of the invention were generated using Chemdraw, level: Professional, version 20.0.0.38 (PerkinElmer Informatics, Inc., Waltham, Massachusetts, United States). To the extent that the generated IUPAC names and the structures provided herein do not fully correspond, the structures are correct and leading.
  • the compound of formula I is compound selected from the group consisting of and pharmaceutically acceptable salts, solvates and hydrates thereof.
  • pharmaceutically acceptable as used herein has its conventional meaning and refers to compounds, material, compositions and/or dosage forms, which are, within the scope of sound medical judgment suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
  • Suitable examples of pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts formed with inorganic acids (e.g.
  • hydrochloric acid hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, methane sulfonic acid, p-toluene sulfonic acid and polygalacturonic acid.
  • the invention concerns a method for preparing a compound as defined herein, said method comprising the steps of: a) providing a first compound according to formula (X) wherein R 1 is selected from the group consisting of hydrogen, methyl optionally substituted with one to three halo, phenyl optionally substituted with one to five halo.
  • R 2 is selected from the group consisting of: wherein each R 2a is independently selected from the group consisting of hydrogen and Ci-C 6 alkyl; wherein each R 2b is independently selected from the group consisting of hydrogen, halo, hydroxy, trifluoromethyl, Ci-Ce alkyl-C(O)-, Ci-Ce alkyl-OC(O)- and Ci-Ce alkoxy Wherein each R 2c is independently selected from the group consisting of hydrogen, halo, hydroxy, oxo, trifluoromethyl, Ci-Ce alkyl ; Ci-Ce alkoxy wherein n, a, b and c are at each occurrence independently selected from 0, 1 and 2; wherein q is at each occurrence independently selected from 0, 1 , 2, 3 and 4; wherein p is at each occurrence independently selected from 0, 1 , 2 and 3; wherein m is at each occurrence independently selected from 0 to 5;
  • R 3 is selected from the group consisting of hydrogen and methyl; b) providing a second compound according to formula (Y) z
  • R 7 is selected from the group consisting of hydroxy, halo and carboxylate
  • R 4 is selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12- membered heterocycloalkyl, C6-C10 aryl and 5- to 10-membered heteroaryl; wherein each R4 group is optionally substituted with one to two R 4a ; or R 3 and R 4 , taken together with the nitrogen and carbon atoms to which they are attached, form a 4- to 12-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, which can be optionally substituted with one to two R 4a ;
  • R 4a is at each occurrence independently selected from the group consisting of R 4b , R 4b -O-, R 4b -NH-, (R 4b ) 2 -N-, R 4b -C(O)NH- and R 4b -OC(O)NH-;
  • each R 4b is at each occurrence independently selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12-membered heterocycloalkyl, Ce- C10 aryl and 5- to 10-membered heteroaryl; wherein each R 4b group is optionally substituted with one to two R 4c ;
  • R 4c is at each occurrence independently selected from the group consisting of R 4d , R 4d -O-, R 4d -NH-, (R 4d ) 2 -N-, R 4d -C(O)NH- and R 4d -OC(O)NH-;
  • each R 4d is at each occurrence is independently selected from the group consisting of Ci-Cs alkyl, C3-C12 cycloalkyl, 4- to 12-membered heterocycloalkyl, Ce- C10 aryl and 5- to 10-membered heteroaryl; wherein each R 4 , R 4b and R 4d is optionally substituted with one to five substituents at each occurrence independently selected from the group consisting of methyl, halo, hydroxy, oxo, imino and sulfanylidene. c) reacting said first compound with said second compound under conditions that result in the formation of a compound of the invention.
  • R 7 preferably represents hydroxy, iodo, bromo, chloro or fluoro, most preferably hydroxy.
  • more than 60 mol%, more than 80 mol%, more than 90 mol%, more than 95 mol%, more than 97 mol%, more than 98.5 mol%, more than 99 mol% of the compound of formula (X) provided in step a) is a compound with absolute configuration as represented by formula (Xa).
  • reaction is performed in a suitable solvent, such as a chloroalkane, e.g. dichloromethane.
  • a suitable solvent such as a chloroalkane, e.g. dichloromethane.
  • the reaction is performed at a suitable temperature, e.g. at room temperature.
  • the reaction is performed in the presence of a base, preferably a sterically hindered base, more preferably a sterically hindered amine base, such as triethylamine or N,N-Diisopropylethylamine, preferably N,N- Diisopropylethylamine.
  • the reaction is performed in the presence of one or more coupling reagents, such as hydroxybenzotriazole, 6-Chloro-1 - hydroxybenzotriazole, 1 -Hydroxy-7-azabenzotriazole, N,N-Diisopropylethylamine, N,N'-Dicyclohexylcarbodiimide or 1 -Ethyl-3-(3-dimethylaminopropyl)carbodiimide, (Benzotriazol-1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate,
  • one or more coupling reagents such as hydroxybenzotriazole, 6-Chloro-1 - hydroxybenzotriazole, 1 -Hydroxy-7-azabenzotriazole, N,N-Diisopropylethylamine, N,N'-Dicyclohexylcarbodiimide or 1 -Ethyl
  • Bromotripyrrolidinophosphonium hexafluorophosphate Bis(2-oxo-3- oxazolidinyl)phosphinic chloride, preferably hydroxybenzotriazole and 1 -Ethyl-3-(3- dimethylaminopropyl)carbodiimide.
  • the reaction is performed in the presence of one or more racemization supressing agents, such as such as hydroxybenzotriazole, 6- Chloro-1 -hydroxybenzotriazole, 1 -Hydroxy-7-azabenzotriazole, (Benzotriazol-1 - yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, (Benzotriazol-1 - yloxy)tripyrrolidinophosphonium hexafluorophosphate, (7-Azabenzotriazol-1 - yloxy)tripyrrolidinophosphonium hexafluorophosphate,
  • racemization supressing agents such as such as hydroxybenzotriazole, 6- Chloro-1 -hydroxybenzotriazole, 1 -Hydroxy-7-azabenzotriazole, (Benzotriazol-1 - yloxy)tris(dimethylamino)phosphonium hexafluoro
  • the invention concerns pharmaceutical composition
  • a pharmaceutically acceptable carrier or diluent comprising a compound of the invention and a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition is provided in a unit dosage form suitable for oral administration, preferably in the form of a tablet or capsule.
  • Another aspect of the invention concerns a method of treating infection by a virus expressing Main Protease (Mpro) and/or treating or preventing a disease or condition caused by infection by a virus expressing Main Protease (Mpro), in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound or a pharmaceutical composition of the invention.
  • Another aspect of the invention concerns a method of inhibiting or preventing replication of a virus expressing Main Protease (MP ro ), the method comprising contacting the viruses with an inhibitory amount of a compound according to the invention.
  • Another aspect of the invention concerns the use of a compound according to the invention, in a method of treating infection by a virus expressing Main Protease (MP ro ) and/or treating or preventing a disease or condition caused by infection by a virus expressing Main Protease (M pro ), in a subject in need thereof.
  • MP ro Main Protease
  • M pro Main Protease
  • Another aspect of the invention concerns the use of a compound according to the invention, in the manufacture of a medicament for treating infection by a virus expressing Main Protease (MP ro ) and/or treating or preventing a disease or condition caused by infection by a virus expressing Main Protease (M pro ), in a subject in need thereof.
  • MP ro Main Protease
  • M pro Main Protease
  • treat when used in conjunction with a specific disease or symptom (for example: “method of treating disease ...”) refers to curing, alleviating or abrogating said disease and/or accompanying symptoms, diminishing extent of disease, stabilizing (i.e. not worsening) the state of disease, delaying or slowing of disease progression, ameliorating the disease state, prolonging survival (as compared to expected survival without treatment), etc.
  • prevent refers to reducing the risk for a subject to acquire a disease and/or accompanying symptoms, delaying the moment a subject acquires disease, etc.
  • treat when used in relation to a patient or subject (for example: “method of treating a subject”), typically refers to the act of administering a therapeutic compound to said patient or subject for whatever therapeutic and/or prophylactic purpose.
  • M Pro main protease
  • M Pro Main Protease
  • Alterative names for M Pro include 3C-like protease, 3CL or 3CL pro .
  • the viral infection is infection with a coronavirus, preferably a coronavirus selected from the group consisting of HCoV-229E, HCoV- OC43, HCoV-NL63, HCoV-HKU1 , MERS-CoV, SARS-CoV, and SARS-CoV-2.
  • a coronavirus selected from the group consisting of HCoV-229E, HCoV- OC43, HCoV-NL63, HCoV-HKU1 , MERS-CoV, SARS-CoV, and SARS-CoV-2.
  • the disease or condition caused by a viral infection is a respiratory illness, such as acute respiratory distress syndrome (ARDS), Middle East respiratory syndrome (MERS) and COVID-19.
  • a "therapeutically effective amount”, “effective amount” or a “sufficient amount” of a compound of the present invention is a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, including clinical results, and, as such, an "effective amount” or synonym thereto depends upon the context in which it is being applied.
  • therapeutically effective amounts of the compounds of the present invention are used to treat, modulate, attenuate, reverse, or effect viral infection in a mammal.
  • An "effective amount” is intended to mean that amount of a compound that is sufficient to treat, prevent or inhibit viral infections and/or diseases associated with such viral infections.
  • compositions as defined herein can exist in the form of a pharmaceutically acceptable salt or solvate.
  • Such forms will typically be equally suitable for use in the present invention although, is as immediately apparent to those skilled in the art, the amount of such a salt, hydrate or solvate to be administered and/or to be incorporated into a unit dose form needs to be adjusted to take account of the molecular weight difference between the free base and salt form.
  • a compartment refers to one or more than one compartment.
  • Figure 1 depicts the antiviral activity against SARS-CoV-2 of UbiQ-CoV-002 compared to control compound GC376 and of UbiQ-CoV-004 compared to control compound PF-07321332.
  • Figure 2 depicts the antiviral activity against MERS-CoV of UbiQ-CoV-004 compared to control compound PF-07321332.
  • LC-MS measurements were performed on a Micromass LCT Premier (Waters) equipped with a 2795 separation module (Alliance HT).
  • Mobile phases: A 1 % CH3CN, 0.1 % formic acid in milliQ water.
  • B 1 % milliQ water and 0.1 % formic acid in CH3CN.
  • GC-376 was obtained according to the method previously described by Kim et al. (J. Virol. 2012, 86, 11754). To a solution of potassium carbonate (0.3 g, 2.1 mmol) in water (5 mL) was added GC-376 (225 mg, 0.44 mmol, Ambeed A1003140, CAS nr. 1416992-39-6) and ethyl acetate (5 mL). After stirring the mixture at 20°C for 2 h, the organic phase was separated and dried with sodium sulfate. Aldehyde GC-373 was obtained as an oil after evaporation of ethyl acetate.
  • Ohira-Bestmann reagent (dimethyl (1 -diazo-2-oxopropyl)phosphonate, 84 pL, 0.53 mmol) was dissolved in CH3CN (5 mL) and potassium carbonate (146 mg, 1 .06 mmol) was added. After stirring this suspension at room temperature for 10 minutes, the crude GC-373 (0.44 mmol) was dissolved in methanol (2 mL) and added to the reaction mixture. After stirring overnight, analysis by TLC and LC-MS showed complete consumption of starting material and formation of UbiQ-CoV-002 (Rf in CH2CI2/methanol 95/5: 0.5).
  • reaction mixture was concentrated in vacuo at 50°C and the residue diluted with water (25 mL). After adding 1 N HCI (25 mL), a white precipitate was formed. Upon adding ethyl acetate (200 mL), the solid dissolved in the organic layer.
  • Amino alkyne 5 (0.45 gr, 2.4 mmol) and building block 6 (1.04 gr, 2.88 mmol) were dissolved in 50 mL CH2CI2 followed by addition of Hydroxybenzotriazole (HOBt, 0.48 mmol, 63 mg), N,N-diispropylethylamine (DiPEA, 7.2 mmol, 1 .25 mL) and 1 -ethyl- 3-(3'-dimethylaminopropyl)carbodiimide HCI (EDC, 0.45 gr, 2.88 mmol). After stirring overnight at room temperature, TLC analysis with KMnCM staining showed complete consumption of 5.
  • HABt Hydroxybenzotriazole
  • DIPEA N,N-diispropylethylamine
  • EDC 1 -ethyl- 3-(3'-dimethylaminopropyl)carbodiimide HCI

Abstract

L'invention concerne des composés de formule (I) dans laquelle R1, R2, R3 et R4 sont tels que définis dans la description, des compositions pharmaceutiques comprenant les composés et des procédés de synthèse de composés selon la formule I. La présente invention concerne en outre des procédés de traitement de la COVID-19 chez un patient par administration de quantités thérapeutiquement efficaces des composés et des procédés d'inhibition ou de prévention de la réplication du SARS-CoV-2 avec les composés de l'invention et des utilisations des composés de l'invention dans ces procédés et dans la fabrication d'un médicament.
PCT/EP2023/079898 2022-10-27 2023-10-26 Inhibiteurs de protéase principale WO2024089159A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020244970A1 (fr) * 2019-06-06 2020-12-10 Basf Se Nouveaux carboxamides de pyridine carbocycliques
WO2021205296A1 (fr) 2020-04-05 2021-10-14 Pfizer Inc. Méthode de traitement de la covid-19
WO2021207409A2 (fr) 2020-04-08 2021-10-14 Arizona Board Of Regents On Behalf Of The University Of Arizona Inhibiteurs à petites molécules de la replication virale du sars-cov-2 et leurs utilisations
WO2021205298A1 (fr) 2020-04-05 2021-10-14 Pfizer Inc. Composés et méthodes destinés au traitement de la covid-19
WO2021205290A1 (fr) 2020-04-05 2021-10-14 Pfizer Inc. Composés et procédé de traitement de la covid-19
WO2021252491A1 (fr) * 2020-06-10 2021-12-16 Aligos Therapeutics, Inc. Composés antiviraux pour le traitement d'infections à coronavirus, picornavirus et norovirus
WO2021250648A1 (fr) 2020-09-03 2021-12-16 Pfizer Inc. Composés antiviraux contenant du nitrile
WO2022013684A1 (fr) 2020-07-11 2022-01-20 Pfizer Inc. Dérivés d'hétéroaryl cétone antiviraux
WO2022040186A1 (fr) 2020-08-18 2022-02-24 Anixa Biosciences, Inc. Inhibiteurs de cystéine protéase mpro

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020244970A1 (fr) * 2019-06-06 2020-12-10 Basf Se Nouveaux carboxamides de pyridine carbocycliques
WO2021205296A1 (fr) 2020-04-05 2021-10-14 Pfizer Inc. Méthode de traitement de la covid-19
WO2021205298A1 (fr) 2020-04-05 2021-10-14 Pfizer Inc. Composés et méthodes destinés au traitement de la covid-19
WO2021205290A1 (fr) 2020-04-05 2021-10-14 Pfizer Inc. Composés et procédé de traitement de la covid-19
WO2021207409A2 (fr) 2020-04-08 2021-10-14 Arizona Board Of Regents On Behalf Of The University Of Arizona Inhibiteurs à petites molécules de la replication virale du sars-cov-2 et leurs utilisations
WO2021252491A1 (fr) * 2020-06-10 2021-12-16 Aligos Therapeutics, Inc. Composés antiviraux pour le traitement d'infections à coronavirus, picornavirus et norovirus
WO2022013684A1 (fr) 2020-07-11 2022-01-20 Pfizer Inc. Dérivés d'hétéroaryl cétone antiviraux
WO2022040186A1 (fr) 2020-08-18 2022-02-24 Anixa Biosciences, Inc. Inhibiteurs de cystéine protéase mpro
WO2021250648A1 (fr) 2020-09-03 2021-12-16 Pfizer Inc. Composés antiviraux contenant du nitrile

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
ANIRUDHAN ET AL., J MED VIROL., vol. 93, 2021, pages 2722
CAS , no. 148893-10-1
CAS, no. 1416992-39-6
KATRITZKY ALAN R ET AL: "A Conceptually New Approach to the Synthesis of Secondary Amides and Thioamides1", J. ORG. CHEM, vol. 53, 1 January 1988 (1988-01-01), pages 5854 - 5856, XP093040301 *
KIM ET AL., J. VIROL., vol. 86, 2012, pages 11754
KIM ET AL., PLOS PATHOG, vol. 12, 2016, pages e1005531
KLAUBER ERIC G. ET AL: "Merging Nucleophilic and Hydrogen Bonding Catalysis: An Anion Binding Approach to the Kinetic Resolution of Propargylic Amines", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 132, no. 39, 15 September 2010 (2010-09-15), pages 13624 - 13626, XP093040298, ISSN: 0002-7863, DOI: 10.1021/ja105337h *
KOLLETH AMANDINE ET AL: "Kinetic resolution of propargylamines via a highly enantioselective non-enzymatic N-acylation process", CHEMICAL COMMUNICATIONS, vol. 48, no. 85, 1 January 2012 (2012-01-01), UK, pages 10511, XP093040295, ISSN: 1359-7345, DOI: 10.1039/c2cc35719d *
MARION GARREAU ET AL: "C-Terminal Bioconjugation of Peptides through Photoredox Catalyzed Decarboxylative Alkynylation", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, VERLAG CHEMIE, HOBOKEN, USA, vol. 58, no. 24, 8 May 2019 (2019-05-08), pages 8182 - 8186, XP072087686, ISSN: 1433-7851, DOI: 10.1002/ANIE.201901922 *
OWEN ET AL., SCIENCE, vol. 374, 2021, pages 1586
PEDERSEN ET AL., J. FELINE MED. SURG., vol. 20, 2018, pages 378
YANG ET AL., CURR. PHARM. DES., vol. 12, 2006, pages 4573
ZHANG ET AL., SCIENCE, vol. 368, 2020, pages 409
ZIEBUHR ET AL., J. GEN. VIROL., vol. 81, 2000, pages 853

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