WO2022224223A1 - Composés et compositions pour le traitement de maladies associées au coronavirus - Google Patents

Composés et compositions pour le traitement de maladies associées au coronavirus Download PDF

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WO2022224223A1
WO2022224223A1 PCT/IB2022/053794 IB2022053794W WO2022224223A1 WO 2022224223 A1 WO2022224223 A1 WO 2022224223A1 IB 2022053794 W IB2022053794 W IB 2022053794W WO 2022224223 A1 WO2022224223 A1 WO 2022224223A1
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substituted
independently selected
membered
unsubstituted
alkyl
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PCT/IB2022/053794
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Matthew James HESSE
Viktor HORNAK
Sajan Joseph
Heinz Ernst Moser
Julien Papillon
Tajesh PATEL
Richard Robinson
David Charles TULLY
Jun Yuan
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Novartis Ag
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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
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds and compositions for the treatment, management and/or prevention of coronaviral related diseases.
  • the present invention relates to compounds which are inhibitors of SARS-CoV-2 main protease (M pro ), to pharmaceutical compositions comprising such compounds, to methods for synthesizing such compounds and to methods of using such compounds and compositions for the treatment, management or prevention of coronaviral related diseases.
  • M pro main protease
  • SARS-CoV-2 is a single positive-stranded RNA virus belonging to the genus Coronavirus ⁇ .
  • the SARS-CoV-2 genome is about 30 kb in length, has untranslated regions (UTR) at both ends, and at least 6 complete open reading frame genes (ORF).
  • ORF 1a/b directly encodes two polyproteins: polyprotein 1a (pp1a) and polyprotein 1ab (pp1ab). These polypeptides are cleaved by the main protease (M pro ), also known as 3C-like protease (3CLpro), and the papain-like protease (PLpro) into 16 non-structural proteins (nsps).
  • M pro main protease
  • 3CLpro 3C-like protease
  • PLpro papain-like protease
  • M pro plays a vital role in the replication cycle of SARS-CoV-2. Therefore, inhibiting the activity of M pro would block viral replication and may provide an effective therapeutic approach for the treatment of COVID-19, the disease caused by SARS-CoV-2, or for diseases caused by other beta-coronaviruses.
  • S surface spike glycoprotein
  • E envelope protein
  • M membrane protein
  • N Nucleocapsid protein
  • Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • Another aspect of the present invention is a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers.
  • the invention provides a method ⁇ s for treating, preventing and/or managing a coronaviral-related disease or disorder, wherein the method comprises administering to a subject in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • the coronaviral-related disease are COVID-19, other acute respiratory syndromes, non-respiratory coronavirus syndromes and post-infectious coronavirus syndromes.
  • the invention provides a method ⁇ s for treating, preventing and/or managing a coronaviral-related disease or disorder, wherein the method comprises administering to a subject in need of such treatment, prevention or management a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • the coronaviral-related disease is COVID-19.
  • the invention provides use of a compound of of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment, prevention and/or management of a coronalviral-related disease or disorder.
  • the invention provides use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment, prevention and/or management of COVID-19.
  • the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the treatment, prevention and/or management of a coronalviral-related disease or disorder.
  • the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the treatment, prevention and/or management of COVID-19.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and/or management of a coronalviral-related disease or disorder.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention and/or management of COVID-19.
  • the invention provides kits comprising a compound of the invention for treating, preventing and/or managing a coronaviral-related disease.
  • the invention provides kits comprising a compound of the invention for treating, preventing and/or managing COVID-19.
  • the invention provides combinations for the treatment, prevention and/or management of a coronaviral related disease, wherein a compound of the invention is used in combination with one or more other active agents.
  • the active agent(s) is selected froma neutralizing antibody and an antiviral agent.
  • the active agent(s) is selected from a neutralizing antibody, an antiviral agent and other agents selected from alvelestat, Lenzilumab, Octagam, Remestemcel-L, RPH-104 + olokizumab, Bucillamine, CD24FC (MK-7110), Tradipitant, Ifenprodil, Tocilizumab, Leronlimab, Fenretinide, ATYR-1923, CYTO-205, APN-01, and Ampion.
  • the neutralizing antibody is selected from Bamlanivimab, bamlanivimab + etesevimab, bamlanivimab + VIR-7831, REGN-COV2, VIR-7831, AZD7442, Regdanvimab/CT-P59, ABP-300, , COVI-AM/STI-2020, VIR-7832, SAB- 185, JS016/etesevimab, C-135LS/C-144LS, BRII-196, BRII-198, SCTA-01, MW-33, DXP593, HFB-30132A, ADG20, COVI-GUARD (STI-1499) and convalescent plasma, and the antiviral agents is selected from remdesivir, Avigan/favipiravir, EIDD-2801/molnupiravir, AT-527, PF- 00835231, PF-07321332, Ensovibep/DARPins, galides
  • the invention provides combinations for the treatment, prevention and/or management of a coronaviral related disease, wherein a compound of the invention is used in combination with remdesivir (also known as 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)-L-alaninate).
  • remdesivir also known as 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2- yl)methoxy
  • the invention provides combinations for the treatment, prevention and/or management of a coronaviral related disease, wherein a compound of the invention is used in combination with an antibody selected from ABBV 47D11, ABP-300, ADG20, Bamlanivimab + VIR-7831, Bamlanivimab+etesevimab, BRII196 + BRII198, C-135LS/C-144LS, Convalescent Plasma, COR-101, CT-P63, DXP593, Etesevimab (JS016), Evusheld/AZD-7442, HFB-30132A, IBIO123, IN-006, JMB2002, LY-CoV1404, Ly-CovMab, MAD0004J08, MW-33, REGEN- COV/Ronapreve, Regkirona/Regdanvimab, SAB-185, SCTA-01, STI-2099/COVIDROPS, TY027, VIR-7832 (GS)-S
  • the invention provides combinations for the treatment, prevention and/or management of a coronaviral related disease, wherein a compound of the invention is used in combination with an antiviral agent selected from ABX-464, alisporivir, alvelestat, ANA-001, Apabetalone, Arakoda (Tafenoquine), ASC-09 + ritonavir, ASC11, AT-100, AT-301, AT-527 (Bemnifosubuvir), AT-H201, ATR-002, boceprivir, brequinar, Bucillamine, Camostat (DWJ1248), Camostat mesylate, Carrimycin, DC-402234 (FB2001), Ebeselen (SPI-1005), EDP-235, Elsulfavirine, Ensitrelvir/S-217622, Ensovibep, Favipiravir, FP-025, Galidesivir, Gamunex-C, Lüvrio/Molnupira
  • the invention provides combinations for the treatment, prevention and/or management of a coronaviral related disease, wherein a compound of the invention is used in combination with Actemra/RoActemra, Ampion, APN-01 (alunacedase alfa), ATR-002, ATYR- 1923, CYTO-205, Fenretinide (LAU-7b), Lenzilumab, Leronlimab, Octagam, Olumiant +/- Veklury , Remestemcel-L, RPH-104 + olokizumab, sarilumab , tocilizumab or Tradipitant.
  • alkyl refers to a fully saturated branched or straight hydrocarbon chain.
  • an alkyl group is a "C 1 -C 2 alkyl", “C 1 -C 3 alkyl", “C 1 -C 4 alkyl", “C 1 - C 5 alkyl", “C 1 -C 6 alkyl”, “C 1 -C 7 alkyl", “C 1 -C 8 alkyl", “C 1 -C 9 alkyl” or "C 1 -C 10 alkyl", wherein the terms "C1-C2alkyl", “C1-C3alkyl", “C1-C4alkyl", “C1-C5alkyl", “C1-C6alkyl”, “C1-C7alkyl", “C1-C8alkyl”, “C1- C 9 alkyl” and “C 1 -C 10 alkyl”, as used herein, refer to an alkyl
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n- octyl, n-nonyl and n-decyl.
  • alkenyl refers to a partially saturated branched or straight hydrocarbon chain having one more double bonds.
  • an alkenyl group is a "C 2 -C 3 alkenyl", “C 2 -C 4 alkenyl", “C 2 -C 5 alkenyl”, “C 2 -C 6 alkenyl”, “C 2 -C 7 alkenyl”, “C 2 -C 8 alkenyl”, “C 2 -C 9 alkenyl” or “C 2 -C 10 alkenyl”, wherein the terms “C 2 -C 3 alkenyl”, “C 2 -C 4 alkenyl”, “C 2 - C 5 alkenyl", “C 2 -C 6 alkenyl”, “C 2 -C 7 alkenyl”, “C 2 -C 8 alkenyl”, “C 2 -C 9 alkenyl” and “C 2 -C 10 alkenyl”, as used herein, refer to an alkenyl group containing at least 2, and at most 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, respectively.
  • alkenyl groups include ethenyl, n- propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, isopentenyl, n-hexenyl, n-heptenyl, n-octenyl, n-nonenyl and n-decenyl.
  • alkoxy refers to -O-alkyl or-alkyl-O-, wherein "alkyl" is as defined herein.
  • an alkoxy group is a "C 1 -C 2 alkoxy", “C 1 -C 3 alkoxy", “C 1 - C 4 alkoxy", “C 1 -C 5 alkoxy", “C 1 -C 6 alkoxy”, “C 1 -C 7 alkoxy”, “C 1 -C 8 alkoxy”, “C 1 -C 9 alkoxy” or “C 1 - C10alkoxy”, wherein the terms "C1-C3alkoxy", “C1-C4alkoxy”, “C1-C5alkoxy”, “C1-C6alkoxy", “C1- C 7 alkoxy", “C 1 -C 8 alkoxy", “C 1 -C 9 alkoxy” and "C 1 -C 10 alkoxy”, as used herein refer to -O-C 1 - C 2 alkyl, -O-C 1 -C 3 alkyl, -O-C 1 -C 4 alkyl, -O-C 1 -C 1
  • alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n- pentoxy, isopentoxy, hexoxy, heptoxy, octoxy, nonoxy and decoxy.
  • C 3 -C 8 cycloalkyl refers to a fully saturated, monocyclic hydrocarbon ring system having 3 to 8 carbon atoms as ring members.
  • C 3 -C 8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • C 5 -C 6 cycloalkenyl refers to a partially saturated (but not aromatic), monocyclic hydrocarbon ring system having 5 to 6 carbon atoms as ring members.
  • C 5 -C 6 cycloalkenyl include cyclopent-1-enyl, cyclopenta-1,3-dienyl, cyclohex-1-enyl and cyclohexa-1,3-dienyl.
  • C 1 -C 6 alkyl-phenyl refer to a C 1 -C 6 alkyl as defined above which is substituted with a phenyl group.
  • Non-limiting example of a C 1 -C 6 alkyl-phenyl is benzyl.
  • haloalkyl refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl is replaced by a halo group (as defined herein).
  • the haloalkyl can be monohaloalkyl, dihaloalkyl, trihaloalkyl, or polyhaloalkyl including perhaloalkyl.
  • a monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group.
  • Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl.
  • the polyhaloalkyl contains up to 6, or 4, or 3, or 2 halo groups.
  • haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • a perhalo-alkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms, e.g., trifluoromethyl.
  • haloalkyl groups include monofluoro-, difluoro- and trifluoro- substituted methyl and ethyl groups, e.g. CF 3 , CHF 2 , CH 2 F, CH 2 CHF 2 and CH 2 CF 3 .
  • C 1 -C 6 haloalkyl refers to the respective "C 1 -C 6 alkyl", as defined herein, wherein at least one of the hydrogen atoms of the "C 1 -C 6 alkyl" is replaced by a halo group (as defined herein).
  • the C1-C6haloalkyl groups can be monoC1-C6haloalkyl, wherein such C 1 -C 6 haloalkyl groups have one iodo, one bromo, one chloro or one fluoro. Additionally, the C 1 - C 6 haloalkyl groups can be diC 1 -C 6 haloalkyl wherein such C 1 -C 6 haloalkyl groups can have two halo atoms independently selected from iodo, bromo, chloro or fluoro.
  • the C 1 - C 6 haloalkyl groups can be polyC 1 -C 6 haloalkyl wherein such C 1 -C 6 haloalkyl groups can have two or more of the same halo atoms or a combination of two or more different halo atoms.
  • Such polyC 1 -C 6 haloalkyl can be perhaloC 1 -C 6 haloalkyl where all the hydrogen atoms of the respective C1-C6alkyl have been replaced with halo atoms and the halo atoms can be the same or a combination of different halo atoms.
  • C 1 -C 6 haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • haloalkoxy refers to the group –O-haloalkyl wherein the term "haloalkyl" is as defined herein.
  • Non-limiting examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy, dichloroethoxy and dichloropropoxy.
  • a perhalo-alkoxy refers to an alkoxy having all hydrogen atoms replaced with halo atoms, e.g., trifluoromethoxy.
  • haloalkoxy groups include monofluoro-, difluoro- and trifluoro- substituted methoxy and ethoxygroups, e.g. -OCF 3 , -OCHF 2 , -OCH 2 F, -OCH 2 CHF 2 and - OCH 2 CF 3 .
  • C 1 -C 6 haloalkoxy refers to the group –O-C 1 -C 6 haloalkyl, wherein the term C 1 -C 6 haloalkyl is as defined herein.
  • Non-limiting examples of "C 1 - C 6 haloalkoxy” groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, difluoropropoxy, dichloroethoxy and dichloropropoxy.
  • halogen or “halo” as used herein, refer to fluoro (F), chloro (Cl), bromo (Br) and iodo (I).
  • heteroatoms refers to nitrogen (N), oxygen (O) or sulfur (S) atoms.
  • heteroaryl refers to an aromatic ring system containing one or more heteroatoms which may be the same or different.
  • heteroaryl also refers to an aromatic ring system having one or more ring members which are each independently selected from N, NR 6 , O and S, where R 6 is as defined herein.
  • Heteroaryl groups may be monocyclic ring systems or fused bicyclic ring systems. Monocyclic heteroaryl rings have from 5 to 6 ring atoms. Bicyclic heteroaryl rings have from 7 to 12 ring member atoms.
  • Bicyclic heteroaryl rings include those ring systems wherein a heteroaryl ring is fused to a phenyl ring.
  • heteroaryl groups include benzofuranyl, benzo[c]thiophenyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, cinnolinyl, furazanyl, furyl, imidazolyl, indolyl, indolizinyl, indazolyl, isoindolyl, isoquinolinyl, isoxazolyl, isothiazolyl, oxazolyl, oxaindolyl, oxadiazolyl (including 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl), purinyl, pyrazolyl, pyrrolyl, phthalazinyl, pyridyl (including 2-, 3-, and 4-
  • 5 or 6 membered heteroaryl refers to an aromatic, 5 or 6 membered monocyclic ring system wherein 1, 2, 3 or 4 ring members are each independently selected from N, NR 6 , O and S, where R 6 is as defined herein.
  • Non-limiting examples of such 5 or 6 membered heteroaryl groups include furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, tetrazolyl, pyridyl (including 2-, 3-, and 4-pyridyl), pyridazinyl, pyrazinyl and pyrimidinyl.
  • the term "5 or 6 membered heteroaryl”, as used herein, also refers to an aromatic, 5 or 6 membered monocyclic ring system wherein 1, 2, or 3 ring members are each independently selected from N, NR 6 , O and S, where R 6 is as defined herein.
  • Non-limiting examples of such 5 or 6 membered heteroaryl groups include furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, pyridyl (including 2-, 3-, and 4-pyridyl), pyridazinyl, pyrazinyl and pyrimidinyl.
  • Non-limiting examples of such 6 membered heteroaryl groups include pyridyl (including 2-, 3-, and 4-pyridyl), pyridazinyl, pyrazinyl and pyrimidinyl.
  • pyridyl including 2-, 3-, and 4-pyridyl
  • pyridazinyl pyrazinyl
  • pyrazinyl pyrazinyl
  • pyrimidinyl pyridyl
  • 5 membered heteroaryl refers to an aromatic, 5 membered monocyclic ring system wherein 1, 2, 3 or 4 ring members are each independently selected from N, NR 6 , O and S, where R 6 is as defined herein.
  • Non-limiting examples of such 5 membered heteroaryl groups include furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and tetrazolyl.
  • the term "5 membered heteroaryl”, as used herein, also refers to an aromatic, 5 membered monocyclic ring system wherein 1, 2, or 3 ring members are each independently selected from N, NR 6 , O and S, where R 6 is as defined herein.
  • Non-limiting examples of such 5 membered heteroaryl groups include furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyrazolyl, thiadiazolyl, thiazolyl, thienyl and triazolyl.
  • the term "9 or 10 membered bicyclic heteroaryl”, as used herein, refers to a 9 or 10 membered fused, bicyclic aromatic ring system wherein 1, 2, 3, 4 or 5 ring members are each independently selected from N, NR 6 , O and S, where R 6 is as defined herein.
  • Non-limiting examples of such bicyclic heteroaryl groups include indolyl, quinolinyl, isoquinolinyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, thieno[2,3- b]furanyl, 1H-pyrazolo[4,3-d]-oxazolyl, imidazo[2,1-b] thiazolyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, pyrazino[2,3- d]pyridazinyl, imidazo[1,2-b][1,2,4]triazinyl, benzoxazolyl, benzimidazolyl, imidazopyridinyl,
  • 4 to 7 membered heterocycloalkyl refers to a 4 to 7 membered, saturated hydrocarbon ring wherein 1, 2, 3 or 4 ring members are each independently selected from N, NR 6 , O or S, where R 6 is as defined herein.
  • the heterocycloalkyl group can be attached to another group at a nitrogen or a carbon atom.
  • Non-limiting examples of 4 to 6 membered heterocycloalkyl groups include azetadinyl (which includes azetadin-1-yl, azetadin-2-yl and azetadin-3-yl), oxetanyl (which includes oxetan-2-yl, oxetan-3-yl and oxetan- 4-yl), thietanyl (which includes thietan-2-yl, thietan-3-yl and thietan-4-yl), pyrrolidinyl (which includes pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolidin-4-yl and pyrrolidin-5-yl), tetrahydrofuranyl (which includes tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-3-y
  • 3 to 6 membered heterocycloalkyl refers to a 3 to 6 membered, saturated hydrocarbon ring wherein 1, 2 or 3 ring members are each independently selected from N, NR 6 , O or S, where R 6 is as defined herein.
  • the heterocycloalkyl group can be attached to another group at a nitrogen or a carbon atom.
  • Non-limiting examples of 3 to 6 membered heterocycloalkyl groups include oxiranyl, aziridinyl, thiiranyl, azetadinyl (which includes azetadin-1-yl, azetadin-2-yl and azetadin-3-yl), oxetanyl (which includes oxetan-2-yl, oxetan-3-yl and oxetan-4-yl), thietanyl (which includes thietan-2-yl, thietan-3-yl and thietan-4-yl), pyrrolidinyl (which includes pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolidin-4-yl and pyrrolidin-5-yl), tetrahydrofuranyl (which includes tetrahydrofuran-2-yl,
  • 4 to 6 membered heterocycloalkyl refers to a 4 to 6 membered, saturated hydrocarbon ring wherein 1, 2, 3 or 4 ring members are each independently selected from N, NR 6 , O or S, where R 6 is as defined herein.
  • the heterocycloalkyl group can be attached to another group at a nitrogen or a carbon atom.
  • Non-limiting examples of 4 to 6 membered heterocycloalkyl groups include azetadinyl (which includes azetadin-1-yl, azetadin-2-yl and azetadin-3-yl), oxetanyl (which includes oxetan-2-yl, oxetan-3-yl and oxetan- 4-yl), thietanyl (which includes thietan-2-yl, thietan-3-yl and thietan-4-yl), pyrrolidinyl (which includes pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolidin-4-yl and pyrrolidin-5-yl), tetrahydrofuranyl (which includes tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-3-y
  • heterocycloalkyl refers to a 5 or 6 membered, saturated hydrocarbon ring wherein 1, 2, 3 or 4 ring members are each independently selected from N, NR 6 , O or S, where R 6 is as defined herein.
  • the heterocycloalkyl group can be attached to another group at a nitrogen or a carbon atom.
  • Non-limiting examples of 5 or 6 membered heterocycloalkyl groups include pyrrolidinyl (which includes pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolidin-4-yl and pyrrolidin-5-yl), tetrahydrofuranyl (which includes tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-4-yl and tetrahydrofuran-5- yl), tetrahydrothienyl (which includes tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydrothien- 4-yl and tetrahydrothien-5-yl), piperidinyl (which includes piperidin-1-yl, piperidin-2-yl, piperidin- 3-yl, piperidin-4-yl,
  • 6 membered heterocycloalkyl refers to a 6 membered, saturated hydrocarbon ring wherein 1, 2, 3 or 4 ring members are each independently selected from N, NR 6 , O or S, where R 6 is as defined herein.
  • the heterocycloalkyl group can be attached to another group at a nitrogen or a carbon atom.
  • Non-limiting examples of 6 membered heterocycloalkyl groups include piperidinyl (which includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl and piperidin-6-yl), tetrahydropyranyl (which includes tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-5-yl and tetrahydropyran-6-yl), tetrahydrothiopyranyl (which includes tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, tetrahydrothiopyran- 5-yl and tetrahydrothiopyran-6-yl), piperazinyl (which includes piperazinyl (which
  • 3 membered heterocycloalkyl refers to a 3 membered, saturated hydrocarbon ring wherein 1or 2 ring members are each independently selected from N, NR 6 , O or S, where R 6 is as defined herein.
  • the heterocycloalkyl group can be attached to another group at a nitrogen or a carbon atom.
  • Non-limiting examples of 3 membered heterocycloalkyl groups, as used herein, include oxiranyl, aziridinyl and thiiranyl.
  • 5 or 6 membered heterocyclyl refers to a partially saturated (but not aromatic) 5 or 6 membered monocyclic ring system wherein 1, 2 or 3 ring members are each independently selected from N, NR 6 , O or S, where R 6 is as defined herein.
  • the 5 or 6 membered heterocyclyl group can be attached to another group at a nitrogen or a carbon atom.
  • Non-limiting examples of 5 or 6 membered heterocyclyl groups include 1,2-dihydropyridinyl and 2,3-dihydro- 1H-pyrrolyl.
  • the 6 membered heterocyclyl group can be attached to another group at a nitrogen or a carbon atom.
  • Non-limiting examples of membered heterocyclyl groups include 1,2-dihydropyridinyl.
  • the 5 membered heterocyclyl group can be attached to another group at a nitrogen or a carbon atom.
  • Non-limiting examples of 5 membered heterocyclyl groups include 2,3-dihydro-1H-pyrrolyl.
  • the C 5 -C 6 heterocycloalkenyl group can be attached to another group at a nitrogen or a carbon atom.
  • Non-limiting examples of 9 or 10 membered bicyclic heterocyclyl groups include isochromanyl, 1,2-dihydroquinolinyl, 3a,7a-dihydro-1H-pyrrolo[2,3-c]pyridinyl and 3a,7a- dihydro-1H-indazolyl.
  • spiro attached refers to the attachment of one ring system to another ring system via one carbon aton common to both rings.
  • the beta ( ⁇ ) position relative to the attachment point indicated by the asterix (*) is located at the beta ( ⁇ ) position relative to the attachment point indicated by the asterix (*) .
  • isomers refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.
  • an optical isomer or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom.
  • the term “chiral” refers to molecules which have the property of non- superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. “Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other.
  • a 1:1 mixture of a pair of enantiomers is a "racemic” mixture.
  • the term is used to designate a racemic mixture where appropriate.
  • "Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry can be specified according to the Cahn- lngold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the absolute stereochemistry of atropisomers can be assigned either as M or P according to the “helicity” rule of Prelog and Helmchen.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289- 1329).
  • coronaviral related disease means a disease caused by a member of the Coronavirus family (i.e., may belong to the Coronaviridae family).
  • Coronaviruses are positive-stranded RNA viruses with a crown-like appearance under an electron microscope due to the presence of spike glycoproteins on the envelope.
  • Any member of the coronavirus family e.g., those belonging to the alphacoronavirus, betacoronavirus, deltacoronavirus, or gammacoronavirus genuses
  • coronavirus family e.g., those belonging to the alphacoronavirus, betacoronavirus, deltacoronavirus, or gammacoronavirus genuses
  • the respiratory virus could be a betacoronavirus such as severe acute respiratory syndrome-related coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Middle East respiratory syndrome related coronavirus (MERS-CoV), OC43 and HKU1, or an alphacoronavirus such as 229E and NL63.
  • the respiratory virus could also be a coronavirus other than SARS-CoV, SARS-CoV-2, MERS-CoV, OC43, HKU1, 229E or NL63.
  • SARS-CoV-2 Patients infected with SARS-CoV-2 present with a wide range of clinical severity varying from asymptomatic to a severe form of interstitial pneumonia, which may progress towards acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI), a form of diffuse alveolar injury, and is a serious lung condition that causes low blood oxygenation and respiratory failure and/or multi organ failure (MOF), associated symptoms and death.
  • ARDS acute respiratory distress syndrome
  • ALI severe form of acute lung injury
  • MOF multi organ failure
  • SARS-CoV-2 uses the same receptor as SARS-CoV, angiotensin-converting enzyme 2 (ACE2), and mainly spreads through the respiratory tract.
  • ACE2 angiotensin-converting enzyme 2
  • Cytokine profiling of patients with severe COVID-19 demonstrates elevated levels of interleukin (IL)-2, IL-7, IL-6, IL-1, granulocyte-colony stimulating factor, interferon- ⁇ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1- ⁇ and tumor necrosis factor- ⁇ .
  • IL interleukin
  • IL-7 interleukin-7
  • IL-6 IL-1
  • granulocyte-colony stimulating factor interferon- ⁇ inducible protein 10
  • monocyte chemoattractant protein 1 ⁇ macrophage inflammatory protein 1- ⁇
  • tumor necrosis factor- ⁇ tumor necrosis factor- ⁇ .
  • the terms “inhibit”, “inhibition” or “inhibiting”, as used herein, refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • subject as used herein may refer to an animal. The animal
  • a subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
  • the subject is a primate.
  • the subject is a human.
  • the terms “patient” or “subject” are used herein interchangeably.
  • the terms “treat,” “treating,” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • the term “prevent”, “preventing” or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.
  • the expression “substituted with 1, 2, 3 or 4 R 4 and optionally substituted with 1 or 2 oxo” means the group is substituted with 1, 2, 3 or 4 R 4 or the group is substituted with 1, 2, 3 or 4 R 4 and is substituted with 1 or 2 oxo.
  • the expression “optionally substituted with oxo” means the group is unsubstituted or is substituted oxo.
  • the terms “manage,” “managing,” and “management” encompass preventing the recurrence of the specified disease or disorder in a patient who has already suffered from the disease or disorder, and/or lengthening the time that a patient who has suffered from the disease or disorder remains in remission.
  • the terms encompass modulating the threshold, development and/or duration of the disease or disorder, or changing the way that a patient responds to the disease or disorder.
  • a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, manage a condition, alleviate conditions, slow or delay disease progression, or prevent a disease.
  • a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing managing and/or ameliorating a condition, or a disorder or a disease (i) mediated by SARS- CoV-2 main protease (M pro ), or (ii) associated with or mediated by SARS-CoV-2 main protease (M pro ) activity, or (iii) characterized by activity (normal or abnormal) of SARS-CoV-2 main protease (M pro ); or (2) reducing or inhibiting the activity of SARS-CoV-2 main protease (M pro ).
  • a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of SARS-CoV-2 main protease (Mpro).
  • co-administer refers to the presence of two active agents in the blood of an individual. Active agents that are co-administered can be concurrently or sequentially delivered.
  • the terms “compound of the invention”, “compounds of the invention”, “compound of the present invention” or “compounds of the present invention” refers to a compound or compounds of Formula (I), or subformulae thereof such as Formula (I-a), (Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), Formula (I-e), Formula (I-f), Formula (I-g), Formula (I-h), Formula (I-i), Formula (I-j), Formula (I-k), Formula (I-l), Formula (I-m), Formula (I-n), Formula (I-o), Formula (I-p), Formula (I-q), Formula (I-r), Formula (I-s), Formula (I-t), Formula (I-u), Formula (I-v), Formula (I-w), Formula (I-x), Formula (I-y), Formula (I-z), Formula (I-aa), Formula (I-ab), Formula (I-ac), Formula (I-ad),
  • Embodiment 1 A compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, as described above in the Summary of the Invention.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof wherein: the dashed line between X 1 and X 2 is a single bond or a double bond;
  • X 2 is N, C or CH;
  • X 3 is N, C or CH;
  • X 4 is C(R 2a ) 2 or
  • Embodiment 3 The compound of Embodiment 1 or Embodiment 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein p is 0 and the compound of Formula (I) has the structure of Formula (IA): X 1 , X 2 , X 3 , R 3 where Ring A, , R 5 , n and the dashed line between X 1 and X 2 are as defined in Embodiment 1.
  • Embodiment 11 The compound of any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: the dashed line between X 1 and X 2 is a single bond; X 1 is NR 1 , C(R 2a ) 2 or O; X 2 is C or CH; X 3 is C or CH; R 1 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, a C 1 -C 6 alkyl substituted with one or more R 12 , or a C 1 -C 6 alkenyl substituted with one or more R 12 , and wherein the cycloalkyl is unsubstituted or the cycloalkyl is substituted with 1 substituent selected from the group consisting of C 1 -C 6 alkyl substituted with CN; each R 2a is independently selected from the group consisting of H, and C 1 -C 6 alkyl; R 3 is selected from the group consisting of:
  • Embodiment 12 The compound of any one of Embodiments 1 to 11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: X 1 is NR 1 ; R 1 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, a C 1 -C 6 alkyl substituted with one or more R 12 , or a C 1 -C 6 alkenyl substituted with one or more R 12 , and wherein the cycloalkyl is unsubstituted or the cycloalkyl is substituted with 1 substituent selected from the group consisting of C 1 -C 6 alkyl substituted with CN; each R 2a is independently selected from the group consisting of H, and C 1 -C 6 alkyl; R 3 is selected from the group consisting of: i) a 6 membered heteroaryl with an attachment point at a carbon atom ring member and a N heteroatom as a ring member which is located at a beta ( ⁇ )
  • Embodiment 16 The compound of any one of Embodiments 1 to 15, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: X 1 is NR 1 ; R 1 is H or C 1 -C 6 alkyl substituted with one or more R 12 ; R 3 is selected from the group consisting of: i) -CHR 13 R 14 ; ii) benzyl which is unsubstituted or is substituted with 1 R 4 ; iii) a 6 membered heteroaryl wherein 1 ring member is selected from N, and wherein the 6 membered heteroaryl is unsubstituted or is substituted with 1 or 2 R 4 ; iv) a 10 membered bicyclic heteroaryl with an attachment point at a carbon atom ring member and a N heteroatom as a ring member which is located at a beta ( ⁇ ) position relative to the attachment point, wherein the 10 membered bicyclic heteroaryl has 0, 1, 2 or 3 additional N heteroatoms
  • Embodiment 17 The compound of any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 1 is H or C 1 -C 6 alkyl substituted with one or more R 12 ; R 3 is selected from the group consisting of: i) a 9 or 10 membered bicyclic heteroaryl wherein 1, 2 or 3 ring members are each independently selected from N, NR 6 and O, wherein the 9 or 10 membered bicyclic heteroaryl is unsubstituted or is substituted with 1 or 2 R 4 ; and ii) a 10 membered bicyclic heteroaryl with an attachment point at a carbon atom ring member and a N heteroatom as a ring member which is located at a beta ( ⁇ ) position relative to the attachment point, wherein the 10 membered bicyclic heteroaryl has 0, 1, 2 or 3 additional N heteroatoms as ring members, and wherein the 10 membered bicyclic heteroaryl is unsubstituted or is
  • Embodiment 22 The compound of any one of Embodiments 1 to 21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the dashed line between X 1 and X 2 is a single bond.
  • Embodiment 23 The compound of any one of Embodiments 1 to 21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the dashed line between X 1 and X 2 is a double bond.
  • Embodiment 24. The compound of any one of Embodiments 1 to 23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is phenyl.
  • Embodiment 25 The compound of any one of Embodiments 1 to 23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is .
  • Embodiment 26 The compound of any one of Embodiments 1 to 23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a 5 or 6 membered heteroaryl wherein 1, 2, 3 or 4 ring members are each independently selected from N, NR 6 , O and S.
  • Embodiment 27 The compound of any one of Embodiments 1 to 23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a 5 or 6 membered heteroaryl wherein 1 or 2 ring members are each independently selected from N, NR 6 , O and S.
  • Embodiment 28 The compound of any one of Embodiments 1 to 23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a 5 or 6 membered heteroaryl wherein 1 or 2 ring members are each independently selected from N, NR 6 , O and S.
  • Embodiment 40 is
  • Embodiment 42 The compound of any one of Embodiments 1 to 23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a 9 or 10 membered bicyclic heterocyclyl wherein 1, 2, 3, 4 or 5 ring members are each independently selected from N, NR 6 , O and S.
  • Embodiment 43 The compound of any one of Embodiments 1 to 23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is a 9 or 10 membered bicyclic heterocyclyl wherein 1 ring member is selected from N, NR 6 , O and S.
  • Embodiment 44 Embodiment 44.
  • Embodiment 50 The compound of any one of Embodiments 1 to 23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Ring A is Embodiment 51.
  • Embodiment 53 The compound of any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from a compound having the structure of the following sub-formulae: Formula (I-aaa), Formula (I-aab) and Formula (I-aac)): (I-aaa) (I-aab) (I-aac).
  • Embodiment 54 The compound of any one of Embodiments 1 to 52, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from a compound having the structure of Formula (I-a), (I-a).
  • Embodiment 55 The compound of any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from a compound having the structure of Formula (I-a), (I-a).
  • Embodiment 56 The compound of any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from a compound having the structure of Formula (I-ay), (I-ay).
  • Embodiment 56 The compound of any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from a compound having the structure of Formula (I-az), Formula (I-ba) or Formula (I-bb), or a pharmaceutically acceptable salt or stereoisomer thereof, (I-az) (I-ba) (I-bb).
  • Embodiment 57 Embodiment 57.
  • Embodiment 58 The compound of any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from a compound having the structure of Formula (I-az), Formula (I-ba), Formula (I-bc) or Formula (I-bd), or a pharmaceutically acceptable salt or stereoisomer thereof, (I-az) (I-ba) (I-bc) (I-bd).
  • Embodiment 60 The compound of any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from a compound having the structure of the Formula (I-be), or a pharmaceutically acceptable salt or stereoisomer thereof, (I-be).
  • Embodiment 62 The compound of any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from a compound having the structure of Formula (I-bk), Formula (I-bl) or Formula (I-bm), or a pharmaceutically acceptable salt or stereoisomer thereof, (I-bk) (I-bl) (I-bm).
  • Embodiment 63 The compound of any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from a compound having the structure of Formula (I-k) or Formula (I-l), or a pharmaceutically acceptable salt or stereoisomer thereof, (I-k) (I-l).
  • Embodiment 64 The compound of any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from a compound having the structure of Formula (I-k) or Formula (I-l), or a pharmaceutically acceptable salt or stereoisomer thereof, (I-k
  • Embodiment 65 The compound of any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from a compound having the structure of Formula (I-bn), Formula (I-bo) or Formula (I-bp), or a pharmaceutically acceptable salt or stereoisomer thereof, (I-bn) (I-bo) (I-bp).
  • Embodiment 65 The compound of any one of Embodiments 1 to 51, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from a compound having the structure of Formula (I-bq), Formula (I-br) or Formula (I-bs), or a pharmaceutically acceptable salt or stereoisomer thereof, (I-bq) (I-br) (I-bs).
  • Embodiment 71 The compound of any one of Embodiment 52 to 65, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: X 1 is NR 1 , C(R 2a ) 2 or O; R 1 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, a C 1 -C 6 alkyl substituted with one or more R 12 , or a C 1 -C 6 alkenyl substituted with one or more R 12 , and wherein the cycloalkyl is unsubstituted or the cycloalkyl is substituted with 1 substituent selected from the group consisting of C 1 -C 6 alkyl substituted with CN; each R 2a is independently selected from the group consisting of H, and C 1 -C 6 alkyl; R 3 is selected from the group consisting of: i) a 6 membered heteroaryl with an attachment point at a carbon atom ring member and a N heteroatom as a
  • Embodiment 72 The compound of any one of Embodiment 52 to 65, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: X1 is NR 1 ; R 1 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, a C 1 -C 6 alkyl substituted with one or more R 12 , or a C 1 -C 6 alkenyl substituted with one or more R 12 , and wherein the cycloalkyl is unsubstituted or the cycloalkyl is substituted with 1 substituent selected from the group consisting of C 1 -C 6 alkyl substituted with CN; R 3 is selected from the group consisting of: i) a 6 membered heteroaryl with an attachment point at a carbon atom ring member and a N heteroatom as a ring member which is located at a beta ( ⁇ ) position relative to the attachment point, wherein the 6 membered heteroaryl has 0, 1 or 2 additional N hetero
  • Embodiment 76 The compound of any one of Embodiments 52 to 65, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: X 1 is NR 1 ; R 1 is H or C 1 -C 6 alkyl substituted with one or more R 12 ; R 3 is selected from the group consisting of: i) -CHR 13 R 14 ; ii) benzyl which is unsubstituted or is substituted with 1 R 4 ; iii) a 6 membered heteroaryl wherein 1 ring member is selected from N, and wherein the 6 membered heteroaryl is unsubstituted or is substituted with 1 or 2 R 4 ; iv) a 10 membered bicyclic heteroaryl with an attachment point at a carbon atom ring member and a N heteroatom as a ring member which is located at a beta ( ⁇ ) position relative to the attachment point, wherein the 10 membered bicyclic heteroaryl has 0, 1, 2 or 3 additional N hetero
  • Embodiment 77 The compound of any one of Embodiments 52 to 65, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 1 is H or C 1 -C 6 alkyl substituted with one or more R 12 ; R 3 is selected from the group consisting of: i) a 9 or 10 membered bicyclic heteroaryl wherein 1, 2 or 3 ring members are each independently selected from N, NR 6 and O, wherein the 9 or 10 membered bicyclic heteroaryl is unsubstituted or is substituted with 1 or 2 R 4 ; and ii) a 10 membered bicyclic heteroaryl with an attachment point at a carbon atom ring member and a N heteroatom as a ring member which is located at a beta ( ⁇ ) position relative to the attachment point, wherein the 10 membered bicyclic heteroaryl has 0, 1, 2 or 3 additional N heteroatoms as ring members, and wherein the 10 membered bicyclic heteroaryl is unsubstituted
  • Embodiment 83 The compound of any one of Embodiments 1 to 81, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 1 is NR 1 .
  • Embodiment 84 The compound of any one of Embodiments 1 to 81, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 1 is N.
  • Embodiment 85 The compound of any one of Embodiments 1 to 81, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 1 is N.
  • Embodiment 85 The compound of any one of Embodiments 1 to 81, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
  • Embodiment 86 The compound of any one of Embodiments 1 to 81, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X1 is C(R 2a )2.
  • Embodiment 86 The compound of any one of Embodiments 1 to 81, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 1 is CR 2a .
  • Embodiment 87 The compound of any one of Embodiments 1 to 81, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 1 is O.
  • Embodiment 89 The compound of any one of Embodiments 1 to 81, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 1 is CR 2a R 2b .
  • Embodiment 91 The compound of any one of Embodiments 1 to 90, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 2 is N.
  • Embodiment 92 The compound of any one of Embodiments 1 to 90, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 2 is C.
  • Embodiment 93 The compound of any one of Embodiments 1 to 90, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 2 is CH.
  • Embodiment 94 The compound of any one of Embodiments 1 to 93, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 3 is N.
  • Embodiment 95 The compound of any one of Embodiments 1 to 93, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 3 is N.
  • Embodiment 96 The compound of any one of Embodiments 1 to 93, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 3 is C.
  • Embodiment 96 The compound of any one of Embodiments 1 to 93, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 3 is CH.
  • Embodiment 97 The compound of any one of Embodiments 1 to 96, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X 4 is C(R 2a ) 2 .
  • Embodiment 1 The compound of any one of Embodiments 1 to 98, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is H.
  • Embodiment 100 The compound of any one of Embodiments 1 to 98, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is C 1 -C 6 alkyl substituted with one or more R 12 .
  • Embodiment 101 The compound of any one of Embodiments 1 to 98, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is –CH2R 12 .
  • Embodiment 102 The compound of any one of Embodiments 1 to 98, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is –CH2R 12 .
  • Embodiment 104 The compound of any one of Embodiments 1 to 98, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is C 1 -C 6 alkenyl substituted with one or more R 12 .
  • Embodiment 104 Embodiment 104.
  • Embodiment 107 The compound of any one of Embodiments 1 to 103, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 12 is CN.
  • Embodiment 105 The compound of any one of Embodiments 1 to 100, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 12 is C 1 -C 6 alkyl substituted with CN.
  • Embodiment 106 The compound of any one of Embodiments 1 to 98, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is –CH 2 CN.
  • Embodiment 107 The compound of any one of Embodiments 1 to 103, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 12 is CN.
  • Embodiment 108 Embodiment 108.
  • Embodiment 110 The compound of any one of Embodiments 1 to 101, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 12 is a 3 membered heterocycloalkyl wherein 1 ring member is N, NR 6 , O and S, and wherein the heterocycloalkyl is unsubstituted.
  • Embodiment 109 The compound of any one of Embodiments 1 to 101, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 12 is oxiranyl.
  • Embodiment 110 The compound of any one of Embodiments 1 to 101, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 12 is oxiranyl.
  • Embodiment 113 The compound of any one of Embodiments 1 to 98, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is C1-C6alkyl.
  • Embodiment 114 The compound of any one of Embodiments 1 to 98, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is methyl, ethyl, propyl or isopropyl.
  • Embodiment 117 Embodiment 117.
  • Embodiment 119 The compound of any one of Embodiments 1 to 117, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 2a is independently selected from the group consisting of H, C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted with CN.
  • Embodiment 120 The compound of any one of Embodiments 1 to 117, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 2a is independently selected from the group consisting of H, C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted with CN.
  • each R 2a is independently selected from the group consisting of H and C 1 -C 6 alkyl.
  • Embodiment 121 The compound of any one of Embodiments 1 to 117, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2b is H.
  • Embodiment 122 The compound of any one of Embodiments 1 to 117, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2b is C 1 -C 6 alkyl.
  • Embodiment 123 is
  • Embodiment 128 The compound of any one of Embodiments 1 to 117, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 2a is independently selected from the group consisting of H and -CH 3 .
  • Embodiment 126 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is -(CH 2 ) 0-6 CHR 13 R 14 .
  • Embodiment 127 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is -CHR 13 R 14 .
  • Embodiment 128 The compound of any one of Embodiments 1 to 117, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 2a is independently selected from the group consisting of H and -CH 3 .
  • Embodiment 126 The compound of any one of Embodiments 1 to 125, or a
  • Embodiment 130 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is benzyl which is unsubstituted or is substituted with 1, 2, 3 or 4 R 4 .
  • Embodiment 129 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is benzyl which is unsubstituted or is substituted with 1 R 4 .
  • Embodiment 130 Embodiment 130.
  • Embodiment 131 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is a 6 membered heteroaryl wherein 1, 2 or 3 ring members are each independently selected from N, O and S, and wherein the 6 membered heteroaryl is unsubstituted or is substituted with 1, 2, 3 or 4 R 4 .
  • Embodiment 131 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is a 6 membered heteroaryl wherein 1, ring member is selected from N, and wherein the 6 membered heteroaryl is unsubstituted or is substituted with 1 or 2 R 4 .
  • Embodiment 132 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is pyridyl which is unsubstituted or is substituted with 1, 2, 3 or 4 R 4 .
  • Embodiment 133 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is pyrid-3-yl which is unsubstituted or is substituted with 1 or 2 R 4 .
  • Embodiment 134 Embodiment 134.
  • Embodiment 136 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is a 9 or 10 membered bicyclic heteroaryl wherein 1, 2 or 3 ring members are each independently selected from N, NR 6 andO and S, and wherein the 9 or 10 membered bicyclic heteroaryl is unsubstituted or is substituted with 1 or 2 R 4 .
  • Embodiment 136 Embodiment 136.
  • Embodiment 137 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is isoquinolinyl, phthalazinyl, cinnolinyl, imidazo[1,2-c]pyrimidinyl, pyrazolo[1,5-a]pyrazinyl, benzo[c]isoxazolyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl or naphthyridinyl, each of which is unsubstituted or substituted with 1, 2, 3 or 4 R 4 .
  • Embodiment 137 Embodiment 137.
  • Embodiment 138 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is isoquinolin-4-yl, phthalazin-4-yl, cinnolin-4-yl, imidazo[1,2-c]pyrimidin-8-yl, pyrazolo[1,5-a]pyrazin-7-yl, benzo[c]isoxazol-3-yl, imidazo[1,2-a]pyrazine-5-yl, imidazo[1,2-a]pyridine-3-yl or naphthyridin-4-yl, each of which is unsubstituted or substituted with 1, 2, 3 or 4 R 4 .
  • Embodiment 138 Embodiment 138.
  • Embodiment 140 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is , , , , , N N N , or , each of which is unsubstituted or substituted with 1 or 2 R 4 .
  • Embodiment 139 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is isoquinolinyl which is unsubstituted or substituted with 1 or 2 R 4 .
  • Embodiment 140 Embodiment 140.
  • Embodiment 141 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is isoquinolin-4-yl which is unsubstituted or substituted with 1 or 2 R 4 .
  • Embodiment 141 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is isoquinolin-4-yl which is unsubstituted.
  • Embodiment 142 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is phthalazinyl which is unsubstituted or substituted with 1 or 2 R 4 .
  • Embodiment 143 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is phthalaziny-4-yl which is unsubstituted or substituted with 1 or 2 R 4 .
  • Embodiment 144 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is phthalaziny-4-yl which is unsubstituted.
  • Embodiment 145 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is phthalaziny-4-yl which is unsubstituted.
  • Embodiment 148 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is a 6 membered heterocyclyl wherein 1 ring member is selected from NR 6 , and wherein the 6 membered heterocyclyl substituted with an oxo.
  • Embodiment 148 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is pyridinyl-2(1H)-one which is unsubstituted or substituted with 1, 2, 3 or 4 R 4 .
  • Embodiment 149 Embodiment 149.
  • Embodiment 150 he compound of any one of Embodiments 1 to 125, or a pharmaceutically Embodiment 151.
  • Embodiment 156 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is , , or , each of which is unsubstituted or substituted with 1 or 2 R 4 .
  • Embodiment 156 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is , , or , each of which is unsubstituted or substituted with 1 or 2 R 4 .
  • R 3 is isoquinolinyl, isochromanyl, pyridyl, phthalazinyl, cinnolinyl, imidazo[1,2-c]pyrimidinyl, pyrazolo[1,5- a]pyrazinyl, 3a,7a-dihydro-1H-pyrrolo[2,3-c]pyridinyl, benzo[c]isoxazolyl, imidazo[1,2- a]pyrazinyl, pyridinyl-2(1H)-one, quinolinyl-2(1H)-one, imidazo[1,2-a]pyridinyl, naphthyridinyl or 3a,7a-dihydro-1H-indazolyl, each of which is unsubstituted or substituted with 1 or 2 R 4 .
  • Embodiment 157 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is Embodiment 158.
  • Embodiment 159 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is a 10 membered bicyclic heteroaryl with an attachment point at a carbon atom ring member and a N heteroatom as a ring member which is located at a beta ( ⁇ ) position relative to the attachment point, wherein the 10 membered bicyclic heteroaryl has 0, 1, 2 or 3 additional N heteroatoms as ring members, and wherein the 10 membered bicyclic heteroaryl is unsubstituted or is substituted with 1, 2, 3 or 4 R 4 .
  • Embodiment 160 Embodiment 160.
  • R 3 is a 9 membered bicyclic heteroaryl with an attachment point at a carbon atom ring member and a N heteroatom as a ring member which is located at a beta ( ⁇ ) position relative to the attachment point, wherein the 9 membered bicyclic heteroaryl further has 0, 1, 2, 3, or 4 ring members each independently selected from N, NR 6 , O and S, and wherein the 9 membered bicyclic heteroaryl is unsubstituted or is substituted with 1, 2, 3 or 4 R 4 .
  • Embodiment 163 is a 9 membered bicyclic heteroaryl with an attachment point at a carbon atom ring member and a N heteroatom as a ring member which is located at a beta ( ⁇ ) position relative to the attachment point, wherein the 9 membered bicyclic heteroaryl further has 0, 1, 2, 3, or 4 ring members each independently selected from N, NR 6 , O and S, and wherein the 9 membered bicyclic heteroaryl is unsubstituted
  • R 3 is a 5 or 6 membered heterocycloalkyl with an attachment point at a carbon atom ring member and a NR 6 as a ring member which is located at a beta ( ⁇ ) position relative to the attachment point, wherein the 5 or 6 membered heterocycloalkyl further has 0, 1, or 2 ring members each independently selected from N, NR 6 , O and S, and wherein the 5 or 6 membered heterocycloalkyl is unsubstituted, substituted with 1 or 2 oxo, or is substituted with 1, 2, 3 or 4 R 4 and optionally substituted with 1 or 2 oxo.
  • Embodiment 164 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is a 5 or 6 membered heterocyclyl with an attachment point at a carbon atom ring member and a NR 6 as a ring member which is located at a beta ( ⁇ ) position relative to the attachment point, wherein the 5 or 6 membered heterocyclyl further has 0, 1, or 2 ring members each independently selected from N, NR 6 , O and S, and wherein the 5 or 6 membered heterocyclyl is unsubstituted, substituted with 1 or 2 oxo, or is substituted with 1, 2, 3 or 4 R 4 and optionally substituted with 1 or 2 oxo.
  • Embodiment 165 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is a 9 or 10 membered bicyclic heterocyclyl with an attachment point at a carbon atom ring member and a NR 6 as a ring member which is located at a beta ( ⁇ ) position relative to the attachment point, wherein the 9 or 10 membered heterocyclyl further has 0, 1, 2, 3, or 4 ring members each independently selected from N, NR 6 , O and S, and wherein the 9 or 10 membered heterocyclyl is unsubstituted, substituted with 1 or 2 oxo, or is substituted with 1, 2, 3 or 4 R 4 and optionally substituted with 1 or 2 oxo.
  • R 3 is a 9 or 10 membered bicyclic heterocyclyl with an attachment point at a carbon atom ring member and a NR 6 as a ring member which is located at a beta ( ⁇ ) position relative to the
  • Embodiment 166 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is a 9 or 10 membered bicyclic heterocyclyl with an attachment point at a carbon atom ring member and a O heteroatom as a ring member which is located at a beta ( ⁇ ) position relative to the attachment point, wherein the 9 or 10 membered heterocyclyl further has 0, 1, 2, 3, or 4 ring members each independently selected from N, NR 6 , O and S, and wherein the 9 or 10 membered heterocyclyl is unsubstituted, substituted with 1 or 2 oxo, or is substituted with 1, 2, 3 or 4 R 4 and optionally substituted with 1 or 2 oxo.
  • R 3 is a 9 or 10 membered bicyclic heterocyclyl with an attachment point at a carbon atom ring member and a O heteroatom as a ring member which is located at a beta ( ⁇ ) position relative to the
  • Embodiment 167 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is a 6 membered heterocyclyl with an attachment point at a carbon atom ring member and a carbon atom as a ring member which is substituted with oxo and located at a beta ( ⁇ ) position relative to the attachment point, wherein the 6 membered heterocyclyl further has 1 or 2 ring members each independently selected from N, NR 6 , O and S, and wherein the 6 membered heterocyclyl is unsubstituted or is substituted with 1, 2, 3 or 4 R 4 and optionally substituted with an oxo.
  • Embodiment 168 Embodiment 168.
  • Embodiment 171 The compound of any one of Embodiments 1 to 125, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is isoquinolin-4-yl which is unsubstituted or is substituted with 1 or 2 R 4 .
  • Embodiment 176 Embodiment 176.
  • Embodiment 177 Embodiment 177.
  • Embodiment 180 The compound of any one of Embodiments 1 to 174, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is C 1 -C 6 haloalkyl, halo or C 1 -C 6 haloalkoxy.
  • Embodiment 181. The compound of any one of Embodiments 1 to 174, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 is -CF 3 , F, Cl, - OCHF 2 or -OCF 3 .
  • each R 5 is independently selected from the group consisting of F, Br, Cl, -CF 3 , -CHF 2 , -CH 2 F, -C(CH 3 )F 2 , -CH 3 , isopropyl, -OCHF 2 , -OCClF 2 , -OCF 3 , -OCH 3 , SF 5 , -C(CH 3 ) 2 OH, -CH 2 CF 3 , -CH(CH 3 )CF 3 , an unsubstituted cyclopropyl, a cyclopropyl substituted with 1 R 9 , and a cyclobutyl substituted with 1 or 2 R 9 .
  • Embodiment 183 The compound of any one of Embodiments 1 to 181, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 6 is independently selected from the group consisting of H and C 1 -C 6 alkyl.
  • Embodiment 185 Embodiment 185.
  • Embodiment 186 The compound of any one of Embodiments 1 to 185, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 7 is H.
  • Embodiment 187 The compound of any one of Embodiments 1 to 185, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 7 is C 1 -C 6 alkyl.
  • Embodiment 188 The compound of any one of Embodiments 1 to 181, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 6 is independently selected from the group consisting of H, -CH 3 , and -CH 2 CH 2 OR 7 .
  • Embodiment 191 The compound of any one of Embodiments 1 to 185, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 7 is independently selected from the group consisting of H and -CH 3 .
  • Embodiment 189 The compound of any one of Embodiments 1 to 188, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 8 is H.
  • Embodiment 190 The compound of any one of Embodiments 1 to 188, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 8 is C 1 -C 6 alkyl.
  • Embodiment 193 The compound of any one of Embodiments 1 to 188, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 8 is C 3 -C 8 cycloalkyl, wherein the cycloalkyl is unsubstituted or is substituted with 1, 2, 3 or 4 R 9 .
  • Embodiment 192 The compound of any one of Embodiments 1 to 188, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 8 is C 3 -C 8 cycloalkyl, wherein the cycloalkyl is unsubstituted or is substituted with 1 or 2 R 9 .
  • Embodiment 195 The compound of any one of Embodiments 1 to 194, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 9 is NR 10 R 11 .
  • Embodiment 196 The compound of any one of Embodiments 1 to 188, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 8 is a 4 to 6 membered heterocycloalkyl wherein 1, 2, 3 or 4 ring members are each independently selected from N, NR 6 , O and S, and wherein the heterocycloalkyl is unsubstituted or is substituted with 1, or 2 R 9 .
  • Embodiment 195 The compound of any one of Embodiments 1 to 194, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 9 is NR 10 R 11 .
  • Embodiment 196 The compound of any one of Embodiments 1 to 188, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 8 is a 4 to 6 membere
  • Embodiment 197 The compound of any one of Embodiments 1 to 194, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 9 is C 1 -C 6 alkyl substituted with -OH or -N(R 7 ) 2 .
  • Embodiment 200 The compound of any one of Embodiments 1 to 198, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10 is H.
  • Embodiment 200 The compound of any one of Embodiments 1 to 198, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10 is C 1 -C 6 alkyl.
  • Embodiment 201 The compound of any one of Embodiments 1 to 198, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10 is H or -CH 3 ;
  • Embodiment 202 The compound of any one of Embodiments 1 to 201, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 11 is H.
  • Embodiment 203 The compound of any one of Embodiments 1 to 198, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 11 is H.
  • Embodiment 203 The compound of any one of Embodiments 1 to 198, or
  • Embodiment 204 The compound of any one of Embodiments 1 to 201, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 11 is C 1 -C 6 alkyl.
  • Embodiment 205 The compound of any one of Embodiments 1 to 204, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 13 is H.
  • Embodiment 206 The compound of any one of Embodiments 1 to 204, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 13 is H.
  • Embodiment 207 The compound of any one of Embodiments 1 to 204, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 13 is a 5 or 6 membered heteroaryl wherein 1, 23 or 4 ring members are each independently selected from N, NR 6 , O and S.
  • Embodiment 208 The compound of any one of Embodiments 1 to 204, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 13 is a 5 or 6 membered heteroaryl wherein 1, 23 or 4 ring members are each independently selected from N, NR 6 , O and S.
  • Embodiment 211 The compound of any one of Embodiments 1 to 207, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 14 is 6 membered heterocyclyl wherein 1 ring member is selected from N, NR 6 , O and S, and wherein the 6 membered heterocyclyl is substituted with an oxo.
  • Embodiment 211 The compound of any one of Embodiments 1 to 207, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 14 is 6 membered heterocyclyl wherein 1 ring member is selected from NR 6 , and wherein the 6 membered heterocyclyl is substituted with an oxo.
  • Embodiment 212 The compound of any one of Embodiments 1 to 207 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 14 is 6 membered heterocyclyl wherein 1 ring member is selected from NR 6 , and wherein the 6 membered heterocyclyl is substituted
  • Embodiment 215. The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from: 7-fluoro-3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione; 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione; 2-(3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4-dihydroquinazolin-1(2H)- yl)acetonitrile; 3-(isoquinolin-4-yl)-6-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione; 3-(isoquinolin-4-yl)-6-(trifluoromethyl)pyrido[2,3-
  • Embodiment 217 The compound of Embodiment 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from:
  • the compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
  • the present invention is meant to include all such possible isomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration.
  • the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
  • the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound of the invention. “Salts” include in particular “pharmaceutical acceptable salts”.
  • pharmaceutically acceptable salt or “pharmaceutically acceptable salts”, as used herein, refers to a salt or salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable.
  • the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • the organic acid or inorganic acids used to form pharmaceutically acceptable acid addition salts of compounds of the present invention include, but are not limited to, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, carbonic acid, camphor sulfonic acid, capric acid, chlorotheophyllinate, citric acid, ethanedisulfonic acid, fumaric acid, D-glycero-D-gulo-Heptonicacid, galactaric aid, galactaric acid/mucic acid, gluceptic acid, glucoheptonoic acid, gluconic acid, glucuronic acid, glutamatic acid, glutaric acid, glycolic acid, hippuric acid,
  • Salt forms of the compounds of the present invention can be converted into the free compounds by treatment with a suitable basic agent.
  • Pharmaceutically acceptable acid addition salts of compounds of the present invention include, but are not limited to, a acetate, adipate, ascorbate, aspartate, benzoate, besylatye, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, bromide/hydrobromide, camphor sulfonate, camsylate, caprate, chloride/hydrochloride, chlorotheophyllinate, citrate, edisylate, ethanedisulfonate, fumarate, gluceptate, glucoheptonate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulphate, malate, maleate, malon
  • Organic bases used to form pharmaceutically acceptable base addition salts of compounds of the present invention include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • Inorganic bases used to form pharmaceutically acceptable base addition salts of compounds of the present invention include, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, ammonium salts and metals from columns I to XII of the periodic table.
  • Pharmaceutically acceptable base addition salts of compounds of the present invention include, but are not limited to, sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper salts; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
  • Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • lsotopically labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Isotopes that can be incorporated into compounds of the present invention include, for example, isotopes of hydrogen. Further, incorporation of certain isotopes, particularly deuterium (i.e., 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index or tolerability. It is understood that deuterium in this context is regarded as a substituent of a compound of the present invention. The concentration of deuterium, may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted as being deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • isotopic enrichment factor can be applied to any isotope in the same manner as described for deuterium.
  • isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 I respectively.
  • the invention includes compounds that incorporate one or more of any of the aforementioned isotopes, including for example, radioactive isotopes, such as 3 H and 14 C, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically- labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.).
  • compounds of the present invention can exist in a deuterated form as shown below: Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration.
  • each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration.
  • Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.
  • a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof. Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p- toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
  • an optically active acid e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p- toluoyl tartaric acid, mandelic acid, malic acid
  • Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • Scheme 2 In scheme 2, starting from an amino-acid, e.g. substituted anthranilic acids, amide bond formation with a commercially available amine, e.g. isoquilonine-4-amine, mediated by a coupling agent, e.g. HATU gives an amide. The amide undergoes cyclization in the presence of a carbonyl donor such as triphosgene, CDI or a mixture of CDI and CDT.
  • Scheme 3 In scheme 3, the product is obtained by addition of an amino-ester to an isocyanate in the presence of a base, e.g. pyridine. The isocyanate is commercially available or can be prepared from the corresponding amine and triphosgene.
  • Scheme 4 The isocyanate is commercially available or can be prepared from the corresponding amine and triphosgene.
  • an amino-ester e.g. an ethyl ester of substituted anthranilic acid is reacted with a chloroformate, e.g. phenylchloroformate or p-nitrophenylchloroformate in the presence of a base. e.g. pyridine, to give a carbamate.
  • a base e.g. pyridine
  • the product is then obtained by addition of an amine, e.g. isoquinoline-4-amine, in the presence of a base, e.g. DBU.
  • Scheme 5 5
  • a urea is formed by first reacting an amino-ester with triphosgene and a base, e.g. triethylamine, to form the corresponding isocyanate, which is trapped by amine to form a urea. Treating the urea with a base, such as potassium carbonate, gives the product.
  • a base such as potassium carbonate
  • Administration and Pharmaceutical Compositions For the therapeutic uses of compounds of the present invention, such compounds are administered either alone or as part of a pharmaceutical composition. Accordingly, in another aspect of the present invention provides a pharmaceutical composition, which comprises a compound of the present invention, or pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration (e.g. by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also pertain to inhalation or intranasal application.
  • the pharmaceutical composition comprising a compound of the present invention can be formulated for intramuscularly, intravenously, subcutaneously, orally, pulmonary, intrathecally, topically or intranasally administration.
  • the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • compositions for oral administration include a compound of the present invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable carriers/excipients which are suitable for the manufacture of tablets.
  • carriers/excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • the parenteral compositions e.g, intravenous (IV) formulation
  • IV intravenous
  • the parenteral compositions are aqueous isotonic solutions or suspensions.
  • the parenteral compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • compositions are generally prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
  • the compound of the present invention or pharmaceutical composition thereof for use in a subject e.g., human
  • the dosage may depend upon the infusion rate at which an iv formulation is administered.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated.
  • the above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • the compounds of the present invention can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution.
  • Certain aspects and examples of the pharmaceutical compositions of the present invention are provided in the following listing of enumerated embodiments. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention. Embodiment 218.
  • a pharmaceutical composition comprising a compound of Formula (I) or any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers.
  • a pharmaceutical composition comprising a compound of Embodiment 218, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition of Embodiment 218 or Embodiment 219 comprising one or more additional therapeutic agents.
  • Pharmacology and Utility The compounds of the invention, in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g.
  • the compounds of the invention may generally be useful in the treatment, management and/or prevention of a coronaviral-related disease.
  • Certain aspects and examples of the use of compounds of the present invention and pharmaceutical compositions of the present invention are provided in the following listing of enumerated embodiments. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention. Embodiment 221.
  • Embodiment 222. A method for treating a disease or disorder associated with the activity of SARS-CoV-2 main protease (M pro ), wherein the method comprises administering to a subject in need of such treatment a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt.
  • Embodiment 224 Use of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with the activity of SARS-CoV-2 main protease (M pro ).
  • Embodiment 224 Use of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof, in the treatment of a disease or disorder associated with the activity of SARS-CoV-2 main protease (M pro ).
  • Embodiment 225 A compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with the activity of SARS-CoV-2 main protease (M pro ).
  • Embodiment 226 A method for treating, managing and/or preventing a coronaviral-related disease in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof.
  • Embodiment 227 A method for treating, managing and/or preventing a coronaviral-related disease in a subject in need thereof, wherein the method comprises administering to the subject a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof.
  • Embodiment 228 A method for treating, managing and/or preventing a coronaviral-related disease in a subject in need thereof, wherein the method comprises administering to the subject a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof.
  • Embodiment 22 Use of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment, management and/or prevention of a coronaviral-related disease.
  • Embodiment 230 A compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof, for use in the treatment, management and/or prevention of a coronaviral-related disease.
  • a method for treating a coronaviral-related disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof.
  • Embodiment 232 A method for treating a coronaviral-related disease in a subject in need thereof, wherein the method comprises administering to the subject a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof.
  • Embodiment 233. Use of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment a coronaviral-related disease.
  • Embodiment 217 Use of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof, in the treatment of a coronaviral-related disease.
  • Embodiment 235 A compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof, for use in the treatmen of a coronaviral-related disease.
  • Embodiment 236 A method for treating, managing and/or preventing COVID-19 disease in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof.
  • Embodiment 237 A method for treating, managing and/or preventing COVID-19 disease in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof.
  • a method for treating, managing and/or preventing COVID-19 disease in a subject in need thereof comprising administering to the subject a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof.
  • Embodiment 238 Use of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment, management and/or prevention of COVID-19 disease.
  • Embodiment 240 Use of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof, in the treatment, management and/or prevention of COVID-19 disease.
  • Embodiment 241 A method for treating COVID-19 disease in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof.
  • Embodiment 242. A method for treating COVID-19 disease in a subject in need thereof, wherein the method comprises administering to the subject a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof.
  • Embodiment 243 A method for treating COVID-19 disease in a subject in need thereof, wherein the method comprises administering to the subject a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof.
  • Embodiment 244 Use of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of COVID-19 disease.
  • Embodiment 245. Use of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof, for use in the treatment of COVID-19 disease.
  • Embodiment 246. The method of any one of Embodiments 221, 222, 226, 227, 231, 232, 236, 237, 241 and 242, wherein the coronaviral-related disease is COVID-19.
  • Embodiment 247 The use of a compound of any one of Embodiments 223, 224, 228, 229, 233, 234, 238, 239, 243 and 244, wherein the coronaviral-related disease is COVID-19.
  • Embodiment 248 The compound for the use in treatment of any one of Embodiments 225, 230, 235, 240 and 245, wherein the coronaviral-related disease is COVID-19.
  • Embodiment 249. A method for inhibiting the activity of SARS-CoV-2 main protease (M pro ), wherein the method comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt.
  • Embodiment 250 A method for inhibiting the activity of SARS-CoV-2 main protease (M pro ), wherein the method comprises administering to a subject in need of such treatment a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt.
  • Embodiment 251. Use of a compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof, in the inhibition of the activity of SARS-CoV-2 main protease (M pro ).
  • Embodiment 252. A compound of any one of Embodiments 1 to 217, or a pharmaceutically acceptable salt thereof, for use in the inhibition of the activity of SARS-CoV-2 main protease (M pro ).
  • a therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the present invention.
  • Compounds of the invention may be administered as the sole active ingredient or together with other active agents useful against a coronaviral-related disease. Accordingly, another aspect of the invention are combination for use in the treatment, prevention and/or management of a coronaviral related disease, wherein a compound of the invention is used in combination with one or more other active agents.
  • the active agent(s) is selected from a neutralizing antibody and an antiviral agent.
  • the active agent(s) is selected from a neutralizing antibody, an antiviral agent and other agents selected from alvelestat, Lenzilumab, Octagam, Remestemcel-L, RPH-104 + olokizumab, Bucillamine, CD24FC (MK-7110), Tradipitant, Ifenprodil, Tocilizumab, Leronlimab, Fenretinide, ATYR-1923, CYTO-205, APN-01, and Ampion.
  • the neutralizing antibody is selected from Bamlanivimab, bamlanivimab + etesevimab, bamlanivimab + VIR-7831, REGN-COV2, VIR-7831, AZD7442, Regdanvimab/CT-P59, ABP-300, , COVI-AM/STI-2020, VIR-7832, SAB- 185, JS016/etesevimab, C-135LS/C-144LS, BRII-196, BRII-198, SCTA-01, MW-33, DXP593, HFB-30132A, ADG20, COVI-GUARD (STI-1499) and convalescent plasma, and the antiviral agents is selected from remdesivir, Avigan/favipiravir, EIDD-2801/molnupiravir, AT-527, PF- 00835231, PF-07321332, Ensovibep/DARPins, galides
  • a compound of the invention is used in combination with remdesivir (also known as 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate) for the treatment, prevention and/or management of a coronaviral related disease.
  • remdesivir also known as 2-ethylbutyl ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy
  • remdesivir also known as 2-ethylbutyl ((((2R,
  • a compound of the invention is used in combination with an antibody for the treatment, prevention and/or management of a coronaviral related disease, wherein the antibody selected from ABBV 47D11, ABP-300, ADG20, Bamlanivimab + VIR- 7831, Bamlanivimab+etesevimab, BRII196 + BRII198, C-135LS/C-144LS, Convalescent Plasma, COR-101, CT-P63, DXP593, Etesevimab (JS016), Evusheld/AZD-7442, HFB-30132A, IBIO123, IN-006, JMB2002, LY-CoV1404, Ly-CovMab, MAD0004J08, MW-33, REGEN- COV/Ronapreve, Regkirona/Regdanvimab, SAB-185, SCTA-01, STI-2099/COVIDROPS, TY027, VIR-7832 (GSK
  • a compound of the invention is used in combination with an antiviral agent for the treatment, prevention and/or management of a coronaviral related disease, wherein the antiviral agent selected from ABX-464, alisporivir, alvelestat, ANA-001, Apabetalone, Arakoda (Tafenoquine), ASC-09 + ritonavir, ASC11, AT-100, AT-301, AT-527 (Bemnifosubuvir), AT-H201, ATR-002, boceprivir, brequinar, Bucillamine, Camostat (DWJ1248), Camostat mesylate, Carrimycin, DC-402234 (FB2001), Ebeselen (SPI-1005), EDP-235, Elsulfavirine, Ensitrelvir/S-217622, Ensovibep, Favipiravir, FP-025, Galidesivir, Gamunex-C, Lüvrio/Molnupir
  • a compound of the invention is used in combination with other active agents for the treatment, prevention and/or management of a coronaviral related disease, wherein active agents is selected from Actemra/RoActemra, Ampion, APN-01 (alunacedase alfa), ATR-002, ATYR-1923, CYTO-205, Fenretinide (LAU-7b), Lenzilumab, Leronlimab, Octagam, Olumiant +/- Veklury , Remestemcel-L, RPH-104 + olokizumab, sarilumab , tocilizumab and Tradipitant.
  • active agents is selected from Actemra/RoActemra, Ampion, APN-01 (alunacedase alfa), ATR-002, ATYR-1923, CYTO-205, Fenretinide (LAU-7b), Lenzilumab, Leronlimab, Octagam, Olumi
  • LCMS conditions LCMS Method 1: Instrument: Agilent 1200 & 6110, ESI; Column: Kinetex C1850mmx2.1mm, 5 ⁇ m; Gradient: mobile phase A: 0.04% trifluoroacetic acid in water, B: 0.02% trifluoroacetic acid in acetonitrile; 5%B for 0.4 min, 5-95% B over 2.6 min, 95% B for 1.0 min, 95-5%B over 0.01 min; Flow rate: 1.0 mL/min; UV detection 215 nm and 254 nm; Mass detection MS
  • LCMS Method 4 Instrument: Agilent 1260 & 6120, ESI; Column: Luna LC-C1850mmx2mm, 5 ⁇ m; Gradient: mobile phase A: 0.05% trifluoroacetic acid in water, B: 0.05% trifluoroacetic acid in acetonitrile; 1%B for 0.4 min, 1-90% B over 3.0 min, 90-100% B over 0.45 min, 100-1%B over 0.01 min; Flow rate: 0.8 mL/min; UV detection 215 nm and 254 nm; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 7 Instrument: Agilent 1200 & G6120B, ESI; Column: Kinetex EVO C18100A 30mm ⁇ 2.1mm, 5 ⁇ m; Gradient: mobile phase A: 0.04% trifluoroacetic acid in water, B: 0.02% trifluoroacetic acid in acetonitrile; 5-95% B over 0.69 min, 95% B for 0.45 min, 95-5%B over 0.01 min; Flow rate: 1.5 mL/min; UV detection 220 and 254 nm; Mass detection MS range 100- 1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 8 Instrument: Agilent 1260 & 6125B, ESI; Column: Kinetex EVO C18 30mm ⁇ 2.1mm, 5 ⁇ m; Gradient: mobile phase A: 0.04% trifluoroacetic acid in water, B: 0.02% trifluoroacetic acid in acetonitrile; 5-95% B over 0.8 min, 95% B for 0.4 min, 95-5%B over 0.01 min; Flow rate: 2.0 mL/min; UV detection 220 nm; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 10 Instrument: Shimadzu LC-20AD&MS 2020, ESI; Column: Kinetex EVO C18 30mm ⁇ 2.1mm, 5 ⁇ m; Gradient: mobile phase A: 0.04% trifluoroacetic acid in water, B: 0.02% trifluoroacetic acid in acetonitrile; 5-95% B over 0.69 min, 95%B for 0.46 min, 95-5% over 0.34 min; Flow rate: 1.5 mL/min; UV detection 220 and 254 nm; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 11 Instrument: Shimadzu LC-20AD&MS 2020, ESI; Column: Halo C18 30mmx3.0mm, 2.7 ⁇ m; Gradient: mobile phase A: 0.04% trifluoroacetic acid in water, B: 0.02% trifluoroacetic acid in acetonitrile; 5% B over 0.01 min., 5-95% B over 0.69 min, 95%B for 0.46 min, 95-5% over 0.34 min; Flow rate: 1.5 mL/min; UV detection 220 and 254 nm; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 12 Instrument: Shimadzu LC-20AB&MS 2010, ESI; Column: Xbridge C18 50mmx2.1mm, 5 ⁇ m; Gradient: mobile phase A: 10 mM NH 4 HCO 3 in water, B: acetonitrile; 5%B for 0.01 min., 5-95% B over 0.69 min, 95%B for 0.46 min, 95-5% over 0.34 min; Flow rate: 1.5 mL/min; UV detection 220 and 254 nm; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 13 Instrument: Agilent 1260 & 6120, ESI; Column: Luna LC-C1850mmx2mm, 5 ⁇ m; Gradient: mobile phase A: 0.04% trifluoroacetic acid in water, B: 0.02% trifluoroacetic acid in acetonitrile; 5%B for 0.4 min, 5-95% B over 2.6 min, 95% B over 1.0 min, 95-5% B over 0.01 min., 5% B over 0.49 min.; Flow rate: 1.0 mL/min; UV detection 215 nm and 254 nm; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 14 Instrument: Shimadzu LC-20AD&MS 2020, ESI; Column: InfinityLab Poroshell SB-C1830mmx3.0mm 2.7 ⁇ m; Gradient: mobile phase A: 0.04% trifluoroacetic acid in water, B: 0.02% trifluoroacetic acid in acetonitrile; 5-95% B over 0.89 min, 95%B for 0.26 min, 95-5% over 0.44 min; Flow rate: 1.5 mL/min; UV detection 220 and 254 nm; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 15 Instrument: Shimadzu LC-20ADXR&MS 2020, ESI; Column: Shim-pack Velox SP-C1830mmx2.1mm 2.7 ⁇ m; Gradient: mobile phase A: 0.04% trifluoroacetic acid in water, B: 0.02% trifluoroacetic acid in acetonitrile; 5%B for 0.01 min., 5-95% B over 0.69 min, 95%B for 0.46 min, 95-5% over 0.34 min; Flow rate: 1.5 mL/min; UV detection 220 and 254 nm; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 16 Instrument: Agilent 1260 & 6120, ESI; Column: Kinetex LC-C18 50mmx2.1mm, 5 ⁇ m; Gradient: mobile phase A: 0.04% trifluoroacetic acid in water, B: 0.02% trifluoroacetic acid in acetonitrile; 5%B for 0.4 min, 5-95% B over 3.0 min, 95% B over 1.0 min, 95-5% B over 0.5 min; Flow rate: 1.0 mL/min; UV detection 215 nm and 254 nm; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 18 Instrument: Shimadzu LC-20AB&MS 2010, ESI; Column: Xbridge C18 50mmx2.1mm, 5 ⁇ m; Gradient: mobile phase A: 10 mM NH 4 HCO 3 in water, B: acetonitrile; 5%B for 0.01 min., 5-95% B over 2.99 min, 95%B for 0.50 min, 95-5% over 0.01 min; 5%B for 0.79 min., Flow rate: 1.0 mL/min; UV detection 220 and 254 nm; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 19 Instrument: Agilent 1200 & 6130, MSD; Column: XBridge C18 50mmx2.1mm, 5 ⁇ m; Gradient: mobile phase A: 10 mM NH 4 HCO 3 in water, B: acetonitrile; 5% B for 0.4 min., 5-95% B over 3.0 min, 95% B for 0.45 min, 95-5%B over 0.01 min, 5% B for 0.64 min; Flow rate: 0.8 mL/min; UV detection 215 nm and 254 nm; Mass detection MS range 100- 1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 20 Instrument: Shimadzu LC-20AB&MS 2010, ESI; Column: Kinetex C18 50mmx2.1mm, 5 ⁇ m; Gradient: mobile phase A: 10 mM NH 4 HCO 3 in water, B: acetonitrile; 5%B for 0.01 min., 5-95% B over 0.69 min, 95%B for 0.46 min, 95-5% over 0.34 min; Flow rate: 1.5 mL/min; UV detection 220 and 254 nm; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 21 Instrument: Shimadzu LC-20AD&MS 2020, ESI; Column: Kinetex EVO C18 30mm ⁇ 2.1mm, 5 ⁇ m; Gradient: mobile phase A: 0.04% trifluoroacetic acid in water, B: 0.02% trifluoroacetic acid in acetonitrile; 5%B over 0.0.01 min., 5-95% B over 0.69 min, 95%B for 0.50 min, 95-5% over 0.01 min; 5%B for 0.29 min Flow rate: 1.5 mL/min; UV detection 220 and 254 nm; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 22 Instrument: Shimadzu LC-20AD&MS 2020, ESI; Column: Xbridge C18 50mmx2.1mm, 5 ⁇ m; Gradient: mobile phase A: 10 mM NH 4 HCO 3 in water, B: acetonitrile; 10%B for 0.01 min., 10-80% B over 3.49 min, 80%B for 0.30 min, 80-10%B over 0.01 min; 10%B for 0.49 min.; Flow rate: 0.8 mL/min; UV detection 220 and 254 nm; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 23 Instrument: Shimadzu LC-20AD&MS 2020, ESI; Column: Xbridge Shield RPC1850mmx2.1, 5 ⁇ m; Gradient: mobile phase A: 10 mM NH 4 HCO 3 in water, B: acetonitrile; 5%B for 0.01 min., 5-95% B over 0.99 min, 95-100%B over 0.80 min, 100-5%B% over 0.0.01 min; 5%B for 0.39 min.; Flow rate: 1.0 mL/min (0.01-1.8 min) and 1.2 mL/min (1.81-2.20 min); Diode array detection; Mass detection MS range 100-1000 Da (ESI); Column temperature : 40 °C.
  • LCMS Method 25 Instrument: Agilent 1200 & 6120, ESI; Column: Kinetex C1830mmx2.1mm, 5 ⁇ m; Gradient: mobile phase A: 0.04% trifluoroacetic acid in water, B: 0.02% trifluoroacetic acid in acetonitrile; 5-95%B over 1.00 min, 95-100% B over 0.8 min, 100-5% B over 0.01 min, 5% B for 0.19 min; Flow rate: 1.0 mL/min(0-1.80min) and 1.2ml/min (1.81-2.00); Diode array detection; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 26 Instrument: Shimadzu LC-20AD&MS 2020, ESI; Column: Kinetix EVO C18 30mmx2.1mm, 5 ⁇ m; Gradient: mobile phase A: 0.04% trifluoroacetic acid in water, B: 0.02% trifluoroacetic acid in acetonitrile; 5% B over 0.01 min., 5-95% B over 2.99 min, 95%B for 0.50 min, 95-5% over 0.50 min, 5% B for 0.30 min; Flow rate: 1.0 mL/min; Diode array detection; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 27 Instrument: Shimadzu LC-20AB MSD: LCMS-2010, ESI; Column: Shim-pack Scepter C1833mmx3.0mm 3 ⁇ m; Gradient: mobile phase A: 10mM NH 4 HCO in water, B: ACN; 0-60%B over 3.5 min., 60% B for 0.30 min, 60-0%B over 0.01 min, 0%B for 0.49 min; Flow rate: 0.8 mL/min 0.01 to 3.8 min., and 1.0 mL/min 3.81 to 4.3 min; UV detection 220 and 254 nm; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • LCMS Method 28 Instrument: Agilent 1200, MSD 6150; Column: Kinetex EVO C18 30mm ⁇ 2.1mm, 5 ⁇ m; Gradient: mobile phase A: 0.04% trifluoroacetic acid in water, B: 0.02% trifluoroacetic acid in acetonitrile; 5% B for 0.01 min., 5-95% B over 3.49 min, 95% B for 0.30 min, 95-5%B over 0.01 min., 5% B for 0.49 min.; Flow rate: 1.0 mL/min; UV detection 220 and 254 nm; Mass detection MS range 100-1000 Da (ESI); Column temperature: 40 °C.
  • the absolute stereochemistry of representative examples of the preferred (most active) atropisomers has been determined by analysis of X-ray crystal structures of complexes in which the respective compounds are bound to the M pro protein. In all other cases where X-ray structures are not available, the stereochemistry has been assigned by analogy, assuming that, for each pair, the atropoisomer exhibiting the highest activity in the Rapid-Fire MS Biochemical Assay (i.e. lowest IC 50 value) has the same configuration as observed by X-ray crystallography for the representative examples mentioned above.
  • Example 16a axial chirality analysis using Cahn–Ingold–Prelog rules for two separate views is shown below with (a) being priority 1, (b) being priority 2, (c) being priority 3 and (d) being priority 4.
  • Example 16a is assigned axial R (R a ) configuration and is the most active atropisomer wherein the phenyl ring of the isoquinoline is pointing upwards.
  • the corresponding compound name for Example 16a using Cahn–Ingold–Prelog rules is also shown.
  • Example 16b is shown for comparison and is assigned axial S (S a ) configuration where the phenyl ring of the isoquinoline is pointing downwards.
  • Such atropisomers are the more active atropisomer(s).
  • the corresponding compound name for Example 16b using Cahn–Ingold–Prelog rules is also shown.
  • Example 16a chirality axis is described by the stereodescriptor M and is the most active atropisomer where the phenyl ring of the isoquinoline is pointing upwards.
  • the corresponding compound name for Example 16a using Prelog and Helmchen rules is also shown.
  • the structure of Example 16b (the less active atropisomer), whose chirality axis is described by the stereodescriptor P, is shown for comparison where the phenyl ring of the isoquinoline is pointing downwards.
  • the corresponding compound name for Example 16b using Prelog and Helmchen rules is also shown.
  • Atropisomers described in the Example section below are named according the Prelog and Helmchen stereodescriptor. All other compounds, including racemates are named using ChemDraw 19.1.
  • stereochemistry assigned to atropisomers in the Examples is by analogy to Example 16, wherein the chirality of the more active atropisomer(s) is assigned as (M) and subsequently the chirality of the less active atropisomer(s) is assigned as (P).
  • Step 3 To a solution of methyl 2-amino-4-fluoro-5-(trifluoromethyl)benzoate (550 mg, crude, 2.32 mmol, 1.0 eq.) in THF/H 2 O (7/3, 10 mL) was added LiOH.H 2 O (292 mg, 6.96 mmol, 3.0 eq.) at 25°C under N 2 . After addition, the mixture reaction was stirred at 25°C for 12 hrs.
  • Step 1 A solution of iodine monochloride (ICl) (5.4 g, 25.12 mmol, 1.5 eq.) in MeOH (15 mL) was added dropwise to a solution of 2-fluoro-4-(trifluoromethyl)aniline (3.0 g, 16.75 mmol, 1.0 eq.) in CH 2 Cl 2 (15 mL) at 0°C and the mixture was stirred at 20°C for 16 hrs. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3).
  • ICl iodine monochloride
  • Step 2 To a solution of tert-butyl (2-bromo-5-chloro-4-(trifluoromethyl)phenyl)(tert- butoxycarbonyl)carbamate (5.0 g, 10.53 mmol, 1.0 eq.) in THF (80 mL) was added n-BuLi (5 mL, 12.64 mmol, 1.2 eq.) at -78°C. The mixture was stirred at -78°C for 1 hrs. The reaction mixture was quenched with H2O (120 mL).
  • Step 4 To a solution of methyl 2-amino-4-chloro-5-(trifluoromethyl)benzoate (400 mg, 1.56 mmol, 1.0 eq.), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (990 mg, 7.89 mmol, 5.0 eq.) and Cs 2 CO 3 (1.0 g, 3.16 mmol, 2.0 eq.) in t-AmylOH (3 mL) was added CataCXiumA Pd G2 (104 mg, 0.16 mmol, 0.1 eq.) and H 2 O (0.5 mL) at N 2 . The mixture was stirred at 80°C for 2 hrs.
  • Step 2 A mixture of ethyl 2-oxo-5-(trifluoromethyl)cyclohexane-1-carboxylate (2.6 g, 10.92 mmol, 1.0 eq.) and AcONH 4 (841 mg, 10.92 mmol, 1.0 eq.) in MeOH (30 mL) was stirred at 20°C for 16 hrs. The solution was concentrated to remove the MeOH, diluted with H2O (30 mL), extracted with CH 2 Cl 2 (3x50 mL). The combined organic phase were dried over Na 2 SO 4 , filtrated and concentrated to give ethyl 2-amino-5-(trifluoromethyl)cyclohex-1-ene-1-carboxylate (Int- A7).
  • Step 2 To a solution of methyl 6-bromo-2-fluoro-3-(trifluoromethyl)benzoate (600 mg, 2.01 mmol, 1.0 eq.), BocNH 2 (350 mg, 3.02 mmol, 1.5 eq.) and Cs 2 CO 3 (1620 mg, 5.02 mmol, 2.5 eq.) in dioxane (20 mL) was added Pd 2 (dba) 3 (114 mg, 0.20 mmol, 0.1 eq.) and Xphos (190 mg, 0.40 mmol, 0.2 eq.). The mixture was stirred at 100°C for 3 hrs. The reaction mixture was quenched with H 2 O (50 mL).
  • Step 3 A solution of methyl 6-((tert-butoxycarbonyl)amino)-2-fluoro-3-(trifluoromethyl)benzoate (400 mg, 1.18 mmol, 1.0 eq.) in HCl (g)/MeOH (4M, 10 mL) was stirred at 20°C for 3 hrs. The mixture was concentrated under reduced pressure to afford c methyl 6-amino-2-fluoro-3- (trifluoromethyl)benzoate (Int-A8).
  • LCMS (Method 7): t R 0.685 min, [M+1] + 238.0.
  • Step 3 The solution of tert-butyl 5-bromo-2-nitrobenzoate (2.7 g, 8.94 mmol, 1.0 eq.) in THF (27 mL) was added Pd(t-Bu 3 P) 2 (457 mg, 0.90 mmol, 0.1 eq.) and (1- (methoxycarbonyl)cyclopropyl)zinc(II) bromide (45 mL, 44.86 mmol, 5.0 eq.) at 25°C under N 2 . The mixture was stirred at 25°C under N 2 for 16 hrs.
  • Step 4 To a mixture of tert-butyl 5-(1-(methoxycarbonyl)cyclopropyl)-2-nitrobenzoate (1.0 g, 3.12 mmol, 1.0 eq.) in CH 2 Cl 2 (10 mL) was added TFA (2 mL) and the mixture was stirred at 25°C for 3 hrs. The reaction mixture was dried under nitrogen gas to give 5-(1- (methoxycarbonyl)cyclopropyl)-2-nitrobenzoic acid (Int-A11).
  • Step 2 To a solution of 4-(chlorodifluoromethoxy)-2-iodoaniline (1.0 g, 3.13 mmol, 1.0 eq.) in CH 3 CN (20 mL) and MeOH (10 mL) was added K 2 CO 3 (1.3 g, 9.40 mmol, 3.0 eq.), TEA (317 mg, 3.13 mmol, 1.0 eq.), DPPF (174 mg, 0.31 mmol, 0.1 eq.) and Pd(OAc) 2 (70 mg, 0.31 mmol, 0.1 eq.) at 25°C under nitrogen. The reaction was stirred for 16 hrs at 60°C under CO (15 psi).
  • Step 1 To a solution of 6-bromoisoquinoline (38.0 g, 182.65 mmol, 1.0 eq.) in DMSO (400 mL) was added MeSO 2 Na (43.0 g, 420.09 mmol, 2.3 eq.), CuI (7.0 g, 36.53 mmol, 0.2 eq.), L-proline (6.3 g, 54.79 mmol, 0.3 eq.) and NaOH (2.2 g, 54.79 mmol, 0.3 eq.) at 25°C. The mixture was stirred at 120°C for 6 hrs. The mixture was quenched with water (500 mL) and extracted with EtOAc (400 mL x 2).
  • Step 2 To a suspension of 6-(methylsulfonyl)isoquinoline (34.0 g, 164.05 mmol, 1.0 eq.) in AcOH (400 mL) was added NBS (44.0 g, 246.08 mmol, 1.5 eq.) at 25°C and the reaction mixture was then heated to 80°C and stirred at 80°C for 16 hrs.
  • Step 3 To a solution of 4-bromo-6-(methylsulfonyl)isoquinoline (29.0 g, 101.07 mmol, 1.0 eq.) and BocNH 2 (24.0 g, 202.13 mmol, 2.0 eq.) in dioxane (350 mL) was added Pd 2 (dba) 3 (4.1 g, 5.05 mmol, 0.05 eq.), Xantphos (6.0 g, 10.11 mmol, 0.1 eq.) and Cs 2 CO 3 (100.0 g, 303.20 mmol, 3.0 eq.) at 25
  • Step 4 To a solution of 5-bromoisoquinoline-4-carboxylic acid (1.0 g, 3.98 mmol, 1.0 eq.) and Et 3 N (1.2 g, 11.94 mmol, 3.0 eq.) in DMF (15 mL) was added DPPA (2.2 g, 7.97 mmol, 2.0 eq.) at 0°C. The mixture was stirred at 25°C for 2 hrs. t-BuOH (5 mL) was dropwise added to the mixture at 25°C. The mixture was stirred at 25°C for 16 hrs. The reaction was poured into water (30 mL) and extracted with EtOAc (20 mL x 2).
  • Step 2 To a mixture of methyl isoquinoline-6-carboxylate (10.0 g, 53.42 mmol, 1.0 eq.) in AcOH (200 mL) was added NBS (12.4 g, 69.45 mmol, 1.3 eq.) at 25°C under N 2 . The reaction mixture was stirred at 80°C for 16 hrs. The mixture was concentrated, added to water (500 mL) and extracted with EtOAc (200 mL x 3).
  • Step 3 To a mixture of methyl 4-bromoisoquinoline-6-carboxylate (25.0 g, 93.95 mmol, 1.0 eq.) and BocNH 2 (14.3 g, 122.14 mmol, 1.3 eq.) in dioxane (1.5 L) was added Cs 2 CO 3 (60.0 g, 187.90 mmol, 2.0 eq.), Pd 2 (dba) 3 (2.5 g, cat.) and Xantphos (2.5 g, cat.) at 25°C under N 2 . The reaction mixture was stirred at 100°C for 16 hrs. The mixture was concentrated, added to water (500 mL) and extracted with EtOAc (200 mL x 3).
  • Step 2 To H 2 SO 4 (75%, 400 mL) was added (E)-2-(2-ethoxyvinyl)-3-fluorobenzonitrile (33.8 g, 176.52 mmol, 1.0 eq.) at 0°C. The reaction was stirred at 85°C for 2 hrs. The mixture was poured into ice water (1.2 L) with stirring, then filtered and the filter cake was dried to give a crude product. The crude product was suspended in water (800 mL) and stirred for 0.5 hrs, then the suspension was filtered and filter cake was dried to give 5-fluoroisoquinolin-1(2H)-one.
  • the mixture was poured into ice water (800 mL), extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine (600 mL), dried over Na 2 SO 4 , filtered and concentrated to give crude product.
  • the crude product was suspended in MTBE/petroleum ether/EtOAc (1/3/1, 300 mL) and stirred for 0.5 hrs, the suspension was filtered and the filter cake was dried to give 5-fluoro-4-nitroisoquinolin-1(2H)- one.
  • Step 4 A solution of 5-fluoro-4-nitroisoquinolin-1(2H)-one (5.0 g, 24.03 mmol, 1.0 eq.) in POCl 3 (60 mL) was stirred at 80°C for 18 hrs. The reaction was concentrated in vacuum to remove POCl 3 to give a residue. The residue was suspended in toluene (100 mL) and concentrated, repeated for three times to give crude product. The crude product was suspended in hexane (100 mL) and ultrasonicated for 5 min.
  • Step 5 To a solution of 1-chloro-5-fluoro-4-nitroisoquinoline (6.0 g, 26.43 mmol, 1.0 eq.) in EtOH (200 mL) was added Pd/C (5.0 g, Cat.) at 25°C and the mixture was stirred at 25°C for 2 hrs under H 2 (15 Psi). The reaction was filtered, the filter cake was washed by EtOH (500 mL x 3), the combined filtrate was concentrated to give a crude product.
  • Pd/C 5.0 g, Cat.
  • Step 3 A mixture of 2-(carboxymethyl)-5-(trifluoromethyl)benzoic acid (3.7 g, 14.92 mmol, 1.0 eq.) and Ac 2 O (4.6 g, 44.76 mmol, 3.0 eq) in toluene (50 ml) was stirred at 120°C under N 2 for 3 hrs.
  • Example 1 Synthesis of 7-fluoro-3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)- dione (1)
  • Step 1 HATU (920 mg, 2.42 mmol, 1.2 eq.) was added to a solution of 2-amino-4-fluoro-5- (trifluoromethyl)benzoic acid (Int-A1) (450 mg, 2.02 mmol, 1.0 eq.) in DMF (5 mL) at 25°C and the reaction mixture stirred at 25°C for 1 hr.
  • Int-A1 2-amino-4-fluoro-5- (trifluoromethyl)benzoic acid
  • Step 2 Triphosgene (200 mg, 0.68 mmol, 1.2 eqv) was added to a mixture of 2-amino-4-fluoro- N-(isoquinolin-4-yl)-5-(trifluoromethyl)benzamide (200 mg, 0.56 mmol, 1.0 eqv) in THF (5 mL) at 0°C. After addition, the reaction mixture was stirred at 15°C for 3 hrs. The mixture was diluted with saturated NaHCO 3 aqueous (20 mL) and extracted with EtOAc (20 mL x 2).
  • Example 2a Synthesis of 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2)
  • Step 1 HATU (1.11 g, 2.93 mmol, 1.2 eq.) and NMM (740.4 mg, 7.32 mmol, 3.0 eq.) were added to a solution of 2-amino-5-(trifluoromethyl)benzoic acid (Int-AA1) (500 mg, 2.44 mmol, 1.0 eq.) in DMF (5 mL) and the mixture was stirred at 20°C for 1 hr.
  • Int-AA1 2-amino-5-(trifluoromethyl)benzoic acid
  • Step 2 DIEA (467 mg, 3.6 mmol, 2 eq.) and triphosgene (804 mg, 2.71 mmol, 1.5 eq.) were added at 0°C to a solution of 2-amino-N-(isoquinolin-4-yl)-5-(trifluoromethyl)benzamide (600 mg, 1.81 mmol, 1.0 eq.) in THF (20 mL) and the mixture was stirred at 25°C for 2 hrs. The reaction was quenched by careful addition of aq.
  • Example 2b Alternative synthesis of 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (2)
  • Step 1 HATU (1.11 g, 2.93 mmol, 1.2 eq.) and NMM (740.4 mg, 7.32 mmol, 3.0 eq.) were added to a solution of 2-amino-5-(trifluoromethyl)benzoic acid (Int-AA1) (500 mg, 2.44 mmol, 1.0 eq.) in DMF (5 mL) and the mixture was stirred at 20°C for 1 hr.
  • Int-AA1 2-amino-5-(trifluoromethyl)benzoic acid
  • Step 2 DIEA (468 mg, 3.60 mmol, 2.0 eq.) and triphosgene (801 mg, 2.70 mmol, 1.5 eq.) were added at 0°C to a solution of 2-amino-N-(isoquinolin-4-yl)-5-(trifluoromethyl)benzamide (600 mg, 1.80 mmol, 1.0 eq.) in DCE (10 mL) and the mixture stirred at 20°C for 3 hrs. The mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (15 mL x 3).
  • Example 3 Synthesis of 2-(3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)acetonitrile (3)
  • K 2 CO 3 116 mg, 0.84 mmol, 3.0 eq.
  • 2-bromoacetonitrile 40 mg, 0.34 mmol, 1.2 eq.
  • 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2) 100 mg, 0.28 mmol, 1.0 eq.
  • Example 4 Synthesis of 3-(isoquinolin-4-yl)-6-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione Step 1: HATU (1.0 g, 2.71 mmol, 1.2 eq.) was added to a solution of 2-amino-5- (trifluoromethoxy)benzoic acid (Int-AA2) (500 mg, 2.26 mmol, 1.0 eq.) in DMF (5 mL) at 20°C and the mixture was stirred at 20°C for 1 hr.
  • HATU 1.0 g, 2.71 mmol, 1.2 eq.
  • Int-AA2 2-amino-5- (trifluoromethoxy)benzoic acid
  • Step 2 To a solution of 2-amino-N-(isoquinolin-4-yl)-5-(trifluoromethoxy)benzamide (210 mg, 0.60 mmol, 1.0 eq.) in DCE (1 mL) was added a solution of triphosgene (179 mg, 0.60 mmol, 1.0 eq.) in DCE (1 mL) and DIEA (156 mg, 1.21 mmol, 2.0 eq.) at 20°C, and the mixture was then stirred at 20°C for 6 hrs.
  • triphosgene 179 mg, 0.60 mmol, 1.0 eq.
  • DIEA DIEA
  • Example 5 Synthesis of 3-(isoquinolin-4-yl)-6-(trifluoromethyl)pyrido[2,3-d]pyrimidine- 2,4(1H,3H)-dione (5)
  • Step 1 HATU (3.8g, 9.89 mmol, 1.2 eq.) and NMM (2.5 g, 24.73 mmol, 3.0 eq.) at 20°C were added to a solution of 2-amino-5-(trifluoromethyl)nicotinic acid hydrochloride (Int-A2) (2.0 g, 8.24 mmol, 1.0 eq.) in DMF (20 mL) and the mixture stirred at 20°C for 1 hr.
  • Int-A2 2-amino-5-(trifluoromethyl)nicotinic acid hydrochloride
  • Step 2 DIEA (163 mg, 1.26 mmol, 3.0 eq.) and triphosgene (63 mg, 0.21 mmol, 0.5 eq.) were added to a solution of 2-amino-N-(isoquinolin-4-yl)-5-(trifluoromethyl)nicotinamide (140 mg, 0.42 mmol, 1.0 eq.) in THF (1.5 mL) at 20°C and the mixture stirred at 20°C for 16 hrs.
  • Example 6 Synthesis of 3-(8-aminoisoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)- dione (6)
  • Step 1 4-bromo-8-nitroisoquinoline (1.1 g, 1.38 mmol, 0.5 eq.), Pd(OAc) 2 (40 mg, 0.18 mmol, 0.06 eq.), BINAP (300 mg, 0.48 mmol, 0.17 eq.) and DPPF (300 mg, 0.54 mmol, 0.2 eq.) were added to a solution of diphenylmethanimine (500 mg, 2.76 mmol, 1.0 eq.) in TEA (0.5 mL, 2.99 mmol, 1.1 eq) at 20°C, and the mixture was then concentrated at 30°C for 15 min.
  • Step 2 4N HCl (10 mL) was added to a mixture of N-(8-nitroisoquinolin-4-yl)-1,1- diphenylmethanimine (2.0 g, 2.00 mmol, 1.0 eq.) in THF (20 ml) at 25°C and the mixture stirred at 25°C for 1 hr. The mixture was poured into NaHCO 3 aq. (100 mL) and then extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give crude product.
  • Step 4 Methyl 2-amino-5-(trifluoromethyl)benzoate (Int-A6) (101 mg, 0.46 mmol, 2.0 eq.) was added to a solution of 4-isocyanato-8-nitroisoquinoline (50 mg, 0.23 mmol, 1.0 eq.) in pyridine (3 mL) at 20°C. The mixture was stirred at 100°C for 12 hrs. The mixture was poured into water (15 mL) and extracted with EtOAc (10 mL x 3).
  • Step 5 NH 4 Cl (35 mg, 0.63 mmol, 5 eq.) and Fe powder (35 mg, 0.63 mmol, 5 eq.) were added to a solution of 3-(8-nitroisoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (50 mg, 0.13 mmol, 1.0 eq.) in EtOH (5 mL) and H 2 O (5 mL) at 20°C, and the mixture stirred at 85°C for 1 hr. The mixture was filtered and the filtrate was concentrated to give crude product.
  • Example 7 Synthesis of 3-(5,6,7,8-tetrahydroisoquinolin-4-yl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (7)
  • Step 1 HATU (1.1 g, 2.93 mmol, 1.2 eq.) was added to a solution of 2-amino-5- (trifluoromethyl)benzoic acid (Int-AA1) (500 mg, 2.44 mmol, 1.0 eq.) in DMF (5 mL) and the mixture stirred at 20°C for 1 hr.5,6,7,8-tetrahydroisoquinolin-4-amine (Int-B1) (397 mg, 2.44 mmol, 1.1 eq.) and NMM (740 mg, 7.32 mmol, 3.0 eq.) were added and the mixture stirred at 45°C for 15 hrs.
  • Int-AA1 2-amino-5- (trifluoromethyl)benzoic acid
  • Step 2 DIEA (617 mg, 4.78mmol, 2.0 eq.) and a solution of triphosgene (1.1g, 3.59 mmol, 1.5 eq.) in THF (4 mL) were added to a mixture of 2-amino-N-(5,6,7,8-tetrahydroisoquinolin-4-yl)-5- (trifluoromethyl)benzamide (800 mg, 2.39 mmol, 1.0 eq.) in THF (8 mL) and the mixture stirred at 25°C for 3 hrs. The mixture was quenched with NaHCO 3 aq. (30 mL) and extracted with EtOAc (30 mL x 2).
  • Example 8 Synthesis of 7-(trifluoromethyl)-1H-[2,4'-biisoquinoline]-1,3(4H)-dione (8)
  • Example 9 Synthesis of 6-bromo-3-(isoquinolin-4-yl)quinazoline-2,4(1H,3H)-dione (9)
  • Step 1 A mixture of isoquinolin-4-amine (3.0 g, 13.80 mmol, 1.0 eq.), HATU (6.3 g, 16.56 mmol, 1.2 eq.) in DMF (20 mL) was stirred at 20°C for 0.5 hr.2-amino-5-bromobenzoic acid (Int-AA3) (2.2 g, 15.18 mmol, 1.1 eq.) and NMM (4.2 g, 41.40 mmol, 3.0 eq.) were then added and the mixture was stirred at 45°C for 16 hrs.
  • Step 2 A solution of Triphosgene (564 mg, 1.90 mmol, 1.0 eq.) in DCE (3.5 mL) and DIEA (491 mg, 3.80 mmol, 2.0 eq.) were added to a solution of 2-amino-5-bromo-N-(isoquinolin-4- yl)benzamide (650 mg, 1.90 mmol, 1.0 eq.) in DCE (3.5 mL) at 20°C and the mixture stirred at 20°C for 16 hrs. The reaction mixture was concentrated to give a residue.
  • Example 9 Alternative synthesis of 6-bromo-3-(isoquinolin-4-yl)quinazoline-2,4(1H,3H)-dione Step 1: To an oven-dried flask was added isoquinolin-4-amine (Int-B1) (6.03 g, 1.05 eq., 41.8 mmol), and 5-bromoindoline-2,3-dione (9.00 g, 1 eq., 39.8 mmol). EtOH (500 mL) was added, followed by acetic acid (239 mg, 228 ⁇ L, 0.1 Eq, 3.98 mmol). A reflux condensor was attached and the reaction was heated at 90 °C for 4 days.
  • isoquinolin-4-amine Int-B1
  • 5-bromoindoline-2,3-dione 9.00 g, 1 eq., 39.8 mmol
  • EtOH 500 mL
  • acetic acid 239 mg, 228 ⁇ L, 0.1 E
  • Step 2 To a 20 mL vial was added (E)-5-bromo-3-(isoquinolin-4-ylimino)indolin-2-one (3.52 g, 1 Eq, 10.00 mmol), DCM (200.00 mL) and TFA (2.280 g, 1.54 mL, 2.0 eq., 20.0 mmol) forming a suspension which was cooled to 0 °C .
  • mCPBA (4.60 g, 75% wt, 2.0 eq., 20.00 mmol) was added as a single portion and the reaction was warmed to rt and stirred overnight. The organic phase was wshed with 200 mL H 2 O.
  • Example 10 Synthesis of 4,4-dimethyl-7-(trifluoromethyl)-1H-[2,4'-biisoquinoline]-1,3(4H)-dione t-BuOK (1.1 mL, 1.12 mmol, 1 M in THF, 2.0 eq.) was added to a solution of 7-(trifluoromethyl)- 1H-[2,4'-biisoquinoline]-1,3(4H)-dione (8) (200 mg, 0.56 mmol, 1.0 eq.) in THF (5 mL) at 0°C and the mixture stirred at 0°C for 0.5 hrs.
  • Methyliodide (398 mg, 2.80 mmol, 5.0 eq.) was then added dropwise at 0°C and the mixture stirred at 20°C for 2 hrs. The reaction was quenched with NH 4 Cl (10 mL) and extracted with EtOAc (8 mL ⁇ 2).
  • Example 11 Synthesis of 8-fluoro-3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (11)
  • Step 1 A mixture of 2-amino-3-fluoro-5-(trifluoromethyl)benzoic acid (Int-A3) (790 mg, 3.54 mmol, 1.0 eq.), HATU (1.03 g, 4.25 mmol, 1.2 eq.) in DMF (10 mL) was stirred at 20°C for 1 hr.
  • Step 2 A solution of triphosgene (382 mg, 1.29 mmol, 1.5 eq.) in THF (2.0 mL) was added dropwise to a solution of 2-amino-3-fluoro-N-(isoquinolin-4-yl)-5-(trifluoromethyl)benzamide (300 mg, 0.86 mmol, 1.0 eq.) and DIEA (220 mg, 1.70 mmol, 2.0 eq.) in THF (8.0 mL) at 0°C under N 2. The mixture was stirred at 25°C for 16 hrs. The reaction mixture was quenched with NaHCO 3 (20 mL) and extracted with EtOAc (20 mL x 3).
  • Example 12 Synthesis of 3-(isoquinolin-4-yl)-6-methoxyquinazoline-2,4(1H,3H)-dione (12) Step 1: HATU (4.6 g, 12.17 mmol, 1.2 eq.) was added to a mixture of 5-methoxy-2-nitrobenzoic acid (Int-AA4) (2.0 g, 10.15 mmol, 1.0 eq.) in DMF (20 mL) and the mixture stirred at 20°C for 1 hr.
  • Int-AA4 5-methoxy-2-nitrobenzoic acid
  • Step 2 A mixture of N-(isoquinolin-4-yl)-5-methoxy-2-nitrobenzamide (1.0 g, 3.09 mmol, 1.0 eq.) and Pd/C (500 mg, 10%) in EtOAc (50 mL) was purged with H 2 (3x) and then stirred at 30°C for 5 hrs under H 2 (50 psi). The mixture was filtered and the filtrate was concentrated to give 2- amino-N-(isoquinolin-4-yl)-5-methoxybenzamide.
  • Step 3 DIEA (106 mg, 0.82 mmol, 2.0 eq.) and triphosgene (181 mg, 0.61 mmol, 1.5 eq.) were added to a solution of 2-amino-N-(isoquinolin-4-yl)-5-methoxybenzamide (120 mg, 0.41 mmol, 1.0 eq.) in DCE (2 mL) and the mixture was stirred at 20°C for 3 hrs.
  • Example 13 Synthesis of 3-(4-methylpyridin-3-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)- dione (13)
  • Step 1 HATU (1.1 g, 2.93 mmol, 1.2 eq.) was added to a solution of 2-amino-5- (trifluoromethyl)benzoic acid (Int-AA1) (500 mg, 2.44 mmol, 1.0 eq.) in DMF (8 mL) and the mixture was stirred at 20°C for 1 hr.4-methylpyridin-3-amine (CAS No.3430-27-1) (527 mg, 4.78 mmol, 2.0 eq.) and NMM (740 mg, 7.32 mmol, 3.0 eq.) were then added and the mixture stirred at 45°C for 15 hrs.
  • Int-AA1 2-amino-5- (trifluoromethyl)benzoic acid
  • DMF 8 mL
  • NMM 740 mg,
  • Step 2 DIEA (174 mg, 1.35 mmol, 2.0 eq.) and triphosgene (302 mg, 1.02 mmol, 1.5 eq.) were added to a solution of 2-amino-N-(4-methylpyridin-3-yl)-5-(trifluoromethyl)benzamide (200 mg, 0.67 mmol, 1.0 eq.) in DCE (3 mL) at 0°C and the mixture stirred at 20°C for 3 hrs.
  • DIEA 174 mg, 1.35 mmol, 2.0 eq.
  • triphosgene 302 mg, 1.02 mmol, 1.5 eq.
  • Example 14 Synthesis of 3-(isoquinolin-4-yl)-6-(trifluoromethyl)-2H-benzo[e][1,3]oxazine- 2,4(3H)-dione (14)
  • Step 1 HATU (1.8 g, 4.80 mmol, 1.2 eq.) and DMF (10 mL) were added to a solution of 2- methoxy-5-(trifluoromethyl)benzoic acid (Int-A4) (880 mg, 4.00 mmol, 1.0 eq.) at 20°C and the mixture was stirred at 20°C for 1 hr.
  • Int-A4 2- methoxy-5-(trifluoromethyl)benzoic acid
  • Step 2 BBr3 (751 mg, 3.03 mmol, 1.5 eq.) was added to a solution of N-(isoquinolin-4-yl)-2- methoxy-5-(trifluoromethyl)benzamide (700 mg, 2.02 mmol, 1.0 eq.) in CH 2 Cl 2 (7 mL) at 0°C and the mixture stirred at 20°C for 3 hrs. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3).
  • Step 3 Triphosgene (353 mg, 1.20 mmol, 1.0 eq.) was added to a solution of 2-hydroxy-N- (isoquinolin-4-yl)-5-(trifluoromethyl)benzamide (400 mg, 1.20 mmol, 1.0 eq.) and DIEA (310 mg, 2.40 mmol, 2.0 eq.) in CH 2 Cl 2 (5mL) at 20°C and the mixture was stirred at 20°C for 4 hrs. The mixture was poured into water (20 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Example 15 Synthesis of 5-(2,4-dioxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)- yl)nicotinamide (15)
  • Step 1 2-amino-5-(trifluoromethyl)benzoic acid (Int-AA1) (2.0 g, 9.75 mmol, 1.0 eq.), 5- aminonicotinamide (CAS No.60524-14-3) (1.5 g, 10.72 mmol, 1.1 eq.), HATU (5.6 g, 14.63 mmol, 1.5 eq.) and NMM (1.5 g, 14.63 mmoL, 1.5 eq.) in DMF (20 mL) were stirred at 50°C for 24 hrs.
  • Step 2 5-(2-amino-5-(trifluoromethyl)benzamido)nicotinamide (300 mg, 0.93 mmol, 1.0 eq.) and CDI (150 mg, 0.93 mmol, 1.0 eq.) in DMF (6 mL)were stirred at 50°C for 16 hrs.
  • Example 16 Synthesis of 3-(3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)propanenitrile (16), 3-[(3M)-3-(Isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4-dihydroquinazolin- 1(2H)-yl]propanenitrile (16a) and 3-[(3P)-3-(Isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4-dihydroquinazolin- 1(2H)-yl]propanenitrile (16b) To a solution of 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2) (400 mg,
  • racemate (16) was separated by SFC (column: DAICEL CHIRALCEL OD (250mmx30mm, 10 ⁇ m); liquid phase: [0.1%NH 3 H 2 O MeOH B%: 50%, 7 min]) to give 2 peaks.
  • Example 17 Synthesis of 1-cyclopropyl-3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (16) To a solution of 2,2-bipyridine (109 mg, 0.70 mmol, 1.0 eq.) in DCE (2 mL) was added Cu(OAc) 2 (140 mg, 0.70 mmol, 1.0 eq.) and the mixture was stirred at 60°C.
  • Step 2 To a mixture of 2-bromo-4-(pentafluoro- ⁇ 6 -sulfaneyl)aniline (1.9 g, 6.37 mmol, 1.0 eq.) in MeOH (60 mL) was added Pd(dppf)Cl 2 (470 mg, 0.64 mmol, 0.1 eq.) and DIEA (1.6 g, 12.74 mmol, 2.0 eq.) at 25°C. The mixture was stirred at 80°C for 16 hrs under CO (50 psi). The mixture was filtered and the filtrate was concentrated to give crude product.
  • Pd(dppf)Cl 2 470 mg, 0.64 mmol, 0.1 eq.
  • DIEA 1.6 g, 12.74 mmol, 2.0 eq.
  • Step 3 To a mixture of NaH (222 mg, 60%, 5.56 mmol, 1.1 eq.) in DMF (16 mL) was added a solution of methyl 2-amino-5-(pentafluoro- ⁇ 6 -sulfaneyl)benzoate (1.4 g, 5.05 mmol, 1.0 eq.) in DMF (4 mL) at 0°C under N 2 . The mixture was stirred at 0°C for 0.5 hrs under N 2 .
  • Phenyl isoquinolin-4-yl(phenoxycarbonyl)carbamate (Int-B7) (1.9 g, 5.05 mmol, 1.0 eq.) in DMF (4 mL) was then added to the mixture at 0°C and the mixture was stirred at 50°C for 12 hrs under N 2 . The reaction was quenched with saturated aqueous NH 4 Cl (100 mL) and extracted with EtOAc (30 mL ⁇ 2). The combined organic layers were washed with brine (120 mL ⁇ 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude product.
  • Example 19 Synthesis of 3-(isoquinolin-4-yl)-7-methyl-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (19)
  • a mixture of 4-isocyanatoisoquinoline (Int-B8) (569 mg, 3.34 mmol, 3.0 eq.) and methyl 2- amino-4-methyl-5-(trifluoromethyl)benzoate (Int-A5) (260 mg, 1.11 mmol, 1.0 eq.) in pyridine (3 mL) was stirred at 100°C for 16 hrs.
  • the reaction mixture was quenched with H2O (20 mL).
  • the reaction mixture was extracted with ethyl acetate (20 mL x 3).
  • Step 1 To a mixture of 5-fluoroisoquinolin-4-amine hydrochloride (Int-B6) (9.1 g, 41.47 mmol, 1.0 eq.) and Et 3 N (12.2 g, 120.96 mmol, 3.5 eq.) in DCE (80 mL) was added a mixture of triphosgen (10.2 g, 34.56 mmol, 1.0 eq.) in DCE (20 mL) at 0°C. The mixture was stirred at 25°C for 2 hrs.
  • Int-B6 5-fluoroisoquinolin-4-amine hydrochloride
  • Et 3 N 12.2 g, 120.96 mmol, 3.5 eq.
  • Step 2 To a solution of 3-(5-fluoroisoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)- dione (500 mg, 1.33 mmol, 1.0 eq.) in DMF (2 mL) was added DBU (400 mg, 2.66 mmol, 2.0 eq.) and acrylonitrile (8 mL) at 25°C. The mixture was stirred at 80°C for 32 hrs. The mixture was poured into water (80 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude product.
  • DBU 400 mg, 2.66 mmol, 2.0 eq.
  • acrylonitrile 8 mL
  • Step 3 The racemate (20) was separated by SFC (DAICEL CHIRALPAK AD (250mmx50mm,10um); liquid phase: 0.1%NH 3 H 2 O EtOH]B%: 10%-70%,8min]) to give 2 peaks: peak 1 and peak 2.
  • Example 21 Synthesis of [(3M,6R or 6S)-3-(5-Fluoroisoquinolin-4-yl)-2,4-dioxo-6- (trifluoromethyl)-3,4,5,6,7,8-hexahydroquinazolin-1(2H)-yl]acetonitrile (21a); [(3M,6R or 6S)-3-(5-Fluoroisoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)- 3,4,5,6,7,8-hexahydroquinazolin-1(2H)-yl]acetonitrile (21b); [(3P,6R or 6S)-3-(5-Fluoroisoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)- 3,4,5,6,7,8-hexahydroquinazolin-1(2H)-yl]aceton
  • Step 1 To a mixture of ethyl 2-amino-5-(trifluoromethyl)cyclohex-1-ene-1-carboxylate (Int-A7) (4.8 g, 20.14 mmol, 1.0 eq.) and Et 3 N (6.2 g, 60.42 mmol, 3.0 eq.) in DCE (200 mL) was added dropwise a solution of triphosgene (3.0 g, 10.07 mmol, 0.5 eq.) in DCE (20 mL) at 0°C. The mixture was stirred at 0°C under nitrogen for 2 hrs.
  • Et-A7 ethyl 2-amino-5-(trifluoromethyl)cyclohex-1-ene-1-carboxylate
  • Et 3 N 6.2 g, 60.42 mmol, 3.0 eq.
  • Step 2 Racemic 3-(5-fluoroisoquinolin-4-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroquinazoline- 2,4(1H,3H)-dione (890 mg, 2.35 mmol) was separated by chiral SFC (column: REGIS(S, S) WHELK-O1 (250mmx25mm, 10um); mobile phase: [0.1% NH 3 H 2 O EtOH]; B%: 60%-60%, 8.5min) to obtain four peaks.
  • t R2 3.239 min.
  • t R3 3.682 min.
  • t R4 3.859 min.
  • Peak 1: LCMS Method 12): t R 0.674 min, [M+1] + 380.2.
  • SFC (column: DAICEL CHIRALPAK AD (150mmx4.6 mm, 3 ⁇ m); mobile phase: A: CO 2 , B: EtOH(0.1% IPAm); 10%B for 0.5 min., 10-50%B, over 3.0 min., 50%B for 1.0 min.
  • Peak 2: LCMS (Method 12): t R 0.663 min, [M+1] + 380.2.
  • Step 3a To a solution of the compound from Peak 1 (70 mg, 0.18 mmol, 1.0 eq.) in DMF (1 mL) was added compound 2-bromoacetonitrile (33 mg, 0.28 mmol, 1.5 eq..) and Cs 2 CO 3 (121 mg, 0.37 mmol, 2.0 eq..) at 25°C.
  • the product was purified by prep-HPLC (Waters Xbridge Prep OBD C18150mmx40mm, 10 ⁇ m; liquid phase: [A:H 2 O (10mM NH 4 HCO 3 ); B:ACN] B%: 25%-60%, 20min]) to obtain [(3M,6R or 6S)-3-(5-Fluoroisoquinolin-4-yl)-2,4-dioxo-6- (trifluoromethyl)-3,4,5,6,7,8-hexahydroquinazolin-1(2H)-yl]acetonitrile (21a)-Peak 1a.
  • Step 3b To a solution of the compound from Peak 2 (65 mg, 0.17 mmol, 1.0 eq.) in DMF (1 mL) was added 2-bromoacetonitrile (31 mg, 0.26 mmol, 1.5 eq.) and Cs 2 CO 3 (112 mg, 0.34 mmol, 2.0 eq.) at 25°C. The reaction was stirred at 25°C under N 2 for 3 hrs. The reaction was quenched with H 2 O (5 mL) and extracted with EtOAc (2 mL ⁇ 3). The combined organic layers were washed with brine (5 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude product.
  • 2-bromoacetonitrile 31 mg, 0.26 mmol, 1.5 eq.
  • Cs 2 CO 3 112 mg, 0.34 mmol, 2.0 eq.
  • the product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150mmx40mm, 10 ⁇ m; liquid phase: [A:H 2 O (10mM NH 4 HCO 3 ); B:ACN] B%: 25%-60%, 20min]) to obtain [(3M,6R or 6S)-3-(5-Fluoroisoquinolin-4-yl)-2,4-dioxo-6- (trifluoromethyl)-3,4,5,6,7,8-hexahydroquinazolin-1(2H)-yl]acetonitrile (21b)-Peak 2a.
  • Step 3c To a solution of the compound from Peak 3 (65 mg, 0.17 mmol, 1.0 eq.) in DMF (1 mL) was added 2-bromoacetonitrile (31 mg, 0.26 mmol, 1.5 eq.) and Cs 2 CO 3 (112 mg, 0.34 mmol, 2.0 eq.) at 25°C. The reaction was stirred at 25°C under N 2 for 3 hrs. The reaction was quenched with H2O (5 mL) and extracted with EtOAc (2 mL ⁇ 3). The combined organic layers were washed with brine (5 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude product.
  • 2-bromoacetonitrile 31 mg, 0.26 mmol, 1.5 eq.
  • Cs 2 CO 3 112 mg, 0.34 mmol, 2.0 eq.
  • the product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150mmx40mm, 10 ⁇ m; liquid phase: [A:H 2 O (10mM NH 4 HCO 3 ); B:ACN] B%: 25%-60%, 20min]) to obtain [(3P,6R or 6S)-3-(5-Fluoroisoquinolin-4-yl)-2,4-dioxo-6- (trifluoromethyl)-3,4,5,6,7,8-hexahydroquinazolin-1(2H)-yl]acetonitrile (21c)-Peak 3a.
  • Step 3d To a solution of the compound from Peak 4 (50 mg, 0.13 mmol, 1.0 eq.) in DMF (1 mL) was added 2-bromoacetonitrile (24 mg, 0.20 mmol, 1.5 eq.) and Cs 2 CO 3 (86 mg, 0.26 mmol, 2.0 eq.) at 25°C.
  • the product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150mmx40mm, 10 ⁇ m; liquid phase: [A:H 2 O (10mM NH 4 HCO 3 ); B:ACN] B%: 25%- 60%, 20min]) to obtain [(3P,6R or 6S)-3-(5-Fluoroisoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)- 3,4,5,6,7,8-hexahydroquinazolin-1(2H)-yl]acetonitrile (21d)-Peak 4a.
  • Example 22 Synthesis of 5-fluoro-3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (21)
  • a solution of methyl 6-amino-2-fluoro-3-(trifluoromethyl)benzoate (Int-A8) (220 mg, 0.93 mmol, 1.0 eq.) in pyridine (10 mL) was added 4-isocyanatoisoquinoline (Int-B8) (173 mg, 1.02 mmol, 1.5 eq.).
  • the mixture was stirred at 100°C for 6 hrs.
  • the mixture was concentrated under reduced pressure to give crude product.
  • Example 23 Synthesis of 5-fluoro-3-(isoquinolin-4-yl)-1-methyl-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (23)
  • 5-fluoro-3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (22) (40 mg, 0.10 mmol, 1.0 eq.) and K 2 CO 3 (41 mg, 0.30 mmol, 3.0 eq.) in DMF (2 mL) was added MeI (21 mg, 0.15 mmol, 1.5 eq.). The mixture was stirred at 0°C for 2 hrs.
  • Example 24 Synthesis of 3-(3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)propanenitrile (24), 3-[(3M)-3-[6-(Methanesulfonyl)isoquinolin-4-yl]-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl]propanenitrile (24a) and 3-[(3P)-3-[6-(Methanesulfonyl)isoquinolin-4-yl]-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl]propanenitrile (24b) Step 1: The solution of 2-amino-5-(trifluoromethyl)benzoic acid (Int
  • reaction mixture was warmed up to 25°C. Then to the reaction mixture was 6- (methylsulfonyl)isoquinolin-4-amine (Int-B2) (2.0 g, 9.00 mmol, 1.0 eq.) and NMM (1.8 g, 18.00 mmol, 2.0 eq.) at 25°C.
  • the reaction mixture was heated up to 80°C and stirred at 80°C for 16 hrs.
  • the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a crude product.
  • Step 2 To a mixture of 2-amino-N-(6-(methylsulfonyl)isoquinolin-4-yl)-5- (trifluoromethyl)benzamide (500 mg, 1.22 mmol, 1.0 eq.) and TEA (865 mg, 8.55 mmol, 7.0 eq.) in THF (3 mL) was added a solution of triphosgene (360 mg, 1.22 mmol, 1.0 eq.) in THF (2 mL) dropwise at 0°C under N 2 . The mixture was then warmed up to 25°C and stirred at 25°C under N 2 for 2 hrs.
  • Step 3 To the solution of -(6-(methylsulfonyl)isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (150 mg, 0.34 mmol, 1.0 eq.) and DBU (105 mg, 0.68 mmol, 2.0 eq.) in DMF (1 mL) was added acrylonitrile (180 mg, 3.40 mmol, 10.0 eq.) at 25°C. The mixture was heated to 100°C and stirred at 100°C for 16 hrs under N 2 . The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 2).
  • Step 4 Racemic 3-(3-(6-(methylsulfonyl)isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)propanenitrile (24) (60 mg, 0.12 mmol, 1.0 eq.) was separated by prep-SFC (column: DAICEL CHIRALCEL OJ (250mmx30mm,10um); liquid phase: [A:IPA; B:ACN] B%: 15%, 12 min]) to give two peaks. (peak 1 and peak 2).
  • Example 25 Synthesis of 3-(isoquinolin-4-yl)-5-methyl-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (25)
  • Step 1 To a solution of 6-fluoro-2-methyl-3-(trifluoromethyl)benzoic acid (Int-A9) (1.1 g, 4.95 mmol, 1.0 eq.) in DMF (20 mL) was added HATU (2.8 g, 7.43 mmol, 1.5 eq.), isoquinolin-4- amine (785 mg, 5.45 mmol, 1.1 eq.) and NMM (1.5 g, 14.85 mmol, 3.0 eq.) at 25°C.
  • Int-A9 6-fluoro-2-methyl-3-(trifluoromethyl)benzoic acid
  • HATU 2.8 g, 7.43 mmol, 1.5 eq.
  • isoquinolin-4- amine 785 mg, 5.45 mmol,
  • Step 2 To a solution of 6-fluoro-N-(isoquinolin-4-yl)-2-methyl-3-(trifluoromethyl)benzamide (1.1g, 3.16 mmol, 1.0 eq.) in NMP (11 mL) was added NaN 3 (350 mg, 5.38 mmol, 1.7 eq.) at 25°C. The mixture was stirred at 100°C for 24 hrs. To the mixture was added NaN 3 (225 mg, 3.46 mmol, 1.1 eq.) at 25°C and the mixture was stirred at 100°C for 16 hrs. The reaction was quenched with H 2 O (100 mL) and extracted with EtOAc (40 mL ⁇ 2).
  • Step 4 To a mixture of 6-amino-N-(isoquinolin-4-yl)-2-methyl-3-(trifluoromethyl)benzamide (350 mg, 1.01 mmol, 1.0 eq.) and TEA (410 mg, 4.04 mmol, 4.0 eq.) in THF (6 mL) was added a solution of triphosgene (300 mg, 1.01 mmol, 1.0 eq.) in THF (4 mL) at 0°C. The mixture was stirred at 25°C for 12 hrs. The reaction was quenched with H 2 O (30 mL) and extracted with EtOAc (20 mL ⁇ 2).
  • Example 26 Synthesis of 3-(isoquinolin-4-yl)-1,5-dimethyl-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (26)
  • 3-(isoquinolin-4-yl)-5-methyl-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (25) (20 mg, 0.05 mmol, 1.0 eq.) in DMF (1 mL) was added Cs 2 CO 3 (35 mg, 0.10 mmol, 2.0 eq.) and MeI (8 mg, 0.06 mmol, 1.1 eq.) at 25°C.
  • the mixture was stirred at 25°C for 2 hrs.
  • Example 27 Synthesis of 3-(isoquinolin-4-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroquinazoline- 2,4(1H,3H)-dione (27); (3M,6R or 6S)-3-(Isoquinolin-4-yl)-6-(trifluoromethyl)-5,6,7,8- tetrahydroquinazoline-2,4(1H,3H)-dione (27a); (3M,6R or 6S)-3-(Isoquinolin-4-yl)-6-(trifluoromethyl)-5,6,7,8- tetrahydroquinazoline-2,4(1H,3H)-dione (27b); (3P,6R or 6S)-3-(Isoquinolin-4-yl)-6-(trifluoromethyl)-5,6,7,8- tetrahydroquinazoline-2,4(1H,3H)-d
  • Step 2 To a solution of ethyl 2-(((4-nitrophenoxy)carbonyl)amino)-5-(trifluoromethyl)cyclohex-1- ene-1-carboxylate (2.0 g, 4.97 mmol, 1.0 eq) in dioxane (40 mL) was added isoquinolin-4-amine (788 mg, 5.47 mmol, 1.1 eq) and DBU (1.5 g, 9.94 mmol, 2.0 eq) at 20°C. The reaction mixture was stirred at 20°C for 14 hrs. The solution was diluted with H 2 O (40 mL) and extracted with EtOAc (3x50 mL).
  • the combined organic phase was dried over Na 2 SO 4 , filtrated and concentrated to give crude product.
  • the crude product was purified by prep-HPLC (Column: Waters Xbridge Prep OBD C18150mmx40mm, 10 ⁇ m; liquid phase: [A:H 2 O(10mM NH 4 HCO 3 ); B:ACN]B%: 20%-40%,20min]) to give racemic 3-(isoquinolin-4-yl)-6-(trifluoromethyl)-5,6,7,8- tetrahydroquinazoline-2,4(1H,3H)-dione.
  • Example 29 Synthesis of [(3M,6R or 6S)-3-(Isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)- 3,4,5,6,7,8-hexahydroquinazolin-1(2H)-yl]acetonitrile (29a); [(3M,6R or 6S)-3-(Isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4,5,6,7,8- hexahydroquinazolin-1(2H)-yl]acetonitrile (29b); [(3P,6R or 6S)-3-(Isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4,5,6,7,8- hexahydroquinazolin-1(2H)-yl]acetonitrile (29c), and [(3P,6
  • Example 30 Synthesis of 1- ⁇ [(3M)-3-(5-Fluoroisoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl]methyl ⁇ cyclopropane-1-carbonitrile (30a) and 1- ⁇ [(3P)-3-(5-Fluoroisoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl]methyl ⁇ cyclopropane-1-carbonitrile (30b) Step 1: To a solution of 3-(5-fluoroisoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)- dione (300 mg, 0.66 mmol, 1.0 eq.) in DMF (6 mL) was added (1-cyanocyclopropyl)methyl
  • Step 2 The racemate (30) was separated by SFC (DAICEL CHIRALPAK AD (250mmx50mm,10um); liquid phase: 0.1%NH 3 H 2 O EtOH]B%: 10%-50%,10min]) to give 2 peaks: peak 1 and peak 2.
  • Example 31 Synthesis of 3-(isoquinolin-4-yl)-6-(trifluoromethyl)pyrido[3,2-d]pyrimidine- 2,4(1H,3H)-dione (31)
  • Step 1 To a mixture of 3-amino-6-(trifluoromethyl)picolinic acid (Int-A10) (1.0 g, crude, 4.85 mmol, 1.0 eq.), isoquinolin-4-amine (699 mg, 4.85 mmol, 1.0 eq.), NMI (1.2 g, 14.55 mmol, 3.0 eq.) in ACN (10 mL) was added TCFH (1.6 g, 5.82 mmol, 1.2 eq.) in portions at 20°C.
  • Int-A10 3-amino-6-(trifluoromethyl)picolinic acid
  • NMI 1.2 g, 14.55 mmol, 3.0 eq.
  • TCFH 1.6 g, 5.82 mmol, 1.2 e
  • Step 2 To a solution of 3-amino-N-(isoquinolin-4-yl)-6-(trifluoromethyl)picolinamide (100 mg, 0.30 mmol, 1.0 eq.) and TEA (183 mg, 1.81 mmol, 6.0 eq.) in THF (1 mL) was added a solution of triphosgene (179 mg, 0.60 mmol, 2.0 eq.) in THF (0.5 mL) dropwise at 0°C. The mixture was stirred at 20°C for 20 hrs under N 2 .
  • Step 1 To a solution of 5-(1-(methoxycarbonyl)cyclopropyl)-2-nitrobenzoic acid (Int-A11) (850 mg, 3.21 mmol, 1.0 eq.) in DMF (8.5 mL) was added HATU (1.5 g, 3.85 mmol, 1.2 eq.). The mixture was stirred at 25°C for 1 hr. Then to the mixture was added isoquinolin-4-amine (508 mg, 3.53 mmol, 1.1 eq.) and NMM (972 mg, 9.62 mmol, 3.0 eq.). The mixture was stirred at 45°C for 15 hrs.
  • Step 2 To a mixture of Raney Ni (1.0 g) in EtOH (10 mL) was added methyl 1-(3-(isoquinolin-4- ylcarbamoyl)-4-nitrophenyl)cyclopropane-1-carboxylate (926 g, 2.37 mmol, 1.0 eq). The suspension was degassed under vacuum and purged with H 2 several times, and the mixture was stirred under H2 (15 psi) at 35°C for 16 hrs. The mixture was filtered though a pad, the filtrate was concentrated to give methyl 1-(4-amino-3-(isoquinolin-4- ylcarbamoyl)phenyl)cyclopropane-1-carboxylate.
  • Step 3 To a solution of methyl 1-(4-amino-3-(isoquinolin-4-ylcarbamoyl)phenyl)cyclopropane-1- carboxylate (679 mg, 1.88 mmol, 1.0 eq.) in THF (7 mL) was added DMAP (23 mg, 0.20 mmol, 0.1 eq.) and CDI (610 mg, 3.76 mmol, 2.0 eq.). The mixture was stirred at 80°C for 6 hrs. The mixture was quenched with H 2 O (10 mL), extracted with CH 2 Cl 2 (30 mL x 2).
  • Step 4 To a solution of methyl 1-(3-(isoquinolin-4-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6- yl)cyclopropane-1-carboxylate (150 mg, 0.39 mmol, 1.0 eq.) in dioxane (1 mL) was added 6 M HCl (1 mL) at 25°C and then the mixture was stirred at 60°C for 16 hrs.
  • Example 33 Synthesis of 6-(1-(hydroxymethyl)cyclopropyl)-3-(isoquinolin-4-yl)quinazoline- 2,4(1H,3H)-dione (33)
  • 1-(3-(isoquinolin-4-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)cyclopropane- 1-carboxylic acid (32) 153 mg, 0.41 mmol, 1.0 eq.
  • TEA 62 mg, 0.61 mmol, 1.5 eq.
  • CDI 100 mg, 0.61 mmol, 1.5 eq.
  • Example 34 Synthesis of 1-isopropyl-3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (34)
  • 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2) 200 mg, 0.56 mmol, 1.0 eq.
  • Cs 2 CO 3 364 mg, 1.12 mmol, 2.0 eq.
  • 2- iodopropane 190 mg, 1.12 mmol, 2.0 eq.
  • Example 35 Synthesis of 6-isopropyl-3-(isoquinolin-4-yl)quinazoline-2,4(1H,3H)-dione (35)
  • a mixture of methyl 2-amino-5-isopropylbenzoate (Int-A12) 1.0 g, 5.18 mmol, 1.0 eq.
  • pyridine 10 mL
  • 4-isocyanatoisoquinoline Int-B8
  • the mixture was stirred at 100°C for 12 hrs under N 2 .
  • the mixture was quenched with H 2 O (10 mL), extracted with EtOAc (10 mL x 3).
  • Example 36 Synthesis of 6-isopropyl-3-(isoquinolin-4-yl)-1-methylquinazoline-2,4(1H,3H)-dione (36) To the mixture of 6-isopropyl-3-(isoquinolin-4-yl)quinazoline-2,4(1H,3H)-dione (35) (160 mg, 0.48 mmol, 1.0 eq.) in DMF (3 mL) were added K 2 CO 3 (133 mg, 0.96 mmol, 2.0 eq.) and MeI (68 mg, 0.48 mmol, 1.0 eq.) at 0°C and the mixture was stirred at 20°C for 12 hrs.
  • K 2 CO 3 133 mg, 0.96 mmol, 2.0 eq.
  • MeI 68 mg, 0.48 mmol, 1.0 eq.
  • Example 37 Synthesis of methyl 2-((3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)methyl)acrylate (37)
  • 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2) 105 mg, 0.30 mmol, 1.0 eq.
  • Cs 2 CO 3 196 mg, 0.60 mmol, 2.0 eq.
  • methyl 2-(bromomethyl)acrylate 54 mg, 0.30 mmol, 1.0 eq.
  • Example 38 Synthesis of 3-(3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)-2-methylpropanoic acid (38) Step 1: To a mixture of methyl 2-((3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)methyl)acrylate (37) (150 mg, 0.33 mmol, 1.0 eq.) in EtOAc (6 mL) was added Pd/C (50 mg, 10%) at 25°C.
  • Step 2 To a mixture methyl 3-(3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)-2-methylpropanoate (120 mg, 0.26 mmol, 1.0 eq.) in dioxane (2 mL) was added trimethylstannanol (95 mg, 0.52 mmol, 2.0 eq.) at 25°C. The mixture was stirred at 100°C for 18 hrs.
  • Example 39 Synthesis of 2-((3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)methyl)acrylic acid (39) To a mixture of methyl 2-((3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)methyl)acrylate (37) (150 mg, 0.33 mmol, 1.0 eq.) in dioxane (2 mL) was added aq. HCl (2 mL, 6 M) at 25°C.
  • Example 40 Synthesis of 2-((3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)methyl)acrylamide (40) To a solution of 2-((3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4-dihydroquinazolin-1(2H)- yl)methyl)acrylic acid (39) (150 mg, 0.34 mmol, 1.0 eq.) in dioxane (3 mL) was added pyridine (0.3 mL) and Boc2O (1.2 g, 5.44 mmol, 16.0 eq.) at 25°C.
  • Example 41 Synthesis of 3-(5-bromoisoquinolin-4-yl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (41)
  • Example 42 Synthesis of 3-(5-methylisoquinolin-4-yl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (42)
  • 3-(5-bromoisoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (41) 50 mg, 0.11 mmol, 1.0 eq.) in dioxane (2 mL) was added MeB(OH) 2 (35 mg, 0.55 mmol, 5.0 eq.), K 3 PO 4 (47 mg, 0.22 mmol, 2.0 eq.) and S-Phos-Pd-G 2 (10 mg, 0.01 mmol, 0.1 eq.) at 25°C under N 2 .
  • Step 1 A mixture of 5-(difluoromethoxy)-2-nitrobenzoic acid (Int-A13) (800 mg, 3.43 mmol, 1.0 eq), isoquinolin-4-amine (495 mg, 3.43 mmol, 1.0 eq), TCFH (962 mg, 3.43 mmol, 1.0 eq) and NMI (985 mg, 12.01 mmol, 3.5 eq) in CH 3 CN (8 mL) was stirred at 20°C for 1 hr. The reaction mixture was quenched with H 2 O (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Int-A13 800 mg, 3.43 mmol, 1.0 eq
  • isoquinolin-4-amine 495 mg, 3.43 mmol, 1.0 eq
  • TCFH 962 mg, 3.43 mmol, 1.0
  • Step 2 To the solution of 5-(difluoromethoxy)-N-(isoquinolin-4-yl)-2-nitrobenzamide (370 mg, 1.03 mmol, 1.0 eq) in EtOH (4 mL) and H 2 O (1 mL) was added Fe (288 mg, 5.15 mmol, 5.0 eq) and NH4Cl (275 mg, 5.15 mmol, 5.0 eq). The mixture was stirred at 70°C for 18 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give 2-amino-5- (difluoromethoxy)-N-(isoquinolin-4-yl)benzamide which was used directly in the next step.
  • Example 44 Synthesis of 1-((3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)methyl)cyclopropane-1-carbonitrile (44)
  • 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2) 200 mg, 0.56 mmol, 1.0 eq.
  • DMF 4 mL
  • Cs 2 CO 3 364 mg, 1.12 mmol, 2.0 eq.
  • (1- cyanocyclopropyl)methyl 4-methylbenzenesulfonate 212 mg, 0.84 mmol, 1.5 eq.
  • NaI 84 mg, 0.56 mmol, 1.0 eq.
  • (1-cyanocyclopropyl)methyl 4-methylbenzenesulfonate was obtained using the following procedure: To a solution of 1-(hydroxymethyl)cyclopropane-1-carbonitrile (700 mg, 7.21 mmol, 1.0 eq.) in CH 2 Cl 2 (4 mL) was added Et 3 N (1.3 g, 9.01 mmol, 1.3 eq.) at 25°C. A solution of TsCl (1.6 g, 8.65 mmol, 1.2 eq.) in CH 2 Cl 2 (2 mL) was added dropwise at 0°C and the reaction was stirred at 25°C for 16 hrs.
  • Example 45 Synthesis of 1-(2-hydroxyethyl)-3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (45)
  • Step 1 A mixture of 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2) (500 mg, 1.51 mmol, 1.0 eq.), 2-((tert-butyldimethylsilyl)oxy)ethyl 4-methylbenzenesulfonate (540 mg, 1.51 mmol, 1.0 eq.), Cs 2 CO 3 (985 mg, 3.02 mmol, 2.0 eq.) and NaI (230 mg, 1.51 mmol, 1.0 eq.) in DMF (5 mL) was stirred at 50°C for 16 hrs.
  • Step 2 To a solution of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(isoquinolin-4-yl)-6- (trifluoromethyl)quinazoline-2,4(1H,3H)-dione (520 mg, 0.19 mmol, 1.0 eq.) in dioxane (5 mL) was added 6 M HCl (5 mL) dropwise at 0°C and the mixture then stirred at 20°C for 1 hr. The reaction mixture was quenched with water (10 mL) and extracted with MTBE (10 mL).
  • reaction mixture was quenched with water (20 mL) and extracted with CH 2 Cl 2 (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude product.
  • Example 46 Synthesis of 1-(2-fluoroethyl)-3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (46) To a mixture of 1-(2-hydroxyethyl)-3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)- dione (45) (300 mg, 0.73 mmol, 1.0 eq.) in MeCN (5 mL) was added Et 3 N (660 mg, 6.57 mmol, 9.0 eq.) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (660 mg, 2.19 mmol, 3.0 eq.) followed by the addition of HF .
  • Et 3 N 660 mg, 6.57 mmol, 9.0 eq.
  • Example 47 Synthesis of 4-(2,4-dioxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)-yl)-N-(2- methoxyethyl)isoquinoline-6-carboxamide (47)
  • Step 1 To a mixture of methyl 4-aminoisoquinoline-6-carboxylate hydrochloride (Int-B4) (2.8 g, 13.58 mmol, 1.2 eq.) in DMF (30 mL) was added HATU (6.5 g, 16.97 mmol, 1.5 eq.) at 45°C. The reaction mixture was stirred at 45°C for 2 hrs.
  • Int-B4 4-aminoisoquinoline-6-carboxylate hydrochloride
  • HATU 6.5 g, 16.97 mmol, 1.5 eq.
  • Step 2 To a mixture of methyl 4-(2-amino-5-(trifluoromethyl)benzamido)isoquinoline-6- carboxylate (400 mg, 1.03 mmol, 1.0 eq.) in DMF (5 mL) was added CDI (334 mg, 2.06 mmol, 2.0 eq.), CDT (338 mg, 2.06 mmol, 2.0 eq.) and DMAP (26 mg, 0.21 mmol, 0.2 eq.) at 20°C. The reaction mixture was stirred at 80°C for 16 hrs. The reaction was poured into water (50 mL) and extracted with EtOAc (20 mL x 3).
  • Step 4 To a mixture of 4-(2,4-dioxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)- yl)isoquinoline-6-carboxylic acid, (200 mg, 0.50 mmol, 1.0 eq.), 2-methoxyethan-1-amine (45 mg, 0.60 mmol, 1.2 eq.) and Et 3 N (253 mg, 2.50 mmol, 5.0 eq.) in CH 2 Cl 2 (5 mL) was added T3P (477 mg, 0.75 mmol, 1.5 eq.) at 25°C. The reaction mixture was stirred at 25°C for 16 hrs.
  • Example 48 Synthesis of 8-bromo-3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (48) To a solution of methyl 2-amino-3-bromo-5-(trifluoromethyl)benzoate (Int-A14) (217 mg, 0.73mmol, 1.4 eq.) in DMF (2 mL) was added NaH (19 mg, 0.78 mmol, 1.5 eq.) at 0°C and the mixture was stirred at 0°C for 1 hr.
  • phenyl isoquinolin-4-yl(phenoxycarbonyl)carbamate (Int-B7) (200 mg, 0.52 mmol, 1.0 eq.) was added to the above mixture at 0°C and the mixture was stirred 25°C for 15 hrs.
  • the aqueous phase was extracted with EtOAc (20 mL x 2).
  • the combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude product.
  • Example 49 Synthesis of 8-(2-hydroxypropan-2-yl)-3-(isoquinolin-4-yl)-6- (trifluoromethyl)quinazoline-2,4(1H,3H)-dione (49)
  • Step 1 To a mixture of 8-bromo-3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)- dione (48) (200 mg, 0.46 mmol, 1.0 eq.) in MeOH (10 mL) was added K 2 CO 3 (159 mg, 1.15 mmol, 2.5 eq.) and Pd(dppf)Cl 2 (37 mg, 0.05 mmol, 0.1 eq.) at 20°C under CO (50 psi).
  • Step 2 To a mixture of methyl 3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-1,2,3,4- tetrahydroquinazoline-8-carboxylate (50 mg, 0.12 mmol, 1.0 eq.) in THF (2 mL) was added MeMgBr (0.2 mL, 0.60 mmol, 5.0 eq.) at 0°C under N 2 . The reaction was stirred at 0°C for 2 hrs. The reaction mixture was quenched with NH 4 Cl (5 mL), extracted with CH 2 Cl 2 (10 mL x 2).
  • Example 50 Synthesis of 3-(isoquinolin-4-yl)-1-methyl-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (50)
  • Step 1 To a mixture of 3-bromoisoquinolin-4-amine (Int-B5) (3.5 g, 15.76 mmol, 1.0 eq.) and pyridine (5 g, 63.07 mmol, 4.0 eq.) in CH 2 Cl 2 (40 mL) was added ClCOOPh (6.1 g, 39.40 mmol, 2.5 eq.) at 0°C. The mixture was stirred at 20°C for 4 hrs. The reaction solution was poured into water (80 mL) and extracted with CH 2 Cl 2 (50 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • ClCOOPh 6.1 g, 39.40 mmol, 2.5 eq.
  • Step 2 To a solution of methyl 2-amino-5-(trifluoromethyl)benzoate (Int-A6) (1.7 g, 7.80 mmol, 1.5 eq.) in DMF (30 mL) was added NaH (292 mg, 7.30 mmol, 1.4 eq.) at 0°C under N 2 . The mixture was stirred at 0°C for 30 mins. Phenyl (3-bromoisoquinolin-4-yl)carbamate (2.4 g, 5.20 mmol, 1.0 eq.) in DMF (20 mL) was added dropwise at 0°C under N2. The mixture was stirred at 20°C for 15.5 hrs.
  • Int-A6 methyl 2-amino-5-(trifluoromethyl)benzoate
  • Step 3 To a solution of 3-(3-bromoisoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)- dione (300 mg, 0.69 mmol, 1.0 eq.) and ZnCN 2 (143 mg, 1.38 mmol, 2.0 eq.) in DMF (5 mL) was added Pd 2 (dba) 3 (30mg) and DPPF (45 mg) at 20°C. The mixture was stirred at 130°C for 16 hrs under N 2 . The reaction solution was poured into H 2 O (10 mL) and extracted with EtOAc (15 mL x 3).
  • Example 52 Synthesis of 3-(3-ethynylisoquinolin-4-yl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (52)
  • Step 1 To the solution of 3-(3-bromoisoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)- dione (400 mg, 0.92 mmol, 1.0 eq.) in TEA/MeCN (4/1mL) was added ethynyltrimethylsilane (451 mg, 4.60 mmol, 5.0 eq.) and Pd(pph 3 ) 2 Cl 2 (40 mg) at 20°C.
  • Step 2 To a solution of 6-(trifluoromethyl)-3-(3-((trimethylsilyl)ethynyl)isoquinolin-4- yl)quinazoline-2,4(1H,3H)-dione (300 mg, 0.66 mmol, 1.0 eq.) in MeOH (6 mL) was added K 2 CO 3 (183 mg, 1.32 mmol, 2.0 eq.) at 0°C. The mixture was stirred at 20°C for 2 hrs. The reaction solution was poured into H 2 O (10 mL) and extracted with EtOAc (20 mL x 3), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the residue.
  • Example 54 Synthesis of 3-(isoquinolin-4-yl)-6-(trifluoromethyl)pyrido[3,4-d]pyrimidine- 2,4(1H,3H)-dione (54)
  • a solution of methyl 5-amino-2-(trifluoromethyl)isonicotinate (Int-A15) 500 mg, 2.27 mmol, 1.0 eq.) in pyridine (5 mL) was added to 4-isocyanatoisoquinoline (Int-B8) (600 mg crude, 2.27 mmol, 1.0 eq.) at 25°C and the mixture was stirred for 12 hrs at 100°C under N 2 .
  • the reaction mixture was concentrated to give a residue.
  • Step 2 To a solution of methyl (E)-4-(3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)but-2-enoate (450 mg, 0.99 mmol, 1.0 eq.) in dioxane (6 mL) was added Me 3 SnOH (358 mg, 1.98 mmol, 2.0 eq.) at 0°C under nitrogen. The reaction was stirred for 12 hrs at 80°C. The reaction was slowly quenched with water (10 mL), adjusted to pH ⁇ 5 with 1N HCl and extracted with EtOAc (10 ⁇ 3 mL).
  • Step 1 To a solution of racemic (E)-4-(3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)but-2-enoic acid (350 mg, 0.79 mmol, 1.0 eq.) in THF (4 mL) was added Boc 2 O (346 mg, 1.58 mmol, 2.0 eq.), NH 4 HCO 3 (125 mg, 1.58 mmol, 2.0 eq.) and pyridine (125 mg, 1.58 mmol, 2.0 eq.) at 20°C under nitrogen. The reaction was stirred for 12 hrs at 20°C.
  • Example 57 Synthesis of 3-(isoquinolin-4-yl)-1-(2-morpholinoethyl)-6- (trifluoromethyl)quinazoline-2,4(1H,3H)-dione (57)
  • 2-morpholinoethyl 4-methylbenzenesulfonate 300 mg, 0.84 mmol, 1.0 eq.
  • Cs 2 CO 3 547 mg, 1.68 mmol, 2.0 eq.
  • NaI 30 mg
  • the reaction mixture was quenched into water (40 mL) and extracted with EtOAc (40 mL x 2). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuum to give crude product.
  • the crude product was purified by prep-HPLC (column: Waters Xbridge BEH C18100mmx30mm, 10 ⁇ m; liquid phase: [A:10mM NH 4 HCO 3 in H 2 O; B:ACN] B%: 30%- 50%, 8min]) to give3-(isoquinolin-4-yl)-1-(2-morpholinoethyl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (57).
  • 2-morpholinoethyl 4-methylbenzenesulfonate was obtained using the following procedure: To a solution of 2-morpholinoethan-1-ol (2.0 g, 15.24 mmol, 1.0 eq.), Et 3 N (3.1 g, 62.24 mmol, 2.0 eq.) in CH 2 Cl 2 (20 mL) was added TsCl (2.9 g, 15.24 mmol, 1.0 eq.) at 20°C, the mixture was stirred at 20°C for 5 hrs. The reaction mixture was quenched with water (20 mL) and extracted with CH 2 Cl 2 (20 mL x 3).
  • Example 58 Synthesis of 3-(isoquinolin-4-yl)-8-methyl-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (58)
  • Step 1 To a solution of 8-bromo-3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)- dione (48) (200 mg, 0.46 mmol, 1.0 eq.) in THF (5 mL) was added methylboronic acid (120 mg, 1.83 mmol, 4.0 eq.), Pd(dppf)Cl 2 (40 mg, 0.05 mmol, 0.1 eq.) and Na 2 CO 3 (100 mg, 0.92 mmol, 2.0 eq.) at 25°C and the mixture was stirred 80°C for 16 hrs.
  • methylboronic acid 120 mg, 1.83 mmol, 4.0 eq.
  • reaction mixture was quenched with saturated aqueous NH 4 Cl (5 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated to give crude product.
  • Example 59 Synthesis of 1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-3-(isoquinolin-4-yl)-6- (trifluoromethyl)quinazoline-2,4(1H,3H)-dione (59)
  • Step 1 To a mixture of 1-(2-hydroxyethyl)-3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (45) (400mg, 1.00 mmol, 1.0 eq.) and Et 3 N (202 mg, 2.00 mmol, 2.0 eq.) in CH 2 Cl 2 (5 mL) was added TsCl (210 mg, 1.10 mmol, 1.1 eq.) at 20°C, the mixture was stirred at 20°C for 16 hrs.
  • the reaction mixture was quenched into water (20 mL) and extracted with CH 2 Cl 2 (20 mL x 3). The combined organic layers were washed by brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the crude product.
  • Step 2 To a mixture of 2-(3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)ethyl 4-methylbenzenesulfonate (300 mg, 0.54 mmol, 1.0 eq.) in DMF (3 mL) was added 4,4-difluoropiperidine (131 mg, 1.08 mmol, 2.0 eq.) and DIEA (210 mg, 1.62 mmol, 3.0 eq.) at 20°C and the mixture was stirred at 50°C for 16 hrs.
  • Example 60 Synthesis of 1-(2-(3,3-difluoropiperidin-1-yl)ethyl)-3-(isoquinolin-4-yl)-6- (trifluoromethyl)quinazoline-2,4(1H,3H)-dione (60)
  • DMF dimethyl methyl
  • alkaline resin a mixture of 3,3-difluoropiperidine hydrochloride (282 mg, 1.80 mmol, 5.0 eq.) in DMF (4 mL) was added alkaline resin to adjust pH to 8, the mixture was stirred 1 hr at 20°C and filtered.
  • Example 61 Synthesis of 3-(isoquinolin-4-yl)-1-(2-(piperazin-1-yl)ethyl)-6- (trifluoromethyl)quinazoline-2,4(1H,3H)-dione (61)
  • Step 1 A mixture of 2-(3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4-dihydroquinazolin- 1(2H)-yl)ethyl 4-methylbenzenesulfonate (300 mg, 0.54 mmol, 1.0 eq.), tert-butyl piperazine-1- carboxylate (150 mg, 0.81 mmol, 1.5 eq.) and DIEA (135 mg, 1.08 mmol, 2.0 eq.) in DMF (5 mL) was stirred at 50°C for 16 hrs.
  • Step 2 A mixture of tert-butyl 4-(2-(3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)ethyl)piperazine-1-carboxylate (160 mg, 0.28 mmol, 1.0 eq.) in HCl (g)/EtOAc (5 mL) was stirred at 20°C for 1 hr. The reaction mixture was poured into water (5 mL) and the precipitate filtered.
  • Example 62 Synthesis of 3-(isoquinolin-4-yl)-1-(2-methoxyethyl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (62)
  • Example 63 Synthesis of 1-ethyl-3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)- dione (63)
  • 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2) 200 mg, 0.56 mmol, 1.0 eq.
  • DMF 2 mL
  • Cs 2 CO 3 364 mg, 1.12 mmol, 2.0 eq.
  • iodoethane 113 mg, 0.72 mmol, 1.3 eq.
  • Example 64 Synthesis of 1-((R)-3-hydroxybutyl)-3-(isoquinolin-4-yl)-6- (trifluoromethyl)quinazoline-2,4(1H,3H)-dione (64)
  • (R)-3-hydroxybutyl 4-methylbenzenesulfonate was obtained using the following procedure: A mixture of (R)-butane-1,3-diol (CAS No.6290-03-5) (1.0 g, 11.10 mmol, 1.0 eq.) and TsOH (2.2 g, 11.65 mmol, 1.1 eq.) in pyridine (10 mL) was stirred at 50°C for 16 hrs. The reaction was quenched with saturated aqueous NH 4 Cl (80 mL) and extracted with EtOAc (30 mL ⁇ 2). The combined organic layers were washed with brine (80 mL ⁇ 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give crude product.
  • Example 65 Synthesis of 1-((S)-4-hydroxybutan-2-yl)-3-(isoquinolin-4-yl)-6- (trifluoromethyl)quinazoline-2,4(1H,3H)-dione (65)
  • Step 1 To a solution of 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2) (140 mg, 0.39 mmol, 1.0 eq.) in DMF (3 mL) was added Cs 2 CO 3 (383 mg, 1.18 mmol, 3.0 eq.) at 25°C.
  • Step 2 To a solution of 1-((S)-4-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-3-(isoquinolin-4-yl)-6- (trifluoromethyl)quinazoline-2,4(1H,3H)-dione (230 mg, 0.34 mmol, 1.0 eq.) in dioxane (2 mL) was added HCl (2 mL, 6M) at 25°C. The reaction was stirred at 25°C for 1 hr under N 2 . The reaction was concentrated to give a residue.
  • Step 1 A mixture of (R)-butane-1,3-diol (CAS No.6290-03-5) (2.0 g, 22.19 mmol, 1.0 eq.) in CH 2 Cl 2 (20 mL) was added Imidizole (3.0 g, 44.38 mmol, 2.0 eq.) at 25°C.
  • Step 2 To a solution of (R)-4-((tert-butyldiphenylsilyl)oxy)butan-2-ol (2.0 g, 6.09 mmol, 1.0 eq.) in CH 2 Cl 2 (20 mL) was added Et 3 N (1.2 g, 12.18 mmol, 2.0 eq.) and DMAP (75 mg, 0.61 mmol, 0.1 eq.) at 25°C. A solution of TsCl (1.5 g, 7.92 mmol, 1.3 eq.) in CH 2 Cl 2 (5 mL) was added into the reaction at 0°C. The mixture was stirred at 25°C for 16 hrs under N 2 .
  • Example 66 Synthesis of 1-((3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)methyl)cyclopropane-1-carboxylic acid (66) Step 1: To a solution of 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2) (300 mg, 0.84 mmol, 1.0 eq.) in DMF (4 mL) was added Cs 2 CO 3 (546 mg, 1.68 mmol, 2.0 eq.), ethyl 1-((tosyloxy)methyl)cyclopropane-1-carboxylate (375 mg, 1.26 mmol, 1.5 eq.) and NaI (126 mg, 0.84 mmol, 1.0 eq.) at 25°C.
  • Step 2 To a solution of thyl 1-((3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)methyl)cyclopropane-1-carboxylate (360 mg, 0.74 mmol, 1.0 eq.) in dioxane (5 mL) was added SnMe 3 OH (270 mg, 1.49 mmol, 2.0 eq.) at 25°C. The mixture was stirred at 100°C for 16 hrs under N 2 . The mixture was concentrated to give a residue. The residue was dissolved in DMF (3 mL) and filtered off.
  • the filtrate was purified by prep-HPLC (column: Phenomenex Luna C18200mmx40mm, 10 ⁇ m; liquid phase: [A:H 2 O (0.1% FA); B:ACN] B%: 50%-90%, 20 min]) to give 1-((3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)methyl)cyclopropane-1-carboxylic acid (66).
  • Ethyl 1-((tosyloxy)methyl)cyclopropane-1-carboxylate was obtained using the following procedure: To a solution of ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (400 mg, 2.77 mmol, 1.0 eq.) in CH 2 Cl 2 (4 mL) was added Et 3 N (561 mg, 5.55 mmol, 2.0 eq.) and DMAP (34 mg, 0.28 mmol, 0.1 eq.) at 25°C. A solution of TsCl (635 mg, 3.33 mmol, 1.2 eq.) in CH 2 Cl 2 (2 mL) was added dropwise at 0°C and the reaction was stirred at 25°C for 16 hrs.
  • Example 67 Synthesis of 6-(1,1-difluoroethyl)-3-(isoquinolin-4-yl)quinazoline-2,4(1H,3H)-dione
  • Step 1 To a solution of 5-acetyl-2-aminobenzoic acid (CAS No.53589-27-8) (2.4 g, 13.41 mmol, 1.0 eq.) in DMF (23 mL) was added HATU (6.1 g, 16.09 mmol, 1.2 eq.) and the mixture was stirred at 25°C for 1 hr.
  • 5-acetyl-2-aminobenzoic acid CAS No.53589-27-8
  • HATU 6.1 g, 16.09 mmol, 1.2 eq.
  • Step 2 To a mixture of 5-acetyl-2-amino-N-(isoquinolin-4-yl)benzamide (375 mg, 1.23 mmol, 1.0 eq.) in THF (4 mL) was added DIEA (952 mg, 7.38 mmol, 6.0 eq.) and triphosgene (365 mg, 1.23 mmol, 1.0 eq.). The mixture was stirred at 25°C for 16 hrs. The mixture was quenched with saturated NaHCO 3 aqueous (15 mL), extracted with EtOAc (15 mL x 2).
  • Step 3 A solution of 6-acetyl-3-(isoquinolin-4-yl)quinazoline-2,4(1H,3H)-dione (106 mg, 0.35 mmol, 1.0 eq.) in BAST (2 mL) was stirred at 60°C for 16 hrs. The reaction was quenched with saturated NaHCO 3 aqueous (20 mL) and extracted with EtOAc (15 mL x 2).
  • Step 1 To a mixture of 5-bromo-N-(isoquinolin-4-yl)-2-nitrobenzamide (1.4 g, 3.76 mmol, 3.0 eq.), cyclopropylboronic acid (387 mg, 4.51 mmol, 1.2 eq.) and Cs 2 CO 3 (3.1 g, 9.40 mmol, 2.5 eq) in 1, 4-dioxane (8 mL) and H 2 O (2 mL) was added Pd(dppf)Cl 2 -CH 2 Cl 2 (307 mg, 376 ⁇ mol. 0.1 eq) under N 2 . The homogeneous reaction mixture was heated to 100°C for 16 h.
  • Step 2 To a mixture of 5-cyclopropyl-N-(isoquinolin-4-yl)-2-nitrobenzamide (400 mg, 1.20 mmol, 1 eq) in H 2 O (1 mL) and EtOH (5 mL) was added NH 4 Cl (321 mg, 6.00 mmol, 5.0 eq) at 25°C. The mixture was heated to 65°C, Fe powder (201 mg, 3.60 mmol, 3.0 eq) was added and the mixture stirred at 65°C for 4 hours. The mixture was poured into water (30 mL) and extracted with EtOAc (10 mL x 3).
  • Step 3 To a mixture of 2-amino-5-cyclopropyl-N-(isoquinolin-4-yl)benzamide (200 mg, 0.06 mmol, 1.0 eq) in 1,2-dichloroethane (2 mL) was added triphosgene (65 mg, 0.02 mmol, 0.3 eq) and DIEA (85 mg, 0.06 mmol, 3.0 eq) at 25°C and the mixture at 25°C for 12 hours. The reaction mixture was diluted with sat. NaHCO 3 (10 mL) and extracted with CH 2 Cl 2 (5 mL x 3). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give the crude product.
  • triphosgene 65 mg, 0.02 mmol, 0.3 eq
  • DIEA 85 mg, 0.06 mmol, 3.0 eq
  • Example 69 Synthesis of 1-((1H-tetrazol-5-yl)methyl)-3-(isoquinolin-4-yl)-6- (trifluoromethyl)quinazoline-2,4(1H,3H)-dione (69)
  • Step 1 A mixture of 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2) (150 mg, 0.42 mmol, 1.0 eq.) and K 2 CO 3 (116 mg, 0.84 mmol, 2.0 eq.) in DMF (2 mL) was cooled to 0°C, then 2-bromoacetonitrile (76 mg, 0.63 mmol, 1.5 eq) was added and the reaction mixture was stirred at 20°C for 2 hrs.
  • Step 2 To a mixture of 2-(3-(isoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl)acetonitrile (130 mg, 0.33 mmol, 1.0 eq.) and NaN 3 (21 mg, 0.33 mmol, 1.0 eq.) in DMF (1 mL) was added NH 4 Cl (1 mL) at 20°C. The result mixture was stirred at 120°C for 3 hrs. The solution was diluted with H 2 O (10 mL) and extracted with EtOAc (3x20 mL).
  • Example 70 Synthesis of 3-(1-aminoisoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)- dione (70)
  • Step 1 A mixture of 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2) (200 mg, 0.56 mmol, 1.0 eq.) in CH 2 Cl 2 (5 mL) was added m-CPBA (228 mg 1.12 mmol, 2.0 eq.) at 0°C. The mixture was stirred at 40°C for 16 hrs.
  • Step 2 To a mixture of 4-(2,4-dioxo-6-(trifluoromethyl)-1,4-dihydroquinazolin-3(2H)- yl)isoquinoline 2-oxide (160 mg, 0.43 mmol, 1.0 eq.) in pyridine (5 mL) was added TsCl (171 mg, 0.52 mmol, 1.2 eq.) at 0°C and stirred at 25°C for 30 min. NH2CH2CH2OH (657 mg, 10.75 mmol, 25.0 eq.) was added to the mixture at 25°C and the mixture stirred at 25°C for 16 hrs.
  • Example 71 Synthesis of 1-(3-hydroxy-3-methylbutyl)-3-(isoquinolin-4-yl)-6- (trifluoromethyl)quinazoline-2,4(1H,3H)-dione (71)
  • 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2) 200 mg, 0.55 mmol, 1.0 eq.
  • 3-hydroxy-3-methylbutyl 4- methylbenzenesulfonate (723 mg, 2.79 mmol, 5.0 eq.) and Cs 2 CO 3 (358 mg, 1.10 mmol, 2.0 eq.) and NaI (24 mg, 0.16 mmol, 0.3 eq.) at 25°C under N 2 .
  • 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate was obtained using the following procedure: To a mixture of 3-methylbutane-1,3-diol (2.0 g, 19.20 mmol, 1.0 eq.) in Pyridine (20 mL) was added 4-methylbenzenesulfonyl chloride (3.6 g, 19.20 mmol, 1.0 eq.) at 0°C under N 2 . The reaction mixture was stirred at 25°C for 16 hrs. The mixture was diluted with saturated NH 4 Cl aqueous (30 mL) and extracted with CH 2 CI 2 (20 mL x 2).
  • Example 72 Synthesis of 3-(isoquinolin-4-yl)-1-(oxiran-2-ylmethyl)-6- (trifluoromethyl)quinazoline-2,4(1H,3H)-dione (72)
  • 3-(isoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (2) 200 mg, 0.56 mmol, 1.0 eq
  • Cs 2 CO 3 365 mg, 1.12 mmol, 2.0 eq
  • 2- (bromomethyl)oxirane 77 mg, 0.56 mmol, 1.0 eq.
  • reaction mixture was stirred for 12 hrs at 20°C.
  • the reaction was poured into water (20 mL) and extracted with EtOAc (20 mL x 2). The organic phases were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated to give crude product.
  • Step 1 To a mixture of 4-chloro-2-nitrobenzoic acid (Int-AA5) (2.00 g, 9.92 mmol, 1.3 eq) and (COCl) 2 (1.64 g, 12.90 mmol, 1.13 mL, 1.7 eq) in CH 2 Cl 2 (12 mL) was added DMF (0.1 mL) at 0 °C under N 2 . The mixture was stirred at 20°C for 1 h.
  • Int-AA5 4-chloro-2-nitrobenzoic acid
  • (COCl) 2 1.64 g, 12.90 mmol, 1.13 mL, 1.7 eq
  • reaction mixture was concentrated to get crude product which was dissolved with THF (12 mL), K2CO3 (1.15 g, 8.33 mmol, 1.2eq), DMAP (896 mg, 694.11 ⁇ mol, 0.1eq) and then isoquinolin-4-amine (1.00 g, 6.94 mmol, 1eq) was added.
  • the mixture was stirred at 65°C for 2 hrs.
  • the mixture was cooled to 25 °C, poured into ice-water (20 mL) and stirred for 3 min.
  • the aqueous phase was extracted with ethyl acetate (20 mL x 3).
  • Step 2 To a mixture of 4-chloro-N-(isoquinolin-4-yl)-2-nitrobenzamide (1 g, 3.05 mmol, 1 eq) in H 2 O (2 mL) and EtOH (10 mL) was added NH 4 Cl (816 mg, 15.26 mmol, 5 eq) in one portion at 25°C. The mixture was heated to 65°C and Fe powder (511 mg, 9.15 mmol, 3 eq) was added. Then the mixture was stirred at 65°C for 4 hours. The mixture was poured into water (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give crude product.
  • Example 74 Synthesis of 6-chloro-3-(isoquinolin-4-yl)quinazoline-2,4(1H,3H)-dione (74)
  • Step 1 To a mixture of triphosgene (576 mg, 0.02 mmol, 3.0 eq.) was added to a suspension of 2-amino-5-chlorobenzoic acid (Int-AA6) (1 g, 0.06 mmol, 3.0 eq.) in 1,4- dioxane (10 mL) at 0°C. The homogeneous reaction mixture was heated to 90°C for 2 hrs.
  • Triphosgene 576 mg, 0.02 mmol, 3.0 eq.
  • 1,4- dioxane 10 mL
  • Step 2 A mixture of 6-chloro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (1.0 g, 5.06 mmol, 1.0 eq.) and isoquinolin-4-amine (700 mg, 5.06 mmol, 1.0 eq.) in H 2 O (20 mL) was stirred at 80°C for 6 hrs. The solution was poured into water (30 mL) and extracted with EtOAc (40 mL x 2).
  • Step 3 A mixture of 2-amino-5-chloro-N-(isoquinolin-4-yl)benzamide (100 mg, 0.33mmol, 3.0 eq.), triphosgene (34 mg, 0.11 mmol, 1.0 eq.) and DIEA (15 mg, 0.11 mmoL, 1.0 eq) in CH 2 Cl 2 (5 mL) was stirred at 25°C for 10 hrs. The solution was poured into water (40 mL) and extracted with EtOAc (40 mL x 2). The organic phase was washed with water (40 mL), brine (40 mL), dried over Na 2 SO 4 , filtered and concentrated to give crude product.
  • Step 1 To a stirred solution of methyl 3-oxocyclopentane-1-carboxylate (5.0 g, 35.17 mmol, 1.0 eq.) in toluene (50 mL) was added ethane-1,2-diol (4.4 g, 70.35 mmol, 2.0 eq.) and TsOH (0.3 g, 1.76 mmol, 0.05 eq.) at 25°C. The mixture was stirred at 140°C for 4 hrs (water removal by Dean–Stark). The reaction mixture was evaporated under reduced pressure to give a residue.
  • ethane-1,2-diol 4.4 g, 70.35 mmol, 2.0 eq.
  • TsOH 0.3 g, 1.76 mmol, 0.05 eq.
  • Step 2 LiAlH 4 (0.9 g, 22.56 mmol, 1.2 eq.) was added dropwise to a stirred solution of methyl 1,4-dioxaspiro[4.4]nonane-7-carboxylate (3.5 g, 18.80 mmol, 1.0 eq.) in THF (50 mL) at 0°C under a N 2 atmosphere and the mixture stirred at 25°C for 3 hrs. The reaction mixture was cooled to 0°C, quenched with H 2 O (2 mL), aqueous NaOH (10%, 10 mL) and stirred at 25°C for 10 mins.
  • Step 3 Under N2 flow and at 0°C, Tf2O (3.2 g, 11.38 mmol, 1.2 eq.) was added to a solution of (1,4-dioxaspiro[4.4]nonan-7-yl)methanol (1.5 g, 9.48 mmol, 1.0 eq.) and pyridine (1.5 g, 18.96 mmol, 1.2 eq.) in CH 2 Cl 2 (30 mL). The reaction mixture was stirred for 0.5 hrs at 0°C. The mixture was quenched with water (30 mL). The aqueous layer was separated from the organic and extracted with CH 2 Cl 2 (5 mL x 2).
  • Step 4 At -30°C, TMAF (1.1 g, 11.38 mmol, 1.2 eq.) was added to a solution of (1,4- dioxaspiro[4.4]nonan-7-yl)methyl trifluoromethanesulfonate (1.5 g, 9.48 mmol, 1.0 eq.) and TMSCF 3 (4.0 g, 28.45 mmol, 3.0 eq.) in DME (50 mL). The reaction mixture was stirred for 0.5 hrs at -30°C and then at 0°C for 1.5 hrs. The mixture was then stirred for 16 hrs at 25°C. The mixture was quenched with water (100 mL).
  • Step 5 At 25°C, HCl (0.5 mL, 2 M) was added to a solution of 7-(2,2,2-trifluoroethyl)-1,4- dioxaspiro[4.4]nonane (100 mg, 0.47 mmol, 1.0 eq.) in EtOAc (1.5 mL). The reaction mixture was stirred at 25°C for 16 hrs. The mixture was quenched with NaHCO3 (10 mL). The aqueous layer was separated from the organic phase and extracted with EtOAc (2 mL x 3). The combined organic solutions were dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure to give 3-(2,2,2-trifluoroethyl)cyclopentan-1-one.
  • Step 6 To a solution of 3-(2,2,2-trifluoroethyl)cyclopentan-1-one (150 mg, 0.90 mmol, 1.0 eq.) in THF (2 mL) was added LiHMDS (1.08 mL, 1.08 mmol, 1.2 eq.) at -70°C under N 2 . The mixture was stirred at -70°C for 0.5 hrs under N 2 . NCCOOEt (99 mg, 0.99 mmol, 1.1 eq.) was added to at -70°C under N 2 and the mixture stirred at -70°C for 1 hr under N 2 .
  • Step 7 To a solution of the mixture of ethyl 2-oxo-4-(2,2,2-trifluoroethyl)cyclopentane-1- carboxylate and ethyl 2-oxo-5-(2,2,2-trifluoroethyl)cyclopentane-1-carboxylate (100 mg, 0.42 mmol, 1.0 eq.) in MeOH (2 mL) was added NH 4 OAc (324 mg, 4.20 mmol, 10.0 eq.) at 25°C and the mixture stirred at 50°C for 2 hrs. The mixture was concentrated to give a residue which was suspended in saturated NaHCO 3 solution (10 mL) and extracted with EtOAc (5 mL ⁇ 3).
  • Step 8 To a mixture of ethyl 2-amino-4-(2,2,2-trifluoroethyl)cyclopent-1-ene-1-carboxylate and ethyl 2-amino-5-(2,2,2-trifluoroethyl)cyclopent-1-ene-1-carboxylate (50 mg, 0.21 mmol, 1.0 eq.) and TEA (64 mg, 0.63 mmol, 3.0 eq.) in DCE (0.5 mL) was added drop-wise a solution of triphosgene (31 mg, 0.11 mmol, 0.5 eq.) in DCE (0.5 mL) at 0°C. The mixture was stirred at 25°C for 2 hrs.
  • Step 9 To a mixture of ethyl 2-(3-(isoquinolin-4-yl)ureido)-4-(2,2,2-trifluoroethyl)cyclopent-1- ene-1-carboxylate and ethyl 2-(3-(isoquinolin-4-yl)ureido)-5-(2,2,2-trifluoroethyl)cyclopent-1-ene- 1-carboxylate (100 mg, crude) in MeOH (2 mL) was added K 2 CO 3 (100 mg, 0.49 mmol, 2.0 eq.) at 0°C. The mixture was stirred at 25°C for 16 hrs.
  • Peak 1 3-(isoquinolin-4-yl)-6-(2,2,2-trifluoroethyl)-1,5,6,7-tetrahydro-2H- cyclopenta[d]pyrimidine-2,4(3H)-dione.
  • Peak 2 3-(isoquinolin-4-yl)-5-(2,2,2-trifluoroethyl)-1,5,6,7-tetrahydro-2H- cyclopenta[d]pyrimidine-2,4(3H)-dione.
  • Step 10 To a mixture of 3-(isoquinolin-4-yl)-5-(2,2,2-trifluoroethyl)-1,5,6,7-tetrahydro-2H- cyclopenta[d]pyrimidine-2,4(3H)-dione (30 mg, 0.08 mmmol, 1.0 eq.) and Cs 2 CO 3 (54 mg, 0.16 mmmol, 2.0 eq.) in DMF (1 mL) was added 2-bromoacetonitrile (15 mg, 0.12 mmmol, 1.5 eq.). The reaction mixture was stirred at 25°C for 16 hrs.
  • Step 1 To a solution of methyl 2-fluoro-5-(trifluoromethyl)benzoate (Int-AA8) (1.0 g, 4.50 mmol, 1.0 eq.), (1-aminocyclopropyl)methanol (508 mg, 5.86 mmol, 1.5 eq.) in NMP (10 mL) was added K 2 CO 3 (1.2 g, 0.90 mmol, 2.0 eq.). The mixture was stirred at 100 °C for 2 hrs under N 2 . The reaction mixture was diluted with H 2 O (20 mL) and extracted with ethyl acetate (15 mL ⁇ 3).
  • Step 4 The solution of 2-((1-(cyanomethyl)cyclopropyl)amino)-5-(trifluoromethyl)benzoic acid (210 mg, 0.74 mmol, 1.0 eq.) and isoquinolin-4-amine (127mg, 0.88 mmol, 1.2 eq.) in MeCN (5 mL) was added TCFH (250 mg, 0.88 mmol, 1.2 eq.) and NMI (240 mg, 2.22 mmol, 3.0 eq.) at 25°C under N 2 . The solution was stirred at 45°C for 1.5 hrs. The reaction was quenched with H 2 O (10 mL) and extracted with EtOAc (20 mL ⁇ 2).
  • Step 5 To a solution of 2-((1-(cyanomethyl)cyclopropyl)amino)-N-(isoquinolin-4-yl)-5- (trifluoromethyl)benzamide (100 mg, 0.50 mmol, 1.0 eq.) in DMF (2 mL) was added CDI (80 mg, 1.01 mmol, 2.0 eq.) and CDT (80 mg, 1.01 mmol, 2.0 eq.). The mixture was stirred at 120°C for 0.5 hr. The reaction mixture was concentrated to dryness to give a residue.
  • CDI 80 mg, 1.01 mmol, 2.0 eq.
  • CDT 80 mg, 1.01 mmol, 2.0 eq.
  • Example 77 Synthesis of ⁇ (1M or 1P)-[(3M)-3-(5-Fluoroisoquinolin-4-yl)-2,4-dioxo-6- (trifluoromethyl)-3,4-dihydroquinazolin-1(2H)-yl]cyclopropyl ⁇ acetonitrile (77a) and ⁇ (1M or 1P)-[(3P)-3-(5-Fluoroisoquinolin-4-yl)-2,4-dioxo-6-(trifluoromethyl)-3,4- dihydroquinazolin-1(2H)-yl]cyclopropyl ⁇ acetonitrile (77b) Step 1: To a solution of 2-((1-(cyanomethyl)cyclopropyl)amino)-5-(trifluoromethyl)benzoic acid (500 mg, 1.76 mmol, 1.0 eq.) and 5-fluoroisoquinolin-4-amine
  • Step 2 To a solution of 2-((1-(cyanomethyl)cyclopropyl)amino)-N-(5-fluoroisoquinolin-4-yl)-5- (trifluoromethyl)benzamide (150 mg, 0.35 mmol, 1.0 eq.), CDI (142 mg, 0.88 mmol, 2.5 eq.) and CDT (144 mg, 0.88 mmol, 2.5 eq.) in NMP (10 mL) was added DBU (160 mg, 1.05 mmol, 3.0 eq.) at 25°C. The mixture was stirred at 25°C for 16 hrs under N 2 .
  • Step 1 To a mixture of ethyl 2-amino-5-(trifluoromethyl)cyclohex-1-ene-1-carboxylate (Int-A7) (3.6 g, 15.10 mmol, 1.0 eq.) and Et 3 N (4.6 g, 45.30 mmol, 3.0 eq.) in DCE (150 mL) was added dropwise a solution of triphosgene (2.2 g, 7.55 mmol, 0.5 eq.) in DCE (15 mL) at 0°C. The mixture was stirred at 0°C for 2 hrs.
  • Int-A7 ethyl 2-amino-5-(trifluoromethyl)cyclohex-1-ene-1-carboxylate
  • Et 3 N 4.6 g, 45.30 mmol, 3.0 eq.
  • Step 2 Racemic 3-(5-fluoroisoquinolin-4-yl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroquinazoline- 2,4(1H,3H)-dione (5.5 g, 14.50 mmol) was separated by chiral SFC (DAICEL CHIRALPAK AD (250mmx50mm, 10 ⁇ m); mobile phase: [0.1% NH 3 H 2 O EtOH]; B%: 30%-30%, 8 min) to obtain four peaks.
  • t R2 3.239 min.
  • t R3 3.682 min.
  • t R4 3.859 min.
  • Peak 1: LCMS Method 12): t R 0.664 min, [M+1] + 380.1.
  • SFC (column: DAICEL CHIRALPAK AD (150mmx4.6mm, 3 ⁇ m); mobile phase: A: CO 2 , B: EtOH(0.1% IPAm); 10%B for 0.5 min., 10- 50%B, over 3.0 min., 50%B for 1.0 min.
  • Peak 2: LCMS (Method 12): t R 0.657 min, [M+1] + 380.1.
  • Step 3a To a solution of the compound from Peak 1 (127 mg, 0.33 mmol, 1.0 eq.) in DMF (8 mL) was added Cs 2 CO 3 (109 mg, 0.33 mmol, 1.0 eq.), NaI (5 mg, 0.03 mmol, 0.1 eq.) and (1- cyanocyclopropyl)methyl 4-methylbenzenesulfonate (127 mg, 0.50 mmol, 1.5 eq.) at 20°C. The reaction was stirred at 40°C under N 2 for 8 hrs.
  • reaction mixture was quenched with saturated aqueous HCl (0.5 M, 80 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated to give crude product.
  • the crude was purified by prep-HPLC (column: Waters Xbridge BEH C18100mmx30mm, 10 ⁇ m; liquid phase: [A:10 mM NH 4 HCO 3 in H 2 O; B:ACN] B%: 35%-55%, 8 min]) to obtain 1- ⁇ [(3M,6R or 6S)-3-(5-Fluoroisoquinolin-4-yl)-2,4-dioxo-6- (trifluoromethyl)-3,4,5,6,7,8-hexahydroquinazolin-1(2H)-yl]methyl ⁇ cyclopropane-1-carbonitrile (78a)-Peak 1a.
  • Step 3b To a solution of the compound from Peak 2 (150 mg, 0.40 mmol, 1.0 eq.) in DMF (8 mL) was added Cs 2 CO 3 (130 mg, 0.40 mmol, 1.0 eq.), NaI (6 mg, 0.04 mmol, 0.1 eq.) and (1- cyanocyclopropyl)methyl 4-methylbenzenesulfonate (127 mg, 0.50 mmol, 1.5 eq.) at 20°C. The reaction was stirred at 40°C under N 2 for 7 hrs. The reaction mixture was quenched with saturated aqueous HCl (0.5 M, 80 mL), extracted with ethyl acetate (30 mL x 3).
  • Step 3c To a solution of the compound from Peak 3 (150 mg, 0.40 mmol, 1.0 eq.) in DMF (8 mL) was added Cs 2 CO 3 (130 mg, 0.40 mmol, 1.0 eq.), NaI (6 mg, 0.04 mmol, 0.1 eq.) and (1- cyanocyclopropyl)methyl 4-methylbenzenesulfonate (150 mg, 0.60 mmol, 1.5 eq.) at 20°C. The reaction was stirred at 40°C under N 2 for 7 hrs. The mixture was quenched with saturated aqueous HCl (0.5 M, 80 mL), extracted with ethyl acetate (30 mL x 3).
  • Step 3d To a solution of the compound from Peak 4150 mg, 0.40 mmol, 1.0 eq.) in DMF (8 mL) was added Cs 2 CO 3 (130 mg, 0.40 mmol, 1.0 eq.), NaI (6 mg, 0.04 mmol, 0.1 eq.) and (1- cyanocyclopropyl)methyl 4-methylbenzenesulfonate (150 mg, 0.60 mmol, 1.5 eq.) at 20°C. The reaction was stirred at 40°C under N 2 for 7 hrs. The mixture was quenched with saturated aqueous HCl (0.5 M, 80 mL), extracted with ethyl acetate (30 mL x 3).
  • Example 79 Synthesis of (3M)-3-(5-Fluoroisoquinolin-4-yl)-6-(trifluoromethyl)quinazoline- 2,4(1H,3H)-dione (79a) and (3P)-3-(5-Fluoroisoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione
  • Step 1 To a solution of 5-fluoroisoquinolin-4-amine (Int-B6) (400 mg, 2.47 mmol, 1.0 eq.) and pyridine (598 mg, 7.41 mmol, 3.0 eq.) in CH 2 Cl 2 (10 mL) was added dropwise phenyl carbonochloridate (966 mg, 6.17 mmmol, 2.5 eq.) at 0°C under N 2 .
  • Step 2 To a mixture of NaH (74 mg, 1.86 mmol, 1.5 eq.) in DMF (5 mL) was added dropwise a solution of methyl 2-amino-5-(trifluoromethyl)benzoate (int-A6) (544 mg, 2.48 mmol, 2.5 eq.) in DMF (2 mL) at 0°C under N 2 . The mixture was stirred at 25°C for 1 hr. Then a solution of phenyl (5-fluoroisoquinolin-4-yl)(phenoxycarbonyl)carbamate (400 mg, 0.10 mmol, 1.0 eq.) in DMF (5 mL) was added dropwise to the system at 0°C under N 2 .
  • int-A6 methyl 2-amino-5-(trifluoromethyl)benzoate
  • the reaction was stirred at 25°C under N 2 for 15 hrs.
  • the reaction mixture was diluted with aq. NH 4 Cl (60 mL) and extracted with EtOAc (30 mL x 3). The organic layers were washed with brine (50 mL), dried over Na 2 SO 4 and concentrated to give a residue.
  • Step 3 Racemic 3-(5-fluoroisoquinolin-4-yl)-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250mmx30mm,10 ⁇ m); IPA (0.1%NH 3 .
  • SFC (column: DAICEL CHIRALPAK AD (150mmx4.6mm, 3 ⁇ m); mobile phase: A: CO 2 , B: IPA(0.1% IPAm); 10%B for 0.5 min., 10- 50%B, over 3.0 min., 50%B for 1.0 min.
  • Step 2 A mixture of methyl 2-amino-5-bromo-4-fluorobenzoate (2.0 g, 8.06 mmol, 1.0 eq.) and 4-isocyanatoisoquinoline (Int-B8) (1.37g, 8.06 mmol, 1.0 eq.) in pyridine (20 mL) was stirred at 100°C for 16 hrs. The reaction mixture was quenched with H 2 O (20 mL) and extracted with ethyl acetate (20 mL x 3).
  • Step 3 To a mixture of 6-bromo-7-fluoro-3-(isoquinolin-4-yl)quinazoline-2,4(1H,3H)-dione (400 mg, 0.36 mmol, 1.0 eq.), cyclopropylboronic acid(48 mg, 1.55 mmol, 1.5 eq.) and K 2 PO 4 (158 mg, 0.04 mmol, 0.1 eq.) in toluene (5 mL) and H 2 O (0.5 mL) was added Sphos (16 mg, 0.04 mmol, 0.1 eq.) and Pd 2 (dba) 3 (37 mg, 0.04 mmol, 0.1 eq.) under N 2 .
  • Example 81 Synthesis of 6-cyclopropyl-7-fluoro-3-(isoquinolin-4-yl)-1-methylquinazoline- 2,4(1H,3H)-dione (81) Step 1: To a mixture of 6-bromo-7-fluoro-3-(isoquinolin-4-yl)quinazoline-2,4(1H,3H)-dione (140 mg, 0.36 mmol, 1.0 eq.) and K 2 CO 3 (150 mg, 1.09 mmol, 3.0 eq.) in DMF (2 mL) was added MeI (77 mg, 0.54 mmol, 1.5 eq.). The mixture was stirred at 0°C for 2 hrs.
  • Step 2 To a mixture of 6-bromo-7-fluoro-3-(isoquinolin-4-yl)-1-methylquinazoline-2,4(1H,3H)- dione (120 mg, 0.30 mmol, 1.0 eq.), cyclopropylboronic acid (39 mg, 0.45 mmol, 1.5 eq.) and K 2 PO 4 (65 mg, 0.03 mmol, 2.5 eq.) in toluene (2 mL) and H 2 O (0.2 mL) was added sphos (13 mg, 0.03 mmol, 0.1 eq.) and Pd 2 (dba) 3 (28 mg, 0.03 mmol, 0.1 eq.).

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Abstract

L'invention concerne des composés de formule (I) et des compositions pour le traitement, la gestion ou la prévention de maladies associées au coronavirus. En particulier, l'invention concerne des composés dione cycliques qui sont des inhibiteurs de la protéase principale du SARS-CoV-2 (M), des compositions pharmaceutiques comprenant de tels composés, un procédé de synthèse de tels composés et des procédés d'utilisation de tels composés et compositions pour le traitement, la gestion ou la prévention de maladies associées au coronavirus.
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WO2020063982A1 (fr) * 2018-09-29 2020-04-02 山东先达农化股份有限公司 Composé contenant un fragment de quinazolinedione, son procédé de préparation, son utilisation et herbicide
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