WO2022195522A1 - Inhibiteurs de l'ano6 et leurs utilisations - Google Patents

Inhibiteurs de l'ano6 et leurs utilisations Download PDF

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Publication number
WO2022195522A1
WO2022195522A1 PCT/IB2022/052412 IB2022052412W WO2022195522A1 WO 2022195522 A1 WO2022195522 A1 WO 2022195522A1 IB 2022052412 W IB2022052412 W IB 2022052412W WO 2022195522 A1 WO2022195522 A1 WO 2022195522A1
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WIPO (PCT)
Prior art keywords
mmol
compound
ring
amino
amine
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PCT/IB2022/052412
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English (en)
Inventor
Changmok OH
Sungwook Kwon
Dami LIM
Eunjung Lee
Seolhee LEE
Hongchul Yoon
Kyung Mi An
Joontae Park
Sung Min Cho
Won Gu Choi
Min Goo Lee
Jae Myun Lee
Wan Namkung
Jungwoo Lee
Original Assignee
Ildong Pharmaceutical Co., Ltd.
Uif (University Industry Foundation), Yonsei University
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Application filed by Ildong Pharmaceutical Co., Ltd., Uif (University Industry Foundation), Yonsei University filed Critical Ildong Pharmaceutical Co., Ltd.
Publication of WO2022195522A1 publication Critical patent/WO2022195522A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links
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    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
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Definitions

  • the present invention relates to compounds capable of inhibiting anoctamin 6 (AN06) protein, compositions comprising the compounds, methods for preparing the compounds, and methods of using the compounds or compositions. More particularly, the present invention relates to using the compounds or compositions to treat virus infection.
  • AN06 anoctamin 6
  • Coronaviruses are enveloped RNA viruses that deliver their viral genome into the host cells by fusing the viral envelope with the host cell membrane.
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), belongs to the b-coronavirus genera and has the spike (S) glycoprotein, a class I viral fusion protein, on the virion envelope.
  • SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
  • SARS-CoV-2 the causative agent of coronavirus disease 2019 (COVID-19)
  • S spike glycoprotein
  • P. V’Kovski A. Kratzel, S. Steiner, H. Stalder, V. Thiel, Nat Rev Microbiol 19, 155 (2021); Gordon, D.E., Jang, G.M., Bouhaddou, M. et al, Nature 583, 459-468 (2020).
  • the SARS-CoV-2 S protein is the primary determinant of cell tropism and mediates binding to angiotensin-converting enzyme 2 (ACE2), the viral entry receptor on the host cells, which constitutes the initial step of the membrane fusion process.
  • ACE2 angiotensin-converting enzyme 2
  • the viral and host cell membrane fusion process is not yet fully understood.
  • AN06 also known as TMEM16F, is a cell membrane protein functioning as a Ca 2+ - activated CT channel (CACC) and Ca 2+ -dependent phospholipid scramblase.
  • CACC Ca 2+ - activated CT channel
  • Ca 2+ -dependent phospholipid scramblase H. Yang, A.
  • PS Phosphatidylserine
  • This cell surface extemalization of PS is mediated by the inactivation of lipid flippases that build membrane PS asymmetry, or by the activation of phospholipid scramblases, such as AN06, that enhance the translocation of anionic phospholipids.
  • a number of studies have shown that the cell surface exposure of PS is associated with membrane fusion events not only between mammalian cell membranes, such as myotube formation, but also between the viral envelope and host cell membrane, which enhances the virus entry into host cells.
  • AN06-mediated PS externalization is involved in coronavirus entry into host cells.
  • enveloped viruses e.g., SARS-CoV-2
  • AN06 inhibition is effective against the enveloped virus infection.
  • Aliphatic hydrocarbon compounds are saturated or unsaturated hydrocarbons based on chains of carbon atoms. They include alkyl, alkenyl, and alkynyl compounds, and their derivatives.
  • alkyl when used alone or as part of a larger moiety such as “arylalkyl,” or “cycloalkyl” refers to a straight- or branch-chained, saturated hydrocarbon containing a certain number of carbon atoms (e.g, 1-14 carbon atoms, 1-10 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms).
  • C 1 -C 6 alkyl refers to alkyl having 1 to 6 carbon atoms and is intended to include Ci, C 2 , C 3 , C 4 , C 5 , Ce alkyl groups.
  • alkyl groups include methyl (Me), ethyl (Et), propyl (e.g, «-propyl and iso propyl), butyl (e.g, «-butyl, .vo-butyl, /-butyl), and pentyl (e.g, «-pentyl, /50-pentyl, neo pentyl), as well as chain isomers thereof.
  • alkenyl when used alone or as part of a larger moiety such as “arylalkenyl,” or “cycloalkenyl” refers to a straight- or branch-chained hydrocarbon containing one or more double bonds and containing a certain number of carbon atoms (e.g., 2-14 carbon atoms, 2-10 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms).
  • C2-C6 alkenyl refers to alkenyl having 2 to 6 carbon atoms and is intended to include C2, C3, C4, C5, Ce alkenyl groups.
  • Non-limiting examples of alkenyl groups include ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl, and the like, as well as chain isomers thereof.
  • alkynyl when used alone or as part of a larger moiety such as “arylalkynyl” or “cycloalkynyl” refers to a straight- or branch-chained hydrocarbon containing one or more triple bonds and containing a certain number of carbon atoms ( e.g ., 2-14 carbon atoms, 2-10 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms).
  • C2-C6 alkynyl refers to alkynyl having 2 to 6 carbon atoms and is intended to include C2, C3, C4, C5, Ce alkynyl groups.
  • Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, 1 -methyl -2-butyn-l-yl, heptynyl, octynyl, and the like, as well as chain isomers thereof.
  • Cycloaliphatic hydrocarbon compounds are saturated or unsaturated hydrocarbons containing one (i.e., monocyclic) or more (i.e., polycyclic) non-aromatic rings of carbons. They include cycloalkyl, cycloalkenyl, and cycloalkynyl compounds, and their derivatives Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl, norbornyl,
  • hetero refers to the replacement of at least one carbon atom member in a ring system with at least one heteroatom such as nitrogen, sulfur, sulfoxide, sulfone, and oxygen.
  • heterocyclo aliphatic means an aliphatic compound having a non-aromatic monocyclic or polycyclic ring with a certain number of carbons (e.g, 2 to 20 carbon atoms, 2-15 carbon atoms, 2-10 carbon atoms, or 2-7 carbon atoms) in the ring and with one or more heteroatoms selected from nitrogen, oxidized nitrogen (e.g, NO and NO2), sulfur, oxidize sulfur (e.g, SO and SO2), and oxygen.
  • the ring or ring system of a heterocyclo aliphatic group of a compound can be linked or fused to one or more different moieties (rings) of the compound via a carbon atom or a heteroatom of the ring.
  • the different ring include a substituted or unsubstituted cycloaliphatic, hetero cycloaliphatic, aromatic, and hetero aromatic ring.
  • a bridged ring may occur when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
  • aromatic refers to aromatic monocyclic or polycyclic groups. It includes carbocyclic aromatic groups (e.g ., phenyl, naphthyl, and the like) and heteroaromatic groups (e.g., pyridyl, pyrimidinyl, and the like).
  • the ring or ring system of an aromatic or heterocyclo aromatic group of a compound can be linked or fused to one or more different moieties (rings) of the compound via at least one carbon atom and/or at least one heteroatom of the ring, which results in fused rings (sharing two adjacent atoms), bridged rings (sharing two non-adjacent atoms), and spiro rings (sharing one atom).
  • Non limiting examples of the different ring include a substituted or unsubstituted cycloaliphatic, hetero cycloaliphatic, aromatic, and hetero aromatic ring.
  • an aliphatic ring may be fused with an aromatic ring, as illustrated below.
  • the arrowed lines drawn from the illustrated ring system indicate that the bond may be attached to any of the suitable ring atoms.
  • a bridged ring may occur when one or more atoms (e.g, C, O, N, or S) link two non- adjacent carbon, two non-adjacent heteroatoms, or one carbon and one heteroatom.
  • bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group.
  • heterocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiomorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-1,1- dioxothienyl, quinuclidinyl, pyridyl, pyrimidinyl,
  • alkoxy refers to the alkyl groups above bound through oxygen, examples of which include methoxy, ethoxy, /.vo-propoxy, tert- butoxy, and the like.
  • alkoxy also refers to polyethers such as -0-(03 ⁇ 4) 2 -0-(2H 3 , and the like.
  • hydroxyalkyl refers to any hydroxyl derivative of alkyl radical.
  • hydroxyalkyl includes any alkyl radical having one or more hydrogen atoms replaced by a hydroxy group.
  • aryl aliphatic refers to aliphatic hydrocarbon compounds having one or more hydrogen atoms replaced by an aryl group.
  • arylalkyl or “alkylaryl” includes any alkyl radical having one or more hydrogen atoms replaced by an aryl group, e.g ., a benzyl group, a phenethyl group, and the like.
  • arylalkenyl includes any alkenyl radical having one or more hydrogen atoms replaced by an aryl group.
  • arylalkynyl includes any alkynyl radical having one or more hydrogen atoms replaced by an aryl group.
  • aryl aliphatic is meant to include arylalkyl, arylalkenyl, and arylakynyl.
  • amine refers to a derivative of ammonia in which one, two, or all three hydrogen atoms are replaced by hydrocarbon groups including aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, and hetero aromatic.
  • alkyl amine or “amine alkyl” refers to ammonia derivative having one, two, or all three hydrogen atoms replaced by an alkyl group. Unless otherwise specified, the term herein includes cyclic amines as well primary, secondary, tertiary amines.
  • Non-limiting examples of amines include, but are not limited to, N(C2H5)2, N(CH3)2, N(C2H5)(benzyl), methyl piperazine, methyl piperidine, ethyl piperazine, and ethyl piperidine.
  • amide refers to a carbonyl group bonded to a nitrogen.
  • the simplest example is CONH2.
  • Non-limiting examples of amines include the ones in which one or two of the hydrogen atoms are replaced by other groups including aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, and hetero aromatic.
  • sulfhydryl refers to any organosulfur compound containing -SH group.
  • the compounds are in the form R-SH, wherein R represents an aliphatic, aromatic ring or other organic substituent.
  • R represents an aliphatic, aromatic ring or other organic substituent.
  • Aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, heteroaromatic, alkoxy, aryl aliphatic (e.g., arylalkyl), carboxyl, carbonyl, hydroxyl, amine, amide, thioalkyl, and sulfhydryl each independently can be unsubstituted or substituted with one or more suitable substituents.
  • Non-limiting examples of the substituents include halogen or halogen derivatives (e.g., F, Br, Cl, I, OCHF2, CF3, CHF2, or OCF3), alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hetero cycloalkyl, hetero cycloalkenyl, hetero cycloalkynyl, alkoxy, aryl, aryloxy, diaryl, arylalkyl, arylalkyloxy, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonyla
  • R x and R y each may be independently selected from hydrogen, alkyl, alkenyl, C3-C7 cycloalkyl, C 5 -C 11 aryl, benzyl, phenylethyl, naphthyl, a 3- to 7-membered heterocycloalkyl, and a 5- to 6-membered heteroaryl.
  • a “substituent” as used herein refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest.
  • a ring substituent may be a moiety such as a halogen, alkyl group, haloalkyl group or other group that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member.
  • Substituents of aromatic groups are generally covalently bonded to a ring carbon atom.
  • substitution refers to replacing a hydrogen atom in a molecular structure with a substituent, such that the valence on the designated atom is not exceeded, and such that a chemically stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity) results from the substitution.
  • the ring or group may be fully unsaturated or partially unsaturated.
  • substituents include, but are not limited to, halo, alkyl, haloalkyl, aryl, hydroxy, alkoxy, hydroxyalkyl, amino, and the like.
  • compound as used herein is meant to include all stereoisomers, geometric isomers, tautomers, isotopes, and prodrug of the chemical structures depicted.
  • the compounds herein described may have asymmetric centers, geometric centers (e.g., double bond), or both. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
  • the compounds described herein have one or more chiral centers. It is understood that if an absolute stereochemistry is not expressly indicated, then each chiral center may independently be of the R-configuration or the S- configuration or a mixture thereof.
  • compounds described herein include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions.
  • Racemic mixtures of R-enantiomer and S-enantiomer, and enantio-enriched stereometric mixtures comprising of R- and S-enantiomers, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.
  • optically active or racemic forms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or through use of chiral auxiliaries.
  • Geometric isomers resulting from the arrangement of substituents around a carbon- carbon double bond or arrangement of substituents around a cycloalkyl or heterocyclic ring, can also exist in the compounds of the present disclosure.
  • cis and trans geometric isomers of the compounds of the present disclosure may also exist and may be isolated as a mixture of isomers or as separated isomeric forms.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Examples of prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • prodrug refers to an agent which is converted into a biologically active drug in vivo by some physiological or chemical process.
  • a prodrug is converted to the desired drug form, when subjected to a biological system at physiological pH.
  • a prodrug is enzymatically converted to the desired drug form, when subjected to a biological system.
  • Prodrug forms of any of the compounds described herein can be useful, for example, to provide particular therapeutic benefits as a consequence of an extension of the half-life of the resulting compound in the body, or a reduction in the active dose required.
  • Pro-drugs can also be useful in some situations, as they may be easier to administer than the parent drug.
  • Prodrug forms or derivatives of a compound of this disclosure generally include a promoiety substituent at a suitable labile site of the compound.
  • the promoiety refers to the group that can be removed by enzymatic or chemical reactions, when a prodrug is converted to the drug in vivo.
  • the promoiety is a group (e.g., an optionally substituted Ci- 6 alkanoyl, or an optionally substituted Ci- 6 alkyl) attached via an ester linkage to a hydroxyl group or a carboxylic acid group of the compound or drug.
  • An aspect of the present invention provides a method for treating or preventing diseases, disorders, or conditions associated with virus infection.
  • the method comprises administering to a subject in need a composition containing a therapeutically effective amount of a compound that can inhibit AN06, a pharmaceutically acceptable salt of the compound, a solvate of the compound, or a hydrate of the compound.
  • Still another aspect of the present invention provides a method for disinfecting or sanitizing an object from virus contamination.
  • the method comprises contacting with or applying to an object a composition containing a therapeutically effective amount of a compound that inhibits AN06, a pharmaceutically acceptable salt of the compound, a solvate of the compound, or a hydrate of the compound.
  • the compound is represented by Formula (I).
  • Ring A and ring B each are independently a monocyclic aliphatic ring, a polycyclic aliphatic ring, a monocyclic aromatic ring, or a polycyclic aromatic ring, which optionally contains at least one heteroatom selected from the group consisting of N, NO, NO 2 , S, SO,
  • ring A and ring B each are optionally and independently substituted with at least one substituent selected from the group consisting of halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, ester, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, and aryl aliphatic.
  • substituent selected from the group consisting of halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, ester, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, and aryl aliphatic.
  • Ri and R 3 each are independently hydrogen, halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, or aryl aliphatic, wherein Ri and R 3 each are optionally and independently substituted with at least one substituent selected from the group consisting of halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, ester, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, and aryl aliphatic;
  • R 2 is hydrogen, C 1-5 alkyl or C 3-6 cycloalkyl.
  • Li and L2 each are independently C1-C1 0 aliphatic, C3-C10 cycloaliphatic, or C3-C10 hetero cycloaliphatic, wherein Li and L 2 each are optionally and independently substituted with at least one substituent selected from the group consisting of CN, C 1-5 alkyl, and C 3-6 cycloalkyl.
  • m and n each are independently 0 or 1.
  • the virus may be an RNA virus.
  • Non-limiting examples of the RNA virus may include Coronaviridae, Amalgaviridae, Birnaviridae, Chrysoviridae, Cystoviridae, Endomaviridae, Hypoviridae, Megabimaviridae, Partitiviridae, Picobimaviridae, Reoviridae, Totiviridae, Quadriviridae, Arteriviridae, Mesoniviridae, Roniviridae, Dicistroviridae, Iflaviridae, Marnaviridae, Piconaviridae, Secoviridae, Alphaflexiviridae, Betaflexiviridae, Gammaflexiviridae, Tymoviridae, Bomaviridae, Filoviridae, Paramyxoviridae, Phabdoviridae, Nyamiviridae, Caliciviridae, Flaviviridae, Luteovi
  • the diseases, disorders, or conditions associated with virus infection comprises cold, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19.
  • SARS severe acute respiratory syndrome
  • MERS Middle East respiratory syndrome
  • COVID-19 COVID-19.
  • a further aspect of the present invention provides a composition for treating or preventing diseases, disorders, or conditions associated with virus infection.
  • the composition contains a therapeutically effective amount of a compound that can inhibit AN06, a pharmaceutically acceptable salt of the compound, a solvate of the compound, or a hydrate of the compound.
  • a still further aspect of the present invention provides a composition for disinfecting or sanitizing an object from virus contamination.
  • the composition contains a therapeutically effective amount of a compound that inhibits AN06, a pharmaceutically acceptable salt of the compound, a solvate of the compound, or a hydrate of the compound.
  • FIG. 1 represents YFP fluorescence traces showing inhibition of AN06 activity of a compound in accordance with an embodiment of the present invention.
  • FIGS. 2A-2E represent results of measurements of AN06 Ca 2+ -activated ion channel and phospholipid scramblase activities.
  • FIGS 2A-2C show the inhibitory effect of a compound in accordance with an embodiment of the present invention on AN06 ion channel activity.
  • the pipette solution contained 10 mM free Ca 2+ Voltage ramps spanning a range of -100 to +100 mV were delivered from a holding potential of -60 mV every 20 s (FIG. 2A).
  • the current-voltage (I-V) relationships at indicated times (1-5) with increasing concentrations of the compound are shown in FIG. 2B.
  • the numbers in parentheses represent the time points to measure I-V relationships.
  • the inward currents in (A) represent AN06 tail currents.
  • 2D and 2E show the dose responses of a compound in accordance with an embodiment of the present invention on AN06 phospholipid scramblase inhibition.
  • FIGS. 3 A-3 J represent test results showing that AN06 is responsible for phosphatidylserine externalization evoked by pseudotyped SARS-CoV-2 S virus (SARS2- PsV).
  • SARS2- PsV pseudotyped SARS-CoV-2 S virus
  • HeLa cells expressing ACE2 HeLa-ACE2 were incubated with a lentivirus-based SARS2-PsV (100 ng p24/ml) for 15 min, and then with Lact-C2-mCherry for 45 min.
  • FIGS. 3A cytosolic Ca 2+
  • FIGS. 3E and 3F are test results showing that silencing of AN06 (siRNAs against AN06, 100 nM, 24 h) inhibits the phosphatidylserine (PS) externalization evoked by SARS2-PsV.
  • Cell nuclei were stained with DAPI.
  • FIG. 31 and 3J are test results showing that authentic SARS-CoV-2 virus evokes Ca 2+ and AN06-dependent PS externalization.
  • FIGS. 4A-4H represent mechanisms involved in the SARS-CoV-2 Spike-mediated PS- scrambling and membrane fusion.
  • FIGS. 4 A and 4B are test results showing that the trypsin inhibitor Camostat (100 pM, 1 h) inhibits the PS externalization evoked by SARS2-PsV, but not by trypsinized SARS2-PsV (trypsin 10 pg/ml, 10 min, 37°C).
  • trypsin 10 pg/ml, 10 min, 37°C trypsin 10 pg/ml, 10 min, 37°C.
  • 4G and 4H are time-lapse imaging of membrane fusion events (8 h, 20 frame/min) between the SARS-CoV-2 Spike-expressing CHO cells labelled with the membrane lipid probe Vybrant-DiO (CHO-Spike, green) and the cytosolic mCherry-labelled ACE2-expressing HEK 293T cells (HEK 293T-ACE2-TMPRSS2, red).
  • the expression of Spike induces the cell-cell adhesion and membrane fusion with ACE2-expressing cells.
  • a compound in accordance with an embodiment of the present invention abolishes the Spike- ACE2 interaction-mediated membrane fusion events, while it does not affect the cell-cell adhesion. Representative images are shown in FIG.
  • FIG. 4H Bar graph data are shown as the mean ⁇ SEM. *P ⁇ 0.05, **P ⁇ 0.01. Data were analyzed using one-way analysis of variance, followed by Tukey’s multiple comparison test. Scale bar: 50 pm.
  • FIGS. 5A-5L represent test results showing that the pseudotyped SARS-CoV-2 S virus (SARS2-PsV) evokes a sustained intracellular Ca 2+ elevation.
  • SARS2-PsV pseudotyped SARS-CoV-2 S virus
  • [Ca 2+ ]i was measured in HEK 293T cells expressing ACE2 and TMPRSS2 with a ratiometric Ca 2+ probe (Fura-2-AM, 5 pM, 30 min). Data are presented as fluorescence emission ratios from the 340/380 nm excitation. Representative [Ca 2+ ]i images with a rainbow scale and the [Ca 2+ ]i values of the indicated regions (arrows) are shown. The 0-second time represents the point of SARS2-PsV or vehicle application.
  • FIGS. 5A and 5B show test results for mock vehicle.
  • FIGS. 5C and 5D show test results for SARS2-PsV alone.
  • FIGS. 5E and 5F show test results for BAPTA pretreatment (BAPTA-AM, 3 pM) plus SARS2-PsV.
  • FIGS. 5G and 5H show test results for Camostat pretreatment (10 pM) plus SARS2-PsV.
  • FIGS. 51 and 5J show test results for a compound in accordance with an embodiment of the present invention pretreatment (10 pM) plus SARS2- PsV.
  • FIG. 5L represents a summary of the time taken to reach the [Ca 2+ ]i peak after SARS2-PsV application.
  • FIG. 5M represents a summary of the slope of the rising phase of [Ca 2+ ]i transients (D [Ca 2+ ]i/At, nM/s). **P ⁇ 0.01: difference from lane 2. n.s.: not significant. Data were analyzed using oneway analysis of variance, followed by Tukey’s multiple comparison test.
  • FIGS. 6A-6F represent test results showing that the single-round infection of pseudotyped SARS-CoV-2 S virus (SARS2PsV) is Ca 2+ - and AN06-dependent.
  • FIGS. 7A-7G represent test results showing that a compound in accordance with an embodiment of the present invention inhibits the viral replication of SARS-CoV-2 in Calu-3, Vero, and human nasal epithelial (HNE) cells.
  • FIGS. 7A and 7B are results of assaying viral replication of authentic SARS-CoV-2 (0.001 MOI) in Calu-3 cells.
  • the qPCR results of virion mRNAs with the indicated concentrations of the compound in accordance with an embodiment of the present invention are shown in FIG.
  • FIGS. 7C-7E are results of assaying viral replication of SARS-CoV-2 (0.001 MOI) in Vero cells.
  • the compound in accordance with an embodiment of the present invention dose-dependently reduced the virus-induced cytolysis (FIG. 7C, 48 h post infection, five independent experiments showed similar results, arrows indicate cytolytic cells).
  • FIGS. 7F and 7G are results of assaying viral replication of SARS-CoV-2 (1 MOI) in HNE cells.
  • the passage #2 HNE cells were cultured under air-liquid interface conditions and apically infected with SARS-CoV-2.
  • the compound in accordance with an embodiment of the present invention (10 mM) was administered to the basolateral compartments.
  • FIGS. 8A-8B represent expression of AN06 in FRT cells and effects of AN06 inhibitors on ANOl (FIG. 8 A) and AN02 (FIG. 8B).
  • FIGS. 9A-9C represent effects of AN06 inhibitors on cytosolic Ca 2+ levels, CFTR CT currents, and cell morphology.
  • Intracellular calcium ([Ca 2+ ]i) was monitored using the Fluo-4 NW calcium indicator.
  • the FRT cells were treated with the indicated concentrations of compounds for 10 min and then ionomycin (10 mM) was applied to evoke [Ca 2+ ]i elevation.
  • Representative traces of intracellular calcium responses pretreated with the compound in accordance with an embodiment of the present invention are shown in FIG. 9 A.
  • FIGS. 9B and 9C show effects of the compound in accordance with an embodiment of the present invention on CFTR CE channel activity.
  • the apical membrane short-circuit currents (Isc) were measured in FRT-CFTR cells cultured on a permeable support.
  • the basolateral membrane was permeabilized with amphotericin B (250 pg/ml).
  • CFTR was stimulated using forskolin (20 pM) and blocked by CFTRinh-172 (20 mM).
  • FIGS. 10A-10E represent additional test results supporting the test results represented by FIGS. 3 and 4.
  • FIG. 10A represents mRNA quantification of AN06/TMEM16F using qPCR. The AN06 expression levels in HEK-293T, HeLa, and HNE cells are shown.
  • FIG. 10B represents results of analyzing the silencing of AN06 mRNA via treatment with siRNAs against AN06 in HeLa- ACE2 cells and HEK 293 T - ACE2-TMPRS S2 cells using qPCR. Cells were treated with scrambled or AN06 siRNAs (100 nM in each case) for 24 h.
  • FIGS. 10A represents mRNA quantification of AN06/TMEM16F using qPCR. The AN06 expression levels in HEK-293T, HeLa, and HNE cells are shown.
  • FIG. 10B represents results of analyzing the silencing of AN06 mRNA via treatment with siRNAs against AN06 in HeLa-
  • IOC and 10D represent effects of Camostat on ionomycin (10 pM, 10 min)-induced PS scrambling.
  • FIG. 10E represents immunoblot analysis of the SARS-CoV-2 Spike glycoprotein.
  • the cell lysates of wild-type and R682S/R685G SARS-PsV infected HEK 293T cells were blotted with primary antibodies against the S2 domain of Spike and aldolase A.
  • the R682S/R685G mutant Spike proteins do not exhibit a protease cleaved form. Bar graph data are shown as the mean ⁇ SEM. Data were analyzed using a two-tailed Student’s t-test (B) or one-way analysis of variance followed by Tukey’s multiple comparison test (D). **P ⁇ 0.01, ns: not significant.
  • FIGS. 11 A-l IF represent test results showing the compound in accordance with an embodiment of the present invention does not affect the ATP -induced Ca 2+ response.
  • FIG. 10D and 10E Representative traces are shown in FIG. 10D and 10E, respectively.
  • FIGS. 12A-12C represent effects of the compound in accordance with an embodiment of the present invention on the viral replication of wild-type SARS-CoV-2 in Vero cells.
  • FIGS. 12A and 12B represent viral replication of SARS-CoV-2 in Vero cells with an infection dose of 0.01 MOI (ten times higher than that of FIGS. 7C-7E).
  • the compound in accordance with an embodiment of the present invention dose-dependently reduced the virus-induced cytolysis (FIG. 12A, 48 h post-infection, two independent experiments showed similar results. Arrows indicate cytolytic cells.).
  • Vero cells were infected with SARS-CoV-2 (0.01 MOI), and cellular viral RNAs were quantified using qPCR at 4 h post-infection (FIG. 12C).
  • Ct threshold cycle
  • GAPDH glyceraldehyde 3-phosphate dehydrogenase. Bar graph data are shown as the mean ⁇ SEM.
  • FIGS. 13A-13D represent analysis results of cell viability of the compound in accordance with an embodiment of the present invention.
  • FRT cells FIG. 13 A
  • Calu-3 cells FIGG. 13B
  • Vero cells FIGG. 13C
  • Cisplatin 50 mM
  • the CC 50 the half-maximal cytotoxic concentration) values are summarized in FIG. 13D.
  • An aspect of the present invention provides a method for treating or preventing diseases, disorders, or conditions associated with virus infection.
  • the method comprises administering to a subject in need a composition comprising a therapeutically effective amount of a compound that can inhibit AN06 or, a pharmaceutically acceptable salt thereof, a diastereomer thereof, an enantiomer thereof, a racemate thereof, a solvate thereof, a hydrate thereof, a prodrug thereof, a crystalline thereof, or a combination thereof.
  • Still another aspect of the present invention provides a method for disinfecting or sanitizing an object from virus contamination.
  • the method comprises contacting with or applying to an object a composition containing a therapeutically effective amount of a compound that inhibits AN06, a pharmaceutically acceptable salt thereof, a diastereomer thereof, an enantiomer thereof, a racemate thereof, a solvate thereof, a hydrate thereof, a prodrug thereof, a crystalline thereof, or a combination thereof.
  • the compound inhibits AN06 phospholipid scramblase activity and reduce phosphatidyl serine (PS) externalization.
  • PS phosphatidyl serine
  • the compound or salt can inhibit the entry of viruses into host cells.
  • the compound or salt inhibits viral replication.
  • the compound or salt can treat or prevent diseases, disorders, or conditions associated with virus infection and can disinfect or sanitize an object from virus contamination.
  • the compound or salt has AN06 inhibition activity, as illustrated in Examples 3 and 4.
  • the compound or salt has anti-viral replication activity and anti-virus activity, as illustrated in Examples 6 and 7.
  • the virus of the present invention is an RNA virus.
  • the RNA virus may be an enveloped positive-strand RNA virus.
  • the enveloped positive-strand RNA virus may be a Coronaviridae.
  • the Coronaviridae includes letovirinae and orthcoromavirinae (known as coronavirus) subfamily.
  • the virus of the present invention may comprise all virus in the orthcoronavirinae (coronavirus).
  • the orthcoronavirinae (coronavirus) may be selected from the group consisting of alphacoronavirus (Group 1 CoV), betacoronavirus (Group 2 CoV), gammacoronavirus (Group 3 CoV) and deltacoronavirus (Group 4 CoV) genus.
  • the virus may be a Betacoronavirus.
  • the genus Betacoronavirus (Group 2 CoV) comprises five subgenera or lineages (A, B, C, and D): Embecovirus (lineage A), Sarbecovirus (lineage B), Merbecovirus (lineage C), Nobecovirus (lineage D) and Hibecovirus.
  • the Embecovirus comprises Betacoronavirus 1 species (ex. Bovine coronavirus and Human coronavirus OC43), China Rattus coronavirus HKU24 species, Human coronavirus HKU1 species, Murine coronavirus species (ex. Mouse hepatitis virus) species, and My odes coronavirus 2JL14 species.
  • the Sarbecovirus subgenera comprises severe acute respiratory syndrome-related coronavirus (SARSr-CoV).
  • the severe acute respiratory syndrome-related coronavirus comprises severe acute respiratory syndrome coronavirus species (also known as SARS-CoV and SARS-CoV-1), severe acute respiratory syndrome coronavirus 2 species (SARS-CoV-2), Bat SARS-like coronavirus WIV1 species (Bat SL- CoV-WIVl), and Bat coronavirus RaTG13 species.
  • the Merbecovirus subgenera (lineage C) comprises Hedgehog coronavirus 1 species, Middle East respiratory syndrome-related coronavirus species (MERS-CoV), Pipistrellus bat coronavirus HKU5 species, and Tylonycteris bat coronavirus HKU4 species.
  • the Nobecovirus subgenera (lineage D) comprises Eidolon bat coronavirus C704 species, Rousettus bat coronavirus GCCDC1 species, and Rousettus bat coronavirus HKU9 species.
  • the Hibecovirus subgenera comprises Bat Hp- betacoronavirus Zhejiang2013 species.
  • the diseases, disorders, or conditions associated with virus infection comprises cold, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), COVID-19; and disorders or conditions thereof.
  • SARS severe acute respiratory syndrome
  • MERS Middle East respiratory syndrome
  • COVID-19 disorders or conditions thereof.
  • the cold also known as common cold, is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms of the cold include coughing, sore throat, runny nose, sneezing, headache, and fever.
  • the severe acute respiratory syndrome (SARS) is a viral respiratory disease of zoonotic origin caused by severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-1).
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • This new strain causes coronavirus disease 2019 (COVID-19), a disease which brought about the COVID-19 pandemic.
  • the middle East respiratory syndrome (MERS) is a viral respiratory infection caused by Middle East respiratory syndrome-related coronavirus (MERS-CoV). Typical symptoms include fever, cough, diarrhea, and shortness of breath.
  • the coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Symptoms of COVID-19 are variable, but often include fever, cough, headache, fatigue, breathing difficulties, loss of smell, and loss of taste.
  • the term “treat,” “treating” or “treatment” refers to methods of alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • disinfect refers to methods of inactivating or killing pathogenic microorganisms including virus.
  • the term “sanitize,” “sanitizing” or “sanitization” refers to methods of removing or decreasing pathogenic microorganisms including virus from a surface of non living or living object.
  • the term “subject” or “patient” encompasses mammals and non mammals.
  • mammals include, but are not limited to, humans, chimpanzees, apes monkeys, cattle, horses, sheep, goats, swine; rabbits, dogs, cats, rats, mice, guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fishes and the like.
  • administering refers to providing a compound of the invention and/or a prodrug thereof to a subject in need of treatment.
  • the term “contacting with” or “applying to” of an object refers to methods of allowing the compositions of the invention to be in contact with or be applied to an object by, for example, wiping, dipping, immersing, or spraying.
  • the term “effective amount” or “therapeutically effective amount” refer to a sufficient amount of an active ingredient(s) described herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • a therapeutically effective amount of a compound of the invention may be in the range of e.g ., about 0.01 mg/kg/day to about 1000 mg/kg/day, from about 0.1 mg/kg/day to about 500 mg/kg/day, from about 0.1 mg (x2)/kg/day to about 500 mg (x2)/kg/day.
  • such compounds and compositions may be administered singly or in combination with one or more additional therapeutic agents.
  • the methods of administration of such compounds and compositions may include, but are not limited to, intravenous administration, inhalation, oral administration, rectal administration, parenteral, intravitreal administration, subcutaneous administration, intramuscular administration, intranasal administration, dermal administration, topical administration, ophthalmic administration, buccal administration, tracheal administration, bronchial administration, sublingual administration or optic administration.
  • compositions provided herein may be administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, lotions, gels, ointments or creams for topical administration, and the like.
  • such pharmaceutical compositions are formulated as tablets, pills, capsules, a liquid, an inhalant, a nasal spray solution, a suppository, a solution, a gel, an emulsion, an ointment, eye drops, or ear drops.
  • the therapeutically effective amount may vary depending on, among others, the disease indicated, the severity of the disease, the age and relative health of the subject, the potency of the compound administered, the mode of administration and the treatment desired.
  • the required dosage will also vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • the compound may be represented by Formula (I).
  • Ring A and ring B each may be independently a monocyclic or polycyclic aliphatic ring or a monocyclic or polycyclic aromatic ring, wherein the aliphatic ring and the aromatic ring each optionally and independently may contain at least one heteroatom selected from the group consisting of N, NO, NO2, S, SO, SO2, and O.
  • Ri R 2 , and R 3 each may be independently hydrogen, halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, or aryl aliphatic.
  • Li and L2 each may be independently aliphatic, cycloaliphatic, hetero cycloaliphatic, or alkoxy.
  • m and n each are independently 0 or 1.
  • the ring A, the ring B, Ri , R 2 , R 3 , Li, and L 2 each may be optionally and independently substituted with at least one substituent selected from the group consisting of halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, ester, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, and aryl aliphatic.
  • substituent selected from the group consisting of halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, ester, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, and aryl ali
  • two or more of the polycyclic rings may be fused or linked with each other.
  • the monocyclic or polycyclic aliphatic ring and the monocyclic or polycyclic aromatic ring of the ring A and the ring B each may be independently a 4- membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10- membered, 11-membered, or 12-membered ring.
  • the monocyclic aliphatic ring and the monocyclic aromatic ring of the ring A may be a 5-membered ring or a 6-membered ring
  • the monocyclic aliphatic ring and the monocyclic aromatic ring of the ring B may be a 5-membered ring or a 6- membered ring
  • the monocyclic aliphatic ring and the monocyclic aromatic ring of the ring A may be 5-membered ring or a 6-membered ring
  • the monocyclic aliphatic ring and the monocyclic aromatic ring of the ring B may be a 6-membered ring.
  • -(Li) m -Ri may be connected to the ring A at the para, meta or ortho position. In some embodiments, -(Li) m -Ri may be connected to the ring A at the para position.
  • the ring A may be a monocyclic or polycyclic aliphatic ring which optionally contains at least one heteroatom selected from the group consisting of N, NO, NO2, S, SO, S0 2 , and O.
  • the ring A may be a monocyclic or polycyclic aromatic ring which optionally contains at least one heteroatom selected from the group consisting of N, NO, NO2, S, SO, S0 2 , and O.
  • the ring A may be phenyl, pyridinyl, diazinyl, pyrimidinyl, triaziny, piperidinyl, oxadiazoline, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the ring A may be , in which X ai , X a2 , X a 3, and X a4 each are independently CH, N, NH, NO, or N0 2 .
  • any one of X ai , X a2 , X a3 , and X a4 is N, NH, NO, or NO2, and the others are CH.
  • two of Xai, X a 2, X a 3, and X a4 are N, NH, NO, or NO2, and the others are CH.
  • three of X ai , X a2 , X a 3, and X a4 are N, NH, NO, or NO2, and the other one is CH.
  • X ai and X a2 are N
  • X a3 and X a4 are CH.
  • X ai and X a3 are N
  • X a2 and X a4 are CH.
  • X ai and X a4 are N
  • X a2 and X a3 are CH.
  • X a2 and X a3 are CH.
  • X a2 and X a3 are N
  • X ai and X a4 are CH.
  • X a2 and X a4 are N, and X ai and X a3 are CH. In certain embodiments, X a3 and X a4 are N, and X ai and X a2 are CH. In certain embodiments, X ai , X a2 , and X a3 are N, and X a4 is
  • the ring A may be , in which Y ai , Y a 2, and Y a3 each are independently CH, N, NH, NO, NO2, S, SH or O.
  • any one of Y ai , Y a 2, and Y a3 is N, NH, NO, NO2, S, SH or O, and the others are CH.
  • two of Y ai , Y a 2, and Y a3 are N, NH, NO, NO2, S, SH or O, and the other is CH.
  • Y ai , and Y a2 are N, NO, NO 2 , or NH
  • Y a3 is S, SH or O.
  • Y a2 , and Y a3 are N, NO, NO 2 , or NH
  • Y ai is S, SH or O.
  • the ring B may be a monocyclic or polycyclic aromatic ring which optionally contains at least one heteroatom selected from the group consisting of N, O, and S.
  • the ring B may be a monocyclic or polycyclic aliphatic ring which optionally contains at least one heteroatom selected from the group consisting of N, O, and S.
  • the ring B may be phenyl, pyridinyl, diazinyl, cyclopentadienyl, cyclopentyl, cyclohexyl, adamantane, or bicyclo[2.2.1]heptane.
  • the ring B may be in which X bi , X b2 , X b3 , and X b4 each are independently CH, N, or NH.
  • any one of X bi , X b2 , X b3 , and X b4 is N, NH, NO, or NO 2 , and the others are CH.
  • two of X bi , X b2 , X b3 , and X b4 are N, NH, NO, or NO 2 , and the others are CH.
  • three of X bi , X b2 , X b3 , and X b4 are N, NH, NO, or NO2, and the other one is CH.
  • X bi and X b2 are N, and X b3 and X b4 are CH.
  • X bi and X b3 are N, and X b2 and X b4 are CH.
  • X bi and X b4 are N, and X b2 and X b3 are CH.
  • X b2 and X b3 are N, and X bi and X b4 are CH.
  • X b2 and X b4 are N, and X bi and X b3 are CH. In certain embodiments, X b3 and X b4 are N, and Xbi and Xb2 are CH. In certain embodiments, X bi , X b2 , and X b3 are N, and X b4 is CH.
  • Li and L 2 each may be independently C 1 -C 10 aliphatic, C 3 -C 10 cycloaliphatic, or C 3 -C 10 hetero cycloaliphatic. In certain embodiments, Li and L 2 each may be independently C 1 -C 10 aliphatic. In certain embodiments, Li and L 2 each may be independently C 1 -C 10 alkyl or cyclopropyl.
  • Li and L 2 each may be optionally and independently substituted with at least one substituent selected from the group consisting of halogen, halogen derivatives, CN, alkoxy, hydroxyl, amine, amide, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, and aryl aliphatic.
  • Li and L 2 each may be optionally and independently substituted with at least one substituent selected from the group consisting of CN, C 1-5 alkyl, and C 3-6 cycloalkyl.
  • R2 may be hydrogen, C1-5 alkyl or C3-6 cycloalkyl.
  • R2 may be hydrogen or C1-3 alkyl.
  • Ri and R3 each may be optionally and independently hydrogen, benzyl, amide, amine, thioalkyl, alkoxy, CN, COOH, Ci-Cn aliphatic, C3-C11 cycloaliphatic, C3-C11 hetero cycloaliphatic, C3-C11 aromatic ring, or C3-C11 hetero aromatic ring.
  • Ri and R3 each may be optionally and independently 3- membered cycloaliphatic; 4-membered cycloaliphatic; 4-membered hetero cycloaliphatic; 5- membered cycloaliphatic; 5-membered hetero cycloaliphatic; 6-membered cycloaliphatic; 6- membered hetero cycloaliphatic; 5-membered aromatic ring; 5-membered hetero aromatic ring; 6-membered aromatic ring; 6-membered hetero aromatic ring; 7-membered cycloaliphatic; 7- membered hetero bicyclic aliphatic; 10-membered tricyclic aliphatic; 6-membered aromatic ring fused or linked with 5-membered cycloaliphatic, 5-membered hetero cycloaliphatic, 5- membered aromatic ring, or 5-membered aromatic ring; 6-membered aromatic ring fused or linked with 6-membered cycloaliphatic, 6-membered hetero cycloaliphatic;
  • Ri , and R3 each may be optionally and independently N(CH ) 2 , N(C 2 H 5 ) 2 , N(C 2 H 5 )(benzyl), or N(C 3 H 7 )(benzyl).
  • Ri , and R3 each may be independently hydrogen, Ci-10 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-11 cycloalkyl, C3-11 hetero-cycloalkyl, C3-11 cycloalkenyl, C3- 11 hetero-cycloalkenyl, C3-11 cycloalkynyl, C3-11 hetero-cycloalkynyl, C5-11 aryl, C5-11 hetero aryl, or CN.
  • Ri may be hydrogen; Ci-10 alkyl; benzyl; alkoxy; CN; COOH; mono or bi aromatic ring which optionally contains at least one heteroatom selected from the group consisting of N, O, and S; mono or bi cycloaliphatic which optionally contains at least one heteroatom selected from the group consisting of N, O, and S; aryl which optionally contains at least one hetero atom selected from the group consisting of N, O, and S; an aromatic ring fused to a non-aromatic ring which optionally contains at least one heteroatom selected from the group consisting of N, O, and S; or an aromatic ring fused to an aromatic ring which optionally contains at least one heteroatom selected from the group consisting of N, O, and S. Ri may be substituted or unsubstituted.
  • Ri may be Ci-4 alkyl, benzyl, phenyl, pyridinyl, diazinyl (such as pyrimidinyl, pyrazinyl, and pyridazinyl), triazinyl, piperidinyl, furanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thiophenyl or oxygen-containing fused heterocycle which is optionally substituted with at least one substituent selected from the group consisting of halogen, halogen derivatives, alkoxy, carboxyl, C 1-5 alkyl ester and C 1-5 alkyl.
  • the substituent is selected from the group consisting of 0(CH 3 ), CH 3 , isopropyl, F, Cl, Br, CF3, NO2, NH 2 , OCHF2, CHF 2 , OCF3, SCH3, COOC(CH )3, COOCH 2 CH , OCH3, OCFFCFF, OCH 2 CH 2 CH 3 , N(C 2 H 5 ) 2 , 6-membered hetero cycloaliphatic, dimethyl amine, diethyl amine, and phenyl.
  • one of the ring A and Ri may be or comprise a hetero aromatic ring which contains at least one N as the heteroatom.
  • both of the ring A and Ri may be or comprise a hetero aromatic ring which contains at least one N as the heteroatom.
  • R 3 may be hydrogen, halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, aryl aliphatic or fused ring.
  • R 3 may be hydrogen, Ci- 10 alkyl, alkyl amine, mono or bi aromatic ring, mono or bi hetero aromatic ring, mono or bi cycloaliphatic, mono or bi hetero cycloaliphatic, aryl, heteroaryl, aromatic ring fused to a non-aromatic ring which optionally contains at least one heteroatom, or aromatic ring fused to aromatic ring which optionally contains at least one heteroatom.
  • heteroatoms include N, O, and S.
  • R 3 may be bicycle, cycloaliphatic ring, aryl, or hetero aryl.
  • R 3 may be Ci- 10 alkyl, alkyl amine, benzyl, COOH, phenyl, pyridinyl, pyrimidinyl, piperidinyl, furanyl, thiophenyl, pyrrolyl, thiazolyl, C 3-7 cycloaliphatic, or oxygen-containing fused heterocycle.
  • R 3 may be optionally substituted with at least one substituent selected from the group consisting of halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, and aryl aliphatic.
  • R 3 may be substituted or unsubstituted.
  • R I, R-2, and R3 each may be optionally and independently substituted with one or more groups selected from the group consisting of halogen, halogen derivatives (e.g ., F, Br, Cl, I, OCHF 2 , CF 3 , CHF 2 , or OCF 3 ), alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hetero cycloalkyl, hetero cycloalkenyl, hetero cycloalkynyl, alkoxy, aryl, aryloxy, diaryl, arylalkyl, arylalkyloxy, cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, alkylthio, aryl
  • halogen
  • R x and R y each may be independently selected from hydrogen, alkyl, alkenyl, C3-C7 cycloalkyl, C 5 -C 11 aryl, benzyl, phenylethyl, naphthyl, a 3- to 7-membered heterocycloalkyl, and a 5- to 6- membered heteroaryl.
  • Ri, and R 3 each may be optionally and independently substituted by at least one substituent selected from the group consisting of 0(CH3), CFF, CH2CH3 , isopropyl, F, Cl, Br, CF 3 , OCHF 2 , CHF 2 , OCF3, SCH3, COOH, COOC(CH )3, COOCH2CH3, COOCH3, OCH2CH3, OCH2CH2CH3, N(C 2 H 5 )2, NHCH3, NO2, NH 2 , CN, dimethyl amine, diethyl amine, phenyl, and 6-membered hetero cycloaliphatic.
  • Ri is a substituted cyclic compound
  • the substituent may be bound at the ortho, meta and/or para position of Ri. In some embodiments, the substituent may be bound at the meta, and/or para position of Ri.
  • L2 may be aliphatic, cycloaliphatic, hetero cycloaliphatic, or alkoxy.
  • L 2 may be C 1-5 alkyl or C 1-5 cycloaliphatic.
  • L 2 may be C 1-3 alkyl or C 1-3 cycloaliphatic.
  • the group may be one of the following groups:
  • the group may be one of the following groups:
  • the compound represented by Formula (I) may be selected from the following compounds.
  • Ring A, Ring B, R 1 R 3 , Li, L2, m, and n are the same as defined with regard to Formula
  • Ri and R 3 each may be independently hydrogen, halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, or aryl aliphatic.
  • A’s and X’s each may be independently CH, N, NO, or NH.
  • L 2 may be independently aliphatic, or cycloaliphatic.
  • N may be 0 or 1.
  • R I, R 3 , and L 2 each may be optionally and independently substituted with at least one substituent selected from the group consisting of halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, ester, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, and aryl aliphatic.
  • substituent selected from the group consisting of halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, ester, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, and aryl aliphatic.
  • Ri , R 3 , L 2 , and n are the same as defined with regard to Formula
  • Ri and R 3 each may be independently hydrogen, halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, or aryl aliphatic.
  • A’s and X’s each may be independently CH, N, NO, or NH.
  • L 2 may be independently aliphatic, or cycloaliphatic.
  • N may be 0 or 1.
  • R I, R 3 , and L 2 may be optionally and independently substituted with at least one substituent selected from the group consisting of halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, ester, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, and aryl aliphatic.
  • substituent selected from the group consisting of halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, ester, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, and aryl aliphatic.
  • Ri , R 3 , L 2 , and n are the same as defined with regard to Formula
  • Ri and R 3 each may be independently hydrogen, halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, or aryl aliphatic.
  • A’s and X’s each may be independently CH, N, or NH.
  • L2 may be independently aliphatic, or cycloaliphatic.
  • N may be 0 or 1.
  • R 1 ,R-3, and L2 may be optionally and independently substituted with at least one substituent selected from the group consisting of halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, ester, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, and aryl aliphatic.
  • substituent selected from the group consisting of halogen, halogen derivatives, CN, alkoxy, carboxyl, carbonyl, ester, hydroxyl, amine, amide, nitro, phosphate, thioalkyl, sulfhydryl, oxo, aliphatic, cycloaliphatic, hetero cycloaliphatic, aromatic, hetero aromatic, and aryl aliphatic.
  • Ri , R3, L2, and n are the same as defined with regard to Formula
  • Non-limiting examples of the compounds of embodiments of the present invention are listed in Table 1 below.
  • the compounds described herein include all stereoisomers, geometric isomers, tautomers, isotopes, and prodrug of the structures depicted.
  • the compounds described herein can be present in various forms including crystalline, powder and amorphous forms of those compounds, pharmaceutically acceptable salts, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • the term “pharmaceutically acceptable” refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein. Such materials are administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compounds described herein.
  • Pharmaceutically acceptable salt forms may include pharmaceutically acceptable acidic/anionic or basic/cationic salts (UK Journal of Pharmaceutical and Biosciences Vol. 2(4), 01-04, 2014, which is incorporated herein by reference).
  • Pharmaceutically acceptable acidic/anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, mucate, napsylate
  • Pharmaceutically acceptable basic/cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, A -m ethyl -D-gl ucami ne, L.-lysine, L.-arginine, ammonium, ethanolamine, piperazine, and triethanolamine salts.
  • a pharmaceutically acceptable acid addition salt of a compound of the invention may be prepared by methods known in the art and may be formed by reaction of the free base form of the compound with a suitable inorganic or organic acid including, but not limited to, hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, p- toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2-naphthalenesulfonic, and hexanoic acid.
  • a suitable inorganic or organic acid including, but not limited to, hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric
  • a pharmaceutically acceptable acid addition salt can comprise or be, for example, a hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, phosphate, succinate, maleate, formarate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, carbonate, benzathine, chloroprocaine, choline, histidine, meglumine, meglumine, procaine, triethylamine, besylate, decanoate, ethylenediamine, salicylate, glutamate, aspartate, /Mol uene sulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate e.g ., 2-naphthalenesulfonate), and hexanoate salt.
  • a pharmaceutically acceptable base addition salt of a compound of the invention may also be prepared by methods known in the art and may be formed by reaction of the free base form of the compound with a suitable inorganic or organic base including, but not limited to, hydroxide or other salt of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, tromethamine, glycolate, hydrabamine, methylbromide, methylnitrate, octanoate, oleate, and the like.
  • a free acid or free base form of a compound of the invention may be prepared by methods known in the art (e.g., for further details see L.D. Bigley, S.M. Berg, D.C.
  • a compound of the invention in an acid addition salt form may be converted to the corresponding free base form by treating with a suitable base (e.g, ammonium hydroxide solution, sodium hydroxide, and the like).
  • a suitable base e.g, ammonium hydroxide solution, sodium hydroxide, and the like
  • a compound of the invention in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid (e.g ., hydrochloric acid, etc.).
  • prodrug forms of any of the compounds described herein Any convenient prodrug forms of the subject compounds can be prepared, for example, according to the strategies and methods described by Rautio et al. (“Prodrugs: design and clinical applications”, Nature Reviews Drug Discovery 7, 255-270 (February 2008)).
  • Prodrug derivatives of the compounds of the invention may be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al, Bioorg. Med. Chem. Letters, 1994, 4, 1985, which is incorporated herein by reference).
  • Protected derivatives of the compounds of the invention may be prepared by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, “Protecting Groups in Organic Chemistry,” 3 rd edition, John Wiley and Sons, Inc., 1999 and “Design of Prodrugs”, ed. 11. Bundgaard, Elsevier, 1985, which are incorporated herein by reference.
  • the compounds of the present disclosure may be prepared as stereoisomers. Where the compounds have at least one chiral center, they may exist as enantiomers. Where the compounds possess two or more chiral centers, they may exist as diastereomers.
  • the compounds of the invention may be prepared as racemic mixtures. Alternatively, the compounds of the invention may be prepared as their individual enantiomers or diastereomers by reaction of a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereo-isomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers.
  • Resolution of enantiomers may be carried out using covalent diastereomeric derivatives of the compounds of the invention, or by using dissociable complexes (e.g, crystalline diastereomeric salts).
  • Diastereomers have distinct physical properties (e.g, melting points, boiling points, solubility, reactivity, etc.) and may be readily separated by taking advantage of these dissimilarities.
  • the diastereomers may be separated by chromatography, or by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • the compounds of the invention may be prepared as solvates (e.g ., hydrates).
  • solvate refers to a complex of variable stoichiometry formed by a solute (for example, a compound of the invention or a pharmaceutically acceptable salt thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include water, acetone, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • the compounds of the invention may be prepared as crystalline forms.
  • the crystalline forms may exist as polymorphs.
  • compositions for use in treating or preventing diseases, disorders, or conditions associated with virus infection contains a therapeutically effective amount of a compound that can inhibit AN06, a pharmaceutically acceptable salt thereof, a diastereomer thereof, an enantiomer thereof, a racemate thereof, a solvate thereof, a hydrate thereof, a prodrug thereof, a crystalline thereof, or a combination thereof.
  • compositions for use in disinfecting or sanitizing an object from virus contamination contains a therapeutically effective amount of a compound that can inhibit AN06, a pharmaceutically acceptable salt thereof, a diastereomer thereof, an enantiomer thereof, a racemate thereof, a solvate thereof, a hydrate thereof, a prodrug thereof, a crystalline thereof, or a combination thereof.
  • the compound inhibits AN06 phospholipid scramblase activity and reduce phosphatidyl serine (PS) externalization.
  • PS phosphatidyl serine
  • the compound or salt can inhibit the entry of virus in host cells.
  • the compound or salt inhibits viral replication.
  • the compound or salt can treat or prevent diseases, disorders, or conditions associated with virus infection and can disinfect or sanitize an object from virus contamination.
  • the compound or salt has AN06 inhibition activity, as illustrated in Examples 3 and 4.
  • the compound or salt has anti-virus activity and anti-viral replication activity, as illustrated in Examples 6 and 7.
  • the compound is represented by Formula (I) above.
  • the virus of the present invention is an RNA virus.
  • the RNA virus may be an enveloped positive-strand RNA virus.
  • the enveloped positive-strand RNA virus may be a Coronaviridae.
  • the Coronaviridae includes letovirinae and orthcoromavirinae (known as coronavirus) subfamily.
  • the virus of the present invention may comprise all virus in the orthcoronavirinae (coronavirus).
  • the orthcoronavirinae (coronavirus) may be selected from the group consisting of alphacoronavirus (Group 1 CoV), betacoronavirus (Group 2 CoV), gammacoronavirus (Group 3 CoV) and deltacoronavirus (Group 4 CoV) genus.
  • the virus may be a Betacoronavirus.
  • the genus Betacoronavirus (Group 2 CoV) comprises five subgenera or lineages (A, B, C, and D): Embecovirus (lineage A), Sarbecovirus (lineage B), Merbecovirus (lineage C), Nobecovirus (lineage D) and Hibecovirus.
  • the Embecovirus comprises Betacoronavirus 1 species (ex. Bovine coronavirus and Human coronavirus OC43), China Rattus coronavirus HKU24 species, Human coronavirus HKU1 species, Murine coronavirus species (ex. Mouse hepatitis virus) species, and My odes coronavirus 2JL14 species.
  • the Sarbecovirus subgenera comprises severe acute respiratory syndrome-related coronavirus (SARSr-CoV).
  • the severe acute respiratory syndrome-related coronavirus comprises severe acute respiratory syndrome coronavirus species (also known as SARS-CoV and SARS-CoV-1), severe acute respiratory syndrome coronavirus 2 species (SARS-CoV-2), Bat SARS-like coronavirus WIV1 species (Bat SL- CoV-WIVl), and Bat coronavirus RaTG13 species.
  • the Merbecovirus subgenera (lineage C) comprises Hedgehog coronavirus 1 species, Middle East respiratory syndrome-related coronavirus species (MERS-CoV), Pipistrellus bat coronavirus HKU5 species, and Tylonycteris bat coronavirus HKU4 species.
  • the Nobecovirus subgenera (lineage D) comprises Eidolon bat coronavirus C704 species, Rousettus bat coronavirus GCCDC1 species, and Rousettus bat coronavirus HKU9 species.
  • the Hibecovirus subgenera comprises Bat Hp- betacoronavirus Zhejiang2013 species.
  • the diseases, disorders, or conditions associated with virus infection comprises cold, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), COVID-19; and disorders or conditions thereof.
  • SARS severe acute respiratory syndrome
  • MERS Middle East respiratory syndrome
  • COVID-19 disorders or conditions thereof.
  • the cold also known as common cold, is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms of the cold include coughing, sore throat, runny nose, sneezing, headache, and fever.
  • the severe acute respiratory syndrome (SARS) is a viral respiratory disease of zoonotic origin caused by severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-1).
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • This new strain causes coronavirus disease 2019 (COVID-19), a disease which brought about the COVID-19 pandemic.
  • the middle East respiratory syndrome (MERS) is a viral respiratory infection caused by Middle East respiratory syndrome-related coronavirus (MERS-CoV). Typical symptoms include fever, cough, diarrhea, and shortness of breath.
  • the coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Symptoms of COVID-19 are variable, but often include fever, cough, headache, fatigue, breathing difficulties, loss of smell, and loss of taste.
  • composition is intended to encompass a product comprising the claimed compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, or a pharmaceutical combination thereof in the therapeutically effective amount, as well as any other product which results, directly or indirectly, from claimed compound, salt, diastereomer, enantiomer, racemate, hydrate, solvate, or a pharmaceutical combination thereof.
  • the term “pharmaceutical composition” refers to a mixture of a therapeutically active component (ingredient) with one or more other components, which may be chemically or biologically active or inactive.
  • a therapeutically active component including, but not limited to, carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, excipients, and adjuvants.
  • the term “pharmaceutical combination” means a product that results from the mixing or combining of more than one therapeutically active ingredient.
  • the term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
  • carrier refers to chemical or biological material that can facilitate the incorporation of a therapeutically active ingredient(s) into cells or tissues.
  • Suitable excipients may include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g ., petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g, ethanol or glycerol), carriers such as natural mineral powders (e.g ., kaoline, clays, talc, chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), sugars (e.g, cane sugar, lactose and glucose), emulsifiers (e.g, lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone), and lubricants (e.g, magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
  • pharmaceutically acceptable organic solvents such as paraffins (e.g ., petroleum fractions), vegetable oils (e.g. groundnut or sesam
  • compositions described herein may be selected and employed in the compositions described herein.
  • suitable pharmaceutically acceptable carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, excipients, and adjuvants known to those of ordinary skill in the art for use in pharmaceutical compositions may be selected and employed in the compositions described herein.
  • the compositions described herein may be in the form of a solid, liquid, or gas (aerosol).
  • tablets for example, they may be in the form of tablets (coated tablets) made of, for example, collidone or shellac, gum Arabic, talc, titanium dioxide or sugar, capsules (gelatin), solutions (aqueous or aqueous-ethanolic solution), syrups containing the active substances, emulsions or inhalable powders (of various saccharides such as lactose or glucose, salts and mixture of these excipients with one another), and aerosols (propellant- containing or -free inhale solutions).
  • the compositions described herein may be formulated for sustained or slow release.
  • compounds used in the reactions described herein may be made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” may be obtained from standard commercial sources including Aldrich Chemical (Milwaukee Wis., including Sigma Chemical and Fluka), Fisher Scientific Co. (Pittsburgh Pa.), and Wako Chemicals USA, Inc. (Richmond Va.), for example.
  • Phenylboronic acid 255 mg, 2.09 mmol
  • 4-bromoaniline 300 mg, 1.74 mmol
  • Pd(PPh3)4 100 mg, 0.087 mmol
  • potassium carbonate 891 mg, 6.45 mmol
  • H2O/DMF 3.5/3.5 mL
  • the reaction mixture was extracted by ethyl acetate (EA) and brine.
  • the organic layer was dried over anhydrous NaiSCE and concentrated.
  • the residue was purified by MPLC to give [I,G- biphenyl]-4-amine (257 mg, 87%) as a yellow solid.
  • Phenylboronic acid 255 mg, 2.09 mmol
  • 5-bromopyrazin-2-amine 303 mg, 1.74 mmol
  • Pd(PPh3)4 100 mg, 0.087 mmol
  • potassium carbonate 891 mg, 6.45 mmol
  • H2O/DMF 3.5/3.5 mL
  • the reaction mixture was extracted by EA and brine.
  • the organic layer was dried over anhydrous Na 2 SC> 4 and concentrated.
  • the residue was purified by MPLC to give 5- phenylpyrazin-2-amine (240 mg, 81%) as a yellow solid.
  • Phenylboronic acid 255 mg, 2.09 mmol
  • 6-bromopyridin-3 -amine 300 mg, 1.74 mmol
  • Pd(PPh3)4 100 mg, 0.087 mmol
  • potassium carbonate 891 mg, 6.45 mmol
  • H2O/DMF 3.5/3.5 mL
  • the reaction mixture was extracted by EA and brine.
  • the organic layer was dried over anhydrous Na 2 S0 4 and concentrated.
  • the residue was purified by MPLC to give 5- phenylpyridin-2-amine (251 mg, 84%) as an orange solid.
  • Step 1 177-Pyrimidin-6-one (10 g, 104 mmol) and POCI3 (100 mL, 1.08 mol) were charged to a pressure flask. Flask was flushed with nitrogen and heated for 6 hours at 100°C. The reaction mixture was concentrated under reduced pressure to remove POCI3. The reaction mixture was poured into EA carefully and stirred for 30 minutes. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate, dried to give 4-chloropyrimidine (3.50 g, crude) as a brown solid.
  • Step 2 A mixture of 4-chloropyrimidine (1.80 g, 15.7 mmol), 4-(4, 4,5,5 -tetram ethyl- 1, 3, 2-dioxaborolan-2-yl)aniline (3.79 g, 17.3 mmol), CS2CO3 (20.5 g, 62.9 mmol), 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (575 mg, 0.79 mmol) in toluene (12 mL), ethanol (4 mL), and H2O (3.6 mL) and the mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred for 12 hours at 100°C under N2 atmosphere.
  • Step 1 To a solution of methyl 3-bromobenzoate (18 g, 83.7 mmol) in 1,4-dioxane (90 mL) was added 6-phenylpyridazin-3 -amine (15.1 g, 87.9 mmol), BrettPhos (8.99 g, 16.7 mmol), and cesium carbonate (68.2 g, 209 mmol). Pd 2 (dba) 3 (2.3 g, 2.51 mmol) was added into the solution. The solution was stirred for 6 hours at 100°C. The reaction was filtered, and the filter cake was triturated with tetrahydrofuran (THF) (180 mL) and MeOH (35 mL) for 2 hours at room temperature.
  • THF tetrahydrofuran
  • Step 2 Methyl 3-[(6-phenylpyridazin-3-yl)amino]benzoate (9 g, 29.5 mmol) was dissolved in MeOH/THF (7/45 mL). aq. NaOH (2 M, 29.4 mL) was added into the solution. The solution was stirred for 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure to remove MeOH and THF to give a residue. The H2O (80 mL) was added into the residue. The pH value of the suspension was adjusted to 2 by aq. HC1 (2 M). THF (30 mL) was added into the suspension. The suspension was filtered, and the filter cake was dried under vacuum to give 3-((6-phenylpyridazin-3-yl)amino)benzoic acid (5 g, 58%) as yellow solid.
  • Step 1 To a solution of 5-phenylpyrimidin-2-amine (22 g, 128 mmol) in 1,4-dioxane (130 mL) were added methyl 3-bromobenzoate (18.4 g, 85.7 mmol), cesium carbonate (83.7 g, 257 mmol), and XPhos (12.3 g, 25.7 mmol). Then Pd 2 (dba) 3 (2.35 g, 2.57 mmol) was added into the solution. Then solution was stirred for 12 hours at 100°C. The reaction solution was poured into H2O (500 mL). The suspension was filtered, and the filter cake was rinsed with H2O (100 mL).
  • the filter cake was dried in vacuum to give the crude product.
  • the crude product was diluted with THF (1 L).
  • the resulting suspension was filtered, and the filter cake was washed with THF (200 mL).
  • the filtrate was purified by column chromatography to give methyl 3-[(5-phenylpyrimidin-2-yl)amino]benzoate (9 g, 34%) as a white solid.
  • Step 2 An aq. NaOH (2 M, 29.5 mL) was added into a solution of methyl 3-[(5- phenylpyrimidin-2-yl)amino]benzoate (9 g, 29.5 mmol) in THF (70 mL). Then MeOH (50 mL) was added into the reaction solution. The solution was stirred for 12 hours at 50°C. The reaction solution was concentrated to give a crude product. The crude product was added into H2O (500 mL). Then pH value of the solution was adjusted to 1-2 by aq. HC1 (1 M).
  • Step 1 5-(3-Fluorophenyl)pyridin-2-amine (700 mg, 3.72 mmol), methyl 3- bromobenzoate (1.2 g, 4.84 mmol), Pd 2 (dba) 3 (340 mg, 0.37 mmol), BrettPhos (339 mg, 0.74 mmol), and cesium carbonate (2.4 g, 7.44 mmol) were mixed in 1,4-dioxane (18.6 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous Na 2 SC> 4 and concentrated. The crude mixture was solidified by using DCM and HEX to give methyl 3- ⁇ [5-(3- fluorophenyl)pyridin-2-yl]amino ⁇ benzoate (539 mg, 45%) as a beige solid.
  • Step 2 Methyl 3- ⁇ [5-(3-fluorophenyl)pyridin-2-yl]amino ⁇ benzoate (400 mg, 1.24 mmol) and LiOH-H 2 0 (521 mg, 12.4 mmol) were mixed in H 2 0/l,4-dioxane (5.2/24.8 mL) and stirred for 18 hours at room temperature.
  • the reaction mixture acidified by adding 1 N HC1 and extracted by EA and brine.
  • the organic layer was dried over anhydrous Na 2 SC> 4 and concentrated.
  • the crude mixture was solidified by using EA to give 3-((5-(3- fluorophenyl)pyridin-2-yl)amino)benzoic acid (348 mg, 91%) as a beige solid.
  • Step 1 To a solution of 5-(3-fluorophenyl)pyrimidin-2-amine (30 g, 158 mmol) in 1,4- dioxane (210 mL) was methyl 3-bromobenzoate (31 g, 144 mmol), XPhos (20.6 g, 43.3 mmol), and cesium carbonate (141 g, 432 mmol). Then Pd 2 (dba) 3 (3.96 g, 4.32 mmol) was added into the solution. The solution was stirred for 12 hours at 100°C. The reaction solution was poured into H2O (500 mL), and the suspension was filtered.
  • Step 2 An aq. NaOH (2 M, 30.9 mL) was added into a solution of methyl 3- ⁇ [5-(3- fluorophenyl)pyrimidin-2-yl]amino ⁇ benzoate (10 g, 30.9 mmol) in THF (70 mL). Then MeOH (50 mL) was added into the reaction solution. The solution was stirred for 12 hours at 50°C.
  • the reaction solution was concentrated to give a crude product.
  • the crude product was added into H2O (500 mL).
  • the pH value of the solution was adjusted to 1-2 by aq. HC1 (1 M).
  • Step 1 To a solution of methyl 3-bromobenzoate (20.8 g, 122 mmol) in 1,4-dioxane (125 mL) was added 5-phenylpyridin-2-amine (25.0 g, 116 mmol), XPhos (16.6 g, 34.8 mmol) and CS2CO3 (113 g, 348 mmol). The solution was degassed and purged with N2 for three times. Pd 2 (dba) 3 (3.19 g, 3.49 mmol) was added into the solution. The solution was degassed and purged with N2 for three times. The solution was stirred for 12 h at 100°C. The mixture suspension was filtered, and the filter cake was rinsed with EA.
  • Step 2 Methyl 3-((5-phenylpyridin-2-yl)amino)benzoate (20.0 g, 65.7 mmol) was dissolved in MeOH (100 mL) and THF (20 mL). aq. NaOH (2 M, 65.7 mL) was added into the solution. The solution was stirred for 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure to remove MeOH and THF to give a residue. The 3 ⁇ 40 (80 mL) was added into the residue. The pH value of the suspension was adjusted to 5 by aq. HC1 (6 M). The suspension was filtered, and the filter cake was concentrated under reduced pressure to give 3-((5-phenylpyridin-2-yl)amino)benzoic acid (10 g, 52%) as white solid.
  • Step 1 5-(Furan-3-yl)pyrimidin-2-amine (400 mg, 2.48 mmol), methyl 3- bromobenzoate (807 mg, 3.23 mmol), Pd2(dba)3 (227 mg, 0.25 mmol), BrettPhos (267 mg, 0.5 mmol), and cesium carbonate (1.6 g, 4.96 mmol) were mixed in 1,4-dioxane (12 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was extracted by EA and brine. The crude mixture was solidified by using EA and HEX to give methyl 3-((5- (furan-3-yl)pyrimidin-2-yl)amino)benzoate (314 mg, 43%) as an orange solid.
  • Step 2 Methyl 3-((5-(furan-3-yl)pyrimidin-2-yl)amino)benzoate (300 mg, 1.02 mmol) and Li0H-H 2 0 (426 mg, 10.2 mmol) were mixed in H 2 0/l,4-dioxane (4.2/20.3 mL) and stirred for 18 hours at room temperature. Then pH value of the solution was adjusted to 1-2 by 1 N HC1. The reaction mixture was extracted by EA and brine. The crude mixture was solidified by using EA to give 3-((5-(furan-3-yl)pyrimidin-2-yl)amino)benzoic acid (199 mg, 70%) as a white solid.
  • Step 1 To a solution of methyl 3-bromobenzoate (2.88 g, 13.4 mmol) in 1,4-dioxane (45 mL) was added 4-(pyridin-2-yl)aniline (1.52 g, 8.93 mmol), BrettPhos (0.96 g, 1.79 mmol), and cesium carbonate (11.64 g, 35.7 mmol). Pd 2 (dba) 3 (0.82 g, 0.89 mmol) was added into the solution. The solution was stirred for 15 hours at 100°C. The reaction mixture was concentrated and purified by MPLC to give methyl 3-((4-(pyridin-2-yl)phenyl)amino)benzoate (1.36 g, 49%) as a yellow solid.
  • Step 2 Methyl 3-((4-(pyridin-2-yl)phenyl)amino)benzoate (1.35 g, 4.43 mmol) and LiOH-H 2 0 (0.75 g, 17.73 mmol) were mixed in THF/H2O (30/15 mL) and stirred for 117 hours at room temperature.
  • the reaction mixture was extracted by EA and aq. HC1 (IN).
  • the organic layer was dried over anhydrous MgSCE and concentrated.
  • the residue was purified by MPLC to give 3-((4-(pyridin-2-yl)phenyl)amino)benzoic acid (321 mg, 25%) as a pale yellow solid.
  • Step 1 To a solution of methyl 3-bromobenzoate (2.18 g, 10.14 mmol) in 1,4-dioxane (46 mL) was 4-(pyridin-3-yl)aniline (1.57 g, 9.22 mmol), XPhos (0.75 g, 1.56 mmol), and cesium carbonate (6.0 g, 18.44 mmol). Pd 2 (dba) 3 (0.68 g, 0.74 mmol) was added into the solution. The solution was stirred for 16 hours at 100°C. The reaction mixture was concentrated and purified by MPLC. The crude mixture was solidified by using acetone to give methyl 3-((4-(pyridin-3-yl)phenyl)amino)benzoate (1.0 g, 36%) as a pale yellow solid.
  • Step 2 Methyl 3-((4-(pyridin-3-yl)phenyl)amino)benzoate (0.35 g, 1.15 mmol) and LiOH-HiO (0.19 g, 4.6 mmol) were mixed in THF/H2O (8/4 mL) and stirred for 24 hours at room temperature. The reaction mixture was extracted by EA and aq. HC1 (IN). The organic layer was dried over anhydrous MgSCL and concentrated. The residue was purified by MPLC to give crude 3-((4-(pyridin-3-yl)phenyl)amino)benzoic acid (125 mg, 37%) as a yellow solid.
  • Step 1 To a solution of methyl 3-bromobenzoate (2.18 g, 10.14 mmol) in 1,4-dioxane (46 mL) was 4-(pyridin-4-yl)aniline (1.57 g, 9.22 mmol), XPhos (0.75 g, 1.56 mmol), and cesium carbonate (6.0 g, 18.44 mmol). Pd 2 (dba) 3 (0.68 g, 0.74 mmol) was added into the solution. The solution was stirred for 16 hours at 100°C. The reaction mixture was concentrated and purified by MPLC. The crude mixture was solidified by using acetone to give methyl 3-((4-(pyridin-4-yl)phenyl)amino)benzoate (1.0 g, 36%) as a pale yellow solid.
  • Step 2 Methyl 3-((4-(pyridin-4-yl)phenyl)amino)benzoate (0.76 g, 2.5 mmol) and Li0H-H 2 0 (0.42 g, 10 mmol) were mixed in THF/H2O (17/8.5 mL) and stirred for 40 hours at room temperature. The reaction mixture was extracted by EA and aq. HC1 (IN). The organic layer was dried over anhydrous MgSCE and concentrated. The crude mixture was solidified by using EA and acetone to give 3-((4-(pyridin-4-yl)phenyl)amino)benzoic acid (244 mg, 34%) as a yellow solid.
  • Step 1 To a solution of methyl 3-bromobenzoate (1.89 g, 8.8 mmol) in 1,4-dioxane (40 mL) was 4-(pyrimidin-2-yl)aniline (1.37 g, 8.0 mmol), XPhos (0.65 g, 1.36 mmol), and cesium carbonate (5.21 g, 16 mmol). Pd 2 (dba) 3 (0.59 g, 0.64 mmol) was added into the solution. The solution was stirred for 16 hours at 100°C. The reaction mixture was concentrated and purified by MPLC. The crude mixture was solidified by using acetone to give methyl 3-((4-(pyrimidin- 2-yl)phenyl)amino)benzoate (1.52 g, 62%) as a beige solid.
  • Step 2 Methyl 3-((4-(pyrimidin-2-yl)phenyl)amino)benzoate (1.50 g, 4.91 mmol) and LiOH-H 2 0 (0.83 g, 19.65 mmol) were mixed in THF/H2O (32/16 mL) and stirred for 40 hours at room temperature.
  • the reaction mixture was extracted by EA and aq. HC1 (IN).
  • the organic layer was dried over anhydrous MgSCE and concentrated.
  • the crude mixture was solidified by using EA and acetone to give 3-((4-(pyrimidin-2-yl)phenyl)amino)benzoic acid (1.10 g, 77%) as a beige solid.
  • Step 1 To a solution of methyl 3-bromobenzoate (1.80 g, 8.35 mmol) in 1,4-dioxane (38 mL) was 4-(pyrazin-2-yl)aniline (1.30 g, 7.59 mmol), XPhos (0.62 g, 1.29 mmol), and cesium carbonate (4.95 g, 15.2 mmol). Pd 2 (dba) 3 (0.56 g, 0.61 mmol) was added into the solution. The solution was stirred for 16 hours at 100°C. The reaction mixture was concentrated and purified by MPLC. The crude mixture was solidified by using acetone to give methyl 3-((4-(pyrazin-2-yl)phenyl)amino)benzoate (1.60 g, 69%) as a brown solid.
  • Step 2 Methyl 3-((4-(pyrazin-2-yl)phenyl)amino)benzoate (1.58 g, 5.74 mmol) and LiOH-HiO (0.87 g, 20.7 mmol) were mixed in THF/H2O (38/19 mL) and stirred for 64 hours at room temperature. The reaction mixture was extracted by EA and aq. HC1 (IN). The organic layer was dried over anhydrous MgSO 4 and concentrated. The residue was purified by MPLC to give 3-((4-(pyrazin-2-yl)phenyl)amino)benzoic acid (1.72 g, >99%) as a yellow solid.
  • Step 1 To a solution of methyl 3-bromobenzoate (2.0 g, 9.32 mmol) in 1,4-dioxane (43 mL) was 4-(pyrimidin-5-yl)aniline (1.45 g, 8.47 mmol), XPhos (0.69 g, 1.44 mmol), and cesium carbonate (5.52 g, 16.94 mmol). Pd 2 (dba) 3 (0.62 g, 0.68 mmol) was added into the solution. The solution was stirred for 16 hours at 100°C. The reaction mixture was concentrated and purified by MPLC. The crude mixture was solidified by using acetone to give methyl 3-((4-(pyrimidin-5-yl)phenyl)amino)benzoate (0.93 g, 36%) as a brown solid.
  • Step 1 To a solution of methyl 3-bromobenzoate (2.14 g, 9.93 mmol) in 1,4-dioxane (15 mL) was 4-(pyrimidin-4-yl)aniline (1.70 g, 9.93 mmol), BrettPhos (1.07 g, 1.99 mmol), and cesium carbonate (8.09 g, 24.8 mmol). Pd 2 (dba) 3 (0.91 g, 0.99 mmol) was added into the solution. The solution was stirred for 12 hours at 100°C under N2 atmosphere. TLC indicated 4-(pyrimidin-4-yl)aniline was consumed completely and one new spot formed. The reaction was clean according to TLC.
  • reaction mixture was diluted with H2O and extracted with EA.
  • the combined organic layers were washed with brine, dried over Na 2 SC> 4 , filtered, and concentrated under reduced pressure to give a residue.
  • the residue was purified by column chromatography to methyl 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoate (1.30 g, 43%) as a yellow solid.
  • Step 2 Methyl 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoate (1.30 g, 4.26 mmol) and KOH (478 mg, 8.52 mmol) were mixed in EtOH/H 2 0 (7/5 mL) and stirred for 4 hours at 100°C. TLC indicated methyl 3-((4-(pyrimidin-4-yl)phenyl)amino)benzoate was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was diluted with H2O and extracted with 2-methyltetrahydrofuran and the pH was adjusted to 5-6 with 0.5 M HC1 for aqueous phase.
  • Step 1 5-Phenylpyridin-2-amine (350 mg, 2.1 mmol), methyl 2-bromoisonicotinate (620 mg, 2.47 mmol), Pd2(dba)3 (188 mg, 0.21 mmol), BrettPhos (221 mg, 0.41 mmol), and cesium carbonate (1.3 g, 4.1 mmol) were mixed in 1,4-dioxane (10 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was extracted by EA and brine. The crude mixture was solidified by using EA and HEX to give methyl 2-((5- phenylpyridin-2-yl)amino)isonicotinate(393 mg, 63%) as an orange solid.
  • Step 2 Methyl 2-((5-phenylpyridin-2-yl)amino)isonicotinate (350 mg, 1.15 mmol) and LiOH-HiO (481 mg, 11.5 mmol) were mixed in H 2 0/l,4-dioxane (4.8/23 mL) and stirred for 18 hours at room temperature. Then pH value of the solution was adjusted to 1-2 by 1 N HC1. The yellow solid was precipitated out of the solution, and the solution was filtered to give 2- ((5-phenylpyridin-2-yl)amino)isonicotinic acid (190 mg, 57%) as a yellow solid.
  • Step 2 Methyl 2-((5-phenylpyrimidin-2-yl)amino)isonicotinate (550 mg, 1.8 mmol) and LiOH-HiO (753 mg, 18 mmol) were mixed in H 2 0/l,4-dioxane (7.5/36 mL) and stirred for 18 hours at room temperature. Then pH value of the solution was adjusted to 3 by 1 N HC1.
  • reaction mixture was extracted by EA and brine.
  • crude mixture was solidified by using EA and HEX to give 2-((5-phenylpyrimidin-2-yl)amino)isonicotinic acid (153 mg, 29%) as a beige solid.
  • Step 1 5-Phenylpyrimidin-2-amine (500 mg, 2.9 mmol), methyl 5-bromonicotinate (757 mg, 3.5 mmol), Pd2(dba)3 (267 mg, 0.29 mmol), BrettPhos (313 mg, 0.58 mmol), and cesium carbonate (1.9 g, 5.8 mmol) were mixed in 1,4-dioxane (15 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was extracted by EA and brine. The grey solid was precipitated out of the solution, and the solution was filtered to give methyl 5-((5-phenylpyrimidin-2-yl)amino)nicotinate (630 mg, 70%) as a grey solid.
  • Step 2 Methyl 5-((5-phenylpyrimidin-2-yl)amino)nicotinate (620 mg, 2 mmol) and Li0H-H 2 0 (849 mg, 20 mmol) were mixed in H 2 0/l,4-dioxane (8.4/40 mL) and stirred for 18 hours at room temperature. Then pH value of the solution was adjusted to 2 by 1 N HC1. The grey solid was precipitated out of the solution, and the solution was filtered to give 5-((5- phenylpyrimidin-2-yl)amino)nicotinic acid (497 mg, 84%) as a grey solid.
  • Step 1 5-Phenylpyrimidin-2-amine (500 mg, 2.9 mmol), methyl 4-bromopicolinate (757 mg, 3.5 mmol), Pd2(dba)3 (267 mg, 0.29 mmol), BrettPhos (313 mg, 0.58 mmol), and cesium carbonate (1.9 g, 5.8 mmol) were mixed in 1,4-dioxane (15 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was extracted by EA and brine. The beige solid was precipitated out of the solution, and the solution was filtered to give methyl 4-((5-phenylpyrimidin-2-yl)amino)picolinate (417 mg, 47%) as a beige solid.
  • Step 2 Methyl 4-((5-phenylpyrimidin-2-yl)amino)picolinate (400 mg, 1.3 mmol) and LiOH-H 2 0 (548 mg, 13 mmol) were mixed in H 2 0/l,4-dioxane (5.4/26 mL) and stirred for 18 hours at room temperature. Then pH value of the solution was adjusted to 1 by 1 N HC1. The beige solid was precipitated out of the solution, and the solution was filtered to give 4-((5- phenylpyrimidin-2-yl)amino)picolinic acid (346 mg, 92%) as a beige solid.
  • the reaction mixture was concentrated and purified by MPLC.
  • the crude mixture was solidified by using acetone to give methyl 3-((5-phenyl-l,3,4-oxadiazol-2-yl)amino)benzoate (0.33 g, 23%) as a beige solid.
  • Step 2 Methyl 3-((5-phenyl-l,3,4-oxadiazol-2-yl)amino)benzoate (0.32 g, 1.08 mmol) and LiOH-HiO (0.18 g, 4.32 mmol) were mixed in THF/H2O (7.2/3.6 mL) and stirred for 24 hours at room temperature. The reaction mixture was extracted by EA and aq. HC1 (IN). The organic layer was dried over anhydrous MgSCL and concentrated to give crude 3-((5- phenyl-l,3,4-oxadiazol-2-yl)amino)benzoic acid (125 mg, 41%) as a pale brown solid.
  • Step 1 In a sealed tube, 3-chloro-6-phenylpyridazine (500 mg, 2.6 mmol) and methyl (H,47)-4-aminobicyclo[2.2.1]heptane-l-carboxylate (578 mg, 3.4 mmol) were mixed in n- butanol (10 mL). To this reaction mixture, trifluoroacetic acid (75 mg, 0.65 mmol) was added at room temperature and allowed to stir for 72 hours at 150°C. Progress of the reaction was monitored by TLC. Reaction was cooled to r.t., water was added, and product was extracted with EA.
  • Step 2 Methyl (ls,4s)-4-((6-phenylpyridazin-3-yl)amino)bicyclo[2.2.1]heptane-l- carboxylate (1.4 g, 4.3 mmol) was dissolved in tetrahydrofuran: H2O (2:1, 15mL) and lithium hydroxide (541 mg, 12.9 mmol) was added at 0°C and reaction was allowed to stir for 6 hours at room temperature. Progress of the reaction was monitored by TLC.
  • Step 1 To a solution of 3 -aminoadamantane-1 -carboxylic acid hydrochloride (20 g, 86 mmol) in EtOH (140 mL) was added SOCE (10.3 g, 86.3 mmol) at room temperature. The reaction mixture was stirred for 4 hours at 80°C. Liquid chromatography-mass spectrometry (LCMS) showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to give a residue. Petroleum ether was then added, and the mixture was once again concentrated under reduced pressure at which point a solid began to precipitate, the process was repeated three more times.
  • LCMS Liquid chromatography-mass spectrometry
  • Step 2 To a solution of 3,6-dichloropyridazine (24 g, 162 mmol) in DMF (147 mL) was added ethyl 3-aminoadamantane-l-carboxylate hydrochloride (21.0 g, 80.8 mmol) and K 2 CO 3 (33.5 g, 243 mmol) at room temperature. The reaction mixture was stirred for 12 hours at 135°C. TLC showed the -50% of 3,6-dichloropyridazine remained and -20% of product was detected. The residue was diluted with water and extracted with EA.
  • Step 3 To a solution of ethyl 3-((6-chloropyridazin-3-yl)amino)adamantane-l- carboxylate (1.8 g, 5.4 mmol) in dimethyl ether (DME) (9 mL) and H2O (1.8 mL) was added phenylboronic acid (719 mg, 5.9 mmol) and Na 2 CC> 3 (2.84 g, 26.8 mmol) at room temperature. Pd(PPh3)2Cl2 (376 mg, 0.54 mmol) was added into above mixture at room temperature. The suspension was degassed under vacuum and purged with N2 three times, and the reaction mixture was stirred for 12 hours at 80°C.
  • DME dimethyl ether
  • N2 N2
  • Step 4 To a solution of ethyl 3-((6-phenylpyridazin-3-yl)amino)adamantane-l- carboxylate (800 mg, 2.12 mmol) in EtOH (3.2 mL) was added H2O (1.6 mL) and LiOH-H 2 0 (445 mg, 10.6 mmol) at room temperature. The reaction mixture was stirred for 12 hours at 40 ⁇ 45°C. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure to remove EtOH.
  • 5-Phenylpyrimidin-2-amine (10 mg, 0.058 mmol), 3-bromo-/V-((5-methylfuran-2- yl)methyl)benzamide (14.5 mg, 0.049 mmol), Pd2(dba)3 (0.9 mg, 0.00098 mmol), BrettPhos (5.3 mg, 0.0098 mmol), and cesium carbonate (32 mg, 0.098 mmol) were mixed in 1,4-dioxane (0.2 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous Na 2 S0 4 and concentrated.
  • [l,l’-Biphenyl]-4-amine (20 mg, 0.12 mmol), 3-bromo-/V-((5-methylfuran-2- yl)methyl)benzamide (29 mg, 0.098 mmol), Pd2(dba)3 (1.8 mg, 0.002 mmol), BrettPhos (10.6 mg, 0.020 mmol), and cesium carbonate (64 mg, 0.2 mmol) were mixed in 1,4-dioxane (1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous Na 2 S0 4 and concentrated.
  • Step 2 6-Phenylpyri din-3 -amine (20 mg, 0.12 mmol), 3-bromo-/V-((5-methylfuran-2- yl)methyl)benzamide (29 mg, 0.098 mmol), Pd 2 (dba) 3 (1.8 mg, 0.002 mmol), BrettPhos (10.5 mg, 0.02 mmol), and cesium carbonate (64 mg, 0.2 mmol) were mixed in 1,4-dioxane (0.8 mL) and heated in a microwave reactor for 60 minutes at 120°C.
  • reaction mixture was concentrated and purified by MPLC to give compound 6, /V-[(5-methylfuran-2-yl)methyl]-3- [(6-phenylpyridin-3-yl)amino]benzamide (34 mg, 91%) as a yellowish white solid.
  • Step 1 Furan-3-ylboronic acid (250 mg, 2.23 mmol), 6-bromopyridazin-3 -amine (324 mg, 1.86 mmol), Pd(PPh3)4 (108 mg, 0.093 mmol), and potassium carbonate (982 mg, 6.9 mmol) were mixed in H 2 0/l,4-dioxane (1.6/6.2 mL) and heated in a microwave reactor for 60 minutes at 100°C. The reaction mixture was concentrated and purified by MPLC to give 6- (furan-3-yl)pyridazin-3 -amine (265 mg, 88%) as a yellow solid.
  • Step 2 6-(Furan-3-yl)pyridazin-3 -amine (20 mg, 0.12 mmol), 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide (30 mg, 0.103 mmol), Pd2(dba)3 (1.9 mg, 0.002 mmol), BrettPhos (11 mg, 0.02 mmol), and cesium carbonate (67 mg, 0.21 mmol) were mixed in 1,4- dioxane (0.5 mL) and heated in a microwave reactor for 60 minutes at 120°C.
  • Step 1 Furan-2-ylboronic acid (250 mg, 2.23 mmol), 6-bromopyridazin-3 -amine (324 mg, 1.86 mmol), Pd(PPli3)4 (108 mg, 0.093 mmol), and potassium carbonate (952 mg, 6.9 mmol) were mixed in H 2 0/l,4-dioxane (1.6/6.2 mL) and heated in a microwave reactor for 60 minutes at 100°C. The reaction mixture was concentrated and purified by MPLC to give 6- (furan-2-yl)pyridazin-3 -amine (216 mg, 72%) as a yellow solid.
  • Step 2 6-(Furan-2-yl)pyridazin-3 -amine (20 mg, 0.12 mmol), 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide (30 mg, 0.103 mmol), Pd2(dba)3 (1.9 mg, 0.002 mmol), BrettPhos (11 mg, 0.02 mmol), and cesium carbonate (67 mg, 0.21 mmol) were mixed in 1,4- dioxane (0.5 mL) and heated in a microwave reactor for 60 minutes at 120°C.
  • Step 1 Pyridin-4-ylboronic acid (600 mg, 4.9 mmol), 6-bromopyridazin-3 -amine (354 mg, 2.03 mmol), Pd(PPh3)4 (227 mg, 0.2 mmol), and potassium carbonate (1 g, 7.5 mmol) were mixed in H 2 0/l,4-dioxane (1.7/6.8 mL) and heated in a microwave reactor for 90 minutes at 150°C. The reaction mixture was concentrated and purified by MPLC to give 6-(pyridin-4- yl)pyridazin-3 -amine (63 mg, 18%) as a yellowish white solid.
  • Step 2 6-(Pyridin-4-yl)pyridazin-3-amine (20 mg, 0.12 mmol), 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide (29 mg, 0.097 mmol), Pd2(dba)3 (1.8 mg, 0.0019 mmol), BrettPhos (10.4 mg, 0.019 mmol), and cesium carbonate (63 mg, 0.19 mmol) were mixed in 1,4-dioxane (0.5 mL) and heated in a microwave reactor for 90 minutes at 120°C.
  • reaction mixture was concentrated and purified by MPLC to give compound 9, A-[(5-methylfuran-2- yl)methyl]-3- ⁇ [6-(pyridin-4-yl)pyridazin-3-yl]amino ⁇ benzamide (18 mg, 48%) as an orange solid.
  • Step 1 Pyridin-3-ylboronic acid (250 mg, 2.03 mmol), 6-bromopyridazin-3 -amine (295 mg, 1.7 mmol), Pd(PPh3)4 (98 mg, 0.085 mmol), and potassium carbonate (867 mg, 6.3 mmol) were mixed in H 2 0/l,4-dioxane (1.4/5.6 mL) and heated in a microwave reactor for 60 minutes at 100°C. The reaction mixture was concentrated and purified by MPLC to give 6-(pyridin-3- yl)pyridazin-3 -amine (65 mg, 22%) as a yellowish white solid.
  • Step 2 6-(Pyri din-3 -yl)pyridazin-3 -amine (20 mg, 0.12 mmol), 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide (29 mg, 0.097 mmol), Pd2(dba)3 (1.8 mg, 0.0019 mmol), BrettPhos (10.4 mg, 0.019 mmol), and cesium carbonate (63 mg, 0.19 mmol) were mixed in 1,4-dioxane (0.5 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 Phenylboronic acid (250 mg, 2.05 mmol), 2-bromopyrimidin-5-amine (297 mg, 1.71 mmol), Pd(PPh3)4 (99 mg, 0.085 mmol), and potassium carbonate (874 mg, 6.3 mmol) were mixed in H 2 0/l,4-dioxane (1.4/5.7 mL) and heated in a microwave reactor for 60 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC to give 2- phenylpyrimidin-5-amine (100 mg, 34%) as a beige solid.
  • Step 2 2-Phenylpyrimidin-5-amine (20 mg, 0.12 mmol), 3-bromo-A-((5-methylfuran- 2-yl)methyl)benzamide (29 mg, 0.098 mmol), Pd2(dba)3 (1.8 mg, 0.002 mmol), BrettPhos (10.5 mg, 0.02 mmol), and cesium carbonate (64 mg, 0.2 mmol) were mixed in 1,4-dioxane (1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 Phenylboronic acid (300 mg, 2.5 mmol), 6-bromo-l,2,4-triazin-3-amine (359 mg, 2.05 mmol), Pd(PPh3)4 (119 mg, 0.103 mmol), and potassium carbonate (1 g, 7.59 mmol) were mixed in H 2 0/l,4-dioxane (1.7/6.8 mL) and heated in a microwave reactor for 60 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC to give 6-phenyl- l,2,4-triazin-3-amine (269 mg, 76%) as a yellowish white solid.
  • Step 2 6-Phenyl- 1, 2, 4-triazin-3 -amine (20 mg, 0.12 mmol), 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide (29 mg, 0.098 mmol), Pd2(dba)3 (1.8 mg, 0.002 mmol), BrettPhos (10.5 mg, 0.02 mmol), and cesium carbonate (64 mg, 0.2 mmol) were mixed in 1,4- dioxane (0.8 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 (4-Methoxyphenyl)boronic acid (200 mg, 1.3 mmol), 6-bromopyridazin-3- amine (191 mg, 1.1 mmol), Pd(PPh3)4 (63 mg, 0.06 mmol), and potassium carbonate (561 mg, 4.06 mmol) were mixed in H 2 0/l,4-dioxane (0.9/3.7 mL) and heated in a microwave reactor for 60 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC to give 6-(4-methoxyphenyl)pyridazin-3-amine (189 mg, 86%) as a white solid.
  • Step 2 6-(4-Methoxyphenyl)pyridazin-3-amine (20 mg, 0.1 mmol), 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide (24 mg, 0.08 mmol), Pd2(dba)3 (1.5 mg, 0.0017 mmol), BrettPhos (8.9 mg, 0.017 mmol), and cesium carbonate (54 mg, 0.17 mmol) were mixed in 1,4- dioxane (0.4 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and 3-morpholinopropan-l- amine (0.11 mL, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 25 hours at room temperature. The reaction mixture was concentrated and purified by MPLC. And the mixture was extracted by EA and brine. The organic layer was dried over anhydrous NaiSCL and concentrated to give 3-bromo- A-(3-morpholi nopropyl )benzamide (338 mg, >99%) as a brownish oil.
  • Step 2 6-Phenylpyridazin-3 -amine (20 mg, 0.12 mmol), 3-bromo-/V-(3- morpholinopropyl)benzamide (32 mg, 0.097 mmol), Pd2(dba)3 (8.9 mg, 0.0097 mmol), BrettPhos (10.5 mg, 0.019 mmol), and cesium carbonate (63 mg, 0.19 mmol) were mixed in 1,4-dioxane (0.5 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 (3,4-Dichlorophenyl)boronic acid (200 mg, 1.05 mmol), 6-bromopyridazin-3- amine (152 mg, 0.87 mmol), Pd(PPli3)4 (51 mg, 0.04 mmol), and potassium carbonate (447 mg, 3.23 mmol) were mixed in H 2 0/l,4-dioxane (0.7/2.9 mL) and heated in a microwave reactor for 60 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC to give 6-(3,4-di chi orophenyl)pyridazin-3 -amine (62 mg, 29%) as a yellowish white solid.
  • Step 2 6-(3,4-Dichlorophenyl)pyridazin-3 -amine (20 mg, 0.083 mmol), 3-bromo-A- ((5-methylfuran-2-yl)methyl)benzamide (20 mg, 0.07 mmol), Pd2(dba)3 (6.4 mg, 0.0069 mmol), BrettPhos (7.5 mg, 0.014 mmol), and cesium carbonate (45 mg, 0.14 mmol) were mixed in 1,4-dioxane (0.35 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and pyridin-4-ylmethanamine (0.08 mL, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.6 mmol) and stirred for 28 hours at room temperature. The reaction mixture was extracted by EA and saturated aq. NELCl. The organic layer was dried over anhydrous NaiSCL and concentrated to give 3 -bromo-A-(pyridin-4-yl methyl )benzamide (246 mg, >99%) as a brown oil.
  • Step 2 6-Phenylpyridazin-3 -amine (30 mg, 0.18 mmol), 3-bromo-/V-(pyridin-4- ylmethyl)benzamide (46 mg, 0.16 mmol), Pd2(dba)3 (14.6 mg, 0.016 mmol), BrettPhos (17 mg, 0.032 mmol), and cesium carbonate (104 mg, 0.32 mmol) were mixed in 1,4-dioxane (1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was extracted by MeOH/DCM (10: 1) and ELO.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and pyridin-2-ylmethanamine (0.08 mL, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 28 hours at room temperature. The reaction mixture was extracted by EA and saturated aq. NELCl. The organic layer was dried over anhydrous Na2SCL and concentrated to give 3 -bromo-A-(pyri din-2-yl methyl )benzamide (268 mg, >99%) as a brown oil.
  • Step 2 6-Phenylpyridazin-3 -amine (30 mg, 0.18 mmol), 3-bromo-/V-(pyridin-2- ylmethyl)benzamide (46 mg, 0.16 mmol), Pd2(dba)3 (14.6 mg, 0.016 mmol), BrettPhos (17 mg, 0.032 mmol), and cesium carbonate (104 mg, 0.32 mmol) were mixed in 1,4-dioxane (1 mL) and heated in a microwave reactor for 90 minutes at 120°C.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and pyridin-3-ylmethanamine (0.08 mL, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 26 hours at room temperature. The reaction mixture was extracted by EA and saturated aq. NELCl. The organic layer was dried over anhydrous Na2SCL and concentrated to give 3 -bromo-A-(pyridin-3-yl methyl )benzamide (268 mg, >99%) as a brown oil.
  • Step 2 6-Phenylpyridazin-3 -amine (30 mg, 0.18 mmol), 3-bromo-/V-(pyridin-3- ylmethyl)benzamide (46 mg, 0.16 mmol), Pd2(dba)3 (14.6 mg, 0.016 mmol), BrettPhos (17 mg, 0.032 mmol), and cesium carbonate (104 mg, 0.32 mmol) were mixed in 1,4-dioxane (1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-/V-(3-(pyrrolidin-l- yl)propyl)benzamide (121 mg, 0.19 mmol), Pd2(dba)3 (18 mg, 0.019 mmol), BrettPhos (21 mg, 0.039 mmol), and cesium carbonate (127 mg, 0.39 mmol) were mixed in 1,4-dioxane (1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was extracted by EA and saturated aq. NELCl. The organic layer was dried over anhydrous NaiSCL and concentrated.
  • Step 1 4-Iodobenzoyl chloride (288 mg, 1.08 mmol) and (5-methylfuran-2- yl)methanamine (0.98 mL, 0.9 mmol) were dissolved in DCM (9 mL), followed up by addition of DIPEA (0.34 mL, 1.9 mmol) and stirred for 22 hours at room temperature. The reaction mixture was extracted by EA and saturated aq. NEECl. The organic layer was dried over anhydrous NaiSCE and concentrated. The residue was purified by MPLC to give 4-iodo-A-((5- methylfuran-2-yl)methyl)benzamide (295 mg, 96%) as a beige solid.
  • Step 2 6-Phenylpyridazin-3 -amine (100 mg, 0.58 mmol), 4-iodo-/V-((5-methylfuran-2- yl)methyl)benzamide (219 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), BrettPhos (63 mg, 0.12 mmol), and cesium carbonate (381 mg, 1.17 mmol) were mixed in 1,4-dioxane (4 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • 6-(Pyridin-2-yl)pyridazin-3-amine (30 mg, 0.17 mmol), 3-bromo-A-((5-methylfuran-2- yl)methyl)benzamide (46 mg, 0.16 mmol), Pd2(dba)3 (14 mg, 0.016 mmol), BrettPhos (17 mg, 0.03 mmol), and cesium carbonate (103 mg, 0.32 mmol) were mixed in 1,4-dioxane (1.1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was extracted by MeOH/DCM (1:10) and brine. The organic layer was dried over anhydrous Na 2 S0 4 and concentrated. The residue was purified by MPLC.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and 2,2-dimethylpropan-l- amine (0.08 mL, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 26 hours at room temperature. The reaction mixture was concentrated and purified by MPLC to give 3-bromo-A-neopentylbenzamide (166 mg, 66%) as a white solid.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-A- neopentylbenzamide (63 mg, 0.23 mmol), Pd 2 (dba) 3 (21 mg, 0.023 mmol), BrettPhos (25 mg, 0.046 mmol), and cesium carbonate (151 mg, 0.46 mmol) were mixed in 1,4-dioxane (1.1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and cyclobutanamine (54 mg, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 25 hours at room temperature. The reaction mixture was concentrated and purified by MPLC to give 3-bromo-A-cyclobutylbenzamide (201 mg, >99%) as a white solid.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-/V- cyclobutylbenzamide (54 mg, 0.21 mmol), Pd 2 (dba) 3 (20 mg, 0.021 mmol), BrettPhos (23 mg, 0.042 mmol), and cesium carbonate (138 mg, 0.42 mmol) were mixed in 1,4-dioxane (1.1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC. The crude mixture was solidified by using DCM to give compound 25, /V-cyclobutyl-3-[(6-phenylpyridazin-3-yl)amino]benzamide (20 mg, 27%) as a white solid.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and oxetan-3 -amine (56 mg, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 23 hours at room temperature. The reaction mixture was concentrated and purified by MPLC to give 3-bromo-A-(oxetan-3-yl)benzamide (197 mg, >99%) as a white solid.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-/V-(oxetan-3- yl)benzamide (54 mg, 0.21 mmol), Pd2(dba)3 (20 mg, 0.021 mmol), BrettPhos (23 mg, 0.042 mmol), and cesium carbonate (138 mg, 0.42 mmol) were mixed in 1,4-dioxane (1.1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and 2-(pyridin-4-yl)ethan-l- amine (93 mg, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 26 hours at room temperature. The reaction mixture was extracted by EA and saturated aq. NELCl. The organic layer was dried over anhydrous Na 2 SC> 4 and concentrated. The residue was purified by MPLC to give 3-bromo-A- (2-(pyridin-4-yl)ethyl)benzamide (170 mg, 73%) as a beige solid.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-/V-(2-(pyridin-4- yl)ethyl)benzamide (65 mg, 0.21 mmol), Pd2(dba)3 (20 mg, 0.021 mmol), BrettPhos (23 mg, 0.042 mmol), and cesium carbonate (138 mg, 0.42 mmol) were mixed in 1,4-dioxane (1.4 mL) and heated in a microwave reactor for 90 minutes at 120°C.
  • Step 1 3-Bromobenzoyl chloride (200 mg, 0.91 mmol) and tetrahydro-2//-pyran-4- amine hydrochloride (104 mg, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.42 mL, 2.4 mmol) and stirred for 20 hours at room temperature. The reaction mixture was concentrated and purified by MPLC to give 3-bromo-A-(tetrahydro-2//- pyran-4-yl)benzamide (206 mg, 96%) as a white solid.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-A-(tetrahydro-2//- pyran-4-yl)benzamide (60 mg, 0.21 mmol), Pd2(dba)3 (20 mg, 0.021 mmol), BrettPhos (23 mg, 0.042 mmol), and cesium carbonate (138 mg, 0.42 mmol) were mixed in 1,4-dioxane (1.1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and 3-fluoroaniline (84 mg, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 22 hours at room temperature. The reaction mixture was concentrated and purified by MPLC to give 3 -bromo-A-(3 -fluorophenyl )benzamide (223 mg, >99%) as a white solid.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-/V-(3- fluorophenyl)benzamide (62 mg, 0.21 mmol), Pd2(dba)3 (20 mg, 0.021 mmol), BrettPhos (23 mg, 0.042 mmol), and cesium carbonate (138 mg, 0.42 mmol) were mixed in 1,4-dioxane (1.1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and cyclobutylmethanamine hydrochloride (92 mg, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.42 mL, 2.4 mmol) and stirred for 19 hours at room temperature. The reaction mixture was concentrated and purified by MPLC to give 3-bromo-A- (cyclobutylmethyl)benzamide (210 mg, >99%) as a white solid.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-A- (cyclobutylmethyl)benzamide (57 mg, 0.21 mmol), Pd 2 (dba) 3 (20 mg, 0.021 mmol), BrettPhos (23 mg, 0.042 mmol), and cesium carbonate (138 mg, 0.42 mmol) were mixed in 1,4-dioxane (1.1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC. The crude mixture was solidified by using EA to give compound 30, /V-(cyclobutylmethyl)-3-[(6-phenylpyridazin-3-yl)amino]benzamide (24 mg, 31%) as a white solid.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and cyclohexylmethanamine (86 mg, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 19 hours at room temperature. The reaction mixture was concentrated and purified by MPLC to give 3 -bromo-A-(cyclohexyl methyl )benzamide (192 mg, 86%) as a white solid.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-A- (cyclohexylmethyl)benzamide (63 mg, 0.21 mmol), Pd 2 (dba) 3 (20 mg, 0.021 mmol), BrettPhos (23 mg, 0.042 mmol), and cesium carbonate (138 mg, 0.42 mmol) were mixed in 1,4-dioxane
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-A- (cyclopropylmethyl)benzamide (59 mg, 0.23 mmol), Pd 2 (dba) 3 (21 mg, 0.023 mmol), BrettPhos (25 mg, 0.046 mmol), and cesium carbonate (152 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.2 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and cyclopentylmethanamine hydrochloride (103 mg, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.42 mL, 2.4 mmol) and stirred for 19 hours at room temperature. The reaction mixture was concentrated and purified by MPLC to give 3-bromo-A- (cyclopentylmethyl)benzamide (210 mg, 98%) as a white solid.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-A- (cyclopentylmethyl)benzamide (66 mg, 0.23 mmol), Pd 2 (dba) 3 (21 mg, 0.023 mmol),
  • Step 1 3-Bromobenzoyl chloride (200 mg, 0.91 mmol) and (tetrahydro-2//-pyran-4- yl)methanamine (88 mg, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 21 hours at room temperature. The reaction mixture was concentrated and purified by MPLC to give 3-bromo-A-((tetrahydro-2//- pyran-4-yl)methyl)benzamide (163 mg, 72%) as a white solid.
  • Step 2 6-Phenylpyridazin-3 -amine (49 mg, 0.29 mmol), 3-bromo-A-((tetrahydro-2//- pyran-4-yl)methyl)benzamide (85 mg, 0.29 mmol), Pd2(dba)3 (26 mg, 0.03 mmol), BrettPhos (31 mg, 0.06 mmol), and cesium carbonate (186 mg, 0.57 mmol) were mixed in 1,4-dioxane (1.4 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and oxetan-3-ylmethanamine (66 mg, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 23 hours at room temperature. The reaction mixture was concentrated and purified by MPLC to give 3 -bromo-A-(oxetan-3 -yl methyl )benzamide (195 mg, 95%) as a yellow oil.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-/V-(oxetan-3- ylmethyl)benzamide (63 mg, 0.23 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), BrettPhos (25 mg, 0.046 mmol), and cesium carbonate (152 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.2 mL) and heated in a microwave reactor for 90 minutes at 120°C.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and (3,4- dichlorophenyl)methanamine (134mg, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 22 hours at room temperature. The reaction mixture was concentrated and purified by MPLC to give 3-bromo-/V-(3,4- dichlorobenzyl)benzamide(268 mg, 98%) as a white solid.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-/V-(3,4- dichlorobenzyl)benzamide (94 mg, 0.23 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), BrettPhos (25 mg, 0.046 mmol), and cesium carbonate (152 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.2 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • 6-Phenylpyridazin-3 -amine 40 mg, 0.23 mmol
  • 3-bromo-A-ethylbenzamide 64 mg, 0.28 mmol
  • Pd2(dba)3 21 mg, 0.023 mmol
  • BrettPhos 25 mg, 0.046 mmol
  • cesium carbonate 152 mg, 0.47 mmol
  • 6-Phenylpyridazin-3 -amine 40 mg, 0.23 mmol
  • 3-bromo-/V-cyclopropylbenzamide 67 mg, 0.28 mmol
  • Pd2(dba)3 21 mg, 0.023 mmol
  • BrettPhos 25 mg, 0.046 mmol
  • cesium carbonate 152 mg, 0.47 mmol
  • 1,4-dioxane 1.2 mL
  • the reaction mixture was concentrated and purified by MPLC.
  • the crude mixture was solidified by using EA to give compound 38, N- cyclopropyl-3-[(6-phenylpyridazin-3-yl)amino]benzamide (25 mg, 33%) as a white solid.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and thiophen-2- ylmethanamine (86 mg, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 18 hours at room temperature. The reaction mixture was concentrated and purified by MPLC to give 3-bromo-A-(thiophen-2- ylmethyl)benzamide (206 mg, 92%) as a beige solid.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-/V-(thiophen-2- ylmethyl)benzamide (76 mg, 0.26 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), BrettPhos (25 mg, 0.046 mmol), and cesium carbonate (152 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.2 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and (5-methylthiophen-2- yl)methanamine hydrochloride (54 mg, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 2.4 mmol) and stirred for 25 hours at room temperature. The reaction mixture was concentrated and purified by MPLC to give 3-bromo-A- ((5-methylthiophen-2-yl)methyl)benzamide (236 mg, >99%) as a beige solid.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-/V-((5- methylthiophen-2-yl)methyl)benzamide (80 mg, 0.26 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), BrettPhos (25 mg, 0.046 mmol), and cesium carbonate (152 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.2 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • 6-Cy cl opropylpyridazin-3 -amine 40 mg, 0.3 mmol
  • 3-bromo-A-((5-methylfuran-2- yl)methyl)benzamide 111 mg, 0.38 mmol
  • Pd2(dba)3 27 mg, 0.03 mmol
  • BrettPhos 32 mg, 0.06 mmol
  • cesium carbonate (193 mg, 0.59 mmol) were mixed in 1,4-dioxane (1.5 mL) and heated in a microwave reactor for 90 minutes at 120°C.
  • the reaction mixture was concentrated and purified by MPLC.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and thiophen-3- ylmethanamine (0.075 mL, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 23 hours at room temperature. The reaction mixture was extracted by EA and saturated aq. NLLCl. The organic layer was dried over anhydrous NaiSCL and concentrated to give 3 -bromo-A-(thi ophen-3-yl methyl )benzamide (259 mg, >99%) as a brown solid.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-/V-(thiophen-3- ylmethyl)benzamide (103 mg, 0.35 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), BrettPhos (25 mg, 0.047 mmol), and cesium carbonate (152 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.2 mL) and heated in a microwave reactor for 90 minutes at 120°C.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and furan-3-ylmethanamine (0.082 mL, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 28 hours at room temperature. The reaction mixture was extracted by EA and saturated aq. NLLCl. The organic layer was dried over anhydrous NaiSCL and concentrated to give 3 -bromo-A-(furan-3 -yl methyl )benzamide (252 mg, >99%) as a brown oil.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-/V-(furan-3- ylmethyl)benzamide (98 mg, 0.35 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), BrettPhos (25 mg, 0.047 mmol), and cesium carbonate (152 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.2 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and furan-2-ylmethanamine (0.08 mL, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 25 hours at room temperature. The reaction mixture was extracted by EA and saturated aq. NELCl. The organic layer was dried over anhydrous NaiSCL and concentrated to give 3 -bromo-A-(furan-2-yl methyl )benzamide (285 mg, >99%) as a brown oil.
  • Step 2 6-Phenylpyridazin-3 -amine (40 mg, 0.23 mmol), 3-bromo-/V-(furan-2- ylmethyl)benzamide (98 mg, 0.35 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), BrettPhos (25 mg, 0.047 mmol), and cesium carbonate (152 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.2 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • 6-Methylpyridazin-3 -amine 35 mg, 0.32 mmol
  • 3-bromo-/V-((5-methylfuran-2- yl)methyl)benzamide 123 mg, 0.42 mmol
  • Pd2(dba)3 29 mg, 0.03 mmol
  • BrettPhos 34 mg, 0.06 mmol
  • cesium carbonate 209 mg, 0.64 mmol
  • 6-(Tetrahydro-2iT-pyran-4-yl)pyridazin-3 -amine 40 mg, 0.22 mmol
  • 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide 85 mg, 0.29 mmol
  • Pd2(dba)3 20 mg, 0.021 mmol
  • BrettPhos 23 mg, 0.042 mmol
  • cesium carbonate 145 mg, 0.45 mmol
  • Step 1 (3-Fluorophenyl)boronic acid (300 mg, 2.1 mmol), 4-bromoaniline (307 mg, 1.79 mmol), Pd(PPli3)4 (103 mg, 0.09 mmol) and potassium carbonate (740 mg, 5.36 mmol) were mixed in H2O/DMF (4.3/4.3 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was concentrated and purified by MPLC to give 3’-fluoro-[l,l’- biphenyl]-4-amine (276 mg, 82%) as a beige solid.
  • Step 2 3’-Fluoro-[l,l’-biphenyl]-4-amine (40 mg, 0.21 mmol), 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide (82 mg, 0.28 mmol), Pd2(dba)3 (20 mg, 0.02 mmol), BrettPhos (23 mg, 0.042 mmol), and cesium carbonate (139 mg, 0.43 mmol) were mixed in 1,4-dioxane (1.1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 (3-Fluorophenyl)boronic acid (300 mg, 2.1 mmol), 5-bromopyrazin-2-amine (311 mg, 1.79 mmol), Pd(PPli3)4 (103 mg, 0.09 mmol) and potassium carbonate (740 mg, 5.36 mmol) were mixed in H2O/DMF (4.3/4.3 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was concentrated and purified by MPLC to give 5-(3- fluorophenyl)pyrazin-2-amine (277 mg, 82%) as a yellowish white solid.
  • Step 2 5-(3-Fluorophenyl)pyrazin-2-amine (40 mg, 0.23 mmol), 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide (80 mg, 0.27 mmol), Pd2(dba)3 (20 mg, 0.021 mmol), BrettPhos (23 mg, 0.042 mmol), and cesium carbonate (138 mg, 0.42 mmol) were mixed in 1,4-dioxane (1.1 mL) and heated in a microwave reactor for 90 minutes at 120°C.
  • 6-Isobutylpyridazin-3 -amine 44 mg, 0.29 mmol
  • 3-bromo-/V-((5-methylfuran-2- yl)methyl)benzamide 110 mg, 0.37 mmol
  • Pd2(dba)3 26 mg, 0.03 mmol
  • BrettPhos 31 mg, 0.06 mmol
  • cesium carbonate 188 mg, 0.58 mmol
  • 6-Cy cl opentylpyridazin-3 -amine 47 mg, 0.29 mmol
  • 3-bromo-/V-((5-methylfuran-2- yl)methyl)benzamide 110 mg, 0.37 mmol
  • Pd2(dba)3 26 mg, 0.03 mmol
  • BrettPhos 31 mg, 0.06 mmol
  • cesium carbonate 188 mg, 0.58 mmol
  • 6-Cy cl ohexylpyridazin-3 -amine 51 mg, 0.29 mmol
  • 3-bromo-/V-((5-methylfuran-2- yl)methyl)benzamide 110 mg, 0.37 mmol
  • Pd2(dba)3 26 mg, 0.03 mmol
  • BrettPhos 31 mg, 0.06 mmol
  • cesium carbonate 188 mg, 0.58 mmol
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and 2-methylpropan-2-amine (0.08 mL, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 31 hours at room temperature. The reaction mixture was extracted by EA and saturated aq. NH 4 CI. The organic layer was dried over anhydrous NaiSCL and concentrated to give 3-bromo-A-(/c/V-butyl)benzamide (209 mg, >99%) as a brown oil.
  • Step 2 6-Phenylpyridazin-3 -amine (45 mg, 0.26 mmol), 3-bromo -N-(tert- butyl)benzamide (88 mg, 0.34 mmol), Pd 2 (dba) 3 (24 mg, 0.026 mmol), BrettPhos (28 mg, 0.053 mmol), and cesium carbonate (171 mg, 0.53 mmol) were mixed in 1,4-dioxane (1.3 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and pentan-3 -amine (0.09 mL, 0.76 mmol) were dissolved in DCM (7.6 mL), followed up by addition of DIPEA (0.28 mL, 1.63 mmol) and stirred for 31 hours at room temperature. The reaction mixture was extracted by EA and saturated aq. NELCl. The organic layer was dried over anhydrous NaiSCL and concentrated to give 3 -bromo-A -(pentan-3 -yl)benzamide (238 mg, >99%) as a brown oil.
  • Step 2 6-Phenylpyridazin-3 -amine (45 mg, 0.26 mmol), 3-bromo-/V-(pentan-3- yl)benzamide (106 mg, 0.39 mmol), Pd2(dba)3 (24 mg, 0.026 mmol), BrettPhos (28 mg, 0.053 mmol), and cesium carbonate (171 mg, 0.53 mmol) were mixed in 1,4-dioxane (1.3 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • 6-(l-Methylpiperidin-4-yl)pyridazin-3 -amine 50 mg, 0.26 mmol
  • 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide 100 mg, 0.34 mmol
  • Pd2(dba)3 24 mg, 0.03 mmol
  • BrettPhos 28 mg, 0.05 mmol
  • cesium carbonate 170 mg, 0.52 mmol
  • Step 1 (3,5-Dimethylisoxazol-4-yl)boronic acid (200 mg, 1.3 mmol), 6- bromopyridazin-3 -amine (150 mg, 0.86 mmol), Pd(PPli3)4 (50 mg, 0.04 mmol) and potassium carbonate (357 mg, 2.59 mmol) were mixed in H2O/DMF (1.7/1.7 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was concentrated and purified by MPLC to give 6-(3,5-dimethylisoxazol-4-yl)pyridazin-3-amine (51 mg, 31%) as a white solid.
  • Step 2 6-(3,5-Dimethylisoxazol-4-yl)pyridazin-3-amine (45 mg, 0.24 mmol), 3-bromo- /V-((5-methylfuran-2-yl)methyl)benzamide (90 mg, 0.31 mmol), Pd2(dba)3 (22 mg, 0.024 mmol), BrettPhos (25 mg, 0.047 mmol), and cesium carbonate (153 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.2 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 Thiophen-3-ylboronic acid (132 mg, 1.03 mmol), 6-bromopyridazin-3 -amine (150 mg, 0.86 mmol), Pd(PPli3)4 (50 mg, 0.04 mmol) and potassium carbonate (357 mg, 2.59 mmol) were mixed in LLO/DMF (1.7/1.7 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was concentrated and purified by MPLC to give 6- (thiophen-3-yl)pyridazin-3 -amine (122 mg, 79%) as a yellowish white solid.
  • Step 2 6-(Thiophen-3-yl)pyridazin-3 -amine (42 mg, 0.24 mmol), 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide (90 mg, 0.31 mmol), Pd2(dba)3 (22 mg, 0.024 mmol), BrettPhos (25 mg, 0.047 mmol), and cesium carbonate (153 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.2 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 (4-Methylthiophen-3-yl)boronic acid (147 mg, 1.03 mmol), 6-bromopyridazin- 3-amine (150 mg, 0.86 mmol), Pd(PPh3)4 (50 mg, 0.04 mmol), and potassium carbonate (357 mg, 2.59 mmol) were mixed in H2O/DMF (1.7/1.7 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was concentrated and purified by MPLC to give 6-
  • Step 2 6-(4-Methylthiophen-3-yl)pyridazin-3 -amine (45 mg, 0.24 mmol), 3-bromo-/V- ((5-methylfuran-2-yl)methyl)benzamide (90 mg, 0.31 mmol), Pd2(dba)3 (22 mg, 0.024 mmol), BrettPhos (25 mg, 0.047 mmol), and cesium carbonate (153 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.2 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 (4-Chlorophenyl)boronic acid (200 mg, 1.28 mmol), 6-bromopyridazin-3 -amine (290 mg, 1.66 mmol), Pd(PPli3)4 (74 mg, 0.064 mmol), and potassium carbonate (530 mg, 3.84 mmol) were mixed in H2O/DMF (2.6/2.6 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous Na 2 S0 4 and concentrated. The crude mixture was solidified by using EA and HEX to give 6-(4-chlorophenyl)pyridazin-3 -amine (175 mg, 66%) as a yellow solid.
  • Step 2 6-(4-Chlorophenyl)pyridazin-3-amine (48 mg, 0.24 mmol), 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide (90 mg, 0.31 mmol), Pd2(dba)3 (22 mg, 0.024 mmol), BrettPhos (25 mg, 0.047 mmol), and cesium carbonate (153 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.2 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • 6-Phenethylpyridazin-3 -amine 47 mg, 0.24 mmol
  • 3-bromo-A-((5-methylfuran-2- yl)methyl)benzamide 90 mg, 0.31 mmol
  • Pd2(dba)3 22 mg, 0.024 mmol
  • BrettPhos 25 mg, 0.047 mmol
  • cesium carbonate 153 mg, 0.47 mmol
  • 6-(4-Fluorophenethyl)pyridazin-3-amine 51 mg, 0.24 mmol
  • 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide 90 mg, 0.31 mmol
  • Pd2(dba)3 22 mg, 0.024 mmol
  • BrettPhos 25 mg, 0.047 mmol
  • cesium carbonate 153 mg, 0.47 mmol
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and 2-(3- methoxyphenyl)ethan-l -amine (0.13 mL, 0.91 mmol) were dissolved in DCM (9.1 mL), followed up by addition of DIPEA (0.34 mL, 1.96 mmol) and stirred for 18 hours at room temperature. The reaction mixture was extracted by EA and saturated aq. NH 4 C 1 . The organic layer was dried over anhydrous NaiSCL and concentrated to give 3-bromo-N-(3- methoxyphenethyl)benzamide (370 mg, >99%) as a yellow oil.
  • Step 2 5-(3-Fluorophenyl)pyrimidin-2-amine (40 mg, 0.21 mmol), 3-bromo-/V-(3- methoxyphenethyl)benzamide (103 mg, 0.25 mmol), Pd2(dba)3 (20 mg, 0.021 mmol), BrettPhos (23 mg, 0.042 mmol), and cesium carbonate (138 mg, 0.42 mmol) were mixed in 1,4-dioxane (1.1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and 2-(3,5- difluorophenyl)ethan-l -amine (0.12 mL, 0.91 mmol) were dissolved in DCM (9.1 mL), followed up by addition of DIPEA (0.34 mL, 1.96 mmol) and stirred for 22 hours at room temperature. The reaction mixture was extracted by EA and saturated aq. NELCl. The organic layer was dried over anhydrous Na2SCL and concentrated to give 3-bromo-A-(3,5- difluorophenethyl)benzamide (320 mg, >99%) as an orange solid.
  • Step 2 5-Phenylpyrimidin-2-amine (40 mg, 0.23 mmol), 3-bromo-/V-(3,5- difluorophenethyl)benzamide (99 mg, 0.28 mmol), Pd 2 (dba) 3 (21 mg, 0.023 mmol), BrettPhos (25 mg, 0.047 mmol), and cesium carbonate (152 mg, 0.47 mmol) were mixed in 1,4-dioxane
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and 2-(4- methoxyphenyl)ethan-l -amine (0.13 mL, 0.91 mmol) were dissolved in DCM (9.1 mL), followed up by addition of DIPEA (0.34 mL, 1.96 mmol) and stirred for 22 hours at room temperature. The reaction mixture was extracted by EA and saturated aq. NELCl. The organic layer was dried over anhydrous Na 2 SC> 4 and concentrated to give 3-bromo-A-(4- methoxyphenethyl)benzamide (325 mg, >99%) as a beige solid.
  • Step 2 5-Phenylpyrimidin-2-amine (40 mg, 0.23 mmol), 3-bromo-/V-(4- methoxyphenethyl)benzamide (100 mg, 0.28 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), BrettPhos (25 mg, 0.047 mmol), and cesium carbonate (152 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.2 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • 6-Ethylpyridazin-3 -amine 28 mg, 0.23 mmol
  • 3-bromo-A-((5-methylfuran-2- yl)methyl)benzamide 80 mg, 0.27 mmol
  • Pd2(dba)3 21 mg, 0.023 mmol
  • BrettPhos 24 mg, 0.045 mmol
  • cesium carbonate 147 mg, 0.45 mmol
  • 6-Isopropylpyridazin-3 -amine 31 mg, 0.23 mmol
  • 3-bromo-A-((5-methylfuran-2- yl)methyl)benzamide 80 mg, 0.27 mmol
  • Pd2(dba)3 21 mg, 0.023 mmol
  • BrettPhos 24 mg, 0.045 mmol
  • cesium carbonate 147 mg, 0.45 mmol
  • 6-(Tetrahydrofuran-2-yl)pyridazin-3 -amine 40 mg, 0.24 mmol
  • 3-bromo-A-((5- methylfuran-2-yl)methyl)benzamide 98 mg, 0.29 mmol
  • Pd2(dba)3 30 mg, 0.024 mmol
  • BrettPhos 26 mg, 0.048 mmol
  • cesium carbonate 158 mg, 0.48 mmol
  • 6-(Tetrahydrofuran-3-yl)pyridazin-3 -amine 40 mg, 0.24 mmol
  • 3-bromo-A-((5- methylfuran-2-yl)methyl)benzamide 98 mg, 0.29 mmol
  • Pd2(dba)3 30 mg, 0.024 mmol
  • BrettPhos 26 mg, 0.048 mmol
  • cesium carbonate 158 mg, 0.48 mmol
  • Step 1 3-Bromobenzoyl chloride (0.12 mL, 0.91 mmol) and 2-(3-fluorophenyl)ethan- 1-amine (0.12 mL, 0.91 mmol) were dissolved in DCM (9.1 mL), followed up by addition of DIPEA (0.34 mL, 1.96 mmol) and stirred for 22 hours at room temperature. The reaction mixture was extracted by EA and saturated aq. NH 4 CI. The organic layer was dried over anhydrous NaiSCL and concentrated to give 3-bromo-A-(3-fluorophenethyl)benzamide (340 mg, >99%) as a yellow oil.
  • Step 2 5-Phenylpyrimidin-2-amine (40 mg, 0.23 mmol), 3-bromo-/V-(3- fluorophenethyl)benzamide (105 mg, 0.28 mmol), Pd 2 (dba) 3 (29 mg, 0.023 mmol), BrettPhos (25 mg, 0.047 mmol), and cesium carbonate (152 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.2 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 (5-Methylfuran-2-yl)boronic acid (144 mg, 0.69 mmol), 5-bromopyrimidin-2- amine (100 mg, 0.57 mmol), Pd(PPli3)4 (33 mg, 0.03 mmol), and potassium carbonate (238 mg, 1.72 mmol) were mixed in H2O/DMF (1.1/1.1 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous NaiSCri and concentrated. The residue was purified by MPLC to give 5- (5-methylfuran-2-yl)pyrimidin-2-amine (66 mg, 66%) as a yellowish white solid.
  • Step 2 5-(5-Methylfuran-2-yl)pyrimidin-2-amine (60 mg, 0.17 mmol), 3-bromo-A-((5- methylfuran-2-yl)methyl)benzamide (60 mg, 0.21 mmol), Pd2(dba)3 (21 mg, 0.017 mmol), BrettPhos (18 mg, 0.034 mmol), and cesium carbonate (112 mg, 0.34 mmol) were mixed in 1,4-dioxane (0.86 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 (2-(Trifluoromethyl)phenyl)boronic acid (131 mg, 0.69 mmol), 5- bromopyrimidin-2-amine (100 mg, 0.57 mmol), Pd(PPh3)4 (33 mg, 0.03 mmol), and potassium carbonate (238 mg, 1.72 mmol) were mixed in H2O/DMF (1.1/1.1 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous NaiSCri and concentrated. The residue was purified by MPLC to give 5-(2-(trifluoromethyl)phenyl)pyrimidin-2-amine (31 mg, 23%) as a yellow solid.
  • Step 2 5-(2-(Trifluoromethyl)phenyl)pyrimidin-2-amine (30 mg, 0.13 mmol), 3- bromo-/V-((5-methylfuran-2-yl)methyl)benzamide (44 mg, 0.15 mmol), Pd 2 (dba) 3 (12 mg, 0.013 mmol), BrettPhos (14 mg, 0.025 mmol), and cesium carbonate (82 mg, 0.25 mmol) were mixed in 1,4-dioxane (0.63 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 (3-(Trifluoromethyl)phenyl)boronic acid (131 mg, 0.69 mmol), 5- bromopyrimidin-2-amine (100 mg, 0.57 mmol), Pd(PPh3)4 (33 mg, 0.03 mmol), and potassium carbonate (238 mg, 1.72 mmol) were mixed in H2O/DMF (1.1/1.1 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous Na 2 S0 4 and concentrated. The crude mixture was solidified by using MeOH to give 5-(3-(trifluoromethyl)phenyl)pyrimidin-2- amine (54 mg, 40%) as a beige solid.
  • Step 2 5-(3-(Trifluoromethyl)phenyl)pyrimidin-2-amine (40 mg, 0.17 mmol), 3- bromo-/V-((5-methylfuran-2-yl)methyl)benzamide (59 mg, 0.2 mmol), Pd 2 (dba) 3 (15 mg, 0.017 mmol), BrettPhos (18 mg, 0.034 mmol), and cesium carbonate (109 mg, 0.33 mmol) were mixed in 1,4-dioxane (0.84 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 (4-(Trifluoromethyl)phenyl)boronic acid (131 mg, 0.69 mmol), 5- bromopyrimidin-2-amine (100 mg, 0.57 mmol), Pd(PPh3)4 (33 mg, 0.03 mmol), and potassium carbonate (238 mg, 1.72 mmol) were mixed in H2O/DMF (1.1/1.1 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous NaiSCri and concentrated. The crude mixture was solidified by using MeOH to give 5-(4-(trifluoromethyl)phenyl)pyrimidin-2- amine (49 mg, 36%) as a beige solid.
  • Step 2 5-(4-(Trifluoromethyl)phenyl)pyrimidin-2-amine (40 mg, 0.17 mmol), 3- bromo-/V-((5-methylfuran-2-yl)methyl)benzamide (59 mg, 0.2 mmol), Pd 2 (dba) 3 (15 mg, 0.017 mmol), BrettPhos (18 mg, 0.034 mmol), and cesium carbonate (109 mg, 0.33 mmol) were mixed in 1,4-dioxane (0.84 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 (3-(Ethoxycarbonyl)phenyl)boronic acid (268 mg, 1.38 mmol), 5- bromopyrimidin-2-amine (200 mg, 1.15 mmol), Pd(PPli3)4 (66 mg, 0.06 mmol), and potassium carbonate (477 mg, 3.45 mmol) were mixed in H2O/DMF (2.3/2.3 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous NaiSCri and concentrated. The crude mixture was solidified by using MeOH to give ethyl 3-(2-aminopyrimidin-5-yl)benzoate (130 mg, 47%) as a beige solid.
  • Step 2 Ethyl 3-(2-aminopyrimidin-5-yl)benzoate (100 mg, 0.41 mmol), 3-bromo-A- ((5-methylfuran-2-yl)methyl)benzamide (145 mg, 0.49 mmol), Pd2(dba)3 (38 mg, 0.041 mmol), BrettPhos (44 mg, 0.082 mmol), and cesium carbonate (268 mg, 0.82 mmol) were mixed in 1,4-dioxane (2.1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 (4-(Ethoxycarbonyl)phenyl)boronic acid (268 mg, 1.38 mmol), 5- bromopyrimidin-2-amine (200 mg, 1.15 mmol), Pd(PPli3)4 (66 mg, 0.06 mmol), and potassium carbonate (477 mg, 3.45 mmol) were mixed in H2O/DMF (2.3/2.3 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous Na 2 S0 4 and concentrated. The crude mixture was solidified by using MeOH to give ethyl 4-(2-aminopyrimidin-5-yl)benzoate (117 mg, 42%) as a beige solid.
  • Step 2 Ethyl 4-(2-aminopyrimidin-5-yl)benzoate (100 mg, 0.41 mmol), 3-bromo-A- ((5-methylfuran-2-yl)methyl)benzamide (145 mg, 0.49 mmol), Pd2(dba)3 (38 mg, 0.041 mmol), BrettPhos (44 mg, 0.082 mmol), and cesium carbonate (268 mg, 0.82 mmol) were mixed in 1,4-dioxane (2.1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 Benzo[ ][l,3]dioxol-5-ylboronic acid (171 mg, 0.69 mmol), 5- bromopyrimidin-2-amine (100 mg, 0.57 mmol), Pd(PPh3)4 (33 mg, 0.03 mmol), and potassium carbonate (238 mg, 1.72 mmol) were mixed in H2O/DMF (1.1/1.1 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous NaiSCri and concentrated. The crude mixture was solidified by using MeOH to give 5-(benzo[ ][l,3]dioxol-5-yl)pyrimidin-2-amine (72 mg, 58%) as a beige solid.
  • Step 2 5-(Benzo[ ][l,3]dioxol-5-yl)pyrimidin-2-amine (40 mg, 0.19 mmol), 3-bromo- /V-((5-methylfuran-2-yl)methyl)benzamide (66 mg, 0.22 mmol), Pd2(dba)3 (17 mg, 0.019 mmol), BrettPhos (20 mg, 0.037 mmol), and cesium carbonate (121 mg, 0.37 mmol) were mixed in 1,4-dioxane (0.9 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 Quinolin-3-ylboronic acid (119 mg, 0.69 mmol), 5-bromopyrimidin-2-amine (100 mg, 0.57 mmol), Pd(PPh3)4 (33 mg, 0.03 mmol), and potassium carbonate (238 mg, 1.72 mmol) were mixed in H2O/DMF (1.1/1.1 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous NaiSCri and concentrated. The residue was purified by MPLC to give 5- (quinolin-3-yl)pyrimidin-2-amine (37 mg, 29%) as a white solid.
  • Step 2 5-(Quinolin-3-yl)pyrimidin-2-amine (35 mg, 0.16 mmol), 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide (56 mg, 0.19 mmol), Pd2(dba)3 (14 mg, 0.016 mmol), BrettPhos (17 mg, 0.032 mmol), and cesium carbonate (103 mg, 0.31 mmol) were mixed in 1,4-dioxane (0.8 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • 6-Aminopyridazine-3-carbonitrile 40 mg, 0.33 mmol
  • 3-bromo-/V-((5-methylfuran-2- yl)methyl)benzamide 118 mg, 0.4 mmol
  • Pd2(dba)3 41 mg, 0.03 mmol
  • BrettPhos 36 mg, 0.07 mmol
  • cesium carbonate 217 mg, 0.67 mmol
  • Step 2 5-(Thiophen-2-yl)pyrimidin-2-amine (70 mg, 0.24 mmol), 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide (84 mg, 0.28 mmol), Pd2(dba)3 (29 mg, 0.024 mmol), BrettPhos (25 mg, 0.047 mmol), and cesium carbonate (154 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.2 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 Benzofuran-2-ylboronic acid (167 mg, 1.03 mmol), 5-bromopyrimidin-2-amine (150 mg, 0.86 mmol), Pd(PPh3)4 (50 mg, 0.043 mmol), and potassium carbonate (357 mg, 2.59 mmol) were mixed in H2O/DMF (1.7/1.7 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous Na 2 S0 4 and concentrated. The crude mixture was solidified by using EA to give 5-(benzofuran-2-yl)pyrimidin-2-amine (67 mg, 37%) as a yellowish white solid.
  • Step 2 5-(Benzofuran-2-yl)pyrimidin-2-amine (50 mg, 0.21 mmol), 3-bromo-/V-((5- methylfuran-2-yl)methyl)benzamide (75 mg, 0.26 mmol), Pd2(dba)3 (26 mg, 0.021 mmol), BrettPhos (23 mg, 0.043 mmol), and cesium carbonate (154 mg, 0.47 mmol) were mixed in 1,4-dioxane (1.1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 1 4,4,5,5-Tetramethyl-2-(2-methylfuran-3-yl)-l,3,2-dioxaborolane (167 mg, 1.03 mmol), 5-bromopyrimidin-2-amine (150 mg, 0.86 mmol), Pd(PPli3)4 (50 mg, 0.043 mmol), and potassium carbonate (357 mg, 2.59 mmol) were mixed in EEO/DMF (1.7/1.7 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous NaiSCE and concentrated. The residue was purified by MPLC to give 5-(2-methylfuran-3-yl)pyrimidin-2-amine (154 mg, >99%) as a yellowish white solid.
  • Step 2 5-(2-Methylfuran-3-yl)pyrimidin-2-amine (60 mg, 0.23 mmol), 3-bro o-A-((5- methylfuran-2-yl)methyl)benzamide (80 mg, 0.27 mmol), Pd2(dba)3 (28 mg, 0.023 mmol), BrettPhos (24 mg, 0.046 mmol), and cesium carbonate (148 mg, 0.45 mmol) were mixed in 1,4-dioxane (1.1 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC.
  • Step 2 6-Phenylpyridazin-3 -amine (30 mg, 0.18 mmol), 2-bromo-A-phenethylthiazole- 5-carboxamide (65 mg, 0.21 mmol), Pd2(dba)3 (21 mg, 0.018 mmol), BrettPhos (19 mg, 0.035 mmol), and cesium carbonate (114 mg, 0.35 mmol) were mixed in 1,4-dioxane (1 mL) and heated in a microwave reactor for 90 minutes at 120°C.
  • reaction mixture was concentrated and purified by MPLC to give compound 113, A-(2-phenylethyl)-2-[(6-phenylpyridazin-3- yl)amino]-l,3-thiazole-5-carboxamide (9 mg, 6%) as a brown foam.
  • reaction mixture was solidified by using EA and DCM to give compound 68, N-[(lR,2S)-2- phenylcyclopropyl]-3-[(6-phenylpyridazin-3-yl)amino]benzamide (376 mg, 54%) as a white solid.
  • Step 1 3-((5-(3-Fluorophenyl)pyrimidin-2-yl)amino)benzoic acid (200 mg, 0.65 mmol), methyl 3-(2-aminoethyl)benzoate hydrochloride (153 mg, 0.71 mmol), and HBTU (368 g, 0.97 mmol) were dissolved in DMF (6.5 mL), followed up by addition of DIPEA (0.34 mL, 1.94 mmol) and stirred for 18 h at room temperature. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous NaiSCE and concentrated.
  • Step 2 Methyl 3-(2-(3-((5-(3-fluorophenyl)pyrimidin-2- yl)amino)benzamido)ethyl)benzoate (100 mg, 0.21 mmol) and LiOH-HiO (89.2 mg, 2.13 mmol) were mixed in H 2 0/l,4-dioxane (0.89/4.25 mL) and stirred for 18 hours at 40°C. Then pH value of the solution was adjusted to 1-2 by 1 N HC1. The crude product was added into water. The suspension was filtered, and the filter cake was washed with water.
  • Methyl 4-(2-(3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)benzamido)ethyl)benzoate 100 mg, 0.21 mmol
  • Li0H-H 2 0 89.2 mg, 2.13 mmol
  • pH value of the solution was adjusted to 1-2 by 1 N HC1.
  • the crude product was added into water.
  • the suspension was filtered, and the filter cake was washed with water.
  • the crude product was added into EA.
  • reaction mixture was solidified by using EA to give compound 177, 3-((5- (3-fluorophenyl)pyrimidin-2-yl)amino)-A-(3-(methylamino)phenyl)benzamide (52 mg, 72%) as a white solid.
  • Step 1 (4-Methylthiophen-3-yl)boronic acid (902 mg, 6.35 mmol), 5-bromopyrimidin- 2-amine (850 mg, 4.88 mmol), Pd(PPh3)4 (282 mg, 0.244 mmol), and potassium carbonate (2.03 g, 14.65 mmol) were mixed in H2O/DMF (10/10 mL) and heated in a microwave reactor for 35 minutes at 110°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous Na 2 SC> 4 and concentrated. The residue was solidified by using EA and HEX to give 5-(4-methylthiophen-3-yl)pyrimidin-2-amine (496 mg, 53%) as a beige solid.
  • Step 2 5-(4-Methylthiophen-3-yl)pyrimidin-2-amine (490 mg, 2.6 mmol), methyl 3- bromobenzoate (661 mg, 3.07 mmol), Pd 2 (dba) 3 (235 mg, 0.26 mmol), BrettPhos (275 mg,
  • Step 3 Methyl 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoate (350 mg, 1.08 mmol) and LiOH-HiO (451 mg, 10.76 mmol) were mixed in H 2 0/l,4-dioxane (4.5/22 mL) and stirred for overnight at room temperature. Then pH value of the solution was adjusted to 3 by 1 N HC1. The reaction mixture was extracted by EA. The organic layer was dried over anhydrous Na 2 SC> 4 and concentrated. The residue was solidified by using EA and HEX to give 3-((5-(4-methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoic acid (311 mg, 93%) as a white solid.
  • Step 4 3-((5-(4-Methylthiophen-3-yl)pyrimidin-2-yl)amino)benzoic acid (100 mg, 0.32 mmol), 3-fluoroaniline (0.039 mg, 0.35 mmol), and HBTE! (183 mg, 0.48 mmol) were dissolved in DMF (3.2 mL), followed up by addition of DIPEA (0.084 mL, 0.48 mmol) and stirred for overnight at 60°C, and stirred for overnight at 70°C. The reaction mixture was extracted by EA and brine. The organic layer was dried over anhydrous Na 2 SC> 4 and concentrated.
  • reaction mixture was solidified by using EA and HEX to give compound 181, 3-((5-(3-fluorophenyl)pyrimidin-2-yl)amino)-/V-(indolin-5-yl)benzamide (26 mg, 59%) as a grey solid.

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Abstract

La présente invention concerne une composition comprenant au moins un agent actif qui peut inhiber la protéine anoctamine 6 et une méthode de traitement ou de prévention d'une maladie, d'un trouble ou d'une affection associé(e) à une infection virale par l'administration de la composition à un sujet. De plus, l'invention concerne un procédé de désinfection ou d'assainissement d'un objet contre une contamination virale par la mise en contact de la composition avec un objet ou l'application de la composition sur l'objet.
PCT/IB2022/052412 2021-03-17 2022-03-17 Inhibiteurs de l'ano6 et leurs utilisations WO2022195522A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002046171A2 (fr) * 2000-12-06 2002-06-13 Signal Pharmaceuticals, Inc. Derives d'anilinopyrimidine utilises comme inhibiteurs de kinase i$g(k)b (ikk), compositions et techniques associees
WO2005026129A1 (fr) * 2003-09-15 2005-03-24 Gpc Biotech Ag Derives d'aminopyrimidine a disubstitution 4,6 actifs sur le plan pharmaceutique en tant que modulateurs des proteine kinases
KR20150025531A (ko) * 2013-08-28 2015-03-11 한국화학연구원 신규한 화합물 또는 이의 약학적으로 허용가능한 염, 및 이를 유효성분으로 함유하는 인플루엔자 바이러스 감염으로 인한 질환의 예방 또는 치료용 약학적 조성물
KR20150064730A (ko) * 2012-08-23 2015-06-11 비로스태틱스 에스알엘 신규한 4,6-이치환된 아미노피리미딘 유도체
WO2020011811A1 (fr) * 2018-07-09 2020-01-16 Abivax Dérivés d'aryle-n-aryle pour le traitement d'une infection par un virus à arn

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002046171A2 (fr) * 2000-12-06 2002-06-13 Signal Pharmaceuticals, Inc. Derives d'anilinopyrimidine utilises comme inhibiteurs de kinase i$g(k)b (ikk), compositions et techniques associees
WO2005026129A1 (fr) * 2003-09-15 2005-03-24 Gpc Biotech Ag Derives d'aminopyrimidine a disubstitution 4,6 actifs sur le plan pharmaceutique en tant que modulateurs des proteine kinases
KR20150064730A (ko) * 2012-08-23 2015-06-11 비로스태틱스 에스알엘 신규한 4,6-이치환된 아미노피리미딘 유도체
KR20150025531A (ko) * 2013-08-28 2015-03-11 한국화학연구원 신규한 화합물 또는 이의 약학적으로 허용가능한 염, 및 이를 유효성분으로 함유하는 인플루엔자 바이러스 감염으로 인한 질환의 예방 또는 치료용 약학적 조성물
WO2020011811A1 (fr) * 2018-07-09 2020-01-16 Abivax Dérivés d'aryle-n-aryle pour le traitement d'une infection par un virus à arn

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