WO2023107870A1 - Inhibitors of fibroblast growth factor receptor kinases - Google Patents

Inhibitors of fibroblast growth factor receptor kinases Download PDF

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WO2023107870A1
WO2023107870A1 PCT/US2022/080874 US2022080874W WO2023107870A1 WO 2023107870 A1 WO2023107870 A1 WO 2023107870A1 US 2022080874 W US2022080874 W US 2022080874W WO 2023107870 A1 WO2023107870 A1 WO 2023107870A1
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mmol
optionally substituted
chloro
bromo
stirred
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PCT/US2022/080874
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French (fr)
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John Tyhonas
Toufike Kanouni
Robert Kania
Jason M. Cox
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Kinnate Biopharma Inc.
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Publication of WO2023107870A1 publication Critical patent/WO2023107870A1/en

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    • 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
    • C07D403/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • Fibroblast growth factor receptors are a subfamily of receptor tyrosine kinases (RTKs) that bind to members of the fibroblast growth factor family of proteins. Deregulation of the fibroblast growth factor/FGF receptor network occurs frequently in tumors. Accordingly, therapies that target abberant FGFR kinase activity are desired for use in the treatment of cancer and other disorders.
  • FGFR fibroblast growth factor receptor
  • One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I) or Formula (II): wherein, R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, or optionally substituted C3-C6 cycloalkyl; R is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3- C7 carbocyclyl, optionally substituted C3-C7 carbocyclylalkyl, optionally substituted C3-C7 heterocyclyl, optionally substituted C3-C7 heterocyclylalkyl, optionally substituted C2-C7 alkenyl,
  • One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer.
  • One embodiment provides a pharmaceutical composition comprising a compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer. [0010] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure presented in Table 1. [0011] One embodiment provides a pharmaceutical composition comprising a compound of Table 1, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. [0012] One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Table 1, or pharmaceutically acceptable salt or solvate thereof.
  • Oxa refers to the -O- radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl).
  • an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl).
  • an alkyl comprises one carbon atom (e.g., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl).
  • the alkyl is attached to the rest of the molecule by a single bond.
  • an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, al
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms.
  • alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
  • ethenyl i.e., vinyl
  • prop-1-enyl i.e., allyl
  • but-1-enyl i.e., pent-1-enyl, penta-1,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen,
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms.
  • an alkynyl comprises two to eight carbon atoms.
  • an alkynyl comprises two to six carbon atoms.
  • an alkynyl comprises two to four carbon atoms.
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen
  • Alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1 alkylene).
  • an alkylene comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene).
  • an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, al
  • alkenylene or "alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkenylene comprises two to eight carbon atoms (e.g., C2-C8 alkenylene).
  • an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene).
  • an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene).
  • an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen,
  • Alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene).
  • an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene).
  • an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene).
  • an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb- OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2,
  • Aralkyl refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • Aralkenyl refers to a radical of the formula –Rd-aryl where Rd is an alkenylene chain as defined above.
  • the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
  • alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
  • "Aralkynyl” refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain as defined above.
  • the aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group.
  • the alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • Carbocyclyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms.
  • a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds).
  • a fully saturated carbocyclyl radical is also referred to as "cycloalkyl.”
  • monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • An unsaturated carbocyclyl is also referred to as "cycloalkenyl.”
  • Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • carbocyclyl is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2,
  • Carbocyclylalkyl refers to a radical of the formula –Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Carbocyclylalkynyl refers to a radical of the formula –Rc-carbocyclyl where Rc is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Carbocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula – O-Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • carboxylic acid bioisostere refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to, .
  • "Halo" or "halogen” refers to bromo, chloro, fluoro or iodo substituents.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
  • Heterocyclyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems.
  • the heteroatoms in the heterocyclyl radical are optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heterocyclyl radical is partially or fully saturated.
  • the heterocyclyl is attached to the rest of the molecule through any atom of the ring(s).
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thio
  • heterocyclyl is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)
  • N-heterocyclyl or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical.
  • An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
  • C-heterocyclyl or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical.
  • a C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.
  • Heterocyclylalkyl refers to a radical of the formula –Rc-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
  • Heterocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula –O-Rc-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.
  • Heteroaryl refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothienyl (benzothion
  • heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-ORa, -Rb-OC(O)-Ra, -Rb
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
  • An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
  • a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • Heteroarylalkyl refers to a radical of the formula –Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
  • Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula – O-Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
  • the compounds disclosed herein in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
  • geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
  • positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
  • a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • tautomeric equilibrium includes: [0056]
  • the compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C).
  • deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions such as iodomethane-d3 (CD3I) are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.
  • Deuterium-transfer reagents such as lithium aluminum deuteride (LiAlD4)
  • LiAlD4 lithium aluminum deuteride
  • Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.
  • the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms.
  • the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 1 H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material. [0066] "Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the inhibitors of fibroblast growth factor receptors (FGFRs) compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.
  • salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • salts of amino acids such as arginates, gluconates, and galacturonates
  • Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid.
  • Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • solvates refers to a composition of matter that is the solvent addition form.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in either unsolvated as well as solvated forms.
  • the term “subject” or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • Fibroblast Growth Factor Receptor [0072] Fibroblast Growth Factor Receptor (FGFR) [0073] Fibroblast growth factor receptors (FGFRs) are a subfamily of receptor tyrosine kinases (RTKs) that bind to members of the fibroblast growth factor family of proteins. FGFR genes generally contain 18 exons, possess similar exon–intron organization, and are randomly dispersed throughout the genome with no apparent linkages to FGF gene locations. FGFRs are differentially expressed in a tissue-specific manner throughout development and into adulthood and comprise an extracellular ligand-binding domain, a single-transmembrane domain, and a split intracellular kinase domain.
  • RTKs receptor tyrosine kinases
  • the extracellular region contains two to three immunoglobulin (Ig)-like domains that are involved in FGF binding. These Ig-like domains regulate both ligand affinity and ligand specificity.
  • the intracellular region has the functional domain responsible for FGFR tyrosine kinase activity, as well as additional sites that play a role in protein binding and phosphorylation or autophosphorylation of the receptor molecule. Fibroblast grouth factor receptor pharmacology has been reviewed in the scientific literature by Porta et al. (Criticial Reviews in Oncology/Hematology 113 (2017) 256-67) and Babina and Turner (Nature Review- Cancer 2017 doi: 10.1038/nrc.2017.8).
  • the FGFR family comprises of four family members - FGFR1, FGFR2, FGFR3, and FGFR4, but the four members are capable of producing multiple receptor isoforms through alternative splicing of primary transcripts.
  • a closely-related receptor which lacks the FGF signaling tyrosine kinase domain, FGFR5, (also known as FGFRL1) was recently discovered on the basis of interaction with FGFR-binding ligands, known as fibroblast growth factors (FGFs) (Trueb B. Biology of FGFRL1, the fifth fibroblast growth factor receptor. Cell Mol Life Sci. 2011;68(6):951–964).
  • FGFR signaling is associated with the activation of multiple cellular cascades and responses such as cell growth, proliferation, differentiation, and survival (Thisse B et al. Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev Biol.2005;287(2):390–402; Wesche J et al. Fibroblast growth factors and their receptors in cancer. Biochem J.2011;437(2):199–213; Haugsten EM et al. Roles of fibroblast growth factor receptors in carcinogenesis. Mol Cancer Res.2010;8(11):1439–1452). [0075] Numerous human pathological conditions are associated with the deregulation of FGFR signaling.
  • FGFR signaling Aberrant FGFR signaling is largely attributed to several underlying mechanisms involving gene amplification, gain-of-function coding mutation, gene fusions, single nucleotide polymorphism (SNP), ligand availability and impaired termination program in FGF-mediated signaling (Tiong KH et al. Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers. Apoptosis.2013;18(12):1447-68).
  • SNP single nucleotide polymorphism
  • FGFRs fibroblast growth factor receptors
  • FGFR Fusions in human cancers are classified into type 1 fusions caused by chromosomal translocations in hematological malignancies, and type 2 fusions caused by chromosomal rearrangements in solid tumors (FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review). Int J Mol Med.2016;38(1):3-15). Both types of FGFR fusion proteins are endowed with oncogenic potential through the acquisition of protein-protein-interaction modules from fusion partners for ligand-independent dimerization and/or recruitment of aberrant substrates.
  • Human FGFR fusion proteins generally consist of two main segments—the anterior being a dimerized domain from a partnering gene and tyrosine kinase domain at the posterior (Garcia-Closas M et al. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet.2008;4(4):e1000054). Unlike wild type receptors, mutant FGFRs are expressed intracellularly and retained in the cytosol, thus they escape the typical receptor degradation processes, further prolonging the activation signal.
  • FGFR fibroblast growth factor
  • FGF fibroblast growth factor
  • FGFR FGF receptor
  • FGFR Heteroaromatic FGFR Inhibitory Compounds
  • a heteroaromatic FGFR inhibitory compound In one aspect, provided herein is a heteroaromatic FGFR inhibitory compound.
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, or optionally substituted C3-C6 cycloalkyl;
  • R is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3- C7 carbocyclyl, optionally substituted C3-C7 carbocyclylalkyl, optionally substituted C3-C7 heterocyclyl, optionally substituted C3-C7 heterocyclylalkyl, optionally substituted C2-C7 alkenyl, -CO 2 R 5 , -CONHR 5 , or –CON(R 5 ) 2 ; each R 5 is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted C3-
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R1 is halogen. [0083] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R2 and R3 are hydrogen. [0084] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R3 is optionally substituted C1-C4 alkyl. [0085] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R3 is optionally substituted C3-C6 cycloalkyl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R4 is optionally substituted C1-C4 alkyl.
  • Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R4 is optionally substituted C3-C6 cycloalkyl.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl is a C1-C3 alkyl substituted with a C1-C3 alkoxy.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C7 carbocyclyl.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C7 carbocyclylalkyl.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C7 heterocyclyl, or an optionally substituted C3-C7 heterocyclylalkyl.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is a -CH2OCH3 group.
  • One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II):
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, or optionally substituted C3-C6 cycloalkyl;
  • R is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3- C7 carbocyclyl, optionally substituted C3-C7 carbocyclylalkyl, optionally substituted C3-C7 heterocyclyl, optionally substituted C3-C7 heterocyclylalkyl, optionally substituted C2-C7 alkenyl, -CO 2 R 5 , -CONHR 5 , or –CON(R 5 ) 2 ; each R 5 is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted C3-C7 carbocyclylalkyl, optionally substituted C3-C7 heterocyclyl, or optionally substituted C
  • Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein R1 is halogen. [0096] Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein R2 and R3 are hydrogen. [0097] Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein R3 is optionally substituted C1-C4 alkyl. [0098] Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein R3 is optionally substituted C3-C6 cycloalkyl.
  • Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein R4 is optionally substituted C1-C4 alkyl.
  • Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein R 4 is optionally substituted C3-C6 cycloalkyl.
  • Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen.
  • Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C6 alkyl.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl is a C1-C3 alkyl substituted with a C1-C3 alkoxy.
  • Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C7 carbocyclyl.
  • Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C7 carbocyclylalkyl.
  • Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C7 heterocyclyl, or an optionally substituted C3-C7 heterocyclylalkyl.
  • Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is a -CH2OCH3 group.
  • the heteroaromatic FGFR kinase inhibitory compound disclosed herein has a structure provided in Table 1. Table 1
  • the heteroaromatic FGFR kinase inhibitory compound described herein is administered as a pure chemical.
  • the heteroaromatic FGFR kinase inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
  • a pharmaceutical composition comprising at least one heteroaromatic FGFR kinase inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers.
  • the carrier(s) or excipient(s)
  • One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition
  • a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the heteroaromatic FGFR kinase inhibitory compound as described by Formula (I), or a pharmaceutically acceptable salt or solvate thereof is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by- products that are created, for example, in one or more of the steps of a synthesis method.
  • One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the heteroaromatic FGFR kinase inhibitory compound as described by Formula (II), or a pharmaceutically acceptable salt or solvate thereof is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by- products that are created, for example, in one or more of the steps of a synthesis method.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition
  • a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the heteroaromatic FGFR kinase inhibitory compound as disclosed in Table 1, or a pharmaceutically acceptable salt or solvate thereof is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract.
  • suitable nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
  • the heteroaromatic FGFR kinase inhibitory compound as described by Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof is formulated for administration by injection.
  • the injection formulation is an aqueous formulation.
  • the injection formulation is a non-aqueous formulation.
  • the injection formulation is an oil-based formulation, such as sesame oil, or the like.
  • the heteroaromatic FGFR kinase inhibitory compound as disclosed in Table 1, or pharmaceutically acceptable salt or solvate thereof is formulated for administration by injection.
  • the injection formulation is an aqueous formulation.
  • the injection formulation is a non-aqueous formulation.
  • the injection formulation is an oil-based formulation, such as sesame oil, or the like.
  • the dose of the composition comprising at least one heteroaromatic FGFR kinase inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.
  • Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient. [00128] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
  • Methods of Treatment [00129] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.
  • One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.
  • One embodiment provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
  • described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof for use in a method of treatment of cancer or neoplastic disease.
  • One embodiment provides a use of a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
  • described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof.
  • described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.
  • One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.
  • One embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
  • described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.
  • described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • Provided herein is the method wherein the pharmaceutical composition is administered orally.
  • the method wherein the pharmaceutical composition is administered by injection.
  • Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way. EXAMPLES I.
  • heteroaromatic FGFR kinase inhibitory compounds disclosed herein are synthesized according to the following examples.
  • the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: °C degrees Celsius ⁇ H chemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH 2 Cl 2 ) DMF dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate ESI electrospray ionization Et ethyl g gram(s) h hour(s) HPLC high performance liquid chromatography Hz hertz J coupling constant (in NMR spectrometry) LCMS liquid chromatography mass spectrometry ⁇ micro m multiplet (spectral); meter(s); milli M molar M + parent molecular ion Me methyl MHz megahertz min minute(s) mol mole
  • Step 2 4-Bromo-N-cyclopropyl-2-methoxy-6-nitroaniline [00145] To a stirred solution of N-cyclopropyl-2-methoxy-6-nitroaniline (0.40 g, 1.92 mmol) in MeOH (0.10 mL) was added Br 2 (0.24 mL, 4.22 mmol) at 0 °C. The reaction mixture was stirred for 1.5 h at room temperature. The resulting mixture was diluted with CH 2 Cl 2 (20 mL) and water (10 mL). The reaction was quenched by the addition of NH 3 ⁇ H 2 O (0.5 mL) at room temperature. The resulting mixture was extracted with CH 2 Cl 2 (3 x 50 mL).
  • Step 3 4-Bromo-N 1 -cyclopropyl-6-methoxybenzene-1,2-diamine [00146] To a stirred mixture of 4-bromo-N-cyclopropyl-2-methoxy-6-nitroaniline (0.35 g, 1.22 mmol) and Fe (0.68 g, 12.19 mmol) in EtOH (6.00 mL) and H 2 O (1.20 mL) was added NH 4 Cl (0.65 g, 12.19 mmol) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was filtered, the filter cake was washed with EA (3 x 30 mL).
  • Step 5 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-7- methoxy-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide
  • 5-bromo-1-cyclopropyl-7-methoxy-1H-benzo[d]imidazole 70 mg, 0.26 mmol
  • 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide 130.25 mg, 0.39 mmol
  • Pd(PPh 3 ) 2 Cl 2 (18.39 mg, 0.03 mmol
  • CuI 9.98 mg, 0.05 mmol
  • reaction mixture was degassed with argon for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product.
  • the crude product (28 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 35% B in 10 min, 35% B; Wave length: 254 nm; RT: 7 min; the fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5- (methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-7-methoxy-1H-benzo[d]imidazol-5- yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (13.4 mg, 10%) as a white solid.
  • reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 80 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product which was further purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH 4 HCO 3 ), 5% to 20% gradient in 10 min; 20% to 50% gradient in 30 min; detector, UV 254 nm.
  • Step 1 Tert-butyl (2R,4S)-4- ⁇ 5-[(tert-butoxycarbonyl)(ethyl)amino]-3-[2-(6-chloro-1- cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-4-cyanopyrazol-1-yl ⁇ -2- (methoxymethyl)pyrrolidine-1-carboxylate [00153] To a stirred solution of tert-butyl (2R,4S)-4- ⁇ 3-bromo-5-[(tert- butoxycarbonyl)(ethyl)amino]-4-cyanopyrazol-1-yl ⁇ -2-(methoxymethyl)pyrrolidine-1- carboxylate (0.30 g, 0.56 mmol), 6-chloro-1-cyclopropyl-5-[2-(trimethylsilyl)ethynyl]-1,3- benzodiazole (0.16 g, 0.56 mmol), Pd(
  • the resulting mixture was degassed with nitrogen for three times and stirred for 1 h at 100 °C.
  • the resulting mixture was diluted with water at room temperature.
  • the resulting mixture was extracted with EtOAc (3 x 50 mL).
  • the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (1/3).
  • Step 2 Tert-butyl (2R,4S)-4- ⁇ 5-[(tert-butoxycarbonyl)(ethyl)amino]-4-carbamoyl-3-[2-(6- chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]pyrazol-1-yl ⁇ -2- (methoxymethyl)pyrrolidine-1-carboxylate [00154] To a stirred solution of tert-butyl (2R,4S)-4- ⁇ 5-[(tert-butoxycarbonyl)(ethyl)amino]-3- [2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-4-cyanopyrazol-1-yl ⁇ -2- (methoxymethyl)pyrrolidine-1-carboxylate (0.35 g, 0.52 mmol) in EtOH (5 mL) and DMSO (1 mL) were added
  • the reaction mixture was stirred for 30 min at 0 °C and then stirred for another 1.5 h at room temperature.
  • the resulting mixture was diluted with water (40 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1).
  • Step 3 3-[2-(6-Chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5-(ethylamino)-1-[(3S,5R)- 5-(methoxymethyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00155] To a stirred solution of tert-butyl (2R,4S)-4- ⁇ 5-[(tert-butoxycarbonyl)(ethyl)amino]-4- carbamoyl-3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]pyrazol-1-yl ⁇ -2- (methoxymethyl)pyrrolidine-1-carboxylate (0.29 g, 0.42 mmol) in DCM (3 mL) was added hydrogen chloride (1.5 mL, 329.13 mmol) dropwise at 0 °C.
  • Step 4 3-[2-(6-Chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5-(ethylamino)-1-[(3S,5R)- 5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00156] To a stirred solution of 3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5- (ethylamino)-1-[(3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (0.10 g, 0.20 mmol) and DIEA (0.13 g, 1.03 mmol) in DCM (2 mL) was added acryloyl chloride (0.83 mL, 0.20 mmol) dropwise at 0 °C.
  • the reaction mixture was stirred for 10 min at 0 °C.
  • the resulting mixture was diluted with water at room temperature.
  • the resulting mixture was extracted with EtOAc (3 x 20 mL).
  • the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product (0.12 g) was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 19 x 250 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 40% B to 55% B in 10 min, 55% B; Wave Length: 254 nm; RT1: 9 min.
  • Example 7 Step 1 (2-Amino-4-bromo-5-fluorophenyl)(cyclopropyl)methanone [00157] To a stirred solution of 2-amino-4-bromo-5-fluoro-N-methoxy-N-methylbenzamide (2.00 g, 7.22 mmol) in THF (20.00 mL) was added bromo(cyclopropyl)magnesium (3.67 g, 25.26 mmol) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at -40 °C under nitrogen atmosphere. The resulting mixture was quenched by the addition of sat. NH4Cl (aq.) (10 mL) at -40 °C.
  • Step 2 5-Bromo-2-(1-cyclopropylvinyl)-4-fluoroaniline
  • t-BuOK 0.32 g, 2.90 mmol
  • the resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere.
  • (2-amino-4-bromo-5- fluorophenyl)(cyclopropyl)methanone (0.50 g, 1.94 mmol) in THF (1.00 mL) dropwise at 0 °C.
  • Step 3 7-Bromo-4-cyclopropyl-6-fluorocinnoline
  • Step 4 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((4-cyclopropyl-6- fluorocinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00160] To a stirred mixture of 7-bromo-4-cyclopropyl-6-fluorocinnoline (150.00 mg, 0.56 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (186.10 mg, 0.56 mmol), Pd(PPh 3 ) 2 Cl 2 (39.42 mg, 0.06 mmol) and CuI (21.39 mg, 0.11 mmol) in DMF (1.50 mL) was added TEA
  • reaction mixture was degassed with argon for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1). The fractions contained desired product were combined and concentrated to afford the crude product. And the crude product was precipitated by the addition of ACN. The precipitated solids were collected by filtration and washed with ACN (3 x 30 mL).
  • Example 8 Step 1 5-Bromo-4-chloro-2-cyclopropanecarbonylaniline [00161] To a stirred solution of 2-amino-4-bromo-5-chloro-N-methoxy-N-methylbenzamide (2 g, 6.81 mmol) in THF (20 mL) was added bromo(cyclopropyl)magnesium (47.69 mL, 23.85 mmol) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at -40 °C under nitrogen atmosphere. The resulting mixture was quenched with sat. NH4Cl (aq.) at -40 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL).
  • Step 3 5-Bromo-4-chloro-2-(1-cyclopropylethenyl)aniline
  • methyltriphenylphosphaniumbromide (1.56 g, 4.37 mmol) in THF (3 mL) was added t-BuOK (0.49 g, 4.37 mmol) in portions at 0 °C under nitrogen atmosphere.
  • t-BuOK 0.49 g, 4.37 mmol
  • the resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere.
  • 5-bromo-4-chloro-2-cyclopropanecarbonylaniline (0.30 g, 1.09 mmol
  • Step 4 7-Bromo-6-chloro-4-cyclopropylcinnoline [00163] To a stirred solution of 5-bromo-4-chloro-2-(1-cyclopropylethenyl)aniline (0.26 g, 0.95 mmol) in H 2 O (2.6 mL) were added con. HCl (1.03 mL, 12.40 mmol) and NaNO 2 (0.86 mL, 1.72 mmol, 2 M) dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water and extracted with EtOAc (3 x 100 mL).
  • Step 5 3-[2-(6-Chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00164] To a stirred solution of 7-bromo-6-chloro-4-cyclopropylcinnoline (102.68 mg, 0.36 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (120 mg, 0.36 mmol) and Pd(PPh 3 ) 2 Cl 2 (25.42 mg, 0.04 mmol) and CuI (13.79 mg, 0.07 mmol) in DMF (1.2 mL) was
  • the reaction mixture was deagassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (9/1) to afford the crude product.
  • the crude product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 39% B in 8 min, 39% B; Wave Length: 254 nm.
  • Example 9 1-(2-Amino-4-bromo-5-chlorophenyl) propan-1-one [00165] To a stirred solution of 2-amino-4-bromo-5-chloro-N-methoxy-N-methylbenzamide (1.0 g, 3.40 mmol) in THF (10 mL) was added ethylmagnesium bromide (11.92 mL, 11.92 mmol) dropwise at -78 °C. The reaction mixture was stirred for 1 h at -40 °C. The reaction was quenched by the addition of sat. NH 4 Cl (aq.) (10 mL) at -40 °C and diluted with water (20 mL).
  • reaction mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with in PE/EA (10/1). The fractions contained desired product were combined and concentrated to afford 1-(2-amino-4-bromo-5-chlorophenyl) propan-1-one (0.79 g, 88%) as a yellow solid.
  • Step 2 5-Bromo-2-(but-1-en-2-yl)-4-chloroaniline
  • THF 1-(2-amino-4-bromo-5-chlorophenyl) propan-1-one
  • potassium 2-methylpropan-2-olate (0.68 g, 6.09 mmol) in portions at 0 °C under nitrogen atmosphere.
  • the resulting mixture was stirred for 40 min at room temperature under nitrogen atmosphere.
  • Step 3 7-Bromo-6-chloro-4-ethylcinnoline [00167] To a stirred mixture of 5-bromo-2-(but-1-en-2-yl)-4-chloroaniline (0.40 g, 1.53 mmol), con. HCl (0.73 g, 19.95 mmol) in H 2 O (4 mL) was added 2 M NaNO 2 (0.84 mL, 1.68 mmol) at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was basified to pH 8 with NaHCO 3 (aq.). The resulting mixture was extracted with EA (3 x 50 mL).
  • Step 4 3-[2-(6-Chloro-4-ethylcinnolin-7-yl)ethynyl]-1-[ 5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00168] To a stirred mixture of 7-bromo-6-chloro-4-ethylcinnoline (70.0 mg, 0.25 mmol) and 3- ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl) pyrrolidin-3-yl]-5-(methylamino) pyrazole-4-carboxamide (0.10 g, 0.31 mmol) in DMF (1 mL) were added Pd(PPh 3 ) 2 Cl 2 (18.09 mg, 0.02 mmol), CuI (9.82 mg, 0.05 mmol) and TEA (78
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under vacuum.
  • the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20/1) to afford the crude product which was purified by reverse phase flash with the following conditions: C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH 4 HCO 3 ), 10% to 50% gradient in 60 min; detector: UV 254 nm.
  • Example 10 Step 1 1-(3-Bromopyridin-2-yl)methanamine [00169] To a stirred solution of 3-bromopyridine-2-carbonitrile (500 mg, 2.73 mmol) in THF (5 mL) was added BH 3 .THF (1.05 mL, 10.92 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was quenched by the addition of MeOH (10 mL) at room temperature. The resulting mixture was concentrated under reduced pressure to afford 1-(3-bromopyridin-2- yl)methanamine (500 mg, crude) as a brown yellow solid.
  • Step 2 N-[(3-Bromopyridin-2-yl)methyl]cyclopropanecarboxamide [00170] To a stirred solution of 1-(3-bromopyridin-2-yl)methanamine (500 mg, 2.67 mmol) and TEA (541.01 mg, 5.34 mmol) in DCM (5 mL) was added cyclopropanecarbonyl chloride (335.32 mg, 3.20 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 0 °C under nitrogen atmosphere.
  • Step 3 6-Bromo-3-cyclopropylimidazo[1,5-a]pyridine [00171] To a stirred solution of N-[(3-bromopyridin-2-yl)methyl]cyclopropanecarboxamide (250 mg, 0.98 mmol) in DCE (2.5 mL) was added POCl 3 (901.55 mg, 5.88 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1).
  • Step 4 3-(2- ⁇ 3-Cyclopropylimidazo[1,5-a]pyridin-8-yl ⁇ ethynyl)-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00172] To a stirred solution of 8-bromo-3-cyclopropylimidazo[1,5-a]pyridine (149.54 mg, 0.63 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (250.80 mg, 0.76 mmol) in DMF (2.02 mL) were added Pd(PPh 3 ) 2 Cl 2 (44.27 mg, 0.06 mmol), CuI (24.02 mg
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (5/1) to afford the crude product.
  • the crude product was purified by reverse flash chromatography with the following conditions: column: C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH 4 HCO 3 ), 10% to 50% gradient in 10 min; detector, UV 254 nm.
  • Example 11 Step 1 4-Bromo-5-chloro-1-cyclopropylindazole [00173] To a stirred mixture of 4-bromo-5-fluoro-1H-indazole (0.47 g, 2.19 mmol), cyclopropylboronic acid (0.34 g, 4.06 mmol) and 2-(pyridin-2-yl)pyridine (0.31 g, 2.03 mmol) in DCE (8.00 mL) was added Cu(OAc) 2 (0.73 g, 4.06 mmol) at room temperature. The reaction mixture was degassed with oxygen for three times and stirred for 16 h at 50 °C. The resulting mixture was concentrated under reduced pressure.
  • Step 2 3-[2-(5-Chloro-1-cyclopropylindazol-4-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00174] To a stirred mixture of 4-bromo-5-chloro-1-cyclopropylindazole (0.10 g, 0.36 mmol), 3- ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.24 g, 0.73 mmol) , Pd(PPh 3 ) 2 Cl 2 (25.85 mg, 0.03 mmol) and CuI (14.03 mg, 0.06 mmol) in DMF (2.00 mL) was added TE
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product.
  • the crude product was purified by reverse flash chromatography with the following conditions: Column: C 18 silica gel; Mobile phase: ACN in water (Plus 10 mmol NH 4 HCO 3 ), 5% to 50% gradient in 30 min; Detector: UV 220/254 nm.
  • Step 2 (2R)-1-(4-Bromo-5-fluoro-2-nitrophenyl)-2-methylpyrrolidine
  • NBS N-(4-Bromo-5-fluoro-2-nitrophenyl)-2-methylpyrrolidine
  • Step 3 5-Bromo-4-fluoro-2-[(2R)-2-methylpyrrolidin-1-yl]aniline [00177] To a stirred mixture of (2R)-1-(4-bromo-5-fluoro-2-nitrophenyl)-2-methylpyrrolidine (1.12 g, 3.70 mmol) in EtOH (11 mL) and H 2 O (22 mL) were added Fe (2.06 g, 36.95 mmol) and NH4Cl (1.98 g, 36.95 mmol) in portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (5 x 40 mL).
  • Step 4 (R)-6-Bromo-7-fluoro-1-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole [00178] To a stirred mixture of 5-bromo-4-fluoro-2-[(2R)-2-methylpyrrolidin-1-yl]aniline (0.43 g, 1.57 mmol) and H 2 O 2 (30%) (0.73 mL, 31.48 mmol) in EtOAc (4.3 mL) was added CH 3 SO 3 H (0.01 mL, 0.16 mmol) dropwise at room temperature under atmosphere. The reaction mixture was stirred for 16 h at 75 °C under nitrogen atmosphere.
  • Example 13 Step 1 -1-(5-Fluoro-2-nitrophenyl)-2-methylpyrrolidine [00180] To a stirred solution of benzene, 2,4-difluoro-1-nitro- (1 g, 6.29 mmol) and DIEA (1.83 g, 14.14 mmol) in EtOH (10 mL) was added (2S)-2-methylpyrrolidine hydrochloride (1.15 g, 9.43 mmol) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL).
  • Step 2 (2S)-1-(4-Bromo-5-fluoro-2-nitrophenyl)-2-methylpyrrolidine [00181] To a stirred solution of (2S)-1-(5-fluoro-2-nitrophenyl)-2-methylpyrrolidine (1.5 g, 6.69 mmol) in AcOH (15 mL) was added NBS (1.25 g, 7.02 mmol) in portions at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (12/1).
  • Step 3 5-Bromo-4-fluoro-2-[(2S)-2-methylpyrrolidin-1-yl] aniline [00182] To a stirred solution of (2S)-1-(4-bromo-5-fluoro-2-nitrophenyl)-2-methylpyrrolidine (0.50 g, 1.65 mmol) and NH 4 Cl (0.88 g, 16.49 mmol) in EtOH (12.5 mL) and H 2 O (2.5 mL) was added Fe (0.92 g, 16.49 mmol) in portions at room temperature. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (5 x 50 mL). The filtrate was concentrated under reduced pressure.
  • Step 5 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-(((S)-7-fluoro-1-methyl-2,3- dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide
  • (3S)-10-bromo-11-fluoro-3-methyl-2,7- diazatricyclo[6.4.0.0 ⁇ 2,6 ⁇ ]dodeca-1(8),6,9,11-tetraene (0.15 g, 0.56 mmol)
  • 3-ethynyl-1- [(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4- carboxamide (0.37 g, 1.11 mmol)
  • the reaction mixture was stirred for 1 h at 90 °C under nitrogen atmosphere.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1). The fractions contained desired product were combined and concentrated to afford the crude product.
  • the crude product (60 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 27% B to 31% B in 12 min, 31% B; Wave Length: 254 nm; RT1: 10 min.
  • Example 14 (2R)-1-(5-Chloro-2-nitrophenyl)-2-methylpyrrolidine [00185] To a stirred mixture of 4-chloro-2-fluoro-1-nitrobenzene (1.00 g, 5.69 mmol) and (2R)- 2-methylpyrrolidine (0.73 g, 8.55 mmol) in EtOH (10 mL) was added DIEA (2.21 g, 17.09 mmol) at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1).
  • Step 2 (2R)-1-(4-Bromo-5-chloro-2-nitrophenyl)-2-methylpyrrolidine
  • (2R)-1-(5-chloro-2-nitrophenyl)-2-methylpyrrolidine 1.40 g, 5.82 mmol
  • AcOH 14 mL
  • N-bromosuccinimide 1.09 g, 6.11 mmol
  • the reaction mixture was stirred for 2 h at room temperature.
  • the resulting mixture was concentrated under vacuum.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (1/1).
  • Step 3 5-Bromo-4-chloro-2-[(2R)-2-methylpyrrolidin-1-yl]aniline [00187] To a stirred mixture of (2R)-1-(4-bromo-5-chloro-2-nitrophenyl)-2-methylpyrrolidine (1.00 g, 3.13 mmol) and NH4Cl (1.67 g, 31.29 mmol) in EtOH (7.5 mL) and H 2 O (15 mL) was added Fe (1.75 g, 31.29 mmol). The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1).
  • Step 4 (R)-6-Bromo-7-chloro-1-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole [00188] To a stirred mixture of 5-bromo-4-chloro-2-[(2R)-2-methylpyrrolidin-1-yl]aniline (0.45 g, 1.55 mmol) and H 2 O 2 (1.05 g, 31.08 mmol) in EA (10 mL) was added ethyl methanesulfonate (19 mg, 0.15 mmol). The reaction mixture was stirred for 16 h at 75 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum.
  • Step 5 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-(((R)-7-chloro-1-methyl- 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide [00189] To a stirred mixture of (R)-6-bromo-7-chloro-1-methyl-2,3-dihydro-1H- benzo[d]pyrrolo[1,2-a]imidazole (0.12 g, 0.43 mmol) and 3-ethynyl-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.14 g, 0.43 mmol) in DMF
  • the reaction mixture was degassed with nitrogen for three times and was stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product.
  • the crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% to 38% B in 8 min; Wave Length: 254 nm; RT1: 8 min.
  • Step 2 (2S)-1-(4-Bromo-5-chloro-2-nitrophenyl)-2-methylpyrrolidine [00191] To a stirred solution of (2S)-1-(5-chloro-2-nitrophenyl)-2-methylpyrrolidine (0.42 g, 1.74 mmol) in AcOH (5.00 mL) was added NBS (0.31 g, 1.72 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1).
  • Step 3 5-Bromo-4-chloro-2-[(2S)-2-methylpyrrolidin-1-yl]aniline [00192] To a stirred solution of (2S)-1-(4-bromo-5-chloro-2-nitrophenyl)-2-methylpyrrolidine (0.45 g, 1.41 mmol) in EtOH (5.00 mL) and H 2 O (1.00 mL) were added Fe (0.79 g, 14.08 mmol) and NH 4 Cl (0.75 g, 14.08 mmol) at room temperature. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was filtered; the filter cake was washed with EtOAc (5.00 mL). The filtrate was concentrated under reduced pressure.
  • Example 16 Step 1 Tert-butyl (3S)-3-[3-bromo-4-cyano-5-(cyclopentylamino) pyrazol-1-yl] pyrrolidine-1- carboxylate [00195] To a stirred solution of tert-butyl (3S)-3-(5-amino-3-bromo-4-cyanopyrazol-1- yl)pyrrolidine-1-carboxylate (0.50 g, 1.40 mmol) and bromocyclopentane (2.09 g, 14.03 mmol) in DMF (10 mL) was added Cs 2 CO 3 (2.74 g, 8.42 mmol). The reaction mixture was stirred for 16 h at 50 °C under nitrogen atmosphere.
  • Step 4 Tert-butyl (3S)-3- ⁇ 5-[(tert-butoxycarbonyl)(cyclopentyl)amino]-4-carbamoyl-3-[2-(1- cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]pyrazol-1-yl ⁇ pyrrolidine-1-carboxylate [00198] To a stirred mixture of tert-butyl (3S)-3- ⁇ 5-[(tert-butoxycarbonyl)(cyclopentyl)amino]- 4-cyano-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]pyrazol-1-yl ⁇ pyrrolidine-1- carboxylate (0.13 g, 0.20 mmol) and LiOH ⁇ H 2 O (0.93 mL, 0.23 mmol) in DMSO (1 mL) and H 2 O (0.2 mL
  • Step 5 5-(Cyclopentylamino)-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1- [(3S)-pyrrolidin-3-yl]pyrazole-4-carboxamide hydrochloride [00199] To a stirred solution of tert-butyl (3S)-3- ⁇ 5-[(tert-butoxycarbonyl)(cyclopentyl)amino]- 4-carbamoyl-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]pyrazol-1- yl ⁇ pyrrolidine-1-carboxylate (41 mg, 0.06 mmol) in DCM (0.4 mL) was added HCl (1.65 mL, 6.58 mmol) dropwise at 0 °C.
  • Step 6 5-(Cyclopentylamino)-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1- [(3S)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide
  • the reaction mixture was stirred for 5 min at 0 °C under nitrogen atmosphere.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by Prep-TLC (CH 2 Cl 2 /MeOH, 12/1) to the crude product.
  • the crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 40% B in 8 min, 40% B; Wave Length: 254 nm; RT1: 7 min.
  • Example 17 5-Chloro-8-methylimidazo[1,5-a]pyridine [00201] To a stirred mixture of 8-bromo-5-chloroimidazo[1,5-a]pyridine (0.30 g, 1.29 mmol), trimethyl-1,3,5,2,4,6-trioxatriborinane (1.30 g, 10.36 mmol) and K 2 CO 3 (0.53 g, 3.88 mmol) in dioxane (3.00 mL) was added Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (0.10 g, 0.13 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 70 °C. The resulting mixture was concentrated under reduced pressure.
  • Step 2 1-[(3S,5R)-5-(Methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)-3-(2- ⁇ 8-methylimidazo[1,5-a]pyridin-5-yl ⁇ ethynyl)pyrazole-4-carboxamide [00202] To a stirred solution of 5-chloro-8-methylimidazo[1,5-a]pyridine (50.00 mg, 0.30 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (198.89 mg, 0.60 mmol), 2nd Generation XPhos Precatalyst (23.61 mg, 0.03 mmol) and CuI (11.43 mg, 0.06 mmol) in DMF (1 mL) was added TEA (91
  • Example 18 Step 1 5-Chloro-8-cyclopropylimidazo[1,5-a]pyridine [00203] To a stirred mixture of 8-bromo-5-chloroimidazo[1,5-a]pyridine (0.30 g, 1.29 mmol), cyclopropylboronic acid (0.22 g, 2.59 mmol) and K 2 CO 3 (0.54 g, 3.88 mmol) in dioxane (3.00 mL) was added Pd(dppf)Cl2 ⁇ CH 2 Cl 2 (0.11 g, 0.13 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 70 °C. The resulting mixture was concentrated under reduced pressure.
  • Step 2 3-(2- ⁇ 8-Cyclopropylimidazo[1,5-a]pyridin-5-yl ⁇ ethynyl)-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide
  • 5-chloro-8-cyclopropylimidazo[1,5-a]pyridine (60.00 mg, 0.31 mmol)
  • 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.15 g, 0.46 mmol)
  • CuI 11.86 mg, 0.06 mmol
  • Xphos G2 24.50 mg, 0.03 mmol
  • Step 2 5-Bromo-4-chloro-2-(1-cyclobutylethenyl)aniline
  • Step 3 7-Bromo-6-chloro-4-cyclobutylcinnoline [00207] To a stirred mixture of 5-bromo-4-chloro-2-(1-cyclobutylethenyl)aniline (0.25 g, 0.87 mmol) in water (5.00 mL) were added conc.HCl (0.41 g, 11.33 mmol) and NaNO 2 (0.48 mL, 0.96 mmol, 2 M) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (3 x 20 mL).
  • Step 4 3-[2-(6-Chloro-4-cyclobutylcinnolin-7-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00208] To a stirred solution of 7-bromo-6-chloro-4-cyclobutylcinnoline (80.00 mg, 0.27 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.11 g, 0.32 mmol), Pd(PPh 3 ) 2 Cl 2 (18.87 mg, 0.02 mmol) and CuI (10.2 mg, 0.05 mmol) in DMF (1.00 mL) was added TEA (8
  • Example 20 Step 1 3- ⁇ 2-[1-(2,2-Difluorocyclopropyl)-5-fluoroindazol-4-yl]ethynyl ⁇ -1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00209] To a stirred solution of 4-bromo-1-(2,2-difluorocyclopropyl)-5-fluoroindazole (60.00 mg, 0.20 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (68.31 mg, 0.20 mmol), 2nd Generation XPhos precatalyst (16.22 mg, 0.02 mmol) and CuI (19.63 mg
  • Example 21 4-Bromo-1-cyclobutyl-5-fluoroindazole [00210] To a stirred solution of 4-bromo-5-fluoro-1H-indazole (0.50 g, 2.32 mmol) and bromocyclobutane (0.94 g, 6.97 mmol) in DMF (5 mL) was added Cs2CO 3 (1.5 g, 4.65 mmol) in portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (2 x 200 mL). The filtrate was concentrated under reduced pressure.
  • Step 2 3-[2-(1-Cyclobutyl-5-fluoroindazol-4-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00211] To a stirred solution of 4-bromo-1-cyclobutyl-5-fluoroindazole (0.10 g, 0.37 mmol), 3- ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.18 g, 0.55 mmol), Pd(PPh 3 ) 2 Cl 2 (0.03 g, 0.03 mmol) and CuI (0.01 g, 0.07 mmol) in DMF (1 mL) was added
  • the reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 90 °C.
  • the resulting mixture was diluted with water at room temperature.
  • the resulting mixture was extracted with EtOAc (3 x 30 mL).
  • the combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product (120 mg) was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 19 x 250 mm, 5 ⁇ m; Mobile Phase A: water (0.05% TFA ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 46% B to 57% B in 10 min, 57% B; Wave Length: 254 nm; RT1: 7.8 min.
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (5/1) to afford the crude product.
  • the residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH 4 HCO 3 ), 20% to 30% gradient in 10 min; detector: UV 254 nm.
  • Example 23 Experimental section Step 1: 4-Bromo-5-chloro-1-cyclobutylindazole [00213] To a stirred solution of 4-bromo-5-chloro-1H-indazole (0.5 g, 2.16 mmol) and Cs 2 CO 3 (1.41 g, 4.32 mmol) in DMF (5 mL) was added bromocyclobutane (0.58 g, 4.32 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1).
  • Step 2 3-[2-(5-Chloro-1-cyclobutylindazol-4-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00214] To a stirred solution of 4-bromo-5-chloro-1-cyclobutylindazole (0.1 g, 0.35 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.17 g, 0.53 mmol) in DMF (2 mL) were added Pd(PPh 3 ) 2 Cl 2 (24.58 mg, 0.04 mmol), CuI (13.34 mg, 0.07 mmol) and TEA (0.11
  • the reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product.
  • the crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 41% B to 51% B in 8 min, 51% B; Wave Length: 254 nm; RT1: 7.17 min.
  • Step 2 Tert-butyl (2R,4S)-4- ⁇ 5-[(tert-butoxycarbonyl)(cyclopropyl)amino]-4-carbamoyl-3-[2- (6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]pyrazol-1-yl ⁇ -2- (methoxymethyl)pyrrolidine-1-carboxylate [00216] To a stirred solution of tert-butyl (2R,4S)-4- ⁇ 5-[(tert- butoxycarbonyl)(cyclopropyl)amino]-3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5- yl)ethynyl]-4-cyanopyrazol-1-yl ⁇ -2-(methoxymethyl)pyrrolidine-1-carboxylate (0.15 g, 0.22 mmol) and NaOH (0.53 mL, 0.27 mmol)
  • Step 3 3-[2-(6-Chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5-(cyclopropylamino)-1- [(3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00217]
  • tert-butyl (2R,4S)-4- ⁇ 5-[(tert- butoxycarbonyl)(cyclopropyl)amino]-4-carbamoyl-3-[2-(6-chloro-1-cyclopropyl-1,3- benzodiazol-5-yl)ethynyl]pyrazol-1-yl ⁇ -2-(methoxymethyl)pyrrolidine-1-carboxylate (0.25 g, 0.36 mmol) in DCM (2.5 mL) was added TFA (0.5 mL) dropwise at 0 °C.
  • Step 4 3-[2-(6-Chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5-(cyclopropylamino)-1- [(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00218] To a stirred solution of 3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5- (cyclopropylamino)-1-[(3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (0.13 g, 0.26 mmol) and DIEA (0.13 g, 1.05 mmol) in DCM (2 mL) was added acryloyl chloride (1.05 mL, 0.26 mmol) dropwise at 0 °C.
  • the resulting mixture was stirred for 20 min at 0 °C.
  • the reaction was diluted with water at room temperature.
  • the resulting mixture was extracted with EtOAc (3 x 50 mL).
  • the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product (0.10 g) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 45% B to 50% B in 8 min, 50% B; Wave Length: 254 nm; RT1: 7.32 min.
  • Example 25 1-(2-Amino-4-bromo-5-chlorophenyl)-2-methylpropan-1-one [00219] To a stirred solution of 2-amino-4-bromo-5-chloro-N-methoxy-N-methylbenzamide (2.00 g, 6.81 mmol) in THF (20.00 mL) was added bromo(isopropyl)magnesium (24.00 mL, 1 M) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at - 40 °C. The resulting mixture was quenched by the addition of sat. NH4Cl (aq.) (35 mL) at 0 °C.
  • Step 2 5-Bromo-4-chloro-2-(3-methylbut-1-en-2-yl)aniline
  • t-BuOK t-BuOK
  • Step 3 7-Bromo-6-chloro-4-isopropylcinnoline [00221] To a stirred mixture of 5-bromo-4-chloro-2-(3-methylbut-1-en-2-yl)aniline (0.39 g, 1.42 mmol) in water (4.00 mL) was added NaNO 2 (0.78 mL, 2 M) and conc.HCl (1.74 g, 18.46 mmol) dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL).
  • Step 4 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((6-chloro-4- isopropylcinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00222] To a stirred mixture of 7-bromo-6-chloro-4-isopropylcinnoline (0.15 g, 0.53 mmol), 3- ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.17 g, 0.53 mmol), Pd(PPh 3 ) 2 Cl 2 (36.87 mg, 0.05 mmol) and CuI (20.01 mg, 0.11 mmol) in DMF (2.00 mL) was added
  • the reaction mixture was degassed with argon for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product.
  • the crude product (0.20 g) was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 ⁇ m; Mobile phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 8 min; Wave length: 254 nm; RT: 7 min.
  • Step 2 N-(5-Bromo-4-chloro-2-cyclopropanecarbonylphenyl)-4-methyl-N-(prop-2-en-1- yl)benzenesulfonamide
  • N-(5-bromo-4-chloro-2-cyclopropanecarbonylphenyl)-4- methylbenzenesulfonamide (0.80 g, 1.87 mmol) and allyl bromide (0.34 g, 2.80 mmol) in portions at room temperature.
  • the reaction mixture was stirred for 2 h at room temperature.
  • the resulting mixture was concentrated under reduced pressure.
  • Step 3 N-[5-Bromo-4-chloro-2-(1-cyclopropylethenyl)phenyl]-4-methyl-N-(prop-2-en-1- yl)benzenesulfonamide [00225] To a stirred mixture of t-BuOK (0.77 g, 6.82 mmol) in THF (5 mL) was added methyltriphenylphosphaniumbromide (2.44 g, 6.82 mmol) in portions at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 40 min at room temperature under nitrogen atmosphere.
  • Step 4 7-Bromo-6-chloro-4-cyclopropyl-1-(4-methylbenzenesulfonyl)-2H-quinoline
  • N-[5-bromo-4-chloro-2-(1-cyclopropylethenyl)phenyl]-4- methyl-N-(prop-2-en-1-yl)benzenesulfonamide 0.4 g, 0.86 mmol
  • DCM 10 mL
  • Grubbs 2nd 72.74 mg, 0.086 mmol
  • Step 5 7-Bromo-6-chloro-4-cyclopropylquinoline [00227] To a stirred solution of 7-bromo-6-chloro-4-cyclopropyl-1-(4-methylbenzenesulfonyl)- 2 H-quinoline (0.35 g, 0.80 mmol) in MeOH (5 mL) was added NaOH (0.32 g, 7.98 mmol). The reaction mixture was stirred for 16 h at 65 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1).
  • Step 6 3-[2-(6-Chloro-4-cyclopropylquinolin-7-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00228] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropylquinoline (0.15 g, 0.53 mmol) and 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-ethynyl-5-(methylamino)-1H- pyrazole-4-carboxamide (0.17 g, 0.53 mmol) in DMF (1.5 mL) were added CuI (20.22 mg, 0.10 mmol), Pd(PPh 3 ) 2 Cl 2 (37.26 mg, 0.05 mmol) and TEA
  • the reaction mixture was degassed with nitrogen for three times and stirred for 40 min at 80 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (15/1) to afford the crude product.
  • the crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 55% B in 8 min, 55% B; Wave Length: 254 nm; RT1: 6.7 min.
  • Example 27 3-[2-(6-Chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-5-(methylamino)-1-[(3S)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00229] To a stirred solution of 7-bromo-6-chloro-4-cyclopropylcinnoline (0.10 g, 0.36 mmol) and 7-bromo-6-chloro-4-cyclopropylcinnoline (0.10 g, 0.36 mmol) in DMF (2 mL) were added CuI (13.26 mg, 0.07 mmol), Pd(PPh 3 ) 2 Cl 2 (24.43 mg, 0.03 mmol) and TEA (0.10 g, 1.04 mmol).
  • Example 28 Step 1 5-Bromo-4-chloro-2-iodoaniline [00230] To a stirred solution of 3-bromo-4-chloroaniline (5.00 g, 24.22 mmol) in AcOH (50.00 mL) was added NIS (5.72 g, 25.43 mmol) in portions at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and was basified to pH 8 with saturated NaHCO 3 (aq.). The resulting mixture was extracted with EtOAc (3 x 150 mL).
  • Step 2 5-Bromo-4-chloro-2-(cyclopent-1-en-1-yl)aniline
  • N-bromo-4-chloro-2-iodoaniline 0.30 g, 0.90 mmol
  • Pd(PPh 3 ) 2 Cl 2 63.36 mg, 0.09 mmol
  • K 2 CO 3 0.37 g, 2.71 mmol
  • DMF 3.00 mL
  • 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.19 g, 0.99 mmol).
  • reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 60 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /PE (1/4) to afford 5- bromo-4-chloro-2-(cyclopent-1-en-1-yl)aniline (0.20 g, 81%) as a yellow oil.
  • Step 3 7-Bromo-8-chloro-2,3-dihydro-1H-cyclopenta[c]cinnoline
  • 5-bromo-4-chloro-2-(cyclopent-1-en-1-yl)aniline (0.19 g, 0.69 mmol) in water (2.00 mL) were added conc.HCl (0.76 mL, 9.06 mmol) and NaNO 2 (0.38 mL, 0.76 mmol, 0.5 M) dropwise at 0 °C.
  • the reaction mixture was stirred for 30 min at 0 °C under nitrogen atmosphere.
  • the resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 15 mL).
  • Step 4 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((8-chloro-2,3-dihydro-1H- cyclopenta[c]cinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide
  • 7-Bromo-8-chloro-2,3-dihydro-1H-cyclopenta[c]cinnoline (0.10 g, 0.35 mmol)
  • 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.12 g, 0.35 mmol)
  • Pd(PPh 3 ) 2 Cl 2 24.75 mg, 0.03 mmol
  • CuI 13
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product.
  • the crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 45% B in 8 min, 45% B; Wave Length: 254 nm; RT1: 7.7 min.
  • Step 2 N-(5-bromo-2-cyclopropanecarbonyl-4-fluorophenyl)-4-methyl-N-(prop-2-en-1 yl)benzenesulfonamide
  • N-(5-bromo-2-cyclopropanecarbonyl-4-fluorophenyl)-4- methylbenzenesulfonamide (1.53 g, 3.71 mmol) in DMF (16.00 mL) were added K 2 CO 3 (0.77 g, 5.56 mmol) and allyl bromide (0.48 mL, 5.56 mmol) at 0 °C. The reaction mixture was stirred for 1 h at 80 °C.
  • Step 3 N-[5-bromo-2-(1-cyclopropylethenyl)-4-fluorophenyl]-4-methyl-N- 2-en-1- yl)benzenesulfonamide [00236] To a stirred solution of methyltriphenylphosphaniumbromide (3.17 g, 8.88 mmol) in THF (10.00 mL) was added t-BuOK (1.00 g, 8.88 mmol) in portions at 0 °C. The reaction mixture was stirred for 30 min at room temperature.
  • Step 4 7-Bromo-4-cyclopropyl-6-fluoro-1-(4-methylbenzenesulfonyl)-2H-quinoline [00237]
  • N-[5-bromo-2-(1-cyclopropylethenyl)-4-fluorophenyl]-4- methyl-N-(prop-2-en-1-yl)benzenesulfonamide (0.54 g, 1.19 mmol)
  • DCM (120.00 mL)
  • Grubbs 2 nd 0.05 g, 0.06 mmol
  • Step 5 7-Bromo-4-cyclopropyl-6-fluoroquinoline [00238] To a stirred solution of 7-bromo-4-cyclopropyl-6-fluoro-1-(4-methylbenzenesulfonyl)- 2H-quinoline (0.15 g, 0.35 mmol) in MeOH (15.00 mL) and THF (6.50 mL) was added NaOH (6.50 mL, 3.50 mmol) dropwise at room temperature. The reaction mixture was stirred for 16 h at 65 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1).
  • Step 6 3-[2-(4-Cyclopropyl-6-fluoroquinolin-7-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00239] To a stirred mixture of 7-bromo-4-cyclopropyl-6-fluoroquinoline (0.08 g, 0.30 mmol), 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-ethynyl-5-(methylamino)-1H- pyrazole-4-carboxamide (0.09 g, 0.60 mmol), Pd(PPh 3 ) 2 Cl 2 (21.10 mg, 0.03 mmol) and CuI (11.45 mg, 0.06 mmol) in DMF (2.00 mL) was added TEA
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product.
  • the crude product was purified by reverse flash chromatography with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 ⁇ m; Mobile phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 50% B in 8 min, 50% B; Wave length: 254 nm; RT: 6.6 min.
  • Example 30 Step 1 1-(5-Chloro-2-nitrophenyl)-2-ethylpyrrolidine [00240] To a stirred solution 4-chloro-2-fluoro-1-nitrobenzene (3.23 g, 18.40 mmol) and DIEA (3.57 g, 27.60 mmol) in EtOH (30.00 mL) was added 2-ethylpyrrolidine hydrochloride (2.50 g, 18.40 mmol) at 0 °C. The reaction mixture was stirred for 4 h at room temperature. The resulting mixture was quenched with water (30 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 50 mL).
  • Step 2 1-(4-Bromo-5-chloro-2-nitrophenyl)-2-ethylpyrrolidine [00241] To a stirred solution of 1-(5-chloro-2-nitrophenyl)-2-ethylpyrrolidine (4.30 g, 16.88 mmol) in AcOH (30.00 mL) was added NBS (3.61 g, 20.26 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1).
  • Step 3 5-Bromo-4-chloro-2-(2-ethylpyrrolidin-1-yl)aniline
  • 1-(4-bromo-5-chloro-2-nitrophenyl)-2-ethylpyrrolidine (4.00 g, 11.99 mmol) in EtOH (60.00 mL) and H 2 O (12.00 mL) were added Fe (6.70 g, 119.90 mmol) and NH4Cl (6.41 g, 119.90 mmol).
  • the reaction mixture was stirred for 16 h at room temperature.
  • the resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 40 mL).
  • the filtrate was concentrated under reduced pressure.
  • Step 4 6-Bromo-7-chloro-1-ethyl-2,3-dihydro-1H- a]imidazole
  • 5-bromo-4-chloro-2-(2-ethylpyrrolidin-1-yl)aniline (2.20 g, 7.24 mmol)
  • EA 2-ethylpyrrolidin-1-yl
  • H 2 O 2 (30%)
  • methanesulfonic acid 69.63 mg, 0.72 mmol
  • Step 6 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-(((S)-7-chloro-1-ethyl-2,3- dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide [00245] To a stirred solution of (S)-6-bromo-7-chloro-1-ethyl-2,3-dihydro-1H- benzo[d]pyrrolo[1,2-a]imidazole (0.10 g, 0.33 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)- 1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.22 g, 0.67 mmol),
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product.
  • the crude product was further purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 8 min, 50% B; Wave Length: 254 nm.
  • the reaction mixture was degassed with nitrogen for three times and stirred for 4 h at 100 °C under nitrogen atmosphere.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product.
  • the crude product was purified by Prep- HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 45% B in 8 min, 45% B; Wave Length: 254 nm; RT1: 7.2 min.
  • Step 1 3-[2-(6-Chloro-4-ethylcinnolin-7-yl)ethynyl]-5-(methylamino)-1-[(3S)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00248] To a stirred mixture of 3-ethynyl-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin- 3-yl]pyrazole-4-carboxamide (0.10 g, 0.34 mmol) and 7-bromo-6-chloro-4-ethylcinnoline (94.51 mg, 0.34 mmol) in DMF (1 mL) were added Pd(PPh 3 ) 2 Cl 2 (24.43 mg, 0.03 mmol), CuI (13.26 mg, 0.07 mmol) and TEA (0.10 g, 1.04 mmol).
  • reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (5/1) to afford the crude product.
  • the crude product (100 mg) was purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18 ExRS, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 32% B in 8 min, 32% B; Wave Length: 254 nm; RT1: 7 min.
  • Example 36 Step 1: 1-((S)-1-Acryloylpyrrolidin-3-yl)-3-(((R)-7-chloro-1-methyl-2,3-dihydro-1H- benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00251] To a stirred mixture of 3-ethynyl-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin- 3-yl]pyrazole-4-carboxamide (90.00 mg, 0.31 mmol) and (R)-6-bromo-7-chloro-1-methyl-2,3- dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (0.17 g, 0.62 mmol) in DMF (0.9 mL, 11.63 mmol) were added TEA (95 mg, 0.
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford crude product (40 mg).
  • the crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 32% B in 8 min, 32% B; Wave Length: 254 nm; RT1: 7 min.
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was diluted with water (30 mL).
  • the resulting mixture was extracted with EtOAc (3 x 80 mL).
  • the combined organic layers were washed with brine (2 x 40 mL), dried over anhydrous Na 2 SO 4 .
  • the filtrate was concentrated under reduced pressure.
  • the reaction mixture was stirred for 30 min at 0 °C and stirred for 30 min at room temperature.
  • the resulting mixture was diluted with water (30 mL).
  • the resulting mixture was extracted with EtOAc (3 x 80 mL).
  • the combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (1/1).
  • Step 2 3-((6-Chloro-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-1-((3S,5R)-5- (methoxymethyl)pyrrolidin-3-yl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00254] To a stirred solution of tert-butyl (2R,4S)-4-(5-((tert-butoxycarbonyl)(methyl)amino)-4- carbamoyl-3-((6-chloro-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-1H- pyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.37 g, 0.54 mmol) in DCM (4.00 mL) was added HCl in EA (8.00 mL, 4 M
  • Step 4 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((6-chloro-1-cyclopropyl- 2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00255] To a stirred mixture of 3-((6-chloro-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-5- yl)ethynyl)-1-((3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl)-5-(methylamino)-1H-pyrazole-4- carboxamide (0.30 g, 0.58 mmol) in DCM (3.00 mL) was added DIEA (0.22 g, 1.74 mmol) and acryloyl chloride (47.14 mg, 0.52 m
  • the reaction mixture was stirred for 10 min at 0 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the crude product (0.20 g) was purified by Prep-HPLC with the following conditions: Column: Xselect CSH C18 OBD Column 30 x 150 mm, 5 ⁇ m; Mobile phase A: water (10 mmol/L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 39% B in 8 min; Wave length: 254 nm; RT: 7 min.
  • Example 39 5-Bromo-4-chloro-2-(cyclohex-1-en-1-yl)aniline [00257] To a stirred mixture of 5-bromo-4-chloro-2-iodoaniline (0.20 g, 0.60 mmol) and cyclohex-1-en-1-ylboronic acid (83.38 mg, 0.66 mmol) in DMF (3.00 mL) and H 2 O (1.00 mL) were added Pd(PPh 3 ) 2 Cl 2 (42.24 mg, 0.06 mmol) and K 2 CO 3 (0.24 g, 1.80 mmol) at room temperature. The resulting mixture was degassed with nitrogen for three times and stirred for 30 min at 60 °C.
  • Step 2 3-Bromo-2-chloro-7H,8H,9H,10H-benzo[c]cinnoline [00258] To a stirred solution of 5-bromo-4-chloro-2-(cyclohex-1-en-1-yl)aniline (0.16 g, 0.55 mmol) in H 2 O (2.00 mL) were added HCl (0.26 g, 7.25 mmol) and NaNO 2 (2 M) (0.31 mL, 0.61 mmol) in portions at 0 °C. The reaction mixture was stirred for 20 min at 0 °C. The resulting mixture was dissolved with water (10 mL) and extracted with EA (3 x 50 mL).
  • Step 3 3-(2- ⁇ 2-Chloro-7H,8H,9H,10H-benzo[c]cinnolin-3-yl ⁇ ethynyl)-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00259] To a stirred mixture of 3-bromo-2-chloro-7H,8H,9H,10H-benzo[c]cinnoline (60.00 mg, 0.20 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (73.50 mg, 0.22 mmol), Pd(PPh 3 ) 2 Cl 2 (14.15 mg, 0.02 mmol) and CuI (7.68 mg,
  • Step 2 8-Bromo-9-chloro-1H,2H,4H-pyrano[3,4-c]cinnoline [00261]
  • 5-bromo-4-chloro-2-(3,6-dihydro-2H-pyran-4-yl)aniline 0.5 g, 1.73 mmol
  • H 2 O 5.50 mL
  • con. HCl 0.82 g, 22.53 mmol
  • 2 M NaNO 2 0.95 mL, 1.90 mmol
  • Step 3 3-(2- ⁇ 9-Chloro-1H,2H,4H-pyrano[3,4-c]cinnolin-8-yl ⁇ ethynyl)-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00262] To a stirred solution of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (40 mg, 0.12 mmol) and 8- bromo-9-chloro-1H,2H,4H-pyrano[3,4-c]cinnoline (36.16 mg, 0.12 mmol) in DMF (0.5 mL) were added Pd(PPh 3 ) 2 Cl 2 (8.47
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (5/1) the crude product.
  • the crude product (48 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% B to 45% B in 8 min, 45% B; Wave Length: 254 nm; RT1: 6.3 min.
  • Example 41 Step 1 3-Bromo-4-chloro-2-methylaniline [00263] To a stirred mixture of 3-bromo-2-methylaniline (19.2 g, 103.20 mmol) in DMF (100 mL) was added NCS (14.47 g, 108.36 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at 50 °C. The resulting mixture was washed with 100 mL of water. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na 2 SO 4 .
  • Step 2 3-Bromo-4-chloro-6-iodo-2-methylaniline
  • NIS 13.39 g, 59.53 mmol
  • the reaction mixture was stirred for 3 h at room temperature.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (9/1). The fractions contained desired product were combined and concentrated to afford 3-bromo-4-chloro-6-iodo-2-methylaniline (18 g, 91%) as a brown solid.
  • Step 4 4-Bromo-5-chloro-7-iodo-1-methyl-1H-indazole [00266] To a stirred mixture of 4-bromo-5-chloro-7-iodo-1H-indazole (2 g, 5.60 mmol) and K 3 PO 4 (3.56 g, 16.79 mmol) in DMF (20 mL) was added methyl iodide (1.19 g, 8.39 mmol) dropwise at room temperature. The reaction mixture was stirred for 16 h at 100 °C.
  • Step 5 4-Bromo-5-chloro-7-cyclopropyl-1-methyl-1H-indazole [00267] To a stirred mixture of 4-bromo-5-chloro-7-iodo-1-methyl-1H-indazole (0.20 g, 0.54 mmol), cyclopropylboronic acid (92.51 mg, 1.08 mmol) and K 2 CO 3 (223.27 mg, 1.62 mmol) in dioxane (4 mL) was added Pd(dppf)Cl2.CH 2 Cl 2 (43.87 mg, 0.05 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for three times and stirred for 16 h at room temperature under nitrogen atmosphere.
  • Step 6 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((5-chloro-7-cyclopropyl- 1-methyl-1H-indazol-4-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00268] To a stirred mixture of 4-bromo-5-chloro-7-cyclopropyl-1-methylindazole (30 mg, 0.11 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (41.77 mg, 0.17 mmol) , Pd(PPh 3 ) 2 Cl 2 (7.37 mg, 0.01 mmol) and CuI (4.00 mg, 0.02 mmol) in DMF (3 mL
  • reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product.
  • the crude product (20 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Phenyl OBD Column, 19 x 250 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 45% B to 55% B in 10 min, 55% B; Wave Length: 254 nm; RT1: 9 min.
  • Example 42 Step 1 5-Methylcyclopent-1-en-1-yl trifluoromethanesulfonate [00269] To a stirred solution of cyclopentanone, 2-methyl- (10.00 g, 101.89 mmol) and comins' reagent (44.01 g, 112.08 mmol) in THF (680 mL) was added KHMDS (111.94 mL, 492.13 mmol) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at -78 °C and stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (200 mL).
  • Step 2 4,4,5,5-Tetramethyl-2-(5-methylcyclopent-1-en-1-yl)-1,3,2-dioxaborolane [00270] To a stirred mixture of 5-methylcyclopent-1-en-1-yl trifluoromethanesulfonate (4.53 g, 19.68 mmol), bis(pinacolato)diboron (5.00 g, 19.69 mmol) , phenoxysodium (3.43 g, 29.54 mmol) and PPh 3 (0.46 g, 1.75 mmol) in Toluene (40 mL) was added Pd(PPh 3 ) 2 Cl 2 (0.41 g, 0.58 mmol) at room temperature.
  • reaction mixture was degassed with nitrogen for three times and stirred for 16 h at 50 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (10/1) to afford 4,4,5,5-tetramethyl-2-(5-methylcyclopent-1-en-1-yl)-1,3,2-dioxaborolane (2.61 g, 63%) as a light yellow oil.
  • Step 3 5-Bromo-4-chloro-2-(5-methylcyclopent-1-en-1-yl)aniline [00271] To a stirred mixture of 4,4,5,5-tetramethyl-2-(5-methylcyclopent-1-en-1-yl)-1,3,2- dioxaborolane (2.61 g, 12.53 mmol), 5-bromo-4-chloro-2-iodoaniline (3.78 g, 11.39 mmol) and K 2 CO 3 (4.72 g, 34.18 mmol) in DMF (30 mL) and water (10 mL) was added Pd(PPh 3 ) 2 Cl 2 (0.80 g, 1.14 mmol) at room temperature under nitrogen atmosphere.
  • Step 4 7-bromo-8-chloro-1-methyl-2,3-dihydro-1H-cyclopenta[c]cinnoline
  • 5-bromo-4-chloro-2-(5-methylcyclopent-1-en-1-yl)aniline (0.20 g, 0.70 mmol) in AcOH (2 mL)
  • NaNO 2 (0.35 mL, 0.70 mmol, 2 M)
  • the reaction mixture was stirred for 5 min at 0 °C under nitrogen atmosphere.
  • Step 5 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((8-chloro-1-methyl-2,3- dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00273] To a stirred mixture of 7-bromo-8-chloro-1-methyl-2,3-dihydro-1H- cyclopenta[c]cinnoline (88.00 mg, 0.30 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.11 g, 0.33 mmol), Pd(PPh 3 ) 2 Cl 2 (20.76 mg, 0.03 mmol
  • Example 44 Step 1 Spiro[2.4]hept-4-en-4-yl trifluoromethanesulfonate [00276] To a stirred solution of spiro[2,4]heptan-4-one (5 g, 45.39 mmol) in THF (50 mL) was added 1 M KHMDS (54.47 mL, 54.47 mmol) dropwise at -78 °C under nitrogen atmosphere. After stirred for 30 min, 1,1,1-trifluoro-N-phenyl-N- trifluoromethanesulfonylmethanesulfonamide (17.67 g, 49.48 mmol) in THF (50 mL) was added dropwise at -78 °C.
  • reaction mixture was stirred for 2 h at -78 °C under nitrogen atmosphere.
  • the resulting mixture was quenched with sat. NH 4 Cl (aq.) at -78 °C.
  • the resulting mixture was extracted with EA (2 x 100 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 2 4,4,5,5-Tetramethyl-2- ⁇ spiro[2.4]hept-4-en-4-yl ⁇ -1,3,2-dioxaborolane [00277] To a stirred mixture of spiro[2.4]hept-4-en-4-yl trifluoromethanesulfonate (5.3 g, 21.88 mmol,), bis(pinacolato)diboron (5.56 g, 21.88 mmol), sodium benzenolate (3.81 g, 32.82 mmol), PPh 3 (0.52 g, 1.97 mmol) and Pd(PPh 3 ) 2 Cl 2 (0.46 g, 0.66 mmol) in toluene (55 mL) was stirred for 16 h at 50 °C under nitrogen atmosphere.
  • spiro[2.4]hept-4-en-4-yl trifluoromethanesulfonate 5.3 g, 21.88 mmol,
  • Step 3 5-Bromo-4-chloro-2- ⁇ spiro[2.4]hept-4-en-4-yl ⁇ aniline
  • 5-bromo-4-chloro-2-iodoaniline 1.1 g, 3.31 mmol
  • 4,4,5,5- tetramethyl-2- ⁇ spiro[2.4]hept-4-en-4-yl ⁇ -1,3,2-dioxaborolane (0.80 g, 3.64 mmol)
  • DMF 11 mL
  • water 3.3 mL
  • K 2 CO 3 (1.37 g, 9.91 mmol
  • Pd(PPh 3 ) 2 Cl 2 (0.23 g, 0.33 mmol
  • Step 4 7-Bromo-8-chloro-2,3-dihydrospiro[cyclopenta[c]cinnoline-1,1'-cyclopropane]
  • 5-bromo-4-chloro-2- ⁇ spiro[2.4]hept-4-en-4-yl ⁇ aniline (0.44 g, 1.47 mmol)
  • 2 M NaNO 2 0.81 mL, 1.62 mmol
  • the reaction mixture was stirred for 5 min at 0 °C.
  • the resulting mixture was diluted with water (20 mL) and extracted with EA (3 x 30 mL).
  • Step 5 3-(2- ⁇ 8-Chloro-2,3-dihydrospiro[cyclopenta[c]cinnoline-1,1'-cyclopropan]-7- yl ⁇ ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide [00280] To a stirred mixture of 7-bromo-8-chloro-2,3-dihydrospiro[cyclopenta[c]cinnoline-1,1'- cyclopropane] (100 mg, 0.32 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (107 mg, 0.32 mmol) in D
  • the reaction mixture was diluted with water at room temperature.
  • the resulting mixture was extracted with EtOAc (3 x 50 mL).
  • the combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na 2 SO 4 .
  • the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (1/1).
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1).
  • the residue was purified by reverse flash chromatography with the following conditions: Column: C18 silica gel; Mobile phase: ACN in water (Plus 10 mmol/L NH 4 HCO 3 ), 25% to 45% gradient in 25 min; Detector: UV 254 nm.
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (5/1) to afford the crude product.
  • the residue was purified by reverse flash chromatography with the following conditions: column: C18 silica gel; mobile phase: ACN in water (Plus 10 mmol/L NH 4 HCO 3 ), 35% to 40% gradient in 10 min; detector: UV 254 nm.
  • Example 47 (Z)-(4-Bromo-5-chloro-2-((2-nitrovinyl)amino)phenyl)(cyclopropyl)methanone [00283] To a stirred solution of NaOH (1.57 g, 39.30 mmol) in water (35.00 mL) was added nitromethane (1.57 g, 25.69 mmol) dropwise at room temperature. The reaction mixture was stirred for 1 h at 40 °C. The resulting mixture was used in the next step directly without further purification.
  • Step 3 7-Bromo-6-chloro-4-cyclopropylquinolin-3-amine [00285] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropyl-3-nitroquinoline (0.93 g, 2.83 mmol) and Fe (0.63 g, 11.31 mmol) in EtOH (10.00 mL) and H 2 O (2.00 mL) was added NH 4 Cl (0.76 g, 14.13 mmol) at room temperature. The reaction mixture was stirred for 1 h at 90 °C. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 80 mL). The filtrate was concentrated under reduced pressure.
  • Step 4 7-Bromo-6-chloro-4-cyclopropyl-3-fluoroquinoline [00286] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropylquinolin-3-amine (0.40 g, 1.34 mmol) in HBF4 (4.00 mL, 50%) was added NaNO 2 (1.34 mL, 2 M) at room temperature. The reaction mixture was stirred for 30 min at room temperature. The precipitated solids were collected by filtration and washed with colded EtOH and Et2O. The solid was dried under reduced pressure. Then the residue was added in Toluene (8 mL). The reaction mixture was stirred for 1 h at 110 °C.
  • Step 5 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((6-chloro-4-cyclopropyl- 3-fluoroquinolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00287] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropyl-3-fluoroquinoline (0.11 g, 0.37 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.12 g, 0.37 mmol), Pd(PPh 3 ) 2 Cl 2 (25.69 mg, 0.04 mmol) and CuI (13.94 mg, 0.07 mmol) in DMF (1
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1). The fractions contained desired product were combined and concentrated to afford the crude product.
  • the crude product (0.12 g) was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 ⁇ m; Mobile phase A: water (10 mmol/L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 60 mL/min; Gradient: 44% B to 54% B in 8 min, 54% B; Wave length: 254 nm; RT: 6.9 min.
  • Example 48 Step 1: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((5-chloro-1,7- dicyclopropyl-1H-indazol-4-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00288] To a stirred mixture of 4-bromo-5-chloro-1,7-dicyclopropylindazole (15 mg, 0.05 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (31.90 mg, 0.10 mmol), Pd(PPh 3 ) 2 Cl 2 (6.76 mg, 0.01 mmol) and CuI (3.67 mg, 0.02 mmol) in DMF (3 mL
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was allowed to cool down to room temperature.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by Prep-TLC (CH 2 Cl 2 / MeOH 10/1) to afford the crude product.
  • the crude product (10 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 43% B to 53% B in 8 min, 53% B; Wave Length: 254 nm; RT1: 7 min.
  • Step 2 3-Bromo-5,6-dichloropyridine-2-carbonitrile
  • 5-bromo-2,3-dichloropyridin-1-ium-1-olate 8.00 g, 32.93 mmol
  • TMSCN 13.07 g, 131.75 mmol
  • TEA 10.00 g, 98.81 mmol
  • the reaction mixture was stirred for 16 h at 100 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (5/1).
  • Step 4 N-[(3-Bromo-5,6-dichloropyridin-2-yl)methyl]formamide
  • 1-(3-bromo-5,6-dichloropyridin-2-yl)methanamine (4.20 g, 16.41 mmol) and EDCI (7.87 g, 41.03 mmol) in DMF (42.00 mL) was added HCOOH (1.51 g, 32.82 mmol) and DIEA (10.61 g, 82.05 mmol).
  • HCOOH 1.51 g, 32.82 mmol
  • DIEA 10.61 g, 82.05 mmol
  • Step 5 8-Bromo-5,6-dichloroimidazo[1,5-a]pyridine [00293] To a stirred solution of N-[(3-bromo-5,6-dichloropyridin-2-yl)methyl]formamide (0.28 g, 0.99 mmol) in Toluene (5.00 mL) was added POCl 3 (0.61 g, 3.96 mmol). The reaction mixture was stirred for 1 h at 110 °C. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH 7-8 with ammonium hydroxide (4.00 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL).
  • Step 6 5,6-Dichloro-8-cyclopropylimidazo[1,5-a]pyridine
  • 8-bromo-5,6-dichloroimidazo[1,5-a]pyridine 80.00 mg, 0.30 mmol
  • cyclopropylboronic acid 51.68 mg, 0.60 mmol
  • Pd(dppf)Cl2•CH 2 Cl 2 24.51 mg, 0.03 mmol
  • K3PO4 (191.57 mg, 0.90 mmol
  • Step 7 3-(2- ⁇ 6-Chloro-8-cyclopropylimidazo[1,5-a]pyridin-5-yl ⁇ ethynyl)-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00295] To a stirred solution of 5,6-dichloro-8-cyclopropylimidazo[1,5-a]pyridine (35.00 mg, 0.15 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (102.15 mg, 0.31 mmol), 2nd Generation XPhos Precatalyst (12.13 mg, 0.02 mmol) and CuI (5.87 mg, 0.03 mmol)
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude solid.
  • the crude product was purified by reverse phase flash with the following conditions: Column: YMC-Actus Triart C18 ExRS, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 40% B in 8 min; Wave Length: 254 nm.
  • Example 50 Bicyclo[2.2.1]hept-2-en-2-yl trifluoromethanesulfonate [00296] To a stirred mixture of norcamphor (5.00 g, 45.39 mmol) and 1,1,1-trifluoro-N-phenyl- N-trifluoromethanesulfonylmethanesulfonamide (17.85 g, 49.97 mmol) in THF (50 mL) was added KHMDS (55 mL, 241.79 mmol) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at -78 °C under nitrogen atmosphere. The resulting mixture was quenched with sat.
  • norcamphor 5.00 g, 45.39 mmol
  • 1,1,1-trifluoro-N-phenyl- N-trifluoromethanesulfonylmethanesulfonamide 17.85 g, 49.97 mmol
  • KHMDS 55
  • Step 2 2- ⁇ Bicyclo[2.2.1]hept-2-en-2-yl ⁇ -4,4,5,5-tetramethyl-1,3,2-dioxaborolane [00297] To a stirred mixture of bicyclo[2.2.1]hept-2-en-2-yl trifluoromethanesulfonate (3.00 g, 12.38 mmol) and bis(pinacolato)diboron (3.15 g, 12.38 mmol) in Toluene (10 mL) were added phenoxysodium (2.16 g, 18.58 mmol), PPh 3 (0.29 g, 1.11 mmol), Pd(PPh 3 ) 2 Cl 2 (0.26 g, 0.37 mmol) at room temperature under nitrogen atmosphere.
  • Step 3 2- ⁇ Bicyclo[2.2.1]hept-2-en-2-yl ⁇ -5-bromo-4-chloroaniline [00298] To a stirred mixture of 2- ⁇ bicyclo[2.2.1]hept-2-en-2-yl ⁇ -4,4,5,5-tetramethyl-1,3,2- dioxaborolane (0.32 g, 1.49 mmol) and 5-bromo-4-chloro-2-iodoaniline (0.45 g, 1.35 mmol) in DMF (5 mL) and H 2 O (1.6 mL) were added K 2 CO 3 (0.56 g, 4.06 mmol) and Pd(PPh 3 ) 2 Cl 2 (95 mg, 0.13 mmol) at room temperature under nitrogen atmosphere.
  • Step 4 8-Bromo-9-chloro-1,2,3,4-tetrahydro-1,4-methanobenzo[c]cinnoline [00299] To a stirred mixture of 2- ⁇ bicyclo[2.2.1]hept-2-en-2-yl ⁇ -5-bromo-4-chloroaniline (0.30 g, 1.00 mmol) in AcOH (3 mL) was added NaNO 2 (0.54 mL, 15.65 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 30 min at 0 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL).
  • Step 5 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((9-chloro-1,2,3,4- tetrahydro-1,4-methanobenzo[c]cinnolin-8-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide [00300] To a stirred mixture of 8-bromo-9-chloro-1,2,3,4-tetrahydro-1,4- methanobenzo[c]cinnoline (80 mg, 0.25 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (171 mg, 0.51 mmol) in DMF (0.8 mL) were added Pd(PPh 3 )
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford crude product.
  • the crude product was purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18 ExRS, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 43% B in 8 min, 43% B; Wave Length: 254 nm; RT1: 7 min.
  • the reaction mixture was degassed with nitrogen for three times and stirred for 2 h at -78 °C.
  • the resulting mixture was quenched by the addition of sat. NH 4 Cl (aq.) (30 mL) at -40 °C.
  • the resulting mixture was extracted with EtOAc (3 x 120 mL).
  • the combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (10/1).
  • Step 2 2-(5,5-Dimethylcyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [00302] To a stirred mixture of 5,5-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate (3.00 g, 12.28 mmol), phenoxysodium (2.14 g, 18.43 mmol) and bis(pinacolato)diboron (3.12 g, 12.28 mmol) in Toluene (30.00 mL) was added Pd(PPh 3 ) 2 Cl 2 (0.26 g, 0.37 mmol) and PPh3 (0.29 g, 1.11 mmol) at room temperature.
  • reaction mixture was degassed with nitrogen for three times and stirred for 16 h at 50 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (10/1). The fractions contained desired product were combined and concentrated to afford 2- (5,5-dimethylcyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.80 g, 66%) as a colorless oil.
  • Step 3 5-Bromo-4-chloro-2-(5,5-dimethylcyclopent-1-en-1-yl)aniline
  • 2-(5,5-dimethylcyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (0.37 g, 1.67 mmol)
  • 5-bromo-4-chloro-2-iodoaniline (0.50 g, 1.51 mmol
  • K 2 CO 3 (0.70 g, 5.03 mmol) in DMF (6.00 mL) and water (2.00 mL) was added Pd(PPh 3 ) 2 Cl 2 (0.12 g, 0.17 mmol) at room temperature.
  • Step 4 7-Bromo-8-chloro-1,1-dimethyl-2,3-dihydro-1H-cyclopenta[c]cinnoline
  • 5-bromo-4-chloro-2-(5,5-dimethylcyclopent-1-en-1-yl)aniline (0.40 g, 1.33 mmol) and NaNO 2 (100.98 mg, 1.46 mmol) in AcOH (4.00 mL) was stirred for 5 min at room temperature.
  • the resulting mixture was extracted with EtOAc (3 x 70 mL).
  • the combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Step 5 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((8-chloro-1,1-dimethyl- 2,3-dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide [00305] To a stirred mixture of 7-bromo-8-chloro-1,1-dimethyl-2,3-dihydro-1H- cyclopenta[c]cinnoline (80.00 mg, 0.26 mmol), 1-((3S,5R)-1-acryloyl-5- (methoxymethyl)pyrrolidin-3-yl)-3-ethynyl-5-(methylamino)-1H-pyrazole-4-carboxamide (85.41 mg, 0.26 mmol), Pd(PPh 3 ) 2 Cl 2 (18.25 mg,
  • reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product.
  • the crude product (0.15 g) was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 ⁇ m; Mobile phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 50% B in 8 min, 50% B; Wave length: 254 nm; RT: 6.4 min.
  • Example 52 Step 1: Tert-butyl (3S)-3-(3,5-dibromo-4-cyanopyrazol-1-yl)pyrrolidine-1-carboxylate [00306] To a stirred solution of 3,5-dibromo-1H-pyrazole-4-carbonitrile (10.00 g, 39.86 mmol) and tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (7.46 g, 39.86 mmol) in THF (200.00 mL) was added PPh 3 (13.59 g, 51.81 mmol) and DIAD (10.48 g, 51.82 mmol) in portions at 0 °C under nitrogen atmosphere.
  • Step 2 Tert-butyl (3S)-3-(3-bromo-4-cyano-5- ⁇ [(4-methoxyphenyl)methyl]amino ⁇ pyrazol-1- yl)pyrrolidine-1-carboxylate [00307] To a stirrred mixture of tert-butyl (3S)-3-(3,5-dibromo-4-cyanopyrazol-1-yl)pyrrolidine- 1-carboxylate (20.00 g, 47.61 mmol) in NMP (100.00 mL) was added benzenemethanamine, 4- methoxy- (32.65 g, 238.03 mmol).
  • Step 3 Tert-butyl (3S)-3-(4-cyano-5- ⁇ [(4-methoxyphenyl)methyl]amino ⁇ -3-[2- (trimethylsilyl)ethynyl]pyrazol-1-yl)pyrrolidine-1-carboxylate [00308] To a stirred mixture of tert-butyl (3S)-3-(3-bromo-4-cyano-5- ⁇ [(4- methoxyphenyl)methyl]amino ⁇ pyrazol-1-yl)pyrrolidine-1-carboxylate (11.00 g, 23.09 mmol), trimethylsilylacetylene (11.34 g, 115.45 mmol) , Pd(PPh 3 ) 2 Cl 2 (1.62 g, 2.31 mmol) and CuI (0.88 g, 4.62 mmol) in DMF (50.00 mL) was added TEA (11.68 g, 115.45 mmol).
  • the reaction mixturre was degassed with nitrogen for three times and stirred for 2 h at 90 °C.
  • the resulting mixture was diluted with water at room temperature.
  • the resulting mixture was extracted with EtOAc (3 x 100 mL).
  • the combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 .
  • the filtrate was concentrated under reduced pressure.
  • the residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH 4 HCO 3 ), 10% to 90% gradient in 30 min; detector: UV 254 nm.
  • Step 4 Tert-butyl (3S)-3-(4-cyano-3-ethynyl-5- ⁇ [(4-methoxyphenyl)methyl]amino ⁇ pyrazol-1- yl)pyrrolidine-1-carboxylate [00309] To a stirred mixture of tert-butyl (3S)-3-(4-cyano-5- ⁇ [(4- methoxyphenyl)methyl]amino ⁇ -3-[2-(trimethylsilyl)ethynyl]pyrazol-1-yl)pyrrolidine-1- carboxylate (0.50 g, 1.01 mmol) in THF (5.00 mL) was added TBAF (1.52 mL, 1.52 mmol, 1 M).
  • the reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere.
  • the resulting mixture was diluted with water at room temperature.
  • the resulting mixture was extracted with EtOAc (3 x 50 mL).
  • the combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (1/1).
  • Step 5 Tert-butyl (3S)-3- ⁇ 3-[2-(6-chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-4-cyano-5- ⁇ [(4- methoxyphenyl)methyl]amino ⁇ pyrazol-1-yl ⁇ pyrrolidine-1-carboxylate [00310] To a stirred mixture of tert-butyl (3S)-3-(4-cyano-3-ethynyl-5- ⁇ [(4- methoxyphenyl)methyl]amino ⁇ pyrazol-1-yl)pyrrolidine-1-carboxylate (0.20 g, 0.47 mmol), 7- bromo-6-chloro-4-cyclopropylcinnoline (134.54 mg, 0.47 mmol) , Pd(PPh 3 ) 2 Cl 2 (33.30 mg, 0.05 mmol) and CuI (18.07 mg, 0.10 mmol) in DMF (2.00 mL
  • the reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 90 °C.
  • the resulting mixture was diluted with water at room temperature.
  • the resulting mixture was extracted with EtOAc (3 x 30 mL).
  • the combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (1/1).
  • Step 6 (S)-5-Amino-3-((6-chloro-4-cyclopropylcinnolin-7-yl)ethynyl)-1-(pyrrolidin-3-yl)-1H- pyrazole-4-carboxamide [00311]
  • the resulting mixture was concentrated under reduced pressure.
  • the resulting mixture was diluted with water (30 mL) at room temperature.
  • the resulting mixture was extracted with EtOAc (3 x 30 mL).
  • the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the residue product was purified by recerse phase chromatography, eluted with 50% ACN in water (Plus 10 mmol/ L NH 4 HCO 3 ).
  • Step 7 5-Amino-3-[2-(6-chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-1-[(3S)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00312] To a stirred solution of 5-amino-3-[2-(6-chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-1- [(3S)-pyrrolidin-3-yl]pyrazole-4-carboxamide (0.04 g, 0.09 mmol) in DCM (0.5 mL) were added acryloyl chloride (0.34 mL, 0.08 mmol) and DIEA (34.83 mg, 0.27 mmol) dropwise at 0 °C.
  • the reaction mixture was stirred for 10 min at 0 °C.
  • the resulting mixture was diluted with water at room temperature.
  • the resulting mixture was extracted with EtOAc (3 x 30 mL).
  • the combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the crude product (30 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 19 x 250 mm, 10 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 25% B to 40% B in 8 min, 40% B; Wave Length: 254 nm; RT1: 6.8 min.
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product.
  • the crude product (35 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 35% B in 8 min, 35% B; Wave Length: 254 nm; RT1: 7 min.
  • Example 54 Step 1: 5-Ethylcyclopent-1-en-1-yl trifluoromethanesulfonate [00314] To a stirred solution of 2-ethylcyclopentan-1-one (5 g, 44.57 mmol) in THF (50 mL) was added KHMDS (9.78 g, 49.03 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C under nitrogen atmosphere.
  • Step 2 2-(5-Ethylcyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [00315] To a stirred solution of 5-ethylcyclopent-1-en-1-yl trifluoromethanesulfonate (3 g, 12.28 mmol), sodium benzenolate (2.14 g, 18.43 mmol), PPh3 (0.29 g, 1.11 mmol) and bis(pinacolato)diboron (3.12 g, 12.28 mmol) in Toluene (30 mL) was added Pd(PPh 3 ) 2 Cl 2 (0.26 g, 0.37 mmol) at room temperature under nitrogen atmosphere.
  • Step 3 5-Bromo-4-chloro-2-(5-ethylcyclopent-1-en-1-yl)aniline
  • 2-(5-ethylcyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (0.70 g, 3.15 mmol)
  • 5-bromo-4-chloro-2-iodoaniline (0.95 g, 2.84 mmol)
  • DMF 7..00 mL
  • H 2 O 2.30 mL
  • K 2 CO 3 (1.31 g, 9.45 mmol
  • Pd(PPh 3 ) 2 Cl 2 (0.23 g, 0.32 mmol
  • Step 5 3-(2- ⁇ 8-Chloro-1-ethyl-1H,2H,3H-cyclopenta[c]cinnolin-7-yl ⁇ ethynyl)-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00318] To a stirred mixture of 7-bromo-8-chloro-1-ethyl-1H,2H,3H-cyclopenta[c]cinnoline (0.19 g, 0.61 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3- yl]-5-(methylamino)pyrazole-4-carboxamide (0.21 g, 0.61 mmol) in DMF (2.00 mL) were added Pd(PP
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was diluted with water (20 mL) at room temperature.
  • the resulting mixture was extracted with EtOAc (3 x 15 mL).
  • the combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na 2 SO 4 .
  • the filtrate was concentrated under reduced pressure.
  • the residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH 4 HCO 3 ), 10% to 50% gradient in 10 min; detector; UV 254 nm.
  • Step 6 3- ⁇ 2-[(1R)-8-chloro-1-ethyl-1H,2H,3H-cyclopenta[c]cinnolin-7-yl]ethynyl ⁇ -1-[(3S,5R)- 5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00319] The 3-(2- ⁇ 8-chloro-1-ethyl-1H,2H,3H-cyclopenta[c]cinnolin-7-yl ⁇ ethynyl)-1-[(3S,5R)- 5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide was purified by Prep-Chiral-SFC with the following conditions: Column: CHIRAL ART Amylose-SA, 2 x 25 cm, 5 ⁇ m
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product.
  • the crude product (40 mg) was purified by Prep-HPLC with the following conditions: Column: X Bridge Shield RP18 OBD Column, 19 x 250 mm, 10 ⁇ m; Mobile phase A: water (10 mmol/L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 25 mL/min; Gradient: 41% B to 51% B in 8 min, 51% B; Wave length: 254 nm; RT: 6.8 min.
  • Example 57 Step 1: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-5-amino-3-(((R)-7-chloro-1- ethyl-2,3-dihydro- imidazol-6-yl)ethynyl)-1H-pyrazole-4- carboxamide [00322] To a stirred mixture of 5-amino-3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (40.00 mg, 0.13 mmol), 1-((3S,5R)-1-acryloyl-5- (methoxymethyl)pyrrolidin-3-yl)-5-amino-3-ethynyl-1H-pyrazole-4-carboxamide (45.32 mg, 0.15 mmol), Pd(PPh
  • reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product.
  • the crude product (0.02 mg) was purified by Prep-HPLC with the following conditions: Column: YMC- Actus Triart C18 ExRS, 30 x 150 mm, 5 ⁇ m; Mobile phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 25 mL/min; Gradient: 33% B to 38% B in 12 min, 38% B; Wave length: 254 nm; RT: 11.45 min.
  • Example 58 3-Chloro-N-cyclopropyl-2-fluoro-6-nitroaniline [00323] To a stirred solution of 1-chloro-2,3-difluoro-4-nitrobenzene (2.00 g, 10.33 mmol) in EtOH (20.00 mL) was added aminocyclopropane (1.77 g, 31.00 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 0 °C under nitrogen atmosphere.
  • Step 2 3-Chloro-N-cyclopropyl-2-fluoro-4-iodo-6-nitroaniline
  • NIS NIS
  • Step 4 6-Chloro-1-cyclopropyl-7-fluoro-5-iodo-1,3-benzodiazole [00326] To a stirred mixture of 5-chloro-N1-cyclopropyl-6-fluoro-4-iodobenzene-1,2-diamine (0.30 g, 0.92 mmol) in MeOH (3.00 mL) was added trimethyl orthoformate (0.15 g, 1.38 mmol) at room temperature under atmosphere. The reaction mixture was stirred for 16 h at 70 °C under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL).
  • Step 5 5-Amino-3-[2-(6-chloro-1-cyclopropyl-7-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1- [(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00327] To a stirred mixture of 6-chloro-1-cyclopropyl-7-fluoro-5-iodo-1,3-benzodiazole (53.02 mg, 0.16 mmol) and 5-amino-3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (50 mg, 0.16 mmol) in DMF (0.50 mL) were added Pd(PPh 3 ) 2 Cl 2 (11.06 mg, 0.02 mmol) and CuI
  • reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH 4 HCO 3 ), 10% to 50% gradient in 10 min; detector: UV 254 nm.
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90°C.
  • the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (5/1) to afford the crude product.
  • the crude product was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH 4 HCO 3 ), 40% to 50% gradient in 10 min; detector: UV 254 nm.
  • Example 60 7-Bromo-6-chlorocinnolin-4-ol [00329] To a stirred solution of 1-(2-amino-4-bromo-5-chlorophenyl)ethanone (2.60 g, 10.46 mmol) and con. HCl (3.81 g, 104.63 mmol) in H 2 O (30 mL) was added NaNO 2 (1.08 g, 15.70 mmol, 2 M) dropwise at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was basified to pH 8 with saturated NaHCO 3 (aq.). The resulting mixture was extracted with EtOAc (3 x 200 mL).
  • Step 2 4,7-Dibromo-6-chlorocinnoline [00330] To a stirred mixture of 7-bromo-6-chlorocinnolin-4-ol (0.45 g, 1.73 mmol) in ACN (5.00 mL) was added POBr 3 (0.29 g, 1.04 mmol) in portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1).
  • Step 3 7-Bromo-6-chloro-4-(2,2-difluorocyclopropyl)cinnoline
  • Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 37.90 mg, 0.05 mmol
  • K 3 PO 4 0.29 g, 1.40 mmol
  • 2-(2,2-difluorocyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.14 g, 0.70 mmol).
  • reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (2/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-6-chloro-4-(2,2- difluorocyclopropyl)cinnoline (46.50 mg, 30%) as a yellow solid.
  • Step 4 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((6-chloro-4-(2,2- difluorocyclopropyl)cinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00332] To a stirred mixture of 7-bromo-6-chloro-4-(2,2-difluorocyclopropyl)cinnoline (28.00 mg, 0.09 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (87.11 mg, 0.26 mmol), Pd(PPh 3 ) 2 Cl 2 (6.15 mg, 0.01 mmol) and CuI (3.34 mg, 0.02
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at room temperature.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product.
  • Example 61 5-Bromo-4-chloro-2-(prop-1-yn-1-yl)aniline [00333] To a stirred mixture of 5-bromo-4-chloro-2-iodoaniline (5 g, 15.04 mmol) and propyne (0.66 g, 16.54 mmol) in DMF (50 mL) and TEA (4.57 g, 45.13 mmol) were added CuI (0.57 g, 3.00 mmol) and Pd(PPh 3 ) 2 Cl 2 (1.06 g, 1.50 mmol). The reaction mixture was stirred for 1 h at 50 °C under nitrogen atmosphere. The resulting mixture was quenched with water at room temperature.
  • Step 2 7-Bromo-6-chloro-3-methylcinnolin-4-ol
  • 5-bromo-4-chloro-2-(prop-1-yn-1-yl)aniline (2.85 g, 11.65 mmol) in H 2 O (10 mL) were added HCl (19.43 mL, 6 M) and NaNO 2 (0.80 g, 11.65 mmol).
  • the reaction mixture was stirred for 1 h at 90 °C under nitrogen atmosphere.
  • the resulting mixture was neutralized to pH 8 with saturated NaHCO 3 (aq.).
  • the resulting mixture was extracted with EtOAc (3 x 50 mL).
  • Step 3 4,7-Dibromo-6-chloro-3-methylcinnoline [00335] To a stirred mixture of 7-bromo-6-chloro-3-methylcinnolin-4-ol (350 mg, 1.28 mmol) in ACN (4 mL) was added POBr 3 (367 mg, 1.28 mmol). The reaction mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 4,7-dibromo-6- chloro-3-methylcinnoline (130 mg, 30%) as a light yellow solid.
  • Step 3 7-Bromo-6-chloro-4-cyclopropyl-3-methylcinnoline [00336] To a stirred mixture of 4,7-dibromo-6-chloro-3-methylcinnoline (100 mg, 0.29 mmol) and cyclopropylboronic acid (28 mg, 0.32 mmol) in 1,4-dioxane (2 mL) were added Pd(dppf)Cl 2 CH 2 Cl 2 (24 mg, 0.03 mmol) and K 3 PO 4 (189 mg, 0.89 mmol). The reaction mixture was stirred for 2 h at 90°C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum.
  • Step 5 3-[2-(6-Chloro-4-cyclopropyl-3-methylcinnolin-7-yl)ethynyl]-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00337] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropyl-3-methylcinnoline (35 mg, 0.11 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (39 mg, 0.12 mmol) in DMF (1 mL) were added CuI (4 mg, 0.02 mmol,), Pd(PPh 3 ) 2 Cl 2 (8 mg, 0.01 mmol) and
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the reaction was diluted with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 8 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1).
  • Example 62 4-Bromo-5-chloro-7-vinyl-1H-indazole [00338] To a stirred mixture of 4-bromo-5-chloro-7-iodo-1H-indazole (0.20 g, 0.56 mmol) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.17 g, 1.12 mmol) in dioxane (3 mL) and H 2 O (0.3 mL) were added K 2 CO 3 (0.23 g, 1.68 mmol) and Pd(PPh3)4 (64.67 mg, 0.06 mmol).
  • reaction mixture was degassed with nitrogen for three times and stirred for 16 h at 90 °C.
  • the resulting mixture was filtered, the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 4-bromo-5- chloro-7-ethenyl-1H-indazole (0.11 g, 76%) as a light orange solid.
  • Step 2 4-Bromo-5-chloro-7-cyclopropyl-1H-indazole [00339] To a stirred solution of diethylzinc (0.73 g, 5.90 mmol) in CH 2 Cl 2 (5 mL) was added TFA (0.67 g, 5.90 mmol) in DCM (5 mL) dropwise. After stirring for 20 min, a solution of diiodomethane (1.58 g, 5.90 mmol) in DCM (3 mL) was added.
  • Step 3 3-[2-(5-Chloro-7-cyclopropyl-1-methylindazol-4-yl)ethynyl]-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00340] To a stirred mixture of 4-bromo-5-chloro-7-cyclopropyl-1-methylindazole (45 mg, 0.16 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (62.66 mg, 0.22 mmol), Pd(PPh 3 ) 2 Cl 2 (11.06 mg, 0.02 mmol) and CuI (6.00 mg, 0.03 mmol) in DMF (3 mL) was added
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by Prep-TLC (CH 2 Cl 2 /MeOH 10/1) to afford the crude product.
  • the crude product (20 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Phenyl OBD Column, 19 x 250 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 45% B to 55% B in 8 min, 55% B; Wave Length: 254 nm; RT1: 7.97 min.
  • the reaction mixture was stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product.
  • the residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water (10 mmol/L NH 4 HCO 3 ), 10% to 50% gradient in 30 min; detector: UV 254 nm.
  • Example 64 3-Bromo-4-fluoro-2-methylaniline [00342] To a stirred mixture of 2-bromo-1-fluoro-3-methyl-4-nitrobenzene (1.00 g, 4.27 mmol) in ethanol (20 mL) and H 2 O (4 mL) were added Fe (2.39 g, 42.73 mmol) and NH 4 Cl (2.29 g, 42.73 mmol). The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was filtered; the filter cake was washed with ethyl acetate (500 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1).
  • Step 2 3-Bromo-4-fluoro-6-iodo-2-methylaniline [00343] To a stirred solution of 3-bromo-4-fluoro-2-methylaniline (0.86 g, 4.22 mmol) in acetic acid (9 mL) was added N-iodosuccinimide (1.00 g, 4.43 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was neutralized with sat. NaHCO 3 (aq.) and extracted with ethyl acetate (3 x 80 mL).
  • Step 3 4-Bromo-5-fluoro-7-iodo-1H-indazole [00344] To a stirred solution of 3-bromo-4-fluoro-6-iodo-2-methylaniline (2.10 g, 6.36 mmol) in acetonitrile (10 mL) was added tert-butyl nitrite (1.46 g, 12.76 mmol) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (4/1).
  • Step 4 4-Bromo-5-fluoro-7-iodo-1-methylindazole [00345] To a stirred mixture of 4-bromo-5-fluoro-7-iodo-1H-indazole (0.54 g, 1.58 mmol) and K3PO4 (1.01 g, 4.75 mmol) in N,N-dimethylformamide (1 mL) was added iodomethane (0.34 g, 2.38 mmol) in N,N-dimethylformamide (1 mL) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 100 °C under nitrogen atmosphere.
  • Step 5 4-Bromo-7-cyclopropyl-5-fluoro-1-methylindazole [00346] To a solution of 4-bromo-5-fluoro-7-iodo-1-methylindazole (0.16 g, 0.45 mmol) and cyclopropylboronic acid (0.19 g, 2.25 mmol) in 1,4-dioxane (4 mL) were added K 2 CO 3 (0.19 g, 1.35 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (36.72 mg, 0.05 mmol).
  • reaction mixture was degassed with nitrogen for three times and stirred for 48 h at 50 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (8/1). The fractions contained desired product were combined and concentrated to afford 4- bromo-7-cyclopropyl-5-fluoro-1-methylindazole (80 mg, 65%) as a yellow solid.
  • Step 6 3-[2-(7-Cyclopropyl-5-fluoro-1-methylindazol-4-yl)ethynyl]-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00347] To a stirred mixture of 4-bromo-7-cyclopropyl-5-fluoro-1-methylindazole (65 mg, 0.24 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.48 g, 1.78 mmol), bis(triphenylphosphine)palladium(II) chloride (33.91 mg, 0.05 mmol) and cuprous iodide (17.48 mg
  • Example 65 Step 1 Methyl 3-amino-6-cyclopropylpyridine-2-carboxylate [00348] To a stirred solution of methyl 3-amino-6-bromopyridine-2-carboxylate (3.00 g, 12.98 mmol) and cyclopropylboronic acid (3.35 g, 38.95 mmol) in dioxane (150.00 mL) were added K 3 PO 4 (8.27 g, 38.95 mmol) and Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (2.12 g, 2.59 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 4 h at 70 °C.
  • Step 2 Methyl 3-amino-4-chloro-6-cyclopropylpyridine-2-carboxylate [00349] To a stirred solution of methyl 3-amino-6-cyclopropylpyridine-2-carboxylate (0.56 g, 2.91 mmol) in NMP (16.00 mL) was added NCS (0.41 g, 3.05 mmol) in portions. The reaction mixture was stirred for 3 h at room temperature.
  • the residue was purified by reverse phase flash with the following conditions: Column: Spherical C18, 20-40 um, 330 g; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 100 mL/min; Gradient (B%): 35% to 50% within 20 min; Detector: UV 254/220 nm.
  • the fractions contained desired product were combined and concentrated to afford methyl 3-amino-4-chloro-6-cyclopropylpyridine-2- carboxylate (0.24 g, 36%) as an orange oil.
  • Step 3 Methyl 3-bromo-4-chloro-6-cyclopropylpyridine-2-carboxylate [00350] To a stirred solution of CuBr 2 (0.41 g, 1.85 mmol) and 2-methyl-2-propylnitrit (0.24 g, 2.31 mmol) in ACN (4.00 mL) was added methyl 3-amino-4-chloro-6-cyclopropylpyridine-2- carboxylate (0.35 g, 1.54 mmol) in ACN (2.00 mL) dropwise at 0 °C. The reaction mixture was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by the addition of sat.
  • Step 4 (3-Bromo-4-chloro-6-cyclopropylpyridin-2-yl)methanol [00351] To a stirred solution of methyl 3-bromo-4-chloro-6-cyclopropylpyridine-2-carboxylate (0.18 g, 0.63 mmol) in EtOH (4.00 mL) and THF (2.00 mL) was added NaBH 4 (96.35 mg, 2.54 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1).
  • Step 5 (3-Bromo-4-chloro-6-cyclopropylpyridin-2-yl)methyl methanesulfonate [00352] To a stirred solution of (3-bromo-4-chloro-6-cyclopropylpyridin-2-yl)methanol (0.19 g, 0.73 mmol) and TEA (0.22 g, 2.21 mmol) in DCM (4.00 mL) was added MsCl (0.13 g, 1.10 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (5 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 x 10 mL).
  • Step 6 2-[(3-Bromo-4-chloro-6-cyclopropylpyridin-2-yl)methyl]isoindole-1,3-dione [00353] To a stirred solution of (3-bromo-4-chloro-6-cyclopropylpyridin-2-yl)methyl methanesulfonate (0.22 g, 0.65 mmol) in DMF (4.00 mL) was added potassium phthalimide (0.13 g, 0.72 mmol). The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1).
  • Step 7 1-(3-Bromo-4-chloro-6-cyclopropylpyridin-2-yl)methanamine [00354] To a stirred solution of 2-[(3-bromo-4-chloro-6-cyclopropylpyridin-2- yl)methyl]isoindole-1,3-dione (0.18 g, 0.47 mmol) in THF (4.00 mL) was added NH 2 NH 2 ⁇ H 2 O (47.29 mg, 0.94 mmol) at room temperature. The resulting mixture was stirred for 1 h at 70 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA 3/1).
  • Step 8 N-[(3-Bromo-4-chloro-6-cyclopropylpyridin-2-yl)methyl]formamide
  • 1-(3-bromo-4-chloro-6-cyclopropylpyridin-2-yl)methanamine (0.12 g, 0.45 mmol) and EDCI (0.21 g, 1.14 mmol) in DMF (4.00 mL) was added HCOOH (42.23 mg, 0.92 mmol).
  • DIEA 0.30 g, 2.29 mmol
  • Step 9 8-Bromo-7-chloro-5-cyclopropylimidazo[1,5-a]pyridine [00356] To a stirred solution of N-[(3-bromo-4-chloro-6-cyclopropylpyridin-2- yl)methyl]formamide (95 mg, 0.32 mmol) in Toluene (5.00 mL) was added POCl 3 (0.20 g, 1.31 mmol) at room temperature. The resulting mixture was stirred for 1 h at 110 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA 3/1).
  • Step 10 3-(2- ⁇ 7-Chloro-5-cyclopropylimidazo[1,5-a]pyridin-8-yl ⁇ ethynyl)-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00357] To a stirred solution of 8-bromo-7-chloro-5-cyclopropylimidazo[1,5-a]pyridine (0.11 g, 0.40 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.27 g, 0.81 mmol), Pd(PPh 3 ) 2 Cl 2 (28.43 mg, 0.04 mmol) and CuI (15.43 mg, 0.08
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product.
  • the crude product was purified by reverse phase flash with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 ⁇ m; Mobile Phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 32% B in 8 min; Wave Length: 254 nm.
  • Step 3 7-Bromo-6-chloro-4-cyclopropyl-3-nitrocinnoline
  • (E)-N'-[(5-bromo-4-chloro-2- cyclopropanecarbonylphenyl)amino]-N,N-dioxomethanimidamide (1.48 g, 4.27 mmol) in H 2 O (3 mL) was added NaOH (0.43 g, 10.67 mmol) at room temperature.
  • the reaction mixture was degassed with nitrogen for three times and stirred for 3 h at 50 °C.
  • the resulting mixture was diluted with H 2 O (10 mL).
  • the resulting mixture was extracted with EtOAc (3 x 10 mL).
  • Step 4 7-Bromo-6-chloro-4-cyclopropylcinnolin-3-amine [00361] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropyl-3-nitrocinnoline (1.04 g, 3.16 mmol) and NH4Cl (0.85 g, 15.82 mmol) in EtOH (10 mL) and H 2 O (2 mL) was added Fe (0.71 g, 12.66 mmol) at room temperature. The reaction mixture was stirred for 2 h at 70 °C. The resulting mixture was filtered, the filter cake was washed with EA (3 x 20 mL). The filtrate was concentrated under reduced pressure.
  • Step 5 7-Bromo-6-chloro-4-cyclopropyl-3-fluorocinnoline [00362] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropylcinnolin-3-amine (0.45 g, 1.53 mmol) in HBF4 (11.45 mL, 50%) was added 2 M NaNO 2 (1.53 ml, 3.06 mmol) at room temperature. The reaction mixture was stirred for 30 min at room temperature. The precipitated solids were collected by filtration and washed with Ethyl ether (3 x 30 mL), and then was added in Toluene (5 mL) at room temperature. The reaction mixture was stirred for 1 h at 110 °C.
  • Step 6 3-[2-(6-Chloro-4-cyclopropyl-3-fluorocinnolin-7-yl)ethynyl]-1-[ -5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00363] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropyl-3-fluorocinnoline (0.08 g, 0.26 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.10 g, 0.31 mmol) in DMF (1.6 mL) were added CuI (10.11 mg, 0.05 mmol), Pd(PPh 3 ) 2 Cl 2 (18.62 mg, 0.02 m
  • Example 69 Step 1: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-5-amino-3-((6-chloro-4- cyclopropyl-3-methylcinnolin-7-yl)ethynyl)-1H-pyrazole-4-carboxamide [00365] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropyl-3-methylcinnoline (40 mg, 0.134 mmol), 5-amino-3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3- yl]pyrazole-4-carboxamide (51.19 mg, 0.17 mmol) , Pd(PPh 3 ) 2 Cl 2 (9.43 mg, 0.013 mmol) and CuI (5.12 mg, 0.027 mmol) in DMF (0.4
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10/1) to afford the crude product.
  • the crude product was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH 4 HCO 3 ), 30% to 45% gradient in 10 min; detector, UV 254 nm.
  • Example 70 Step 1 4-Bromo-5-chloro-1-cyclopropyl-7-iodo-1H-indazole [00366] To a stirred mixture of 4-bromo-5-chloro-7-iodo-1H-indazole (1.00 g, 2.80 mmol), cyclopropylboronic acid (0.48 g, 5.60 mmol) and 2-(pyridin-2-yl)pyridine (0.44 g, 2.80 mmol) in 1,2-Dichloroethane (10.00 mL) was added Copper (II) acetate (1.02 g, 5.59 mmol) dropwise at room temperature. The reaction mixture was stirred for 2 h at 70 °C under oxygen atmosphere.
  • Step 2 4-Bromo-5-chloro-1,7-dicyclopropyl-1H-indazole [00367] To a stirred mixture of 4-bromo-5-chloro-1-cyclopropyl-7-iodo-1H-indazole (1.20 g, 3.02 mmol) and cyclopropylboronic acid (0.31 g, 3.62 mmol) in 1,4-dioxane (12.00 mL) were added Potassium Carbonate (1.25 g, 9.06 mmol) and [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.25 g, 0.30 mmol) at room temperature.
  • Step 3 (S)-1-(1-Acryloylpyrrolidin-3-yl)-5-amino-3-((5-chloro-1,7-dicyclopropyl-1H-indazol- 4-yl)ethynyl)-1H-pyrazole-4-carboxamide [00368] To a stirred mixture of 3-ethynyl-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin- 3-yl]pyrazole-4-carboxamide (0.11 g, 0.39 mmol), 4-bromo-5-chloro-1,7-dicyclopropylindazole (80.00 mg, 0.26 mmol), trans-dichlorobis(triphenylphosphine)palladium (18.02 mg, 0.03 mmol) and CuI (9.78 mg, 0.05 mmol) in N,N-dimethylformamide (1.00 mL) was added triethylamine (
  • reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford the crude product.
  • the crude product (0.02 g) was purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18 ExRS, 30 x 150 mm, 5 ⁇ m; Mobile phase A: water (10 mmol/L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 25 mL/min; Gradient: 40% B to 50% B in 10 min, 50% B; Wave length: 254 nm; RT: 9 min.
  • Example 71 3-Bromo-N-methyl-2-nitroaniline [00369] To a stirred solution of 1-bromo-3-fluoro-2-nitrobenzene (10.00 g, 45.45 mmol) in THF (50 mL) was added Methylamine, 2 M in THF (202.28 mL, 404.55 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 .
  • Step 2 3-Bromo-4-chloro-N-methyl-2-nitroaniline [00370] To a stirred solution of 3-bromo-N-methyl-2-nitroaniline (8.80 g, 38.08 mmol) in DMF (88 mL) was added NCS (5.34 g, 39.99 mmol) in portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 3 h at 50 °C under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 .
  • Step 3 3-Bromo-4-chloro-6-iodo-N-methyl-2-nitroaniline [00371] To a stirred solution of 3-bromo-4-chloro-N-methyl-2-nitroaniline (2.00 g, 7.53 mmol) in AcOH (20 mL) was added NIS (6.78 g, 30.13 mmol) at 0 °C. The reaction mixture was stirred for 6 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was neutralized with sat. NaHCO 3 and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate.
  • Step 4 3-Bromo-4-chloro-6-iodo-N1-methylbenzene-1,2-diamine [00372] To a stirred mixture of 3-bromo-4-chloro-6-iodo-N-methyl-2-nitroaniline (0.60 g, 1.53 mmol) in AcOH (6 mL) was added Fe (0.43 g, 7.66 mmol) at room temperature. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was filtered, the filter cake was washed with EA (3 x 20 ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/DCM (10/1).
  • Step 5 4-Bromo-5-chloro-7-iodo-1-methyl-1,2,3-benzotriazole [00373] To a stirred mixture of 3-bromo-4-chloro-6-iodo-N1-methylbenzene-1,2-diamine (0.36 g, 0.99 mmol) and con.HCl (1.08 mL, 12.94 mmol) in H 2 O (6 mL) was added 2 M NaNO 2 (0.60 mL, 1.19 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 h at 0 °C. The resulting mixture was diluted with H 2 O (20 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL).
  • Step 6 4-Bromo-5-chloro-7-cyclopropyl-1-methyl-1,2,3-benzotriazole [00374] To a stirred solution of 4-bromo-5-chloro-7-iodo-1-methyl-1,2,3-benzotriazole (0.17 g, 0.45 mmol) and cyclopropylboronic acid (47.06 mg, 0.54 mmol) in 1,4-dioxane (2 mL) were added Pd(dppf)Cl 2 CH 2 Cl 2 (0.06 g, 0.07 mmol) and K3PO4 (0.29 g, 1.37 mmol) in portions at room temperature .
  • reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 70 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE/EA (31%). The fractions contained desired product were combined and concentrated to afford 4-bromo-5-chloro-7- cyclopropyl-1-methyl-1,2,3-benzotriazole (0.11 g, 88 %) as a white solid.
  • Step 7 3-[2-(5-Chloro-7-cyclopropyl-1-methyl-1,2,3-benzotriazol-4-yl)ethynyl]-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00375] To a stirred mixture of 4-bromo-5-chloro-7-cyclopropyl-1-methyl-1,2,3-benzotriazole (40 mg, 0.14 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin- 3-yl]-5-(methylamino)pyrazole-4-carboxamide (92.51 mg, 0.28 mmol) in DMF (1 mL) were added Pd(PPh 3 ) 2 Cl 2 (9.80 mg, 0.01 mmol), Cu
  • Example 72 2,4-Dichloro-6-iodopyridin-3-amine [00376] To a stirred solution of 2,4-dichloropyridin-3-amine (10 g, 61.35 mmol) in acetonitrile (85 mL) were added trifluoroacetic acid (1.37 mL, 18.44 mmol) and N-iodosuccinimide (15.18 g, 67.47 mmol) in portions at room temperature. The reaction mixture was stirred for 48 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 20% ethyl acetate in petroleum ether.
  • Step 2 2,4-Dichloro-6-cyclopropylpyridin-3-amine
  • 2,4-dichloro-6-iodopyridin-3-amine 9.4 g, 32.54 mmol
  • cyclopropylboronic acid 5.59 g, 65.07 mmol
  • 1,4-dioxane 95 mL
  • potassium trimethylsilanolate 8.35 g, 65.07 mmol
  • bis(triphenylphosphine)palladium(II) chloride 2.28 g, 3.25 mmol
  • Step 3 3-Bromo-2,4-dichloro-6-cyclopropylpyridine [00378] To a stirred mixture of 2-methyl-2-propylnitrit (2.85 g, 24.84 mmol) and dibromocopper (4.41 g, 19.74 mmol) in acetonitrile (20 mL) was added 2,4-dichloro-6- cyclopropylpyridin-3-amine (3.34 g, 16.45 mmol5) in acetonitrile (20 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure.
  • Step 4 3-Bromo-4-chloro-6-cyclopropyl-2-hydrazineylidene-1,2-dihydropyridine
  • 3-bromo-2,4-dichloro-6-cyclopropylpyridine (3.6 g, 13.49 mmol) in 1,4-dioxane (40 mL) was added hydrazine hydrate (16.88 g, 269.75 mmol, purity 80%) at room temperature.
  • the reaction mixture was stirred for 16 h at 80 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • Step 5 N'-(3-Bromo-4-chloro-6-cyclopropyl-1H-pyridin-2-ylidene)cyclopropanecarbohydrazide
  • 3-bromo-4-chloro-6-cyclopropyl-2-hydrazineylidene-1,2- dihydropyridine (0.24 g, 0.90 mmol)
  • cyclopropanecarboxylic acid (0.23 g, 2.69 mmol)
  • 1- hydroxybenzotriazole (0.18 g, 1.34 mmol)
  • N-(3-dimethylaminopropyl)-N’- ethylcarbodiimide hydrochloride (0.26 g, 1.34 mmol) in dimethylformamide (3 mL) was added triethylamine (0.50 mL, 3.58 mmol).
  • Step 6 8-Bromo-7-chloro-3,5-dicyclopropyl-[1,2,4]triazolo[4,3-a]pyridine
  • N'-(3-bromo-4-chloro-6-cyclopropyl-1H-pyridin-2- ylidene)cyclopropanecarbohydrazide (0.15 g, 0.45 mmol) in toluene (4 mL) was added phosphorus oxychloride (0.34 mL, 3.65 mmol).
  • the reaction mixture was stirred for 2 h at 110 °C.
  • the resulting mixture was basified to pH 8 with saturated NaHCO 3 (aq.).
  • Step 7 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((7-chloro-3,5- dicyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide
  • 8-bromo-7-chloro-3,5-dicyclopropyl-[1,2,4]triazolo[4,3- a]pyridine 40 mg, 0.13 mmol
  • 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide 169.61 mg, 0.51 mmol)
  • Pd(PPh 3 ) 2 Cl 2 17
  • Step 3 (S)-5-Amino-3-((6-chloro-1-cyclopropyl-7-fluoro-1H-benzo[d]imidazol-5-yl)ethynyl)- 1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide [00385] A solution of tert-butyl (S)-3-(4-carbamoyl-3-((6-chloro-1-cyclopropyl-7-fluoro-1H- benzo[d]imidazol-5-yl)ethynyl)-5-((4-methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1- carboxylate (0.12 g, 0.18 mmol) in trifluoroacetic acid (0.
  • reaction mixture was stirred for 5 min at 0 °C.
  • resulting mixture was quenched with methyl alcohol at 0 °C.
  • the residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH 4 HCO 3 ), 10% to 50% gradient in 30 min; detector, UV 254 nm.
  • Example 74 Step 1: Tert-butyl (S)-3-(3-((6-chloro-1-cyclopropyl- 5-yl)ethynyl)-4- cyano-5-((4-methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [00387] To a stirred solution of 6-chloro-1-cyclopropyl-5-iodo-1,3-benzodiazole (0.38 g, 1.19 mmol) and tert-butyl (3S)-3-(4-cyano-3-ethynyl-5- ⁇ [(4-methoxyphenyl)methyl]amino ⁇ pyrazol- 1-yl)pyrrolidine-1-carboxylate (0.50 g, 1.19 mmol) and trans- dichlorobis(triphenylphosphine)palladium (83.29 mg, 0.12 mmol) and cuprous iodide (45
  • the resulting mixture was allowed to cool down to room temperature.
  • the resulting mixture was basified to pH 8 with saturated sodium bicarbonate (aq.).
  • the residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, acetonitrile in water (Plus 10 mmol/L NH 4 HCO 3 ), 10% to 50% gradient in 30 min; detector: UV 254 nm.
  • Step 3 (S)-1-(1-Acryloylpyrrolidin-3-yl)-5-amino-3-((6-chloro-1-cyclopropyl-1H- benzo[d]imidazol-5-yl)ethynyl)-1H-pyrazole-4-carboxamide [00389] To a stirred solution of (S)-5-amino-3-((6-chloro-1-cyclopropyl-1H-benzo[d]imidazol- 5-yl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide (30.00 mg, 0.07 mmol) in N,N- dimethylformamide (0.50 mL) was added N,N-diisopropylethylamine (28.38 mg, 0.22 mmol) and acryloyl chloride (5.96 mg, 0.07 mmol) dropwise at 0 °C.
  • Step 2 8-Bromo-7-chloro-3,5-dicyclopropylimidazo[1,5-a]pyridine [00391] To a stirred solution of N-[(3-bromo-4-chloro-6-cyclopropylpyridin-2- yl)methyl]cyclopropanecarboxamide (0.28 g, 0.85 mmol) in Toluene (3.00 mL) was added POCl 3 (1.04 g, 6.79 mmol) dropwise at room temperature. The reaction mixture was stirred for 1.5 h at 110 °C. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH 8 with saturated NaHCO 3 (aq.).
  • the reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product.
  • the crude product (0.12 g) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Phenyl OBD Column, 19 x 250 mm, 5 ⁇ m; Mobile phase A: water (Plus 10 mmol/L NH 4 HCO 3 ), Mobile phase B: ACN; Flow rate: 25 mL/min; Gradient: 44% B to 50% B in 12 min, 50% B; Wave length: 254 nm; RT: 8.3 min.
  • Example 76 Step 1: Tert-butyl (S)-3-(3-((5-chloro-1,7-dicyclopropyl-1H-indazol-4-yl)ethynyl)-4-cyano-5- ((4-methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [00393] To a stirred mixture of tert-butyl (3S)-3-(4-cyano-3-ethynyl-5- ⁇ [(4- methoxyphenyl)methyl]amino ⁇ pyrazol-1-yl)pyrrolidine-1-carboxylate (0.20 g, 0.48 mmol), 4- bromo-5-chloro-1,7-dicyclopropylindazole (0.15 g, 0.48 mmol), trans- dichlorobis(triphenylphosphine)palladium (33.79 mg, 0.05 mmol) and cuprous iod
  • Example 1 FGFR2 Kinase Assay
  • Small molecule inhibition of FGFR2 kinase activity was evaluated using a fluorescence- based microfluidic mobility shift assay.
  • FGFR2 catalyzes the production of ADP from ATP during phosphoryl transfer to the substrate peptide, FLPeptide30 (5-FAM-KKKKEEIYFFF- CONH2) (Perkin Elmer, 760430).
  • the mobility shift assay electrophoretically separates the fluorescently labeled peptides (substrate and phosphorylated product) following the kinase reaction.
  • Biochemical assay IC 50 data are designated within the following ranges: A: ⁇ 0.10 ⁇ M C: > 1.0 ⁇ M to ⁇ 10 ⁇ M B: > 0.10 ⁇ M to ⁇ 1.0 ⁇ M D: > 10 ⁇ M to 30 ⁇ M III.
  • Oral capsule [00399] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.
  • a capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.
  • Example 2 Solution for injection
  • the active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg-eq/mL.

Abstract

Provided herein are heteroaryl inhibitors of fibroblast growth factor receptor kinases, pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of diseases.

Description

INHIBITORS OF FIBROBLAST GROWTH FACTOR RECEPTOR KINASES CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims benefit of U.S. Patent Application No.63/287,468, filed on December 8, 2021, which is hereby incorporated by reference in its entirety. BACKGROUND [0002] Fibroblast growth factor receptors (FGFRs) are a subfamily of receptor tyrosine kinases (RTKs) that bind to members of the fibroblast growth factor family of proteins. Deregulation of the fibroblast growth factor/FGF receptor network occurs frequently in tumors. Accordingly, therapies that target abberant FGFR kinase activity are desired for use in the treatment of cancer and other disorders. [0003] BRIEF SUMMARY OF THE INVENTION [0004] Provided herein are inhibitors of fibroblast growth factor receptor (FGFR) kinases, pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of diseases. [0005] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I) or Formula (II):
Figure imgf000002_0001
wherein, R1, R2, R3, and R4 are each independently selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, or optionally substituted C3-C6 cycloalkyl; R is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3- C7 carbocyclyl, optionally substituted C3-C7 carbocyclylalkyl, optionally substituted C3-C7 heterocyclyl, optionally substituted C3-C7 heterocyclylalkyl, optionally substituted C2-C7 alkenyl, -CO2R5, -CONHR5, or –CON(R5)2; each R5 is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted C3-C7 carbocyclylalkyl, optionally substituted C3-C7 heterocyclyl, or optionally substituted C3-C7 heterocyclylalkyl; and R6 is an optionally substituted alkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl. [0006] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. [0007] One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer. [0008] One embodiment provides a pharmaceutical composition comprising a compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. [0009] One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer. [0010] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure presented in Table 1. [0011] One embodiment provides a pharmaceutical composition comprising a compound of Table 1, or pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. [0012] One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Table 1, or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the disease or disorder is cancer. INCORPORATION BY REFERENCE [0013] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION OF THE INVENTION [0014] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of" or "consist essentially of" the described features. Definitions [0015] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. [0016] "Amino" refers to the –NH2 radical. [0017] "Cyano" refers to the -CN radical. [0018] "Nitro" refers to the -NO2 radical. [0019] "Oxa" refers to the -O- radical. [0020] "Oxo" refers to the =O radical. [0021] "Thioxo" refers to the =S radical. [0022] "Imino" refers to the =N-H radical. [0023] "Oximo" refers to the =N-OH radical. [0024] "Hydrazino" refers to the =N-NH2 radical. [0025] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0026] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above. [0027] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0028] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0029] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0030] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0031] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tRa (where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0032] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb- OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, - Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [0033] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group. [0034] "Aralkenyl" refers to a radical of the formula –Rd-aryl where Rd is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group. [0035] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain. [0036] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group. [0037] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, - Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [0038] "Carbocyclylalkyl" refers to a radical of the formula –Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above. [0039] "Carbocyclylalkynyl" refers to a radical of the formula –Rc-carbocyclyl where Rc is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above. [0040] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula – O-Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above. [0041] As used herein, “carboxylic acid bioisostere” refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,
Figure imgf000012_0001
. [0042] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents. [0043] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group. [0044] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, - Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, - Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb- S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [0045] "N-heterocyclyl" or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. [0046] "C-heterocyclyl" or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like. [0047] "Heterocyclylalkyl" refers to a radical of the formula –Rc-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group. [0048] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula –O-Rc-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group. [0049] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, - Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, - Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb- S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [0050] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals. [0051] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals. [0052] "Heteroarylalkyl" refers to a radical of the formula –Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group. [0053] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula – O-Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group. [0054] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring. [0055] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
Figure imgf000016_0001
[0056] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs. [0057] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure. [0058] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, 125I are all contemplated. In some embodiments, isotopic substitution with 18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [0059] In certain embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods. [0060] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32. [0061] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co. [0062] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.
Figure imgf000018_0001
[0063] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below.
Figure imgf000018_0002
[0064] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.
Figure imgf000018_0003
[0065] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 1H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material. [0066] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the inhibitors of fibroblast growth factor receptors (FGFRs) compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. [0067] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar. [0068] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra. [0069] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in either unsolvated as well as solvated forms. [0070] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human. [0071] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. [0072] Fibroblast Growth Factor Receptor (FGFR) [0073] Fibroblast growth factor receptors (FGFRs) are a subfamily of receptor tyrosine kinases (RTKs) that bind to members of the fibroblast growth factor family of proteins. FGFR genes generally contain 18 exons, possess similar exon–intron organization, and are randomly dispersed throughout the genome with no apparent linkages to FGF gene locations. FGFRs are differentially expressed in a tissue-specific manner throughout development and into adulthood and comprise an extracellular ligand-binding domain, a single-transmembrane domain, and a split intracellular kinase domain. The extracellular region contains two to three immunoglobulin (Ig)-like domains that are involved in FGF binding. These Ig-like domains regulate both ligand affinity and ligand specificity. The intracellular region has the functional domain responsible for FGFR tyrosine kinase activity, as well as additional sites that play a role in protein binding and phosphorylation or autophosphorylation of the receptor molecule. Fibroblast grouth factor receptor pharmacology has been reviewed in the scientific literature by Porta et al. (Criticial Reviews in Oncology/Hematology 113 (2017) 256-67) and Babina and Turner (Nature Review- Cancer 2017 doi: 10.1038/nrc.2017.8). [0074] The FGFR family comprises of four family members - FGFR1, FGFR2, FGFR3, and FGFR4, but the four members are capable of producing multiple receptor isoforms through alternative splicing of primary transcripts. A closely-related receptor which lacks the FGF signaling tyrosine kinase domain, FGFR5, (also known as FGFRL1) was recently discovered on the basis of interaction with FGFR-binding ligands, known as fibroblast growth factors (FGFs) (Trueb B. Biology of FGFRL1, the fifth fibroblast growth factor receptor. Cell Mol Life Sci. 2011;68(6):951–964). Collectively, FGFR signaling is associated with the activation of multiple cellular cascades and responses such as cell growth, proliferation, differentiation, and survival (Thisse B et al. Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev Biol.2005;287(2):390–402; Wesche J et al. Fibroblast growth factors and their receptors in cancer. Biochem J.2011;437(2):199–213; Haugsten EM et al. Roles of fibroblast growth factor receptors in carcinogenesis. Mol Cancer Res.2010;8(11):1439–1452). [0075] Numerous human pathological conditions are associated with the deregulation of FGFR signaling. Aberrant FGFR signaling is largely attributed to several underlying mechanisms involving gene amplification, gain-of-function coding mutation, gene fusions, single nucleotide polymorphism (SNP), ligand availability and impaired termination program in FGF-mediated signaling (Tiong KH et al. Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers. Apoptosis.2013;18(12):1447-68). In addition, a further layer of complexity is added by the fact that FGFRs are subjected to alternative splicing, giving rise to multiple isoforms which may promote or repress tumorigenesis, under different circumstances. [0076] FGFR Fusions [0077] FGFR fusions in human cancers are classified into type 1 fusions caused by chromosomal translocations in hematological malignancies, and type 2 fusions caused by chromosomal rearrangements in solid tumors (FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review). Int J Mol Med.2016;38(1):3-15). Both types of FGFR fusion proteins are endowed with oncogenic potential through the acquisition of protein-protein-interaction modules from fusion partners for ligand-independent dimerization and/or recruitment of aberrant substrates. Human FGFR fusion proteins generally consist of two main segments—the anterior being a dimerized domain from a partnering gene and tyrosine kinase domain at the posterior (Garcia-Closas M et al. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet.2008;4(4):e1000054). Unlike wild type receptors, mutant FGFRs are expressed intracellularly and retained in the cytosol, thus they escape the typical receptor degradation processes, further prolonging the activation signal. [0078] Deregulation of the fibroblast growth factor (FGF)/FGF receptor (FGFR) network occurs frequently in tumors, resulting in the development of FGF/FGFR-targeting therapies as the focus of several basic, preclinical, and clinical studies. [0079] Heteroaromatic FGFR Inhibitory Compounds [0080] In one aspect, provided herein is a heteroaromatic FGFR inhibitory compound. [0081] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):
Figure imgf000022_0001
wherein, R1, R2, R3, and R4 are each independently selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, or optionally substituted C3-C6 cycloalkyl; R is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3- C7 carbocyclyl, optionally substituted C3-C7 carbocyclylalkyl, optionally substituted C3-C7 heterocyclyl, optionally substituted C3-C7 heterocyclylalkyl, optionally substituted C2-C7 alkenyl, -CO2R5, -CONHR5, or –CON(R5)2; each R5 is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted C3-C7 carbocyclylalkyl, optionally substituted C3-C7 heterocyclyl, or optionally substituted C3-C7 heterocyclylalkyl; and R6 is an optionally substituted alkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl. [0082] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R1 is halogen. [0083] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R2 and R3 are hydrogen. [0084] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R3 is optionally substituted C1-C4 alkyl. [0085] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R3 is optionally substituted C3-C6 cycloalkyl. [0086] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R4 is optionally substituted C1-C4 alkyl. [0087] Another embodiment provides the compound of Formula (I), or pharmaceutically acceptable salt or solvate thereof, wherein R4 is optionally substituted C3-C6 cycloalkyl. [0088] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen. [0089] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C6 alkyl. Another embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl is a C1-C3 alkyl substituted with a C1-C3 alkoxy. [0090] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C7 carbocyclyl. [0091] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C7 carbocyclylalkyl. [0092] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C7 heterocyclyl, or an optionally substituted C3-C7 heterocyclylalkyl. [0093] Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is a -CH2OCH3 group. [0094] One embodiment provides a compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II):
Figure imgf000024_0001
wherein, R1, R2, R3, and R4 are each independently selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, or optionally substituted C3-C6 cycloalkyl; R is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3- C7 carbocyclyl, optionally substituted C3-C7 carbocyclylalkyl, optionally substituted C3-C7 heterocyclyl, optionally substituted C3-C7 heterocyclylalkyl, optionally substituted C2-C7 alkenyl, -CO2R5, -CONHR5, or –CON(R5)2; each R5 is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted C3-C7 carbocyclylalkyl, optionally substituted C3-C7 heterocyclyl, or optionally substituted C3-C7 heterocyclylalkyl; and R6 is an optionally substituted alkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl. [0095] Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein R1 is halogen. [0096] Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein R2 and R3 are hydrogen. [0097] Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein R3 is optionally substituted C1-C4 alkyl. [0098] Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein R3 is optionally substituted C3-C6 cycloalkyl. [0099] Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein R4 is optionally substituted C1-C4 alkyl. [00100] Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt or solvate thereof, wherein R4 is optionally substituted C3-C6 cycloalkyl. [00101] Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen. [00102] Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C6 alkyl. Another embodiment provides the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl is a C1-C3 alkyl substituted with a C1-C3 alkoxy. [00103] Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C7 carbocyclyl. [00104] Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C7 carbocyclylalkyl. [00105] Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C7 heterocyclyl, or an optionally substituted C3-C7 heterocyclylalkyl. [00106] Another embodiment provides the compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is a -CH2OCH3 group. [00107] In some embodiments, the heteroaromatic FGFR kinase inhibitory compound disclosed herein has a structure provided in Table 1. Table 1
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Preparation of Compounds [00108] The compounds used in the reactions described herein are 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" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA). [00109] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527- 29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471- 57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes. [00110] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002. [00111] Pharmaceutical Compositions [00112] In certain embodiments, the heteroaromatic FGFR kinase inhibitory compound described herein is administered as a pure chemical. In other embodiments, the heteroaromatic FGFR kinase inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). [00113] Provided herein is a pharmaceutical composition comprising at least one heteroaromatic FGFR kinase inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition. [00114] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. [00115] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. [00116] In certain embodiments, the heteroaromatic FGFR kinase inhibitory compound as described by Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by- products that are created, for example, in one or more of the steps of a synthesis method. [00117] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof. [00118] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. [00119] In certain embodiments, the heteroaromatic FGFR kinase inhibitory compound as described by Formula (II), or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by- products that are created, for example, in one or more of the steps of a synthesis method. [00120] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. [00121] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. [00122] In certain embodiments, the heteroaromatic FGFR kinase inhibitory compound as disclosed in Table 1, or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method. [00123] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). [00124] In some embodiments, the heteroaromatic FGFR kinase inhibitory compound as described by Formula (I) or (II), or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like. [00125] In some embodiments, the heteroaromatic FGFR kinase inhibitory compound as disclosed in Table 1, or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like. [00126] The dose of the composition comprising at least one heteroaromatic FGFR kinase inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors. [00127] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient. [00128] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. Methods of Treatment [00129] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. [00130] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. [00131] One embodiment provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease. [00132] In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. [00133] One embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. [00134] One embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. [00135] One embodiment provides a use of a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease. [00136] In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. [00137] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body. [00138] One embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease. [00139] One embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease. [00140] In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. [00141] Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection. [00142] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way. EXAMPLES I. Chemical Synthesis [00143] In some embodiments, the heteroaromatic FGFR kinase inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: °C degrees Celsius δH chemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH2Cl2) DMF dimethylformamide DMSO dimethylsulfoxide EA ethyl acetate ESI electrospray ionization Et ethyl g gram(s) h hour(s) HPLC high performance liquid chromatography Hz hertz J coupling constant (in NMR spectrometry) LCMS liquid chromatography mass spectrometry μ micro m multiplet (spectral); meter(s); milli M molar M+ parent molecular ion Me methyl MHz megahertz min minute(s) mol mole(s); molecular (as in mol wt) mL milliliter MS mass spectrometry nm nanometer(s) NMR nuclear magnetic resonance pH potential of hydrogen; a measure of the acidity or basicity of an aqueous solution PE petroleum ether RT room temperature s singlet (spectral) t triplet (spectral) T temperature TFA trifluoroacetic acid THF tetrahydrofuran Example 1
Figure imgf000057_0001
Step 1: N-Cyclopropyl-2-methoxy-6-nitroaniline [00144] To a stirred solution of 2-bromo-1-methoxy-3-nitrobenzene (2.00 g, 8.62 mmol) in dioxane (10.00 mL) was added aminocyclopropane (2.48 g, 43.44 mmol). The reaction mixture was stirred for 3 d at 115 °C. The resulting mixture was concentrated under reduced pressure and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1). The fractions contained desired product were combined and concentrated to afford N-cyclopropyl-2-methoxy-6-nitroaniline (0.60 g, 33%) as a red oil. MS ESI calculated for C10H12N2O3 [M + H]+, 209.08, found 209.00. Step 2: 4-Bromo-N-cyclopropyl-2-methoxy-6-nitroaniline [00145] To a stirred solution of N-cyclopropyl-2-methoxy-6-nitroaniline (0.40 g, 1.92 mmol) in MeOH (0.10 mL) was added Br2 (0.24 mL, 4.22 mmol) at 0 °C. The reaction mixture was stirred for 1.5 h at room temperature. The resulting mixture was diluted with CH2Cl2 (20 mL) and water (10 mL). The reaction was quenched by the addition of NH3·H2O (0.5 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1). The fractions contained desired product were combined and concentrated to afford 4-bromo-N-cyclopropyl-2-methoxy-6-nitroaniline (0.46 g, 83%) as a red solid. MS ESI calculated for C10H11BrN2O3 [M + H]+, 287.00, 289.00, found 286.90, 288.90. Step 3: 4-Bromo-N1-cyclopropyl-6-methoxybenzene-1,2-diamine [00146] To a stirred mixture of 4-bromo-N-cyclopropyl-2-methoxy-6-nitroaniline (0.35 g, 1.22 mmol) and Fe (0.68 g, 12.19 mmol) in EtOH (6.00 mL) and H2O (1.20 mL) was added NH4Cl (0.65 g, 12.19 mmol) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was filtered, the filter cake was washed with EA (3 x 30 mL). The filtrate was concentrated under reduced pressure to afford 4-bromo-N1-cyclopropyl-6- methoxybenzene-1,2-diamine (0.30 g, crude) as a brown oil. MS ESI calculated for C10H13BrN2O [M + H]+, 257.02, 259.02, found 257.10, 259.10. Step 4: 5-Bromo-1-cyclopropyl-7-methoxy-1H-benzo[d]imidazole [00147] To a stirred solution of 4-bromo-N1-cyclopropyl-6-methoxybenzene-1,2-diamine (0.30 g, 1.17 mmol) in DCE (3.60 mL) was added DMF-DMA (0.24 mL) at room temperature. The reaction mixture was stirred for 2 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/(EA:EtOH=3:1) (3/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-1-cyclopropyl-7-methoxy-1H-benzo[d]imidazole (80.00 mg, 25%) as a light yellow solid. MS ESI calculated for C11H11BrN2O [M + H]+, 267.01, 269.01, found 266.85, 269.85. Step 5: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-7- methoxy-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00148] To a stirred mixture of 5-bromo-1-cyclopropyl-7-methoxy-1H-benzo[d]imidazole (70 mg, 0.26 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (130.25 mg, 0.39 mmol), Pd(PPh3)2Cl2 (18.39 mg, 0.03 mmol) and CuI (9.98 mg, 0.05 mmol) in DMF (1.00 mL) was added TEA (79.55 mg, 0.79 mmol) at room temperature. The reaction mixture was degassed with argon for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product (28 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 35% B in 10 min, 35% B; Wave length: 254 nm; RT: 7 min; the fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5- (methoxymethyl)pyrrolidin-3-yl)-3-((1-cyclopropyl-7-methoxy-1H-benzo[d]imidazol-5- yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (13.4 mg, 10%) as a white solid. MS ESI calculated for C27H31N7O4 [M + H]+, 518.24, found 518.30; 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 6.98 (s, 1H), 6.89-6.48 (m, 2H), 6.20-6.15 (m, 1H), 5.72-5.65 (m, 1H), 5.29-5.20 (m, 1H), 4.63-4.30 (m, 1H), 4.12-3.80 (m, 4H), 3.77-3.71 (m, 1H), 3.65-3.39 (m, 2H), 3.31 (d, J = 9.4 Hz, 4H), 2.97-2.92 (m, 3H), 2.48-2.22 (m, 2H), 1.31-0.68 (m, 4H). Example 2
Figure imgf000059_0001
Figure imgf000059_0002
Step 1: (S)-1-(1-Acryloylpyrrolidin-3-yl)-3-((6-chloro-1-cyclopropyl-7-fluoro-1H- benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00149] To a stirred mixture of 5-bromo-6-chloro-1-cyclopropyl-7-fluoro-1,3-benzodiazole (50.00 mg, 0.17 mmol), 3-ethynyl-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin-3- yl]pyrazole-4-carboxamide (0.20 g, 0.70 mmol), trans-dichlorobis(triphenylphosphine)palladium (25.00 mg, 0.04 mmol) and cuprous iodide (20.00 mg, 0.11 mmol) in N,N-dimethylformamide (0.50 mL) was added triethylamine (98.95 mg, 0.52 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: Xselect CSH C18 OBD Column, 30 x 150 mm, 5 μm; Mobile phase A: water (Plus 10 mmol/L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 38% B in 8 min, 38% B; Wave length: 254 nm; RT: 7 min. The fractions contained desired product were combined and concentrated to afford (S)-1-(1- acryloylpyrrolidin-3-yl)-3-((6-chloro-1-cyclopropyl-7-fluoro-1H-benzo[d]imidazol-5- yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (17.20 mg, 33%) as a white solid. MS ESI calculated for C24H23ClFN7O2 [M + H]+, 496.16, 498.16, found 496.05, 498.05; 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.92 (s, 1H), 7.49 (s, 1H), 6.85 (s, 1H), 6.70-6.54 (m, 2H), 6.20-6.15 (m, 1H), 5.72-5.68 (m, 1H), 5.18-5.14 (m, 1H), 3.90-3.81 (m, 1H), 3.79-3.67 (m, 2H), 3.65-3.50 (m, 1H), 2.96 (dd, J = 5.6, 2.6 Hz, 3H), 2.43-2.40 (m, 1H), 2.33-2.29 (m, 1H), 1.21- 1.17 (m, 2H), 1.11 (dd, J = 7.4, 5.3 Hz, 2H). Example 3
Figure imgf000060_0001
Step 1: 1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)-3-(2- {5-methylimidazo[1,5-a]pyridin-8-yl}ethynyl)pyrazole-4-carboxamide [00150] To a stirred mixture of 3-(2-{5-chloroimidazo[1,5-a]pyridin-8-yl}ethynyl)-1-[(3S,5R)- 5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.10 g, 0.21 mmol) and trimethyl-1,3,5,2,4,6-trioxatriborinane (78.14 mg, 0.62 mmol) in dioxane (1 mL) was added K2CO3 (86.03 mg, 0.62 mmol) and 2nd Generation XPhos Precatalyst (16.33 mg, 0.021 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (20/1) to afford the crude product which was further purified by reverse flash chromatography with the following conditions: column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 µm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 22% B to 42% B in 10 min, 42% B; Wave Length: 220 nm; RT: 9 min. The fractions contained desired product were combined and concentrated to afford 1- [(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)-3-(2-{5- methylimidazo[1,5-a]pyridin-8-yl}ethynyl)pyrazole-4-carboxamide (25.5 mg, 26%) as a light green solid. MS ESI calculated for C24H27N7O3 [M + H]+, 462.22, found 462.10; 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.68 (s, 1H), 7.07 (d, J = 6.7 Hz, 1H), 6.89-6.67 (m, 2H), 6.51-6.40 (m, 3H), 5.77-5.73 (m, 1H), 5.58-.27 (m, 2H), 4.58 (d, J = 9.0 Hz, 1H), 4.12-4.08 (m, 2H), 3.95- 3.92 (m, 1H), 3.49-3.36 (m, 4H), 3.15-3.08 (m, 3H), 2.65 (s, 4H), 2.42-2.37 (m, 1H). Example 4
Figure imgf000061_0001
Figure imgf000061_0002
Step 1: 3-(2-{5-Cyclopropylimidazo[1,5-a]pyridin-8-yl}ethynyl)-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00151] To a stirred solution of 3-(2-{5-chloroimidazo[1,5-a]pyridin-8-yl}ethynyl)-1-[(3S,5R)- 5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.10 g, 0.20 mmol), cyclopropylboronic acid (35.65 mg, 0.41 mmol) and 2nd Generation XPhos Precatalyst (16.33 mg, 0.02 mmol) in dioxane (2.00 mL) was added K2CO3 (86.03 mg, 0.62 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 16 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product which was further purified by reverse phase flash with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 24% B to 34% B in 8 min; Wave Length: 254 nm. The fractions contained desired product were combined and concentrated to afford 3-(2-{5-cyclopropylimidazo[1,5- a]pyridin-8-yl}ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (12.30 mg, 11%) as a white solid. MS ESI calculated for C26H29N7O3 [M + H]+, 488.23, found 488.20; 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.68 (s, 1H), 7.04 (t, J = 6.4 Hz, 1H), 6.89-6.62 (m, 2H), 6.556.37 (m, 3H), 5.73-5.70 (m, 1H), 5.57- 5.24 (m, 2H), 4.61-4.33 (m, 1H), 4.08-4.01.(m, 2H), 3.93-3.90 (m, 1H), 3.593.33 (m, 4H), 3.07- 3.02 (m, 3H), 2.73-2.70 (m, 1H), 2.42-2.27 (m, 1H), 2.10-2.08 (m, 1H), 1.22-1.19(m, 2H), 0.90- 0.86 (m, 2H). Example 5
Figure imgf000062_0001
Step 1: 3-(2-{5-Chloroimidazo[1,5-a]pyridin-8-yl}ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00152] To a stirred mixture of 8-bromo-5-chloroimidazo[1,5-a]pyridine (50 mg, 0.22 mmol) and 3-ethynyl-1-[(5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (71.58 mg, 0.22 mmol) in DMF (5 mL) were added CuI (8.23 mg, 0.04 mmol), Pd(PPh3)2Cl2 (15.16 mg, 0.02 mmol) and TEA (0.66 g, 6.48 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product which was further purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 5% to 20% gradient in 10 min; 20% to 50% gradient in 30 min; detector, UV 254 nm. The fractions contained desired product were combined and concentrated to afford 3-(2-{5-chloroimidazo[1,5- a]pyridin-8-yl}ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (21.9 mg, 21%) as a light yellow solid. MS ESI calculated for C23H24ClN7O3 [M + H]+, 482.16, 484.16, found 482.10, 484.10; 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.80 (s, 1H), 7.10 (d, J = 7.2 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 6.48-6.42 (m, 2H), 5.77-5.73 (m, 1H), 5.58-5.49 (m, 1H), 4.59 (d, J = 8.9 Hz, 1H), 4.16-4.02 (m, 2H), 3.97-3.92 (m, 1H), 3.47 (d, J = 8.6 Hz, 1H), 3.39 (s, 3H), 3.08 (s, 3H), 2.78-2.71 (m, 1H), 2.38-2.34 (m, 1H).
Figure imgf000063_0001
Step 1: Tert-butyl (2R,4S)-4-{5-[(tert-butoxycarbonyl)(ethyl)amino]-3-[2-(6-chloro-1- cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-4-cyanopyrazol-1-yl}-2- (methoxymethyl)pyrrolidine-1-carboxylate [00153] To a stirred solution of tert-butyl (2R,4S)-4-{3-bromo-5-[(tert- butoxycarbonyl)(ethyl)amino]-4-cyanopyrazol-1-yl}-2-(methoxymethyl)pyrrolidine-1- carboxylate (0.30 g, 0.56 mmol), 6-chloro-1-cyclopropyl-5-[2-(trimethylsilyl)ethynyl]-1,3- benzodiazole (0.16 g, 0.56 mmol), Pd(PPh3)2Cl2 (39.31 mg, 0.06 mmol), CuI (21.28 mg, 0.11 mmol) and TBAI (0.05 g, 0.14 mmol) in DMF (0.5 mL) was added K2CO3 (0.23 g, 1.70 mmol) at room temperature. The resulting mixture was degassed with nitrogen for three times and stirred for 1 h at 100 °C. The resulting mixture was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/3). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R,4S)-4-{5-[(tert- butoxycarbonyl)(ethyl)amino]-3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-4- cyanopyrazol-1-yl}-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.28 g, 74%) as a yellow solid. MS ESI calculated for C34H42ClN7O5 [M + H]+, 664.29, 666.29, found 664.20, 666.20. Step 2: Tert-butyl (2R,4S)-4-{5-[(tert-butoxycarbonyl)(ethyl)amino]-4-carbamoyl-3-[2-(6- chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]pyrazol-1-yl}-2- (methoxymethyl)pyrrolidine-1-carboxylate [00154] To a stirred solution of tert-butyl (2R,4S)-4-{5-[(tert-butoxycarbonyl)(ethyl)amino]-3- [2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-4-cyanopyrazol-1-yl}-2- (methoxymethyl)pyrrolidine-1-carboxylate (0.35 g, 0.52 mmol) in EtOH (5 mL) and DMSO (1 mL) were added NaOH (1.26 mL, 0.63 mmol) and H2O2 (30%) (0.20 g, 6.14 mmol) dropwise at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and then stirred for another 1.5 h at room temperature. The resulting mixture was diluted with water (40 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R,4S)-4-{5-[(tert-butoxycarbonyl)(ethyl)amino]-4-carbamoyl-3-[2-(6-chloro-1-cyclopropyl- 1,3-benzodiazol-5-yl)ethynyl]pyrazol-1-yl}-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.29 g, 80%) as a light yellow solid. MS ESI calculated for C34H44ClN7O6 [M + H-Boc]+, 582.30, 584.30, found 582.40, 584.40. Step 3: 3-[2-(6-Chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5-(ethylamino)-1-[(3S,5R)- 5-(methoxymethyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00155] To a stirred solution of tert-butyl (2R,4S)-4-{5-[(tert-butoxycarbonyl)(ethyl)amino]-4- carbamoyl-3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]pyrazol-1-yl}-2- (methoxymethyl)pyrrolidine-1-carboxylate (0.29 g, 0.42 mmol) in DCM (3 mL) was added hydrogen chloride (1.5 mL, 329.13 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5-(ethylamino)-1-[(3S,5R)-5- (methoxymethyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (0.20 g, crude) as a yellow solid. MS ESI calculated for C24H28ClN7O2 [M + H]+, 482.20, 484.20, found 482.15, 484.15; 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.33 (s, 1H), 8.69 (s, 1H), 5.26 (s, 1H), 3.72 (s, 1H), 3.67- 3.50 (m, 4H), 3.36 (s, 3H), 3.29-3.21 (m, 2H), 3.00 (s, 4H), 2.71-2.52 (m,1H), 2.42-1.88 (m, 1H), 1.20-1.05 (m, 7H). Step 4: 3-[2-(6-Chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5-(ethylamino)-1-[(3S,5R)- 5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00156] To a stirred solution of 3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5- (ethylamino)-1-[(3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (0.10 g, 0.20 mmol) and DIEA (0.13 g, 1.03 mmol) in DCM (2 mL) was added acryloyl chloride (0.83 mL, 0.20 mmol) dropwise at 0 °C. The reaction mixture was stirred for 10 min at 0 °C. The resulting mixture was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (0.12 g) was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 19 x 250 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 40% B to 55% B in 10 min, 55% B; Wave Length: 254 nm; RT1: 9 min. The fractions contained desired product were combined and concentrated to afford 3-[2-(6-chloro-1-cyclopropyl-1,3- benzodiazol-5-yl)ethynyl]-5-(ethylamino)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (0.02 g, 19%) as a white solid. MS ESI calculated for C27H30ClN7O3 [M + H]+, 536.21, 538.21, found 536.30, 538.30; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 6.0 Hz, 2H), 7.68 (s, 1H), 7.19 (s, 1H), 6.60-6.38 (m, 2H), 5.72-5.70 (m, 1H), 5.55-5.09 (m, 2H), 4.59-4.56 (m, 1H), 4.07-4.05 (m, 2H), 3.92-4.90 (m, 1H), 3.60-3.18 (m, 7H), 2.73-2.71 (m, 1H), 2.33-2.31 (m, 1H), 1.37-1.20 (m, 5H), 1.10 (s, 2H). Example 7
Figure imgf000065_0001
Step 1: (2-Amino-4-bromo-5-fluorophenyl)(cyclopropyl)methanone [00157] To a stirred solution of 2-amino-4-bromo-5-fluoro-N-methoxy-N-methylbenzamide (2.00 g, 7.22 mmol) in THF (20.00 mL) was added bromo(cyclopropyl)magnesium (3.67 g, 25.26 mmol) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at -40 °C under nitrogen atmosphere. The resulting mixture was quenched by the addition of sat. NH4Cl (aq.) (10 mL) at -40 °C. The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford (2-amino-4-bromo-5- fluorophenyl)(cyclopropyl)methanone (1.46 g, 78%) as a light yellow oil. MS ESI calculated for C10H9BrFNO [M + H]+, 257.99, 259.98, found 257.90, 259.90; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 9.6 Hz, 1H), 6.85 (d, J = 5.8 Hz, 1H), 5.98 (s, 2H), 2.49-2.42 (m, 1H), 1.28-1.08 (m, 2H), 0.12-0.97 (m, 2H). Step 2: 5-Bromo-2-(1-cyclopropylvinyl)-4-fluoroaniline [00158] To a stirred solution of bromo(methyl)triphenyl-λ5-phosphane (1.04 g, 2.91 mmol) in THF (5.00 mL) was added t-BuOK (0.32 g, 2.90 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. To the above mixture was added (2-amino-4-bromo-5- fluorophenyl)(cyclopropyl)methanone (0.50 g, 1.94 mmol) in THF (1.00 mL) dropwise at 0 °C. The reaction mixture was stirred for additional 1 h at room temperature. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-2-(1-cyclopropylethenyl)-4- fluoroaniline (0.42 g, 85%) as a light yellow oil. MS ESI calculated for C11H11BrFN [M + H]+, 256.01, 258.01, found 255.95, 257.95. Step 3: 7-Bromo-4-cyclopropyl-6-fluorocinnoline [00159] To a stirred mixture of 5-bromo-2-(1-cyclopropylethenyl)-4-fluoroaniline (0.37 g, 1.46 mmol) in water (5.00 mL) was added NaNO2 (0.8 mL, 1.60 mmol, 2 M) and con. HCl (1.87 g, 12 M) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 7- bromo-4-cyclopropyl-6-fluorocinnoline (0.32 g, 82%) as a light yellow solid. MS ESI calculated for C11H8BrFN2 [M + H]+, 266.99, 268.99, found 266.95, 268.95; 1H NMR (400 MHz, DMSO- d6) δ 9.05 (s, 1H), 8.89 (d, J = 7.0 Hz, 1H), 8.42 (d, J = 9.9 Hz, 1H), 2.63-2.59 (m, 1H), 1.36- 1.00 (m, 4H). Step 4: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((4-cyclopropyl-6- fluorocinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00160] To a stirred mixture of 7-bromo-4-cyclopropyl-6-fluorocinnoline (150.00 mg, 0.56 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (186.10 mg, 0.56 mmol), Pd(PPh3)2Cl2 (39.42 mg, 0.06 mmol) and CuI (21.39 mg, 0.11 mmol) in DMF (1.50 mL) was added TEA (170.48 mg, 1.69 mmol) at room temperature. The reaction mixture was degassed with argon for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford the crude product. And the crude product was precipitated by the addition of ACN. The precipitated solids were collected by filtration and washed with ACN (3 x 30 mL). The fractions contained desired product were combined and concentrated 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3- yl)-3-((4-cyclopropyl-6-fluorocinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide (158.90 mg, 55%) as an off-white solid. MS ESI calculated for C27H28FN7O3 [M + H]+, 518.22, found 518.20; 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.82 (d, J = 7.1 Hz, 1H), 8.37 (d, J = 10.5 Hz, 1H), 7.47 (s, 1H), 6.91 (s, 1H), 6.78-6.48 (m, 2H), 6.18 (d, J = 16.6 Hz, 1H), 5.83-5.63 (m, 1H), 5.29-5.24 (m, 1H), 4.49 (d, J = 53.0 Hz, 1H), 4.15-3.69 (m, 2H), 3.65-3.41 (m, 3H), 2.96 (t, J = 5.0 Hz, 3H), 2.64-2.58 (m, 2H), 2.55 (s, 2H), 2.34 (s, 1H), 1.31- 1.20 (m, 2H), 1.14-1.05 (m, 2H). Example 8
Figure imgf000067_0001
Step 1: 5-Bromo-4-chloro-2-cyclopropanecarbonylaniline [00161] To a stirred solution of 2-amino-4-bromo-5-chloro-N-methoxy-N-methylbenzamide (2 g, 6.81 mmol) in THF (20 mL) was added bromo(cyclopropyl)magnesium (47.69 mL, 23.85 mmol) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at -40 °C under nitrogen atmosphere. The resulting mixture was quenched with sat. NH4Cl (aq.) at -40 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/PE (1/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-4-chloro-2-cyclopropanecarbonylaniline (1.3 g, 69%) as a yellow solid. MS ESI calculated for C10H9BrClNO [M + H]+, 273.96, 275.96, found 273.95, 275.95; 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 6.90-6.89 (m, 1H), 6.07 (s, 2H), 2.48-2.41 (m, 1H), 1.16-1.08 (m, 2H), 1.03-0.88 (m, 2H). Step 3: 5-Bromo-4-chloro-2-(1-cyclopropylethenyl)aniline [00162] To a stirred solution of methyltriphenylphosphaniumbromide (1.56 g, 4.37 mmol) in THF (3 mL) was added t-BuOK (0.49 g, 4.37 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. To the above mixture was added 5-bromo-4-chloro-2-cyclopropanecarbonylaniline (0.30 g, 1.09 mmol) at 0 °C. The reaction mixture was stirred for additional 30 min at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/PE (1/4). The fractions contained desired product were combined and concentrated to afford 5-bromo-4-chloro-2-(1- cyclopropylethenyl)aniline (0.29 g, 97%) as a light yellow solid. MS ESI calculated for C11H11BrClN [M + H]+, 271.98, 273.98, found 271.90, 273.90; 1H NMR (400 MHz, CDCl3) δ 7.04 (s, 1H), 6.92 (s, 1H), 5.21-5.20 (m, 1H), 4.94 (d, J = 1.20 Hz, 1H), 3.86 (s, 2H), 1.61-1.54 (m, 1H), 0.82-0.67 (m, 2H), 0.52-0.43 (m, 2H). Step 4: 7-Bromo-6-chloro-4-cyclopropylcinnoline [00163] To a stirred solution of 5-bromo-4-chloro-2-(1-cyclopropylethenyl)aniline (0.26 g, 0.95 mmol) in H2O (2.6 mL) were added con. HCl (1.03 mL, 12.40 mmol) and NaNO2 (0.86 mL, 1.72 mmol, 2 M) dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-6- chloro-4-cyclopropylcinnoline (0.24 g, 88%) as a light yellow solid. MS ESI calculated for C11H8BrClN2 [M + H]+, 282.96, 284.96, found 282.85, 284.85; 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.86 (s, 1H), 8.40 (s, 1H), 2.37-2.30 (m, 1H), 1.36-1.30 (m, 2H), 1.04-1.00 (m, 2H). Step 5: 3-[2-(6-Chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00164] To a stirred solution of 7-bromo-6-chloro-4-cyclopropylcinnoline (102.68 mg, 0.36 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (120 mg, 0.36 mmol) and Pd(PPh3)2Cl2 (25.42 mg, 0.04 mmol) and CuI (13.79 mg, 0.07 mmol) in DMF (1.2 mL) was added TEA (109.93 mg, 1.09 mmol). The reaction mixture was deagassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (9/1) to afford the crude product. The crude product was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 39% B in 8 min, 39% B; Wave Length: 254 nm. The fractions contained desired product were combined and concentrated to afford 3-[2-(6-chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-1- [(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4- carboxamide (58.00 mg, 29%) as a yellow solid. MS ESI calculated for C27H28ClN7O3 [M + H]+, 534.19, 536.19, found 534.25, 536.25; 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.85 (s, 1H), 8.38 (s, 1H), 7.00 (s, 1H), 6.56-6.36 (m, 2H), 5.72-5.69 (m, 1H), 5.58-5.25 (m, 2H), 4.58 (d, J = 8.80 Hz, 1H), 4.12-3.98 (m, 2H), 3.91 (dd, J = 12.8 Hz, 1H), 3.49-3.36 (m, 4H), 3.05 (d, J = 14.8 Hz, 3H), 2.78-2.65 (m, 1H), 2.35 (s, 2H), 1.41-1.31 (m, 2H), 1.07-1.02 (m, 2H).
Example 9
Figure imgf000070_0001
Step 1: 1-(2-Amino-4-bromo-5-chlorophenyl) propan-1-one [00165] To a stirred solution of 2-amino-4-bromo-5-chloro-N-methoxy-N-methylbenzamide (1.0 g, 3.40 mmol) in THF (10 mL) was added ethylmagnesium bromide (11.92 mL, 11.92 mmol) dropwise at -78 °C. The reaction mixture was stirred for 1 h at -40 °C. The reaction was quenched by the addition of sat. NH4Cl (aq.) (10 mL) at -40 °C and diluted with water (20 mL). The reaction mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with in PE/EA (10/1). The fractions contained desired product were combined and concentrated to afford 1-(2-amino-4-bromo-5-chlorophenyl) propan-1-one (0.79 g, 88%) as a yellow solid. MS ESI calculated for C9H9BrClNO [M + H]+, 261.96, 263.96, found 261.90, 263.90; 1H NMR (400 MHz, Chloroform-d) δ 7.78 (s, 1H), 6.97 (s, 1H), 6.25 (s, 2H), 2.92-2.86 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H). Step 2: 5-Bromo-2-(but-1-en-2-yl)-4-chloroaniline [00166] To a stirred mixture of 1-(2-amino-4-bromo-5-chlorophenyl) propan-1-one (0.4 g, 1.52 mmol) in THF (4 mL) was added potassium 2-methylpropan-2-olate (0.68 g, 6.09 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 40 min at room temperature under nitrogen atmosphere. To the above mixture was added a solution of methyltriphenylphosphanium bromide (2.18 g, 6.09 mmol) in THF (20 mL) dropwise at 0 °C. The resulting mixture was stirred for additional 1 h at room temperature. The reaction was diluted wih H2O (50 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/DCM (2/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-2-(but-1-en-2-yl)-4- chloroaniline (0.35 g, 88%) as a light yellow oil. MS ESI calculated for C10H11BrClN [M + H]+, 259.98, 261.98, found 259.80, 261.80; 1H NMR (400 MHz, Chloroform-d) δ 7.03 (s, 1H), 6.94 (s, 1H), 5.37-5.30 (m, 1H), 5.04 (d, J = 1.5 Hz, 1H), 3.88 (s, 2H), 2.38-2.28 (m, 2H), 1.04 (t, J = 7.4 Hz, 3H). Step 3: 7-Bromo-6-chloro-4-ethylcinnoline [00167] To a stirred mixture of 5-bromo-2-(but-1-en-2-yl)-4-chloroaniline (0.40 g, 1.53 mmol), con. HCl (0.73 g, 19.95 mmol) in H2O (4 mL) was added 2 M NaNO2 (0.84 mL, 1.68 mmol) at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was basified to pH 8 with NaHCO3 (aq.). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-6-chloro-4-ethylcinnoline (0.36 g, 86%) as a light solid. MS ESI calculated for C10H8BrClN2 [M + H]+, 270.96, 272.96, found 270.80, 272.80; 1H NMR (400 MHz, Chloroform-d) δ 9.21 (s, 1H), 8.86 (s, 1H), 8.15 (s, 1H), 3.08-2.94 (m, 2H), 1.44 (t, J = 7.6 Hz, 3H). Step 4: 3-[2-(6-Chloro-4-ethylcinnolin-7-yl)ethynyl]-1-[ 5R)-5-(methoxymethyl)-1-(prop-2-
Figure imgf000071_0001
enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00168] To a stirred mixture of 7-bromo-6-chloro-4-ethylcinnoline (70.0 mg, 0.25 mmol) and 3- ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl) pyrrolidin-3-yl]-5-(methylamino) pyrazole-4-carboxamide (0.10 g, 0.31 mmol) in DMF (1 mL) were added Pd(PPh3)2Cl2 (18.09 mg, 0.02 mmol), CuI (9.82 mg, 0.05 mmol) and TEA (78.26 mg, 0.77 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20/1) to afford the crude product which was purified by reverse phase flash with the following conditions: C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 10% to 50% gradient in 60 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford 3-[2-(6-chloro-4- ethylcinnolin-7-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (42 mg, 31%) as a light yellow solid. MS ESI calculated for C26H28ClN7O3 [M + H]+, 522.19, 524.19, found 522.25, 524.25; 1H NMR (400 MHz, Chloroform-d) δ 9.21 (s, 1H), 8.84 (d, J = 6.3 Hz, 1H), 8.11 (s, 1H), 7.18-5.97 (m, 3H), 5.90- 5.11 (m, 3H), 4.58 (d, J = 9.0 Hz, 1H), 4.12 (t, J = 9.0 Hz, 1H), 4.08-3.97 (m, 1H), 3.91-3.87 (m, 1H), 3.52 (d, J = 3.9 Hz, 1H), 3.45-3.40 (m, 1H), 3.38 (d, J = 5.4 Hz, 3H), 3.14-3.01 (m, 5H), 2.78-2.65 (m, 1H), 2.37-2.30 (m, 1H), 1.45 (t, J = 7.5 Hz, 3H). Example 10
Figure imgf000072_0001
Step 1: 1-(3-Bromopyridin-2-yl)methanamine [00169] To a stirred solution of 3-bromopyridine-2-carbonitrile (500 mg, 2.73 mmol) in THF (5 mL) was added BH3.THF (1.05 mL, 10.92 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was quenched by the addition of MeOH (10 mL) at room temperature. The resulting mixture was concentrated under reduced pressure to afford 1-(3-bromopyridin-2- yl)methanamine (500 mg, crude) as a brown yellow solid. MS ESI calculated for C6H7BrN2 [M + H]+, 186.98, 188.98, found 186.90, 188.90. Step 2: N-[(3-Bromopyridin-2-yl)methyl]cyclopropanecarboxamide [00170] To a stirred solution of 1-(3-bromopyridin-2-yl)methanamine (500 mg, 2.67 mmol) and TEA (541.01 mg, 5.34 mmol) in DCM (5 mL) was added cyclopropanecarbonyl chloride (335.32 mg, 3.20 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford N-[(3-bromopyridin-2-yl)methyl]cyclopropanecarboxamide (250 mg, 36%) as a brown yellow solid. MS ESI calculated for C10H11BrN2O [M + H]+, 255.01, 257.01, found 254.90, 256.90. Step 3: 6-Bromo-3-cyclopropylimidazo[1,5-a]pyridine [00171] To a stirred solution of N-[(3-bromopyridin-2-yl)methyl]cyclopropanecarboxamide (250 mg, 0.98 mmol) in DCE (2.5 mL) was added POCl3 (901.55 mg, 5.88 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1). The fractions contained desired product were combined and concentrated to afford 6-bromo-3- cyclopropylimidazo[1,5-a]pyridine (300 mg, crude) as a brown yellow solid. MS ESI calculated for C10H9BrN [M + H]+, 236.99, 238.99, found 236.90, 238.90. Step 4: 3-(2-{3-Cyclopropylimidazo[1,5-a]pyridin-8-yl}ethynyl)-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00172] To a stirred solution of 8-bromo-3-cyclopropylimidazo[1,5-a]pyridine (149.54 mg, 0.63 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (250.80 mg, 0.76 mmol) in DMF (2.02 mL) were added Pd(PPh3)2Cl2 (44.27 mg, 0.06 mmol), CuI (24.02 mg, 0.13 mmol) and TEA (190.89 mg, 1.89 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (5/1) to afford the crude product. The crude product was purified by reverse flash chromatography with the following conditions: column: C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. The fractions contained desired product were combined and concentrated to afford 3-(2-{3-cyclopropylimidazo[1,5- a]pyridin-8-yl}ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (28.3 mg, 9%) as a light yellow solid. MS ESI calculated for C26H29N7O3 [M + H]+, 488.23, found 488.25; 1H NMR (400 MHz, Chloroform-d) δ 8.04- 8.01 (m, 1H), 7.45-7.40 (s, 1H), 7.01-7.00 (m, 1H), 6.90-6.66 (m, 2H), 6.61-6.57 (m, 1H), 6.51- 6.36 (m, 2H), 5.72 (m, 1H), 5.58 -5.24 (m, 2H), 4.62-4.38 (m, 1H), 4.06-4.05 (m, 2H), 3.91-3.90 (m, 1H), 3.55-3.44 (m, 1H), 3.39-3.38 (m, 3H), 3.05-3.04 (m, 3H), 2.71-2.70 (m, 1H), 2.45-2.27 (m, 1H), 2.04-2.03 (s, 1H), 1.12-1.1 (m, 4H). Example 11
Figure imgf000074_0001
Step 1: 4-Bromo-5-chloro-1-cyclopropylindazole [00173] To a stirred mixture of 4-bromo-5-fluoro-1H-indazole (0.47 g, 2.19 mmol), cyclopropylboronic acid (0.34 g, 4.06 mmol) and 2-(pyridin-2-yl)pyridine (0.31 g, 2.03 mmol) in DCE (8.00 mL) was added Cu(OAc)2 (0.73 g, 4.06 mmol) at room temperature. The reaction mixture was degassed with oxygen for three times and stirred for 16 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (4/1). The fractions contained desired product were combined and concentrated to afford 4-bromo-5-chloro-1-cyclopropylindazole (250 mg, 42%) as a yellow solid. MS ESI calculated for C10H8BrClN2 [M + H]+, 269.96, 271.96, found 269.90, 271.90. Step 2: 3-[2-(5-Chloro-1-cyclopropylindazol-4-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00174] To a stirred mixture of 4-bromo-5-chloro-1-cyclopropylindazole (0.10 g, 0.36 mmol), 3- ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.24 g, 0.73 mmol) , Pd(PPh3)2Cl2 (25.85 mg, 0.03 mmol) and CuI (14.03 mg, 0.06 mmol) in DMF (2.00 mL) was added TEA (0.15 mL, 1.10 mmol) dropwise at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product was purified by reverse flash chromatography with the following conditions: Column: C18 silica gel; Mobile phase: ACN in water (Plus 10 mmol NH4HCO3), 5% to 50% gradient in 30 min; Detector: UV 220/254 nm. The fractions contained desired product were combined and concentrated to afford 3-[2-(5- chloro-1-cyclopropylindazol-4-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (41.4 mg, 21%) as a white solid. MS ESI calculated for C26H28ClN7O3 [M + H]+, 522.19, 524.19, found 522.30, 524.30; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.60 (d, J = 9.3Hz, 1H), 7.44 (d, J = 4.5Hz, 1H), 7.28 (s, 1H), 6.52-6.45 (m, 2H), 5.75-5.32 (m, 1H), 5.58-5.49 (m, 2H), 4.60 (d, J = 4.8 Hz, 1H), 4.18- 4.13 (m, 1H), 4.08-3.91 (m, 2H), 3.66-3.60 (m, 1H), 3.54-3.46 (m, 1H), 3.40 (d, J = 4.8 Hz, 3H), 3.06 (d, J = 5.3 Hz, 3H), 2.78-2.64 (m, 1H), 2.44-2.32 (m, 1H), 1.29-1.19 (m, 4H). Example 12
Figure imgf000075_0001
Step 1: (2R)-1-(5-Fluoro-2-nitrophenyl)-2-methylpyrrolidine [00175] To a stirred mixture of benzene, 2,4-difluoro-1-nitro- (1.00 g, 6.29 mmol) and (2R)-2- methylpyrrolidine (0.80 g, 9.43 mmol) in EtOH (10 mL) was added DIEA (2.44 g, 18.86 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1). The fractions contained desired product were combined and concentrated to afford (2R)- 1-(5-fluoro-2-nitrophenyl)-2-methylpyrrolidine (1.18 g, 83%) as a light yellow oil. MS ESI calculated for C11H13FN2O2 [M + H]+, 225.10, found 225.05; 1H NMR (400 MHz, Chloroform- d) δ 7.85 (dd, J = 9.1, 6.3 Hz, 1H), 6.64 (dd, J = 12.2, 2.6 Hz, 1H), 6.46-6.38 (m, 1H), 3.95-3.82 (m, 1H), 3.59-3.68 (m, 1H), 2.75-2.69 (m, 1H), 2.40-2.27 (m, 1H), 2.09-1.92 (m, 1H), 1.85-1.62 (m, 2H), 1.25 (d, J = 6.0 Hz, 3H). Step 2: (2R)-1-(4-Bromo-5-fluoro-2-nitrophenyl)-2-methylpyrrolidine [00176] To a stirred mixture of (2R)-1-(5-fluoro-2-nitrophenyl)-2-methylpyrrolidine (1.18 g, 5.26 mmol) in AcOH (11 mL) was added NBS (1.40 g, 7.89 mmol) in portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford (2R)-1- (4-bromo-5-fluoro-2-nitrophenyl)-2-methylpyrrolidine (1.12 g, 70%) as a brown yellow oil. MS ESI calculated for C11H12BrFN2O2 [M + H]+.303.01, 305.01, found 303.03, 305.03. Step 3: 5-Bromo-4-fluoro-2-[(2R)-2-methylpyrrolidin-1-yl]aniline [00177] To a stirred mixture of (2R)-1-(4-bromo-5-fluoro-2-nitrophenyl)-2-methylpyrrolidine (1.12 g, 3.70 mmol) in EtOH (11 mL) and H2O (22 mL) were added Fe (2.06 g, 36.95 mmol) and NH4Cl (1.98 g, 36.95 mmol) in portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (5 x 40 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-4-fluoro-2-[(2R)-2-methylpyrrolidin-1-yl]aniline (430 mg, 42%) as a brown oil. MS ESI calculated for C11H14BrFN2 [M + H]+.273.03, 275.03, found 273.05, 275.05; 1H NMR (400 MHz, Chloroform-d) δ 6.87 (d, J = 6.9 Hz, 1H), 6.80 (d, J = 10.2 Hz, 1H), 3.88 (s, 2H), 3.56-3.50 (m, 1H), 3.40 (d, J = 6.2 Hz, 1H), 2.61-2.57 (m, 1H), 2.22-2.10 (m, 1H), 1.94 (s, 1H), 1.87-1.76 (m, 1H), 1.57 (t, J = 10.2 Hz, 1H), 1.02 (d, J = 6.0 Hz, 3H). Step 4: (R)-6-Bromo-7-fluoro-1-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole [00178] To a stirred mixture of 5-bromo-4-fluoro-2-[(2R)-2-methylpyrrolidin-1-yl]aniline (0.43 g, 1.57 mmol) and H2O2 (30%) (0.73 mL, 31.48 mmol) in EtOAc (4.3 mL) was added CH3SO3H (0.01 mL, 0.16 mmol) dropwise at room temperature under atmosphere. The reaction mixture was stirred for 16 h at 75 °C under nitrogen atmosphere. The reaction was diluted with water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford (R)-6-bromo-7-fluoro-1-methyl-2,3-dihydro- 1H-benzo[d]pyrrolo[1,2-a]imidazole (110 mg, 25%) as a brown yellow solid. MS ESI calculated for C11H10BrFN2 [M + H]+, 269.00, 271.00, found 268.95, 270.95. Step 5: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-(((R)-7-fluoro-1-methyl- 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide [00179] To a stirred mixture of (R)-6-bromo-7-fluoro-1-methyl-2,3-dihydro-1H- benzo[d]pyrrolo[1,2-a]imidazole (75 mg, 0.28 mmol) and 3-ethynyl-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.19 g, 0.56 mmol) in DMF (1 mL) were added Pd(PPh3)2Cl2 (19.56 mg, 0.03 mmol), CuI (10.62 mg, 0.06 mmol) and TEA (84.60 mg, 0.84 mmol) .The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was diluted with water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-(((R)-7-fluoro-1-methyl- 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide (17.8 mg, 12%) as an off-white solid. MS ESI calculated for C27H30FN7O3 [M + H]+.520.24, found 520.20; 1H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 6.1 Hz, 1H), 7.14 (d, J = 9.0 Hz, 2H), 6.83 (s, 1H), 6.57-6.37 (m, 2H), 5.72 (dd, J = 8.6, 3.8 Hz, 1H), 5.51-5.36 (m, 2H), 4.67-4.54 (m, 2H), 4.12 (t, J = 9.1 Hz, 2H), 3.91 (dd, J = 9.7, 2.9 Hz, 1H), 3.55-3.39 (m, 4H), 3.16-2.94 (m, 6H), 2.73-2.69 (m, 1H), 2.34-2.28 (m, 2H), 1.62 (d, J = 6.4 Hz, 3H). Example 13
Figure imgf000077_0001
Step 1: -1-(5-Fluoro-2-nitrophenyl)-2-methylpyrrolidine [00180] To a stirred solution of benzene, 2,4-difluoro-1-nitro- (1 g, 6.29 mmol) and DIEA (1.83 g, 14.14 mmol) in EtOH (10 mL) was added (2S)-2-methylpyrrolidine hydrochloride (1.15 g, 9.43 mmol) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (2S)-1-(5-fluoro-2-nitrophenyl)-2- methylpyrrolidine (1.50 g, 98%) as an orange oil. MS ESI calculated for C11H13FN2O2 [M + H]+, 225.10, found 225.20; 1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J = 9.1, 6.3 Hz, 1H), 6.64 (dd, J = 12.2, 2.6 Hz, 1H), 6.48-6.43( m, 1H), 3.91-3.86 (m, 1H), 3.62-3.42 (m, 1H), 2.79-2.70 (m, 1H), 2.40-2.27 (m, 1H), 2.05-1.90 (m, 1H), 1.62-1.53 (m, 1H), 1.47 (d, J = 6.6 Hz, 1H), 1.25 (t, J = 6.1 Hz, 3H). Step 2: (2S)-1-(4-Bromo-5-fluoro-2-nitrophenyl)-2-methylpyrrolidine [00181] To a stirred solution of (2S)-1-(5-fluoro-2-nitrophenyl)-2-methylpyrrolidine (1.5 g, 6.69 mmol) in AcOH (15 mL) was added NBS (1.25 g, 7.02 mmol) in portions at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (12/1). The fractions contained desired product were combined and concentrated to afford (2S)-1-(4-bromo-5-fluoro-2-nitrophenyl)-2-methylpyrrolidine (1.4 g, 69%) as an orange oil. MS ESI calculated for C11H12BrFN2O2 [M + H]+, 303.01, 305.01, found 302.90, 304.90. Step 3: 5-Bromo-4-fluoro-2-[(2S)-2-methylpyrrolidin-1-yl] aniline [00182] To a stirred solution of (2S)-1-(4-bromo-5-fluoro-2-nitrophenyl)-2-methylpyrrolidine (0.50 g, 1.65 mmol) and NH4Cl (0.88 g, 16.49 mmol) in EtOH (12.5 mL) and H2O (2.5 mL) was added Fe (0.92 g, 16.49 mmol) in portions at room temperature. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (5 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (12/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-4-fluoro-2-[(2S)- 2-methylpyrrolidin-1-yl] aniline (1.30 g, 92%) as a dark red solid. MS ESI calculated for C11H14BrFN2 [M + H]+, 275.04, 277.04, found 274.95, 276.95. Step 4: (3S)-10-Bromo-11-fluoro-3-methyl-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11- tetraene [00183] To a stirred solution of 5-bromo-4-fluoro-2-[(2S)-2-methylpyrrolidin-1-yl]aniline (1.30 g, 4.76 mmol) and CH3SO3H (0.03 mL, 0.48 mmol) in EtOAc (13 mL) was added H2O2 (30%) (7.39 mL, 95.18 mmol). The reaction mixture was stirred for 16 h at 75 °C. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1). The fractions contained desired product were combined and concentrated to afford the crude product. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 10% to 50% gradient in 60 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford (3S)-10-bromo-11-fluoro-3-methyl-2,7-diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraene (0.17 g, 13%) as a light brown oil. MS ESI calculated for C11H10BrFN2 [M + H]+, 271.01, 273.01, found 271.00, 273.00; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 6.2 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 4.64-4.53 (m, 1H), 3.23-3.01 (m, 2H), 2.97-2.89 (m, 1H), 2.40-2.27 (m, 1H), 1.61 (d, J = 6.4 Hz, 3H). Step 5: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-(((S)-7-fluoro-1-methyl-2,3- dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide [00184] To a stirred mixture of (3S)-10-bromo-11-fluoro-3-methyl-2,7- diazatricyclo[6.4.0.0^{2,6}]dodeca-1(8),6,9,11-tetraene (0.15 g, 0.56 mmol), 3-ethynyl-1- [(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4- carboxamide (0.37 g, 1.11 mmol) , Pd(PPh3)2Cl2 (39.12 mg, 0.06 mmol) and CuI (21.23 mg, 0.11 mmol) in DMF (2 mL) was added TEA (0.17 g, 1.67 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford the crude product. The crude product (60 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 27% B to 31% B in 12 min, 31% B; Wave Length: 254 nm; RT1: 10 min. The fractions contained desired product were combined and concnetrated to afford 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)- 3-(((S)-7-fluoro-1-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5- (methylamino)-1H-pyrazole-4-carboxamide (24.7 mg, 8%) as an off-white solid. MS ESI calculated for C27H30FN7O3 [M + H]+, 520.25, found 520.30; 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.14 (s, 2H), 6.82 (s, 1H), 6.43 (d, J = 9.1 Hz, 2H), 5.71 (dd, J = 8.4, 3.9 Hz, 2H), 5.59-5.18 (m, 1H), 4.57 (d, J = 10.3 Hz, 2H), 4.14-3.76 (m, 3H), 3.56-3.36 (m, 4H), 3.21-2.92 (m, 6H), 2.76-2.71 (m, 1H), 2.36-2.27 (m, 2H), 1.60 (d, J = 6.3 Hz, 3H). Example 14
Figure imgf000080_0001
Step 1：(2R)-1-(5-Chloro-2-nitrophenyl)-2-methylpyrrolidine [00185] To a stirred mixture of 4-chloro-2-fluoro-1-nitrobenzene (1.00 g, 5.69 mmol) and (2R)- 2-methylpyrrolidine (0.73 g, 8.55 mmol) in EtOH (10 mL) was added DIEA (2.21 g, 17.09 mmol) at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1). The fractions contained desired product were combined and concentrated to afford (2R)-1-(5-chloro-2-nitrophenyl)-2-methylpyrrolidine (1.40 g, 92%) as a yellow oil. MS ESI calculated for C11H13ClN2O2 [M + H]+, 241.07, 243.07, found 241.20, 243.20; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 2.1 Hz, 1H), 6.72 (dd, J = 8.8, 2.1 Hz, 1H), 3.93-3.57 (m, 2H), 2.81-2.65 (m, 1H), 2.32-1.88 (m, 2H), 1.84-1.60 (m, 2H), 1.26 (d, J = 6.0 Hz, 3H). Step 2: (2R)-1-(4-Bromo-5-chloro-2-nitrophenyl)-2-methylpyrrolidine [00186] To a stirred mixture of (2R)-1-(5-chloro-2-nitrophenyl)-2-methylpyrrolidine (1.40 g, 5.82 mmol) in AcOH (14 mL) was added N-bromosuccinimide (1.09 g, 6.11 mmol) in portions at room temperature. The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford (2R)-1-(4-bromo-5-chloro-2-nitrophenyl)-2- methylpyrrolidine (1.10 g, 59%) as a yellow oil. MS ESI calculated for C11H12BrClN2O2 [M + H]+, 318.98, 320.98, found 319.10, 321.10; 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.09 (s, 1H), 3.90 (dd, J = 10.4, 4.4 Hz, 1H), 3.54-1.94 (m, 4H), 1.83-1.72 (m, 2H), 1.25 (d, J = 1.4 Hz, 3H). Step 3: 5-Bromo-4-chloro-2-[(2R)-2-methylpyrrolidin-1-yl]aniline [00187] To a stirred mixture of (2R)-1-(4-bromo-5-chloro-2-nitrophenyl)-2-methylpyrrolidine (1.00 g, 3.13 mmol) and NH4Cl (1.67 g, 31.29 mmol) in EtOH (7.5 mL) and H2O (15 mL) was added Fe (1.75 g, 31.29 mmol). The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-4-chloro-2-[(2R)-2-methylpyrrolidin-1-yl]aniline (0.45 g, 50%) as a yellow solid. MS ESI calculated for C11H14BrClN2 [M + H]+, 289.00, 291.00, found 289.05, 291.05; 1H NMR (400 MHz, CDCl3) δ 7.05 (s, 1H), 6.97 (s, 1H), 4.00 (s, 1H), 3.44 (d, J = 34.6 Hz, 2H), 2.60 (s, 1H), 2.15 (d, J = 11.1 Hz, 1H), 1.89 (d, J = 22.6 Hz, 2H), 1.01 (s, 3H). Step 4: (R)-6-Bromo-7-chloro-1-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole [00188] To a stirred mixture of 5-bromo-4-chloro-2-[(2R)-2-methylpyrrolidin-1-yl]aniline (0.45 g, 1.55 mmol) and H2O2 (1.05 g, 31.08 mmol) in EA (10 mL) was added ethyl methanesulfonate (19 mg, 0.15 mmol). The reaction mixture was stirred for 16 h at 75 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford (R)-6-bromo-7-chloro-1-methyl-2,3- dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (0.34 g, 77%) as a pink oil. MS ESI calculated for C11H10BrClN2 [M + H]+ 284.97, 286.97, found 284.95, 286.95; 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.71 (s, 1H), 3.63 (s, 1H), 2.62 (d, J = 72.3 Hz, 2H), 2.30-1.87 (m, 2H), 1.75 (s, 3H). Step 5: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-(((R)-7-chloro-1-methyl- 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide [00189] To a stirred mixture of (R)-6-bromo-7-chloro-1-methyl-2,3-dihydro-1H- benzo[d]pyrrolo[1,2-a]imidazole (0.12 g, 0.43 mmol) and 3-ethynyl-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.14 g, 0.43 mmol) in DMF (2 mL) were added CuI (16 mg, 0.08 mmol), Pd(PPh3)2Cl2 (30 mg, 0.04 mmol) and TEA (0.13 g, 1.29 mmol). The reaction mixture was degassed with nitrogen for three times and was stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% to 38% B in 8 min; Wave Length: 254 nm; RT1: 8 min. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5- (methoxymethyl)pyrrolidin-3-yl)-3-(((R)-7-chloro-1-methyl-2,3-dihydro-1H- benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (15 mg, 6%) as a white solid. MS ESI calculated for C27H30ClN7O3 [M + H]+, 536.21, 538.21, found 536.30, 538.30; 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 2H), 7.51 (s, 1H), 6.86 (s, 1H), 6.77- 6.54 (m, 2H), 6.24-6.08 (m, 1H), 5.69-5.27 (m, 2H), 4.69-4.62 (m, 1H), 4.47 (d, J = 57.4 Hz, 1H), 4.10-3.80 (m, 2H), 3.53-3.40 (m, 2H), 3.31 (d, J = 5.4 Hz, 3H), 3.18-2.54 (m, 7H), 2.35- 2.17 (m, 2H), 1.51 (d, J = 6.4 Hz, 3H). Example 15
Figure imgf000082_0001
Step 1: (2S)-1-(5-Chloro-2-nitrophenyl)-2-methylpyrrolidine [00190] To a stirred solution of 4-chloro-2-fluoro-1-nitrobenzene (0.40 g, 2.27 mmol) and DIEA (1.35 g, 10.25 mmol) in EtOH (4.00 mL) was added (2S)-2-methylpyrrolidine hydrochloride (0.42 g, 3.41 mmol) at 0 °C. The reaction mixture was stirred for 4 h at room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (2S)-1-(5-chloro- 2-nitrophenyl)-2-methylpyrrolidine (0.42 g, crude) as an orange oil. MS ESI calculated C11H13ClN2O2 [M + H]+, 241.07, 243.07, found 241.10, 243.10; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 2.1 Hz, 1H), 6.72-6.69 (m, 1H), 3.95-3.90 (m, 1H), 3.59- 3.52 (m, 1H), 2.7-2.72 (m, 1H), 2.35-2.32 (m, 1H), 2.06-1.89 (m, 1H), 1.87-1.61 (m, 2H), 1.25 (d, J = 6.0 Hz, 3H). Step 2: (2S)-1-(4-Bromo-5-chloro-2-nitrophenyl)-2-methylpyrrolidine [00191] To a stirred solution of (2S)-1-(5-chloro-2-nitrophenyl)-2-methylpyrrolidine (0.42 g, 1.74 mmol) in AcOH (5.00 mL) was added NBS (0.31 g, 1.72 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford (2S)-1-(4-bromo-5-chloro-2-nitrophenyl)-2-methylpyrrolidine (0.45 g, 81%) as an orange oil. MS ESI calculated for C11H12BrClN2O2 [M + H]+, 318.98, 320.98; found 319.00, 321.00; 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.10 (s, 1H), 3.93-3.90 (m, 1H), 3.62-3.42 (m, 1H), 2.78 -2.68 (m, 1H), 2.35-2.30 (m, 1H), 2.06-1.94 (m, 1H), 1.85-1.56 (m, 2H), 1.31-1.18 (m, 3H). Step 3: 5-Bromo-4-chloro-2-[(2S)-2-methylpyrrolidin-1-yl]aniline [00192] To a stirred solution of (2S)-1-(4-bromo-5-chloro-2-nitrophenyl)-2-methylpyrrolidine (0.45 g, 1.41 mmol) in EtOH (5.00 mL) and H2O (1.00 mL) were added Fe (0.79 g, 14.08 mmol) and NH4Cl (0.75 g, 14.08 mmol) at room temperature. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was filtered; the filter cake was washed with EtOAc (5.00 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1). The fractions contained to afford 5- bromo-4-chloro-2-[(2S)-2-methylpyrrolidin-1-yl]aniline (0.19 g, 48%) as a brown semi-solid. MS ESI calculated for C11H14BrClN2 [M+ H] +, 289.00, 291.00; found 289.10, 291.10; 1H NMR (400 MHz, CDCl3) δ 7.05 (s, 1H), 6.98 (s, 1H), 4.01 (s, 1H), 3.45 (d, J = 33.3 Hz, 2H), 2.62 (s, 1H), 2.16 (s, 1H), 1.91 (s, 2H), 1.02 (s, 3H) Step 4: (S)-6-Bromo-7-chloro-1-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole [00193] To a stirred solution of 5-bromo-4-chloro-2-[(2S)-2-methylpyrrolidin-1-yl]aniline (0.84 g, 2.90 mmol) in EtOAc (10.00 mL) were added CH3SO3H (0.02 mL, 0.29 mmol) and H2O2 (6.58 g, 58.02 mmol) at room temperature. The reaction mixture was stirred for 16 h at 75 °C. The resulting mixture was quenched with water (5.00 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with the following conditions: Column: Spherical C18, 20-40 um, 40 g; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient (B%) 5%-45% within 30 min; Detector: UV 254/220 nm. The fractions contained desired product were combined and concentrated to afford (S)-6-Bromo-7-chloro-1-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2- a]imidazole (0.27 g, 32%) as a light orange solid. MS ESI calculated for C11H10BrClN2 [M + H]+, 284.97, 286.97, found 285.00, 287.00; 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.53 (s, 1H), 4.66-4.61 (m, 1H), 3.25-3.05 (m, 2H), 3.00-2.88 (m, 1H), 2.39-2.27 (m, 1H), 1.62 (d, J = 6.4 Hz, 3H). Step 5: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-(((S)-7-chloro-1-methyl- 2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide [00194] To a stirred solution of (S)-6-Bromo-7-chloro-1-methyl-2,3-dihydro-1H- benzo[d]pyrrolo[1,2-a]imidazole (0.15 g, 0.52 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)- 1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.35 g, 1.05 mmol), Pd(PPh3)2Cl2 (36.87 mg, 0.05 mmol) and CuI (20.01 mg, 0.11 mmol) in DMF (3.00 mL) was added TEA (0.16 g, 1.57 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20/1) to afford the crude solid which was further purified by reverse phase flash with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min, 45% B; Wave Length: 254 nm. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5- (methoxymethyl)pyrrolidin-3-yl)-3-(((S)-7-chloro-1-methyl-2,3-dihydro-1H- benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (44.20 mg, 15%) as a white solid. MS ESI calculated for C27H30ClN7O3 [M + H] + 536.21, 538.21, found 536.20, 538.20; 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.49 (s, 1H), 7.28 (s, 1H), 6.82 (d, J = 5.7 Hz, 1H), 6.54-6.32 (m, 2H), 5.72-5.70 (m, 1H), 5.57-5.19 (m, 2H), 4.68- 4.41 (m, 2H), 4.15-4.10 (m, 2H), 3.93-3.89 (m, 1H), 3.53-3.35 (m, 4H), 3.09-3.01 (m, 5H), 2.91 (s, 1H), 2.77-2.69 (m, 1H), 2.34-2.29 (m, 2H), 1.62 (s, 3H).
Example 16
Figure imgf000085_0001
Step 1: Tert-butyl (3S)-3-[3-bromo-4-cyano-5-(cyclopentylamino) pyrazol-1-yl] pyrrolidine-1- carboxylate [00195] To a stirred solution of tert-butyl (3S)-3-(5-amino-3-bromo-4-cyanopyrazol-1- yl)pyrrolidine-1-carboxylate (0.50 g, 1.40 mmol) and bromocyclopentane (2.09 g, 14.03 mmol) in DMF (10 mL) was added Cs2CO3 (2.74 g, 8.42 mmol). The reaction mixture was stirred for 16 h at 50 °C under nitrogen atmosphere. The resulting mixture was diluted with water (80 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (4 x 30 mL), dried over anhydrous Na2SO4. After filtration, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (3S)-3-[3-bromo-4-cyano-5-(cyclopentylamino)pyrazol-1-yl]pyrrolidine-1-carboxylate (0.33 g, 55%) as a light yellow solid. MS ESI calculated for C18H26BrN5O2 [M - 56]+, 368.13, 370.13, found 368.10, 370.10. Step 2: Tert-butyl (3S)-3-[4-cyano-5-(cyclopentylamino)-3-[2-(1-cyclopropyl-6-fluoro-1,3- benzodiazol-5-yl)ethynyl]pyrazol-1-yl]pyrrolidine-1-carboxylate [00196] To a stirred mixture of tert-butyl (3S)-3-[3-bromo-4-cyano-5- (cyclopentylamino)pyrazol-1-yl]pyrrolidine-1-carboxylate (0.10 g, 0.24 mmol) and 1- cyclopropyl-6-fluoro-5-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazole (64.19 mg, 0.24 mmol) in DMF (1.00 mL) were added Pd(PPh3)2Cl2 (16.54 mg, 0.02 mmol), CuI (8.98 mg, 0.04 mmol), TBAI (0.13 g, 0.35 mmol) and K2CO3 (97.71 mg, 0.71 mmol) in portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (3S)-3-[4-cyano- 5-(cyclopentylamino)-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]pyrazol-1- yl]pyrrolidine-1-carboxylate (0.12 g, 94%) as a light yellow oil. MS ESI calculated for C30H34FN7O2 [M + H]+, 544.70, found 544.35. Step 3: Tert-butyl (3S)-3-{5-[(tert-butoxycarbonyl)(cyclopentyl)amino]-4-cyano-3-[2-(1- cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]pyrazol-1-yl}pyrrolidine-1-carboxylate [00197] To a stirred mixture of tert-butyl (3S)-3-[4-cyano-5-(cyclopentylamino)-3-[2-(1- cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]pyrazol-1-yl]pyrrolidine-1-carboxylate (0.12 g, 0.22 mmol) and DMAP (26.97 mg, 0.22 mmol) in DCM (1.2 mL) were added Boc2O (48.17 mg, 0.22 mmol) and TEA (0.95 mL, 0.66 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (3S)-3-{5-[(tert- butoxycarbonyl)(cyclopentyl)amino]-4-cyano-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5- yl)ethynyl]pyrazol-1-yl}pyrrolidine-1-carboxylate (0.15 g, 87%) as a light yellow oil. MS ESI calculated for C35H42FN7O4 [M + H]+, 644.80, found 644.60; 1H NMR (400 MHz, CDCl3) δ 8.11-7.45 (m, 3H), 4.80-4.75 (m, 1H), 4.52 (t, J = 8.6 Hz, 1H), 4.19-4.12 (m, 2H), 3.57-3.48 (m, 2H), 3.45-3.38 (m, 2H), 2.30 (s, 3H), 2.23-2.17 (m, 2H), 2.06 (s, 4H), 1.46 (s, 18H), 1.12 (t, J = 4.9 Hz, 4H). Step 4: Tert-butyl (3S)-3-{5-[(tert-butoxycarbonyl)(cyclopentyl)amino]-4-carbamoyl-3-[2-(1- cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]pyrazol-1-yl}pyrrolidine-1-carboxylate [00198] To a stirred mixture of tert-butyl (3S)-3-{5-[(tert-butoxycarbonyl)(cyclopentyl)amino]- 4-cyano-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]pyrazol-1-yl}pyrrolidine-1- carboxylate (0.13 g, 0.20 mmol) and LiOH·H2O (0.93 mL, 0.23 mmol) in DMSO (1 mL) and H2O (0.2 mL) was added H2O2 (80.14 mg, 0.71 mmol, 30%) dropwise at 0 °C. The reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was washed with water (3 x 10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/2). The fractions contained desired product were combined and concentrated to afford tert-butyl (3S)-3- {5-[(tert-butoxycarbonyl)(cyclopentyl)amino]-4-carbamoyl-3-[2-(1-cyclopropyl-6-fluoro-1,3- benzodiazol-5-yl)ethynyl]pyrazol-1-yl}pyrrolidine-1-carboxylate (41 mg, 31%) as an off-white solid. MS ESI calculated for C35H44FN7O5 [M + H]+, 662.34, found 662.65. Step 5: 5-(Cyclopentylamino)-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1- [(3S)-pyrrolidin-3-yl]pyrazole-4-carboxamide hydrochloride [00199] To a stirred solution of tert-butyl (3S)-3-{5-[(tert-butoxycarbonyl)(cyclopentyl)amino]- 4-carbamoyl-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]pyrazol-1- yl}pyrrolidine-1-carboxylate (41 mg, 0.06 mmol) in DCM (0.4 mL) was added HCl (1.65 mL, 6.58 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 5-(cyclopentylamino)-3-[2- (1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S)-pyrrolidin-3-yl]pyrazole-4- carboxamide hydrochloride (38 mg, 98%) as an off-white solid. MS ESI calculated for C25H28FN7O [M + H]+, 462.60, found 462.20. Step 6: 5-(Cyclopentylamino)-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1- [(3S)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00200] To a stirred solution of 5-(cyclopentylamino)-3-[2-(1-cyclopropyl-6-fluoro-1,3- benzodiazol-5-yl)ethynyl]-1-[(3S)-pyrrolidin-3-yl]pyrazole-4-carboxamide (38 mg, 0.08 mmol) and DIEA (31.92 mg, 0.24 mmol) in DCM (0.5 mL) was added acryloyl chloride (0.29 mL, 0.07 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 5 min at 0 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2/MeOH, 12/1) to the crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 40% B in 8 min, 40% B; Wave Length: 254 nm; RT1: 7 min. The fractions contained desired product were combined and concentrated to afford 5-(cyclopentylamino)-3-[2-(1-cyclopropyl-6-fluoro-1,3-benzodiazol-5- yl)ethynyl]-1-[(3S)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (6.8 mg, 16%) as an off-white solid. MS ESI calculated for C28H30FN7O2 [M + H]+, 516.60, found 516.30; 1H NMR (400 MHz, CDCl3) δ 7.99-7.92 (m, 2H), 7.32 (dd, J = 9.0, 1.6 Hz, 1H), 7.16 (s, 1H), 6.59- 6.38 (m, 3H), 5.78-5.69 (m, 1H), 5.37 (s, 1H), 5.10-4.94 (m, 1H), 4.18-3.89 (m, 3H), 3.82-3.63 (m, 2H), 3.39 (tt, J = 7.2, 3.8 Hz, 1H), 2.79-2.54 (m, 1H), 2.50-2.33 (m, 1H), 1.95-1.78 (m, 4H), 1.64 (d, J = 6.7 Hz, 4H), 1.30-1.19 (m, 2H), 1.19-1.04 (m, 2H). Example 17
Figure imgf000088_0001
Step 1: 5-Chloro-8-methylimidazo[1,5-a]pyridine [00201] To a stirred mixture of 8-bromo-5-chloroimidazo[1,5-a]pyridine (0.30 g, 1.29 mmol), trimethyl-1,3,5,2,4,6-trioxatriborinane (1.30 g, 10.36 mmol) and K2CO3 (0.53 g, 3.88 mmol) in dioxane (3.00 mL) was added Pd(dppf)Cl2·CH2Cl2 (0.10 g, 0.13 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 70 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1). The fractions contained desired product were combined and concentrated to afford 5-chloro-8-methylimidazo[1,5-a]pyridine (0.12 g, 56%) as a yellow solid. MS ESI calculated for C8H7ClN2 [M + H]+, 167.03, 169.03, found 166.90, 168.90; 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.55 (s, 1H), 6.61 (d, J = 7.0 Hz, 1H), 6.51- 6.43 (m, 1H), 2.46 (d, J = 1.2 Hz, 3H). Step 2: 1-[(3S,5R)-5-(Methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)-3-(2- {8-methylimidazo[1,5-a]pyridin-5-yl}ethynyl)pyrazole-4-carboxamide [00202] To a stirred solution of 5-chloro-8-methylimidazo[1,5-a]pyridine (50.00 mg, 0.30 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (198.89 mg, 0.60 mmol), 2nd Generation XPhos Precatalyst (23.61 mg, 0.03 mmol) and CuI (11.43 mg, 0.06 mmol) in DMF (1 mL) was added TEA (91.10 mg, 0.90 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude solid which was further purified by reverse phase flash with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 35% B in 8 min, 35% B; Wave Length: 254 nm. The fractions contained desired product were combined and concentrated to afford 1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)-3-(2-{8-methylimidazo[1,5-a]pyridin-5- yl}ethynyl)pyrazole-4-carboxamide (47.20 mg, 34%) as a yellow solid. MS ESI calculated for C24H27N7O3 [M + H]+, 462.22, found 462.15; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.70 (d, J = 30.1 Hz, 1H), 6.96 (d, J = 6.8 Hz, 1H), 6.80 (d, J = 5.9 Hz, 1H), 6.67-6.38 (m, 3H), 5.75- 5.71 (m, 1H), 5.59-5.31 (m, 1H), 4.63-4.42 (m, 1H), 4.23-3.81 (m, 3H), 3.56-3.38 (m, 4H), 3.09- 3.04 (m, 3H), 2.78-2.63 (m, 1H), 2.51 (s, 3H), 2.37-2.32 (m, 1H). Example 18
Figure imgf000089_0001
Step 1: 5-Chloro-8-cyclopropylimidazo[1,5-a]pyridine [00203] To a stirred mixture of 8-bromo-5-chloroimidazo[1,5-a]pyridine (0.30 g, 1.29 mmol), cyclopropylboronic acid (0.22 g, 2.59 mmol) and K2CO3 (0.54 g, 3.88 mmol) in dioxane (3.00 mL) was added Pd(dppf)Cl2·CH2Cl2 (0.11 g, 0.13 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 70 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1). The fractions contained desired product were combined and concentrated to afford 5-chloro-8-cyclopropylimidazo[1,5-a]pyridine (0.13 g, 54%) as a light yellow solid. MS ESI calculated for C10H9ClN2 [M + H]+, 193.05, 195.05, found 192.90, 194.90.1H NMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 7.70 (s, 1H), 6.59 (d, J = 7.1 Hz, 1H), 6.35-6.24 (m, 1H), 2.17-2.02 (m, 1H), 1.11-1.01 (m, 2H), 0.86-0.78 (m, 2H). Step 2: 3-(2-{8-Cyclopropylimidazo[1,5-a]pyridin-5-yl}ethynyl)-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00204] To a stirred mixture of 5-chloro-8-cyclopropylimidazo[1,5-a]pyridine (60.00 mg, 0.31 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.15 g, 0.46 mmol), CuI (11.86 mg, 0.06 mmol) and Xphos G2 (24.50 mg, 0.03 mmol) in DMF (0.60 mL, 7.75 mmol) was added TEA (94.55 mg, 0.93 mmol) dropwise at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeOH) (10/1) to afford the crude product. The crude product (70 mg) was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 19 x 250 mm, 5 μm; Mobile Phase A: water (0.05% TFA ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 60% B to 60% B in 15 min, 60% B; Wave Length: 254 nm; RT1: 11.2 min. The fractions contained desired product were combined and concentrated to afford 3-(2-{8-cyclopropylimidazo[1,5-a]pyridin-5- yl}ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (41.50 mg, 27%) as a yellow solid. MS ESI calculated for C26H29N7O3 [M + H]+, 488.23, found,488.30; 1H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 7.79 (s, 1H), 6.99 (d, J = 7.1 Hz, 1H), 6.70 (s, 1H), 6.58-6.41 (m, 3H), 5.73-5.64 (m, 1H), 5.59-5.33 (m, 1H), 4.65-4.44 (m, 1H), 4.15-3.88 (m, 3H), 3.57-3.38 (m, 4H), 3.06-2.87 (m, 3H), 2.76-2.66 (m, 1H), 2.35-2.22 (m, 1H), 2.13-1.82 (m, 1H), 1.19-1.09 (m, 2H), 0.92-0.82 (m, 2H). Example 19
Figure imgf000090_0001
Step 1: 5-Bromo-4-chloro-2-cyclobutanecarbonylaniline [00205] To a stirred solution of 2-amino-4-bromo-5-chloro-N-methoxy-N-methylbenzamide (1.00 g, 3.40 mmol) in THF (10.00 mL) was added bromo(cyclobutyl)magnesium (11.92 mL, 11.92 mmol) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 5 h at 0 °C under nitrogen atmosphere. The resulting mixture was quenched with sat. NH4Cl (aq.) at -40 °C and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/DCM (4/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-4-chloro-2-cyclobutanecarbonylaniline (0.30 g, 30%) as a yellow solid. MS ESI calculated for C11H11BrClNO [M + H]+, 287.97, 289.97, found 288.00, 290.00; 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 6.97 (s, 1H), 6.30 (brs, 2H), 3.91- 3.87 (m, 1H), 2.45-2.30 (m, 4H), 2.29-1.87 (m, 2H). Step 2: 5-Bromo-4-chloro-2-(1-cyclobutylethenyl)aniline [00206] To a stirred mixture of bromo(methyl)triphenyl-λ5-phosphane (1.44 g, 4.02 mmol) in THF (6.00 mL) was added t-BuOK (0.45 g, 4.02 mmol) in portions at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 30 min at room temperature under nitrogen atmosphere. To the above mixture was added a solution of 5-bromo-4-chloro-2- cyclobutanecarbonylaniline (0.29 g, 1.01 mmol) in THF (1.50 mL) dropwise at 0 °C. The reaction mixture was stirred for additional 30 min at room temperature. The resulting mixture was quenched by the addition of H2O (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-4-chloro-2-(1- cyclobutylethenyl)aniline (0.26 g, 90%) as a light yellow oil. MS ESI calculated for C12H13BrClN [M + H]+, 285.99, 287.99, found 286.00, 288.00; 1H NMR (400 MHz, CDCl3) δ 7.01 (s, 1H), 6.98 (s, 1H), 5.31 (s, 1H), 5.09 (s, 1H), 4.00-3.92 (m, 2H), 3.26-3.18 (m, 1H), 2.12- 2.07 (m, 2H), 1.99-1.73 (m, 4H). Step 3: 7-Bromo-6-chloro-4-cyclobutylcinnoline [00207] To a stirred mixture of 5-bromo-4-chloro-2-(1-cyclobutylethenyl)aniline (0.25 g, 0.87 mmol) in water (5.00 mL) were added conc.HCl (0.41 g, 11.33 mmol) and NaNO2 (0.48 mL, 0.96 mmol, 2 M) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-6- chloro-4-cyclobutylcinnoline (80.00 mg, 30%) as a yellow solid. MS ESI calculated for C12H10BrClN2 [M + H]+, 296.97, 298.97, found 296.95, 298.95; 1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.87 (s, 1H), 8.04 (s, 1H) , 4.13-4.09 (m, 1H), 2.68-2.60 (m, 2H), 2.45-2.25 (m, 3H), 2.08-2.03 (m, 1H). Step 4: 3-[2-(6-Chloro-4-cyclobutylcinnolin-7-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00208] To a stirred solution of 7-bromo-6-chloro-4-cyclobutylcinnoline (80.00 mg, 0.27 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.11 g, 0.32 mmol), Pd(PPh3)2Cl2 (18.87 mg, 0.02 mmol) and CuI (10.2 mg, 0.05 mmol) in DMF (1.00 mL) was added TEA (81.6 mg, 0.81 mmol) dropwise at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EtOAc/EtOH (3/1) in PE (100%). The crude product was purified by trituration with ACN (5 mL) to afford 3-[2-(6-chloro-4- cyclobutylcinnolin-7-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3- yl]-5-(methylamino)pyrazole-4-carboxamide (30.40 mg, 20%) as a light yellow solid. MS ESI calculated for C28H30ClN7O3 [M + H]+, 548.21, 550.21, found 548.30, 550.30; 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.83 (s, 1H), 8.31 (s, 1H), 7.60 (brs, 1H), 6.95 (brs, 1H), 6.66- 6.57 (m, 2H), 6.20 (d, J = 16.4 Hz, 1H), 5.71 (d, J = 10.0 Hz, 1H), 5.30-5.26 (m, 1H), 4.41-4.26 (m, 2H), 4.05-3.87 (m, 2H), 3.61-3.45 (m, 2H), 3.33-3.31 (m, 4H), 2.97-2.95 (m, 3H), 2.57-2.50 (m, 2H), 2.38-2.31 (m, 3H), 2.19-2.14 (m, 1H), 19.2-1.90 (m, 1H). Example 20
Figure imgf000092_0001
Figure imgf000092_0002
Step 1: 3-{2-[1-(2,2-Difluorocyclopropyl)-5-fluoroindazol-4-yl]ethynyl}-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00209] To a stirred solution of 4-bromo-1-(2,2-difluorocyclopropyl)-5-fluoroindazole (60.00 mg, 0.20 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (68.31 mg, 0.20 mmol), 2nd Generation XPhos precatalyst (16.22 mg, 0.02 mmol) and CuI (19.63 mg, 0.10 mmol) in DMF (1.50 mL) was added TEA (0.10 g, 1.03 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product which was further purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 19 x 250 mm, 10 μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: MeOH-HPLC; Flow rate: 25 mL/min; Gradient: 55% B to 55% B in 20 min, 55% B; Wave Length: 254 nm. The fractions contained desired product were combined and concentrated to afford 3-{2-[1-(2,2- difluorocyclopropyl)-5-fluoroindazol-4-yl]ethynyl}-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (18.70 mg, 16%) as a white solid. MS ESI calculated for C26H26F3N7O3 [M + H]+, 542.20, found 542.15; 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.54 (dd, J = 9.1, 4.0 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 7.05 (s, 1H), 6.81 (d, J = 45.6 Hz, 1H), 6.54-6.41 (m, 2H), 5.74-5.71 (m, 1H), 5.58-5.22 (m, 2H), 4.62- 4.42 (m, 1H), 4.15-4.05 (m, 3H), 3.94-3.90 (m, 1H), 3.55-3.38 (m, 4H), 3.08 (d, J = 5.4 Hz, 3H), 2.81-2.60 (m, 1H), 2.52-2.40 (m, 1H), 2.40-2.18 (m, 2H). Example 21
Figure imgf000093_0001
Step 1: 4-Bromo-1-cyclobutyl-5-fluoroindazole [00210] To a stirred solution of 4-bromo-5-fluoro-1H-indazole (0.50 g, 2.32 mmol) and bromocyclobutane (0.94 g, 6.97 mmol) in DMF (5 mL) was added Cs2CO3 (1.5 g, 4.65 mmol) in portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (2 x 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/CH2Cl2 (2/1). The fractions contained desired product were combined and concentrated to afford 4- bromo-1-cyclobutyl-5-fluoroindazole (0.34 g, 54%) as an off-white solid. MS ESI calculated for C11H10BrFN2 [M + H]+, 269.00, 271.00, found 268.90, 270.90; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J= 0.8 Hz, 1H), 7.31 (s, 1H), 7.15 (s, 1H), 5.07-4.94 (m, 1H), 2.86-2.70 (m, 2H), 2.61- 2.46 (m, 2H),2.06-1.95 (m, 1H), 1.99-1.85 (m, 1H). Step 2: 3-[2-(1-Cyclobutyl-5-fluoroindazol-4-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00211] To a stirred solution of 4-bromo-1-cyclobutyl-5-fluoroindazole (0.10 g, 0.37 mmol), 3- ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.18 g, 0.55 mmol), Pd(PPh3)2Cl2 (0.03 g, 0.03 mmol) and CuI (0.01 g, 0.07 mmol) in DMF (1 mL) was added TEA (0.11 g, 1.12 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 90 °C. The resulting mixture was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by Prep-HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 19 x 250 mm, 5 μm; Mobile Phase A: water (0.05% TFA ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 46% B to 57% B in 10 min, 57% B; Wave Length: 254 nm; RT1: 7.8 min. The fractions contained desired product were combined and concentrated to afford 3-[2-(1-cyclobutyl-5-fluoroindazol-4-yl)ethynyl]-1- [(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4- carboxamide (25.9 mg, 13%) as a white solid. MS ESI calculated for C27H30FN7O3 [M + H]+, 520.24, found 520.25; 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.45 (s, 1H), 7.19 (s, 1H), 6.49-6.39 (m, 2H), 5.75-5.74 (m, 1H), 5.53-5.51 (m, 2H), 5.07-5.05 (m, 1H), 4.60-4.59 (m, 1H), 4.14-4.12 (m, 1H), 4.07-4.05 (m, 1H), 3.94-3.92 (m, 1H), 3.54 (s, 1H), 3.40-3.39 (m, 4H), 3.08 (s, 3H), 2.90-2.76 (m, 3H), 2.56 (s, 2H), 2.36-2.34 (m, 1H), 2.02 (t, J = 6.8 Hz, 2H); 19F NMR (376 MHz, CDCl3) -119.21 (1F). Example 22
Figure imgf000094_0001
Experimental section Step 1: 3-{2-[5-Chloro-1-(2,2-difluorocyclopropyl)indazol-4-yl]ethynyl}-1 -5-
Figure imgf000094_0002
(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00212] To a stirred solution of 4-bromo-5-chloro-1-(2,2-difluorocyclopropyl)indazole (0.11 g, 0.35 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.17 g, 0.53 mmol) in DMF (2.00 mL) were added Pd(PPh3)2Cl2 (25.11 mg, 0.03 mmol) and CuI (13.62 mg, 0.07 mmol) and TEA (0.11 g, 1.07 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (5/1) to afford the crude product. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 20% to 30% gradient in 10 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford 3-{2-[5-chloro-1-(2,2- difluorocyclopropyl)indazol-4-yl]ethynyl}-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (40.2 mg, 20%) as an off-white solid. MS ESI calculated for C26H26ClF2N7O3 [M + H]+, 558.18, 560.18, found 558.25, 560.25; 1H NMR (400 MHz, Chloroform-d) δ 8.23-8.20 (s, 1H), 7.50-7.49 (s, 2H), 7.09-7.08 (s, 1H), 6.82-6.80 (s, 1H), 6.61-6.38 (m, 2H), 5.74-5.72 (m, 1H), 5.59-5.26 (m, 2H), 4.67-4.42 (m, 1H), 4.22-3.86 (m, 4H), 3.57-3.34 (m, 4H), 3.07-2.80 (m, 3H), 2.74-2.72 (m, 1H), 2.55-2.22 (m, 3H). Example 23
Figure imgf000095_0001
Experimental section Step 1: 4-Bromo-5-chloro-1-cyclobutylindazole [00213] To a stirred solution of 4-bromo-5-chloro-1H-indazole (0.5 g, 2.16 mmol) and Cs2CO3 (1.41 g, 4.32 mmol) in DMF (5 mL) was added bromocyclobutane (0.58 g, 4.32 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 4- bromo-5-chloro-1-cyclobutylindazole (249 mg, 40%) as an off-white solid. MS ESI calculated for C11H10BrClN2 [M + H]+, 284.60, 286.60, found 284.90, 286.90; 1H NMR (400 MHz, CDCl3) δ 8.13-8.05 (m, 1H), 7.42-7.36 (m, 1H), 7.33-7.25 (m, 1H), 5.02-4.95 (m, 1H), 2.87-2.81 (m, 2H), 2.61-2.49 (m, 2H), 2.09-1.87 (m, 2H). Step 2: 3-[2-(5-Chloro-1-cyclobutylindazol-4-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00214] To a stirred solution of 4-bromo-5-chloro-1-cyclobutylindazole (0.1 g, 0.35 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.17 g, 0.53 mmol) in DMF (2 mL) were added Pd(PPh3)2Cl2 (24.58 mg, 0.04 mmol), CuI (13.34 mg, 0.07 mmol) and TEA (0.11 g, 1.05 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 41% B to 51% B in 8 min, 51% B; Wave Length: 254 nm; RT1: 7.17 min. The fractions contained desired product were combined and concentrated to afford 3-[2-(5-chloro-1-cyclobutylindazol-4-yl)ethynyl]-1- [(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4- carboxamide (18.3 mg, 10%) as an off-white solid. MS ESI calculated for C27H30ClN7O3 [M + H]+, 536.21, 538.21, found 536.25, 538.25; 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 5.5 Hz, 1H), 7.46-7.35 (m, 2H), 7.16 (s, 1H), 6.84-6.78 (m, 1H), 6.62-6.38 (m, 2H), 5.78-5.72 (m, 1H), 5.59-5.46 (m, 1H), 5.42-5.29 (m, 1H), 5.13-5.08 (m, 1H), 4.60 (d, J = 9.0 Hz, 1H), 4.16 (t, J = 8.9 Hz, 1H), 4.10-3.89 (m, 2H), 3.56-3.44 (m, 1H), 3.40 (d, J = 5.4 Hz, 3H), 3.05 (dd, J = 15.8, 5.9 Hz, 3H), 2.79-2.75 (m, 3H), 2.62-2.50 (m, 2H), 2.38-2.32 (m, 1H), 2.08-1.88 (m, 2H).
Example 24
Figure imgf000097_0001
Step 1: butyl (2R,4S)-4-{5-[(tert-butoxycarbonyl)(cyclopropyl)amino]-3-[2-(6-chloro-1- cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-4-cyanopyrazol-1-yl}-2- (methoxymethyl)pyrrolidine-1-carboxylate [00215] To a stirred solution of tert-butyl (2R,4S)-4-{3-bromo-5-[(tert- butoxycarbonyl)(cyclopropyl)amino]-4-cyanopyrazol-1-yl}-2-(methoxymethyl)pyrrolidine-1- carboxylate (0.15 g, 0.27 mmol), 6-chloro-1-cyclopropyl-5-[2-(trimethylsilyl)ethynyl]-1,3- benzodiazole (0.32 g, 1.11 mmol), Pd(PPh3)2Cl2 (18.95 mg, 0.03 mmol), CuI (0.02 g, 0.11 mmol) and K2CO3 (0.23 g, 1.66 mmol) in DMF (1.5 mL) was added TBAI (0.15 g, 0.42 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 90 °C under nitrogen atmosphere. The resulting mixture was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:4). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R,4S)-4-{5-[(tert- butoxycarbonyl)(cyclopropyl)amino]-3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5- yl)ethynyl]-4-cyanopyrazol-1-yl}-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.26 g, 69%) as a brown solid. MS ESI calculated for C35H42ClN7O5 [M + H]+, 676.29, 678.29, found 676.30, 678.30.1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.59-7.55 (m, 1H), 7.51-7.49 (m, 1H), 4.92 (s, 1H), 4.23 (s, 1H), 4.15-4.13 (m, 3H), 3.75-3.65 (m, 3H), 3.18-3.16 (m, 1H), 2.67 (s, 1H), 2.33 (s, 1H), 2.17 (s, 1H), 2.11 (s, 1H), 1.51-1.49 (m, 18H), 1.22-1.21 (m, 1H), 1.10 (s, 2H), 0.92 (s, 3H), 0.69 (s, 1H), 0.50 (s, 1H). Step 2: Tert-butyl (2R,4S)-4-{5-[(tert-butoxycarbonyl)(cyclopropyl)amino]-4-carbamoyl-3-[2- (6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]pyrazol-1-yl}-2- (methoxymethyl)pyrrolidine-1-carboxylate [00216] To a stirred solution of tert-butyl (2R,4S)-4-{5-[(tert- butoxycarbonyl)(cyclopropyl)amino]-3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5- yl)ethynyl]-4-cyanopyrazol-1-yl}-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.15 g, 0.22 mmol) and NaOH (0.53 mL, 0.27 mmol) in DMSO (0.4 mL) and EtOH (2 mL) was added H2O2 (0.08 mg, 0.78 mmol, 30%) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/5). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R,4S)-4-{5-[(tert- butoxycarbonyl)(cyclopropyl)amino]-4-carbamoyl-3-[2-(6-chloro-1-cyclopropyl-1,3- benzodiazol-5-yl)ethynyl]pyrazol-1-yl}-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.12 g, 77%) as a yellow oil. MS ESI calculated for C35H44ClN7O6 [M + H]+, 694.30, 696.30, found 694.35, 696.35; 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 8.04 (s, 1H), 7.69 (s, 1H), 5.56 (s, 1H), 5.01 (s, 1H), 4.33-4.22 (m, 1H), 3.96-3.48 (m, 2H), 3.40-3.37 (m, 3H), 2.82-2.58 (m, 1H), 2.18-2.11 (m, 1H), 1.69 (s, 4H), 1.58-1.36 (m, 18H), 1.32-1.02 (m, 3H), 0.95-0.64 (m, 2H), 0.43 (s, 1H) . Step 3: 3-[2-(6-Chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5-(cyclopropylamino)-1- [(3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00217] To a stirred solution of tert-butyl (2R,4S)-4-{5-[(tert- butoxycarbonyl)(cyclopropyl)amino]-4-carbamoyl-3-[2-(6-chloro-1-cyclopropyl-1,3- benzodiazol-5-yl)ethynyl]pyrazol-1-yl}-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.25 g, 0.36 mmol) in DCM (2.5 mL) was added TFA (0.5 mL) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5- (cyclopropylamino)-1-[(3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (0.15 g, crude) as a yellow oil. MS ESI calculated for C25H28ClN7O2 [M + H]+, 494.20, 496.20, found 494.35, 494.35. Step 4: 3-[2-(6-Chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5-(cyclopropylamino)-1- [(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00218] To a stirred solution of 3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5- (cyclopropylamino)-1-[(3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (0.13 g, 0.26 mmol) and DIEA (0.13 g, 1.05 mmol) in DCM (2 mL) was added acryloyl chloride (1.05 mL, 0.26 mmol) dropwise at 0 °C. The resulting mixture was stirred for 20 min at 0 °C. The reaction was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (0.10 g) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 45% B to 50% B in 8 min, 50% B; Wave Length: 254 nm; RT1: 7.32 min. The fractions contained desired product were combined and concentrated to afford 3-[2-(6-chloro-1-cyclopropyl-1,3- benzodiazol-5-yl)ethynyl]-5-(cyclopropylamino)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (0.03 g, 19%) as a white solid. MS ESI calculated for C28H30ClN7O3 [M + H] +, 548.21, 550.21, found 548.25, 550.25; 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.53 (s, 1H), 7.32-7.23 (m, 1H), 6.82 (s, 1H), 6.68-6.67 (m, 1H), 6.20-6.18 (m, 1H), 5.85-5.66 (m, 2H), 4.56-4.43 (m, 1H), 4.13-3.75 (m, 2H), 3.58-3.43 (m, 3H), 3.29 (s, 3H), 2.84 (s, 1H), 2.52 (s, 1H), 2.35-2.33 (m, 1H), 1.17-1.02 (m, 4H), 0.84-0.78 (m, 2H), 0.64 (s, 2H). Example 25
Figure imgf000099_0001
Experimental section Step 1: 1-(2-Amino-4-bromo-5-chlorophenyl)-2-methylpropan-1-one [00219] To a stirred solution of 2-amino-4-bromo-5-chloro-N-methoxy-N-methylbenzamide (2.00 g, 6.81 mmol) in THF (20.00 mL) was added bromo(isopropyl)magnesium (24.00 mL, 1 M) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at - 40 °C. The resulting mixture was quenched by the addition of sat. NH4Cl (aq.) (35 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (9/1). The fractions contained desired product were combined and concentrated to afford 1-(2-amino-4-bromo-5-chlorophenyl)-2-methylpropan-1- one (0.30 g, 16%) as a brown oil. ESI calculated for C10H11BrClNO [M + H]+, 275.97, 277.97, found 275.95, 277.95. Step 2: 5-Bromo-4-chloro-2-(3-methylbut-1-en-2-yl)aniline [00220] To a stirred mixture of bromo(methyl)triphenyl-λ5-phosphane (2.41 g, 6.76 mmol) in THF (5.00 mL) was added t-BuOK (0.76 g, 6.76 mmol) in portions at 0 °C. The reaction mixture was degassed with nitrogen for three times and stirred for 0.5 h at 0 °C. To the above mixture was added 1-(2-amino-4-bromo-5-chlorophenyl)-2-methylpropan-1-one (0.47 g, 1.69 mmol) in THF (5.00 mL) dropwise at 0 °C. The reaction mixture was stirred for additional 1 h at room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 5- bromo-4-chloro-2-(3-methylbut-1-en-2-yl)aniline (0.39 g, 84%) as a brown solid. MS ESI calculated for C11H13BrClN [M + H]+, 273.99, 275.99, found 273.90, 275.90. Step 3: 7-Bromo-6-chloro-4-isopropylcinnoline [00221] To a stirred mixture of 5-bromo-4-chloro-2-(3-methylbut-1-en-2-yl)aniline (0.39 g, 1.42 mmol) in water (4.00 mL) was added NaNO2 (0.78 mL, 2 M) and conc.HCl (1.74 g, 18.46 mmol) dropwise at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 7- bromo-6-chloro-4-isopropylcinnoline (0.21 g, 52%) as a brown solid. MS ESI calculated for C11H10BrClN2 [M + H]+, 284.97, 286.97, found 284.95, 286.95; 1H NMR (400 MHz, Chloroform-d) δ 9.28 (s, 1H), 8.88 (s, 1H), 8.21 (s, 1H), 3.68-3.60 (m, 1H), 1.48 (d, J = 0.9 Hz, 3H), 1.46 (d, J = 0.9 Hz, 3H). Step 4: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((6-chloro-4- isopropylcinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00222] To a stirred mixture of 7-bromo-6-chloro-4-isopropylcinnoline (0.15 g, 0.53 mmol), 3- ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.17 g, 0.53 mmol), Pd(PPh3)2Cl2 (36.87 mg, 0.05 mmol) and CuI (20.01 mg, 0.11 mmol) in DMF (2.00 mL) was added TEA (0.16 g, 1.57 mmol) at room temperature. The reaction mixture was degassed with argon for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product (0.20 g) was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile phase A: water (Plus 10 mmol/L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 8 min; Wave length: 254 nm; RT: 7 min. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5- (methoxymethyl)pyrrolidin-3-yl)-3-((6-chloro-4-isopropylcinnolin-7-yl)ethynyl)-5- (methylamino)-1H-pyrazole-4-carboxamide (0.12 g, 44%) as a light yellow solid. MS ESI calculated for C27H30ClN7O3 [M + H]+, 536.21, 538.21, found 536.25, 538.25; 1H NMR (400 MHz, Chloroform-d) δ 9.29 (s, 1H), 8.85 (d, J = 6.6 Hz, 1H), 8.18 (s, 1H), 7.23-6.68 (m, 1H), 6.61-6.32 (m, 2H), 5.77-5.71 (m, 1H), 5.61-5.25 (m, 2H), 4.65-4.40 (m, 1H), 4.21-3.85 (m, 3H), 3.67-3.61 (m, 1H), 3.55-3.43 (m, 1H), 3.39 (s, 3H), 3.09 (s, 3H), 2.80-2.67 (m, 1H), 2.42-2.35 (m, 1H), 1.50 (s, 6H). Example 26
Figure imgf000101_0001
Step 1: N-(5-Bromo-4-chloro-2-cyclopropanecarbonylphenyl)-4-methylbenzenesulfonamide [00223] To a stirred solution of 5-bromo-4-chloro-2-cyclopropanecarbonylaniline (1 g, 3.64 mmol) in Pyridine (10 mL) was added TsCl (0.83 g, 4.37 mmol) at room temperature. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford N-(5-bromo-4-chloro-2-cyclopropanecarbonylphenyl)-4- methylbenzenesulfonamide (1.4 g, 89%) as a light yellow solid. MS ESI calculated for C17H15BrClNO3S [M + H]+, 427.96, 429.96, found 427.90, 429.90; 1H NMR (400 MHz, CDCl3) δ 11.06 (s, 1H), 8.04 (d, J = 1.3 Hz, 2H), 7.75-7.69 (m, 2H), 7.28 (d, J = 8.4 Hz, 2H), 2.53-2.42 (m, 1H), 2.41 (s, 3H), 1.23-1.16 (m, 2H), 1.11-1.05 (m, 2H). Step 2: N-(5-Bromo-4-chloro-2-cyclopropanecarbonylphenyl)-4-methyl-N-(prop-2-en-1- yl)benzenesulfonamide [00224] To a stirred mixture of N-(5-bromo-4-chloro-2-cyclopropanecarbonylphenyl)-4- methylbenzenesulfonamide (0.80 g, 1.87 mmol) and allyl bromide (0.34 g, 2.80 mmol) in DMF (8 mL) was added K2CO3 (0.77 g, 5.58 mmol) in portions at room temperature. The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1). The fractions contained desired product were combined and concentrated to afford N-(5-bromo-4-chloro-2-cyclopropanecarbonylphenyl)-4-methyl-N-(prop-2-en-1- yl)benzenesulfonamide (0.70 g, 80%) as a colorless oil. MS ESI calculated for C20H19BrClNO3S [M + H]+, 468.00, 470.00, found 468.00, 470.00. Step 3: N-[5-Bromo-4-chloro-2-(1-cyclopropylethenyl)phenyl]-4-methyl-N-(prop-2-en-1- yl)benzenesulfonamide [00225] To a stirred mixture of t-BuOK (0.77 g, 6.82 mmol) in THF (5 mL) was added methyltriphenylphosphaniumbromide (2.44 g, 6.82 mmol) in portions at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 40 min at room temperature under nitrogen atmosphere. To the above mixture was added N-(5-bromo-4-chloro-2- cyclopropanecarbonylphenyl)-4-methyl-N-(prop-2-en-1-yl)benzenesulfonamide (0.80 g, 1.70 mmol) in THF (5 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford N-[5-bromo-4-chloro-2-(1-cyclopropylethenyl)phenyl]-4-methyl-N-(prop-2-en-1- yl)benzenesulfonamide (0.7 g, 88%) as a brown solid. MS ESI calculated for C21H21BrClNO2S [M + H]+, 466.02, 468.02, found 465.95, 467.95; 1H NMR (400 MHz, CDCl3) δ 7.74-7.67 (m, 2H), 7.45 (s, 1H), 7.37 (d, J = 8.1 Hz, 2H), 7.03 (s, 1H), 5.67-5.52 (m, 1H), 5.06-4.92 (m, 2H), 5.04-4.93 (m, 1H), 4.20-3.99 (m, 2H), 2.50 (s, 3H), 2.07 (s, 1H), 1.71-1.61 (m, 1H), 1.28-1.16 (m, 1H), 0.93-0.79 (m, 2H), 0.70-0.61 (m, 2H). Step 4: 7-Bromo-6-chloro-4-cyclopropyl-1-(4-methylbenzenesulfonyl)-2H-quinoline [00226] To a stirred mixture of N-[5-bromo-4-chloro-2-(1-cyclopropylethenyl)phenyl]-4- methyl-N-(prop-2-en-1-yl)benzenesulfonamide (0.4 g, 0.86 mmol) in DCM (10 mL)was added Grubbs 2nd (72.74 mg, 0.086 mmol). The reaction mixture was stirred for 1 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (4/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-6-chloro-4-cyclopropyl-1-(4- methylbenzenesulfonyl)-2H-quinoline (0.35 g, 93%) as a grey solid. MS ESI calculated for C19H17BrClNO2S [M + H]+, 437.99, 439.99, found 437.90, 439.90; 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.53 (s, 1H), 7.36-7.28 (m, 2H), 7.13 (d, J = 8.1 Hz, 2H), 5.40-5.26 (m, 1H), 4.37-4.22 (m, 2H), 2.38 (s, 3H), 1.24-1.13 (m, 1H), 0.67-0.55 (m, 2H), 0.05-0.14 (m, 2H). Step 5: 7-Bromo-6-chloro-4-cyclopropylquinoline [00227] To a stirred solution of 7-bromo-6-chloro-4-cyclopropyl-1-(4-methylbenzenesulfonyl)- 2H-quinoline (0.35 g, 0.80 mmol) in MeOH (5 mL) was added NaOH (0.32 g, 7.98 mmol). The reaction mixture was stirred for 16 h at 65 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-6-chloro-4-cyclopropylquinoline (0.15 g, 66%) as a white solid. MS ESI calculated for C12H9BrClN [M + H]+, 281.96, 283.96, found 281.95, 283.95; 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 4.6 Hz, 1H), 8.45 (d, J = 4.7 Hz, 2H), 7.08-6.92 (m, 1H), 2.36-2.18 (m, 1H), 1.32- 1.18 (m, 2H), 0.94-0.85 (m, 2H). Step 6: 3-[2-(6-Chloro-4-cyclopropylquinolin-7-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00228] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropylquinoline (0.15 g, 0.53 mmol) and 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-ethynyl-5-(methylamino)-1H- pyrazole-4-carboxamide (0.17 g, 0.53 mmol) in DMF (1.5 mL) were added CuI (20.22 mg, 0.10 mmol), Pd(PPh3)2Cl2 (37.26 mg, 0.05 mmol) and TEA (0.16 g, 1.59 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 40 min at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (15/1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 55% B in 8 min, 55% B; Wave Length: 254 nm; RT1: 6.7 min. The fractions contained desired product were combined and concentrated to afford 3-[2-(6-chloro-4-cyclopropylquinolin-7-yl)ethynyl]-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (103 mg, 36%) as a white solid. MS ESI calculated for C28H29ClN6O3 [M + H]+, 533.20, 535.20, found 533.15, 535.15; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 4.7 Hz, 1H), 8.61 (s, 1H), 8.35 (s, 1H), 7.52 (s, 1H), 7.23 (d, J = 4.7 Hz, 1H), 6.91 (s, 1H), 6.79-6.55 (m, 2H), 6.18 (d, J = 16.4 Hz, 1H), 5.69-5.55 (m, 1H), 5.28-5.12 (m, 1H), 4.48 (d, J = 55.6 Hz, 1H), 4.08-3.73 (m, 2H), 3.65-3.44 (m, 2H), 3.31 (s, 1H), 2.97-2.80 (m, 3H), 2.63 (d, J = 6.9 Hz, 1H), 2.33 (s, 1H), 1.24-1.14 (m, 2H), 0.95-0.86 (m, 2H). Example 27
Figure imgf000104_0001
Figure imgf000104_0002
Step 1: 3-[2-(6-Chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-5-(methylamino)-1-[(3S)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00229] To a stirred solution of 7-bromo-6-chloro-4-cyclopropylcinnoline (0.10 g, 0.36 mmol) and 7-bromo-6-chloro-4-cyclopropylcinnoline (0.10 g, 0.36 mmol) in DMF (2 mL) were added CuI (13.26 mg, 0.07 mmol), Pd(PPh3)2Cl2 (24.43 mg, 0.03 mmol) and TEA (0.10 g, 1.04 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product which was purified by reverse flash chromatography with the following conditions: column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 45% B in 8 min, 45% B; Wave Length: 254 nm. The fractions contained desired product were combined and concentrated to afford 3-[2-(6-chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-5- (methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (63.7 mg, 37%) as a light yellow solid. MS ESI calculated for C25H24ClN7O2 [M + H]+, 490.17, 492.17, found 490.10, 492.10; 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.82 (s, 1H), 8.71 (s, 1H), 7.24 (d, J = 224.9 Hz, 2H), 6.72-6.56 (m, 2H), 6.18-6.08 (m, 1H), 5.70-5.60 (m, 1H), 5.17-5.07 (m, 1H), 4.11-3.52 (m, 4H), 2.96-2.86 (m, 3H), 2.74-2.65 (m, 1H), 2.47-2.41 (m, 1H), 2.36-2.29 (m, 1H), 1.31-1.22 (m, 2H), 1.16-1.05 (m, 2H). Example 28
Figure imgf000105_0001
Step 1: 5-Bromo-4-chloro-2-iodoaniline [00230] To a stirred solution of 3-bromo-4-chloroaniline (5.00 g, 24.22 mmol) in AcOH (50.00 mL) was added NIS (5.72 g, 25.43 mmol) in portions at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/DCM (4/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-4-chloro-2-iodoaniline (3.99 g, 49%) as a light yellow solid. MS ESI calculated for C6H4BrClIN [M + H]+, 331.83, 333.83.99, found 331.70, 333.70; 1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 1.1 Hz, 1H), 7.06 (s, 1H), 5.58 (s, 2H). Step 2: 5-Bromo-4-chloro-2-(cyclopent-1-en-1-yl)aniline [00231] To a stirred mixture of 5-bromo-4-chloro-2-iodoaniline (0.30 g, 0.90 mmol), Pd(PPh3)2Cl2 (63.36 mg, 0.09 mmol) and K2CO3 (0.37 g, 2.71 mmol) in DMF (3.00 mL) and water (1.00 mL) was added 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.19 g, 0.99 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 60 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/PE (1/4) to afford 5- bromo-4-chloro-2-(cyclopent-1-en-1-yl)aniline (0.20 g, 81%) as a yellow oil. MS ESI calculated for C11H11BrClN [M + H]+, 271.98, 273.98, found 271.95, 273.95; 1H NMR (400 MHz, Chloroform-d) δ 7.13 (s, 1H), 6.95 (s, 1H), 6.03 (s, 1H), 2.69-2.61 (m, 2H), 2.55-2.49 (m, 2H), 1.99-1.90 (m, 2H). Step 3: 7-Bromo-8-chloro-2,3-dihydro-1H-cyclopenta[c]cinnoline [00232] To a stirred mixture of 5-bromo-4-chloro-2-(cyclopent-1-en-1-yl)aniline (0.19 g, 0.69 mmol) in water (2.00 mL) were added conc.HCl (0.76 mL, 9.06 mmol) and NaNO2 (0.38 mL, 0.76 mmol, 0.5 M) dropwise at 0 °C. The reaction mixture was stirred for 30 min at 0 °C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2/1) to afford 7-Bromo-8-chloro-2,3-dihydro-1H-cyclopenta[c]cinnoline (0.12 g, 59%) as a yellow solid. MS ESI calculated for C11H8BrClN2 [M + H]+, 282.96, 284.96, found 282.85, 284.85; 1H NMR (400 MHz, Chloroform-d) δ 8.88 (s, 1H), 7.93 (s, 1H), 3.52 (t, J = 7.7 Hz, 2H), 3.32 (t, J = 7.5 Hz, 2H), 2.39-2.32 (m, 2H). Step 4: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((8-chloro-2,3-dihydro-1H- cyclopenta[c]cinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00233] To a stirred solution of 7-Bromo-8-chloro-2,3-dihydro-1H-cyclopenta[c]cinnoline (0.10 g, 0.35 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.12 g, 0.35 mmol), Pd(PPh3)2Cl2 (24.75 mg, 0.03 mmol) and CuI (13.43 mg, 0.07 mmol) in DMF (1.00 mL) was added TEA (0.11 g, 1.06 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 45% B in 8 min, 45% B; Wave Length: 254 nm; RT1: 7.7 min. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)- 3-((8-chloro-2,3-dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-5-(methylamino)-1H- pyrazole-4-carboxamide (70.50 mg, 37%) as a light yellow solid. MS ESI calculated for C27H28ClN7O3 [M + H]+, 534.19, 534.19, found 534.25, 536.25; 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.28 (s, 1H), 7.49 (s, 1H), 6.92 (s, 1H), 6.78-6.54 (m, 2H), 6.17 (dd, J = 16.6, 2.3 Hz, 1H), 5.69 (dd, J = 10.2, 2.6 Hz, 1H), 5.29-5.23 (m, 1H), 4.48 (d, J = 55.7 Hz, 1H), 4.11-3.70 (m, 2H), 3.61 (dd, J = 9.4, 5.2 Hz, 1H), 3.53-3.36 (m, 4H), 3.34 (d, J = 7.8 Hz, 2H), 3.30 (s, 3H), 2.96 (t, J = 5.1 Hz, 3H), 2.70-2.55 (m, 1H), 2.29-2.25 (m, 2H). Example 29
Figure imgf000107_0001
Step 1: N-(5-Bromo-2-cyclopropanecarbonyl-4-fluorophenyl)-4-methylbenzenesulfonamide [00234] To a stirred solution of 5-bromo-2-cyclopropanecarbonyl-4-fluoroaniline (1.23 g, 4.76 mmol) in DCM (12.30 mL) were added TsCl (2.73 g, 14.29 mmol) and Pyridine (0.75 mL, 9.53 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (4/1). The fractions contained desired product were combined and concentrated to afford N-(5-bromo-2-cyclopropanecarbonyl-4-fluorophenyl)-4- methylbenzenesulfonamide (1.53 g, 77%) as a white solid. MS ESI calculated for C17H15BrFNO3S [M + H + 2]+, 411.99, 413.99, found 412.05, 414.05; 1H NMR (400 MHz, CDCl3) δ 10.83 (s, 1H), 8.00 (d, J = 8 Hz, 1H), 7.70-7.66 (m, 3H), 7.28-7.25 (m, 2H), 2.40 (s, 3H), 2.39-2.33 (m, 1H), 1.23-1.16 (m, 2H), 1.10-1.05 (m, 2H). Step 2: N-(5-bromo-2-cyclopropanecarbonyl-4-fluorophenyl)-4-methyl-N-(prop-2-en-1 yl)benzenesulfonamide [00235] To a stirred solution of N-(5-bromo-2-cyclopropanecarbonyl-4-fluorophenyl)-4- methylbenzenesulfonamide (1.53 g, 3.71 mmol) in DMF (16.00 mL) were added K2CO3 (0.77 g, 5.56 mmol) and allyl bromide (0.48 mL, 5.56 mmol) at 0 °C. The reaction mixture was stirred for 1 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (4/1). The fractions contained desired product were combined and concentrated to afford N-(5-bromo-2- cyclopropanecarbonyl-4-fluorophenyl)-4-methyl-N-(prop-2-en-1-yl)benzenesulfonamide (1.56 g, 92%) as a white solid. MS ESI calculated for C20H19BrFNO3S [M + H + 2]+, 452.03, 454.03, found 452.00, 454.00; 1H NMR (400 MHz, CDCl3) δ 7.57-7.54 (m, 2H), 7.45 (d, J = 12.2 Hz, 1H), 7.34 (d, J = 14.2 Hz, 2H), 6.94 (d, J = 8 Hz, 1H), 5.14-5.07 (m, 2H), 4.18 (s, 3H), 2.58-2.52 (m, 1H), 2.48 (s, 3H), 1.33-1.28 (m, 2H), 1.14 (s, 2H). Step 3: N-[5-bromo-2-(1-cyclopropylethenyl)-4-fluorophenyl]-4-methyl-N- 2-en-1-
Figure imgf000108_0001
yl)benzenesulfonamide [00236] To a stirred solution of methyltriphenylphosphaniumbromide (3.17 g, 8.88 mmol) in THF (10.00 mL) was added t-BuOK (1.00 g, 8.88 mmol) in portions at 0 °C. The reaction mixture was stirred for 30 min at room temperature. To the above mixture was added N-(5- bromo-2-cyclopropanecarbonyl-4-fluorophenyl)-4-methyl-N-(prop-2-en-1- yl)benzenesulfonamide (0.80 g, 1.77 mmol) at 0 °C and stirred for another 16 h at room temperature. The resulting mixture was diluted in water (100 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (4/1). The fractions contained desired product were combined and concentrated to afford N-[5-bromo-2-(1- cyclopropylethenyl)-4-fluorophenyl]-4-methyl-N-(prop-2-en-1-yl)benzenesulfonamide (440 mg, 55%) as a yellow solid. MS ESI calculated for C21H21BrFNO2S [M + H]+, 450.05, 452.05, found 450.05, 452.05; 1H NMR (400 MHz, CDCl3) δ 7.72-7.69 (m, 2H), 7.37 (d, J = 8 Hz, 2H), 7.14 (d, J = 12.2 Hz, 1H), 6.96 (d, J = 12.2 Hz, 1H), 5.73-5.63 (m, 1H), 5.08-5.05 (m, 2H), 5.03 (s, 1H), 5.01 (s, 1H), 4.12-4.10 (m, 2H), 2.50 (s, 3H), 1.68-1.62 (m, 1H), 0.92-0.79 (m, 2H), 0.68- 0.64 (m, 2H). Step 4: 7-Bromo-4-cyclopropyl-6-fluoro-1-(4-methylbenzenesulfonyl)-2H-quinoline [00237] To a stirred solution of N-[5-bromo-2-(1-cyclopropylethenyl)-4-fluorophenyl]-4- methyl-N-(prop-2-en-1-yl)benzenesulfonamide (0.54 g, 1.19 mmol) in DCM (120.00 mL) was added Grubbs 2nd (0.05 g, 0.06 mmol) in portions at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 16 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-4-cyclopropyl-6-fluoro-1-(4- methylbenzenesulfonyl)-2H-quinoline (0.22 g, 43%) as a dark grey solid. MS ESI calculated for C19H17BrFNO2S [M + H + 1]+, 422.01, 424.01, found 421.90, 423.90. Step 5: 7-Bromo-4-cyclopropyl-6-fluoroquinoline [00238] To a stirred solution of 7-bromo-4-cyclopropyl-6-fluoro-1-(4-methylbenzenesulfonyl)- 2H-quinoline (0.15 g, 0.35 mmol) in MeOH (15.00 mL) and THF (6.50 mL) was added NaOH (6.50 mL, 3.50 mmol) dropwise at room temperature. The reaction mixture was stirred for 16 h at 65 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-4-cyclopropyl-6- fluoroquinoline (85 mg, 89%) as a light orange solid. MS ESI calculated for C12H9BrFN [M + H + 2]+, 265.99, 267.99, found 266.05; 268.05; 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 12.2 Hz, 1H), 8.72 (s, 1H), 8.08 (d, J = 15.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 2.52-2.38 (m, 1H), 1.38-1.38 (m, 1H), 1.28 (s, 1H),1.02-1.00 (s, 1H), 0.86 (s, 1H). Step 6: 3-[2-(4-Cyclopropyl-6-fluoroquinolin-7-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00239] To a stirred mixture of 7-bromo-4-cyclopropyl-6-fluoroquinoline (0.08 g, 0.30 mmol), 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-ethynyl-5-(methylamino)-1H- pyrazole-4-carboxamide (0.09 g, 0.60 mmol), Pd(PPh3)2Cl2 (21.10 mg, 0.03 mmol) and CuI (11.45 mg, 0.06 mmol) in DMF (2.00 mL) was added TEA (0.13 mL, 0.90 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product. The crude product was purified by reverse flash chromatography with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile phase A: water (Plus 10 mmol/L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 50% B in 8 min, 50% B; Wave length: 254 nm; RT: 6.6 min. The fractions contained desired product were combined and concentrated to afford 3-[2-(4-cyclopropyl-6-fluoroquinolin-7-yl)ethynyl]-1- [(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4- carboxamide (49.40 mg, 31%) as a white solid. MS ESI calculated for C28H29FN6O3 [M + H]+, 517.23, found 517.30; 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 14.6 Hz, 1H), 8.34-8.28 (m, 2H), 7.50 (s, 1H), 7.21 (d, J = 8 Hz, 1H), 6.88 (s, 1H), 6.74-6.57 (m, 2H), 6.20-6.15 (m, 1H), 5.71-5.67 (m, 1H), 5.31-5.25 (m, 1H), 4.55-4.41 (m, 1H), 4.06-3.75 (m, 2H), 3.63-3.60 (m, 1H), 3.51-3.46 (m, 2H), 3.45 (s, 3H), 2.96 (t, J = 14.6 Hz, 3H), 2.62 (s, 1H), 2.50 (s, 1H), 1.21-1.16 (m, 2H), 0.92-0.88 (m, 2H). Example 30
Figure imgf000110_0001
Step 1: 1-(5-Chloro-2-nitrophenyl)-2-ethylpyrrolidine [00240] To a stirred solution 4-chloro-2-fluoro-1-nitrobenzene (3.23 g, 18.40 mmol) and DIEA (3.57 g, 27.60 mmol) in EtOH (30.00 mL) was added 2-ethylpyrrolidine hydrochloride (2.50 g, 18.40 mmol) at 0 °C. The reaction mixture was stirred for 4 h at room temperature. The resulting mixture was quenched with water (30 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 1-(5-chloro-2-nitrophenyl)-2-ethylpyrrolidine (4.30 g, crude) as an orange oil. MS ESI calculated for C12H15ClN2O2 [M + H]+ 255.08, 257.08, found 254.95, 256.95; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 2.1 Hz, 1H), 6.70-6.67 (m, 1H), 3.83-3.80 (m, 1H), 3.55-3.43 (m, 1H), 2.77-2.69 (m, 1H), 2.29-2.26 (m, 1H), 2.03-1.93 (m, 1H), 1.85-1.63 (m, 3H), 1.48-1.43 (m, 1H), 0.92 (t, J = 7.5 Hz, 3H). Step 2: 1-(4-Bromo-5-chloro-2-nitrophenyl)-2-ethylpyrrolidine [00241] To a stirred solution of 1-(5-chloro-2-nitrophenyl)-2-ethylpyrrolidine (4.30 g, 16.88 mmol) in AcOH (30.00 mL) was added NBS (3.61 g, 20.26 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 1-(4- bromo-5-chloro-2-nitrophenyl)-2-ethylpyrrolidine (4.00 g, 71%) as an orange oil. MS ESI calculated for C12H14BrClN2O2 [M + H]+ 332.99, 334.99, found 333.15, 335.15; 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.28 (s, 1H) 3.88-3.72 (m, 1H), 3.51- 3.45 (m, 1H), 2.73-2.69 (m, 1H), 2.31-2.25 (m, 1H), 2.03-1.92 (m, 1H), 1.87 -1.69 (m, 3H), 1.54-1.36 (m, 1H), 0.92 (t, J = 7.4 Hz, 3H). Step 3: 5-Bromo-4-chloro-2-(2-ethylpyrrolidin-1-yl)aniline [00242] To a stirred solution of 1-(4-bromo-5-chloro-2-nitrophenyl)-2-ethylpyrrolidine (4.00 g, 11.99 mmol) in EtOH (60.00 mL) and H2O (12.00 mL) were added Fe (6.70 g, 119.90 mmol) and NH4Cl (6.41 g, 119.90 mmol). The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 40 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-4-chloro-2-(2-ethylpyrrolidin-1-yl)aniline (2.20 g, 60%) as a brown oil. MS ESI calculated for C12H16BrClN2 [M + H]+, 303.02, 305.02, found 303.15, 305.15; 1H NMR (400 MHz, CDCl3) δ 7.06 (s, 1H), 6.96 (s, 1H), 4.01 (s, 2H), 3.45 (s, 1H), 3.30-3.17 (m, 1H), 2.66-2.55 (m, 1H), 2.19-2.05 (m, 1H), 1.91-1.84 (m, 2H), 1.55- 1.50 (m, 2H), 1.25-1.16 (m, 1H), 0.83 (t, J = 7.5 Hz, 3H). Step 4: 6-Bromo-7-chloro-1-ethyl-2,3-dihydro-1H- a]imidazole
Figure imgf000111_0001
[00243] To a stirred solution of 5-bromo-4-chloro-2-(2-ethylpyrrolidin-1-yl)aniline (2.20 g, 7.24 mmol) in EA (20.00 mL) were added H2O2 (30%) (16.43 g, 144.92 mmol) and methanesulfonic acid (69.63 mg, 0.72 mmol) at room temperature. The reaction mixture was stirred for 16 h at 75 °C. The resulting mixture was quenched with water (15.00 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford 6-bromo-7-chloro-1-ethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (0.76 g, 35%) as a yellow oil. MS ESI calculated for C12H12BrClN2 [M + H]+ 298.99, 300.99, found 299.00, 301.00. Step 5: (R)-6-Bromo-7-chloro-1-ethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole & (S)- 6-bromo-7-chloro-1-ethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole [00244] The 6-bromo-7-chloro-1-ethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (0.76 g, 2.53 mmol) was separated by Prep-Chiral HPLC with the following conditions: Column: CHIRAL ART Amylose-C NED, 3 x 25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MEOH(0.1% 2M NH3-MeOH); Flow rate: 70 mL/min; Gradient: isocratic 50% B; Wave Length: 220 nm; RT1(min): 7.24; RT2(min): 10.23. The faster peak contained desired product were combined and concentrated under reduced pressure to afford (R)-6-bromo-7-chloro-1- ethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (0.24 g, 32%) as a light orange solid. MS ESI calculated for C12H12BrClN [M + H]+, 298.99, 300.99, found 298.95, 300.95; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.49 (s, 1H), 4.49-4.43 (m, 1H), 3.17-3.08 (m, 2H), 2.89-2.80 (m, 1H), 2.46-2.34 m, 1H), 2.17-2.11 (m, 1H), 1.89-1.80 (m, 1H), 0.98 (t, J = 7.4 Hz, 3H). The slower peak contained desired product were combined and concentrated to afford (S)-6-bromo- 7-chloro-1-ethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (0.22 g, 29%) as a light orange solid. MS ESI calculated for C12H12BrClN [M + H]+, 298.99, 300.99, found 298.95, 300.95; 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.50 (s, 1H), 4.49-4.43 (m, 1H), 3.19-2.98 (m, 2H), 2.92-2.78 (m, 1H), 2.45-2.40 (ddt, J = 13.8, m, 1H), 2.18-2.11 (m, 1H), 1.92-1.76 (m, 1H), 0.99 (t, J = 7.4 Hz, 3H). Step 6: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-(((S)-7-chloro-1-ethyl-2,3- dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide [00245] To a stirred solution of (S)-6-bromo-7-chloro-1-ethyl-2,3-dihydro-1H- benzo[d]pyrrolo[1,2-a]imidazole (0.10 g, 0.33 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)- 1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.22 g, 0.67 mmol), Pd(PPh3)2Cl2 (23.43 mg, 0.03 mmol) and CuI (12.71 mg, 0.06 mmol) in DMF (2.00 mL) was added TEA (0.10 g, 1.00 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude solid which was further purified by reverse phase flash with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 8 min, Wave Length: 254 nm. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5- (methoxymethyl)pyrrolidin-3-yl)-3-(((S)-7-chloro-1-ethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2- a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (27.00 mg, 14 %) as a white solid. MS ESI calculated for C28H32ClN7O3 [M + H]+, 550.23, found 550.40; 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 6.6 Hz, 2H), 7.49 (s, 1H), 6.86 (s, 1H), 6.77-6.54 (m, 2H), 6.19-6.15 (m, 1H), 5.70-5.67 (m, 1H), 5.29-5.23 (m, 1H), 4.56-4.53(m, 1H), 4.41-4.40 (m, 1H), 4.05-4.02 (m, 1H), 3.93-3.71 (m, 1H), 3.63-3.60 (m, 1H), 3.49-3.42 (m, 1H), 3.31 (s, 3H), 3.11- 2.87 (m, 5H), 2.84-2.71 (m, 1H), 2.71-2.53 (m, 1H), 2.36-2.32 (m, 2H), 2.10-2.00 (m, 1H), 1.84- 1.71 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H). Example 31
Figure imgf000113_0001
Figure imgf000113_0002
Step 1: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-(((R)-7-chloro-1-ethyl-2,3- dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide [00246] To a stirred solution of (R)-6-bromo-7-chloro-1-ethyl-2,3-dihydro-1H- benzo[d]pyrrolo[1,2-a]imidazole (50 mg, 0.17 mmol) and 3-ethynyl-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (110.61 mg, 0.33 mmol) and Pd(PPh3)2Cl2 (11.71 mg, 0.02 mmol) and CuI (6.36 mg, 0.03 mmol) in DMF (1 mL) was added TEA (0.12 mL, 0.84 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product was further purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 8 min, 50% B; Wave Length: 254 nm. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)- 3-(((R)-7-chloro-1-ethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5- (methylamino)-1H-pyrazole-4-carboxamide (22.5 mg, 24%) as an off-white solid. MS ESI calculated for C28H32ClN7O3 [M + H]+, 550.23, 552.23, found 550.30, 552.30; 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 6.80 Hz, 2H), 7.48 (s, 1H), 6.85 (s, 1H), 6.77-6.53 (m, 2H), 6.19-6.14 (m, 1H), 5.70-5.66 (m, 1H), 5.32-5.20 (m, 1H), 4.58-4.52 (m, 1H), 4.40-4.39 (m, 1H), 4.05-4.01 (m, 1H), 3.91-3.84 (m, 1H), 3.79-3.57 (m, 1H), 3.52-3.40 (m, 1H), 3.30 (s, 3H), 3.10- 2.88 (m, 5H), 2.82-2.56 (m, 2H), 2.36-2.27 (m, 2H), 2.10-2.08 (m, 1H), 1.82-1.71 (m, 1H), 0.87- 0.83 (m, 3H). Example 32
Figure imgf000114_0001
Step 1: 5-Amino-3-[2-(6-chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00247] To a stirred solution of 5-amino-3-bromo-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (50 mg, 0.13 mmol), 6-chloro-4-cyclopropyl-7- [2-(trimethylsilyl)ethynyl]cinnoline (48.50 mg, 0.16 mmol), Pd(PPh3)2Cl2 (9.43 mg, 0.01 mmol) and CuI (5.12 mg, 0.02 mmol) in DMF (1 mL) were added TBAI (74.42 mg, 0.20 mmol) and K2CO3 (54.21 mg, 0.39 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 4 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product. The crude product was purified by Prep- HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 45% B in 8 min, 45% B; Wave Length: 254 nm; RT1: 7.2 min. The fractions contained desired product were combined and concentrated to afford 5-amino-3- [2-(6-chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (5.4 mg, 7%) as a light yellow solid. MS ESI calculated for C26H26ClN7O3 [M + H]+, 520.18, 522.18, found, 520.30, 522.30; 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.82 (s, 1H), 8.72 (s, 1H), 7.38 (s, 1H), 6.79-6.67 (m, 3H), 6.17 (d, J = 16.5 Hz, 1H), 5.70 (d, J = 10.2 Hz, 1H), 5.23-5.14 (m, 1H), 4.48 (d, J = 47.4 Hz, 1H), 3.99 (s, 1H), 3.80 (s, 2H), 3.52 (s, 2H), 3.32 (s, 3H), 2.69 (s, 1H), 2.30 (s, 1H), 1.27-1.21 (m, 2H), 1.11 (d, J = 5.4 Hz, 2H).
Figure imgf000115_0001
Step 1: 3-[2-(6-Chloro-4-ethylcinnolin-7-yl)ethynyl]-5-(methylamino)-1-[(3S)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00248] To a stirred mixture of 3-ethynyl-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin- 3-yl]pyrazole-4-carboxamide (0.10 g, 0.34 mmol) and 7-bromo-6-chloro-4-ethylcinnoline (94.51 mg, 0.34 mmol) in DMF (1 mL) were added Pd(PPh3)2Cl2 (24.43 mg, 0.03 mmol), CuI (13.26 mg, 0.07 mmol) and TEA (0.10 g, 1.04 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 4 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20/1) to afford the crude product which was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 39% B in 8 min, 39% B; Wave Length: 254 nm; RT1: 7.5 min. The fractions contained desired product were combined and concentrated to afford 3-[2-(6-chloro-4- ethylcinnolin-7-yl)ethynyl]-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole- 4-carboxamide (36.6 mg, 22%) as a light yellow solid. MS ESI calculated for C24H24ClN7O2 [M + H]+, 478.17, 480.17, found 478.20, 480.20; 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.83 (s, 1H), 8.51 (s, 1H), 7.50 (s, 1H), 6.94 (s, 1H), 6.71-6.59 (m, 1H), 6.63-6.55 (m, 1H), 6.17- 6.02 (m, 1H), 5.70-5.65 (m, 1H), 5.18-5.05 (m, 1H), 4.16-3.81 (m, 2H), 3.81-3.49 (m, 2H), 3.13 (q, J = 7.5 Hz, 2H), 2.96-2.85 (m, 3H), 2.42-2.39 (m, 1H), 2.32-2.26 (m, 1H), 1.32 (t, J = 7.5 Hz, 3H). Example 34
Figure imgf000116_0001
Step 1: 1-((S)-1-acryloylpyrrolidin-3-yl)-3-(((S)-7-chloro-1-methyl-2,3-dihydro-1H- benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00249] To a stirred solution of 3-ethynyl-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin- 3-yl]pyrazole-4-carboxamide (120.74 mg, 0.42 mmol), 1-((S)-1-acryloylpyrrolidin-3-yl)-3-(((S)- 7-chloro-1-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5- (methylamino)-1H-pyrazole-4-carboxamide (60.00 mg, 0.210 mmol), Pd(PPh3)2Cl2 (14.75 mg, 0.02 mmol) and CuI (8.00 mg, 0.04 mmol) in DMF (3.00 mL) was added TEA (63.78 mg, 0.63 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude solid which was further purified by reverse phase flash with the following conditions: Column: YMC- Actus Triart C18 ExRS, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 33% B in 8 min, Wave Length: 254 nm. The fractions contained desired product were combined and concentrated to afford 1-((S)-1-acryloylpyrrolidin-3-yl)-3-(((S)-7-chloro-1-methyl-2,3-dihydro-1H- benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (12.30 mg, 5%) as a white solid. MS ESI calculated for C25H26ClN7O2 [M + H]+, 492.18, 494.18, found 492.15, 494.15; 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 6.4 Hz, 2H), 7.49 (s, 1H), 6.87 (s, 1H), 6.73-6.52 (m, 2H), 6.19-6.14 (m, 1H), 5.72-5.66 (m, 1H), 5.21-5.17 (m, 1H), 4.65-4.63 (m, 1H), 4.09-3.80 (m, 2H), 3.77-3.46 (m, 2H), 3.17-2.91 (m, 5H), 2.83-2.81 (m, 1H), 2.43-2.40 (m, 1H), 2.33-2.19 (m, 2H), 1.52 (d, J = 6.4 Hz, 3H). Example 35
Figure imgf000117_0001
Step 1: 3-[2-(6-Chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5-(methylamino)-1-[(3S)- 1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00250] To a stirred solution of 3-ethynyl-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin- 3-yl]pyrazole-4-carboxamide (135.30 mg, 0.47 mmol) and 6-chloro-1-cyclopropyl-5-iodo-1,3- benzodiazole (100 mg, 0.31 mmol) in DMF (1.5 mL) were added Pd(PPh3)2Cl2 (22.03 mg, 0.03 mmol) and CuI (11.96 mg, 0.06 mmol) and TEA (95.30 mg, 0.94 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (5/1) to afford the crude product. The crude product (100 mg) was purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18 ExRS, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 32% B in 8 min, 32% B; Wave Length: 254 nm; RT1: 7 min. The fractions contained desired product were combined and concentrated to afford 3-[2-(6-chloro-1-cyclopropyl-1,3-benzodiazol-5-yl)ethynyl]-5- (methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (33.9 mg, 22%) as an off-white solid. MS ESI calculated for C24H24ClN7O2 [M + H]+, 478.17, 480.17, found 478.25, 480.25; 1H NMR (400 MHz, DMSO-d6) δ 8.39-8.38 (s, 1H), 8.04-8.03 (s, 1H), 7.88- 7.87 (s, 1H), 7.49-7.48 (s, 1H), 6.90-6.89 (m, 1H), 6.69-6.54 (m, 2H), 6.21-6.12 (m, 1H), 5.73- 5.63 (m, 1H), 5.18-5.10 (m, 1H), 4.10-3.52 (m, 5H), 2.96-2.95 (m, 3H), 2.45-2.38 (m, 1H), 2.36- 2.28 (m, 1H), 1.16-1.03 (m, 4H). Example 36
Figure imgf000118_0001
Step 1: 1-((S)-1-Acryloylpyrrolidin-3-yl)-3-(((R)-7-chloro-1-methyl-2,3-dihydro-1H- benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00251] To a stirred mixture of 3-ethynyl-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin- 3-yl]pyrazole-4-carboxamide (90.00 mg, 0.31 mmol) and (R)-6-bromo-7-chloro-1-methyl-2,3- dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (0.17 g, 0.62 mmol) in DMF (0.9 mL, 11.63 mmol) were added TEA (95 mg, 0.94 mmol) Pd(PPh3)2Cl2 (21 mg, 0.03 mmol), CuI (11.93 mg, 0.06 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford crude product (40 mg). The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 32% B in 8 min, 32% B; Wave Length: 254 nm; RT1: 7 min. The fractions contained desired product were combined and concentrated to afford 1-((S)-1-acryloylpyrrolidin-3-yl)-3-(((R)-7-chloro-1-methyl-2,3-dihydro- 1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (20.3 mg, 13%) as an off-white solid. MS ESI calculated for C25H26ClN7O2 [M + H]+, 492.18, found 492.20; 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 7.1 Hz, 2H), 7.49 (s, 1H), 6.87 (s, 1H), 6.74-6.55 (m, 2H), 6.17 (dd, J = 16.7, 4.4, 2.4 Hz, 1H), 5.70 (d, J = 10.7, 2.4 Hz, 1H), 5.20- 5.12 (m, 1H), 4.71-4.58 (m, 1H), 4.06 (dd, J = 10.8, 7.1 Hz, 2H), 3.80-3.69 (m, 2H), 3.12-2.94 (m, 5H), 2.89 (dd, J = 21.8, 6.6 Hz, 1H), 2.82 (s, 1H), 2.37-2.31 (m, 1H), 2.29-2.16 (m, 1H), 1.52 (d, J = 6.3 Hz, 3H). Example 37
Figure imgf000119_0001
Step 1: Tert-butyl (2R,4S)-4-(5-((tert-butoxycarbonyl)(methyl)amino)-3-((6-chloro-1- cyclopropyl-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-4-cyano-1H-pyrazol-1-yl)-2- (methoxymethyl)pyrrolidine-1-carboxylate [00252] To a stirred mixture of tert-butyl (2R,4S)-4-{3-bromo-5-[(tert- butoxycarbonyl)(methyl)amino]-4-cyanopyrazol-1-yl}-2-(methoxymethyl)pyrrolidine-1- carboxylate (0.50 g, 0.97 mmol), 6-chloro-1-cyclopropyl-2-methyl-5-[2-(trimethylsilyl)ethynyl]- 1,3-benzodiazole (0.30 g, 0.97 mmol), Pd(PPh3)2Cl2 (68.22 mg, 0.09 mmol), CuI (37.02 mg, 0.19 mmol) and TBAI (0.54 g, 1.46 mmol) in DMF (5.00 mL) was added K2CO3 (0.40 g, 2.92 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/(EA/EtOH = 3/1) (1/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (2R,4S)-4-(5-((tert-butoxycarbonyl)(methyl)amino)-3-((6- chloro-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-4-cyano-1H-pyrazol-1-yl)- 2-(methoxymethyl)pyrrolidine-1-carboxylate (0.42 g, 65%) as a dark green solid. MS ESI calculated for C34H42ClN7O5 [M + H]+, 664.29, 666.29, found 664.35, 666.35. Step 1：Tert-butyl (2R,4S)-4-(5-((tert-butoxycarbonyl)(methyl)amino)-4-carbamoyl-3-((6- chloro-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-1H-pyrazol-1-yl)-2- (methoxymethyl)pyrrolidine-1-carboxylate [00253] To a stirred solution of tert-butyl (2R,4S)-4-(5-((tert-butoxycarbonyl)(methyl)amino)-3- ((6-chloro-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-4-cyano-1H-pyrazol-1- yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.40 g, 0.60 mmol) in EtOH (4.00 mL) and DMSO (4.00 mL) was added NaOH (1.36 mL, 0.5 M) and H2O2 (0.24 mL, 9.98 M) dropwise at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and stirred for 30 min at room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford tert- butyl (2R,4S)-4-(5-((tert-butoxycarbonyl)(methyl)amino)-4-carbamoyl-3-((6-chloro-1- cyclopropyl-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-1H-pyrazol-1-yl)-2- (methoxymethyl)pyrrolidine-1-carboxylate (0.37 g, 89%) as a light yellow solid. MS ESI calculated for C34H44ClN7O6 [M + H]+, 682.30, 684.30, found 682.30, 684.30. Step 2: 3-((6-Chloro-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-1-((3S,5R)-5- (methoxymethyl)pyrrolidin-3-yl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00254] To a stirred solution of tert-butyl (2R,4S)-4-(5-((tert-butoxycarbonyl)(methyl)amino)-4- carbamoyl-3-((6-chloro-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-1H- pyrazol-1-yl)-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.37 g, 0.54 mmol) in DCM (4.00 mL) was added HCl in EA (8.00 mL, 4 M) at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated to afford 3-((6-chloro-1-cyclopropyl- 2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-1-((3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl)-5- (methylamino)-1H-pyrazole-4-carboxamide (0.33 g, 94%) as a white solid. MS ESI calculated for C24H28ClN7O2 [M + H]+, 482.20, 484.20, found 482.15, 484.15. Step 4: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((6-chloro-1-cyclopropyl- 2-methyl-1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00255] To a stirred mixture of 3-((6-chloro-1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-5- yl)ethynyl)-1-((3S,5R)-5-(methoxymethyl)pyrrolidin-3-yl)-5-(methylamino)-1H-pyrazole-4- carboxamide (0.30 g, 0.58 mmol) in DCM (3.00 mL) was added DIEA (0.22 g, 1.74 mmol) and acryloyl chloride (47.14 mg, 0.52 mmol) at 0 °C. The reaction mixture was stirred for 10 min at 0 °C. The resulting mixture was concentrated under reduced pressure. The crude product (0.20 g) was purified by Prep-HPLC with the following conditions: Column: Xselect CSH C18 OBD Column 30 x 150 mm, 5 μm; Mobile phase A: water (10 mmol/L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 39% B in 8 min; Wave length: 254 nm; RT: 7 min. The fractions contained desired product were combined and concentrated to afford 1- ((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((6-chloro-1-cyclopropyl-2-methyl- 1H-benzo[d]imidazol-5-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (0.12 g, 38%) as a white solid. MS ESI calculated for C27H30ClN7O3 [M + H]+, 536.21, 538.21, found 536.21, 538.21; 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.71 (s, 1H), 7.51 (s, 1H), 6.86 (s, 1H), 6.77-6.52 (m, 2H), 6.17 (dd, J = 16.8, 2.4 Hz, 1H), 5.72-5.67 (m, 1H), 5.28 (dd, J = 15.6, 7.9 Hz, 1H), 4.47 (d, J = 53.8 Hz, 1H), 4.13-3.52 (m, 3H), 3.46 (s, 2H), 3.31 (d, J = 5.3 Hz, 3H), 2.96 (t, J = 5.0 Hz, 3H), 2.60 (s, 3H), 2.31 (d, J = 11.6 Hz, 1H), 1.23-1.17 (m, 2H), 1.06-1.03 (m, 2H). Example 38
Figure imgf000121_0001
Step 1: (S)-1-(1-Acryloylpyrrolidin-3-yl)-3-((8-chloro-2,3-dihydro-1H-cyclopenta[c]cinnolin-7- yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00256] To a stirred mixture of 7-bromo-8-chloro-2,3-dihydro-1H-cyclopenta[c]cinnoline (98.00 mg, 0.34 mmol) , Pd(PPh3)2Cl2 (24.26 mg, 0.03 mmol), CuI (13.16 mg, 0.07 mmol) and 3- ethynyl-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (0.15 g, 0.52 mmol) in DMF (1.00 mL) was added TEA (0.14 mL, 1.04 mmol). The reaction mixture degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product which was further purified by trituration with MeCN (5 mL) to afford (S)-1-(1-acryloylpyrrolidin-3-yl)-3- ((8-chloro-2,3-dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole- 4-carboxamide (64.30 mg, 37%) as a light yellow solid. MS ESI calculated for C25H24ClN7O2 [M + H]+, 490.17, 492.17, found 490.00, 492.00; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.27 (s, 1H), 7.48 (s, 1H), 6.93 (s, 1H), 6.73-6.50 (m, 2H), 6.17-6.13 (m, 1H), 5.74-5.69 (m, 1H), 5.19-5.16 (m, 1H), 4.17-3.82 (m, 2H), 3.82-3.49 (m, 2H), 3.40 (t, J = 7.7 Hz, 2H), 3.34 (d, J = 7.8 Hz, 2H), 2.96 (dd, J = 5.6, 2.3 Hz, 3H), 2.46-2.42 (m, 1H), 2.33 (t, J = 6.9 Hz, 1H), 2.25- 2.21 (m, 2H). Example 39
Figure imgf000122_0001
Step 1: 5-Bromo-4-chloro-2-(cyclohex-1-en-1-yl)aniline [00257] To a stirred mixture of 5-bromo-4-chloro-2-iodoaniline (0.20 g, 0.60 mmol) and cyclohex-1-en-1-ylboronic acid (83.38 mg, 0.66 mmol) in DMF (3.00 mL) and H2O (1.00 mL) were added Pd(PPh3)2Cl2 (42.24 mg, 0.06 mmol) and K2CO3 (0.24 g, 1.80 mmol) at room temperature. The resulting mixture was degassed with nitrogen for three times and stirred for 30 min at 60 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-4-chloro-2-(cyclohex-1-en- 1-yl)aniline (160 mg, 92%) as a yellow oil. MS ESI calculated for C12H13BrClN [M + H]+, 285.99, 287.99, found 286.00, 288.00; 1H NMR (400 MHz, CDCl3) δ 7.07 (s, 1H), 7.02 (s, 1H), 5.88-5.70 (m, 1H), 4.34 (s, 2H), 2.35-2.16 (m, 4H), 1.81-1.66 (m, 4H). Step 2: 3-Bromo-2-chloro-7H,8H,9H,10H-benzo[c]cinnoline [00258] To a stirred solution of 5-bromo-4-chloro-2-(cyclohex-1-en-1-yl)aniline (0.16 g, 0.55 mmol) in H2O (2.00 mL) were added HCl (0.26 g, 7.25 mmol) and NaNO2 (2 M) (0.31 mL, 0.61 mmol) in portions at 0 °C. The reaction mixture was stirred for 20 min at 0 °C. The resulting mixture was dissolved with water (10 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 6 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 3-bromo-2-chloro-7H,8H,9H,10H- benzo[c]cinnoline (90 mg, 54%) as a yellow solid. MS ESI calculated for C12H10BrClN2 [M + H]+, 296.97, 298.97, found 297.00, 299.00. Step 3: 3-(2-{2-Chloro-7H,8H,9H,10H-benzo[c]cinnolin-3-yl}ethynyl)-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00259] To a stirred mixture of 3-bromo-2-chloro-7H,8H,9H,10H-benzo[c]cinnoline (60.00 mg, 0.20 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (73.50 mg, 0.22 mmol), Pd(PPh3)2Cl2 (14.15 mg, 0.02 mmol) and CuI (7.68 mg, 0.04 mmol) in DMF (0.60 mL) was added TEA (0.08 mL, 0.60 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product. The residue was purified by reverse flash chromatography with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile phase A: water (10 mmol/L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 42% B in 8 min, 42% B; Wave length: 254 nm; RT1: 7 min. The fractions contained desired product were combined and concentrated to afford 3-(2-{2-chloro-7H,8H,9H,10H-benzo[c]cinnolin-3- yl}ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (29.1 mg, 26%) as a white solid. MS ESI calculated for C28H30ClN7O3 [M + H]+, 548.21, 550.21, found 548.40, 550.40; 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.33 (s, 1H), 7.49 (s, 1H), 6.93 (s, 1H), 6.77-6.57 (m, 2H), 6.20-6.15 (m, 1H), 5.72- 5.69 (m, 1H), 5.33-5.24 (m, 1H), 4.56-4.42 (m, 1H), 4.07-3.74 (m, 2H), 3.63-3.45 (m, 2H), 3.32 (s, 3H), 3.29-3.15 (m, 2H), 2.96 (s, 3H), 2.65-2.59 (m, 1H), 2.51 (s, 2H), 2.50 (s, 1H), 1.95-1.89 (m, 4H). Example 40
Figure imgf000124_0001
Step 1: 5-Bromo-4-chloro-2-(3,6-dihydro-2H-pyran-4-yl)aniline [00260] To a stirred solution of 5-bromo-4-chloro-2-iodoaniline (1 g, 3.00 mmol) and 2-(3,6- dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.63 g, 3.00 mmol) in dioxane (8 mL) and H2O (2 mL) were added Pd(dppf)Cl2·CH2Cl2 (0.24 g, 0.30 mmol) and Na2CO3 (0.95 g, 9.02 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 5- bromo-4-chloro-2-(3,6-dihydro-2H-pyran-4-yl)aniline (600 mg, 69%) as a brown yellow solid. MS ESI calculated for C11H11BrClNO [M + H]+, 287.97, 289.97, found 287.90, 289.90. Step 2: 8-Bromo-9-chloro-1H,2H,4H-pyrano[3,4-c]cinnoline [00261] To a stirred solution of 5-bromo-4-chloro-2-(3,6-dihydro-2H-pyran-4-yl)aniline (0.5 g, 1.73 mmol) in H2O (5.50 mL) were added con. HCl (0.82 g, 22.53 mmol) and 2 M NaNO2 (0.95 mL, 1.90 mmol) dropwise at 0 °C. The resulting mixture was stirred for 30 min at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 8-bromo-9- chloro-1H,2H,4H-pyrano[3,4-c]cinnoline (0.40 g, 77%) as a light yellow solid. MS ESI calculated for C11H8BrClN2O [M + H]+, 298.95, 300.95, found 298.85, 300.85. Step 3: 3-(2-{9-Chloro-1H,2H,4H-pyrano[3,4-c]cinnolin-8-yl}ethynyl)-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00262] To a stirred solution of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (40 mg, 0.12 mmol) and 8- bromo-9-chloro-1H,2H,4H-pyrano[3,4-c]cinnoline (36.16 mg, 0.12 mmol) in DMF (0.5 mL) were added Pd(PPh3)2Cl2 (8.47 mg, 0.01 mmol), CuI (4.60 mg, 0.02 mmol) and TEA (36.64 mg, 0.36 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (5/1) the crude product. The crude product (48 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40% B to 45% B in 8 min, 45% B; Wave Length: 254 nm; RT1: 6.3 min. The crude product were combined and concentrated to afford 3-(2-{9-chloro-1H,2H,4H- pyrano[3,4-c]cinnolin-8-yl}ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin- 3-yl]-5-(methylamino)pyrazole-4-carboxamide (1.8 mg, 2%) as an off-white solid. MS ESI calculated for C27H28ClN7O4 [M + H]+, 550.19, 552.19, found 550.25, 552.25; 1H NMR (400 MHz, DMSO-d6) δ 8.84-8.83 (s, 1H), 8.37-8.36 (s, 1H), 7.49-7.48 (s, 1H), 6.93-6.92 (s, 1H), 6.79-6.54 (m, 2H), 6.18-6.17 (m, 1H), 5.70-6.69 (m, 1H), 5.28-5.27 (m,1H), 5.17-5.16 (s, 2H), 4.49-4.48 (m, 1H), 4.07-4.06 (m, 2H), 3.94-3.71 (m, 2H), 3.65-3.44 (m, 2H), 3.28-3.21 (m, 4H), 2.96-2.95 (m, 3H), 2.70-2.60 (m, 1H), 2.40-2.38 (m, 2H),. Example 41
Figure imgf000125_0001
Step 1: 3-Bromo-4-chloro-2-methylaniline [00263] To a stirred mixture of 3-bromo-2-methylaniline (19.2 g, 103.20 mmol) in DMF (100 mL) was added NCS (14.47 g, 108.36 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at 50 °C. The resulting mixture was washed with 100 mL of water. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with PE/EA (12/1). The fractions contained desired product were combined and concentrated to afford 3-bromo-4-chloro-2-methylaniline (12.5 g, 55%) as a brown solid. MS ESI calculated for C7H7BrClN [M + H]+, 220.49, 222.49, found 220.40, 222.40. Step 2: 3-Bromo-4-chloro-6-iodo-2-methylaniline [00264] To a stirred mixture of 3-bromo-4-chloro-2-methylaniline (12.5 g, 56.69 mmol) in AcOH (80 mL) was added NIS (13.39 g, 59.53 mmol) in portions at room temperature. The reaction mixture was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (9/1). The fractions contained desired product were combined and concentrated to afford 3-bromo-4-chloro-6-iodo-2-methylaniline (18 g, 91%) as a brown solid. MS ESI calculated for C7H6BrClIN [M + H]+, 345.85, 347.85, found 346.00, 348.00; 1H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 5.32 (s, 2H), 2.36 (s, 3H). Step 3: 4-Bromo-5-chloro-7-iodo-1H-indazole [00265] To a stirred solution of 3-bromo-4-chloro-6-iodo-2-methylaniline (14 g, 40.42 mmol) in AcOH (170 mL) was added NaNO2 (3.07 g, 44.46 mmol, 2 M) dropwise at room temperature. The resulting mixture was stirred for 30 min at room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 4-bromo-5-chloro-7-iodo-1H-indazole (9.9 g, 68%) as a light brown solid. MS ESI calculated for C7H3BrClIN2 [M + H]+-, 356.82, 358.82, found 356.75, 358.75. Step 4: 4-Bromo-5-chloro-7-iodo-1-methyl-1H-indazole [00266] To a stirred mixture of 4-bromo-5-chloro-7-iodo-1H-indazole (2 g, 5.60 mmol) and K3PO4 (3.56 g, 16.79 mmol) in DMF (20 mL) was added methyl iodide (1.19 g, 8.39 mmol) dropwise at room temperature. The reaction mixture was stirred for 16 h at 100 °C. The resulting mixture was filtered, the filter cake was washed with DMF (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 10% to 50% gradient in 20 min, 50% to 75% gradient in 30 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford 4-bromo-5-chloro-7-iodo-1-methyl-1H-indazole (160 mg, 7%) as a light yellow solid. MS ESI calculated for C8H5BrClIN2 [M + H]+, 370.84, 372.84, found 370.80, 372.80; 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.89 (s, 1H), 4.42 (d, J = 4.1 Hz, 3H). Step 5: 4-Bromo-5-chloro-7-cyclopropyl-1-methyl-1H-indazole [00267] To a stirred mixture of 4-bromo-5-chloro-7-iodo-1-methyl-1H-indazole (0.20 g, 0.54 mmol), cyclopropylboronic acid (92.51 mg, 1.08 mmol) and K2CO3 (223.27 mg, 1.62 mmol) in dioxane (4 mL) was added Pd(dppf)Cl2.CH2Cl2 (43.87 mg, 0.05 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for three times and stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (7/1). The fractions contained desired product were combined and concentrated to afford 4-bromo-5-chloro-7-cyclopropyl-1-methylindazole (70 mg, 45%) as a light yellow solid. MS ESI calculated for C11H10BrClN2 [M + H]+, 284.97, 286.97, found 284.95, 286.95; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 3.7 Hz, 1H), 7.13 (d, J = 1.1 Hz, 1H), 4.45 (d, J = 12.2 Hz, 3H), 2.35-2.28 (m, 1H), 1.16-1.06 (m, 2H), 1.03-0.86 (m, 2H). Step 6: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((5-chloro-7-cyclopropyl- 1-methyl-1H-indazol-4-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00268] To a stirred mixture of 4-bromo-5-chloro-7-cyclopropyl-1-methylindazole (30 mg, 0.11 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (41.77 mg, 0.17 mmol) , Pd(PPh3)2Cl2 (7.37 mg, 0.01 mmol) and CuI (4.00 mg, 0.02 mmol) in DMF (3 mL) was added TEA (31.89 mg, 0.32 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product (20 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Phenyl OBD Column, 19 x 250 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 45% B to 55% B in 10 min, 55% B; Wave Length: 254 nm; RT1: 9 min. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin- 3-yl)-3-((5-chloro-7-cyclopropyl-1-methyl-1H-indazol-4-yl)ethynyl)-5-(methylamino)-1H- pyrazole-4-carboxamide (7.6 mg, 13%) as an off-white solid. MS ESI calculated for C27H30ClN7O3 [M + H]+, 536.21, 538.21, found 536.25, 538.25; 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 3.5 Hz, 1H), 7.53 (s, 1H), 7.17 (s, 1H), 6.94 (s, 1H), 6.78-6.47 (m, 2H), 6.18 (d, J = 16.1 Hz, 1H), 5.79-5.66 (m, 1H), 5.26 (d, J = 17.9 Hz, 1H), 4.42 (s, 4H), 4.07-3.69 (m, 2H), 3.64-3.49 (m, 1H), 3.46 (t, J = 5.4 Hz, 1H), 2.99-2.91 (m, 3H), 2.63-2.59 (m, 2H), 2.58-2.48 (m, 3H), 2.32 (s, 1H), 1.08 (d, J = 8.2 Hz, 2H), 0.94 (t, J = 5.3 Hz, 2H). Example 42
Figure imgf000128_0001
Step 1: 5-Methylcyclopent-1-en-1-yl trifluoromethanesulfonate [00269] To a stirred solution of cyclopentanone, 2-methyl- (10.00 g, 101.89 mmol) and comins' reagent (44.01 g, 112.08 mmol) in THF (680 mL) was added KHMDS (111.94 mL, 492.13 mmol) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at -78 °C and stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (2 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/PE (1/10) to afford 5-methylcyclopent-1-en-1-yl trifluoromethanesulfonate (4.53 g, 19%) as a light yellow oil.1H NMR (400 MHz, Chloroform-d) δ 5.63-5.61 (m, 1H), 2.93-2.89 (m, 1H), 2.48-2.21 (m, 3H), 1.60-1.54 (m, 1H), 1.16 (d, J = 6.9 Hz, 3H). Step 2: 4,4,5,5-Tetramethyl-2-(5-methylcyclopent-1-en-1-yl)-1,3,2-dioxaborolane [00270] To a stirred mixture of 5-methylcyclopent-1-en-1-yl trifluoromethanesulfonate (4.53 g, 19.68 mmol), bis(pinacolato)diboron (5.00 g, 19.69 mmol) , phenoxysodium (3.43 g, 29.54 mmol) and PPh3 (0.46 g, 1.75 mmol) in Toluene (40 mL) was added Pd(PPh3)2Cl2 (0.41 g, 0.58 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 16 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1) to afford 4,4,5,5-tetramethyl-2-(5-methylcyclopent-1-en-1-yl)-1,3,2-dioxaborolane (2.61 g, 63%) as a light yellow oil.1H NMR (400 MHz, Chloroform-d) δ 6.48-6.42 (m, 1H), 2.93-2.80 (m, 1H), 2.50-2.24 (m, 2H), 2.12-1.92 (m, 1H), 1.45-1.32 (m, 1H), 1.27 (d, J = 4.2 Hz, 12H), 1.06 (d, J = 6.9 Hz, 3H). Step 3: 5-Bromo-4-chloro-2-(5-methylcyclopent-1-en-1-yl)aniline [00271] To a stirred mixture of 4,4,5,5-tetramethyl-2-(5-methylcyclopent-1-en-1-yl)-1,3,2- dioxaborolane (2.61 g, 12.53 mmol), 5-bromo-4-chloro-2-iodoaniline (3.78 g, 11.39 mmol) and K2CO3 (4.72 g, 34.18 mmol) in DMF (30 mL) and water (10 mL) was added Pd(PPh3)2Cl2 (0.80 g, 1.14 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 60 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/PE (1/4) to afford 5-bromo-4-chloro-2-(5-methylcyclopent-1-en-1-yl)aniline (2.69 g, 82%) as a light yellow oil. MS ESI calculated for C12H13BrClN [M + H]+, 285.99, 287.99, found 285.95, 287.95; 1H NMR (400 MHz, Chloroform-d) δ 7.08 (s, 1H), 7.04 (d, J = 2.7 Hz, 1H), 5.90-5.84 (m, 1H), 4.58 (s, 2H), 3.10 (s, 1H), 2.64-2.36 (m, 2H), 2.29-2.25 (m, 1H), 1.56-1.52 (m, 1H), 0.98 (d, J = 6.9 Hz, 3H). Step 4: 7-bromo-8-chloro-1-methyl-2,3-dihydro-1H-cyclopenta[c]cinnoline [00272] To a stirred mixture of 5-bromo-4-chloro-2-(5-methylcyclopent-1-en-1-yl)aniline (0.20 g, 0.70 mmol) in AcOH (2 mL) was added NaNO2 (0.35 mL, 0.70 mmol, 2 M) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 5 min at 0 °C under nitrogen atmosphere. The precipitated solids were collected by filtration and washed with water (3 x 10 mL) and EtOH (3 x 5 mL) to afford 7-bromo-8-chloro-1-methyl-2,3-dihydro-1H- cyclopenta[c]cinnoline (95.00 mg, 45%) as an off-white solid. MS ESI calculated for C12H10BrClN2 [M + H]+, 296.97, 298.97, found 296.95, 298.95; 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.43 (s, 1H), 3.90-3.85 (m, 1H), 3.49-3.42 (m, 1H), 3.36-3.30 (m, 1H), 2.43-2.38 (m, 1H), 1.94-1.89 (m, 1H), 1.34 (d, J = 7.1 Hz, 3H). Step 5: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((8-chloro-1-methyl-2,3- dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00273] To a stirred mixture of 7-bromo-8-chloro-1-methyl-2,3-dihydro-1H- cyclopenta[c]cinnoline (88.00 mg, 0.30 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (0.11 g, 0.33 mmol), Pd(PPh3)2Cl2 (20.76 mg, 0.03 mmol) and CuI (11.26 mg, 0.06 mmol) in DMF (1.00 mL) was added TEA (89.77 mg, 0.89 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((8-chloro-1-methyl-2,3- dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (82.00 mg, 50%) as a brown solid. MS ESI calculated for C28H30ClN7O3 [M + H]+, 548.21, 550.21, found 548.25, 550.25. Step 6: 1-( 5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-(((R)-8-chloro-1-methyl- 2,3-dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide [00274] The 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((8-chloro-1-methyl- 2,3-dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide (80.00 mg, 0.14 mmol) was purified by Prep-Chrial-HPLC with the following conditions: Column: CHIRALPAK IH, 2 x 25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3- MeOH)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 25% B to 25% B in 14 min; Wave Length: 220/254 nm; RT1: 9.30 min; Sample Solvent: MeOH: DCM=1: 1--HPLC; Injection Volume: 0.6 mL. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)- 3-(((R)-8-chloro-1-methyl-2,3-dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-5- (methylamino)-1H-pyrazole-4-carboxamide (17.60 mg, 23%) as a light yellow solid. MS ESI calculated for C28H30ClN7O3 [M + H]+, 548.21, 550.21, found 548.25, 550.25; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 4.7 Hz, 1H), 8.37 (d, J = 4.4 Hz, 1H), 7.49 (s, 1H), 6.93 (s, 1H), 6.68-6.51 (m, 2H), 6.18 (d, J = 16.6 Hz, 1H), 5.70 (d, J = 10.2 Hz, 1H), 5.28 (s, 1H), 4.48 (d, J = 55.8 Hz, 1H), 4.04 (s, 1H), 3.90 (s, 2H), 3.83-3.70 (m, 1H), 3.66-3.57 (m, 1H), 3.54-3.41 (m, 5H), 2.99-2.93 (m, 3H), 2.74-2.55 (m, 2H), 2.43-2.36 (m, 1H), 1.92 (s, 1H), 1.35 (dd, J = 7.0, 4.5 Hz, 3H).
Example 43
Figure imgf000131_0001
Step 1: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-(((S)-8-chloro-1-methyl- 2,3-dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide [00275] The 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((8-chloro-1-methyl- 2,3-dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide (80.00 mg, 0.14 mmol) was purified by Prep-Chrial-HPLC with the following conditions: Column: CHIRALPAK IH, 2 x 25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3- MeOH)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 25% B to 25% B in 14 min; Wave Length: 220/254 nm; RT2: 12.19 min; Sample Solvent: MeOH: DCM=1: 1--HPLC; Injection Volume: 0.6 mL. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin- 3-yl)-3-(((S)-8-chloro-1-methyl-2,3-dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-5- (methylamino)-1H-pyrazole-4-carboxamide (17.60 mg, 23%) as a light yellow solid. MS ESI calculated for C28H30ClN7O3 [M + H]+, 548.21, 550.21, found 548.25, 550.25; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 4.7 Hz, 1H), 8.37 (d, J = 4.4 Hz, 1H), 7.49 (s, 1H), 6.93 (s, 1H), 6.68-6.51 (m, 2H), 6.18 (d, J = 16.6 Hz, 1H), 5.70 (d, J = 10.2 Hz, 1H), 5.28 (s, 1H), 4.48 (d, J = 55.8 Hz, 1H), 4.04 (s, 1H), 3.90 (s, 2H), 3.83-3.70 (m, 1H), 3.66-3.57 (m, 1H), 3.54-3.41 (m, 5H), 2.99-2.93 (m, 3H), 2.74-2.55 (m, 2H), 2.43-2.36 (m, 1H), 1.92 (s, 1H), 1.35 (dd, J = 7.0, 4.5 Hz, 3H). Example 44
Figure imgf000132_0001
Step 1: Spiro[2.4]hept-4-en-4-yl trifluoromethanesulfonate [00276] To a stirred solution of spiro[2,4]heptan-4-one (5 g, 45.39 mmol) in THF (50 mL) was added 1 M KHMDS (54.47 mL, 54.47 mmol) dropwise at -78 °C under nitrogen atmosphere. After stirred for 30 min, 1,1,1-trifluoro-N-phenyl-N- trifluoromethanesulfonylmethanesulfonamide (17.67 g, 49.48 mmol) in THF (50 mL) was added dropwise at -78 °C. The reaction mixture was stirred for 2 h at -78 °C under nitrogen atmosphere. The resulting mixture was quenched with sat. NH4Cl (aq.) at -78 °C. The resulting mixture was extracted with EA (2 x 100 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE as eluent to afford spiro[2.4]hept-4-en-4-yl trifluoromethanesulfonate (5.3 g, 48%) as a light yellow oil; 1H NMR (400 MHz, CDCl3) δ 5.61 (t, J = 2.7 Hz, 1H), 2.55-2.50 (m, 2H), 2.07-2.03 (m, 2H), 0.90- 0.87 (m, 2H), 0.74-0.62 (m, 2H). Step 2: 4,4,5,5-Tetramethyl-2-{spiro[2.4]hept-4-en-4-yl}-1,3,2-dioxaborolane [00277] To a stirred mixture of spiro[2.4]hept-4-en-4-yl trifluoromethanesulfonate (5.3 g, 21.88 mmol,), bis(pinacolato)diboron (5.56 g, 21.88 mmol), sodium benzenolate (3.81 g, 32.82 mmol), PPh3 (0.52 g, 1.97 mmol) and Pd(PPh3)2Cl2 (0.46 g, 0.66 mmol) in toluene (55 mL) was stirred for 16 h at 50 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE as eluent to afford 4,4,5,5-tetramethyl-2-{spiro[2.4]hept-4-en-4-yl}-1,3,2-dioxaborolane (3.56 g, 73%) as a light yellow oil.1H NMR (300 MHz, CDCl3) δ 6.47 (t, J = 2.5 Hz, 1H), 2.55-2.49 (m, 2H), 1.87 (t, J = 7.7 Hz, 2H), 1.21 (s, 12H), 0.98-0.95 (m, 2H), 0.56-0.53 (m, 2H). Step 3: 5-Bromo-4-chloro-2-{spiro[2.4]hept-4-en-4-yl}aniline [00278] To a solution of 5-bromo-4-chloro-2-iodoaniline (1.1 g, 3.31 mmol) and 4,4,5,5- tetramethyl-2-{spiro[2.4]hept-4-en-4-yl}-1,3,2-dioxaborolane (0.80 g, 3.64 mmol) in DMF (11 mL) and water (3.3 mL) were added K2CO3 (1.37 g, 9.91 mmol) and Pd(PPh3)2Cl2 (0.23 g, 0.33 mmol) under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 60 °C under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL) and extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (4 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-4-chloro-2-{spiro[2.4]hept-4-en-4- yl}aniline (0.87 g, 88%) as a yellow oil. MS ESI calculated for C13H13BrClN [M + H]+, 297.99, 299.99, found 298.00, 300.00; 1H NMR (400 MHz, CDCl3) δ 6.96 (s, 1H), 6.92 (s, 1H), 5.74 (t, J = 2.4 Hz, 1H), 2.64 -2.59 (m, 2H), 2.11-2.08 (m, 2H), 0.64-0.53 (m, 2H), 0.53-0.46 (m, 2H). Step 4: 7-Bromo-8-chloro-2,3-dihydrospiro[cyclopenta[c]cinnoline-1,1'-cyclopropane] [00279] To a stirred solution of 5-bromo-4-chloro-2-{spiro[2.4]hept-4-en-4-yl}aniline (0.44 g, 1.47 mmol) in AcOH (4.4 mL) was added 2 M NaNO2 (0.81 mL, 1.62 mmol) dropwise at 0 °C. The reaction mixture was stirred for 5 min at 0 °C. The resulting mixture was diluted with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with water (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (4/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-8- chloro-2,3-dihydrospiro[cyclopenta[c]cinnoline-1,1'-cyclopropane] (0.37 g, 81%) as a yellow solid. MS ESI calculated for C13H10BrClN2 [M + H]+, 308.97, 310.97, found 309.00, 311.00; 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.58 (s, 1H), 3.60-3.52 (m, 2H), 2.35-2.27 (m, 2H), 1.78-1.71 (m, 2H), 1.29-1.23 (m, 2H). Step 5: 3-(2-{8-Chloro-2,3-dihydrospiro[cyclopenta[c]cinnoline-1,1'-cyclopropan]-7- yl}ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide [00280] To a stirred mixture of 7-bromo-8-chloro-2,3-dihydrospiro[cyclopenta[c]cinnoline-1,1'- cyclopropane] (100 mg, 0.32 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (107 mg, 0.32 mmol) in DMF (1 mL) and were added Pd(PPh3)2Cl2 (23 mg, 0.03 mmol) and CuI (12 mg, 0.06 mmol) was stirred for 2 h at 90 °C. The reaction mixture was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 3-(2-{8-chloro-2,3-dihydrospiro[cyclopenta[c]cinnoline- 1,1'-cyclopropan]-7-yl}ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3- yl]-5-(methylamino)pyrazole-4-carboxamide (54 mg, 30%) as a white solid. MS ESI calculated for C29H30ClN7O3 [M + H]+, 560.21, 562.21, found 560.25, 562.25; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 7.69 (s, 1H), 7.51 (s, 1H), 6.92 (s, 1H), 6.81-6.52 (m, 1H), 6.26-6.10 (m, 2H), 5.70 (dd, J = 10.3, 2.7 Hz, 1H), 5.28-5.23 (m, 1H), 4.48 (d, J = 56.5 Hz, 1H), 3.91-3.33 (m, 7H), 3.31 (s, 2H), 2.96 (t, J = 5.1 Hz, 3H), 2.62 (d, J = 11.3 Hz, 1H), 2.28 (t, J = 8.0 Hz, 3H), 1.83-1.78 (m, 2H), 1.32-1.02 (m, 2H). Example 45
Figure imgf000134_0001
Figure imgf000134_0002
Step 1: 3-(2-{2-Chloro-7H,8H,9H,10H-benzo[c]cinnolin-3-yl}ethynyl)-5-(methylamino)-1- [(3S)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00281] To a stirred mixture of 3-bromo-2-chloro-7H,8H,9H,10H-benzo[c]cinnoline (40.00 mg, 0.13 mmol), 3-ethynyl-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4- carboxamide (115.86 mg, 0.40 mmol), Pd(PPh3)2Cl2 (9.43 mg, 0.01 mmol) and CuI (5.12 mg, 0.02 mmol) in DMF (0.40 mL) was added TEA (40.81 mg, 0.40 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1). The residue was purified by reverse flash chromatography with the following conditions: Column: C18 silica gel; Mobile phase: ACN in water (Plus 10 mmol/L NH4HCO3), 25% to 45% gradient in 25 min; Detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford 3-(2-{2-chloro- 7H,8H,9H,10H-benzo[c]cinnolin-3-yl}ethynyl)-5-(methylamino)-1-[(3S)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (9.1 mg, 13%) as a white solid. MS ESI calculated for C26H26ClN7O2 [M + H]+, 504.18, 506.18, found 504.35, 506.35; 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.34 (s, 1H), 6.94 (s, 1H), 6.70 (s, 1H), 6.67-6.58 (m, 2H), 6.21- 6.15 (m, 1H), 5.73-5.67 (m, 1H), 5.20-5.14 (m, 1H), 3.90-3.84 (m, 2H), 3.75-3.66 (m, 2H), 3.29 (s, 2H), 3.18-3.15 (m, 1H), 2.97-2.94 (m, 2H), 2.51 (s, 3H), 2.45-2.32 (m, 1H), 1.92 (s, 4H). Example 46
Figure imgf000135_0001
Figure imgf000135_0002
Step 1: 3-[2-(6-Chloro-1-cyclopropyl-4-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00282] To a stirred solution of 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (100 mg, 0.30 mmol) and 6- chloro-1-cyclopropyl-4-fluoro-5-iodo-1,3-benzodiazole (101.56 mg, 0.30 mmol) in DMF (1 mL) were added Pd(PPh3)2Cl2 (21.18 mg, 0.03 mmol), CuI (11.49 mg, 0.06 mmol) and TEA (91.61 mg, 0.90 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (5/1) to afford the crude product. The residue was purified by reverse flash chromatography with the following conditions: column: C18 silica gel; mobile phase: ACN in water (Plus 10 mmol/L NH4HCO3), 35% to 40% gradient in 10 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford 3-[2-(6-chloro-1-cyclopropyl-4-fluoro-1,3- benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (42.7 mg, 26%) as an off-white solid. MS ESI calculated for C26H27ClFN7O3 [M + H]+, 540.18, 542.18, found 540.20, 542.20; 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 6.81-6.68 (m, 2H), 6.60-6.59 (m, 1H), 6.17- 6.16 (m, 1H), 5.69 (s,1H), 5.28 (s, 1H), 4.47 (s, 1H), 4.08-3.84 (m, 2H), 3.64-3.44 (m, 3H), 3.31-2.98 (m, 3H), 2.97-2.96 (m, 3H), 2.71-2.57 (m, 1H), 2.31 (s, 1H), 1.15-1.05 (m, 4H). Example 47
Figure imgf000136_0001
Step 1: (Z)-(4-Bromo-5-chloro-2-((2-nitrovinyl)amino)phenyl)(cyclopropyl)methanone [00283] To a stirred solution of NaOH (1.57 g, 39.30 mmol) in water (35.00 mL) was added nitromethane (1.57 g, 25.69 mmol) dropwise at room temperature. The reaction mixture was stirred for 1 h at 40 °C. The resulting mixture was used in the next step directly without further purification. To the above mixture was added the solution of 5-bromo-4-chloro-2- cyclopropanecarbonylaniline (3.52 g, 12.81 mmol) and HCl (148.40 mL) in water (875.00 mL) at room temperature. The resulting mixture was stirred for additional 16 h at room temperature. The precipitated solids were collected by filtration and washed with water (3 x 200 mL) to afford (Z)-(4-bromo-5-chloro-2-((2-nitrovinyl)amino)phenyl)(cyclopropyl)methanone (1.92 g, 22%) as a yellow solid. MS ESI calculated for C12H10BrClN2O3 [M + H]+, 344.96, 346.96, found 345.15, 347.15. Step 2: 7-Bromo-6-chloro-4-cyclopropyl-3-nitroquinoline [00284] To a stirred solution of (Z)-(4-bromo-5-chloro-2-((2- nitrovinyl)amino)phenyl)(cyclopropyl)methanone (1.40 g, 4.05 mmol) in Ac2O (15.00 mL) was added K2CO3 (1.68 g, 12.15 mmol) at room temperature. The reaction mixture was stirred for 1 h at 90 °C. The precipitated solids were collected by filtration and washed with acetic acid (3 x 50 mL) to afford 7-bromo-6-chloro-4-cyclopropyl-3-nitroquinoline (1.30 g, crude) as a grey solid. MS ESI calculated for C12H8BrClN2O2 [M + H]+, 326.94, 328.94, found 326.95, 328.95. Step 3: 7-Bromo-6-chloro-4-cyclopropylquinolin-3-amine [00285] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropyl-3-nitroquinoline (0.93 g, 2.83 mmol) and Fe (0.63 g, 11.31 mmol) in EtOH (10.00 mL) and H2O (2.00 mL) was added NH4Cl (0.76 g, 14.13 mmol) at room temperature. The reaction mixture was stirred for 1 h at 90 °C. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 80 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 7-bromo-6-chloro-4-cyclopropylquinolin-3-amine (0.80 g, 95%) as a brown solid. MS ESI calculated for C12H10BrClN2 [M + H]+, 296.97, 298.97, found 297.00, 299.00; 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 5.85 (s, 2H), 1.75-1.70 (m, 1H), 1.35-1.07 (m, 2H), 0.58-0.39 (m, 2H). Step 4: 7-Bromo-6-chloro-4-cyclopropyl-3-fluoroquinoline [00286] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropylquinolin-3-amine (0.40 g, 1.34 mmol) in HBF4 (4.00 mL, 50%) was added NaNO2 (1.34 mL, 2 M) at room temperature. The reaction mixture was stirred for 30 min at room temperature. The precipitated solids were collected by filtration and washed with colded EtOH and Et2O. The solid was dried under reduced pressure. Then the residue was added in Toluene (8 mL). The reaction mixture was stirred for 1 h at 110 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/DCM (4/1). The fractions contained desired product were combined and concentrated under pressure to afford 7- bromo-6-chloro-4-cyclopropyl-3-fluoroquinoline (0.20 g, 49%) as a white solid. MS ESI calculated for C12H8BrClFN [M + H]+, 299.95, 301.95, found 299.90, 301.90; 1H NMR (400 MHz, Chloroform-d) δ 8.66 (d, J = 2.5 Hz, 1H), 8.41 (d, J = 15.7 Hz, 2H), 2.04-1.98 (m, 1H), 1.31-1.18 (m, 2H), 1.03-0.92 (m, 2H). Step 5: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((6-chloro-4-cyclopropyl- 3-fluoroquinolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00287] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropyl-3-fluoroquinoline (0.11 g, 0.37 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.12 g, 0.37 mmol), Pd(PPh3)2Cl2 (25.69 mg, 0.04 mmol) and CuI (13.94 mg, 0.07 mmol) in DMF (1.00 mL) was added TEA (0.11 g, 1.10 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford the crude product. The crude product (0.12 g) was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile phase A: water (10 mmol/L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL/min; Gradient: 44% B to 54% B in 8 min, 54% B; Wave length: 254 nm; RT: 6.9 min. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin- 3-yl)-3-((6-chloro-4-cyclopropyl-3-fluoroquinolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole- 4-carboxamide (84.50 mg, 42%) as a white solid. MS ESI calculated for C28H28ClFN6O3 [M + H]+, 551.19, 553.19, found 551.25, 553.25; 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 2.5 Hz, 1H), 8.55 (s, 1H), 8.38 (s, 1H), 7.51 (s, 1H), 6.89 (s, 1H), 6.76-6.42 (m, 1H), 6.17 (dd, J = 16.7, 2.3 Hz, 1H), 5.69 (dd, J = 10.2, 2.6 Hz, 1H), 5.30-5.26 (m, 1H), 4.48 (d, J = 55.3 Hz, 1H), 4.13-3.69 (m, 2H), 3.66-3.39 (m, 2H), 3.32 (s, 3H), 2.96 (t, J = 5.1 Hz, 3H), 2.64-2.61 (m, 1H), 2.31 (t, J = 10.3 Hz, 1H), 2.26-2.22 (m, 1H), 1.32-1.18 (m, 2H), 0.95 (t, J = 5.6 Hz, 2H). Example 48
Figure imgf000138_0001
Figure imgf000138_0002
Step 1: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((5-chloro-1,7- dicyclopropyl-1H-indazol-4-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00288] To a stirred mixture of 4-bromo-5-chloro-1,7-dicyclopropylindazole (15 mg, 0.05 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (31.90 mg, 0.10 mmol), Pd(PPh3)2Cl2 (6.76 mg, 0.01 mmol) and CuI (3.67 mg, 0.02 mmol) in DMF (3 mL) was added TEA (14.61 mg, 0.15 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10/1) to afford the crude product. The crude product (10 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 43% B to 53% B in 8 min, 53% B; Wave Length: 254 nm; RT1: 7 min. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1- acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((5-chloro-1,7-dicyclopropyl-1H-indazol-4- yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (0.7 mg, 2%) as an off-white solid. MS ESI calculated for C29H32ClN7O3 [M + H]+, 562.23, 564.23, found 562.25, 564.25; 1H NMR (400 MHz, CDCl3) δ 8.09-8.02 (m, 1H), 7.30-7.26 (m, 1H), 7.15 (s, 1H), 7.04 (t, J = 3.9 Hz, 1H), 6.85-6.42 (m, 2H), 5.78-5.69 (m, 1H), 5.52 (d, J = 12.1 Hz, 1H), 5.35 (s, 1H), 4.59 (s, 1H), 4.17-3.96 (m, 3H), 3.92 (d, J = 8.6 Hz, 1H), 3.48 (s, 1H), 3.38 (dd, J = 8.2, 5.2 Hz, 3H), 3.08- 3.01 (m, 3H), 2.81-2.72 (m, 2H), 2.34 (s, 1H), 1.47 (m, 2H), 1.28 (s, 1H), 1.18 (d, J = 15.2 Hz, 3H), 0.99-0.95 (m, 2H). Example 49
Figure imgf000139_0001
Step 1: 5-Bromo-2,3-dichloropyridin-1-ium-1-olate [00289] To a stirred solution of 5-bromo-2,3-dichloropyridine (20.00 g, 88.15 mmol) in DCM (200.00 mL) was added m-CPBA (60.85 g, 352.60 mmol) in portions over 2 h at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of Na2SO3 and H2O (200.00 mL) at 0 °C. The resulting mixture was exacted with EA (3 x 200 mL) and washed with water (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-2,3- dichloropyridin-1-ium-1-olate (8.00 g, 37%) as an off-white solid. MS ESI calculated C5H2BrCl2NO [M + H] +, 241.87, 243.87, found 241.80, 243.80; 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H). Step 2: 3-Bromo-5,6-dichloropyridine-2-carbonitrile [00290] To a stirred solution of 5-bromo-2,3-dichloropyridin-1-ium-1-olate (8.00 g, 32.93 mmol) and TMSCN (13.07 g, 131.75 mmol) in ACN (80.00 mL) was added TEA (10.00 g, 98.81 mmol) at room temperature. The reaction mixture was stirred for 16 h at 100 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 3-bromo-5,6-dichloropyridine-2-carbonitrile (2.80 g, 33%) as a light yellow solid.1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H). Step 3: 1-(3-Bromo-5,6-dichloropyridin-2-yl)methanamine [00291] To a stirred solution of 3-bromo-5,6-dichloropyridine-2-carbonitrile (2.80 g, 11.12 mmol) in THF (90.00 mL) was added BH3-THF (55.58 mL, 55.58 mmol) dropwise over 15 min at 0 °C. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was quenched with MeOH (50.00 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure to afford 1-(3-bromo-5,6-dichloropyridin-2- yl)methanamine (4.20 g, crude) as a light yellow solid. MS ESI calculated for C6H5BrCl2N2 [M+ H] +, 254.90, 256.90, found 254.85, 256.85. Step 4: N-[(3-Bromo-5,6-dichloropyridin-2-yl)methyl]formamide [00292] To a solution of 1-(3-bromo-5,6-dichloropyridin-2-yl)methanamine (4.20 g, 16.41 mmol) and EDCI (7.87 g, 41.03 mmol) in DMF (42.00 mL) was added HCOOH (1.51 g, 32.82 mmol) and DIEA (10.61 g, 82.05 mmol). The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford N-[(3-bromo-5,6-dichloropyridin-2- yl)methyl]formamide (0.28 g, 6%) as a light yellow solid. MS ESI calculated for C7H5BrCl2N2O [M + H] +, 282.90, 284.90; found 282.90, 284.90; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.01 (s, 1H), 4.67 (d, J = 4.8 Hz, 2H). Step 5: 8-Bromo-5,6-dichloroimidazo[1,5-a]pyridine [00293] To a stirred solution of N-[(3-bromo-5,6-dichloropyridin-2-yl)methyl]formamide (0.28 g, 0.99 mmol) in Toluene (5.00 mL) was added POCl3 (0.61 g, 3.96 mmol). The reaction mixture was stirred for 1 h at 110 °C. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH 7-8 with ammonium hydroxide (4.00 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA 3/1). The fractions contained desired product were combined and concentrated to afford 8-bromo-5,6- dichloroimidazo[1,5-a]pyridine (80.00 mg, 30%) as an off-white solid. MS ESI calculated for C7H3BrCl2N2 [M + H]+, 264.89, 266.89, found 264.85, 266.85; 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.70 (s, 1H), 7.11 (s, 1H). Step 6: 5,6-Dichloro-8-cyclopropylimidazo[1,5-a]pyridine [00294] To a solution of 8-bromo-5,6-dichloroimidazo[1,5-a]pyridine (80.00 mg, 0.30 mmol) and cyclopropylboronic acid (51.68 mg, 0.60 mmol) in dioxane (2.00 mL) were added Pd(dppf)Cl2•CH2Cl2 (24.51 mg, 0.03 mmol) and K3PO4 (191.57 mg, 0.90 mmol) . The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was filtered; the filter cake was washed with EtOAc (3 x 4 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA 1/1). The fractions contained desired product were combined and concentrated to afford 5,6-dichloro-8- cyclopropylimidazo[1,5-a]pyridine (35.00 mg, 51%) as an off-white solid.. MS ESI calculated for C10H8Cl2N2 [M + H] + 227.01, 229.01; found 226.95, 228.95. Step 7: 3-(2-{6-Chloro-8-cyclopropylimidazo[1,5-a]pyridin-5-yl}ethynyl)-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00295] To a stirred solution of 5,6-dichloro-8-cyclopropylimidazo[1,5-a]pyridine (35.00 mg, 0.15 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (102.15 mg, 0.31 mmol), 2nd Generation XPhos Precatalyst (12.13 mg, 0.02 mmol) and CuI (5.87 mg, 0.03 mmol) in DMF (1.50 mL) was added TEA (46.79 mg, 0.46 mmol) dropwise at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude solid. The crude product was purified by reverse phase flash with the following conditions: Column: YMC-Actus Triart C18 ExRS, 30 x 150 mm, 5μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 40% B in 8 min; Wave Length: 254 nm. The fractions contained desired product were combined and concentrated to afford 3-(2-{6-chloro-8- cyclopropylimidazo[1,5-a]pyridin-5-yl}ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (3.10 mg, 3%) as a yellow solid. MS ESI calculated for C26H28ClN7O3 [M + H] +, 522.19, 524.19, found 522.25, 524.25; 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.74 (s, 1H), 7.35 (s, 1H), 6.85-6.84 (m, 1H), 6.47-6.38 (m, 3H), 5.74 (d, J = 9.0 Hz, 1H), 5.52 (s, 1H), 4.59 (s, 1H), 4.22-4.06 (m, 1H), 4.03-3.94 (m, 1H), 3.53-3.46 (m, 2H), 3.39 (s, 3H), 3.09-3.01 (m, 3H), 2.72 (s, 1H), 2.34 (d, J = 10.3 Hz, 1H), 2.15 (s, 1H), 1.33-1.10 (m, 2H), 1.01-0.76 (m, 2H). Example 50
Figure imgf000142_0001
Step 1: Bicyclo[2.2.1]hept-2-en-2-yl trifluoromethanesulfonate [00296] To a stirred mixture of norcamphor (5.00 g, 45.39 mmol) and 1,1,1-trifluoro-N-phenyl- N-trifluoromethanesulfonylmethanesulfonamide (17.85 g, 49.97 mmol) in THF (50 mL) was added KHMDS (55 mL, 241.79 mmol) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at -78 °C under nitrogen atmosphere. The resulting mixture was quenched with sat. NH4Cl (aq.) at -78 °C. The resulting mixture was extracted with PE (3 x 500 mL). The combined organic layers were washed with water (3 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE. The fractions contained desired product were combined and concentrated to afford bicyclo[2.2.1]hept-2-en-2- yl trifluoromethanesulfonate (7 g, 63%) as a yellow oil. MS ESI calculated for C8H9F3O3S [M + H]+, 243.02,.1H NMR (400 MHz, CDCl3) δ 6.82 (d, J = 3.0 Hz, 1H), 3.11-3.05 (m, 1H), 2.92- 2.85 (m, 1H), 1.77-1.58 (m, 2H), 1.29 (d, J = 5.0 Hz, 2H), 1.27-1.20 (m, 2H). Step 2: 2-{Bicyclo[2.2.1]hept-2-en-2-yl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [00297] To a stirred mixture of bicyclo[2.2.1]hept-2-en-2-yl trifluoromethanesulfonate (3.00 g, 12.38 mmol) and bis(pinacolato)diboron (3.15 g, 12.38 mmol) in Toluene (10 mL) were added phenoxysodium (2.16 g, 18.58 mmol), PPh3 (0.29 g, 1.11 mmol), Pd(PPh3)2Cl2 (0.26 g, 0.37 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 50 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with PE (3 x 300 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE. The fractions contained desired product were combined and concentrated to afford 2-{bicyclo[2.2.1]hept-2- en-2-yl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a yellow oil.1H NMR (400 MHz, CDCl3) δ 6.82 (d, J = 3.0 Hz, 1H), 3.11-3.05 (m, 1H), 2.92-2.85 (m, 1H), 1.77-1.58 (m, 2H), 1.29 (d, J = 5.0 Hz, 13H), 1.27-1.20 (m, 2H), 1.16-1.10 (m, 1H). Step 3: 2-{Bicyclo[2.2.1]hept-2-en-2-yl}-5-bromo-4-chloroaniline [00298] To a stirred mixture of 2-{bicyclo[2.2.1]hept-2-en-2-yl}-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (0.32 g, 1.49 mmol) and 5-bromo-4-chloro-2-iodoaniline (0.45 g, 1.35 mmol) in DMF (5 mL) and H2O (1.6 mL) were added K2CO3 (0.56 g, 4.06 mmol) and Pd(PPh3)2Cl2 (95 mg, 0.13 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 60 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 2-{bicyclo[2.2.1]hept-2-en-2-yl}-5-bromo-4-chloroaniline (0.40 g, 98%) as a yellow oil. MS ESI calculated for C13H13BrClN [M + H]+, 297.99, 299.99, found 297.95, 299.95. Step 4: 8-Bromo-9-chloro-1,2,3,4-tetrahydro-1,4-methanobenzo[c]cinnoline [00299] To a stirred mixture of 2-{bicyclo[2.2.1]hept-2-en-2-yl}-5-bromo-4-chloroaniline (0.30 g, 1.00 mmol) in AcOH (3 mL) was added NaNO2 (0.54 mL, 15.65 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 30 min at 0 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 8-bromo-9-chloro-1,2,3,4-tetrahydro-1,4-methanobenzo[c]cinnoline (100 mg, 32%) as a yellow oil. MS ESI calculated for C13H10BrClN2 [M + H]+, 308.97, 310.97, found 308.95, 310.95. Step 5: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((9-chloro-1,2,3,4- tetrahydro-1,4-methanobenzo[c]cinnolin-8-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide [00300] To a stirred mixture of 8-bromo-9-chloro-1,2,3,4-tetrahydro-1,4- methanobenzo[c]cinnoline (80 mg, 0.25 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (171 mg, 0.51 mmol) in DMF (0.8 mL) were added Pd(PPh3)2Cl2 (18 mg, 0.03 mmol), CuI (9 mg, 0.05 mmol) and TEA (78 mg, 0.77 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18 ExRS, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 43% B in 8 min, 43% B; Wave Length: 254 nm; RT1: 7 min. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5- (methoxymethyl)pyrrolidin-3-yl)-3-((9-chloro-1,2,3,4-tetrahydro-1,4-methanobenzo[c]cinnolin- 8-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (77.7 mg, 53%) as a white solid. MS ESI calculated for C29H30ClN7O3 [M + H]+, 560.21, 562.21, found 560.25, 562.25; 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.49 (s, 1H), 7.50 (s, 1H), 6.92 (s, 1H), 6.79-6.55 (m, 2H), 6.18 (dd, J = 16.7, 2.3 Hz, 1H), 5.70 (d, J = 10.3, 2.7 Hz, 1H), 5.28 (d, J = 15.7, 7.3 Hz, 1H), 4.55 (d, J = 6.4 Hz, 1H), 4.21 (s, 1H), 3.95-3.84 (m, 3H), 3.89 (s, 2H), 3.75-3.62 (m, 3H), 3.53- 3.43 (m, 3H), 2.67-2.53 (m, 1H), 2.33 (s, 1H), 2.19-2.12 (m, 2H), 1.92 (d, J = 9.3 Hz, 1H), 1.81- 1.73 (m, 1H), 1.13 (d, J = 10.9 Hz, 2H). Example 51
Figure imgf000144_0001
Step 1: 5,5-Dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate [00301] To a stirred solution of 2,2-dimethylcyclopentan-1-one (5.00 g, 44.57 mmol) in THF (100.00 mL) was treated with 1,1,1-trifluoro-N-phenyl-N- trifluoromethanesulfonylmethanesulfonamide (19.11 g, 53.49 mmol) for 30 min at -78 °C followed by the addition of KHMDS (49.00 mL, 1 M) dropwise at -78 °C. The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at -78 °C. The resulting mixture was quenched by the addition of sat. NH4Cl (aq.) (30 mL) at -40 °C. The resulting mixture was extracted with EtOAc (3 x 120 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1). The fractions contained desired product were combined and concentrated to afford 5,5-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate (5.50 g, 50%) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 5.53 (t, J = 2.6 Hz, 1H), 2.37-2.33 (m, 2H), 1.91-1.78 (m, 2H), 1.14 (s, 6H). Step 2: 2-(5,5-Dimethylcyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [00302] To a stirred mixture of 5,5-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate (3.00 g, 12.28 mmol), phenoxysodium (2.14 g, 18.43 mmol) and bis(pinacolato)diboron (3.12 g, 12.28 mmol) in Toluene (30.00 mL) was added Pd(PPh3)2Cl2 (0.26 g, 0.37 mmol) and PPh3 (0.29 g, 1.11 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 16 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1). The fractions contained desired product were combined and concentrated to afford 2- (5,5-dimethylcyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.80 g, 66%) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 6.37 (t, J = 2.4 Hz, 1H), 2.36-2.32 (m, 2H), 1.64 (t, J = 7.3 Hz, 2H), 1.25 (s, 12H), 1.12 (s, 6H). Step 3: 5-Bromo-4-chloro-2-(5,5-dimethylcyclopent-1-en-1-yl)aniline [00303] To a stirred mixture of 2-(5,5-dimethylcyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (0.37 g, 1.67 mmol), 5-bromo-4-chloro-2-iodoaniline (0.50 g, 1.51 mmol) and K2CO3 (0.70 g, 5.03 mmol) in DMF (6.00 mL) and water (2.00 mL) was added Pd(PPh3)2Cl2 (0.12 g, 0.17 mmol) at room temperature. The reaction mixture was stirred for 3 h at 60 °C. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-4- chloro-2-(5,5-dimethylcyclopent-1-en-1-yl)aniline (0.40 g, 79%) as a brown oil. MS ESI calculated for C13H15BrClN [M + H]+, 300.01, 302.01, found 299.80, 301.80; 1H NMR (400 MHz, Chloroform-d) δ 6.99 (d, J = 4.1 Hz, 2H), 5.67 (t, J = 2.4 Hz, 1H), 2.47-2.48 (m, 2H), 1.88 (t, J = 7.1 Hz, 2H), 1.09 (s, 6H). Step 4: 7-Bromo-8-chloro-1,1-dimethyl-2,3-dihydro-1H-cyclopenta[c]cinnoline [00304] To a stirred mixture of 5-bromo-4-chloro-2-(5,5-dimethylcyclopent-1-en-1-yl)aniline (0.40 g, 1.33 mmol) and NaNO2 (100.98 mg, 1.46 mmol) in AcOH (4.00 mL) was stirred for 5 min at room temperature. The resulting mixture was extracted with EtOAc (3 x 70 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-8-chloro-1,1-dimethyl-2,3-dihydro- 1H-cyclopenta[c]cinnoline (0.20 g, 46%) as a yellow solid. MS ESI calculated for C13H12BrClN2 [M + H]+, 310.99, 312.99, found 311.15, 313.15. Step 5: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((8-chloro-1,1-dimethyl- 2,3-dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide [00305] To a stirred mixture of 7-bromo-8-chloro-1,1-dimethyl-2,3-dihydro-1H- cyclopenta[c]cinnoline (80.00 mg, 0.26 mmol), 1-((3S,5R)-1-acryloyl-5- (methoxymethyl)pyrrolidin-3-yl)-3-ethynyl-5-(methylamino)-1H-pyrazole-4-carboxamide (85.41 mg, 0.26 mmol), Pd(PPh3)2Cl2 (18.25 mg, 0.03 mmol) and CuI (9.78 mg, 0.05 mmol) in DMF (1.00 mL) was added TEA (77.94 mg, 0.77 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product (0.15 g) was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile phase A: water (Plus 10 mmol/L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 50% B in 8 min, 50% B; Wave length: 254 nm; RT: 6.4 min. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)- 3-((8-chloro-1,1-dimethyl-2,3-dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-5- (methylamino)-1H-pyrazole-4-carboxamide (72.30 mg, 50%) as a light yellow solid. MS ESI calculated for C29H32ClN7O3 [M + H]+, 562.23, 564.23, found 562.40, 564.40; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.38 (s, 1H), 7.50 (s, 1H), 6.92 (s, 1H), 6.80-6.49 (m, 2H), 6.18 (d, J = 16.7 Hz, 1H), 5.77-5.58 (m, 1H), 5.30-5.26 (m, 1H), 4.48 (d, J = 55.6 Hz, 1H), 4.05 (t, J = 9.1 Hz, 1H), 3.92-3.87 (m, 1H), 3.81-3.68 (m, 1H), 3.61 (dd, J = 9.4, 5.2 Hz, 1H), 3.39 (s, 3H), 3.31 (d, J = 5.7 Hz, 2H), 2.96 (t, J = 5.1 Hz, 3H), 2.70-2.56 (m, 1H), 2.31 (d, J = 13.2 Hz, 1H), 2.09 (t, J = 7.5 Hz, 2H), 1.56 (s, 6H). Example 52
Figure imgf000147_0001
Step 1: Tert-butyl (3S)-3-(3,5-dibromo-4-cyanopyrazol-1-yl)pyrrolidine-1-carboxylate [00306] To a stirred solution of 3,5-dibromo-1H-pyrazole-4-carbonitrile (10.00 g, 39.86 mmol) and tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (7.46 g, 39.86 mmol) in THF (200.00 mL) was added PPh3 (13.59 g, 51.81 mmol) and DIAD (10.48 g, 51.82 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (3S)-3- (3,5-dibromo-4-cyanopyrazol-1-yl)pyrrolidine-1-carboxylate (10 g, 59 %) as a colorless solid. MS ESI calculated for C13H16Br2N5O3 [M + H]+, 364.99, 366.99, 368.99, found 364.80, 366.80, 368.80. Step 2: Tert-butyl (3S)-3-(3-bromo-4-cyano-5-{[(4-methoxyphenyl)methyl]amino}pyrazol-1- yl)pyrrolidine-1-carboxylate [00307] To a stirrred mixture of tert-butyl (3S)-3-(3,5-dibromo-4-cyanopyrazol-1-yl)pyrrolidine- 1-carboxylate (20.00 g, 47.61 mmol) in NMP (100.00 mL) was added benzenemethanamine, 4- methoxy- (32.65 g, 238.03 mmol). The reaction mixture was stirred for 16 h at 50 °C under nitrogen atmosphere. The resulting mixture was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column: C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 10% to 60% gradient in 20 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford tert-butyl (3S)-3-(3-bromo- 4-cyano-5-{[(4-methoxyphenyl)methyl]amino}pyrazol-1-yl)pyrrolidine-1-carboxylate (10 g, 44%) as a yellow oil. MS ESI calculated for C21H26BrN5O3 [M + H]+, 476.12, 478.12, found 476.10, 478.10. Step 3: Tert-butyl (3S)-3-(4-cyano-5-{[(4-methoxyphenyl)methyl]amino}-3-[2- (trimethylsilyl)ethynyl]pyrazol-1-yl)pyrrolidine-1-carboxylate [00308] To a stirred mixture of tert-butyl (3S)-3-(3-bromo-4-cyano-5-{[(4- methoxyphenyl)methyl]amino}pyrazol-1-yl)pyrrolidine-1-carboxylate (11.00 g, 23.09 mmol), trimethylsilylacetylene (11.34 g, 115.45 mmol) , Pd(PPh3)2Cl2 (1.62 g, 2.31 mmol) and CuI (0.88 g, 4.62 mmol) in DMF (50.00 mL) was added TEA (11.68 g, 115.45 mmol). The reaction mixturre was degassed with nitrogen for three times and stirred for 2 h at 90 °C. The resulting mixture was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 10% to 90% gradient in 30 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford tert-butyl (3S)-3-(4-cyano-5-{[(4- methoxyphenyl)methyl]amino}-3-[2-(trimethylsilyl)ethynyl]pyrazol-1-yl)pyrrolidine-1- carboxylate (10 g, 87%) as a brown oil. MS ESI calculated for C26H35N5O5Si [M + H]+, 494.25, found 494.50. Step 4: Tert-butyl (3S)-3-(4-cyano-3-ethynyl-5-{[(4-methoxyphenyl)methyl]amino}pyrazol-1- yl)pyrrolidine-1-carboxylate [00309] To a stirred mixture of tert-butyl (3S)-3-(4-cyano-5-{[(4- methoxyphenyl)methyl]amino}-3-[2-(trimethylsilyl)ethynyl]pyrazol-1-yl)pyrrolidine-1- carboxylate (0.50 g, 1.01 mmol) in THF (5.00 mL) was added TBAF (1.52 mL, 1.52 mmol, 1 M). The reaction mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford tert- butyl (3S)-3-(4-cyano-3-ethynyl-5-{[(4-methoxyphenyl)methyl]amino}pyrazol-1-yl)pyrrolidine- 1-carboxylate (400 mg, 93%) as a white solid. MS ESI calculated for C23H27N5O3 [M + H]+, 422.21, found 422.40. Step 5: Tert-butyl (3S)-3-{3-[2-(6-chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-4-cyano-5-{[(4- methoxyphenyl)methyl]amino}pyrazol-1-yl}pyrrolidine-1-carboxylate [00310] To a stirred mixture of tert-butyl (3S)-3-(4-cyano-3-ethynyl-5-{[(4- methoxyphenyl)methyl]amino}pyrazol-1-yl)pyrrolidine-1-carboxylate (0.20 g, 0.47 mmol), 7- bromo-6-chloro-4-cyclopropylcinnoline (134.54 mg, 0.47 mmol) , Pd(PPh3)2Cl2 (33.30 mg, 0.05 mmol) and CuI (18.07 mg, 0.10 mmol) in DMF (2.00 mL) was added TEA (144.04 mg, 1.42 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 90 °C. The resulting mixture was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (3S)-3-{3-[2-(6-chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-4-cyano-5-{[(4- methoxyphenyl)methyl]amino}pyrazol-1-yl}pyrrolidine-1-carboxylate (220 mg, 75 %) as a yellow oil. MS ESI calculated for C34H34ClN7O3 [M + H]+, 624.24, 626.24, found 624.35, 626.35. Step 6: (S)-5-Amino-3-((6-chloro-4-cyclopropylcinnolin-7-yl)ethynyl)-1-(pyrrolidin-3-yl)-1H- pyrazole-4-carboxamide [00311] A stirred solution of tert-butyl (3S)-3-{3-[2-(6-chloro-4-cyclopropylcinnolin-7- yl)ethynyl]-4-cyano-5-{[(4-methoxyphenyl)methyl]amino}pyrazol-1-yl}pyrrolidine-1- carboxylate (0.15 g, 240 mmol) in TFA (0.2 mL) was stirred 2 h at 70 °C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue product was purified by recerse phase chromatography, eluted with 50% ACN in water (Plus 10 mmol/ L NH4HCO3). The fractions contained desired product were combined and concentrated to afford 5-amino-3-[2-(6-chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-1-[(3S)-pyrrolidin-3-yl]pyrazole-4- carboxamide (0.05 g, 49%) as a yellow oil. MS ESI calculated for C21H20ClN7O [M + H]+, 422.15, 424.15, found 422.15, 424.15. Step 7: 5-Amino-3-[2-(6-chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-1-[(3S)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00312] To a stirred solution of 5-amino-3-[2-(6-chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-1- [(3S)-pyrrolidin-3-yl]pyrazole-4-carboxamide (0.04 g, 0.09 mmol) in DCM (0.5 mL) were added acryloyl chloride (0.34 mL, 0.08 mmol) and DIEA (34.83 mg, 0.27 mmol) dropwise at 0 °C. The reaction mixture was stirred for 10 min at 0 °C. The resulting mixture was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (30 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 19 x 250 mm, 10 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 25% B to 40% B in 8 min, 40% B; Wave Length: 254 nm; RT1: 6.8 min. The fractions contained desired product were combined and concentrated to afford 5-amino-3-[2-(6-chloro-4-cyclopropylcinnolin-7-yl)ethynyl]-1-[(3S)-1- (prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (3.4 mg, 7%) as a white solid. MS ESI calculated for C24H22ClN7O2 [M + H]+, 476.15, 478.15, found 476.15, 478.15; 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.84 (s, 1H), 8.72 (s, 1H), 7.42 (s, 1H), 6.73-6.52 (m, 4H), 6.23-6.13 (m, 1H), 5.72-5.70 (m, 1H), 5.05-4.98 (m, 1H), 4.10-3.78 (m, 2H), 3.76-3.49 (m, 2H), 2.76-2.64 (m, 1H), 2.44-2.34 (m, 1H), 2.27 (d, J = 6.6 Hz, 1H), 1.31-1.22 (m, 2H), 1.15-1.07 (m, 2H). Example 53
Figure imgf000150_0001
Step 1: 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-5-amino-3-((8-chloro-2,3- dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-1H-pyrazole-4-carboxamide [00313] To a stirred mixture of 7-bromo-8-chloro-2,3-dihydro-1H-cyclopenta[c]cinnoline (35.00 mg, 0.12 mmol), 5-amino-3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin- 3-yl]pyrazole-4-carboxamide (47.01 mg, 0.15 mmol) , Pd(PPh3)2Cl2 (8.66 mg, 0.01 mmol) and CuI (4.70 mg, 0.02 mmol) in DMF (0.80 mL) was added TEA (37.47 mg, 0.36 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product (35 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 35% B in 8 min, 35% B; Wave Length: 254 nm; RT1: 7 min. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)- 5-amino-3-((8-chloro-2,3-dihydro-1H-cyclopenta[c]cinnolin-7-yl)ethynyl)-1H-pyrazole-4- carboxamide (12.70 mg, 19%) as an off-white solid. MS ESI calculated for C26H26ClN7O3 [M + H]+, 520.18, 522.18, found 520.20, 522.20; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.29 (s, 1H), 7.36 (s, 1H), 6.71 (dd, J = 16.0, 6.0 Hz, 3H), 6.64-6.45 (m, 1H), 6.21-6.12 (m, 1H), 5.69 (d, J = 10.3 Hz, 1H), 5.14-5.08 (m, 1H), 4.60-4.32 (m, 1H), 3.98 (t, J = 9.1 Hz, 1H), 3.84-3.65 (m, 2H), 3.51 (d, J = 5.5 Hz, 1H), 3.41 (dd, J = 9.9, 6.1 Hz, 3H), 3.34 (d, J = 7.9 Hz, 2H), 3.32 (s, 3H), 2.45 (s, 1H), 2.27-2.23 (m, 2H). Example 54
Figure imgf000151_0001
Step 1: 5-Ethylcyclopent-1-en-1-yl trifluoromethanesulfonate [00314] To a stirred solution of 2-ethylcyclopentan-1-one (5 g, 44.57 mmol) in THF (50 mL) was added KHMDS (9.78 g, 49.03 mmol) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C under nitrogen atmosphere. To the above mixture was added 1,1,1-trifluoro-N-(pyridin-2-yl)-N-trifluoromethanesulfonylmethanesulfonamide (19.16 g, 53.49 mmol) dropwise over 30 min at -78 °C. The reaction mixture was stirred for additional 16 h at -78 °C. The resulting mixture was quenched with sat. NH4Cl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (4 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE. The fractions contained desired product were combined and concentrated to afford 5-ethylcyclopent-1-en-1-yl trifluoromethanesulfonate (7.89 g, 72%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 5.65 (s, 1H), 2.86-2.74 (m, 1H), 2.45- 2.30 (m, 2H), 2.28-2.14 (m, 1H), 1.79-1.61 (m, 2H), 1.48-1.26 (m, 1H), 0.97-0.95 (m, 3H). Step 2: 2-(5-Ethylcyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [00315] To a stirred solution of 5-ethylcyclopent-1-en-1-yl trifluoromethanesulfonate (3 g, 12.28 mmol), sodium benzenolate (2.14 g, 18.43 mmol), PPh3 (0.29 g, 1.11 mmol) and bis(pinacolato)diboron (3.12 g, 12.28 mmol) in Toluene (30 mL) was added Pd(PPh3)2Cl2 (0.26 g, 0.37 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 50 °C. The resulting mixture was diluted with water at room temperature. The resulting mixture was extracted with EtOAc (4 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1). The ffractions contained desired product were combined and concentrated to afford 2-(5-ethylcyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane) (2.01 g, 73%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 6.52 (s, 1H), 2.76- 2.75 (m, 1H), 2.52-2.25 (m, 2H), 2.00 (s, 1H), 1.83-1.62 (m, 1H),1.51-1.50 (m, 1H), 1.31-1.14 (m, 13H), 0.89 (t, J = 7.6 Hz, 3H). Step 3: 5-Bromo-4-chloro-2-(5-ethylcyclopent-1-en-1-yl)aniline [00316] To a stirred mixture of 2-(5-ethylcyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (0.70 g, 3.15 mmol) and 5-bromo-4-chloro-2-iodoaniline (0.95 g, 2.84 mmol) in DMF (7.00 mL) and H2O (2.30 mL) were added K2CO3 (1.31 g, 9.45 mmol) and Pd(PPh3)2Cl2 (0.23 g, 0.32 mmol) in portions at room temperature under atmosphere. The reaction mixture was stirred for 3 h at 60 °C under nitrogen atmosphere. The reaction was diluted with water (40 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 5-bromo-4-chloro-2-(5-ethylcyclopent-1-en- 1-yl)aniline (820 mg, 86%) as a brown yellow oil. MS ESI calculated for C13H15BrClN [M + H]+, 300.01, 302.01, found 300.05, 302.05. Step 4: 7-bromo-8-chloro-1-ethyl-1H,2H,3H-cyclopenta[c]cinnoline [00317] To a stirred mixture of 5-bromo-4-chloro-2-(5-ethylcyclopent-1-en-1-yl)aniline (0.40 g, 1.33 mmol) in AcOH (4.00 mL) was added NaNO2 (0.80 mL, 1.60 mmol, 2 M) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 30 min at room temperature under atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) to afford 7-bromo- 8-chloro-1-ethyl-1H,2H,3H-cyclopenta[c]cinnoline (190 mg, 45%) as a brown solid. MS ESI calculated for C13H12BrClN2 [M + H]+, 310.99, 312.99, found 310.90, 312.90. Step 5: 3-(2-{8-Chloro-1-ethyl-1H,2H,3H-cyclopenta[c]cinnolin-7-yl}ethynyl)-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00318] To a stirred mixture of 7-bromo-8-chloro-1-ethyl-1H,2H,3H-cyclopenta[c]cinnoline (0.19 g, 0.61 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3- yl]-5-(methylamino)pyrazole-4-carboxamide (0.21 g, 0.61 mmol) in DMF (2.00 mL) were added Pd(PPh3)2Cl2 (0.05 g, 0.06 mmol), CuI (0.02 g, 0.12 mmol) and TEA (0.19 g, 1.83 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was diluted with water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector; UV 254 nm. The fractions contained desired product were combined and concentrated to afford 3-(2-{8-chloro-1-ethyl-1H,2H,3H-cyclopenta[c]cinnolin-7- yl}ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (30 mg, 8%) as a light yellow solid. MS ESI calculated for C29H32ClN7O3 [M + H]+, 562.23, 564.23, found 562.50, 564.50. Step 6: 3-{2-[(1R)-8-chloro-1-ethyl-1H,2H,3H-cyclopenta[c]cinnolin-7-yl]ethynyl}-1-[(3S,5R)- 5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00319] The 3-(2-{8-chloro-1-ethyl-1H,2H,3H-cyclopenta[c]cinnolin-7-yl}ethynyl)-1-[(3S,5R)- 5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide was purified by Prep-Chiral-SFC with the following conditions: Column: CHIRAL ART Amylose-SA, 2 x 25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 20 min; Wave Length: 220/254 nm; RT1: 15.12 min; Sample Solvent: MeOH: DCM=1: 1--HPLC; Injection Volume: 1 mL. The fractions contained desired product were combined and cocnentrated to afford 3-{2-[(1R)-8-chloro-1-ethyl-1H,2H,3H-cyclopenta[c]cinnolin-7- yl]ethynyl}-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (9.6 mg, 32%) as an off-white solid. MS ESI calculated for C29H32ClN7O3 [M + H]+, 562.23, 564.23, found 562.25, 563.25; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 1.9 Hz, 1H), 8.37 (s, 1H), 7.49 (s, 1H), 6.91 (s, 1H), 6.79-6.62 (m, 2H), 6.18 (d, J = 16.6 Hz, 1H), 5.74-5.67 (m, 1H), 5.34-5.27 (m, 1H), 4.55 (s, 1H), 4.41 (s, 1H), 4.05 (t, J = 9.1 Hz, 1H), 3.90-3.85 (m, 2H), 3.65-3.57 (m, 3H), 3.52-3.41 (m, 3H), 2.96 (d, J = 4.9 Hz, 3H), 2.62 (s, 1H), 2.34 (s, 2H), 2.08 (t, J = 11.1 Hz, 1H), 1.99 (s, 1H), 1.80 (s, 1H), 1.59- 1.52 (m, 3H). Example 55
Figure imgf000154_0001
Figure imgf000154_0002
Step 1: 3-{2-[(1S)-8-Chloro-1-ethyl-1H,2H,3H-cyclopenta[c]cinnolin-7-yl]ethynyl}-1-[(3S,5R)- 5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00320] The 3-(2-{8-chloro-1-ethyl-1H,2H,3H-cyclopenta[c]cinnolin-7-yl}ethynyl)-1-[(3S,5R)- 5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide was purified by Prep-Chiral-SFC with the following conditions: Column: CHIRAL ART Amylose-SA, 2 x 25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 20 min; Wave Length: 220/254 nm; RT2: 18.40 min; Sample Solvent: MeOH: DCM=1: 1--HPLC; Injection Volume: 1 mL. The fractions contained desired product were combined and concentrated desired product were combined and concentrated to afford 3-{2-[(1S)-8-chloro-1- ethyl-1H,2H,3H-cyclopenta[c]cinnolin-7-yl]ethynyl}-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (10.4 mg, 34%) as an off-white solid. MS ESI calculated for C29H32ClN7O3[M + H]+, 562.23, 564.23, found 562.25, 564.25; 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 1.9 Hz, 1H), 8.37 (s, 1H), 7.49 (s, 1H), 6.91 (s, 1H), 6.79-6.62 (m, 2H), 6.18 (d, J = 16.6 Hz, 1H), 5.74-5.67 (m, 1H), 5.34-5.27 (m, 1H), 4.55 (s, 1H), 4.41 (s, 1H), 4.05 (t, J = 9.1 Hz, 1H), 3.90-3.85 (m, 2H), 3.65-3.57 (m, 3H), 3.52-3.41 (m, 3H), 2.96 (d, J = 4.9 Hz, 3H), 2.62 (s, 1H), 2.34 (s, 2H), 2.08 (t, J = 11.1 Hz, 1H), 1.99 (s, 1H), 1.80 (s, 1H), 1.59-1.52 (m, 3H). Example 56
Figure imgf000155_0001
Step 1: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-5-amino-3-((8-chloro-2,3- dihydrospiro[cyclopenta[c]cinnoline-1,1'-cyclopropan]-7-yl)ethynyl)-1H-pyrazole-4- carboxamide [00321] To a stirred mixture of 7-bromo-8-chloro-2,3-dihydrospiro[cyclopenta[c]cinnoline-1,1'- cyclopropane] (40.00 mg, 0.13 mmol), 5-amino-3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (49.20 mg, 0.16 mmol), Pd(PPh3)2Cl2 (9.07 mg, 0.01 mmol) and CuI (4.92 mg, 0.03 mmol) in DMF (0.50 mL) was added TEA (39.22 mg, 0.39 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product (40 mg) was purified by Prep-HPLC with the following conditions: Column: X Bridge Shield RP18 OBD Column, 19 x 250 mm, 10 μm; Mobile phase A: water (10 mmol/L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL/min; Gradient: 41% B to 51% B in 8 min, 51% B; Wave length: 254 nm; RT: 6.8 min. The fractions contained desired product were combined and concentrated to afford 1- ((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-5-amino-3-((8-chloro-2,3- dihydrospiro[cyclopenta[c]cinnoline-1,1'-cyclopropan]-7-yl)ethynyl)-1H-pyrazole-4- carboxamide (29.40 mg, 42%) as a white solid. ESI calculated for C28H28ClN7O3 [M + H]+, 546.19, 548.19, found 546.25, 548.25; 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.38 (s, 1H), 6.70 (s, 3H), 6.64-6.50 (m, 1H), 6.27-6.04 (m, 1H), 5.69 (dd, J = 10.4, 2.5 Hz, 1H), 5.20-5.00 (m, 1H), 4.48 (d, J = 48.1 Hz, 1H), 3.99 (t, J = 9.1 Hz, 1H), 3.84-3.64 (m, 2H), 3.54-3.45 (m, 3H), 3.44-3.39 (m, 1H), 2.52 (s, 1H), 2.50 (s, 1H), 2.37- 2.15 (m, 4H), 1.83 (s, 2H), 1.26 (s, 2H). Example 57
Figure imgf000156_0001
Step 1: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-5-amino-3-(((R)-7-chloro-1- ethyl-2,3-dihydro- imidazol-6-yl)ethynyl)-1H-pyrazole-4-
Figure imgf000156_0002
carboxamide [00322] To a stirred mixture of 5-amino-3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (40.00 mg, 0.13 mmol), 1-((3S,5R)-1-acryloyl-5- (methoxymethyl)pyrrolidin-3-yl)-5-amino-3-ethynyl-1H-pyrazole-4-carboxamide (45.32 mg, 0.15 mmol), Pd(PPh3)2Cl2 (8.85 mg, 0.01 mmol,) and CuI (4.80 mg, 0.03 mmol) in DMF (0.50 mL) was added TEA (38.26 mg, 0.38 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product (0.02 mg) was purified by Prep-HPLC with the following conditions: Column: YMC- Actus Triart C18 ExRS, 30 x 150 mm, 5 μm; Mobile phase A: water (Plus 10 mmol/L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL/min; Gradient: 33% B to 38% B in 12 min, 38% B; Wave length: 254 nm; RT: 11.45 min. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin- 3-yl)-5-amino-3-(((R)-7-chloro-1-ethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6- yl)ethynyl)-1H-pyrazole-4-carboxamide (3.20 mg, 4%) as a white solid. ESI calculated for C27H30ClN7O3 [M + H]+, 536.21, 538.21, found 536.30, 538.30; 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 5.2 Hz, 2H), 7.36 (s, 1H), 6.88-6.44 (m, 4H), 6.17 (d, J = 16.6 Hz, 1H), 5.69 (d, J = 10.1 Hz, 1H), 5.14-5.09 (m, 1H), 4.66-4.32 (m, 2H), 4.04-3.61 (m, 2H), 3.51 (d, J = 3.6 Hz, 1H), 3.42 (d, J = 5.8 Hz, 1H), 3.32 (s, 3H), 3.13-2.89 (m, 2H), 2.83-2.69 (m, 1H), 2.47-2.17 (m, 3H), 2.09-2.05 (m, 1H), 1.80-1.76 (m, 1H), 0.86 (t, J = 7.3 Hz, 3H). Example 58
Figure imgf000157_0001
Step 1: 3-Chloro-N-cyclopropyl-2-fluoro-6-nitroaniline [00323] To a stirred solution of 1-chloro-2,3-difluoro-4-nitrobenzene (2.00 g, 10.33 mmol) in EtOH (20.00 mL) was added aminocyclopropane (1.77 g, 31.00 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. The precipitated solids were collected by filtration and washed with water (3 x 30 mL) and dried to afford 3-chloro-N-cyclopropyl-2-fluoro-6-nitroaniline (1.6 g, crude) as an orange solid. MS ESI calculated for C9H8ClFN2O2 [M + H]+, 231.03, 233.03, found 231.05,233.05; 1H NMR (400 MHz, Chloroform-d) δ 7.98 (s, 1H), 7.92 (dd, J = 9.4, 2.1 Hz, 1H), 6.71 (dd, J = 9.4, 6.4 Hz, 1H), 3.19-3.13 (m, 1H), 0.96-0.80 (m, 2H), 0.74-0.65 (m, 2H). Step 2: 3-Chloro-N-cyclopropyl-2-fluoro-4-iodo-6-nitroaniline [00324] To a stirred mixture of 3-chloro-N-cyclopropyl-2-fluoro-6-nitroaniline (1.60 g, 6.94 mmol) in CH3SO3H (16.00 mL) was added NIS (1.64 g, 7.29 mmol) in portions at 0 °C under nitrogen atmosphere.The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3-chloro-N-cyclopropyl-2-fluoro-4- iodo-6-nitroaniline (2.6 g, crude) as a brown yellow oil. MS ESI calculated for C9H7ClIN2O2 [M + H]+, 356.92, 358.92, found 356.95, 358.95. Step 3: 5-chloro-N1-cyclopropyl-6-fluoro-4-iodobenzene-1,2-diamine [00325] To a stirred mixture of 3-chloro-N-cyclopropyl-2-fluoro-4-iodo-6-nitroaniline (2.6 g, 7.29 mmol) in EtOH (26.00 mL) and H2O (5.20 mL) were added NH4Cl (1.95 g, 36.47 mmol) and Fe (2.04 g, 36.47 mmol, 5 equiv) in portions at room temperature under atmosphere.The resulting mixture was stirred for 16 h at room temperature under atmosphere. The precipitated solids were collected by filtration and washed with EtOAc (3 x 40 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 5-chloro-N1-cyclopropyl-6-fluoro-4-iodobenzene-1,2- diamine (302 mg, 12%) as a light yellow oil. MS ESI calculated for C9H9ClFIN2 [M + H]+, 326.95, 328.95, found 326.90, 328.90. Step 4: 6-Chloro-1-cyclopropyl-7-fluoro-5-iodo-1,3-benzodiazole [00326] To a stirred mixture of 5-chloro-N1-cyclopropyl-6-fluoro-4-iodobenzene-1,2-diamine (0.30 g, 0.92 mmol) in MeOH (3.00 mL) was added trimethyl orthoformate (0.15 g, 1.38 mmol) at room temperature under atmosphere. The reaction mixture was stirred for 16 h at 70 °C under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 6-chloro-1-cyclopropyl-7-fluoro-5-iodo-1,3- benzodiazole (200 mg, 64%) as a yellow solid. MS ESI calculated for C10H7ClFIN2 [M + H]+, 336.93, 338.93, found 337.10, 339.10; 1H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J = 1.2 Hz, 1H), 7.91 (s, 1H), 3.60-3.54 (m, 1H), 1.30-1.10 (m, 4H). Step 5: 5-Amino-3-[2-(6-chloro-1-cyclopropyl-7-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1- [(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00327] To a stirred mixture of 6-chloro-1-cyclopropyl-7-fluoro-5-iodo-1,3-benzodiazole (53.02 mg, 0.16 mmol) and 5-amino-3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (50 mg, 0.16 mmol) in DMF (0.50 mL) were added Pd(PPh3)2Cl2 (11.06 mg, 0.02 mmol) and CuI (6.00 mg, 0.03 mmol) and TEA (47.83 mg, 0.47 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 10% to 50% gradient in 10 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford 5-amino-3-[2-(6-chloro-1-cyclopropyl-7-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1- [(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (27 mg, 32%) as an off-white solid. MS ESI calculated for C25H25ClFN7O3 [M + H]+, 526.17, 528.17, found 526.30, 528.30; 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.91 (s, 1H), 7.34 (s, 1H), 6.78-6.63 (m, 4H), 6.16 (d, J = 17.5 Hz, 1H), 5.69 (d, J = 10.2 Hz, 1H), 5.12 (m, 1H), 4.57-4.50 (m, 1H), 3.81-3.68 (m, 2H), 3.51 (s, 1H), 3.42 (d, J = 5.8 Hz, 1H), 3.34 (d, J = 4.2 Hz, 3H), 2.45 (d, J = 12.6 Hz, 1H), 2.27 (s, 1H), 1.18 (d, J = 3.5 Hz, 2H), 1.11 (t, J = 6.6 Hz, 2H). Example 59
Figure imgf000159_0001
Figure imgf000159_0002
Step 1: 5-Amino-3-[2-(6-chloro-1-cyclopropyl-4-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1- [(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00328] To a stirred solution of 5-amino-3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (51.87 mg, 0.16 mmol) and 6-chloro-1- cyclopropyl-4-fluoro-5-iodo-1,3-benzodiazole (50 mg, 0.14 mmol) in DMF (0.5 mL) were added Pd(PPh3)2Cl2 (10.43 mg, 0.01 mmol), CuI (5.66 mg, 0.03 mmol) and TEA (45.10 mg, 0.44 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90°C. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (5/1) to afford the crude product. The crude product was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 40% to 50% gradient in 10 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford 5-amino-3-[2-(6- chloro-1-cyclopropyl-4-fluoro-1,3-benzodiazol-5-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1- (prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (9.3 mg, 11%) as an off-white solid. MS ESI calculated for C25H25ClFN7O3 [M + H]+, 526.17, 528.17, found 526.25, 528.25; 1H NMR (400 MHz, DMSO-d6) δ 8.45-8.44 (s, 1H), 7.80 (s, 1H), 7.44 (s, 1H), 6.76-6.52 (m, 4H), 6.16- 6.15 (m, 1H), 5.69-5.65 (m, 1H), 5.12-5.11 (m, 1H), 4.46-4.45 (m, 1H), 3.97-3.96 (m, 1H), 3.84 -3.67 (m, 1H), 3.61-3.54 (m, 1H), 3.50-3.49 (m, 1H), 3.42-3.41 (m, 1H), 3.32-3.30 (m, 3H), 2.32-2.30 (s, 1H), 2.27-2.26 (s, 1H), 1.13-1.10 (m, 4H). Example 60
Figure imgf000160_0001
Step 1: 7-Bromo-6-chlorocinnolin-4-ol [00329] To a stirred solution of 1-(2-amino-4-bromo-5-chlorophenyl)ethanone (2.60 g, 10.46 mmol) and con. HCl (3.81 g, 104.63 mmol) in H2O (30 mL) was added NaNO2 (1.08 g, 15.70 mmol, 2 M) dropwise at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-6-chlorocinnolin-4-ol (0.95 g, 35%) as a black solid. MS ESI calculated for C8H4BrClN2O [M + H]+, 258.92, 260.92, found 259.10, 261.10. Step 2: 4,7-Dibromo-6-chlorocinnoline [00330] To a stirred mixture of 7-bromo-6-chlorocinnolin-4-ol (0.45 g, 1.73 mmol) in ACN (5.00 mL) was added POBr3 (0.29 g, 1.04 mmol) in portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1). The fractions contained desired product were combined and concentrated to afford 4,7-dibromo-6-chlorocinnoline (0.17 g, 30%) as a brown solid. MS ESI calculated for C8H3Br2ClN2 [M + H]+, 320.84, 322.84, 324.84, found 320.85, 322.85, 324.85. Step 3: 7-Bromo-6-chloro-4-(2,2-difluorocyclopropyl)cinnoline [00331] To a stirred mixture of 4,7-dibromo-6-chlorocinnoline (0.15 g, 0.47 mmol), Pd(dppf)Cl2·CH2Cl2 (37.90 mg, 0.05 mmol) and K3PO4 (0.29 g, 1.40 mmol) in dioxane (2.00 mL) was added 2-(2,2-difluorocyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.14 g, 0.70 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-6-chloro-4-(2,2- difluorocyclopropyl)cinnoline (46.50 mg, 30%) as a yellow solid. MS ESI calculated for C11H6BrClF2N2 [M + H]+, 318.94, 320.94, found 318.90, 320.90; 1H NMR (400 MHz, DMSO- d6) δ 9.41-9.36 (m, 1H), 9.01 (d, J = 1.4 Hz, 1H), 8.57 (d, J = 1.2 Hz, 1H), 3.86-3.80 (m, 1H), 2.50-2.41 (m, 1H), 2.37-2.31 (m, 1H). Step 4: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((6-chloro-4-(2,2- difluorocyclopropyl)cinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00332] To a stirred mixture of 7-bromo-6-chloro-4-(2,2-difluorocyclopropyl)cinnoline (28.00 mg, 0.09 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (87.11 mg, 0.26 mmol), Pd(PPh3)2Cl2 (6.15 mg, 0.01 mmol) and CuI (3.34 mg, 0.02 mmol) in DMF (0.60 mL) was added TEA (26.60 mg, 0.26 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product was purified by trituration with MeCN (2 mL) to afford 1- ((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((6-chloro-4-(2,2- difluorocyclopropyl)cinnolin-7-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (21.70 mg, 43%) as a yellow solid. MS ESI calculated for C27H26ClF2N7O3 [M + H]+, 570.18, 572.18, found 570.25, 572.25; 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.90 (s, 1H), 8.50 (s, 1H), 7.48 (s, 1H), 6.95 (s, 1H), 6.80-6.52 (m, 2H), 6.17 (dd, J = 16.7, 2.2 Hz, 1H), 5.70 (dd, J = 10.2, 2.7 Hz, 1H), 5.27-5.24 (m, 1H), 4.48 (d, J = 53.1 Hz, 1H), 4.04 (dd, J = 10.7, 7.4 Hz, 1H), 3.98-3.84 (m, 2H), 3.75 (d, J = 12.1 Hz, 3H), 3.64-3.61 (m, 2H), 2.96 (t, J = 5.1 Hz, 3H), 2.70-2.62 (m, 1H), 2.46 (s, 1H), 2.40-2.26 (m, 2H). Example 61
Figure imgf000162_0001
Step 1: 5-Bromo-4-chloro-2-(prop-1-yn-1-yl)aniline [00333] To a stirred mixture of 5-bromo-4-chloro-2-iodoaniline (5 g, 15.04 mmol) and propyne (0.66 g, 16.54 mmol) in DMF (50 mL) and TEA (4.57 g, 45.13 mmol) were added CuI (0.57 g, 3.00 mmol) and Pd(PPh3)2Cl2 (1.06 g, 1.50 mmol). The reaction mixture was stirred for 1 h at 50 °C under nitrogen atmosphere. The resulting mixture was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (4 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) to afford 5-bromo-4-chloro-2-(prop- 1-yn-1-yl)aniline (2.85 g, 77%) as a light yellow solid. MS ESI calculated for C9H7BrClN [M + H]+, 243.95, 245.95, found 243.95, 245.95; 1H NMR (400 MHz, Chloroform-d) δ 6.64-6.49 (m, 2H), 1.41-1.38 (m, 3H). Step 2: 7-Bromo-6-chloro-3-methylcinnolin-4-ol [00334] To a stirred mixture of 5-bromo-4-chloro-2-(prop-1-yn-1-yl)aniline (2.85 g, 11.65 mmol) in H2O (10 mL) were added HCl (19.43 mL, 6 M) and NaNO2 (0.80 g, 11.65 mmol). The reaction mixture was stirred for 1 h at 90 °C under nitrogen atmosphere. The resulting mixture was neutralized to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-6- chloro-3-methylcinnolin-4-ol (400 mg, 13%) as a light yellow solid. MS ESI calculated for C9H6BrClN2O [M + H]+, 272.94, 274.94, found 272.80, 274.80. Step 3: 4,7-Dibromo-6-chloro-3-methylcinnoline [00335] To a stirred mixture of 7-bromo-6-chloro-3-methylcinnolin-4-ol (350 mg, 1.28 mmol) in ACN (4 mL) was added POBr3 (367 mg, 1.28 mmol). The reaction mixture was stirred for 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 4,7-dibromo-6- chloro-3-methylcinnoline (130 mg, 30%) as a light yellow solid. MS ESI calculated for C9H5Br2ClN2 [M + H]+, 334.85, 336.85, 338.85, found 334.70, 336.70, 338.75; 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 3.9 Hz, 1H), 8.31 (s, 1H), 2.99 (d, J = 15.0 Hz, 3H). Step 3: 7-Bromo-6-chloro-4-cyclopropyl-3-methylcinnoline [00336] To a stirred mixture of 4,7-dibromo-6-chloro-3-methylcinnoline (100 mg, 0.29 mmol) and cyclopropylboronic acid (28 mg, 0.32 mmol) in 1,4-dioxane (2 mL) were added Pd(dppf)Cl2 CH2Cl2 (24 mg, 0.03 mmol) and K3PO4 (189 mg, 0.89 mmol). The reaction mixture was stirred for 2 h at 90°C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-6-chloro-4-cyclopropyl-3-methylcinnoline (40 mg, 45%) as a light yellow solid. MS ESI calculated for C12H10BrClN2 [M + H]+ 296.97, 298.97, found 296.90, 298.90. Step 5: 3-[2-(6-Chloro-4-cyclopropyl-3-methylcinnolin-7-yl)ethynyl]-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00337] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropyl-3-methylcinnoline (35 mg, 0.11 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (39 mg, 0.12 mmol) in DMF (1 mL) were added CuI (4 mg, 0.02 mmol,), Pd(PPh3)2Cl2 (8 mg, 0.01 mmol) and TEA (35 mg, 0.35 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The reaction was diluted with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 8 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford 3-[2-(6-chloro-4-cyclopropyl-3-methylcinnolin-7- yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (10 mg, 16%) as a white solid. MS ESI calculated for C28H30ClN7O3 [M + H]+, 548.21, 550.21, found 548.25, 550.25; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.56 (s, 1H), 6.77-6.51 (m, 4H), 6.18 (d, J = 16.5 Hz, 1H), 5.70 (d, J = 10.4 Hz, 1H), 5.29 (dd, J = 15.5, 7.9 Hz, 1H), 4.40-3.52 (m, 5H), 3.31 (d, J = 5.7 Hz, 3H), 3.04-2.83 (m, 5H), 2.19 (d, J = 7.7 Hz, 1H), 1.40-1.10 (m, 5H), 0.73-0.68 (m, 2H). Example 62
Figure imgf000164_0001
Step 1: 4-Bromo-5-chloro-7-vinyl-1H-indazole [00338] To a stirred mixture of 4-bromo-5-chloro-7-iodo-1H-indazole (0.20 g, 0.56 mmol) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.17 g, 1.12 mmol) in dioxane (3 mL) and H2O (0.3 mL) were added K2CO3 (0.23 g, 1.68 mmol) and Pd(PPh3)4 (64.67 mg, 0.06 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 16 h at 90 °C. The resulting mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 4-bromo-5- chloro-7-ethenyl-1H-indazole (0.11 g, 76%) as a light orange solid. MS ESI calculated for C9H6BrClN2 [M - H]-, 256.94, 258.94, found 256.95, 258.95; 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.46 (d, J = 0.7 Hz, 1H), 6.91 (dd, J = 17.7, 11.3 Hz, 1H), 5.92 (d, J = 17.7 Hz, 1H), 5.65 (d, J = 11.2 Hz, 1H), 1.33-1.24 (m, 1H). Step 2: 4-Bromo-5-chloro-7-cyclopropyl-1H-indazole [00339] To a stirred solution of diethylzinc (0.73 g, 5.90 mmol) in CH2Cl2 (5 mL) was added TFA (0.67 g, 5.90 mmol) in DCM (5 mL) dropwise. After stirring for 20 min, a solution of diiodomethane (1.58 g, 5.90 mmol) in DCM (3 mL) was added. After stirred for 20 min, a solution of 4-bromo-5-chloro-7-ethenyl-1H-indazole (0.19 g, 0.74 mmol) in DCM (10 mL) was added, and the ice bath was removed. The reaction mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction mixture was quenched by the addition of sat. NH4Cl (aq.) (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA 10/1) to afford 4-bromo-5-chloro-7-cyclopropyl-1H-indazole (80 mg, 39%) as a light yellow solid. MS ESI calculated for C10H8BrClN2 [M + H]+, 270.96, 272.96, found 270.95, 272.95. Step 3: 3-[2-(5-Chloro-7-cyclopropyl-1-methylindazol-4-yl)ethynyl]-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00340] To a stirred mixture of 4-bromo-5-chloro-7-cyclopropyl-1-methylindazole (45 mg, 0.16 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (62.66 mg, 0.22 mmol), Pd(PPh3)2Cl2 (11.06 mg, 0.02 mmol) and CuI (6.00 mg, 0.03 mmol) in DMF (3 mL) was added TEA (47.84 mg, 0.47 mmol) dropwise at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2/MeOH 10/1) to afford the crude product. The crude product (20 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Phenyl OBD Column, 19 x 250 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 45% B to 55% B in 8 min, 55% B; Wave Length: 254 nm; RT1: 7.97 min. The fractions contained desired product were combined and concentrated to afford 3-[2-(5-chloro-7-cyclopropyl-1-methylindazol-4- yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (12.6 mg, 11%) as an off-white solid. MS ESI calculated for C26H28ClN7O3 [M + H]+, 522.19, 524.19, found 522.20, 524.20; 1H NMR (400 MHz, DMSO-d6) δ 13.81 (s, 1H), 8.12 (s, 1H), 7.54 (s, 1H), 7.01 (s, 2H), 6.80-6.48 (m, 2H), 6.18 (dd, J = 16.7, 2.5 Hz, 1H), 5.69 (d, J = 10.6 Hz, 1H), 5.26-5.21 (m, 1H), 4.03 (t, J = 9.0 Hz, 1H), 3.97-3.87 (m, 1H), 3.87-3.70 (m, 1H), 3.61 (dd, J = 9.3, 5.3 Hz, 1H), 3.53-3.43 (m, 2H), 2.96 (d, J = 5.6 Hz, 3H), 2.74-2.59 (m, 1H), 2.42-2.21 (m, 3H), 1.25 (s, 1H), 1.15 (d, J = 2.7 Hz, 2H), 0.95 (d, J = 5.4 Hz, 2H). Example 63
Figure imgf000166_0001
Step 1: 5-Amino-3-[2-(5-chloro-7-cyclopropyl-1-methylindazol-4-yl)ethynyl]-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00341] To a stirred solution of 4-bromo-5-chloro-7-cyclopropyl-1-methylindazole (30 mg, 0.11 mmol), 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-5-amino-3-ethynyl-1H- pyrazole-4-carboxamide (51.31 mg, 0.16 mmol), Pd(PPh3)2Cl2 (7.37 mg, 0.01 mmol) and CuI (4.00 mg, 0.02 mmol) in DMF (0.4 mL) was added TEA (31.89 mg, 0.32 mmol) dropwise at room temperature. The reaction mixture was stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water (10 mmol/L NH4HCO3), 10% to 50% gradient in 30 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford 5-amino-3-[2-(5-chloro-7-cyclopropyl-1-methylindazol-4-yl)ethynyl]-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide (1.7 mg, 3%) as an off-white solid. MS ESI calculated for C26H28ClN7O3 [M + H]+, 522.19, 524.19, found 522.25, 524.25; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 4.1 Hz, 1H), 7.10 (s, 2H), 6.49-6.42 (m, 2H), 5.75 (dd, J = 8.4, 3.9 Hz, 1H), 5.59 (s, 3H), 5.19-5.02 (m, 1H), 4.61 (d, J = 8.8 Hz, 1H), 4.48 (s, 3H), 4.10-4.06 (m, 1H), 3.91 (dd, J = 9.5, 3.1 Hz, 1H), 3.49 (d, J = 8.5 Hz, 1H), 3.40 (d, J = 2.2 Hz, 3H), 2.43-2.37 (m, 1H), 2.37-2.30 (m, 2H), 1.14 (d, J = 8.1 Hz, 2H), 0.95 (d, J = 5.5 Hz, 2H). Example 64
Figure imgf000167_0001
Step 1: 3-Bromo-4-fluoro-2-methylaniline [00342] To a stirred mixture of 2-bromo-1-fluoro-3-methyl-4-nitrobenzene (1.00 g, 4.27 mmol) in ethanol (20 mL) and H2O (4 mL) were added Fe (2.39 g, 42.73 mmol) and NH4Cl (2.29 g, 42.73 mmol). The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was filtered; the filter cake was washed with ethyl acetate (500 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 3-bromo-4-fluoro-2-methylaniline (0.85 g, 97%) as an off- white solid. MS ESI calculated for C7H7BrFN [M + H]+, 203.97, 205.97, found 203.85, 205.85; 1H NMR (400 MHz, CDCl3) δ 6.82 (t, J = 8.4 Hz, 1H), 6.57 (dd, J = 8.7, 4.7 Hz, 1H), 3.56 (s, 2H), 2.29 (s, 3H). Step 2: 3-Bromo-4-fluoro-6-iodo-2-methylaniline [00343] To a stirred solution of 3-bromo-4-fluoro-2-methylaniline (0.86 g, 4.22 mmol) in acetic acid (9 mL) was added N-iodosuccinimide (1.00 g, 4.43 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was neutralized with sat. NaHCO3 (aq.) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford 3-bromo-4-fluoro-6-iodo-2-methylaniline (1.26 g, 90%) as a purple solid. MS ESI calculated for C7H6BrFIN [M + H]+, 329.87, 331.87, found 329.80, 331.80; 1H NMR (400 MHz, CDCl3) δ 7.38-7.32 (m, 1H), 3.97 (s, 2H), 2.38 (s, 3H). Step 3: 4-Bromo-5-fluoro-7-iodo-1H-indazole [00344] To a stirred solution of 3-bromo-4-fluoro-6-iodo-2-methylaniline (2.10 g, 6.36 mmol) in acetonitrile (10 mL) was added tert-butyl nitrite (1.46 g, 12.76 mmol) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (4/1). The fractions contained desired product were combined and concentrated to afford 4-bromo-5-fluoro-7-iodo-1H-indazole (0.46 g, 21%) as a light yellow solid. MS ESI calculated for C7H3BrFIN2 [M + H]+, 340.85, 342.85, found 340.80, 342.80; 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H). Step 4: 4-Bromo-5-fluoro-7-iodo-1-methylindazole [00345] To a stirred mixture of 4-bromo-5-fluoro-7-iodo-1H-indazole (0.54 g, 1.58 mmol) and K3PO4 (1.01 g, 4.75 mmol) in N,N-dimethylformamide (1 mL) was added iodomethane (0.34 g, 2.38 mmol) in N,N-dimethylformamide (1 mL) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 100 °C under nitrogen atmosphere. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (Plus 0.1% FA), 40% to 65% gradient in 20 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford 4-bromo-5-fluoro-7-iodo-1-methylindazole (0.16 g, 28%) as an off-white solid. MS ESI calculated for C8H5BrFIN2 [M + H]+, 354.87, 356.87, found 354.80, 356.80; 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 4.41 (s, 3H). Step 5: 4-Bromo-7-cyclopropyl-5-fluoro-1-methylindazole [00346] To a solution of 4-bromo-5-fluoro-7-iodo-1-methylindazole (0.16 g, 0.45 mmol) and cyclopropylboronic acid (0.19 g, 2.25 mmol) in 1,4-dioxane (4 mL) were added K2CO3 (0.19 g, 1.35 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (36.72 mg, 0.05 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 48 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (8/1). The fractions contained desired product were combined and concentrated to afford 4- bromo-7-cyclopropyl-5-fluoro-1-methylindazole (80 mg, 65%) as a yellow solid. MS ESI calculated for C11H10BrFN2 [M + H]+, 269.00, 271.00, found 268.95, 270.95; 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 6.91-6.88 (m, 1H), 4.44 (s, 3H), 2.35-2.28 (m, 1H), 1.15-1.03 (m, 2H), 0.92-0.81 (m, 2H). Step 6: 3-[2-(7-Cyclopropyl-5-fluoro-1-methylindazol-4-yl)ethynyl]-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00347] To a stirred mixture of 4-bromo-7-cyclopropyl-5-fluoro-1-methylindazole (65 mg, 0.24 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.48 g, 1.78 mmol), bis(triphenylphosphine)palladium(II) chloride (33.91 mg, 0.05 mmol) and cuprous iodide (17.48 mg, 0.09 mmol) in N
Figure imgf000169_0001
N-dimethylformamide (1 mL) was added triethylamine (0.13 mL, 0.94 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product (50 mg), which was further purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: acetonitrile; Flow rate: 60 mL/min; Gradient: 30% to 40% B in 8 min; UV 254 nm. The fractions contained desired product were combined and concentrated to afford 3-[2-(7-cyclopropyl-5-fluoro-1-methylindazol-4-yl)ethynyl]-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (11.6 mg, 1%) as a white solid. MS ESI calculated for C27H30FN7O3 [M + H]+, 520.24, found 520.25; 1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 3.6 Hz, 1H), 7.54 (s, 1H), 7.08 (d, J = 11.2 Hz, 1H), 6.90 (s, 1H), 6.77- 6.55 (m, 1H), 6.17 (dd, J = 16.7, 2.4 Hz, 1H), 5.71-5.67 (m, 1H), 5.29-5.21 (m, 1H), 4.55-4.42 (m, 4H), 4.03-3.72 (m, 2H), 3.60-3.44 (m, 2H), 3.31 (d, J = 5.6 Hz, 3H), 2.94 (t, J = 5.5 Hz, 3H), 2.68-2.54 (m, 2H), 2.34-2.29 (m, 1H), 1.10-1.06 (m, 2H), 0.96-0.94 (m, 2H). Example 65
Figure imgf000169_0002
Step 1: Methyl 3-amino-6-cyclopropylpyridine-2-carboxylate [00348] To a stirred solution of methyl 3-amino-6-bromopyridine-2-carboxylate (3.00 g, 12.98 mmol) and cyclopropylboronic acid (3.35 g, 38.95 mmol) in dioxane (150.00 mL) were added K3PO4 (8.27 g, 38.95 mmol) and Pd(dppf)Cl2·CH2Cl2 (2.12 g, 2.59 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 4 h at 70 °C. The resulting mixture was filtered; the filter cake was washed with EtOAc (50.00 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1). The fractions contained desired product were combined and concentrated to afford methyl 3-amino-6-cyclopropylpyridine-2-carboxylate (0.58 g, 23%) as a light yellow solid. MS ESI calculated C10H12N2O2 [M + H]+, 193.09, found 193.00; 1H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 8.6 Hz, 1H), 6.92-6.90 (m, 1H), 5.14-4.37 (m, 2H), 3.97 (d, J = 1.1 Hz, 3H), 2.18-2.14 (m, 1H), 1.03-0.93 (m, 2H), 0.91-0.78 (m, 2H). Step 2: Methyl 3-amino-4-chloro-6-cyclopropylpyridine-2-carboxylate [00349] To a stirred solution of methyl 3-amino-6-cyclopropylpyridine-2-carboxylate (0.56 g, 2.91 mmol) in NMP (16.00 mL) was added NCS (0.41 g, 3.05 mmol) in portions. The reaction mixture was stirred for 3 h at room temperature. The residue was purified by reverse phase flash with the following conditions: Column: Spherical C18, 20-40 um, 330 g; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 100 mL/min; Gradient (B%): 35% to 50% within 20 min; Detector: UV 254/220 nm. The fractions contained desired product were combined and concentrated to afford methyl 3-amino-4-chloro-6-cyclopropylpyridine-2- carboxylate (0.24 g, 36%) as an orange oil. MS ESI calculated C10H11ClN2O2 [M + H] +, 227.05, 229.05, found 226.95, 228.95; 1H NMR (400 MHz, CDCl3) δ 7.09 (s, 1H), 6.08 (s, 2H), 3.98 (s, 3H), 2.13-2.05 (m, 1H), 1.05-0.95 (m, 2H), 0.95-0.81 (m, 2H). Step 3: Methyl 3-bromo-4-chloro-6-cyclopropylpyridine-2-carboxylate [00350] To a stirred solution of CuBr2 (0.41 g, 1.85 mmol) and 2-methyl-2-propylnitrit (0.24 g, 2.31 mmol) in ACN (4.00 mL) was added methyl 3-amino-4-chloro-6-cyclopropylpyridine-2- carboxylate (0.35 g, 1.54 mmol) in ACN (2.00 mL) dropwise at 0 °C. The reaction mixture was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by the addition of sat. NH4Cl (aq.) (4.00 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford methyl 3-bromo-4-chloro-6-cyclopropylpyridine-2-carboxylate (0.21 g, 47%) as a yellow oil. MS ESI calculated for C10H9BrClNO2 [M+ H]+, 289.95, 291.95; found 290.10, 292.10; 1H NMR (400 MHz, CDCl3) δ 7.31 (s, 1H), 3.99 (s, 3H), 2.05-2.00 (m, 1H), 1.07 (d, J = 6.5 Hz, 4H). Step 4: (3-Bromo-4-chloro-6-cyclopropylpyridin-2-yl)methanol [00351] To a stirred solution of methyl 3-bromo-4-chloro-6-cyclopropylpyridine-2-carboxylate (0.18 g, 0.63 mmol) in EtOH (4.00 mL) and THF (2.00 mL) was added NaBH4 (96.35 mg, 2.54 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1). The fractions contained desired product were combined and concentrated to afford (3-bromo-4-chloro-6-cyclopropylpyridin-2-yl)methanol (0.13 g, 79%) as a white solid.. MS ESI calculated C9H9BrClNO [M + H] +, 261.96, 263.96, found 261.85, 263.85; 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 4.70 (s, 2H), 2.06-2.02 (m, 1H), 1.10 (d, J = 6.4 Hz, 4H). Step 5: (3-Bromo-4-chloro-6-cyclopropylpyridin-2-yl)methyl methanesulfonate [00352] To a stirred solution of (3-bromo-4-chloro-6-cyclopropylpyridin-2-yl)methanol (0.19 g, 0.73 mmol) and TEA (0.22 g, 2.21 mmol) in DCM (4.00 mL) was added MsCl (0.13 g, 1.10 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (5 mL). The resulting mixture was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (3-bromo-4-chloro-6- cyclopropylpyridin-2-yl)methyl methanesulfonate (0.22 g, 89 %) as a light yellow oil. MS ESI calculated for C10H11BrClNO3S [M + H] +, 339.93, 341.93, found 339.95, 341.95. Step 6: 2-[(3-Bromo-4-chloro-6-cyclopropylpyridin-2-yl)methyl]isoindole-1,3-dione [00353] To a stirred solution of (3-bromo-4-chloro-6-cyclopropylpyridin-2-yl)methyl methanesulfonate (0.22 g, 0.65 mmol) in DMF (4.00 mL) was added potassium phthalimide (0.13 g, 0.72 mmol). The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1). The fractions contained desired product were combined and concentrated to afford 2-[(3-bromo-4-chloro-6-cyclopropylpyridin-2- yl)methyl]isoindole-1,3-dione (0.18 g, 71%) as a light yellow solid.. MS ESI calculated for C17H12BrClN2O2 [M + H] +, 390.98, 392.98, found 390.85, 392.85; 1H NMR (400 MHz, CDCl3) δ 7.96-7.92 (m, 2H), 7.82-7.77 (m, 2H), 7.19 (s, 1H), 5.05 (s, 2H), 1.28 (s, 1H), 0.69-0.66(m, 2H), 0.50-0.41 (m, 2H). Step 7: 1-(3-Bromo-4-chloro-6-cyclopropylpyridin-2-yl)methanamine [00354] To a stirred solution of 2-[(3-bromo-4-chloro-6-cyclopropylpyridin-2- yl)methyl]isoindole-1,3-dione (0.18 g, 0.47 mmol) in THF (4.00 mL) was added NH2NH2·H2O (47.29 mg, 0.94 mmol) at room temperature. The resulting mixture was stirred for 1 h at 70 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA 3/1). The fractions contained desired product were combined and concentrated to afford 1-(3-bromo-4-chloro-6-cyclopropylpyridin-2-yl)methanamine (0.12 g, 97%) as a colorless oil. MS ESI calculated for C9H10BrClN2 [M + H] + 260.97, 262.97, found 260.95, 262.95; 1H NMR (400 MHz, CDCl3) δ 7.18 (s, 1H), 4.06 (s, 2H), 1.99 (d, J = 1.6 Hz, 1H), 1.09-1.07 (m, 2H), 1.05-1.02 (m, 2H). Step 8: N-[(3-Bromo-4-chloro-6-cyclopropylpyridin-2-yl)methyl]formamide [00355] To a stirred solution of 1-(3-bromo-4-chloro-6-cyclopropylpyridin-2-yl)methanamine (0.12 g, 0.45 mmol) and EDCI (0.21 g, 1.14 mmol) in DMF (4.00 mL) was added HCOOH (42.23 mg, 0.92 mmol). To the above mixture was added DIEA (0.30 g, 2.29 mmol). The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA 3/1). The fractions contained desired product were combined and concentrated to afford N-[(3-bromo-4-chloro-6- cyclopropylpyridin-2-yl)methyl]formamide (95 mg, 71%) as a white solid. MS ESI calculated for C10H10BrClN2O [M + H] +, 288.97, 290.97, found 288.90, 290.90; 1H NMR (400 MHz, CDCl3) 7.24 (s, 1H), 7.17 (s, 1H), 4.68-.59 (m, 2H), 2.15-1.97 (m, 1H), 1.32-1.24 (m, 1H), 1.16- 1.01 (m, 4H). Step 9: 8-Bromo-7-chloro-5-cyclopropylimidazo[1,5-a]pyridine [00356] To a stirred solution of N-[(3-bromo-4-chloro-6-cyclopropylpyridin-2- yl)methyl]formamide (95 mg, 0.32 mmol) in Toluene (5.00 mL) was added POCl3 (0.20 g, 1.31 mmol) at room temperature. The resulting mixture was stirred for 1 h at 110 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA 3/1). The fractions contained desired product were combined and concentrated to afford 8-bromo-7-chloro-5-cyclopropylimidazo[1,5-a]pyridine (0.12 g, crude) as a light orange oil. MS ESI calculated for C10H8BrClN2 [M + H] +, 270.96, 272.96, found 271.00, 273.00. Step 10: 3-(2-{7-Chloro-5-cyclopropylimidazo[1,5-a]pyridin-8-yl}ethynyl)-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00357] To a stirred solution of 8-bromo-7-chloro-5-cyclopropylimidazo[1,5-a]pyridine (0.11 g, 0.40 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.27 g, 0.81 mmol), Pd(PPh3)2Cl2 (28.43 mg, 0.04 mmol) and CuI (15.43 mg, 0.08 mmol) in DMF (4.00 mL) was added TEA (0.12 g, 1.21 mmol) dropwise at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product was purified by reverse phase flash with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 32% B in 8 min; Wave Length: 254 nm. The fractions contained desired product were combined and concentrated to afford 3-(2-{7-chloro-5- cyclopropylimidazo[1,5-a]pyridin-8-yl}ethynyl)-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (5.00 mg, 2%) as a yellow solid. MS ESI calculated for C26H28ClN7O3 [M + H] +, 522.19, 524.19, found 522.10, 524.10; 1H NMR(400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.54 (s, 2H), 7.07-6.29 (m, 3H), 6.17 (d, J = 17.3 Hz, 1H), 5.69 (d, J = 10.8 Hz, 1H), 5.26 (s, 1H), 4.39 (s, 1H), 4.04-3.40 (m, 4H), 3.34-3.30 (m, 3H), 2.94 (t, J = 5.7 Hz, 3H), 2.34 (s, 3H), 1.13 (s, 2H), 0.97 (d, J = 5.1 Hz, 2H). Example 66
Figure imgf000173_0001
Step 1: 3-[2-(5-Chloro-7-cyclopropyl-1-methylindazol-4-yl)ethynyl]-5-(methylamino)-1-[(3S)- 1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00358] To a stirred solution of 4-bromo-5-chloro-7-cyclopropyl-1-methylindazole (30 mg, 0.11 mmol), 3-ethynyl-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4- carboxamide (45.28 mg, 0.16 mmol), Pd(PPh3)2Cl2 (7.37 mg, 0.01 mmol) and CuI (1.34 mg, 0.02 mmol) in DMF (0.4 mL) was added TEA (31.89 mg, 0.32 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 34% B to 44% B in 8 min, 44% B; Wave Length: 254 nm; RT1: 7 min. The fractions contained desired product were combined and concentrated to afford 3-[2-(5-chloro-7-cyclopropyl-1- methylindazol-4-yl)ethynyl]-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole- 4-carboxamide (2 mg, 4%) as an off-white solid. MS ESI calculated for C25H26ClN7O2 [M + H]+, 492.18, 494.18, found, 492.30, 494.30; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 3.9 Hz, 1H), 7.10 (s, 2H), 6.68 (dd, J = 12.5, 6.2 Hz, 1H), 6.59-6.45 (m, 1H), 6.45-6.38 (m, 1H), 5.79- 5.70 (m, 1H), 5.39 (s, 1H), 5.14-4.99 (m, 1H), 4.48 (s, 3H), 4.16-3.99 (m, 3H), 3.82-3.70 (m, 1H), 3.02 (dd, J = 5.9, 4.4 Hz, 3H), 2.78-2.63 (m, 1H), 2.47-2.34 (m, 2H), 1.20-1.08 (m, 2H), 0.99-0.89 (m, 2H). Example 67
Figure imgf000174_0001
Step 1: (E)-N'-[(5-Bromo-4-chloro-2-cyclopropanecarbonylphenyl)amino]-N,N- dioxomethanimidamide [00359] To a stirred solution of HCl (0.39 g, 10.61 mmol) in H2O (33 mL) were added 5-bromo- 4-chloro-2-cyclopropanecarbonylaniline hydrochloride (3.30 g, 10.61 mmol) and 2 M NaNO2 (5.31 mL, 10.61 mmol) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C. Meanwhile a solution of nitromethane (0.65 g, 10.61 mmol) in EtOH (5 mL) was added to a solution of NaOH (0.42 g, 10.61 mmol) in H2O (330 mL) . Then the diazonium solution was poured into the above solution. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 80 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 5% to 60% gradient in 35 min; detector, UV 254 nm. The fractions contained desired product were combined and concentrated to afford (E)-N'-[(5-bromo-4-chloro-2- cyclopropanecarbonylphenyl)amino]-N,N-dioxomethanimidamide (1.18 g, 32%) as a light yellow solid. MS ESI calculated for C11H9BrClN3O3 [M + H]+, 345.95, 347.95, found 345.80, 347.80; 1H NMR (400 MHz, Chloroform-d) δ 14.59 (s, 1H), 8.18 (d, J = 10.4 Hz, 2H), 7.47 (s, 1H), 2.60-256 (m, 1H), 1.36-1.31 (m, 2H), 1.15-1.11 (m, 2H). Step 3: 7-Bromo-6-chloro-4-cyclopropyl-3-nitrocinnoline [00360] To a stirred mixture of (E)-N'-[(5-bromo-4-chloro-2- cyclopropanecarbonylphenyl)amino]-N,N-dioxomethanimidamide (1.48 g, 4.27 mmol) in H2O (3 mL) was added NaOH (0.43 g, 10.67 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 3 h at 50 °C. The resulting mixture was diluted with H2O (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-6-chloro-4-cyclopropyl-3- nitrocinnoline (1.04 g, 74%) as a dark yellow. MS ESI calculated for C11H7BrClN3O2 [M + H]+, 327.94, 329.94, found 327.95, 329.95. Step 4: 7-Bromo-6-chloro-4-cyclopropylcinnolin-3-amine [00361] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropyl-3-nitrocinnoline (1.04 g, 3.16 mmol) and NH4Cl (0.85 g, 15.82 mmol) in EtOH (10 mL) and H2O (2 mL) was added Fe (0.71 g, 12.66 mmol) at room temperature. The reaction mixture was stirred for 2 h at 70 °C. The resulting mixture was filtered, the filter cake was washed with EA (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-6-chloro-4-cyclopropylcinnolin-3-amine (0.45 g, 48%) as a yellow solid. MS ESI calculated for C11H9BrClN3 [M + H]+, 297.97, 299.97, found 297.95, 299.95; 1H NMR (400 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.28 (s, 1H), 5.34-5.31 (m, 2H), 1.82-1.80 (m, 1H), 1.34-1.27 (m, 2H), 0.76-0.71 (m, 2H). Step 5: 7-Bromo-6-chloro-4-cyclopropyl-3-fluorocinnoline [00362] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropylcinnolin-3-amine (0.45 g, 1.53 mmol) in HBF4 (11.45 mL, 50%) was added 2 M NaNO2 (1.53 ml, 3.06 mmol) at room temperature. The reaction mixture was stirred for 30 min at room temperature.The precipitated solids were collected by filtration and washed with Ethyl ether (3 x 30 mL), and then was added in Toluene (5 mL) at room temperature. The reaction mixture was stirred for 1 h at 110 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (4/1). The fractions contained desired product were combined and concentrated to afford 7-bromo-6-chloro-4-cyclopropyl-3-fluorocinnoline (0.17 g, 38%) as a yellow solid. MS ESI calculated for C11H7BrClFN2 [M + H]+, 300.95, 302.95, found 300.85, 302.85; 1H NMR (400 MHz, Chloroform-d) δ 8.81 (s, 1H), 8.43 (s, 1H), 2.13- 2.10 (m, 1H), 1.39-1.11 (m, 4H). Step 6: 3-[2-(6-Chloro-4-cyclopropyl-3-fluorocinnolin-7-yl)ethynyl]-1-[ -5-
Figure imgf000176_0001
(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00363] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropyl-3-fluorocinnoline (0.08 g, 0.26 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (0.10 g, 0.31 mmol) in DMF (1.6 mL) were added CuI (10.11 mg, 0.05 mmol), Pd(PPh3)2Cl2 (18.62 mg, 0.02 mmol) and TEA (0.08 g, 0.79 mmol) . The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 80 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product which was further purified by reverse flash chromatography with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 19 x 250 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: MeOH--HPLC; Flow rate: 20 mL/min; Gradient: 65% B to 65% B in 15 min, 65% B; Wave Length: 254 nm; RT1: 13.7 min. The fractions contained desired product were combined and concentrated to afford 3-[2-(6-chloro-4-cyclopropyl-3-fluorocinnolin-7- yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5- (methylamino)pyrazole-4-carboxamide (75 mg, 51%) as a light yellow solid. MS ESI calculated for C27H27ClFN7O3 [M + H]+, 552.18, 554.18, found 552.25, 554.25; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 7.48 (s, 1H), 6.93 (s, 1H), 6.66- 6.61 (m, 2H), 6.17 (d, J = 16.9 Hz, 1H), 5.69 (d, J = 10.0 Hz, 1H), 5.28-5.21 (m, 1H), 4.48 (d, J = 54.9 Hz, 1H), 3.90-3.85 (m, 2H), 3.66-3.39 (m, 2H), 3.30-3.25 (m, 3H), 3.00-2.92 (m, 3H), 2.64-2.61 (m, 1H), 2.43 (s, 1H), 2.33 (s, 1H), 1.27 (d, J = 8.3 Hz, 2H), 1.13 (d, J = 5.5 Hz, 2H).
Example 68
Figure imgf000177_0001
Step 1: 5-Amino-3-[2-(6-chloro-4-cyclopropyl-3-fluorocinnolin-7-yl)ethynyl]-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]pyrazole-4-carboxamide [00364] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropyl-3-fluorocinnoline (0.06 g, 0.19 mmol) and 5-amino-3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3- yl]pyrazole-4-carboxamide (0.07 g, 0.23 mmol) in DMF (1 mL) were added CuI (2.53 mg, 0.04 mmol), Pd(PPh3)2Cl2 (13.97 mg, 0.02 mmol) and TEA (0.06 g, 0.59 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product which was further purified by reverse flash chromatography with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 19 x 250 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: MeOH--HPLC; Flow rate: 20 mL/min; Gradient: 65% B to 65% B in 15 min, 65% B; Wave Length: 254 nm; RT1: 13.7 min. The fractions contained desired product were combined and concentrated to afford 5-amino-3-[2-(6-chloro-4-cyclopropyl-3- fluorocinnolin-7-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3- yl]pyrazole-4-carboxamide (27.4 mg, 25%) as a light yellow solid. MS ESI calculated for C26H25ClFN7O3 [M + H]+, 538.17, 540.17, found 538.20, 540.20; 1H NMR (400 MHz, DMSO- d6) δ 8.85 (s, 1H), 8.68 (s, 1H), 7.40 (s, 1H), 6.72-6.61 (m, 3H), 6.58-6.51 (m, 1H), 6.17-6.11 (m, 1H), 5.70-5.66 (m, 1H), 5.14-5.03 (m, 1H), 4.54 (d, J = 6.1 Hz, 1H), 4.45-4.38 (m, 1H), 3.99-3.86 (m, 1H), 3.84-3.74 (m, 1H), 3.70-3.47 (m, 1H), 3.42 (d, J = 5.7 Hz, 1H), 3.31 (s, 2H), 2.44-2.33 (m, 2H), 2.27-2.11 (m, 1H), 1.32-1.19 (m, 2H), 1.18-1.09 (m, 2H). Example 69
Figure imgf000178_0001
Step 1: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-5-amino-3-((6-chloro-4- cyclopropyl-3-methylcinnolin-7-yl)ethynyl)-1H-pyrazole-4-carboxamide [00365] To a stirred mixture of 7-bromo-6-chloro-4-cyclopropyl-3-methylcinnoline (40 mg, 0.134 mmol), 5-amino-3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3- yl]pyrazole-4-carboxamide (51.19 mg, 0.17 mmol) , Pd(PPh3)2Cl2 (9.43 mg, 0.013 mmol) and CuI (5.12 mg, 0.027 mmol) in DMF (0.4 mL) was added TEA (40.81 mg, 0.40 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 30% to 45% gradient in 10 min; detector, UV 254 nm. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1-acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)- 5-amino-3-((6-chloro-4-cyclopropyl-3-methylcinnolin-7-yl)ethynyl)-1H-pyrazole-4- carboxamide (13.6 mg, 18%) as an off-white solid. MS ESI calculated for C27H28ClN7O3 [M + H]+, 534.19, 536.19, found 534.25, 536.25; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.56 (s, 1H), 7.39 (brs, 1H), , 6.79-6.65 (m, 3H), 6.57 (dd, J = 16.6, 10.3 Hz, 1H), 6.16 (d, J = 16.6 Hz, 1H), 5.69 (d, J = 10.3 Hz, 1H), 5.18-5.10 (m, 1H), 4.47 (d, J = 48.3 Hz, 1H), 3.98-3.95 (m, 1H), 3.85-3.62 (m, 2H), 3.51 (s, 1H), 3.42 (d, J = 5.6 Hz, 1H), 3.32 (s, 3H), 2.97 (s, 3H), 2.36- 2.24 (m, 1H), 2.19 (t, J = 7.2 Hz, 1H), 1.30 (d, J = 8.5 Hz, 2H), 0.73 (d, J = 5.5 Hz, 2H). Example 70
Figure imgf000179_0001
Step 1: 4-Bromo-5-chloro-1-cyclopropyl-7-iodo-1H-indazole [00366] To a stirred mixture of 4-bromo-5-chloro-7-iodo-1H-indazole (1.00 g, 2.80 mmol), cyclopropylboronic acid (0.48 g, 5.60 mmol) and 2-(pyridin-2-yl)pyridine (0.44 g, 2.80 mmol) in 1,2-Dichloroethane (10.00 mL) was added Copper (II) acetate (1.02 g, 5.59 mmol) dropwise at room temperature. The reaction mixture was stirred for 2 h at 70 °C under oxygen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/dichlormethane (3/1). The fractions contained desired product were combined and concentrated under pressure to afford 4-bromo-5-chloro-1-cyclopropyl-7-iodo-1H-indazole (0.18 g, 16%) as a yellow solid. MS ESI calculated for C10H7BrClIN2 [M + H]+, 396.85, 398.85, found 396.85, 398.85; 1H NMR (400 MHz, Chloroform-d) δ 7.90 (d, J = 23.9 Hz, 2H), 4.10-4.05 (m, 1H), 1.49-1.44 (m, 2H), 1.29-1.24 (m, 2H). Step 2: 4-Bromo-5-chloro-1,7-dicyclopropyl-1H-indazole [00367] To a stirred mixture of 4-bromo-5-chloro-1-cyclopropyl-7-iodo-1H-indazole (1.20 g, 3.02 mmol) and cyclopropylboronic acid (0.31 g, 3.62 mmol) in 1,4-dioxane (12.00 mL) were added Potassium Carbonate (1.25 g, 9.06 mmol) and [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.25 g, 0.30 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 48 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/dichlormethane (2/1). The fractions contained desired product were combined and concentrated to afford 4-bromo-5-chloro-1,7-dicyclopropyl-1H-indazole (0.50 g, 53%) as a light yellow solid. MS ESI calculated for C13H12BrClN2 [M + H]+, 310.99, 312.99, found 310.95, 312.95. Step 3: (S)-1-(1-Acryloylpyrrolidin-3-yl)-5-amino-3-((5-chloro-1,7-dicyclopropyl-1H-indazol- 4-yl)ethynyl)-1H-pyrazole-4-carboxamide [00368] To a stirred mixture of 3-ethynyl-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin- 3-yl]pyrazole-4-carboxamide (0.11 g, 0.39 mmol), 4-bromo-5-chloro-1,7-dicyclopropylindazole (80.00 mg, 0.26 mmol), trans-dichlorobis(triphenylphosphine)palladium (18.02 mg, 0.03 mmol) and CuI (9.78 mg, 0.05 mmol) in N,N-dimethylformamide (1.00 mL) was added triethylamine (77.94 mg, 0.77 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford the crude product. The crude product (0.02 g) was purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18 ExRS, 30 x 150 mm, 5 μm; Mobile phase A: water (10 mmol/L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL/min; Gradient: 40% B to 50% B in 10 min, 50% B; Wave length: 254 nm; RT: 9 min. The fractions contained desired product were combined and concentrated to afford (S)-1-(1- acryloylpyrrolidin-3-yl)-5-amino-3-((5-chloro-1,7-dicyclopropyl-1H-indazol-4-yl)ethynyl)-1H- pyrazole-4-carboxamide (15.10 mg, 11%) as a white solid. MS ESI calculated for C27H28ClN7O2 [M + H]+, 518.20, 520.20, found 518.25, 520.25; 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 1.1 Hz, 1H), 7.50 (s, 1H), 7.14 (s, 1H), 6.93 (s, 1H), 6.71-6.57 (m, 1H), 6.53-6.50 (m, 1H), 6.19- 6.15 (m, 1H), 5.72-5.67 (m, 1H), 5.17-5.13 (m, 1H), 4.24-4.20 (m, 1H), 4.09-3.80 (m, 2H), 3.76- 3.49 (m, 2H), 2.94 (dd, J = 5.7, 2.4 Hz, 3H), 2.86-2.82 (m, 1H), 2.44-2.40 (m, 1H), 2.35-2.30 (m, 1H), 1.32-1.28 (m, 2H), 1.22-1.07 (m, 4H), 1.02-0.88 (m, 2H). Example 71
Figure imgf000180_0001
Step 1: 3-Bromo-N-methyl-2-nitroaniline [00369] To a stirred solution of 1-bromo-3-fluoro-2-nitrobenzene (10.00 g, 45.45 mmol) in THF (50 mL) was added Methylamine, 2 M in THF (202.28 mL, 404.55 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-bromo-N-methyl-2-nitroaniline (8.00 g, 76%) as a reddish brown solid. MS ESI calculated for C7H7BrN2O2 [M + H]+, 231.05, 233.05, found 230.95, 232.95; 1H NMR (400 MHz, Chloroform-d) δ 7.16-7.03 (m, 1H), 6.94-6.81 (m, 1H), 6.73-6.61 (m, 1H), 5.78 (s, 1H), 2.91 (s, 3H). Step 2: 3-Bromo-4-chloro-N-methyl-2-nitroaniline [00370] To a stirred solution of 3-bromo-N-methyl-2-nitroaniline (8.80 g, 38.08 mmol) in DMF (88 mL) was added NCS (5.34 g, 39.99 mmol) in portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 3 h at 50 °C under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10/1). The fractions contained desired product were combined and concentrated to afford 3- bromo-4-chloro-N-methyl-2-nitroaniline (9.67 g, 95%) as a Brick red solid. MS ESI calculated for C7H6BrClN2O2 [M + H]+, 264.93, 266.93, found 264.90, 266.90; 1H NMR (400 MHz, Chloroform-d) δ 7.40 (d, J = 9.1 Hz, 1H), 6.71 (d, J = 9.1 Hz, 1H), 5.30 (s, 1H), 2.90 (s, 3H). Step 3: 3-Bromo-4-chloro-6-iodo-N-methyl-2-nitroaniline [00371] To a stirred solution of 3-bromo-4-chloro-N-methyl-2-nitroaniline (2.00 g, 7.53 mmol) in AcOH (20 mL) was added NIS (6.78 g, 30.13 mmol) at 0 °C. The reaction mixture was stirred for 6 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was neutralized with sat. NaHCO3 and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/DCM (5/1). The fractions contained desired product were combined and concentrated to afford 3-bromo-4-chloro-6-iodo-N-methyl-2- nitroaniline (1.57 g, 53%) as a yellow solid. MS ESI calculated for C7H5BrClIN2O2 [M + H]+, 390.83, 392.83, found 390.75, 392.75; 1H NMR (400 MHz, Chloroform-d) δ 7.85 (s, 1H), 4.33 (s, 1H), 2.86 (d, J = 5.9 Hz, 3H). Step 4: 3-Bromo-4-chloro-6-iodo-N1-methylbenzene-1,2-diamine [00372] To a stirred mixture of 3-bromo-4-chloro-6-iodo-N-methyl-2-nitroaniline (0.60 g, 1.53 mmol) in AcOH (6 mL) was added Fe (0.43 g, 7.66 mmol) at room temperature. The reaction mixture was stirred for 16 h at room temperature. The resulting mixture was filtered, the filter cake was washed with EA (3 x 20 ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/DCM (10/1). The fractions contained desired product were combined and concentrated to afford 3-bromo-4- chloro-6-iodo-N1-methylbenzene-1,2-diamine (0.40 g, 72%) as a light yellow solid. MS ESI calculated for C7H4BrClIN2 [M + H]+, 360.85, 362.85, found 360.75, 362.75; 1H NMR (400 MHz, Chloroform-d) δ 7.26 (s, 1H), 4.71 (s, 1H), 2.66 (d, J = 22.5 Hz, 2H). Step 5: 4-Bromo-5-chloro-7-iodo-1-methyl-1,2,3-benzotriazole [00373] To a stirred mixture of 3-bromo-4-chloro-6-iodo-N1-methylbenzene-1,2-diamine (0.36 g, 0.99 mmol) and con.HCl (1.08 mL, 12.94 mmol) in H2O (6 mL) was added 2 M NaNO2 (0.60 mL, 1.19 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 h at 0 °C. The resulting mixture was diluted with H2O (20 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 3 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1). The fractions contained desired product were combined and concentrated to afford 4-bromo-5-chloro-7-iodo-1-methyl- 1,2,3-benzotriazole (0.26 g, 71%) as a light yellow solid. MS ESI calculated for C7H4BrClIN3 [M + H]+, 371.83, 373.83, found 371.80, 373.80; 1H NMR (400 MHz, Chloroform-d) δ 7.97 (s, 1H), 4.55 (s, 3H). Step 6: 4-Bromo-5-chloro-7-cyclopropyl-1-methyl-1,2,3-benzotriazole [00374] To a stirred solution of 4-bromo-5-chloro-7-iodo-1-methyl-1,2,3-benzotriazole (0.17 g, 0.45 mmol) and cyclopropylboronic acid (47.06 mg, 0.54 mmol) in 1,4-dioxane (2 mL) were added Pd(dppf)Cl2CH2Cl2 (0.06 g, 0.07 mmol) and K3PO4 (0.29 g, 1.37 mmol) in portions at room temperature . The reaction mixture was degassed with nitrogen for three times and stirred for 2 h at 70 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (31%). The fractions contained desired product were combined and concentrated to afford 4-bromo-5-chloro-7- cyclopropyl-1-methyl-1,2,3-benzotriazole (0.11 g, 88 %) as a white solid. MS ESI calculated for C10H9BrClN3 [M + H]+, 285.97, 287.97, found 285.90, 287.90; 1H NMR (400 MHz, Chloroform-d) δ 7.20 (d, J = 1.1 Hz, 1H), 4.60 (s, 3H), 2.28-213 (m, 1H), 1.19-1.04 (m, 2H), 0.98-0.86 (m, 2H). Step 7: 3-[2-(5-Chloro-7-cyclopropyl-1-methyl-1,2,3-benzotriazol-4-yl)ethynyl]-1-[(3S,5R)-5- (methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide [00375] To a stirred mixture of 4-bromo-5-chloro-7-cyclopropyl-1-methyl-1,2,3-benzotriazole (40 mg, 0.14 mmol) and 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin- 3-yl]-5-(methylamino)pyrazole-4-carboxamide (92.51 mg, 0.28 mmol) in DMF (1 mL) were added Pd(PPh3)2Cl2 (9.80 mg, 0.01 mmol), CuI (5.32 mg, 0.02 mmol) and TEA (42.38 mg, 0.42 mmol). The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product which was further purified by reverse flash chromatography with the following conditions: Column: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (Plus 10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 46% B in 8 min, 46% B; Wave Length: 254 nm; RT1: 7 min. The fractions contained desired product were combined and concentrated to afford 3-[2-(5-chloro-7-cyclopropyl-1- methyl-1,2,3-benzotriazol-4-yl)ethynyl]-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (22.30 mg, 29%) as a white solid.. MS ESI calculated for C26H29ClN8O3 [M + H]+, 537.21, 539.21, found 537.25, 539.25; 1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.32 (s, 1H), 7.04 (s, 1H), 6.92-6.51 (m, 2H), 6.16- 6.01 (m, 1H), 5.68-5.53 (m, 1H), 5.30-5.21 (m, 1H), 4.59 (s, 3H), 4.58-4.40 (m, 1H), 4.05-3.99 (m, 1H), 3.91-3.89 (m, 1H), 3.83-3.53 (m, 1H), 3.52-3.43 (m, 2H), 3.31-3.21 (m, 3H), 2.98-2.88 (m, 3H), 2.72-2.51 (m, 1H), 2.32-2.24 (m, 1H), 1.10-1.09 (m, 2H), 1.02-0.93 (m, 2H). Example 72
Figure imgf000183_0001
Step 1: 2,4-Dichloro-6-iodopyridin-3-amine [00376] To a stirred solution of 2,4-dichloropyridin-3-amine (10 g, 61.35 mmol) in acetonitrile (85 mL) were added trifluoroacetic acid (1.37 mL, 18.44 mmol) and N-iodosuccinimide (15.18 g, 67.47 mmol) in portions at room temperature. The reaction mixture was stirred for 48 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 20% ethyl acetate in petroleum ether. The fractions contained desired product were combined and concentrated to afford 2,4- dichloro-6-iodopyridin-3-amine (9.4 g, 53%) as a light orange solid. MS ESI calculated for C5H3Cl2IN2 [M + H]+, 288.87, found 288.85.1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 4.48 (s, 2H). Step 2: 2,4-Dichloro-6-cyclopropylpyridin-3-amine [00377] To a solution of 2,4-dichloro-6-iodopyridin-3-amine (9.4 g, 32.54 mmol) and cyclopropylboronic acid (5.59 g, 65.07 mmol) in 1,4-dioxane (95 mL) were added potassium trimethylsilanolate (8.35 g, 65.07 mmol) and bis(triphenylphosphine)palladium(II) chloride (2.28 g, 3.25 mmol). After stirring for 16 h at 90 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (30 mL) and extracted with EA (3 x 70 mL). The combined organic layers were washed with brine (4 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% EA in PE to afford the crude product which was further purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, acetonitrile in water (Plus 10 mmol/L NH4HCO3), 35% to 70% gradient in 20 min; detector, UV 254 nm. The fractions contained desired product were combined and concentrated to afford 2,4-dichloro-6-cyclopropylpyridin-3- amine (3.3 g, 49%) as a light yellow oil. MS ESI calculated for C8H8Cl2N2 [M + H]+, 203.01, 205.01, found 203.00, 205.00; 1H NMR (400 MHz, CDCl3) δ 6.98 (s, 1H), 4.16 (brs, 2H), 1.93- 1.86 (m, 1H), 0.95-0.86 (m, 4H). Step 3: 3-Bromo-2,4-dichloro-6-cyclopropylpyridine [00378] To a stirred mixture of 2-methyl-2-propylnitrit (2.85 g, 24.84 mmol) and dibromocopper (4.41 g, 19.74 mmol) in acetonitrile (20 mL) was added 2,4-dichloro-6- cyclopropylpyridin-3-amine (3.34 g, 16.45 mmol5) in acetonitrile (20 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 8% ethyl acetate in petroleum ether. The fractions contained desired product were combined and concentrated to afford 3-bromo-2,4-dichloro-6- cyclopropylpyridine (3.6 g, 81%) as a light yellow oil. MS ESI calculated for C8H6BrCl2N [M + H]+, 265.91, 267.91, found 265.90, 267.90; 1H NMR (400 MHz, CDCl3) δ 7.17 (s, 1H), 1.97- 1.90 (m, 1H), 1.05-1.03 (m, 4H). Step 4: 3-Bromo-4-chloro-6-cyclopropyl-2-hydrazineylidene-1,2-dihydropyridine [00379] To a stirred solution of 3-bromo-2,4-dichloro-6-cyclopropylpyridine (3.6 g, 13.49 mmol) in 1,4-dioxane (40 mL) was added hydrazine hydrate (16.88 g, 269.75 mmol, purity 80%) at room temperature. The reaction mixture was stirred for 16 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, acetonitrile in water (plus 10 mmol/L NH4HCO3), 10% to 60% gradient in 30 min; detector, UV 254 nm. The fractions contained desired product were combined and concentrated to afford 3-bromo-4- chloro-6-cyclopropyl-2-hydrazineylidene-1,2-dihydropyridine (1.34 g, 37 %) as a red solid. MS ESI calculated for C8H9BrClN3 [M + H]+, 261.97, 263.97, found 262.00, 264.00; 1H NMR (400 MHz, CDCl3) δ 6.71 (s, 1H), 6.30 (s, 1H), 3.63(brs, 2H), 1.99-1.87 (m, 1H), 1.07-0.95 (m, 4H). Step 5: N'-(3-Bromo-4-chloro-6-cyclopropyl-1H-pyridin-2-ylidene)cyclopropanecarbohydrazide [00380] To a stirred mixture of 3-bromo-4-chloro-6-cyclopropyl-2-hydrazineylidene-1,2- dihydropyridine (0.24 g, 0.90 mmol), cyclopropanecarboxylic acid (0.23 g, 2.69 mmol), 1- hydroxybenzotriazole (0.18 g, 1.34 mmol) and N-(3-dimethylaminopropyl)-N’- ethylcarbodiimide hydrochloride (0.26 g, 1.34 mmol) in
Figure imgf000185_0001
dimethylformamide (3 mL) was added triethylamine (0.50 mL, 3.58 mmol). The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (5 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1), The fractions contained desired product were combined and concentrated to afford N'-(3-bromo-4-chloro-6-cyclopropyl- 1H-pyridin-2-ylidene)cyclopropanecarbohydrazide (0.15 g, 50%) as a pink solid. MS ESI calculated for C12H13BrClN3O [M + H]+, 329.99, 331.99, found 329.95, 331.95; 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.26 (s, 1H), 6.76 (s, 1H), 1.93-1.87 (m, 1H), 1.58-1.52 (m, 1H), 1.06-1.02 (m, 2H), 0.97-0.94 (m, 4H), 0.89-0.85 (m, 2H). Step 6: 8-Bromo-7-chloro-3,5-dicyclopropyl-[1,2,4]triazolo[4,3-a]pyridine [00381] To a stirred solution of N'-(3-bromo-4-chloro-6-cyclopropyl-1H-pyridin-2- ylidene)cyclopropanecarbohydrazide (0.15 g, 0.45 mmol) in toluene (4 mL) was added phosphorus oxychloride (0.34 mL, 3.65 mmol). The reaction mixture was stirred for 2 h at 110 °C. The resulting mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 80% ethyl acetate in petroleum ether to afford 8-bromo-7-chloro-3,5-dicyclopropyl- [1,2,4]triazolo[4,3-a]pyridine (0.11 g, 80%) as a white solid. MS ESI calculated for C12H11BrClN3 [M + H]+, 311.98, 313.98, found 312.00, 314.00; 1H NMR (400 MHz, CDCl3) δ 6.52 (s, 1H), 2.67-2.60 (m, 2H), 1.40-1.36 (m, 2H), 1.23-1.18 (m, 2H), 1.14-1.10 (m, 2H), 1.06- 1.01 (m, 2H). Step 7: 1-((3S,5R)-1-Acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((7-chloro-3,5- dicyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4- carboxamide [00382] To a stirred solution of 8-bromo-7-chloro-3,5-dicyclopropyl-[1,2,4]triazolo[4,3- a]pyridine (40 mg, 0.13 mmol), 3-ethynyl-1-[(3S,5R)-5-(methoxymethyl)-1-(prop-2- enoyl)pyrrolidin-3-yl]-5-(methylamino)pyrazole-4-carboxamide (169.61 mg, 0.51 mmol) , Pd(PPh3)2Cl2 (17.96 mg, 0.03 mmol) and CuI (9.75 mg, 0.05 mmol) in DMF (0.4 mL) was added TEA (64.74 mg, 0.64 mmol) The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10/1) to afford the crude product. The crude product was purified by Prep- HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 47% B in 8 min, 47% B; Wave Length: 254 nm; RT1: 7.08 min. The fractions contained desired product were combined and concentrated to afford 1-((3S,5R)-1- acryloyl-5-(methoxymethyl)pyrrolidin-3-yl)-3-((7-chloro-3,5-dicyclopropyl-[1,2,4]triazolo[4,3- a]pyridin-8-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide (17.4 mg, 24%) as a light yellow solid. MS ESI calculated for C28H31ClN8O3 [M + H]+, 563.22, 565.22, found 563.25, 565.25; 1H NMR (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.20 (s, 1H), 6.92 (dd, J = 13.9, 7.3 Hz, 1H), 6.87 (s, 1H), 6.66-6.62 (m, 1H), 6.16 (dd, J = 16.9, 2.5 Hz, 1H), 5.68 (dd, J = 10.2, 2.9 Hz, 1H), 5.34-5.28 (m, 1H), 4.46 (d, J = 58.9 Hz, 1H), 4.12-3.70 (m, 2H), 3.70-3.39 (m, 2H), 3.30 (d, J = 5.6 Hz, 3H), 2.97 (t, J = 5.3 Hz, 3H), 2.85-2.71 (m, 2H), 2.71-2.56 (m, 1H), 2.32 (s, 1H), 1.27-0.92 (m, 8H).
Example 73
Figure imgf000187_0001
Step 1: Tert-butyl (S)-3-(3-((6-chloro-1-cyclopropyl-7-fluoro-1H-benzo[d]imidazol-5- yl)ethynyl)-4-cyano-5-((4-methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [00383] To a stirred mixture of tert-butyl (3S)-3-(4-cyano-3-ethynyl-5-{[(4- methoxyphenyl)methyl]amino}pyrazol-1-yl)pyrrolidine-1-carboxylate (0.50 g, 1.18 mmol), 5- bromo-6-chloro-1-cyclopropyl-7-fluoro-1,3-benzodiazole (0.26 g, 0.91 mmol), trans- dichlorobis(triphenylphosphine)palladium (63.76 mg, 0.09 mmol) and cuprous iodide (34.60 mg, 0.18 mmol) in N
Figure imgf000187_0002
N-dimethylformamide (3.00 mL) was added TEA (0.27 g, 2.72 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (S)-3- (3-((6-chloro-1-cyclopropyl-7-fluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-4-cyano-5-((4- methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (0.35 g, 61%) as a brown solid. MS ESI calculated for C33H33ClFN7O3 [M + H]+, 630.23, 632.23, found 630.20, 632.20. Step 2: Tert-butyl (S)-3-(4-carbamoyl-3-((6-chloro-1-cyclopropyl-7-fluoro-1H- benzo[d]imidazol-5-yl)ethynyl)-5-((4-methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1- carboxylate [00384] To a stirred mixture of tert-butyl (S)-3-(3-((6-chloro-1-cyclopropyl-7-fluoro-1H- benzo[d]imidazol-5-yl)ethynyl)-4-cyano-5-((4-methoxybenzyl)amino)-1H-pyrazol-1- yl)pyrrolidine-1-carboxylate (0.30 g, 0.48 mmol) in dioxane (3.00 mL) and water (0.60 mL) was added Hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito- kP)]platinum(II) (40.68 mg, 0.10 mmol). The reaction mixture was stirred for 16 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (S)-3-(4-carbamoyl-3-((6-chloro-1- cyclopropyl-7-fluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-5-((4-methoxybenzyl)amino)-1H- pyrazol-1-yl)pyrrolidine-1-carboxylate (0.14 g, 45%) as a light yellow solid. MS ESI calculated for C33H35ClFN7O4 [M + H]+, 648.24, 650.24, found 648.30, 650.30. Step 3: (S)-5-Amino-3-((6-chloro-1-cyclopropyl-7-fluoro-1H-benzo[d]imidazol-5-yl)ethynyl)- 1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide [00385] A solution of tert-butyl (S)-3-(4-carbamoyl-3-((6-chloro-1-cyclopropyl-7-fluoro-1H- benzo[d]imidazol-5-yl)ethynyl)-5-((4-methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1- carboxylate (0.12 g, 0.18 mmol) in trifluoroacetic acid (0.20 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. The fractions contained desired product were combined and concentrated to afford (S)-5-amino-3-((6-chloro-1-cyclopropyl-7-fluoro-1H-benzo[d]imidazol-5-yl)ethynyl)- 1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide (0.10 g, 95%) as a brown solid. MS ESI calculated for C20H19ClFN7O [M + H]+, 428.13, 430.13, found 428.10, 430.10. Step 4: (S)-1-(1-Acryloylpyrrolidin-3-yl)-5-amino-3-((6-chloro-1-cyclopropyl-7-fluoro-1H- benzo[d]imidazol-5-yl)ethynyl)-1H-pyrazole-4-carboxamide [00386] To a stirred solution of (S)-5-amino-3-((6-chloro-1-cyclopropyl-7-fluoro-1H- benzo[d]imidazol-5-yl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide (70.00 mg, 0.16 mmol) in N,N-dimethylformamide (1.00 mL) was added N,N-diisopropylethylamine (49.67 mg, 0.49 mmol) and acryloyl chloride (13.33 mg, 0.15 mmol) dropwise at 0 °C. The reaction mixture was stirred for 5 min at 0 °C. The resulting mixture was quenched with methyl alcohol at 0 °C. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, ACN in water (Plus 10 mmol/L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 254 nm. The fractions contained desired product were combined and concentrated to afford (S)-1-(1-acryloylpyrrolidin-3-yl)-5-amino-3-((6-chloro-1- cyclopropyl-7-fluoro-1H-benzo[d]imidazol-5-yl)ethynyl)-1H-pyrazole-4-carboxamide (21.70 mg, 27%) as a white solid. MS ESI calculated for C23H21ClFN7O2 [M + H]+, 482.14, 484.14, found 482.15, 484.15; 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.93 (s, 1H), 7.37 (s, 1H), 6.76-6.51 (m, 3H), 6.19-6.15 (m, 1H), 5.72-5.68 (m, 1H), 5.02-4.98 (m, 1H), 4.09-3.58 (m, 5H), 3.57-3.44 (m, 1H), 2.34-2.30 (m, 2H), 1.19-1.15 (m, 2H), 1.13-1.02 (m, 2H). Example 74
Figure imgf000189_0001
Step 1: Tert-butyl (S)-3-(3-((6-chloro-1-cyclopropyl- 5-yl)ethynyl)-4-
Figure imgf000189_0002
cyano-5-((4-methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [00387] To a stirred solution of 6-chloro-1-cyclopropyl-5-iodo-1,3-benzodiazole (0.38 g, 1.19 mmol) and tert-butyl (3S)-3-(4-cyano-3-ethynyl-5-{[(4-methoxyphenyl)methyl]amino}pyrazol- 1-yl)pyrrolidine-1-carboxylate (0.50 g, 1.19 mmol) and trans- dichlorobis(triphenylphosphine)palladium (83.29 mg, 0.12 mmol) and cuprous iodide (45.20 mg, 0.24 mmol) in N
Figure imgf000189_0003
N-dimethylformamide (4.00 mL) was added triethylamine (0.49 mL, 3.56 mmol) dropwise at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 40 min at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (8/1). The fractions contained desired product were combined and concentrated under pressure to afford tert-butyl (S)-3-(3-((6-chloro-1-cyclopropyl-1H-benzo[d]imidazol-5- yl)ethynyl)-4-cyano-5-((4-methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (0.50 g, 69%) as a yellow solid. MS ESI calculated for C33H34ClN7O3 [M + H]+, 612.24, 614.24, found 612.25, 614,25. Step 2: (S)-5-Amino-3-((6-chloro-1-cyclopropyl-1H-benzo[d]imidazol-5-yl)ethynyl)-1- (pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide [00388] A solution of tert-butyl (S)-3-(3-((6-chloro-1-cyclopropyl-1H-benzo[d]imidazol-5- yl)ethynyl)-4-cyano-5-((4-methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (0.16 g, 0.26 mmol) in Phosphoric acid (1.50 mL) was stirred for 1 h at 130 °C. The resulting mixture was allowed to cool down to room temperature. The resulting mixture was basified to pH 8 with saturated sodium bicarbonate (aq.). The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, acetonitrile in water (Plus 10 mmol/L NH4HCO3), 10% to 50% gradient in 30 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford (S)-5-amino-3- ((6-chloro-1-cyclopropyl-1H-benzo[d]imidazol-5-yl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazole- 4-carboxamide (30.00 mg, 28%) as a grey solid. MS ESI calculated for C20H20ClN7O [M + H]+, 410.24, 412.24, found 410.10, 412.10. Step 3: (S)-1-(1-Acryloylpyrrolidin-3-yl)-5-amino-3-((6-chloro-1-cyclopropyl-1H- benzo[d]imidazol-5-yl)ethynyl)-1H-pyrazole-4-carboxamide [00389] To a stirred solution of (S)-5-amino-3-((6-chloro-1-cyclopropyl-1H-benzo[d]imidazol- 5-yl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide (30.00 mg, 0.07 mmol) in N,N- dimethylformamide (0.50 mL) was added N,N-diisopropylethylamine (28.38 mg, 0.22 mmol) and acryloyl chloride (5.96 mg, 0.07 mmol) dropwise at 0 °C. The reaction mixture was stirred for 5 min at 0 °C. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, acetonitrile in water, 10% to 50% gradient in 30 min; detector, UV 254 nm. The fractions contained desired product were combined and concentrated under pressure to afford (S)-1-(1-acryloylpyrrolidin-3-yl)-5-amino-3-((6-chloro-1- cyclopropyl-1H-benzo[d]imidazol-5-yl)ethynyl)-1H-pyrazole-4-carboxamide (5.80 mg, 17%) as a white solid. MS ESI calculated for C23H22ClN7O2 [M + H]+, 464.15, 466,15, found 464.25, 466.25; 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.04 (s, 1H), 7.89 (s, 1H), 7.36 (s, 1H), 6.75-6.52 (m, 3H), 6.17 (d, J = 16.9 Hz, 1H), 5.70 (t, J = 10.1 Hz, 1H), 5.06-4.83 (m, 2H), 3.87- 3.67 (m, 2H), 3.76-3.66 (m, 1H), 3.65 (d, J = 13.8 Hz, 1H), 3.54 (dd, J = 9.5, 5.2 Hz, 1H), 2.40- 2.19 (m, 2H), 1.20-0.99 (m, 4H). Example 75
Figure imgf000190_0001
Step 1: N-((3-Bromo-4-chloro-6-cyclopropylpyridin-2-yl)methyl)cyclopropanecarboxamide [00390] To a stirred solution of 1-(3-bromo-4-chloro-6-cyclopropylpyridin-2-yl)methanamine (0.90 g, 3.44 mmol), EDCI (0.99 g, 5.16 mmol) and HOBT (0.70 g, 5.16 mmol) in dichlormethane (10.00 mL) was added cyclopropanecarboxylic acid (0.89 g, 10.32 mmol) at room temperature. The reaction mixture was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1). The fractions contained desired product were combined and concentrated to afford N-((3-bromo-4-chloro-6-cyclopropylpyridin-2- yl)methyl)cyclopropanecarboxamide (0.58 g, 51%) as a white solid. MS ESI calculated for C13H14BrClN2O [M + H]+, 329.00, 331.00, found 328.95, 330.95. Step 2: 8-Bromo-7-chloro-3,5-dicyclopropylimidazo[1,5-a]pyridine [00391] To a stirred solution of N-[(3-bromo-4-chloro-6-cyclopropylpyridin-2- yl)methyl]cyclopropanecarboxamide (0.28 g, 0.85 mmol) in Toluene (3.00 mL) was added POCl3 (1.04 g, 6.79 mmol) dropwise at room temperature. The reaction mixture was stirred for 1.5 h at 110 °C. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1). The fractions contained desired product were combined and concentrated under pressure to afford 8-bromo-7-chloro-3,5-dicyclopropylimidazo[1,5-a]pyridine (0.26 g, 97%) as a grey solid. MS ESI calculated for C13H12BrClN2 [M + H]+, 310.99, 312.99, found 310.85, 312.85. Step 3: (S)-1-(1-Acryloylpyrrolidin-3-yl)-3-((7-chloro-3,5-dicyclopropylimidazo[1,5-a]pyridin- 8-yl)ethynyl)-5-(methylamino)-1H-pyrazole-4-carboxamide [00392] To a stirred mixture of 8-bromo-7-chloro-3,5-dicyclopropylimidazo[1,5-a]pyridine (70.00 mg, 0.23 mmol), 3-ethynyl-5-(methylamino)-1-[(3S)-1-(prop-2-enoyl)pyrrolidin-3- yl]pyrazole-4-carboxamide (96.82 mg, 0.34 mmol), trans- dichlorobis(triphenylphosphine)palladium (15.77 mg, 0.02 mmol) and cuprous iodide (8.56 mg, 0.04 mmol) in N,N-dimethylformamide (1.00 mL) was added triethylamine (68.20 mg, 0.68 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the crude product. The crude product (0.12 g) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep Phenyl OBD Column, 19 x 250 mm, 5 μm; Mobile phase A: water (Plus 10 mmol/L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL/min; Gradient: 44% B to 50% B in 12 min, 50% B; Wave length: 254 nm; RT: 8.3 min. The fractions contained desired product were combined and concentrated to afford (S)-1-(1- acryloylpyrrolidin-3-yl)-3-((7-chloro-3,5-dicyclopropylimidazo[1,5-a]pyridin-8-yl)ethynyl)-5- (methylamino)-1H-pyrazole-4-carboxamide (15.20 mg, 13%) as a yellow solid. MS ESI calculated for C27H28ClN7O2 [M + H]+, 518.20, 520.20, found 518.20, 520.20; 1H NMR (400 MHz, DMSO-d6) δ 7.29 (s, 2H), 7.03-6.28 (m, 4H), 6.27-6.01 (m, 1H), 5.69 (s, 1H), 5.29-5.02 (m, 1H), 3.95 (d, J = 76.6 Hz, 2H), 3.71 (s, 2H), 2.86 (d, J = 58.3 Hz, 5H), 2.36 (d, J = 38.7 Hz, 2H), 1.40-0.77 (m, 8H). Example 76
Figure imgf000192_0001
Step 1: Tert-butyl (S)-3-(3-((5-chloro-1,7-dicyclopropyl-1H-indazol-4-yl)ethynyl)-4-cyano-5- ((4-methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [00393] To a stirred mixture of tert-butyl (3S)-3-(4-cyano-3-ethynyl-5-{[(4- methoxyphenyl)methyl]amino}pyrazol-1-yl)pyrrolidine-1-carboxylate (0.20 g, 0.48 mmol), 4- bromo-5-chloro-1,7-dicyclopropylindazole (0.15 g, 0.48 mmol), trans- dichlorobis(triphenylphosphine)palladium (33.79 mg, 0.05 mmol) and cuprous iodide (18.34 mg, 0.10 mmol) in N,N-dimethylformamide (2.0 mL) was added triethylamine (0.15 g, 1.44 mmol) at room temperature. The reaction mixture was degassed with nitrogen for three times and stirred for 1 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (S)-3- (3-((5-chloro-1,7-dicyclopropyl-1H-indazol-4-yl)ethynyl)-4-cyano-5-((4- methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (57.00 mg, 18%) as a brown solid. MS ESI calculated for C36H38ClN7O3 [M + H]+, 652.27, 654.27, found 652.30, 654.30. Step 2: Tert-butyl (S)-3-(4-carbamoyl-3-((5-chloro-1,7-dicyclopropyl-1H-indazol-4-yl)ethynyl)- 5-((4-methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [00394] To a stirred solution of tert-butyl (S)-3-(3-((5-chloro-1,7-dicyclopropyl-1H-indazol-4- yl)ethynyl)-4-cyano-5-((4-methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (0.10 g, 0.15 mmol) in 1,4-dioxane (1.00 mL) and water (0.20 mL) was added Hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (13.10 mg, 0.03 mmol) at room temperature. The reaction mixture was stirred for 16 h at 80 °C. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1). The fractions contained desired product were combined and concentrated to afford tert-butyl (S)-3-(4-carbamoyl-3-((5-chloro-1,7-dicyclopropyl-1H-indazol-4-yl)ethynyl)-5-((4- methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (38.00 mg, 37%) as a grey solid. MS ESI calculated for C36H40ClN7O4 [M + H]+, 670.28, 672.28, found 670.25, 672.25. Step 3: (S)-5-Amino-3-((5-chloro-1,7-dicyclopropyl-1H-indazol-4-yl)ethynyl)-1-(pyrrolidin-3- yl)-1H-pyrazole-4-carboxamide [00395] A solution of tert-butyl (S)-3-(4-carbamoyl-3-((5-chloro-1,7-dicyclopropyl-1H-indazol- 4-yl)ethynyl)-5-((4-methoxybenzyl)amino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (75.00 mg, 0.11 mmol) in trifluoroacetic acid (0.30 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water (Plus 10 mmol/L NH4HCO3), 10% to 50% gradient in 30 min; detector: UV 254 nm. The fractions contained desired product were combined and concentrated to afford (S)-5-Amino-3- ((5-chloro-1,7-dicyclopropyl-1H-indazol-4-yl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazole-4- carboxamide (30.00 mg, 59%) as a grey solid. MS ESI calculated for C23H24ClN7O [M + H]+, 450.17, 452.17, found 450.15, 452.15. Step 4: (S)-1-(1-Acryloylpyrrolidin-3-yl)-5-amino-3-((5-chloro-1,7-dicyclopropyl-1H-indazol- 4-yl)ethynyl)-1H-pyrazole-4-carboxamide [00396] To a stirred solution of (S)-5-Amino-3-((5-chloro-1,7-dicyclopropyl-1H-indazol-4- yl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide (25.00 mg, 0.06 mmol) in N,N- dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (21.54 mg, 0.17 mmol) and acryloyl chloride (4.53 mg, 0.05 mmol) dropwise at 0 °C. The reaction mixture was stirred for 5 min at 0 °C. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 μm; Mobile phase A: water (10 mmol/L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 46% B in 8 min, 46% B; Wave length: 254 nm; RT: 6.4 min. The fractions contained desired product were combined and concentrated to afford (S)-1-(1-acryloylpyrrolidin-3-yl)-5-amino-3-((5-chloro- 1,7-dicyclopropyl-1H-indazol-4-yl)ethynyl)-1H-pyrazole-4-carboxamide (2.60 mg, 9%) as a white solid. MS ESI calculated for C26H26ClN7O2 [M + H]+, 504.18, 506.18, found 504.20, 506.20; 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 2.3 Hz, 1H), 7.41 (s, 1H), 7.15 (s, 1H), 6.74-6.50 (m, 4H), 6.19-6.14 (m, 1H), 5.72-5.68 (m, 1H), 5.01-4.97 (m, 1H), 4.24-4.20 (m, 1H), 4.09-3.75 (m, 2H), 3.74-3.42 (m, 2H), 2.86-2.81 (m, 1H), 2.38 (d, J = 6.9 Hz, 1H), 2.30-2.25 (m, 1H), 1.34-1.29 (m, 2H), 1.25- 1.06 (m, 4H), 1.01-0.97 (m, 2H). II. Biological Evaluation [00397] Example 1: FGFR2 Kinase Assay [00398] Small molecule inhibition of FGFR2 kinase activity was evaluated using a fluorescence- based microfluidic mobility shift assay. FGFR2 catalyzes the production of ADP from ATP during phosphoryl transfer to the substrate peptide, FLPeptide30 (5-FAM-KKKKEEIYFFF- CONH2) (Perkin Elmer, 760430). The mobility shift assay electrophoretically separates the fluorescently labeled peptides (substrate and phosphorylated product) following the kinase reaction. Both substrate and product were measured and the ratio of these values used to generate % conversion of substrate to product by the LabChip EZ reader (Perkin Elmer). Wild type FGFR2 (Carna Bioscience, 08-134) at 0.06 nM was prepared with 1.5 ^M substrate, 10 mM MgCl and 100 ^M ATP in a buffer containing 50 nM HEPES, 1 mM EGTA, 0.01% Brij-35, 0.05% BSA, and 2 mM DTT prior to addition of compounds in DMSO and incubation for 80 minutes at room temperature. The reaction was terminated by addition of 0.5 M EDTA. IC50 values were calculated using the inhibition of conversion ratio using Dotmatics Knowledge Solutions Studies curve fitting (Dotmatics, Bishops Stortford, UK, CM23) and are presented in Table 2. Table 2
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Note: Biochemical assay IC50 data are designated within the following ranges: A: ≤ 0.10 µM C: > 1.0 µM to ≤ 10 µM B: > 0.10 µM to ≤ 1.0 µM D: > 10 µM to 30 µM III. Preparation of Pharmaceutical Dosage Forms Example 1: Oral capsule [00399] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. A capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration. Example 2: Solution for injection [00400] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg-eq/mL. [00401] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMS 1. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I) or Formula (II):
Figure imgf000198_0001
wherein, R1, R2, R3, and R4 are each independently selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, or optionally substituted C3-C6 cycloalkyl; R is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3- C7 carbocyclyl, optionally substituted C3-C7 carbocyclylalkyl, optionally substituted C3-C7 heterocyclyl, optionally substituted C3-C7 heterocyclylalkyl, optionally substituted C2-C7 alkenyl, -CO2R5, -CONHR5, or –CON(R5)2; each R5 is independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C7 carbocyclyl, optionally substituted C3-C7 carbocyclylalkyl, optionally substituted C3-C7 heterocyclyl, or optionally substituted C3-C7 heterocyclylalkyl; and R6 is an optionally substituted alkyl, optionally substituted carbocyclylalkyl, or optionally substituted heterocyclylalkyl.
2. The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I).
3. The compound of claim 1, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II).
4. The compound of any one of claims 1-3, or pharmaceutically acceptable salt or solvate thereof, wherein R1 is halogen.
5. The compound of any one of claims 1-4, or pharmaceutically acceptable salt or solvate thereof, wherein R2 and R3 are hydrogen.
6. The compound of any one of the preceeding claims, or pharmaceutically acceptable salt or solvate thereof, wherein R3 is optionally substituted C1-C4 alkyl.
7. The compound of any one of claims 1-5, or pharmaceutically acceptable salt or solvate thereof, wherein R3 is optionally substituted C3-C6 cycloalkyl.
8. The compound of any one of the preceeding claims, or pharmaceutically acceptable salt or solvate thereof, wherein R4 is optionally substituted C1-C4 alkyl.
9. The compound of any one of claims 1-7, or pharmaceutically acceptable salt or solvate thereof, wherein R4 is optionally substituted C3-C6 cycloalkyl.
10. The compound of any one of the preceeding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen.
11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C6 alkyl.
12. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C7 carbocyclyl.
13. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C7 carbocyclylalkyl.
14. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C7 heterocyclyl, or an optionally substituted C3-C7 heterocyclylalkyl.
15. The compound of claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl is a C1-C3 alkyl substituted with a C1-C3 alkoxy.
16. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein R is a -CH2OCH3 group.
17. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of a compound selected from Table 1.
18. A pharmaceutical composition comprising a compound of any one of claims 1-17, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
19. A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt or solvate thereof, of any one of claims 1-17, and a pharmaceutically acceptable carrier.
20. Use of a compound of any one of claims 1-17, or pharmaceutically acceptable salt or solvate thereof, for the inhibition of an FGFR kinase enzyme.
21. A method of inhbibiting an FGFR kinase enzyme comprising contacting the enzyme with a compound of any one of claims 1-17.
22. A compound of any one of claims 1-17, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.
23. A compound of any one of claims 1-17, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or neoplastic disease.
24. Use of a compound of any one of claims 1-17, or pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or neoplastic disease.
25. A method of treating cancer in a patient in need thereof comprising administering to the patient a compound as described in any one of claims 1-17, or pharmaceutically acceptable salt or solvate thereof.
26. A method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of any one of claims 1-17, or pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
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Citations (3)

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US20200339541A1 (en) * 2016-09-19 2020-10-29 Beijing Innocare Pharma Tech Co., Ltd. Alkynyl-substituted heterocyclic compound, preparation method therefor and medical use thereof
WO2020236524A1 (en) * 2019-05-17 2020-11-26 Kinnate Biopharma Inc. Inhibitors of fibroblast growth factor receptor kinases
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US20200339541A1 (en) * 2016-09-19 2020-10-29 Beijing Innocare Pharma Tech Co., Ltd. Alkynyl-substituted heterocyclic compound, preparation method therefor and medical use thereof
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DATABASE PUBCHEM COMPOUND 2 September 2021 (2021-09-02), ANONYMOUS : "gunagratinib", XP093072983, retrieved from PUBCHEM Database accession no. 442878695 *
JIANG KAILI, TANG XIA, GUO JING, HE RUI, CHAN SHINGPAN, SONG XIAOJUAN, TU ZHENGCHAO, WANG YUTING, REN XIAOMEI, DING KE, ZHANG ZHAN: "GZD824 overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo", CANCER MEDICINE, vol. 10, no. 14, 1 July 2021 (2021-07-01), GB , pages 4874 - 4884, XP093072979, ISSN: 2045-7634, DOI: 10.1002/cam4.4041 *

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