WO2023028054A1 - Quinazoline compounds for treatment of disease - Google Patents

Quinazoline compounds for treatment of disease Download PDF

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Publication number
WO2023028054A1
WO2023028054A1 PCT/US2022/041218 US2022041218W WO2023028054A1 WO 2023028054 A1 WO2023028054 A1 WO 2023028054A1 US 2022041218 W US2022041218 W US 2022041218W WO 2023028054 A1 WO2023028054 A1 WO 2023028054A1
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WIPO (PCT)
Prior art keywords
oxy
amino
prop
methoxyquinazolin
fluorophenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2022/041218
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English (en)
French (fr)
Inventor
Shunqi Yan
Litain YEH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Arthrosi Therapeutics Inc
Original Assignee
Arthrosi Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Arthrosi Therapeutics Inc filed Critical Arthrosi Therapeutics Inc
Priority to JP2024511970A priority Critical patent/JP2024532249A/ja
Priority to KR1020247009297A priority patent/KR20240069728A/ko
Priority to US18/685,798 priority patent/US20250243171A1/en
Priority to EP22861983.9A priority patent/EP4392423A4/en
Priority to IL310870A priority patent/IL310870A/en
Priority to CA3229692A priority patent/CA3229692A1/en
Priority to AU2022332906A priority patent/AU2022332906A1/en
Publication of WO2023028054A1 publication Critical patent/WO2023028054A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—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
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D471/06—Peri-condensed systems
    • 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
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/12—Heterocyclic compounds containing pteridine ring systems containing pteridine ring systems condensed with carbocyclic rings or ring 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
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    • 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
    • C07D487/06—Peri-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
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein X is cyclobutylene optionally substituted with one, two, three, or four R 8 .
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein X is cyclopentylene optionally substituted with one, two, three, or four R 8 .
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof Formula (Ia).
  • R 7 is hydrogen.
  • R 1 is selected from C 3-8 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C3-8cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, are optionally substituted with one, two, three, or four R 9 ;
  • R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(
  • a compound of Formula (I), (Ia), or (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is C 6-10 aryl optionally substituted with one, two, three, or four R 9 .
  • R 1 is a compound of Formula (I), (Ia), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is phenyl optionally substituted with one, two, three, or four R 9 .
  • a compound of Formula (I), (Ia), or (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is C 1-9 heteroaryl optionally substituted with one, two, three, or four R 9 .
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is unsubstituted C 1-9 heteroaryl.
  • R 1 is unsubstituted C 1-9 heteroaryl.
  • R 5 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 5 is a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is - OR 10 .
  • R 3 is hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl.
  • R 3 is hydrogen.
  • R 3 is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is halogen.
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 5 is -OR 10 and R 10 is C 1-6 alkyl substituted with one group selected from C 1-6 alkoxy, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl.
  • R 5 is -OR 10 and R 10 is C 1-6 alkyl substituted with one group selected from C 1-6 alkoxy, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl.
  • R 5 is -OR 10 and R 10 is unsubstituted C 1-6 alkyl.
  • R 5 is -OR 10 and R 10 is -CH 3 .
  • R 1 is C 1- 9 heteroaryl optionally substituted with one, two, three, or four R 9 , wherein C 1-9 heteroaryl is a quinolinyl, indolyl, or benzothiazolyl.
  • R 9 is independently selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl; or two R 9 substituents are combined to form a cylcloalkyl or heterocycloalkyl ring.
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 1-6 alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 1-6 haloalkyl.
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 4 is hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl.
  • R 4 is hydrogen, halogen, C 1-6 alkyl, or C 1-6 haloalkyl.
  • R 4 is hydrogen.
  • R 4 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 is halogen.
  • R 4 is C 1-6 alkyl.
  • R 5 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -OR 10 .
  • R 5 is hydrogen.
  • R 5 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is halogen.
  • R 5 is -OR 10 and R 10 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 1-6 haloalkyl, C3- 6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl.
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 5 is -OR 10 and R 10 is C 1-6 alkyl optionally substituted with one, two, or three groups selected from C 1-6 alkoxy, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl.
  • R 5 is -OR 10 and R 10 is C 1-6 alkyl substituted with one, two, or three groups selected from C 1-6 alkoxy, C 3- 6cycloalkyl, and C 2-9 heterocycloalkyl.
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 5 is -OR 10 and R 10 is C 1-6 haloalkyl.
  • R 5 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is -OR 10 and R 10 is C 3-6 cycloalkyl.
  • R 5 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is -OR 10 and R 10 is C 2-9 heterocycloalkyl.
  • R 6 is .
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 6 is and R 14 is C 1- 6 alkyl optionally substituted with -N(R 10 )(R 11 ).
  • R 6 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is .
  • R 6 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 is and R 14 is hydrogen.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion, are useful for the applications described herein.
  • the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that are incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and pharmaceutically acceptable salts, esters, solvate, hydrates, or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Pharmaceutically acceptable salts [0095] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization 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 the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Synthesis of Compounds [0099] In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary. [00100] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.
  • compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • therapeutically effective amounts of a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated.
  • the mammal is a human.
  • a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, for the treatment of cancer.
  • a pharmaceutical composition comprising a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, for the treatment of cancer, wherein the cancer is characterized by the overexpression of EGFR/Erb-B2 or mutations of EGFR/Erb-B2.
  • a pharmaceutical composition comprising a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, for the treatment of cancer, wherein the cancer comprises exon 20 insertions.
  • a pharmaceutical composition comprising a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, for the treatment of lung cancer.
  • the pharmaceutical formulations described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self- emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • compositions including a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • Dosage Forms [00111] The pharmaceutical compositions described herein can be formulated for administration to a mammal via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal, or transdermal administration routes.
  • the term “subject” or “individual” is used to mean an animal, preferably a mammal, including a human or non-human. The terms individual, patient and subject may be used interchangeably.
  • the pharmaceutical compositions described herein which include a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, can be formulated into any suitable dosage form, including but not limited to, solid oral dosage forms, controlled release formulations, fast melt formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
  • compositions for oral use can be obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the solid dosage forms disclosed herein may be in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol.
  • a tablet including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet
  • a pill including a sterile packaged powder
  • the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a fast-melt tablet. Additionally, pharmaceutical formulations described herein may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets. [00116] In some embodiments, solid dosage forms, e.g., tablets, effervescent tablets, and capsules, are prepared by mixing particles of a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, with one or more pharmaceutical excipients to form a bulk blend composition.
  • solid dosage forms e.g., tablets, effervescent tablets, and capsules, are prepared by mixing particles of a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, with one or more pharmaceutical excipients to form
  • compositions When referring to these bulk blend compositions as homogeneous, it is meant that the particles of a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.
  • the individual unit dosages may also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent.
  • These formulations can be manufactured by conventional pharmacological techniques.
  • Conventional pharmacological techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy (1986).
  • Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like.
  • the pharmaceutical solid dosage forms described herein can include a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof.
  • a compatible carrier such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination
  • Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
  • disintegrants are used in the formulation, especially when the dosage forms are compressed with binder.
  • Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel ® , or sodium starch glycolate such as Promogel ® or Explotab ® , a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel ® , Avicel ® PH101, Avicel ® PH102, Avicel ® PH105, Elcema ® P100, Emcocel ® , Vivacel ® , Ming Tia ® , and Solka-Floc ® , methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol ® ), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked
  • the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, or a gum.
  • the disintegrating agent is croscarmellose sodium.
  • Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step.
  • Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel ® ), hydroxypropylmethylcellulose (e.g.
  • binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binder. Formulators skilled in art can determine the binder level for the formulations, but binder usage level of up to 70% in tablet formulations is common.
  • Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali-metal and alkaline earth metal salts, such as calcium, magnesium, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet ® , boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as CarbowaxTM, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.
  • stearic acid calcium hydroxide, talc, corn starch
  • the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. In some embodiments provided herein, the lubricant is magnesium stearate.
  • Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like.
  • the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. In some embodiments provided herein, the diluent is microcrystalline cellulose.
  • non water-soluble diluent represents compounds typically used in the formulation of pharmaceuticals, such as calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose (e.g., having a density of about 0.45 g/cm 3 , e.g. Avicel, powdered cellulose), and talc.
  • Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10 ® ), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS, and the like.
  • quaternary ammonium compounds e.g., Polyquat 10 ®
  • Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic ® (BASF), and the like.
  • the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide.
  • the surfactant is sodium lauryl sulfate.
  • Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate- 80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such
  • Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
  • BHT butylated hydroxytoluene
  • sodium ascorbate sodium ascorbate
  • tocopherol sodium ascorbate
  • additives used in the solid dosage forms described herein there is considerable overlap between additives used in the solid dosage forms described herein.
  • the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms described herein.
  • the amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.
  • Methods [00132] is a method for treating cancer comprising administering to the individual in need thereof a therapeutically effective amount of a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, described herein.
  • a method for treating cancer comprising administering to the individual in need thereof a therapeutically effective amount of a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, described herein, wherein the cancer is characterized by the overexpression of EGFR/Erb-B2 or mutations of EGFR/Erb-B2.
  • a method for treating cancer comprising administering to the individual in need thereof a therapeutically effective amount of a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, described herein, wherein the cancer is characterized by the overexpression of EGFR/Erb-B2.
  • a method for treating cancer comprising administering to the individual in need thereof a therapeutically effective amount of a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, described herein, wherein the cancer is characterized by mutations of EGFR/Erb-B2.
  • a method of treating cancer in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), (Ia), (II), or (III) described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer comprises exon 20 insertions.
  • a method for treating cancer comprising administering to the individual in need thereof a therapeutically effective amount of a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, described herein, wherein the cancer is lung cancer.
  • a method for treating cancer comprising administering to the individual in need thereof a therapeutically effective amount of a compound of Formula (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, described herein, wherein the cancer is non-small-cell lung cancer.
  • Methods of Dosing and Treatment Regimens [00133]
  • a compound of Formula (I), (Ia), (II), or (III) is used in the preparation of medicaments for the treatment of diseases or conditions that would benefit from inhibition of EGFR exon 20 insertion mutants.
  • a compound of Formula (I), (Ia), (II), or (III) is used in the preparation of medicaments for the treatment of cancer that would benefit from inhibition of EGFR exon 20 insertion mutants.
  • a method for treating any of the diseases or conditions described herein in an individual in need of such treatment involves administration of pharmaceutical compositions containing a compound of Formula (I), (Ia), (II), or (III), or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said individual.
  • compositions containing a compound of Formula (I), (Ia), (II), or (III) are administered for prophylactic, therapeutic, or maintenance treatment.
  • compositions containing a compound of Formula (I), (Ia), (II), or (III) are administered for therapeutic applications.
  • compositions containing a compound of Formula (I), (Ia), (II), or (III) are administered for prophylactic applications.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
  • a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition is defined to be a "prophylactically effective amount or dose.”
  • dose a pharmaceutically effective amount or dose.
  • the precise amounts also depend on the patient's state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • a maintenance dose is administered, if necessary.
  • the dosage or the frequency of administration, or both can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder, or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 – about 1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the unit dosage may be in the form of a package containing discrete quantities of the formulation.
  • Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
  • Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50.
  • Example 1 Preparation of 1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)azetidin-1-yl)prop-2-en-1-one (Compound 1) [00150] Step A: To a solution of 2-amino-4-methoxybenzoic acid (50 g, 0.3 mol) in MeOH (500 mL) was added concentrated sulfuric acid (50 mL) dropwise at 0 o C. After addition, the mixture was heated to reflux for 2 days. The reaction mixture was cooled to room temperature. MeOH was removed in vacuo and the residue was poured into water (1 L). Na 2 CO 3 was added with stirring until the pH > 8.
  • Step C A mixture of methyl 2-amino-5-iodo-4-methoxybenzoate (58.1 g, 189.3 mmol) and formamidine acetate (59 g, 567.7 mmol) in 2-methoxyethanol (200 mL) was warmed to 125 o C overnight. The mixture was cooled to room temperature and concentrated in vacuo. To the residue was added water (300 mL). A precipitate was filtered and washed with water. The solid was triturated with EtOAc (200 mL), filtered and dried to afford 6-iodo-7-methoxyquinazolin- 4(3H)-one (54 g, 95% yield ) as a white solid.
  • Step D To a solution of 6-iodo-7-methoxyquinazolin-4(3H)-one (54 g, 178.8 mmol) in SOCl 2 (500 mL) was added DMF (1 mL). The mixture was stirred at 80 o C for 1 h. The mixture was cooled to room temperature, concentrated in vacuum, and the residue was dried to give 4- chloro-6-iodo-7-methoxyquinazoline (57 g, 99% yield) as a yellow solid.
  • LC/MS (ESI, m/z): [M + H] + 321.07.
  • Step E A mixture of 4-chloro-6-iodo-7-methoxyquinazoline (57 g, 178 mmol) and 3,4- dichloro-2-fluoroaniline (32 g, 178 mmol) in iPrOH ( 500 mL) was stirred at 80 o C for 1 h. The reaction mixture was cooled to room temperature, then a precipitate was filtered.
  • Step F A mixture of Zn (950 mg, 14.83 mmol) in dry DMF (20 mL) was degassed with nitrogen.1,2-dibromoethane (183 mg, 0.98 mmol) in DMF (5 mL) was added to the mixture at RT. The mixture was stirred at 70 o C for 10 min and then cooled to RT. Trimethyl chlorosilane (106 mg, 0.98 mmol) was added and the mixture was stirred at RT for 1 hour.
  • Step G A solution of tert-butyl 3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)azetidine-1-carboxylate (500 mg, 1.01 mmol) in DCM (10 mL) was slowly added trifluoroacetic acid and stirred at RT for 1 h. The reaction was then concentrated in vacuum to give the 6-(azetidin-3-yl)-N-(3,4- dichloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine (398 mg, 99 % yield) as a yellow oil.
  • Step H To a solution of 6-(azetidin-3-yl)-N-(3,4-dichloro-2-fluorophenyl)-7- methoxyquinazolin-4-amine (398 mg, 1.01 mmol) in DCM (30 mL) was added DIPEA (261 mg,2.02 mmol), acryloyl chloride (90 mg,1.01 mmol). The mixture was stirred at RT for 1 hour. The reaction mixture was quenched by water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum.
  • Step A To a solution of 2-chloro-1,3-difluoro-4-nitrobenzene (970 mg, 4 mmol) and phenylmethanol (600 mg, 4.4 mmol) in DMF (15 mL) was added K2CO3 (1.33 g, 8 mmol). The mixture was stirred at room temperature for 16 hours. H2O was added and the mixture extracted with EA. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered, concentrated and purified by column (PE 100%) to give 1-(benzyloxy)-2-chloro-3-fluoro-4-nitrobenzene (660 mg, 47 % yield) as a white solid.
  • Example 11 Preparation of 1-(3-(4-((1H-indol-5-yl)amino)-7-methoxyquinazolin-6- yl)azetidin-1-yl)prop-2-en-1-one (Compound 11) [00165]
  • Step A To a solution of methyl 2-amino-5-iodo-4-methoxybenzoate (5 g, 16.3 mmol), TEA (3.5 mL, 24 mmol) in THF (100 mL) was dropwise added a solution of TFAA (3.8 g, 17.9 mmol) in THF (10 mL) over 10 min. The mixture was stirred at RT for 1.5 h.
  • Step B A mixture of Zn (2.9 g, 44.64 mmol) in dry DMF (50 mL) was degassed with nitrogen, 1,2-Dibromoethane (668 mg, 3.57 mmol) in DMF (5 mL) was added in at RT, the mixture was stirred at 70 o C for 10 min and then cooled to RT. Then, trimethyl chlorosilane (386 mg, 3.57 mmol) was added and the mixture was stirred at RT for 1 hour.
  • Step D A mixture of tert-butyl 3-(4-amino-2-methoxy-5- (methoxycarbonyl)phenyl)azetidine-1-carboxylate (1.8 g, 5.36 mmol), formamidine acetate (1.7 g, 16.34 mmol) in 2-metholyethenol (12 mL) was stirred at 125 o C for 6 h under N2.
  • Step E To a solution of tert-butyl 3-(4-hydroxy-7-methoxyquinazolin-6-yl)azetidine-1- carboxylate (1.7 g, 94% yield) as a brown solid.
  • LC/MS (ESI, m/z): [M+H] + 332.2.
  • Step E To a solution of tert-butyl 3-(4-hydroxy-7-methoxyquinazolin-6-yl)azetidine-1- carboxylate (1.7 g, 5.1 mmol) in DCM (20 mL) was added TFA (10 mL) at 0 o C.
  • Step F To a solution of 6-(azetidin-3-yl)-7-methoxyquinazolin-4-ol hydrochloride (1.2 g, 5.11 mmol) and TEA (4.8 g, 76.59 mmol) in DCM 50 mL) was added TFAA (7.7 g, 30.63 mmol) in DCM (5 mL) at 0 o C. The mixture was stirred at RT for 3 h.
  • Step G A mixture of 2,2,2-trifluoro-1-(3-(4-hydroxy-7-methoxyquinazolin-6- yl)azetidin-1-yl)ethan-1-one (500 mg, 1.53 mmol) in SOCl 2 (12 mL) and DMF (2 drop) was stirred at 80 o C for 30 min. After concentration, the residue (529 mg, 100% yield) was used in the next step without any purification.
  • LC/MS (ESI, m/z): [M+H] + 346.2.
  • Step H A mixture of 1-(3-(4-chloro-7-methoxyquinazolin-6-yl)azetidin-1-yl)-2,2,2- trifluoroethan-1-one (150 mg, 0.43 mmol) and 1H-indol-5-amine (57 mg, 0.43 mmol) in i-PrOH (4 mL) was stirred at 80 o C for 2 h.
  • Step I A mixture of 1-(3-(4-((1H-indol-5-yl)amino)-7-methoxyquinazolin-6- yl)azetidin-1-yl)-2,2,2- trifluoroethan-1-one (105 mg, 0.24 mmol) and K 2 CO 3 (98 mg, 0.71 mmol) in MeOH (6 mL) and H 2 O (0.6 mL) was stirred at RT for 1 h.
  • Step J To a solution of 6-(azetidin-3-yl)-N-(1H-indol-5-yl)-7-methoxyquinazolin-4- amine (35 mg, 0.10 mmol) and TEA (9.1 mg, 0.30 mmol) in DCM (1.5 mL) was added acryloyl chloride (3.9 mg, 0.10 mmol) at 0 o C. The reaction was stirred at 0 o C for 30 min.
  • Example 12 Preparation of 1-(3-(4-(indolin-5-ylamino)-7-methoxyquinazolin-6- yl)azetidin-1-yl)prop-2-en-1-one (Compound 12) [00176] Step A: To a solution of 5-nitroindoline (200 mg, 1.22 mmol) in THF (5 mL) was added (Boc) 2 C (531 mg, 2.44 mmol) and DMAP (15 mg, 0.122 mmol). The reaction was stirred at RT for 1 h.
  • Steps B, C, and D were completed in a similar manner as described in Example 17 steps E, F, and G to afford 1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-(2-(4-methylpiperazin-1- yl)ethoxy)quinazolin-6-yl)azetidin-1-yl)prop-2-en-1-one (Compound 21).
  • LC/MS (ESI, m/z): [M + H] + 559.4, 561.4.
  • Step B A mixture of N-(3,4-dichloro-2-fluorophenyl)-6-iodo-7-methoxyquinazolin-4- amine (26 g, 56.15 mmol) and pyridine hydrochloride (129.8 g, 1120 mmol) was warmed to 185 o C. The mixture was heated gradually under magnetic stirring. Then the reaction mixture was maintained at 185 o C for 1 h. The reaction mixture was cooled to room temperature. Water (1 L) was added to quench the reaction ant the precipitate was filtered. The filtrate cake was washed with water and dried to give the crude compound.
  • Step C A mixture of 4-((3,4-dichloro-2-fluorophenyl)amino)-6-iodoquinazolin-7-ol (21.4 g, 47.66 mmol), (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (11.53 g, 47.66 mmol) and K2CO3 (13 g, 95.32 mmol) in DMA (200 mL) was warmed to 115 o C and stirred for 1 h. The reaction mixture was cooled to room temperature, then poured into water, extracted with EA (3 x 200 mL).
  • Step D A mixture of Zn (7.1 g, 110.98 mmol)in dry DMF (160 mL) was degassed with nitrogen, 1,2-Dibromoethane (1.65 g, 8.88 mmol) was added in at RT, the mixture was stirred at 70 o C for 10 min and then cooled to RT. Then, trimethyl chlorosilane (959 mg, 8.88 mmol) was added and the mixture was stirred at RT for 1 hour.
  • Example 23 Preparation of 1-(3-(4-((3,4-dichloro-2-fluorophenyl)amino)-7- (difluoromethoxy)quinazolin-6-yl)azetidin-1-yl)prop-2-en-1-one (Compound 23) [00204] Step A: To a solution of 4-((3,4-dichloro-2-fluorophenyl)amino)-6-iodoquinazolin-7-ol (500 mg, 1.11 mmol) in DMF (10 mL) and H 2 O (1 mL) was added Sodium 2-chloro-2,2- difluoroacetate (508 mg, 3.34 mmol) and Cs2CO3 (726 mg, 2.22 mmol).
  • Step D To a solution of (Z)-tert-butyl ((4-((3,4-dichloro-2-fluorophenyl)imino)-1- trideuteriomethyl-1,4,6,7-tetrahydrofuro[3,2-g]quinazolin-6-yl)methyl)carbamate (128 mg, 0.258 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuum.
  • Step E To a mixture of (Z)-N-(6-(aminomethyl)-1-trideuteriomethyl -6,7- dihydrofuro[3,2-g]quinazolin-4(1H)-ylidene)-3,4-dichloro-2-fluoroaniline 2,2,2-trifluoroacetate (130 mg, 0.258 mmol) and DIPEA (66.5 mg, 0.516 mmol) in DCM (5 mL) was added acryloyl chloride (23 mg, 0.258 mmol). The mixture was stirred at RT for 1 hour. The reaction mixture was quenched by addition of MeOH and concentrated in vacuum.
  • Example 36 Preparation of N-(((Z)-4-((3,4-dichloro-2-fluorophenyl)imino)-1-((S)- tetrahydrofuran-3-yl)-1,4,6,7-tetrahydrofuro[3,2-g]quinazolin-6-yl)methyl)acrylamide (Compound 36) [00214] Step A: A mixture of tert-butyl ((4-((3,4-dichloro-2-fluorophenyl)amino)-6,7- dihydrofuro[3,2-g]quinazolin-6-yl)methyl)carbamate (100 mg, 0.21 mmol) , (R)- tetrahydrofuran-3-yl 4-methylbenzenesulfonate (66 mg, 0.273 mmol) and Cs 2 CO 3 (137 mg, 0.42 mmol) in DMA (5 mL) was warmed to 120 o C and stirred for 3 h
  • Step C To a mixture of (Z)-N-(6-(aminomethyl)-1-((S)-tetrahydrofuran-3-yl)-6,7- dihydrofuro[3,2-g]quinazolin-4(1H)-ylidene)-3,4-dichloro-2-fluoroaniline 2,2,2-trifluoroacetate (35.9 mg, 0.064 mmol) and DIPEA(16.5 mg, 0.128 mmol) in DCM (5 mL) was added acryloyl chloride (5.8 mg, 0.064 mmol). The mixture was stirred at RT for 1 hour. The reaction mixture was quenched by MeOH and concentrated in vacuo.
  • Example 65 Preparation of 3-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-3-oxopropanenitrile (Compound 65) [00219]
  • Step A To a mixture of tert-butyl 4-((4-chloro-7-methoxyquinazolin-6- yl)oxy)piperidine-1-carboxylate (226 mg, 0.57 mmol) and 3,4-dichloro-2-fluoroaniline (103 mg, 0.57 mmol) in isopropanol was degassed with nitrogen, heated to 80 o C and stirred for 1 hour under nitrogen atmosphere.
  • Step B A solution of tert-butyl 4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (308 mg, 0.57 mmol) in 4M HCl(g)- dioxane (5 mL) was stirred at rt for 30 min. The reaction mixture was concentrated in vacuo to afford N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine (251 mg, crude, 100% yield).
  • Step C A mixture of N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4- yloxy)quinazolin-4-amine (251 mg, 0.57 mmol), 2-cyanoacetic acid (48 mg, 0.57 mmol), HATU (542 mg, 1.43 mmol) and DIPEA (296 mg, 2.28 mmol) in DMF (15 mL) was degassed with nitrogen, stirred at RT for 1 hour under a nitrogen atmosphere. Water (30 mL) was added and the mixture was extracted with EA.
  • Step D A solution of 3-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-3-oxopropanenitrile (30 mg, 0.06 mmol), acetaldehyde (5.2 mg, 0.12 mmol) and piperidine (10.2 mg, 0.12 mmol) in MeOH (5 mL) was stirred at RT for 1 h.
  • Step C To a solution of 4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin- 6-yl acetate in MeOH (4 mL) was slowly added ammonium hydroxide (2 mL) at RT. After addition, the reaction mixture was stirred at RT for 2 h. The reaction was then filtered and the cake was dried to give 4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (260 mg, 85% yield) as a white solid.
  • Step E tert-butyl ((1s,3s)-3-((4-((3,4-dichloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)oxy)cyclobutyl)carbamate (356 mg, 680 umol) in 4M HCl dioxane(5 mL) was stirred for 1 hour at room temperature.
  • Example 67 Preparation of N-(3-((7-methoxy-4-((7-methyl-2,3-dihydro-1H-inden-4- yl)amino)quinazolin-6-yl)oxy)cyclobutyl)acrylamide (Compound 67) [00229] Step A: A mixture of 2,3-dihydro-1H-inden-4-amine (500 mg, 3.75 mmol) and acetic anhydride (5 mL) was stirred from 0 o C to RT for 1 h. The mixture was filtered.
  • Step B A solution of N-(2,3-dihydro-1H-inden-4-yl)acetamide (500 mg, 0.23 mmol) in AcOH was added Br 2 (912 mg, 5.7 mmol) dropwise at 0 o C.
  • Steps E, F, G, H, and I were completed in a similar manner as described in Example 66 steps B, C, D, E, and F to afford N-(3-((7-methoxy-4-((7-methyl-2,3-dihydro-1H-inden-4- yl)amino)quinazolin-6-yl)oxy)cyclobutyl)acrylamide (Compound 67).
  • LC/MS (ESI, m/z): [M + H] + 445.2.
  • Example 69 Preparation of N-(3-((4-((7-fluoro-1-hydroxy-2,3-dihydro-1H-inden-4- yl)amino)-7-methoxyquinazolin-6-yl)oxy)cyclobutyl)acrylamide (Compound 69) [00237] A solution of N-(3-((4-((7-fluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)amino)-7- methoxyquinazolin-6-yl)oxy)cyclobutyl)acrylamide (Compound 68) (10 mg, 0.03 mmol) in MeOH (5 mL) was added NaBH 4 (3 mg, 0.04 mmol) in one portion.
  • Example 71 Preparation of N-(3-((4-((5-hydroxy-5,6,7,8-tetrahydronaphthalen-2- yl)amino)-7-methoxyquinazolin-6-yl)oxy)cyclobutyl)acrylamide (Compound 71) [00240] N-(3-((4-((5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)amino)-7-methoxyquinazolin- 6-yl)oxy)cyclobutyl)acrylamide (Compound 71) was prepared from N-(3-((7-methoxy-4-((5- oxo-5,6,7,8-tetrahydronaphthalen-2-yl)amino)quinazolin-6-yl)oxy)cyclobutyl)acrylamide (Compound 70) in a similar manner as described in Example 69.
  • Step A To a solution of 3-((tert-butoxycarbonyl)amino)cyclobutyl 4- methylbenzenesulfonate (350 mg, 1.03 mmol) in dry DMF (5 mL) was added NaH (62 mg, 1.55 mmol) (60% in mineral oil) at 0 o C under N2. The reaction mixture was stirred at 0 o C for 20 min. Then MeI (176 mg, 1.236 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature of 2 h. The reaction mixture was poured into ice water, extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4.
  • Steps B, C, and D were completed in a similar manner as described in Example 66 steps D, E, and F to afford N-(3-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6- yl)oxy)cyclobutyl)-N-methylacrylamide (Compound 72).
  • LC/MS (ESI, m/z): [M +1] + 491.1, 493.1.
  • Example 92 Preparation of N-(3-((4-((3,4-dichloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)amino)cyclobutyl)acrylamide (Compound 92) [00244]
  • Step A A mixture of N-(3,4-dichloro-2-fluorophenyl)-6-iodo-7-methoxyquinazolin-4- amine (231 mg, 0.50 mmol), tert-butyl (3-aminocyclobutyl)carbamate (140 mg, 0.75 mmol), Pd 2 dba 3 (46 mg, 0.05 mmol), XantPhos (58 mg, 0.10 mmol) and Cs 2 CO 3 (325 mg, 1.00 mmol) in dry 1,4-dioxane (10 mL) was stirred at 130 o C in a sealed tube.
  • Step B To a solution of tert-butyl (3-((4-((3,4-dichloro-2-fluorophenyl)amino)-7- methoxyquinazolin-6-yl)amino)cyclobutyl)carbamate (113 mg, 022 mmol) in DCM (2 mL) was added TFA (1 mL) at 0 o C. The mixture was stirred at room temperature for 0.5 hour.
  • Step B A mixture of 4-chloro-7-methoxyquinazolin-6-ol (1.45 g, 6.9 mmol), 3-((tert- butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate (2.8 g, 8.3 mmol) and K 2 CO 3 (1.9 g, 13.8 mmol) in DMA (10 mL) was degassed with nitrogen, heated to 120 o C and stirred for 2 hours under nitrogen atmosphere. Then the mixture was quenched with water (50 mL) and extracted with EtOAc (40 mL x 3).
  • Step C A mixture of tert-butyl (3-((4-chloro-7-methoxyquinazolin-6- yl)oxy)cyclobutyl)carbamate (150 mg, 0.39 mmol), (3-chlorophenyl)methanamine (112 mg, 0.79 mmol) in isopropanol was degassed with nitrogen, heated to 80 o C and stirred for 10 hours under nitrogen atmosphere. The reaction was cooled to room temperature and concentrated in vacuo.
  • Step D To a solution of tert-butyl (3-((4-((3-chlorobenzyl)amino)-7- methoxyquinazolin-6-yl)oxy)cyclobutyl)carbamate (110 mg, 0.23 mmol) in DCM (5 mL) was added HCl (4 mol/L in 1,4-dioxane, 1 mL, 4 mmol, 17.2 equiv) at 0 o C. The mixture was stirred for 2 hours at room temperature.
  • Step E To a solution of 6-(3-aminocyclobutoxy)-N-(3-chlorobenzyl)-7- methoxyquinazolin-4-amine hydrochloride (120 mg, 0.28 mmol) and triethylamine (84 mg, 0.84mmol) in DCM (5 mL) was added acryloyl chloride (28 mg , 0.31 mmol) at 0 °C. The reaction solution was stirred at the room temperature for 1 hour. Then the reaction solution was quenched with water (5 mL) and extracted with EtOAc (15 mL x 3). The combined organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Example 94 Preparation of 6-((1-acryloylpiperidin-4-yl)oxy)-N-(4-fluorobenzyl)-7- methoxyquinazoline-4-carboxamide (Compound 94) [00252]
  • Step A To 4-chloro-7-methoxyquinazolin-6-yl acetate (2 g, 7.94 mmol) and PdCl 2 (dppf) (580 mg, 0.794 mmol) was added a mixture of Et 3 N (2.4 g, 23.82 mmol) and MeOH (50 mL). The mixture was bubbled with CO (gas) to 20 atm. The mixture was warmed to 60 o C at 20 atm and stirred for 10 h.
  • Step C To a solution of methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-7- methoxyquinazoline-4-carboxylate (404 mg, 0.969 mmol) in DCM (3 mL) was slowly added trifluoroacetic acid (1 mL). The mixture was stirred at RT for 1 h. The reaction mixture was then concentrated in vacuum. The residue was dried to give methyl 7-methoxy-6-(piperidin-4- yloxy)quinazoline-4-carboxylate 2,2,2-trifluoroacetate (418 mg, 100%) which was used directly in the next step without further purification.
  • Step E To a solution of methyl 6-((1-acryloylpiperidin-4-yl)oxy)-7- methoxyquinazoline-4-carboxylate (237 mg, 0.637 mmol) in THF(5 mL) was added NaOH (51.1 mg, 1.27 mmol) in H2O (1 mL).
  • Step F To a mixture of 6-((1-acryloylpiperidin-4-yl)oxy)-7-methoxyquinazoline-4- carboxylic acid (40 mg, 0.112 mmol), 4-fluorophenyl)methanamine (17 mg, 0.134 mmol), HATU (46.8 mg, 0.123 mmol) in DCM (5 mL) was added DIPEA (43 mg, 0.336 mmol). The mixture was stirred at RT for 2 hours. The reaction mixture was poured into water and extracted with EA (3 x 20 mL).
  • Examples 95-97 were prepared using similar procedures as described in the preceding Examples.
  • 96 97 Example 98: Preparation of N-(6-((1-acryloylpiperidin-4-yl)oxy)-7-methoxyquinazolin-4- yl)-4-fluorobenzamide (Compound 98)
  • Step A To a solution of tert-butyl 4-((4-chloro-7-methoxyquinazolin-6- yl)oxy)piperidine-1-carboxylate (250 mg, 0.63 mmol) in EtOH (6 mL) was added NH4OH (6 mL), the mixture was stirred at 60 o C under N2 atmosphere overnight.
  • Step B To a solution of tert-butyl 4-((4-amino-7-methoxyquinazolin-6- yl)oxy)piperidine-1-carboxylate (195 mg, 0.44 mmol), 4-fluorobenzoic acid (93 mg, 0.66 mmol) and HATU (252 mg, 0.66mmol) in dry DMF was added DIPEA (171 mg, 1.33 mmol) at 0 o C. The mixture was stirred at RT overnight.
  • Step B To a solution of 6-((1s,3s)-3-aminocyclobutoxy)-4-((3,4-dichloro-2- fluorophenyl)amino)quinazolin-7-ol hydrochloride (140 mg, 342 umol) in H 2 O (10 mL) was added THF (5 mL) and (Boc) 2 O (224 mg, 1.02 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was quenched with water (30 mL) and extracted with EtOAc (10 mL x 3).
  • Step F To a solution of 6-((1s,3R)-3-aminocyclobutoxy)-N-(3,4-dichloro-2- fluorophenyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-aminehydrochloride was added N- isopropyl-N-methylpropan-2-amine (45.1 mg, 348.98 umol) in DCM (1 mL). Acryloyl chloride (7.9 mg, 87.24 umol) was then added. The reaction was stirred for 0.5 h at r.t., quenched by water, and extracted with DCM.
  • Example 100 Preparation of N-((1s,3s)-3-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-(2- hydroxyethoxy)quinazolin-6-yl)oxy)cyclobutyl)acrylamide (Compound 100) [00269] Step A: To a solution of tert-butyl ((1s,3s)-3-((4-((3,4-dichloro-2-fluorophenyl)amino)- 7-hydroxyquinazolin-6-yl)oxy)cyclobutyl)carbamate (150 mg, 294 umol) in DMF (5 mL).
  • Steps B and C were completed in a similar manner as described in Example 99 steps E and F to afford N-((1s,3s)-3-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-(2- hydroxyethoxy)quinazolin-6-yl)oxy)cyclobutyl)acrylamide (Compound 100).
  • LC/MS (ESI, m/z): [M+H] + 507.2, 509.2.
  • Example 101 Preparation of N-((1s,3s)-3-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-(2- (dimethylamino)ethoxy)quinazolin-6-yl)oxy)cyclobutyl)acrylamide (Compound 101) [00271]
  • Step A A mixture of tert-butyl ((1s,3s)-3-((4-((3,4-dichloro-2-fluorophenyl)amino)-7- hydroxyquinazolin-6-yl)oxy)cyclobutyl)carbamate (100 mg, 0.196 mmol), 2-bromo-N,N- dimethylethanamine hydrobromide (46 mg, 0.196 mmol) and K2CO3 (135 mg, 0.98 mmol) in DMF (5 mL) was degassed with nitrogen, heated to 40 o C and stirred for 2 hours under nitrogen atmosphere.
  • Step A To a solution of tert-butyl ((1s,3s)-3-((4-((3,4-dichloro-2-fluorophenyl)amino)- 7-hydroxyquinazolin-6-yl)oxy)cyclobutyl)carbamate (260 mg, 0.512 mmol) in dry DMF (5 mL) was added K 2 CO 3 (106 mg, 0.767 mmol) and N-phenyl-O-((trifluoromethyl)sulfonyl)-N- (((trifluoromethyl)sulfonyl)oxy)hydroxylamine (219 mg, 0.563 mmol)at room temperature.
  • Steps C and D were completed in a similar manner as described in Example 99 steps E and F to afford N-((1s,3s)-3-((4-((3,4-dichloro-2-fluorophenyl)amino)-7- (methylamino)quinazolin-6-yl)oxy)cyclobutyl)acrylamide (Compound 103).
  • LC/MS (ESI, m/z): [M+ H] + 476.0, 478.0.
  • Examples 104-105 were prepared using similar procedures as described in the preceding Examples.
  • Example 106 Preparation of 1-(4-((4-((3-chlorobenzyl)amino)-7-methoxyquinazolin-6- yl)oxy)piperidin-1-yl)prop-2-en-1-one (Compound 106)
  • Step A (method A): To a mixture of tert-butyl 4-((4-chloro-7-methoxy-5,6- dihydroquinazolin-6-yl)oxy)piperidine-1-carboxylate (109 mg, 0.277 mmol) in isopropanol (8 mL) was added Et 3 N (42 mg, 0.416 mmol) and (3-chlorophenyl)methanamine (78 mg, 0.544 mmol).
  • Step A (method B): A mixture of tert-butyl 4-((4-chloro-7-methoxy-5,6- dihydroquinazolin-6-yl)oxy)piperidine-1-carboxylate (0.3 mmol) in isopropanol (8 mL) was added (3-chlorophenyl)methanamine (0.6 mmol). The reaction mixture was stirred at 80 o C for 5 h. The mixture was concentrated in vacuum.
  • Steps B and C were completed in a similar manner as described in Example 106 steps B and C to afford 1-(4-((4-((3-chlorobenzyl)oxy)-7-methoxyquinazolin-6-yl)oxy)piperidin-1- yl)prop-2-en-1-one (Compound 107).
  • LC/MS (ESI, m/z): [M +1] + 454.2.
  • Example 126 Preparation of 2-((6-((1-acryloylpiperidin-4-yl)oxy)-7-methoxyquinazolin-4- yl)amino)-2-(3-chlorophenyl)acetic acid (Compound 126)
  • Step B A mixture of methyl 2-amino-2-(3-chlorophenyl)acetate (200 mg, 1.00 mmol), tert-butyl 4-((4-chloro-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (393 mg, 1.00 mmol), and Et3N (303mg, 3.00 mmol) in isopropanol (8 mL) was degassed with nitrogen. The reaction mixture was heated to 90 o C for 24 hour under nitrogen atmosphere. The reaction was cooled to r.t. and concentrated in vacuum.
  • Step C A solution of tert-butyl 4-((4-((1-(3-chlorophenyl)-2-methoxy-2- oxoethyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (140 mg, 0.25 mmol) in DCM (10 mL) was slowly added TFA (5 mL) and stirred at r.t. for 1 h.
  • Step D To a solution of methyl 2-(3-chlorophenyl)-2-((7-methoxy-6-(piperidin-4- yloxy)quinazolin-4-yl) amino)acetate (113 mg, 0.24 mmol) in DCM (5 mL) was added acryloyl chloride (23 mg, 0.24 mmol) and DIPEA (96 mg,0.74 mmol). The mixture was stirred at r.t. for 1 hour. Then, the reaction mixture was quenched by water, and extracted with DCM.
  • Step E A solution of methyl 2-((6-((1-acryloylpiperidin-4-yl)oxy)-7- methoxyquinazolin-4-yl)amino) -2-(3-chlorophenyl)acetate (60 mg, 0.11 mmol) in THF (10 mL) was slowly added NaOH (aq) (9 mg, 0.24 mmol) at r.t.. The mixture was stirred at r.t. for 2 h. The pH was adjusted to 5 with 1 N HCl(aq) and the mixture was then extracted with EA.
  • Example 127 Preparation of 2-((6-((1-acryloylpiperidin-4-yl)oxy)-7-methoxyquinazolin-4- yl)amino)-2-(3-chlorophenyl)acetamide (Compound 127) [00291] Step A: A solution of tert-butyl 4-((4-((1-(3-chlorophenyl)-2-methoxy-2- oxoethyl)amino)-7-methoxy quinazolin -6-yl)oxy)piperidine-1-carboxylate (70 mg, 0.12 mmol) was added Ammonia solution in methanol(5 mL, 7M) and stirred at r.t.
  • Step D To a solution of compound tert-butyl 4-((4-((1-(3-chlorophenyl)-3-methoxy-3- oxopropyl)amino)-7-methoxyquinazolin-6-yl)oxy) piperidine-1-carboxylate (80 mg, 0.14 mmol, 1 equiv) in DCM (2 mL) was added HCl (4M in 1,4-dioxane, 3.5 mL, 100 equiv), the reaction solution was stirred at room temperature for 1 hour, and then concentrated in vacuo to give crude compound methyl 3-(3-chlorophenyl)-3-((7-methoxy-6-(piperidin-4-yloxy) quinazolin-4- yl) amino) propanoate hydrochloride as a white solid (71 mg crude).
  • Step E To a solution of methyl 3-(3-chlorophenyl)-3-((7-methoxy-6-(piperidin-4- yloxy) quinazolin-4-yl)amino) propanoate hydrochloride (71 mg, 0.14 mmol, 1 equiv) and triethylamine (56 mg, 0.56mmol, 4 equiv) in DCM (5 mL) was added acryloyl chloride (14 mg, 0.15 mmol, 1.1 equiv) at 0 °C. The reaction solution was stirred at room temperature for 1 hour.
  • Step F To a solution of methyl 3-((6-((1-acryloylpiperidin-4-yl)oxy)-7- methoxyquinazolin-4-yl) amino)-3-(3-chlorophenyl) propanoate (60 mg, 0.11 mmol, 1 equiv) in THF/H2O (5 mL/0.25 mL) was added lithium hydroxide (9 mg, 0.22 mmol, 2 equiv). The mixture was stirred at 50 °C for 4 hours. The reaction mixture was concentrated in vacuo. To the residue was added EtOAc (10 mL) and the mixture was washed by 1N HCl solution (10 mL x 2).
  • Step C To a solution of compound 3-(3-chlorophenyl)-3-((7-methoxy-6-(piperidin-4- yloxy) quinazolin-4-yl)amino)propanamide hydrochloride (80 mg, 0.14 mmol, 1.0 equiv) and triethylamine (58 mg, 0.56 mmol, 4.0 equiv) in DCM (5 mL) was added acryloyl chloride (14 mg, 0.15 mmol, 1.1 equiv) at 0 °C. The reaction solution was stirred at the room temperature for 1 hour.
  • Example 131 Preparation of 1-(4-((4-((1-(3-chlorophenyl)-3-hydroxypropyl)amino)- 7- methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one (Compound 131) [00303] Step A: To a solution of tert-butyl 4-((4-((1-(3-chlorophenyl)-3-methoxy-3- oxopropyl)amino)- 7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (150 mg, 0.26 mmol, 1 equiv) in Et2O (10 mL) was added lithium borohydride (8.6 mg, 0.39 mmol, 1.5 equiv).
  • Step B To a solution of tert-butyl 4-((4-((1-(3-chlorophenyl)-3-hydroxypropyl)amino)- 7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (84 mg, 0.15 mmol, 1 equiv) in DCM (2 mL) was added HCl (4 mol/L in 1,4-dioxane, 5 mL, 131 equiv).
  • Step C A mixture of N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4- yloxy)quinazolin-4-amine (80 mg, 0.18 mmol), acryloyl chloride (17 mg ,0.18 mmol) ,Et3N (37 mg, 0.37mmol) in DCM (10 mL) was stirred for 0.5 h at r.t. The reaction was cooled to r.t and quenched by water, extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.
  • Example 134 Preparation of 1-(4-((7-methoxy-4-((1-(methylsulfonyl)indolin-5- yl)amino)quinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one (Compound 134) [00312] Step A: To a solution of 5-nitroindoline(600 mg, 3.66 mmol), Et3N (444.4 mg, 4.40 mmol) in DCM (21 mL) at 0 o C was slowly added methanesulfonyl chloride (542.6 mg, 4.76 mmol). The mixture was warmed up and stirred at rt for 1.5 h.
  • Step B A mixture of 1-(methylsulfonyl)-5-nitroindoline (100 mg, 0.41 mmol) and 10% Pd/C (43.5 mg, 0.041 mmol) in methanol (15 mL) was stirred at RT under H2 atmosphere for 18 h. The reaction mixture was filtered and washed with methanol (10 mL).
  • Step C To a mixture of tert-butyl 4-((4-chloro-7-methoxyquinazolin-6- yl)oxy)piperidine-1-carboxylate (125.7 mg, 0.32 mmol) in IPA (15 mL) was added 1- (methylsulfonyl)indolin-5-amine (68.8 mg, 0.32 mmol). The reaction mixture was stirred at 80 o C for 3 h. The mixture was concentrated in vacuum.
  • Step D To a mixture of tert-butyl 4-((7-methoxy-4-((1-(methylsulfonyl)indolin-5- yl)amino)quinazolin-6-yl)oxy)piperidine-1-carboxylate (79.2 mg, 0.14 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at rt for 2 h. The mixture was concentrated in vacuum.
  • Example 166 Preparation of 1-(4-((4-((1H-indol-7-yl)amino)-7-methoxyquinazolin-6- yl)oxy)piperidin-1-yl)prop-2-en-1-one (Compound 166) [00318] Step A: To a solution of 7-nitro-1H-indole (324 mg, 2 mmol) in acetone (20 mL) was added Zn dust (1.3 g, 20 mmol) and saturated ammonium chloride solution (1 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and concentrated in vacuum.
  • Step B A mixture of 1-(4-((4-chloro-7-methoxyquinazolin-6-yl)oxy)piperidin-1- yl)prop-2-en-1-one (30 mg, 0.086 mmol) and 1H-indol-7-amine (11.4 mg, 0.086 mmol) in i- PrOH (5 mL) was warmed to 80 o C and stirred for 2 h.
  • Step A A solution of 1-bromo-4-methylnaphthalene (500 mg, 2.26 mmol) in dioxane was added tert-butyl carbamate (397 mg, 3.39 mmol), xantphos (262 mg, 0.45 mmol), palladium (II) acetate (51 mg, 0.23mmol), Cs2CO3 (2.2 g, 6.78 mmol), the mixture was degassed with nitrogen, heated to 105
  • Step B was completed in a similar manner as described in Example 106 step B and step C was completed in a similar manner as described in Example 134 step C to afford 1-(4-((7- methoxy-4-((4-methylnaphthalen-1-yl)amino)quinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1- one (Compound 167).
  • LC/MS (ESI, m/z): [M +1] + 469.2.
  • Step C To a solution of tert-butyl 5-nitroindoline-1-carboxylate (33.68 mg, 144 umol) and 1-(4-((4-chloro-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one (50 mg, 144 umol) in isopropanol (5 mL) was added 4 M HCl(g)-dioxane (cat. one drop).
  • Step D To a solution of tert-butyl 5-((6-((1-acryloylpiperidin-4-yl)oxy)-7- methoxyquinazolin-4-yl)amino)indoline-1-carboxylate (60 mg, 109.8 umol) in DCM (3 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at RT for 1 hour.
  • Example 174 Preparation of 1-(4-((7-methoxy-4-(4-methoxybenzoyl)quinazolin-6- yl)oxy)piperidin-1-yl)prop-2-en-1-one (Compound 174) [00327] Step A: To a solution of tert-butyl 4-((4-chloro-7-methoxyquinazolin-6- yl)oxy)piperidine-1-carboxylate (100 mg, 0.25 mmol), 4-methoxybenzaldehyde (42 mg, 0.31 mmol) and 1,3-dimethyl-1H-imidazol-3-ium iodide (19 mg, 0.08 mmol) in dry 1,4-dioxane (5 mL) was added NaH (60% in oil, 12 mg, 0.31 mmol) under Ar at room temperature.
  • Step C To a solution of (7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-yl)(4- methoxyphenyl)methanone TFA salt (80 mg, 0.15 mmol) and TEA (46 mg, 0.46 mmol) in dry DCM (4 mL) was dropwise added a solution of acryloyl chloride (28 mg ,0.30 mmol) in DCM (1 mL) over 2 min at 0 o C. The reaction was stirred at 0 o C for 30 min.
  • Step E To a slurry of crude N-(3,4-dichloro-2-fluorophenyl)-6-(piperidin-3- yl)quinazolin-4-amine hydrochloride (60 mg, 0.14 mmol) in CH 2 Cl 2 (2 mL) was added DIPEA (54 mg, 0.42 mmol). The reaction mixture was turned to a clear solution. To the reaction mixture was added acryloyl chloride (1.3 mL, 0.13 mmol) (0.1 M in CH 2 Cl2 at 0 oC. The reaction mixture was stirred at room temperature for 1 h.
  • Example 188 Preparation of N-(3,4-dichloro-2-fluorophenyl)-6-(1- (vinylsulfonyl)piperidin-3-yl)quinazolin-4-amine (Compound 188) [00353] To a solution of N-(3,4-dichloro-2-fluorophenyl)-6-(piperidin-3-yl)quinazolin-4-amine (39 mg, 0.1 mmol) in DCM (2 mL) was added DIPEA (39 mg, 0.3 mmol) and 2-chloroethane-1- sulfonyl chloride (18 mg, 0.11 mmol) at 0 oC.
  • Step A To a stirred solution of 4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxy-5- nitroquinazolin-6-ol (1.3 g, 3.26 mmol) in anhydrous CH 2 Cl2 (10 mL) was added anhydrous pyridine (0.91 mL, 11.23 mmol) at 0 o C and stirred for 30 min then Tf 2 O (1.11 mL, 6.52 mmol) was added at same temperature under nitrogen atmosphere. The reaction mixture was stirred for 4 h at room temperature, then cooled to 0 o C and quenched with 1N HCl (till pH of the reaction mixture becomes neutral) to remove excess pyridine.
  • Examples 205-216 were prepared using similar procedures as described in the preceding Examples.
  • Example 217 Preparation of 1-(4-((4-(3,4-dichloro-2-fluorophenyl)-8-methoxy-5-methyl- 4H-pyrido[2,3,4-de]quinazolin-7-yl)oxy)piperidin-1yl)prop-2-en-1-one (Compound 217)
  • Step C A mixture of 4-(3,4-dichloro-2-fluorophenyl)-8-methoxy-5-methyl-7-(piperidin- 4-yloxy)-4H-pyrido[2,3,4-de]quinazoline hydrochloride (33 mg, 64 umol), acryloyl chloride (6.95 mg ,76.8 umol), DIPEA (33 mg, 256 umol) in DCM (3 mL) was stirred for 0.5 h at r.t. The reaction was cooled to r.t and quenched by water, extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum.
  • Example 218 Preparation of 1-(4-((4-(3,4-dichloro-2-fluorophenyl)-8-methoxy-4H- pyrido[2,3,4-de]quinazolin-7-yl)oxy) piperidin-1-yl)prop-2-en-1-one (Compound 218) [00379]
  • Step A To a solution of tert-butyl 4-((5-bromo-4-((3,4-dichloro-2-fluorophenyl)amino)- 7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (400 mg, 651 umol), 2-allyl-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (1.09 g, 6.51mol), K 2 CO 3 (269.5 mg, 1.95mmol) and PdCl2(dppf) (95 mg, 130 umol) in 1.4-dioxane:
  • Step B To a solution of tert-butyl 4-((5-bromo-4-((3,4-dichloro-2-fluorophenyl)amino)- 7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (50 mg, 88 umol) in MeOH (5 mL). The reaction was cooled to -78 o C and bubbled with ozone for 0.5 h until the reaction mixture turned to blue solution. The reaction mixture was stirred under nitrogen atmosphere for 10 min and dimethyl sulfide (1 mL) was added.
  • Step C To a solution of tert-butyl 4-((4-(3,4-dichloro-2-fluorophenyl)-5-hydroxy-8- methoxy-5,6-dihydro-4H-pyrido[2,3,4-de]quinazolin-7-yl)oxy)piperidine-1-carboxylate (30 mg, 51.8 umol) in DCM (3 mL). Et 3 N (52 mg, 518 umol) and MsCl (41.5 mg, 363 umol) were added. The reaction was stirred at room temperature for 4 hours and quenched by water, extracted with DCM.
  • Step E A mixture of 4-(3,4-dichloro-2-fluorophenyl)-8-methoxy-7-(piperidin-4-yloxy)- 4H-pyrido[2,3,4-de]quinazoline hydrochloride (9 mg, 18 umol), acryloyl chloride (1.96 mg ,21.6umol), DIPEA (7 mg, 54 umol) in DCM (2 mL) was stirred for 0.5 h at r.t. The reaction was cooled to r.t and quenched by water, extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum.
  • Step C To a solution of 7-methoxy-5-nitro-4-oxo-3,4-dihydroquinazolin-6-yl acetate (3.0 g, 10.74 mmol, 1.00 equiv), thionyl chloride (30 mL), N,N-dimethylformamide (0.1 mL). The resulting solution was stirred for 1.5 h at 85 o C. The resulting solution was evaporated in vacuum, extracted with EtOAc (3 x 100 mL) and the organic layers were combined and dried over Na2SO4.
  • Step D A mixture of 4-chloro-7-methoxy-5-nitroquinazolin-6-yl acetate (825 mg, 2.8 mmol), 3,4-dichloro-2-fluoroaniline (499 mg, 2.77 mmol) in isopropanol was degassed with nitrogen, heated to 80 o C and stirred for 1 hour under nitrogen atmosphere.
  • Step E A solution of 4-((3,4-dichloro-2-fluorophenyl)amino)-7-methoxy-5-nitroquinazolin-6-yl acetate (1.1g, 2.5 mmol) in MeOH (10 mL) was slowly added ammonium hydroxide at RT.
  • Example 220 Preparation of (E)-3-(3,4-dichloro-2-fluorophenyl)-9-((1-(4- (dimethylamino)but-2-enoyl)piperidin-4-yl)oxy)-8-methoxy-1H-pyrimido[4,5,6- de]quinazolin-2(3H)-one (Compound 220) [00389] To a solution of 3-(3,4-dichloro-2-fluorophenyl)-8-methoxy-9-(piperidin-4-yloxy)-1H- pyrimido[4,5,6-de]quinazolin-2(3H)-one hydrochloride (60 mg, 0.12 mmol) in DMF (3 mL) was added HATU (68.4 mg, 0.18 mmol) and DIPEA (46 mg, 0.36 mmol), (E)-4- (dimethylamino)but-2-enoic acid (23 mg, 0.18 m
  • Step C To a mixture of 5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidin-4-amine (12 g, 30.7 mmol), quinolin-3-ylboronic acid (6.387 g, 36.9 mmol), and Na2CO3 (6.523 g, 61.5 mmol) in 1,4-dioxane (100 mL) and H2O (50 mL) were added Pd(PPh3)4 (3.555 g, 3.07 mmol), and the reaction mixture was stirred at 100 o C for 16 hours under N 2 .
  • Step D To a solution of 5-(quinolin-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo [2,3-d]pyrimidin-4-amine (10 g, 25.5 mmol) in DMF (100 mL) was added NBS (5.0 g, 28.4 mmol) in an ice-salt bath, and the reaction mixture was stirred at the same temperature for 1 hr. The mixture was diluted with water (100 mL) and then extracted with EA (100 x 3 mL).
  • Step F To a solution of 6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-(quinolin-3-yl) -7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.4 g, 2.68 mmol) in DCM (15 mL) was added TFA (3.0 g, 26.8 mmol). The reaction mixture was stirred at the room temperature for 4 hr. The mixture was neutralized with Na2CO3, then concentrated under reduced pressure.
  • Step G A mixture of 3-((4-amino-5-(quinolin-3-yl)-7-((2- (trimethylsilyl)ethoxy)methyl) -7H-pyrrolo[2,3-d]pyrimidin-6-yl)oxy)propane-1,2-diol (1.1 g, 2.28 mmol), Bu2SnO (114 mg, 0.45 mmol), TEA (634 mL, 4.57 mmol) and DMAP (56 mg, 0.45 mmol) in CH 3 CN (10 mL) was stirred at the room temperature for 10 min. To this mixture was added a solution of TsCl (480 mg, 2.51 mmol) in CH 3 CN (4 mL).
  • Step H To a solution of 3-((4-amino-5-(quinolin-3-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)oxy)-2-hydroxypropyl 4- methylbenzenesulfonate (1.0 g, 1.57 mmol) in DCM (10 mL) was added TFA (10 mL). The mixture was stirred at 80 o C for 16 hours and then concentrated under reduced pressure. The residue was dissolved in CH 3 CN (10 mL). To this solution was added NH3.H2O (480 mg, 2.51 mmol). The resulting solution was stirred at the room temperature for 1 hr.
  • Step I To a mixture of 4-amino-5-(quinolin-3-yl)-8,9-dihydro-7H-pyrimido[5',4':4,5] pyrrolo[2,1-b][1,3]oxazin-8-ol (300 mg, 0.90 mmol) and TEA (0.25 mL, 1.80 mmol) in THF (4 mL) was added MsCl (0.077 mL, 0.99 mmol).
  • Step J To a solution of 4-amino-5-(quinolin-3-yl)-8,9-dihydro-7H- pyrimido[5',4':4,5]pyrrolo [2,1-b][1,3]oxazin-8-yl methanesulfonate (136 mg, 0.33 mmol) in DMF (2 mL) was added NaN3 (64 mg, 0.99 mmol). The mixture was heated at 80 o C for 16 hr. The mixture was cooled to room temperature, diluted with water (5 mL), and extracted with EA (10 x 3 mL). The organic layers were washed with water and brine, dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure.
  • Step K To a mixture of 5-(quinolin-3-yl)-8,9-dihydro-7H- pyrimido[5',4':4,5]pyrrolo[2,1-b] [1,3]oxazine-4,8-diamine (20 mg, 0.06 mmol), TEA (12 mg, 0.12 mmol) in DCM (1 mL) was added acryloyl chloride (6 mg, 0.06 mmol). The mixture was stirred at room temperature for 1 hr.
  • Step B To a solution of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (4.126 g, 14,0 mmol) in THF (40 mL) was added n-BuLi (13.2 mL, 21.1 mmol) at -78 °C under N2. The reaction solution was stirred at the same temperature for 1 hr. Then a solution of tert- butyl 4-formylpiperidine-1-carboxylate (3.9 g, 18.3 mmol) in THF (20 mL) was added dropwise to this mixture. The resulting reaction solution was stirred at -78°C for 1hr.
  • Step C To a solution of tert-butyl 4-((4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3- d]pyrimidin-6-yl) (hydroxy)methyl)piperidine-1-carboxylate (2.0 g, 3.95 mmol) in DCM (10 mL) was added TFA (10 mL).
  • Step D To a solution of (4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6- yl)(piperidin-4-yl) methanol (400 mg, 0.76 mmol) and TEA (0.853 mL, 6.15mmol) in DCM (5 mL) was added acryloyl chloride (70 mg, 0.76 mmol) at 0 °C. The reaction solution was stirred at 0°C for 1h and then the reaction solution was quenched with water (10 mL). The mixture was extracted with EA (10 mL x 3).
  • Step E To a solution of 1-(4-((4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3- d]pyrimidin-6-yl)(hydroxy) methyl)piperidin-1-yl)prop-2-en-1-one (160 mg, 0.347 mmol) and 3, 4-dichloro-2-fluoroaniline (94 mg, 0.521 mmol) in n-BuOH (3 mL) was added HCl (0.043 mL, 0.173 mmol, 4M in 1, 4-dioxane). The reaction solution was stirred at 80°C for 2h.
  • Step F To a solution of 1-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7- (phenylsulfonyl)-7H-pyrrolo [2,3-d]pyrimidin-6-yl)(hydroxy)methyl)piperidin-1-yl)prop-2-en- 1-one (30 mg, 0.049 mmol) in THF (1 mL) was added NaOH (1 mL, 10% in water). The reaction solution was stirred at 65 °C for 16 h.
  • Example 230 Preparation of 1-(4-(butoxy(4-((3,4-dichloro-2-fluorophenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-6-yl)methyl)piperidin-1-yl)prop-2-en-1-one (Compound 230) [00409] Step A: To a solution of 1-(4-((4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3- d]pyrimidin-6-yl)(hydroxy) methyl)piperidin-1-yl)prop-2-en-1-one (50 mg, 0.108 mmol) and 3,4-dichloro-2-fluoroaniline (20 mg, 0.108 mmol) in n-BuOH (2 mL) was added HCl (0.013 mL, 0.054 mmol, 4M in 1,4-dioxane).
  • reaction solution was stirred at 80°C for 1 6 h.
  • the reaction solution was cooled to room temperature, diluted with water (5 mL), and extracted with EA (5 mL x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give a residue which was purified by prep-TLC with EA to give the 1-(4-(butoxy(4-((3,4-dichloro-2-fluorophenyl)amino)-7-(phenylsulfonyl)-7H-pyrrolo [2,3- d]pyrimidin-6-yl)methyl)piperidin-1-yl)prop-2-en-1-one as a white solid (50 mg , 0.075 mmol 70.4 % yield).
  • Step B To a solution of 1-(4-(butoxy(4-((3,4-dichloro-2-fluorophenyl)amino)-7- (phenylsulfonyl)-7H- pyrrolo[2,3-d]pyrimidin-6-yl)methyl)piperidin-1-yl)prop-2-en-1-one (50 mg, 0.049 mmol) in THF (1 mL) was added NaOH (1 mL, 10% in water). The reaction solution was stirred at 65°C for 1 6 h.
  • Example 231 Preparation of 1-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-6-yl)(hydroxy)methyl)piperidin-1-yl)-3-methoxypropan-1-one (Compound 231) [00411] To a solution of 1-(4-((4-((3,4-dichloro-2-fluorophenyl)amino)-7-(phenylsulfonyl)-7H- pyrrolo[2,3-d] pyrimidin-6-yl)(hydroxy)methyl)piperidin-1-yl)prop-2-en-1-one (30 mg, 0.049 mmol) in THF (1 mL) and MeOH (1 mL) was added NaOH (1 mL, 10% in water).
  • Biological Data Example 232 EC50 assay [00412] 4,000 Ba/F3 stable cells/90 ⁇ L/well were plated onto 96-well cell culture plate (Grenier, Cat.No.655180) and incubated at 37°C with a humidified atmosphere of 5% CO2 for 2h. Then the cells were treated with 10 ⁇ L compounds at serial titration. The final DMSO concentration is 0.1%. The cells treated with 0.1% DMSO (Vetec, Cat.No.V900090) as a positive control (Max), and medium with 0.1% DMSO was as a negative control (Min). Incubated the cells at 37°C for 72h.10 ⁇ L the cell proliferation reagent CCK-8 (Dojindo, Cat.No. CK041000T) was added into each well and incubated the plate at 37°C for 4 hours, the OD value was measured by SPECTRAmax plus (Molecular Devices) at 450 nm. Data processing with Graphpad 7.0.
  • A EC50 ⁇ 200 nM
  • B 200 nM ⁇ EC50 ⁇ 1000 nM
  • C EC50 > 1000 nM

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US12145917B2 (en) 2018-12-06 2024-11-19 Arthrosi Therapeutics, Inc. Crystalline forms of a compound for treating or preventing gout or hyperuricemia
US12037346B2 (en) 2021-04-13 2024-07-16 Nuvalent, Inc. Amino-substituted heteroaryls for treating cancers with EGFR mutations
CN115894486A (zh) * 2021-09-30 2023-04-04 北京赛特明强医药科技有限公司 一种氢化吡啶并喹唑啉类化合物、组合物及其应用
CN115894486B (zh) * 2021-09-30 2024-02-09 北京赛特明强医药科技有限公司 一种氢化吡啶并喹唑啉类化合物、组合物及其应用
WO2024059169A1 (en) * 2022-09-14 2024-03-21 Blueprint Medicines Corporation Egfr inhibitors

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