WO2021030711A1 - Alkynyl quinazoline compounds - Google Patents

Alkynyl quinazoline compounds Download PDF

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Publication number
WO2021030711A1
WO2021030711A1 PCT/US2020/046425 US2020046425W WO2021030711A1 WO 2021030711 A1 WO2021030711 A1 WO 2021030711A1 US 2020046425 W US2020046425 W US 2020046425W WO 2021030711 A1 WO2021030711 A1 WO 2021030711A1
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WIPO (PCT)
Prior art keywords
alkyl
compound
halogen
optionally substituted
aryl
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PCT/US2020/046425
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English (en)
French (fr)
Inventor
Matthew C. Lucas
Fernando Padilla
Alexander Flohr
Luca Arista
Elizabeth Buck
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Black Diamond Therapeutics Inc
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Black Diamond Therapeutics Inc
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Priority to MX2022001952A priority Critical patent/MX2022001952A/es
Priority to KR1020227008023A priority patent/KR102910319B1/ko
Priority to US17/635,578 priority patent/US12435046B2/en
Priority to KR1020267000069A priority patent/KR20260013506A/ko
Priority to BR112022002518A priority patent/BR112022002518A2/pt
Priority to AU2020328598A priority patent/AU2020328598A1/en
Priority to JP2022508853A priority patent/JP7649289B2/ja
Priority to EP20764505.2A priority patent/EP4013749B1/en
Priority to CN202080072199.2A priority patent/CN114787150A/zh
Priority to CN202411509578.XA priority patent/CN119390683A/zh
Application filed by Black Diamond Therapeutics Inc filed Critical Black Diamond Therapeutics Inc
Priority to CA3150701A priority patent/CA3150701A1/en
Publication of WO2021030711A1 publication Critical patent/WO2021030711A1/en
Priority to IL290561A priority patent/IL290561A/en
Priority to MX2025010928A priority patent/MX2025010928A/es
Anticipated expiration legal-status Critical
Priority to JP2025036468A priority patent/JP7807589B2/ja
Priority to US19/278,530 priority patent/US20260049063A1/en
Priority to JP2026005252A priority patent/JP2026063185A/ja
Ceased legal-status Critical Current

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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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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    • C07D401/10—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 aromatic rings
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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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    • C07D403/10—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 carbon chain containing aromatic rings
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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
    • C07D405/10—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 carbon chain containing aromatic rings
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    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • 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
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    • 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
    • C07D487/08—Bridged systems
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    • 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
    • C07D491/10—Spiro-condensed systems
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    • 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
    • C07D491/10—Spiro-condensed systems
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    • 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
    • C07D498/08—Bridged systems

Definitions

  • the present disclosure provides a compound or pharmaceutically acceptable salts or stereoisomers thereof of formula I wherein W is CH or N, preferably CH; X 1 is –O–, –S–, or –NR3–; R a , R b are independently of each other hydrogen or C 1-4 alkyl or one of R a is –(CH 2 )p– which forms a ring with X 1 if X 1 is NR 3 or one of R a is –(CH 2 )p– which forms a ring with R 2 ; R c , R d are independently of each other hydrogen or C 1-4 alkyl; R 1 is H or F; R 2 is hydrogen or C 1-4 alkyl, or is –(CH 2 ) q – which forms a ring with R 3 or with one of R a ; R 3 is hydrogen or C 1-4 alkyl, preferably hydrogen or methyl, or is –(CH 2 ) p – which forms a
  • R 2 is methyl or R 2 is –(CH 2 )– or –(CH 2 ) 2 – which forms a ring with R 3 , or R 2 is –(CH 2 )– or –(CH 2 ) 2 – which forms a ring with one of R a .
  • R c and R d are hydrogen.
  • R b , R c and R d are hydrogen.
  • Ar 1 is of formula iii-1, iii-2, iii-3 or iii-4, iii-5, iii-6 or iii-7 or pharmaceutically acceptable salts or stereoisomers thereof wherein X 3 is CH or N; o is 0 or 1; R 4 is hydrogen or halogen, preferably F or C1; R 5 , R 6 are independently of each other hydrogen, -CF 3 or halogen, preferably F or C1; R 7 is hydrogen or halogen, preferably F. [0026] In some embodiments, R 5 is F and/or R 6 is F or Cl. [0027] In some embodiments, R 1 is hydrogen.
  • Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached.
  • the BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment.
  • At least one R Z is C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za .
  • at least one R Z is C 3 -C 10 cycloalkyl optionally substituted with one or more R Za .
  • At least one R T is -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl)2; wherein the O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 is optionally substituted with one or more R Ta .
  • At least one R T is C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R Ta .
  • at least one R T is 3- to 10-membered heterocycloalkyl optionally substituted with one or more R Ta .
  • Ar 1 is of formula i or pharmaceutically acceptable salts or stereoisomers thereof wherein R 4 hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, hydroxy C 1-5 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 6 aryl, C 1-6 alkoxy-C 5-6 heteroaryl, amino C 1-4 alkyl, C 1-6 alkylamino, C 1-6 aminoalkyl-C 6 aryl, C 1-6 aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyaminocarbonyl, aryl C 1-6 alkoxy, or C 6 aryl; R 5 , R 5’ , R 6 , R 6’ are independently of each other hydrogen, -CF 3 or halogen, preferably F, Cl.
  • Ar 1 is of formula ii-2, ii-3 or ii-4 or pharmaceutically acceptable salts or stereoisomers thereof wherein X 2 is O, NH or NMe; X 3 is CH or N; o is 0 or 1; R 5 , R 5 ’, R 6 , R 6 ’ are independently of each other hydrogen, -CF 3 or halogen, preferably F or C1; R 7 is hydrogen or halogen, preferably F. [0412] The skilled person understands that if X 3 stands for CH, R 7 may in general also be bound to this carbon, such that X 3 may be CR 7 .
  • R 2 is methyl or R 2 is —(CH 2 )– or –(CH 2 ) 2 – which forms a ring with R 3 , or R 2 is – (CH 2 )– or –(CH 2 ) 2 – which forms a ring with one of R a .
  • R c and R d are hydrogen.
  • Ar 1 is of formula iii-1 or pharmaceutically acceptable salts or stereoisomers thereof wherein R 4 is hydrogen or halogen, preferably F or C1; R 5 , R 6 are independently of each other hydrogen, -CF 3 or halogen, preferably F, Cl.
  • Ar 1 is of formula ii-2, ii-3 or ii-4 or pharmaceutically acceptable salts or stereoisomers thereof wherein X 2 is O, NH or NMe; X 3 is C or N; o is 0 or 1; R 5 , R 5 ’, R 6 , R 6 ’ are independently of each other hydrogen, -CF 3 or halogen, preferably F or C1; R 7 is hydrogen or halogen, preferably F.
  • Ar 1 is of formula ii-1b, ii- 2b, ii-3b or ii-4b, r is 0 and s is 1 or 2, or r is 1 and s is 1 or 2, or r is 0 or 1 and s is 1, or r is 0 or 1 and s is 2.
  • Ar 1 is of formula ii-1c or pharmaceutically acceptable salts or stereoisomers thereof wherein R 4 is hydrogen, F or C1; R 5 , R 5 ’, R 6 , R 6 ’ are independently of each other hydrogen, -CF 3 or halogen, preferably F, Cl.
  • X 2 is O and X 3 is N, such that Ar 1 is of formula ii-2c, ii-3c, ii-4c, ii-5c or pharmaceutically acceptable salts or stereoisomers thereof wherein o is 0 or 1; R 5 , R 5 ’, R 6 , R 6 ’ are independently of each other hydrogen, -CF 3 or halogen, preferably F or C1; R 7 is hydrogen or halogen, preferably F.
  • R 2 is methyl or is —(CH 2 )– or –(CH 2 ) 2 – which forms a ring with R 3 .
  • R 7 is F.
  • R 1 may be hydrogen.
  • the compound is selected from the compounds described in Tables 1 and 2, pharmaceutically acceptable salts thereof, and stereoisomers thereof.
  • the compound is selected from the compounds described in Tables 1 and 2 and pharmaceutically acceptable salts thereof.
  • the compound is selected from the compounds described in Tables 1 and 2.
  • the oncogenic variant of the HER2 receptor comprises an allosteric mutation.
  • the oncogenic variant of an EGFR comprises an EGFR variant III (EGFR-Viii) mutation.
  • the oncogenic variant of EGFR comprises an EGFR variant II (EGFR-Vii) mutation.
  • the oncogenic variant of EGFR comprises an EGFR variant VI (EGFR-Vvi) mutation.
  • the oncogenic variant of an EGFR comprises a substitution of a valine (V) for an alanine (A) at position 289 of SEQ ID NO: 1.
  • the cancer, or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, a nucleotide sequence encoding the oncogenic variant of a HER2 receptor comprises an insertion within a sequence encoding exon 20 or a portion thereof.
  • the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMAGVGSPYVSR(SEQ ID NO: 8).
  • the oncogenic variant of a HER4 receptor comprises deletion of exon 16 (HER4-D16).
  • the cancer, or a tumor or a cell thereof expresses an oncogenic variant of an EGFR, wherein the sequence encoding the oncogenic variant of the EGFR comprises a deletion of exon 20 or a portion thereof and wherein the the cancer, the tumor or the cell thereof does not comprise a second oncogenic variation in a sequence other than exon 20 of EGFR.
  • the second oncogenic variation comprises a sequence encoding one or more of an EGFR kinase domain (KD), BRAF, NTRK, and KRAS.
  • the cancer, or a tumor or a cell thereof is insensitive or resistant to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 and AZD9291.
  • the subject has an adverse reaction to treatment with a therapeutic agent different from the compound of the present disclosure.
  • the subject has an adverse reaction to treatment with a Type I inhibitor.
  • the subject has an adverse reaction to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 and AZD9291.
  • Hedgehog antagonists Vismodegib (or GDC-0449, described in WO 06/028958); PI3K inhibitors: Pictilisib (or GDC-0941 described in WO 09/036082 and WO 09/055730 ), Dactolisib (or BEZ 235 or NVP- BEZ 235, described in WO 06/122806); Phospholipase A2 inhibitors: Anagrelide (e.g.
  • Estramustine e.g. Emcyl(R)
  • Cathepsin K inhibitors Odanacatib (or MK-0822, by Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, described in WO 03/075836
  • Epothilone B analogs Ixabepilone (e.g. Lxempra(
  • FulexinTM Fluoxymesterone (e.g. halotestin(R)); Proteasome inhibitors: Bortezomib (e.g. Velcade(R)); CDK1 inhibitors: Alvocidib (e.g. flovopirdol or HMR-1275, described in US 5,621,002); Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide or leuprolide acetate (e.g.
  • T is —O-(C 1 -C 6 alkyl), –NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the —O-(C 1 -C 6 alkyl), –NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the –O-(C 1 -C 6 alkyl), –NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
  • Embodiment No.6 The compound of any one of the preceding Embodiments, wherein the compound is of Formula (I’) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: W is CH; Z is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R Z ; each R Z independently is halogen, -O-(C 1 -C 6 alkyl), or C 1 -C 6 alkyl; wherein the -O-(C 1 -C 6 alkyl) or C 1 -C 6 alkyl is optionally substituted with one or more halogen; T is –O-(C 1 -C 6 alkyl), –NH-(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alky
  • Embodiment No.68 The compound of any one of the preceding Embodiments, wherein at least one R T is -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 ; wherein the O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), or -N(C 1 -C 6 alkyl) 2 is optionally substituted with one or more R Ta .
  • Embodiment No.94 The compound of any one of the preceding Embodiments, wherein at least one R A1 is -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein the -O-(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl)2, C 1- C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more R A1a .
  • Embodiment No.95 The compound of any one of the preceding Embodiments, wherein at least one R A1 is -O-(C 1 -C 6 alkyl) substituted with one or more C 6 -C 10 aryl or 5- to 10-membered heteroaryl, wherein the C 6 -C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen.
  • Embodiment No.150 The compound of any one of the preceding Embodiments, wherein R 5 is F and/or wherein R 6 is F or Cl.
  • Embodiment No.151 The compound of any one of the preceding Embodiments, wherein R 1 is hydrogen.
  • Embodiment No.152 The compound of any one of the preceding Embodiments, being of formula V-1, V-2, V-3 or V-4
  • Embodiment No.165 The composition of any one of the preceding Embodiments, further comprising a second therapeutically active agent.
  • Embodiment No.166 A method of inhibiting an oncogenic variant of an ErbB receptor, comprising administering the subject in need thereof a therapeutically effective amount of the compound of any one of the preceding Embodiments.
  • Embodiment No.167 A method of inhibiting an oncogenic variant of an ErbB receptor, comprising administering the subject in need thereof the composition of any one of the preceding Embodiments.
  • Embodiment No.168 A method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of the compound of any one of the preceding Embodiments.
  • Embodiment No.185 The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.
  • Embodiment No.186 The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the oncogenic variant of the HER2 receptor comprises an allosteric mutation.
  • Embodiment No.187 The method, the compound for use, or the composition for use of any one of the preceding Embodiments, wherein the oncogenic variant or the oncogenic mutation is detiected by a Food and Drug Aministration (FDA)-approved diagnosis.
  • FDA Food and Drug Aministration
  • reaction mixture was filtered and the filtration was purified by prep-HPLC (column: Xtimate C18150 ⁇ 25mm ⁇ 5um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 48%-78%,10min) and lyophilized to give N- (4-((3-chloro-2-fluorophenyl)amino)-7-((1,3- dimethylpyrrolidin-3-yl)ethynyl)quinazolin-6- yl)acrylamide 1 (35.3 mg, 74.5 umol, 12% yield, 98% purity) as a yellow solid.
  • S68 A mixture of tert-butyl 3-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-6- nitroquinazolin-7-yl) ethynyl)-3-methylpyrrolidine-1-carboxylate S67 (0.862 g, 1.40 mmol, 1.00 eq) in hydrochloric acid /ethyl acetate (2.00 mL) was stirred at 25 °C for 1 h.
  • the solution was purified by prep-HPLC (column: Waters Xbridge 150*255u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 30%-60%,10min) and further purified by prep-HPLC (column: Phenomenex Synergi C18150*30mm*4um;mobile phase: [water(0.225%FA)-ACN];B%: 8%-38%,10min).
  • the residue was purified by reverse-phase flash [acetonitrile/(0.1% NH3 . H2O in water), 0% to 90%] and further purified by prep-HPLC [column: Phenomenex Gemini-NX C1875*30mm*3um;mobile phase: [water (0.05% ammonium hydroxide v/v)-acetonitrile];B%: 27%-57%,11.5min] to give 30 mg crude product.
  • Example 30 Synthesis of Compound No.32 (N-(4-((3-chloro-2-fluorophenyl)amino)-7-((2,4- dimethylmorpholin-2-yl)ethynyl)quinazolin-6-yl)acrylamide) [0880]
  • Step 1 To a solution of 4-(tert-butyl) 2-ethyl morpholine-2,4-dicarboxylate (5 g, 19.3 mmol) in tetrahydrofuran (38 mL) was added LiHMDS (1 M, 38.6 mL) dropwise under N 2 at -65 °C over 1 h. Then the mixture was stirred at -65 °C for 1.5 h.
  • Example 31 Synthesis of Compound No. 33 (N-(4-((3,4-dichloro-2-fluorophenyl)amino)-7- (((1S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)ethynyl)quinazolin-6-yl)acrylamide) and Compound No. 34 (N-(4-((3,4-dichloro-2-fluorophenyl)amino)-7-(((1R,5S)-3-methyl-3- azabicyclo[3.1.0]hexan-1-yl)ethynyl)quinazolin-6-yl)acrylamide) [0889] Step 1.

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