WO2024123102A1 - Kras g12d 저해제로서 신규한 3환 화합물 및 이의 용도 - Google Patents

Kras g12d 저해제로서 신규한 3환 화합물 및 이의 용도 Download PDF

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WO2024123102A1
WO2024123102A1 PCT/KR2023/020084 KR2023020084W WO2024123102A1 WO 2024123102 A1 WO2024123102 A1 WO 2024123102A1 KR 2023020084 W KR2023020084 W KR 2023020084W WO 2024123102 A1 WO2024123102 A1 WO 2024123102A1
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methoxy
octan
diazabicyclo
pyrrolizin
methyl
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PCT/KR2023/020084
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English (en)
French (fr)
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송지영
장은성
이동호
김민정
김소현
윤지연
정지은
홍범진
임선아
신용제
문미진
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에스케이바이오팜 주식회사
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Publication of WO2024123102A1 publication Critical patent/WO2024123102A1/ko

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    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/08—Bridged 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

Definitions

  • This application relates to novel tricyclic compounds, pharmaceutical compositions containing them and their use as medicaments.
  • KRAS Kristen rat sarcoma virus
  • NRAS, HRAS, KRAS a protein belonging to the RAS family (NRAS, HRAS, KRAS) that transmits important signals in cell proliferation and differentiation. It receives signals from cell membrane receptors and activates the downstream signal proteins PI3K, Raf, It transmits signals to MEK, ERK, etc.
  • KRAS protein is a molecular switch and is in an “activation (GTP-bound form, turn-on) state” in which GDP at the nucleotide binding site is exchanged for GTP through an intrinsic nucleotide exchange, thereby transducing signals to downstream signal transduction proteins. It becomes. Conversely, when GTP bound to the KRAS protein is intrinsically hydrolyzed to GDP and enters an “inactive (GDP-bound form, turn-off) state,” downstream signaling does not occur. At this time, in actual cells, the exchange of GDP to GTP is promoted by guanine exchange factor (GEF), and the hydrolysis of GTP to GDP is rapidly increased by GTPase activating protein (GAP). .
  • GTP-bound form, turn-on guanine exchange factor
  • KRAS gene mutation has been found to play an important role in cancer cell proliferation in many malignant tumors, and approximately 89% of KRAS gene mutation cancer patients are caused by a mutation in which glycine (KRAS G12) in codon 12 of the KRAS gene is changed to a different amino acid. .
  • KRAS G12 mutations occur in 86% of pancreatic adenocarcinoma (PDAC), 41% of colorectal cancer (CRC), and 32% of non-small cell lung cancer (NSCLC), and among all KRAS G12 mutations, G12D (36%) and G12V (23%) ), G12C (14%), and the mutation frequency is reported in that order.
  • PDAC pancreatic adenocarcinoma
  • CRC colorectal cancer
  • NSCLC non-small cell lung cancer
  • KRAS G12 mutant protein inhibits the hydrolysis of GTP by GAP and maintains the activated (GTP bound form) state, thereby rapidly increasing the proliferation and survival of cancer cells
  • KRAS inhibitors created competitive inhibitors of GTP binding to inhibit activated KRAS, but many KRAS inhibitors failed because GTP exists in a significantly higher concentration than the concentration of the inhibitor in the actual cell. For this reason, it was considered impossible to develop a targeted treatment that directly targets KRAS, and as an alternative to suppress KRAS mutant cancer, it is possible to inhibit downstream signaling proteins other than the KRAS protein such as PI3K, MEK, AKT, and mTOR or to modify the KRAS protein post-translationally. An attempt was made to indirectly inhibit the activity of KRAS mutant cancer cells, such as by inhibiting KRAS fanesyltransferase (post-translation modification), but no good clinical effect was achieved.
  • KRAS fanesyltransferase post-translation modification
  • Sotorasib (LUMAKRASTM), a small molecule that selectively inhibits KRAS G12C targeting, was developed and approved by the FDA for non-small cell lung cancer.
  • one object of the present application is a novel compound based on the tricyclic ring of Formula 1, which exhibits an excellent activity inhibitory effect of KRAS G12D, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate, or pharmaceutically thereof. This is to provide an acceptable salt.
  • Another object of the present application is to provide a pharmaceutical composition containing the novel tricyclic ring-based compound, its optical isomer, stereoisomer, isotopic variant, hydrate, solvate, or pharmaceutically acceptable salt thereof as an active ingredient. It is provided.
  • a compound of the following formula (1), its optical isomer, stereoisomer, isotopic variant, hydrate, solvate, or pharmaceutically acceptable salt thereof is provided:
  • A is , , , or and
  • X is C or N
  • R 1 is hydrogen, halogen, C 1-3 alkyl, or C 1-3 alkoxy
  • L is a direct bond, O, or NR 6 ;
  • R 2 is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 2-6 alkoxyalkyl, C 1-6 haloalkyl , R x , -Z 1 -R x , -Z 1 -R y -R x , -Z 1 -R y -Z 2 -N(R 15 ) 2 , -Z 1 -R y -Z 2 -R x , -N(R 15 ) 2 , -Z 1 -N (R 15 ) 2 , -Z 1 -C(O)N(R 15 ) 2 , or -Z 1 -OR 15 ;
  • R or may be substituted with multiple R 7 ;
  • Z 1 to Z 3 are independently C 1-4 alkyl; optionally substituted with hydroxy, C 1-4 hydroxyalkyl, or 6- to 20-membered heteroaryl;
  • R 6 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21 are each independently H or C 1-3 alkyl;
  • R 3 is 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 20-membered aryl, or 6- to 20-membered heteroaryl, optionally with one or more R 8 may be substituted;
  • R 4 is , , or -NH-R 9 -R 10 ;
  • R 9 is a direct bond or C 1-4 alkyl
  • R 10 is 3- to 10-membered cycloalkyl or 3- to 10-membered heterocycloalkyl, and may be optionally substituted with one or more R 11 ;
  • R 11 is C 1-3 alkyl, hydroxy, N(R 19 ) 2 , C 1-3 alkyl-N(R 19 ) 2 , C 1-3 cyanoalkyl, 3- to 10-membered heterocyclyl. ;
  • R 12 is H, C 1-3 alkyl, OH, -N(R 20 ) 2 , -CH 2 N(R 20 ) 2 , cyano, cyanomethyl, or 3- to 10-membered heterocyclyl;
  • R 14 is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -N(R 6 ) 2 , -OR 6 , -SR 6 , 3- to 10-membered cycloalkyl, 3-membered cycloalkenyl of 3 to 10 members, cycloalkynyl of 3 to 10 members, heterocyclyl of 3 to 10 members, aryl of 6 to 20 members, or heteroaryl of 6 to 20 members;
  • n is an integer from 0 to 4.
  • R 5 is H, halogen, C 1-6 alkyl, C 1-3 haloalkyl, 3- to 6-membered Cycloalkyl, 3 to 6 membered Heterocycloalkyl, cyano, cyanoC 1-3 alkyl, hydroxy, C 1-3 hydroxyalkyl, C(O)(NR 21 ) 2 , 6- to 20-membered aryl, C 1-3 alkyl- 3- to 6-membered cycloalkyl, C 1-3 alkyl-3- to 6-membered heterocycloalkyl, C 1-3 alkyl-6- to 20-membered aryl, or C 1-3 alkyl-6 to 20 membered It is a heteroaryl of a circle.
  • the A is , , or It can be.
  • R 1 may be hydrogen, halogen, or C 1-3 alkyl.
  • L may be a direct bond or O.
  • the R 2 is R x , -Z 1 -R x , -Z 1 -R y -R x , -Z 1 -R y -Z 2 -N(R 15 ) 2 , or -Z 1 -R It may be y -Z 2 -R x .
  • R x is a 3- to 10- membered heterocyclyl
  • R y is a 3- to 10 - membered cycloalkyl
  • R It may be something that can be replaced. More specifically, R It may be a 3- to 10-membered heterocycle containing an atom.
  • R [2.2.1]heptanyl (2-oxa-5-azabicyclo[2.2.1]heptanyl), pyrrolizidinyl, methylenepyrrolizidinyl, tetrahydro-1' H , 3' H -spiro[cyclopropane-1,2'-pyrrolizidinyl] (tetrahydro-1' H ,3' H -spiro[cyclopropane-1,2'-pyrrolizidinyl]), 6-azaspiro[2.5]octanyl ( 6-azaspiro[2.5]octanyl), quinolizidinyl, indolinyl, benzimidazolyl, azaspirooctanyl, benztriazolyl, thioxanthinyl, carbazolyl, carbazolyl It is carbolinyl, or acridinyl, and may be optionally substituted with one or more R 7 .
  • R azabicyclo[2.2.1]heptanyl
  • pyrrolizidinyl methylenepyrrolizidinyl
  • tetrahydro-1' H ,3' H -spiro[cyclopropane-1,2'-pyrrolizidi Nyl] tetrahydro-1' H ,3' H -spiro[cyclopropane-1,2'-pyrrolizidinyl]
  • 6-azaspiro[2.5]octanyl 6-azaspiro[2.5]octanyl
  • it may be substituted with multiple R 7s .
  • R y is a 3- to 5-membered cycloalkyl (for example, cyclopropyl or cyclobutyl), and may be optionally substituted with one or more R 7 .
  • R 2 is R x , -Z 1 -R x , -Z 1 -R y -R x , -Z 1 -R y -Z 2 -N(R 15 ) 2 , or -Z 1 -R y -Z 2 -R x , wherein R It may be replaced with one or more R 7 .
  • R 2 is R x , -Z 1 -R x , -Z 1 -R y -R x , -Z 1 -R y -Z 2 -N(R 15 ) 2 , or - Z 1 -R y -Z 2 -R x
  • R x is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2-oxa-5-azabicyclo [2.2.1] Heptanyl (2-oxa-5-azabicyclo[2.2.1]heptanyl), pyrrolizidinyl, methylenepyrrolizidinyl, tetrahydro-1' H ,3' H -spiro[cyclopropane -1,2'-pyrrolizidinyl] (tetrahydro-1' H ,3' H -spiro[cyclopropane-1,2'-pyrrolizidinyl]),
  • R 2 is azetidinyl, Z 1 -pyrrolizidinyl, Z 1 -tetrahydro- 1'H , 3'H -spiro[cyclopropane-1,2'- Pyrrolizidinyl] (tetrahydro-1' H ,3' H -spiro[cyclopropane-1,2'-pyrrolizidinyl]), or Z 1 -R y -Z 2 -R x , wherein R y is 3 to is 5-membered cycloalkyl (e.g., cyclopropyl or cyclobutyl), and R x is 3- to 10-membered heterocyclyl (e.g., pyrrolidinyl, piperidinyl, morpholinyl, 2- Oxa-5-azabicyclo[2.2.1]heptanyl (2-oxa-5-azabicyclo[2.2.1]heptanyl), or 6-azaspiro[
  • R 3 is 6- to 20-membered aryl, or 6- to 20-membered heteroaryl, and may be optionally substituted with one or more R 8 .
  • R 3 is phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, pyridinyl, anthracenyl, indenyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzthiazolyl ( benzothiazolyl), benzothiophenyl, benzfuranyl, or indazolyl, and may be optionally substituted with one or more R 8 .
  • R 3 is phenyl, naphthyl, naphthalenyl, pyridinyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzothiophenyl, benzfuranyl, or It is indazolyl and may be optionally substituted with one or more R 8 .
  • R 8 is H, halogen, hydroxy, -N(R 18 ) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 haloalkyl, It may be C 1-3 hydroxyalkyl, or cyano.
  • R 10 is a 3- to 10-membered cycloalkyl and may be optionally substituted with one or more R 11 .
  • R 11 may be C 1-3 alkyl, hydroxy, N(R 19 ) 2 , C 1-3 alkyl-N(R 19 ) 2 , or cyano C 1-3 alkyl.
  • R 9 may be C 1-3 alkyl
  • R 10 may be 3- to 5-membered cycloalkyl
  • R 11 may be N(R 19 ) 2 .
  • R 12 may be H.
  • R 14 is a 3- to 10-membered heterocyclyl, a 3- to 10-membered heterocyclyl containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, N, O and It may be a 3- to 5-membered heterocyclyl containing 1 to 2 heteroatoms selected from the group consisting of S, for example, oxirane.
  • R 5 may be H or C 1-3 alkyl.
  • LR 2 may be selected from the structures below. When it has the structure below, it not only has excellent KRAS G12D inhibitory activity, but is also suitable for the various purposes of the present application mentioned above.
  • R 3 may be selected from the structures below. When it has the structure below, it not only has excellent KRAS G12D inhibitory activity, but is also suitable for the various purposes of the present application mentioned above.
  • R 4 may be selected from the structures below. When it has the structure below, it not only has excellent KRAS G12D inhibitory activity, but is also suitable for the various purposes of the present application mentioned above.
  • the present application provides the aforementioned compounds, their optical isomers, stereoisomers, isotopic variants, hydrates, solvates, or pharmaceutically acceptable salts thereof.
  • Examples of compounds of Formula 1 according to the present application are those prepared in Examples 1 to 120 below. Each example number corresponds to a compound number. For example, the final compound prepared in Example 90 is numbered Compound 90.
  • representative compounds of Formula 1 according to an example of the present application include, but are not limited to, those listed in Table 1 below.
  • Example Compound name (One) 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H - pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol (2) 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H - pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-y
  • (22) 1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidine.
  • (31) 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((( S )-3-fluoropiperidin-1-yl )methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • (32) 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 S ,7a R )-2-fluoro-6-methylenetetrahydro -1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen -2-ol.
  • (33) 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((( R )-2-methylenetetrahydro-1H - pyrrolizin-7a( 5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • (42) 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H - pyrrolizin-7a( 5H )-yl)methoxy)-8-methylfuro[3,2 -f ]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • halogen herein, when used alone or in combination with additional terms (e.g., haloalkyl), refers to fluorine, chlorine, bromine, or iodine, and specifically refers to fluorine, chlorine, bromine, or iodine. Examples include fluorine and chlorine, but are not limited to these.
  • alkoxy herein means alkyloxy, eg, alkyloxy having 1 to 7 carbon atoms.
  • haloalkyl herein means alkyl as defined herein in which one or more hydrogens are replaced by the same or different halogen.
  • haloalkyl groups include, but are not limited to -CH 2 Cl, -CH 2 CF 3 , -CH 2 CCl 3 , -CF 3 , etc.
  • hydroxyalkyl herein includes substitution of one or more hydrogen atoms in an alkyl group with one or more hydroxy (-OH), such as divalent or trivalent hydroxy.
  • aminoalkyl herein includes substitution of one or more hydrogen atoms in an alkyl group with one or more amino(-NH 2 ), such as divalent or trivalent amino.
  • alkyl refers to a saturated, straight-chain or branched, monovalent hydrocarbon radical, unless otherwise indicated.
  • the alkyl may be C 1-10 alkyl, C 1-8 alkyl, C 1-6 alkyl, C 1-4 alkyl, or C 1-3 alkyl.
  • alkenyl refers to a monovalent hydrocarbon radical containing at least one carbon-carbon double bond, where each double bond is in the E- or Z-configuration. It can have a shape.
  • the alkenyl may be C 2-10 alkenyl, C 2-8 alkenyl, C 2-6 alkenyl, or C 2-4 alkenyl.
  • alkynyl refers to a monovalent group derived from an unsaturated, straight-chain or branched hydrocarbon moiety having at least one carbon-carbon triple bond.
  • the alkynyl may be C 2-10 alkynyl, C 2-8 alkynyl, C 2-6 alkynyl, or C 2-4 alkynyl.
  • alkyl alkenyl
  • alkynyl may be straight or branched when used alone or in combination with additional terms (e.g., haloalkyl).
  • 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, or 1 to 3 carbons in the alkyl group It refers to a radical of a group of saturated aliphatic hydrocarbons having atoms.
  • Examples of common alkyls are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl and tert-pentyl, 1 -Includes, but is not limited to, methylpentyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, n-hexyl, 3,3-dimethylbutyl, and isohexyl.
  • alkenyl and alkynyl group can be substituted at any position.
  • alkenyl and alkynyl include ethenyl, prop-1-enyl, prop-2-enyl, but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, including but not limited to hex-3-enyl, hex-4-enyl, prop-2-ynyl, but-2-ynyl, but-3-ynyl, hex-4-enyl, or hex-5-ynyl. .
  • cycloalkyl refers to cyclic alkyl which may be substituted or unsubstituted and may be unsaturated, partially or fully saturated (e.g., 3 refers to a hydrocarbon radical forming a single or fused ring having from 24 to 24 carbon atoms.
  • the cycloalkyl, cycloalkenyl, or cycloalkynyl is 3 to 10, 3 to 8, 3 to 6, 3 to 5, 4 to 10, 4 to 8, 4 to 6, or may have 4 to 5 carbon atoms.
  • the cycloalkyl includes, but is not limited to, carbocyclyl, spirocarbocyclyl, fused carbocyclyl, and cross-linked carbocyclyl.
  • the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclohexenyl, cyclooctyl, cyclooctenyl, 2,5-cyclohexadienyl, Spiro[3.5]nonane, Spiro[3.3]heptane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octyl, adamant-1-yl, decahydronaphthyl, oxocyclohexyl, di It may be oxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-enyl, benzene, naphthalene, and may include without limitation all possible isomers thereof, but is not limited thereto.
  • saturated or unsaturated heterocyclyl refers to one or more heteroatoms selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S), for example 1 to 8 It refers to a 3- to 24-membered hydrocarbon that may be substituted or unsubstituted and forms an unsaturated, partially or fully saturated single or fused cyclic ring containing two heteroatoms.
  • the heterocyclyl may be a hydrocarbon of 3 to 10 members, 3 to 8 members, 3 to 6 members, 4 to 10 members, 4 to 8 members, or 4 to 6 members having 1 to 3 heteroatoms.
  • the heterocycle may include, but is not limited to, heteroaryl, heterocyclyl, heterospirocarbocyclyl, fused heterocyclyl, and bridged heterocyclyl.
  • the heterocyclyl is pyrrolidinyl, morpholinyl, pyrrolizidinyl, quinolizidinyl, azaspirooctanyl, piperidinyl, pyrrolidinyl, imida.
  • aryl refers to an aromatic group that may be substituted or unsubstituted, and may have, for example, 6 to 20 members.
  • the aryl may include phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, indenyl, indanyl, or all possible isomers thereof without limitation.
  • heteroaryl refers to a heteroaryl group containing one or more heteroatoms selected from O, N and S, for example, 1 to 4, 1 to 3, or 1 to 2 heteroatoms. It refers to a monocyclic or bicyclic or more aromatic group, and may have, for example, 6 to 20 members.
  • monocyclic heteroaryls include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxa.
  • examples of bicyclic heteroaryl include pyrrolizidinyl, indolyl, indolinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzthiazolyl, benzthiophenyl, Benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, indazolyl, quinolinyl, isoquinolinyl, azaspirooctaneyl, purinyl, furopyridinyl or similar groups. It may be mentioned, but it is not limited to this.
  • examples of tricyclic heteroaryl include, but are not limited to, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, or similar groups. That is not the case.
  • the numerical range indicated using the term “to” refers to a range that includes the numerical values written before and after the term “to” as the lower limit and upper limit, respectively.
  • the compounds of the present application may have asymmetric carbon centers and asymmetric axes or asymmetric planes, and therefore all optical and stereoisomers, including mixed racemates, as well as substantially pure enantiomers such as the R and S enantiomers. All of these isomers and mixtures are included within the scope of the present application.
  • the optical purity of these enantiomers and pharmaceutically acceptable salts thereof represented by Formula 1 is preferably 60% ee or higher, more preferably 95 % ee or higher, and most preferably 98 %. It's more than ee.
  • ee refers to optical purity (enantiomeric excess). For example, one enantiomer in a particular compound is present in a greater amount than the other enantiomer in the compound as a mixture of enantiomers.
  • An enantiomeric form is one in which the concentration of a single enantiomer in an enantiomeric mixture of a particular compound is greater than 50%, more typically greater than 60%, 70%, 80%, or 90% relative to the other enantiomers of the compound. , or more (e.g., >95%, >97%, >99%, >99.5%) of a particular compound.
  • the compound of Formula 1 includes all compounds of Formula 1, optical isomers, stereoisomers, isotopic variants, solvates, hydrates, and pharmaceutically acceptable salts thereof. It is used as.
  • isotopic variant refers to a compound containing an abnormal ratio of isotopes at one or more atoms constituting the compound.
  • isotopic variants of a compound may be radioactively labeled, for example the hydrogen atom may be selected from hydrogen, deuterium and tritium, carbon-13 ( 13 C), nitrogen-15 ( 15 N), etc. It may contain.
  • the compound of Formula 1 according to the present application, its optical isomer, stereoisomer or isotopic variant can form a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salts include both acid or base addition salts and stereochemical isomeric forms thereof.
  • the salt includes any salt that maintains the activity of the parent compound in the subject to be administered and does not cause undesirable effects, and is not particularly limited.
  • Such salts include inorganic and organic salts, such as acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, and hydrobromic acid.
  • propionic acid benzenesulfonic acid
  • benzoic acid stearic acid, esylic acid, lactic acid, bicarboxylic acid, bisulfuric acid, bitartaric acid, oxalic acid, butyric acid, calcium idetic acid, camsilic acid, carbonic acid, chlorobenzoic acid, citric acid, ide.
  • Tritic acid Tritic acid, toluenesulfonic acid, edicillic acid, esilinic acid, fumaric acid, gluceptic acid, pamoic acid, gluconic acid, glycolylarxanilic acid, methylnitric acid, polygalatroxynic acid, hexylysorcinonic acid, malonic acid , hydrabamic acid, hydrochloric acid, hydroiodoic acid, hydroxynaphtholic acid, isethionic acid, lactobionic acid, mandelic acid, estolinic acid, mucinic acid, naphsilic acid, muconic acid, p-nitromethanesulfonic acid.
  • the basic salt forms include, for example, ammonium salts, lithium salts, sodium salts, potassium salts, magnesium salts and calcium salts, as well as alkali and alkaline earth metal salts, for example benzathine, N-methyl-D- Salts with organic bases such as glucamine, hydrabamine salts and salts with amino acids such as arginine, lysine, for example.
  • the salt form may be converted to the free form by treatment with a suitable base or acid.
  • additional salt includes solvates that compounds of Formula 1 and salts thereof can form. Such solvent compounds are, for example, hydrates and alcoholates.
  • the present application also provides methods for preparing compounds of Formula 1.
  • a method for preparing the compound of Formula 1 will be described based on an exemplary reaction scheme.
  • those of ordinary skill in the technical field to which this application pertains can prepare the compound of Formula 1 by various methods using known compounds or compounds that can be easily prepared therefrom based on the structure of Formula 1. It can be done, and all of these methods should be interpreted as being included in the scope of this application. That is, the compound of Formula 1 can be prepared by arbitrarily combining various synthetic methods described in this specification or disclosed in the prior art, and therefore, the following description regarding the method for preparing the compound of Formula 1 merely presents exemplary methods. Also, the order of unit operations, etc. can be selectively changed as needed, and the scope of the manufacturing method of the present application is not limited thereto.
  • Step A Add phosphoryl trichloride and N -ethyl- N -isopropylpropan-2-amine to Compound 1 of Scheme 1 and heat to obtain Compound 2.
  • Step B Compound 2 of Scheme 1 undergoes a S N AR reaction with a nucleophile having the formula H-Y1-X-R1 to form a solvent such as dimethyl chloride and N -ethyl- N -isopropylpropan-2-amine
  • a solvent such as dimethyl chloride and N -ethyl- N -isopropylpropan-2-amine
  • Compound 3 is synthesized in the presence of a base.
  • Step C In Scheme 1 above, the substituent -Y2-R2 is introduced by the 2-chlorine substituent of the nucleophile of the compound having the formula H-Y2-R2 using a strong base such as sodium hydride in a non-polar solvent such as tetrahydrofuran.
  • Step D To synthesize compound 5 of Scheme 1, use compound 4 and boronic acid or aryl stannane and Suzuki reaction or Stilliban in step D.
  • a therapeutically effective amount of the compound of Formula 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof is used as an active ingredient.
  • a pharmaceutical composition for preventing or treating diseases associated with KRAS G12D mutant protein is provided. Specifically, the pharmaceutical composition may prevent or treat diseases associated with the KRAS G12D mutant protein by inhibiting the activity of the KRAS G12D mutant protein.
  • the compound of Formula 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof is GDP-/ GppNHp-KRAS G12D It has a high binding ability to mutant proteins and can act as a KRAS G12D mutation-specific inhibitor by inhibiting the phosphorylation of extracellular signal-regulated kinases (Phospho-ERK, pERK) induced by KRAS G12D mutation.
  • Phospho-ERK, pERK extracellular signal-regulated kinases
  • an example of the present application includes a compound according to an example of the present application, an optical isomer, a stereoisomer, a racemate, an isotopic variant, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula 1 according to an example of the present application can prevent, improve, or treat diseases or conditions related to KRAS G12D mutant protein, specifically diseases or conditions caused by KRAS G12D mutant protein.
  • the compound of Formula 1 according to the present application is an inhibitor of the KRAS G12D mutant protein, can effectively inhibit the growth signal of cancer cells caused by the KRAS G12D mutation, and is useful as a pharmaceutical composition for the prevention or treatment of cancer. It can be used easily.
  • a therapeutically effective amount of the compound of Formula 1 or its optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof is used as an active ingredient.
  • a pharmaceutical composition for preventing or treating cancer including:
  • the pharmaceutical composition may further include one or more additives selected from the group consisting of pharmaceutically acceptable carriers, diluents, and adjuvants.
  • treatment means stopping, delaying, or alleviating the progression of a disease when used in a subject showing symptoms of the disease.
  • prevention means reducing or eliminating the possibility of contracting a disease.
  • pharmaceutical composition may include other chemical ingredients such as carriers, diluents, excipients, etc. in addition to the active compounds according to the present application. Accordingly, the pharmaceutical composition may include a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof, if necessary. These pharmaceutical compositions facilitate administration of the active compound into an organism. Various techniques for administering pharmaceutical compositions containing a compound are known, including but not limited to oral, injection, aerosol, parenteral, and topical administration.
  • the pharmaceutical composition may be sterilized or may further contain auxiliaries such as preservative stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and may further contain other therapeutically useful substances.
  • auxiliaries such as preservative stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and may further contain other therapeutically useful substances.
  • carrier refers to a compound that facilitates the introduction of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • carrier facilitates the introduction of many organic compounds into the cells or tissues of an organism.
  • diluent is defined as a compound diluted in water that not only stabilizes the biologically active form of the compound of interest, but also dissolves the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer is phosphate buffered saline, which mimics the salt form of human solutions. Because buffer salts can control the pH of a solution at low concentrations, it is rare for buffer diluents to modify the biological activity of a compound.
  • pharmaceutically acceptable means a property that does not impair the biological activity and physical properties of a compound.
  • the pharmaceutical composition may be a composition for preventing and/or treating diseases related to KRAS G12D mutant protein.
  • the disease associated with the KRAS G12D mutant protein may be, for example, cancer and may include any other disease known to be associated with the KRAS G12D mutation.
  • the cancer includes angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyomas, fibroids, lipomas, and teratomas; Squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated multicellular carcinoma, adenocarcinoma, alveolar (bronchiolar) cancer, bronchiolar adenoma, sarcoma, lymphoma, chondrocarcinoma, mesothelioma, esophageal cancer, stomach cancer, pancreatic cancer, small intestine cancer, colon cancer, kidney cancer, bladder cancer, Urethral cancer, prostate cancer, testicular cancer, liver cancer, gallbladder cancer, hepatoblastoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary cancer, osteosarcoma, malignant fibrous histiocytoma,
  • astrocytoma medulloblastoma, ependymoma, blastoma, oligodendroglioma, schwannoma, retinoblastoma, spinal neurofibroma, endometrial cancer, cervical cancer, ovarian cancer, blood cancer, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia , monocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, mixed lineage leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant melanoma, basal cell carcinoma, psoriatic cancer, and neuroblastoma.
  • the pharmaceutical composition may be formulated into various oral or parenteral dosage forms.
  • it can be in any dosage form for oral administration, such as tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, and elixirs.
  • These formulations for oral administration may contain, in addition to the above active ingredients, diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, silica, and talc, depending on the typical composition of each formulation. , stearic acid and its magnesium or calcium salts, and/or lubricants such as polyethylene glycol.
  • the dosage form for oral administration when it is a tablet, it may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidine. Depending on this, it may additionally include a disintegrant such as starch, agar, alginic acid or its sodium salt, a boiling mixture and/or an absorbent, a colorant, a flavoring agent, or a sweetener.
  • a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidine.
  • a disintegrant such as starch, agar, alginic acid or its sodium salt, a boiling mixture and/or an absorbent, a colorant, a flavoring agent, or a sweetener.
  • the pharmaceutical composition may be formulated in a parenteral administration form, in which case it is administered by parenteral administration methods such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • parenteral administration methods such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the active ingredient that is, the compound of Formula 1 or an optical isomer, stereoisomer, isotopic variant, or pharmaceutically acceptable salt thereof, is added as a stabilizer or They can be mixed in water with a buffer to form solutions or suspensions, which can be prepared in unit dosage form in ampoules or vials.
  • the pharmaceutical composition may be sterilized or may further contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and may further contain other therapeutically useful substances. and can be formulated according to conventional methods of mixing, granulating, or coating.
  • the active ingredient that is, the compound of Formula 1 or a pharmaceutically acceptable salt thereof, is administered in an amount of 0.1 to 500 mg/kg (body weight), preferably 0.5 to 100 mg/kg (body weight) per day for mammals, including humans. ) may be included in the pharmaceutical composition in an effective amount, and this pharmaceutical composition may be administered through oral or parenteral routes once a day, divided into two or more times.
  • the pharmaceutical composition may be used to treat cancer by additionally comprising the compound according to an example of the present application and at least one different therapeutic agent.
  • the compound according to an example of the present application may be used in combination with a different therapeutic agent to exhibit synergistic effect.
  • the term “synergistic” refers to a therapeutic combination that is more effective than the additive effect of two or more single agents. Combination treatments provide “synergism” and demonstrate “synergistic,” meaning that the effect achieved when the active ingredients are used together is greater than the sum of the effects resulting from the compounds being used separately. Synergistic effects occur when the active ingredients: (1) are co-formulated and administered or delivered simultaneously in a combined unit dose formulation; or (2) by substitution, when delivered as a separate dosage form.
  • synergistic effects may be obtained when the compounds are administered or delivered sequentially, for example by different injections in separate syringes.
  • effective doses of each active ingredient are administered sequentially, i.e., serially in time.
  • synergy is evidenced by lower toxicity of the combination compared to the same dose of any single component at the same total dose.
  • the toxicity of a 50:50 (w/w) combination comprising the compound of Formula 1 and the different therapeutic agent is 100% (w/w)
  • the toxicity of the Formula 1 compound, and/or 100% (w/w) may be lower than that of the different therapeutic agents, wherein the combination has approximately the same level of efficacy or higher.
  • the toxicity of the combination of the compound of Formula 1 and other therapeutic agents is less than that of a single component, and the efficacy of the combination is greater than that of a single component.
  • the one or more therapeutic agents include RTK/Ras-MAPK pathway-related protein inhibitors (EGFR inhibitor, FGFR inhibitor, ALK inhibitor, ROS inhibitor, MET inhibitor, RAF inhibitor, ERK inhibitor, MEK inhibitor, SHP-2 inhibitor, PI3K inhibitor, KRAS inhibitor, Includes, but is not limited to, KRAS-G12C inhibitor, SOS1 inhibitor), DNA damage inducer, EGFR antibody, or immunotherapy agent.
  • RTK/Ras-MAPK pathway-related protein inhibitors EGFR inhibitor, FGFR inhibitor, ALK inhibitor, ROS inhibitor, MET inhibitor, RAF inhibitor, ERK inhibitor, MEK inhibitor, SHP-2 inhibitor, PI3K inhibitor, KRAS inhibitor.
  • RTK/Ras-MAPK pathway inhibitors include EGFR inhibitors (Erlotinib, Gefitinib, Afatinib or Osimertinib), FGFR inhibitors (Pemigatinib) or Infigratinib (BGJ398)), ALK/ROS/MET inhibitor (Crizotinib, Carbozantinib or Foretinib), RAF inhibitor (Vemurafenib, Dabra) Dabrafenib or Belvarafenib), ERK/MEK inhibitors (Trametinib or Cobimetinib), SHP-2 inhibitors (TNO155 and RMC4630), PI3K inhibitors (AMG 511 and Bupalisib), KRAS inhibitors and KRAS-G12C inhibitors (Sotorasib, Adagrasib and Divarasib, including but not limited to one or more of these inhibitors) .
  • EGFR inhibitors Erlotinib, Ge
  • chemotherapy substances for DNA damage-inducing substances include alkylating agents (platinum-based chemotherapy drugs: Cisplatin, Carboplatin, Oxaliplatin/Ntrogen mustard drugs: mechlorethamine) (Mechlorethamine, nitrogen mustard), Cyclophosphamide, Ifosfamide, Melphalan, Chlorambucil/Nitrosourea drugs: Carmustine, BCNU ), Lomustine (CCNU), Nimustine/ Others: Altretamine, Busulfan, dacarbazlne, Procarbazine, Temozolomide , Thiotepa, Lurbinectedin, etc.), antimetabolites (Fluorouracil (5-FU), Capecitabine, Cytarabine, Gemcitabine, Methotrexate, Mercaptopurine (6-MP), leucovorin, pemetrexed, etc.), topoisomerase inhibitors (Epipodophyllotoxin): Etoposide ( Etoposide (
  • EGFR antibodies include, but are not limited to, cetuximab.
  • immunotherapy agents include, but are not limited to, AMG-404, pembrolizumab, or nivolumab.
  • a tricyclic derivative compound exhibiting an excellent KRAS G12D inhibitory effect or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, may be provided. Therefore, these compounds or their optical isomers, stereoisomers or isotopic variants, or pharmaceutically acceptable salts thereof, can be effectively used for the prevention or treatment of diseases associated with KRAS G12D mutant protein, such as cancer.
  • the compounds according to the present application may have superior efficacy or improved pharmacokinetic properties.
  • Step 1 6-Chloro-3-nitropicolinonitrile (10 g, 54.48 mmol) was dissolved in H 2 SO 4 (276 g, 2.53 mol) and heated to 70 °C for 3.5 hours. After completion of the reaction, the reaction mixture was cooled to 20°C, ice water (1200 mL) was added dropwise, and the precipitate was filtered, washed with water, dried, and concentrated under reduced pressure to obtain 6-chloro-3-nitropicolinamide as a white solid. (9.85 g, crude compound) was obtained.
  • Step 2 A solution of 6-chloro-3-nitropicolinamide (7.35 g, 36.46 mmol) was dissolved in ethanol (30 mL), and then saturated 28% ammonia (27.30 g, 218.09 mmol) solution was added dropwise. The reaction was carried out in a 100 mL sealed tube at 100°C for 48 hours. After completion of the reaction, the mixture was cooled and concentrated under reduced pressure to obtain a residue. The residue was diluted with aqueous Na 2 CO 3 solution (100 mL) and the mixture was stirred at 20° C. for 1 hour, then filtered and the filter cake was washed with water (50 mL). Concentrated under reduced pressure to obtain a residue.
  • 6-amino-3-nitro-pyridine-2-carboxamide (4.85 g, unrefined compound) was obtained as a yellow solid.
  • Step 3 Dissolve 6-amino-3-nitro-pyridine-2-carboxamide (4.85 g, 26.63 mmol) in DMF (49 mL), then add NBS (5.69 g, 31.95 mmol), and cool the reaction mixture at 25°C. It was stirred for 4 hours. After completion of the reaction, most of the solvent was removed under reduced pressure, and the residue was suspended in purified water (100 mL). The solid was filtered and dried under reduced pressure. The product was stirred with petroleum ether (45 mL) and ethyl acetate (40 mL) at 20°C for 30 minutes, and the solid was filtered and dried under reduced pressure.
  • Step 4 Dissolve 6-amino-3-nitropicolinamide (5.9 g, 22.60 mmol) in Ethanol (59 mL) and distilled water (59 mL), then dissolve 2-bromo-1,1-diethoxyethane (6.68 g, 33.90 mmol) and HBr. (9.14 g, 45.21 mmol) were added dropwise at 20°C, respectively.
  • the reaction mixture was heated at 100° C. for 16 hours.
  • the reaction mixture was concentrated in vacuo to remove ethanol, the pH of the residue was adjusted to 8 using NaHCO 3 aqueous solution, the solid was precipitated, and then filtered.
  • Step 5 8-bromo-6-nitroimidazo[1,2-a]pyridine-5-carboxamide (4.5 g, 15.79 mmol), Fe (3.53 g, 63.15 mmol) in Ethanol (90 mL) and distilled water (18 mL) and NH 4 Cl (6.76 g, 126.29 mmol) were added and stirred at 85°C for 16 hours.
  • the reaction mixture was filtered and the filter cake was washed with 800 mL EA/MeOH (10:1). The organic phases were combined to give a residue. The residue was then washed with saturated sodium bicarbonate, filtered, and the filter cake was concentrated under reduced pressure to obtain the residue.
  • Step 6 Dissolve 6-amino-8-bromoimidazo[1,2- a ]pyridine-5-carboxamide (10.47 g, 35.28 mmol) in 1,4-Dioxane (100 mL). The resulting suspension was refluxed at 110°C for 16 hours under nitrogen. After the starting materials were consumed, the reaction solution was cooled to 20°C, distilled water (20 mL) was added, and the reaction was terminated by stirring for 10 minutes. The mixture was filtered and the solid was washed with ethyl acetate (200 mL) and dried.
  • Step 7 POCl 3 (117.84 g, 768.50 mmol) was added to 6-bromoimidazo[1',2':1,6]pyrido[3,2- d ]pyrimidine-1 obtained in Step 6 in a 250 mL round three-necked flask. ,3( 2H , 4H )-dione (5.4 g, 19.21 mmol) was added dropwise. Then, DIPEA (6.21 g, 48.03 mmol) was slowly added dropwise. The reaction mixture was charged with nitrogen and stirred at 110° C. for 20 hours.
  • Step 1 Dissolve 4-bromo-5-fluoro-2-nitrobezoic acid (50.0 g, 189 mmol) in distilled water (600 mL), add 12 M KOH (63.8 g, 1.14 mol), and cool the reaction solution at 80 o. It was stirred at C for one day. 1 N HCl aqueous solution was added to the reaction mixture to adjust pH to 3, and then ethyl acetate was added to extract the organic layer, washed with saturated NaCl aqueous solution, and dried over anhydrous MgSO 4 . The solvent was concentrated to synthesize 4-bromo-5-hydroxy-2-nitrobenzoic acid (49.5 g, 189 mmol, crude compound).
  • 1 H NMR 400 MHz, DMSO- d 6, ppm): ⁇ 13.7 (s, 1H), 12.1 (s, 1H), 8.27 (s, 1H), 7.14 (s, 1H).
  • Step 2 Dissolve 4-bromo-5-hydroxy-2-nitrobenzoic acid (49.5 g, 189 mmol) obtained in Step 1 in methanol (599 mL), and add sulfuric acid (51.6 mL) at 0 o C to prepare the reaction solution. It was stirred at 70 o C for one day. After the reaction was completed by adding distilled water to the reaction mixture, ethyl acetate was added to extract the organic layer, washed with a saturated aqueous NaCl solution, and dried over anhydrous MgSO 4 . The solvent was concentrated to synthesize methyl 4-bromo-5-hydroxy-2-nitrobenzoate (52.2 g, 189 mmol, crude compound).
  • Step 3 Dissolve methyl 4-bromo-5-hydroxy-2-nitrobenzoate (52.2 g, 189 mmol) and TEA (79.0 mL, 567 mmol) obtained in Step 2 in DCM (798 mL) and add acetyl chloride ( 20.2 mL, 283 mmol) was added and the reaction solution was stirred at the same temperature for 2 hours. Purified water was added to the reaction mixture to terminate the reaction, and the organic layer was extracted by adding DCM and dried over anhydrous MgSO 4 . The solvent was concentrated to synthesize methyl 5-acetoxy-4-bromo-2-nitrobenzoate (60.1 g, 189 mmol, crude compound).
  • 1 H NMR 400 MHz, DMSO- d 6, ppm): ⁇ 8.55 (s, 1H), 7.94 (s, 1H), 3.87 (s, 3H), 2.39 (s, 3H).
  • Step 4 Dissolve methyl 5-acetoxy-4-bromo-2-nitrobenzoate (60.0 g, 189 mmol) obtained in Step 3 in ethanol (700 mL), purified water (300 mL), and acetic acid (75.5 mL, 1.32 mol). , Fe (26.3 g, 472 mmol) was added slowly. The reaction solution was stirred at room temperature for 3 hours. The reaction mixture was neutralized by adding 6 N KOH aqueous solution, the solvent was removed, and the mixture was filtered. Ethyl acetate was added to the filtrate to extract the organic layer, washed with saturated aqueous NaCl solution, and dried over anhydrous MgSO 4 .
  • Step 5 Dissolve methyl 5-acetoxy-2-amino-4-bromobenzoate (2.28 g, 7.91 mmol) obtained in Step 4 in MeOH (120 mL) and react by adding K 2 CO 3 (2.19 g, 15.8 mmol) The solution was stirred at room temperature for 2 hours. The reaction mixture was acidified by adding 1 N HCl aqueous solution, and then the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO 4 . The solvent was concentrated to synthesize methyl 2-amino-4-bromo-5-hydroxybenzoate (1.95 g, 7.91 mmol, crude compound).
  • Step 6 Dissolve methyl 2-amino-4-bromo-5-hydroxybenzoate (1.95 g, 7.92 mmol) obtained in Step 5 in DMF (50 mL), and dissolve 9.2 M 3-bromopropane (1.21 mL, 11.1 mmol) in toluene. ) and K 2 CO 3 (2.19 g, 15.8 mmol) were sequentially added and the reaction solution was stirred at room temperature for one day. Purified water was added to the reaction mixture to terminate the reaction, and ethyl acetate was added to extract the organic layer, washed with saturated aqueous NaCl solution, and dried over anhydrous MgSO 4 .
  • Step 7 Dissolve methyl 2-amino-4-bromo-5-(prop-2-yn-1-yloxy)benzoate (1.66 g, 5.84 mmol) obtained in Step 6 in N , N -diethylaniline (10 mL), CsF (1.33 g, 8.76 mmol) was added, the reaction solution was heated to reflux, and stirred for 1 hour. It was diluted with ethyl acetate, washed twice with 1 N aqueous hydrochloric acid, and dried with anhydrous MgSO 4 .
  • the material obtained by concentrating the solvent was purified by silica gel chromatography to synthesize solid methyl 5-amino-7-bromo-2-methylbenzofuran-4-carboxylate (1.41 g, 4.96 mmol, 85% yield).
  • Step 8 Dissolve methyl 5-amino-7-bromo-2-methylbenzofuran-4-carboxylate (1.41 g, 4.96 mmol) obtained in Step 7 in THF (50 mL), and trichloroacetyl isocyanate (0.651 mL, 5.46 mmol) at 0°C. ) was added and the reaction solution was stirred at the same temperature for 30 minutes. 7 N ammonia solution (1.69 g, 99.0 mmol) dissolved in methanol was added to the material obtained by concentrating the solvent, and stirred at room temperature for one day.
  • Step 9 6-bromo-8-methylfuro[3,2- f ]quinazoline-1,3( 2H , 4H )-dione (1.22 g, 4.13 mmol) obtained from Step 8 was added to POCl 3 (15.4 mL, 165 mmol) was added, DIPEA (1.80 mL, 10.3 mmol) was added, and the reaction solution was stirred at 110°C for 1.5 hours. The solvent was concentrated, saturated NaHCO 3 solution was added to the reaction mixture to terminate the reaction, and ethyl acete was added to extract the organic layer, which was then dried over anhydrous MgSO 4 .
  • Step 1 Dissolve methyl 5-acetoxy-2-amino-4-bromobenzoate (20.0 g, 69.4 mmol) in acetonitrile (1 L), add selectfluor (27.1 g, 76.4 mmol), and store the reaction solution at 80°C for one day. It was stirred for a while. Saturated NaHCO 3 aqueous solution was added to the reaction mixture to adjust pH to 8, then ethyl acetate was added to extract the organic layer, washed with saturated NaCl aqueous solution, and dried over anhydrous MgSO 4 .
  • Step 2 Dissolve methyl 5-acetoxy-2-amino-4-bromo-3-fluorobenzoate (5.50 g, 18.0 mmol) obtained in Step 1 in methanol (275 mL), and dissolve K 2 CO 3 (4.97 g, 35.9 mmol). was added and the reaction solution was stirred at room temperature for 2 hours.
  • the reaction mixture was acidified by adding 1 N HCl aqueous solution, and then the organic layer was extracted with ethyl acetate and dried over anhydrous MgSO 4 .
  • the solvent was concentrated to synthesize methyl 2-amino-4-bromo-3-fluoro-5-hydroxybenzoate (4.74 g, 18.0 mmol, crude compound).
  • Step 3 Dissolve methyl 2-amino-4-bromo-3-fluoro-5-hydroxybenzoate (2.00 g, 7.57 mmol) obtained in Step 2 in DMF (47.8 mL), and add 9.2 M Propargyl bromide (1.15 mL) dissolved in toluene. , 10.6 mmol) and K 2 CO 3 (2.09 g, 15.1 mmol) were sequentially added, and the reaction solution was stirred at room temperature for one day. Purified water was added to the reaction mixture to terminate the reaction, and ethyl acetate was added to extract the organic layer, washed with saturated aqueous NaCl solution, and dried over anhydrous MgSO 4 .
  • Step 4 methyl 2-amino-4-bromo-3-fluoro-5-(prop-2-yn-1-yloxy)benzoate (1.02 g, 3.38 mmol) obtained from Step 3 was mixed with N , N -diethylaniline (10 mL) ), CsF (769 mg, 5.06 mmol) was added, the reaction solution was heated to reflux, and stirred for 1 hour. It was diluted with ethyl acetate, washed twice with 1 N HCl aqueous solution, and dried with anhydrous MgSO 4 .
  • Step 5 Dissolve methyl 5-amino-7-bromo-6-fluoro-2-methylbenzofuran-4-carboxylate (910 mg, 3.01 mmol) obtained in Step 4 in THF (30.3 mL), and trichloroacetyl isocyante (0.395%) at 0°C. mL, 3.31 mmol) was added and the reaction solution was stirred at the same temperature for 30 minutes. 7N NH 4 in methanol (8.62 mL, 60.3 mmol) was added to the material obtained by concentrating the solvent, and stirred at room temperature for one day.
  • Step 6 POCl 3 (8.93 mL) was added to the bromo-5-fluoro-8-methylfuro[3,2-f]quinazoline-1,3( 2H , 4H )-dione (750 mg, 2.40 mmol) obtained from Step 5. , 95.80 mmol) was added, DIPEA (1.04 mL, 5.99 mmol) was added, and the reaction solution was stirred at 110 °C for 7 hours. After the reaction was terminated by adding saturated NaHCO 3 solution to the reaction mixture, the organic layer was extracted by adding ethyl acetate and dried over anhydrous MgSO 4 .
  • Step 1 Dissolve 7-bromo-5-nitro-1 H -indazole (20 g, 82.6 mmol) in THF (200 mL), add NaH (8.3 g, 124 mmol) at 0 °C, and cool the mixture at 20 °C. It was stirred. After stirring at 20° C. for 30 minutes, MeI (35.2 g, 248 mmol) was added. The reaction mixture was stirred under nitrogen at 20° C. for 1 hour. After completion of the reaction, purified water (80 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (40 mL*3) and dried over Na 2 SO 4 .
  • Step 2 Add 7-bromo-2-methyl-5-nitro-2 H -indazole (20 g, 78.1 mmol), Fe (21.8 g, 391 mmol) and NH 4 Cl (5.01 g, 93.7 mmol) were added and stirred at 90°C for 1 hour. The reaction mixture was filtered through Celite to obtain a residue. The residue was purified by silica gel chromatography. 7-bromo-2-methly-2 H -indazole-5-amine (7 g, 31 mmol, 40% yield) was obtained as a yellow solid.
  • Step 3 7-bromo-2-methly- 2H -indazole-5-amine (6.67 g, 29.5 mmol), chloral hydrate (9.76 g, 29.5 mmol), Na 2 SO 4 (33.5 g, 236 mmol) in purified water After dissolving in (70 mL), HCl (4 mL) was slowly added dropwise, and stirred at 90°C for 30 minutes. Next, N -chlorohydroxylamine (11.9 g, 177 mmol) was added and stirred at 90°C for 1 hour. After cooling the reaction mixture to room temperature, purified water (70 mL) was added and stirred for 10 minutes. The solid was allowed to settle and then filtered.
  • Step 4 Slowly add concentrated sulfuric acid (60 mL) dropwise to N -(7-bromo-2-methyl-2 H -indazole-5-yl-2-( N -hydroxy imino)acetamide (9g, 30.3 mmol) and react. The mixture was stirred at 90°C for 30 minutes, ice was added, the solid was precipitated, and the solid was filtered. 2 H , 6 H , 7 H , 8 H -pyrolo[3,2-e]indazole-7,8-dione (5.1g, 18.2 mmol, 60% yield) was obtained by LCMS (ES-API, m/z).
  • Step 5 4-bromo-2-mehtyl- 2H , 6H , 7H , 8H- pyrolo[3,2-e]indazole-7,8-dione (5.1 g, 18.2 mmol) in 2N NaOH aqueous solution After dissolving in (7.28 g, 182 mmol), H 2 O 2 (3.1 g, 91 mmol) was slowly added dropwise and stirred for 1 hour. Acetic acid was added to the reaction mixture at 0°C to adjust the pH to 3, and the precipitated solid was filtered.
  • Step 6 Dissolve 5-amino-7-bromo-2-methyl- 2H -indazole-4-carboxylic acid (962 mg, 3.56 mmol) in methanol (14 mL) and toluene (42 mL) and then dissolve in 2 M (diazomethyl) )trimethylsilane (488 mg, 4.27 mmol) was slowly added dropwise at 0°C. It was heated to room temperature and stirred for 5 minutes. The compound was extracted with ethyl acetate (200 mL*3), and then the organic layer was dried with Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel chromatography.
  • Step 7 Dissolve methyl 5-amino-7-bromo-2-methyl- 2H -indazole-4-carboxylate (276 mg, 0.971 mmol) in THF (13 mL) and then dissolve trichloroethanecarbonylisocyanate (220 mg, 1.17 mmol) in 0 It was added dropwise at °C and reacted for 5 minutes. Most of the solvent was removed under reduced pressure, and the residue was suspended in ether (10 mL). The solid was filtered and dried under reduced pressure.
  • Step 8 methyl 7-bromo-2-methyl-5[[(2,2,2-trichloroacetyl)carbamoyl]amino]-2H -indazole -4- obtained in Step 7 in 7N NH 4 in Methanol (100 mL) Dissolve carboxylate (459 mg, 0.971 mmol). The resulting suspension was refluxed at 110°C for 36 hours under nitrogen. After completion of the reaction, it was cooled to 20°C, the solvent was removed with nitrogen, and the mixture was filtered.
  • Step 9 POCl 3 (5.9 g, 38.9 mmol) was added to 4-bromo-2-methyl- 2H , 6H , 7H ,8H,9H - pyrazolo[4,3 - f ]quinazoline- obtained in Step 8. 7,9-dione (287 mg, 0.973 mmol) was added dropwise. Then, DIPEA (377 mg, 2.92 mmol) was slowly added dropwise, and the mixture was filled with nitrogen and stirred at 110°C for 20 hours.
  • Step 1 Dissolve 7-Bromo-6-fluoro-2 H -indazole (40.0 g, 186 mmol) in ethyl acetate (500 mL), then add Me 3 OBF 4 (41.3 g, 279 mmol) and leave at room temperature for 12 hours. Stirred. The reaction was terminated with purified water (500 mL) and extracted with ethyl acetate (500 mL*2). The extracted organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous Na 2 SO 4 and concentrated.
  • Step 2 H 2 SO 4 (370 mL) was cooled to 0 o C, and 7-bromo-6-fluoro-2-methyl-2 H -indazole (37.0 g, 162 mmol) was added dropwise. KNO 3 (19.8 g, 1956 mmol) was slowly added dropwise to the reaction mixture at 0 o C and stirred at room temperature for 12 hours. After confirming the reaction, the reaction was terminated with cold purified water and slowly neutralized with NaHCO 3 aqueous solution at 0 o C. The organic layer was extracted with ethyl acetate (500 mL*3) and washed with saturated aqueous NaCl solution.
  • Step 3 7-bromo-6-fluoro-2-methyl-5-nitro- 2H -indazole (38.0 g, 139 mmol) and NH 4 Cl (59.3 g, 1.11 mol) were dissolved in EtOH (400 mL) and H 2 It was dissolved in O (200 mL), Fe (62.0 g, 1.11 mol) was added dropwise, and stirred at 80 o C for 2 hours. After confirming the reaction, the resulting solid was filtered, washed with EtOH, and dried. The mixture was subjected to silica gel chromatography to obtain 7-bromo-6-fluoro-2-methyl-2 H -indazol-5-amine (30.0 g, 123 mmol, 89% yield) as a yellow solid.
  • Step 4 2-((benzyloxy)imino)acetic acid (34.5 g, 193 mmol) was dissolved in DMF (245 mL) and HATU (54.9 g, 144 mmol), DIPEA (99.6 g, 770 mmol) and 7-bromo- 6-fluoro-2-methyl- 2H -indazol-5-amine (23.5 g, 96.3 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, and the reaction was terminated with cold purified water. The organic layer was extracted with ethyl acetate (400 mL*2), washed with saturated aqueous NaCl solution, dried over anhydrous Na 2 SO 4 and concentrated.
  • HATU 54.9 g, 144 mmol
  • DIPEA 99.6 g, 770 mmol
  • 7-bromo- 6-fluoro-2-methyl- 2H -indazol-5-amine 23.5 g, 96.3 mmol
  • Step 5 ( E )-2-((Benzyloxy)imino) -N- (7-bromo-6-fluoro-2-methyl- 2H -indazol-5-yl)acetamide (34.0 g, 83.9 mmol) was reacted with H 2 SO 4 (680 mL) was dissolved and stirred at 90°C for 2 hours. After confirming the reaction, it was cooled and the reaction was terminated with cold purified water. The organic layer was extracted with ethyl acetate (1.00 L*5) and freeze-dried.
  • Step 6 4-bromo-5-fluoro-2-methyl-2,6-dihydropyrrolo[3,2-e]indazole-7,8-dione (10.5 g, 35.2 mmol) and NaOH (14.1 g, 352 mmol) Dissolve in 1,4-dioxane (200 mL). H 2 O 2 (20.5 g, 180 mmol) was added dropwise to the reaction mixture at 0 o C and stirred at room temperature for 1 hour. After confirming the reaction, the reaction was terminated with Na 2 SO 3 aqueous solution (500 mL) and concentrated under reduced pressure. The pH was adjusted to 4 using 6 N HCl aqueous solution, and the resulting yellow solid was filtered and dried.
  • Step 7 5-Amino-7-bromo-6-fluoro-2-methyl- 2H -indazole-4-carboxylic acid (9.00 g, 31.2 mmol) and K 2 CO 3 (8.64 g, 62.5 mmol) were dissolved in DMF ( 90.0 mL) and CH 3 I (5.10 g, 35.9 mmol) was slowly added dropwise. The reaction solution was stirred at room temperature for 2 hours. After confirming the reaction, the NH 4 Cl aqueous solution (500 mL) was terminated, and the organic layer was extracted with ethyl acetate (300 mL*3).
  • Step 8 Methyl 5-amino-7-bromo-6-fluoro-2-methyl- 2H -indazole-4-carboxylate (9.70 g, 32.1 mmol) was dissolved in THF (100 mL) and 2,2,2-trichloroacetyl Isocyanate (12.1 g, 64.2 mmol) was added slowly dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 hours, and concentrated after confirming the reaction. The resulting white solid was dissolved in NH 3 ⁇ H 2 O (91.0 g, 727 mmol) and MeOH (100 mL) and stirred at 40°C for 2 hours.
  • Step 9 4-bromo-5-fluoro-2-methyl-2,6-dihydro-7 H -pyrazolo[4,3-f]quinazoline-7,9(8H)-dione (8.10 g, 25.9 mmol) It was dissolved in toluene (80.0 mL), and POCl 3 (39.7 g, 259 mmol) and DIPEA (7.36 g, 56.9 mmol) were slowly added dropwise. The reaction mixture was stirred at 115 °C for 40 hours. After confirming the reaction, the reaction was cooled, purified water was added, and the organic layer was extracted with ethyl acetate (500 mL*2).
  • Step 1 1-(Methoxycarbonyl)cyclopropane-1-carboxylic acid (1 g, 6.94 mmol) was dissolved in DCM (10 mL), then oxalyl chloride (1.76 g, 13.88 mmol) and DMF (50.72 mg, 694.00 ⁇ mol) were added at 0 o C. I added it slowly. The reaction mixture was stirred at room temperature under nitrogen for 3 hours. methyl 1-(chlorocarbonyl)cyclopropane-1-carboxylate (1.1 g, unrefined mixture) was obtained as a yellow oil without purification.
  • Step 2 methyl 1-(chlorocarbonyl)cyclopropane-1-carboxylate obtained in Step 1 (1.1 g, 6.77 mmol) was dissolved in THF (22 mL) and TEA (1.37 g, 13.53 mmol) was added dropwise at 0 o C. Afterwards, morpholine (884.22 mg, 10.15 mmol) was added and stirred at room temperature for 16 hours. After completion of the reaction, purified water was added and extracted with ethyl acetate. Purified by silica gel chromatography, methyl 1-(morpholine-4-carbonyl)cyclopropane-1-carboxylate (650 mg, 3.05 mmol, 45% yield) was obtained as a yellow oil.
  • Step 3 Methyl 1-(morpholine-4-carbonyl)cyclopropane-1-carboxylate (650 mg, 3.05 mmol) was dissolved in THF (13 mL), and LAH (289.25 mg, 7.62 mmol) was added dropwise at 0 o C. The reaction mixture was stirred under nitrogen for 16 hours at room temperature. Purified water was slowly added to complete the reaction, saturated NaOH aqueous solution was added, the reaction mixture was filtered, and the filtrate was concentrated. (1-(morpholinomethyl)cyclopropyl)methanol (520 mg, crude mixture) was obtained as a yellow oil.
  • 1,1-difluoro-6-azaspiro[2.5]octane was synthesized using the same method as Intermediate 6 to produce (1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methanol (820 mg, crude mixture) was obtained as a yellow oil.
  • Step 1 Dissolve 1-( tert -Butyl) 2-methyl (2 R ,4 R )-4-hydroxypyrrolidine-1,2-dicarboxylate (2.5 g, 10.19 mmol) in DCM (25 mL) and add imidazole (1.73 g) , 25.48 mmol) was added and stirred at 0 o C for 10 minutes. Afterwards, TBSCl (1.84 g, 12.23 mmol) was slowly added and stirred at room temperature for 12 hours.
  • Step 2 1-( tert -Butyl) 2-methyl (2 R ,4 R )-4-(( tert -butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (2.18 g, 6.06 mmol) was dissolved in THF (21 mL) ) and then LiHMDS (1 M, 12.13 mL) was added at -78 o C under nitrogen. The reaction mixture was stirred at -78 o C for 15 minutes. Afterwards, 3-chloro-2-(chloromethyl)prop-1-ene (1.89 g, 15.16 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours.
  • Step 3 1-( tert -butyl) 2-methyl (2 R ,4 R )-4-(( tert -butyldimethylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-1,2-dicarboxylate ( 4 g, 8.93 mmol) was dissolved in THF (40 mL), then TBAF ⁇ 3H 2 O (1 M, 10.71 mL) was added and stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was purified by silica gel chromatography.
  • Step 4 1-( tert -Butyl) 2-methyl (2 R ,4 R )-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.9 g, 8.69 mmol) in DCM After dissolving in (30 mL), BAST (2.88 g, 13.03 mmol, 2.85 mL) was slowly added dropwise at -78 o C. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was purified by silica gel chromatography.
  • Step 5 1-( tert -Butyl) 2-methyl (2 R ,4 S )-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylate (1.8 g, 5.36 mmol) in DCM After dissolving in (15 mL), TFA (7.68 g, 67.31 mmol, 5 mL) was slowly added dropwise at 0 o C. The reaction mixture was stirred at room temperature for 2 hours. After confirming that the starting material had disappeared, 7M NH 4 in MeOH was added. The reaction was terminated by adding water and then extracted with DCM.
  • the compound was purified by silicagel chromatography to obtain methyl (2 S , 7a R )-2-fluoro-6-methylenetetrahydro-1 H -pyrrolizine-7a(5 H )-carboxylate (950 mg, 4.29 mmol, 80% yield) as a pale yellow color. Obtained from oil.
  • Step 6 Methyl ( 2S , 7aR )-2-fluoro-6-methylenetetrahydro- 1H- pyrrolizine-7a( 5H )-carboxylate (940 mg, 4.72 mmol) was dissolved in THF (10 mL) and then LAH ( 2.5 M, 1.89 mL) was added under nitrogen at 0 o C and stirred at room temperature for 2 hours. When the starting material was consumed, the reaction was terminated with water and 15% aqueous NaOH.
  • Step 1,2 Dissolve 1-( tert -butyl) 2-methyl ( S )-5-oxopyrrolidine-1,2-dicarboxylate (40 g, 164.44 mmol) in DCM (600 mL) and add DIBAL-H (1 M , 500 mL) was slowly added dropwise at -68°C and stirred for 30 minutes. After that, the reaction was continued for 2 more hours at room temperature. MeOH (200 mL) and HCl solution (2 M, 180 mL) were added under nitrogen at 0 °C and stirred at 20 ° C for 2 hours.
  • Step 3 A solution of NaH (6.58 g, 164.44 mmol) in DMF (190 mL) was added to tert -butyl (2 S )-2-(hydroxymethyl)-5-methoxypyrrolidine-1-carboxylate (19 g, 82.15 mmol) and stirred for 15 minutes. Then MeI (23.32 g, 164.30 mmol, 10.23 mL) was added at 0 o C and stirred at 20 o C for 2 hours. After completion of the reaction, purified water was added to the reaction mixture to terminate the reaction, and the organic layer was extracted by adding ethyl acetae and dried over anhydrous MgSO 4 .
  • Step 4 Dissolve tert -Butyl (5 S )-2-methoxy-5-(methoxymethyl)pyrrolidine-1-carboxylate (10.7 g, 43.62 mmol) in DCM (100 mL) and add TMSOTf (969.44 mg, 4.36 mmol) After adding dropwise at 0 o C and stirring for 15 minutes, TMSCN (6.49 g, 65.43 mmol, 8.19 mL) was slowly added dropwise and reacted at 0 o C for 2 hours. After completion of the reaction, purified water was added to the reaction mixture to terminate the reaction, and the organic layer was extracted by adding ethyl acetae and dried over anhydrous MgSO 4 .
  • Step 5 Add tert -butyl ( 5S )-2-cyano-5-(methoxymethyl)pyrrolidine-1-carboxylate (3 g, 12.48 mmol) in HCl/MeOH (2 M, 30.00 mL) and incubated for 12 minutes at 20 o C. reacted over time. After completion of the reaction, purified water was added to the reaction mixture to terminate the reaction, and the organic layer was extracted by adding ethyl acetate and dried over anhydrous MgSO 4 . After removal of the solvent, methyl (5 S )-5-(methoxymethyl)pyrrolidine-2-carboxylate (1.5 g, 8.66 mmol, 69% yield) was obtained as a yellow oil.
  • Step 6 Methyl (5 S )-5-(methoxymethyl)pyrrolidine-2-carboxylate (1.5 g, 8.66 mmol) and Boc 2 O (1.89 g, 8.66 mmol) were dissolved in MeOH (30 mL) and incubated at 20°C for 12 days. Time responded. After completion of the reaction, purified water was added to the reaction mixture to terminate the reaction, and the organic layer was extracted by adding ethyl acetate and dried over anhydrous MgSO 4 . By purification, 1-( tert -butyl) 2-methyl (5 S )-5-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (2 g, 7.32 mmol, 84% yield) was obtained as a yellow oil.
  • Step 7 Dissolve 1-( tert -Butyl) 2-methyl (5 S )-5-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (2.4 g, 8.78 mmol) in THF (24 mL) and add LiHMDS (1 M , 17.56 mL) was stirred at -68 o C for 0.5 hours. (2.2 g, 17.56 mmol, 2.04 mL) was added to the reaction and reacted at room temperature for 12 hours. After completion of the reaction, purified water was added to the reaction mixture to terminate the reaction, and the organic layer was extracted by adding ethyl acetate and dried over anhydrous MgSO 4 .
  • Step 8 1-( tert -Butyl)2-methyl ( 5S )-2-(2-(chloromethyl)allyl)-5-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (600 mg, 1.66 mmol) in DCM After dissolving in (6 mL), TFA (2.4 mL) was added at 0°C and reacted at room temperature for 2 hours. After completion of the reaction, the reaction was concentrated to obtain methyl (5 S )-2-(2-(chloromethyl)allyl)-5-(methoxymethyl)pyrrolidine-2-carboxylate (434 mg, unrefined mixture) as a brown oil.
  • LCMS (ES-API, m/z): [M+H] + 490.2.
  • Step 9 Methyl (5 S )-2-(2-(chloromethyl)allyl)-5-(methoxymethyl)pyrrolidine-2-carboxylate (434 mg, 1.66 mmol) and K 2 CO 3 (458.32 mg, 3.32 mmol) It was dissolved in MeOH (6 mL) and stirred at room temperature for 3 hours. After completion of the reaction, purified water was added to the reaction mixture to terminate the reaction, and the organic layer was extracted by adding ethyl acetae and dried over anhydrous MgSO 4 .
  • Step 10 Dissolve Methyl (5 S , 7a S )-5-(methoxymethyl)-2-methylenetetrahydro-1 H -pyrrolizine-7a(5 H )-carboxylate (234 mg, 1.04 mmol) in THF (2.5 mL) LiAlH 4 (2.5 M, 415.48 ⁇ L) was added at 0 °C and stirred at room temperature for 1 hour. After completion of the reaction, purified water was added to the reaction mixture to terminate the reaction, and the organic layer was extracted by adding ethyl acetate and dried over anhydrous MgSO 4 .
  • Step 1 Dissolve 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (2.5 g, 6.97 mmol) in DCM (17.5 mL) and then dissolve diethylamine (3.60 g, 27.89 mmol) and Tf 2 O (4.13 g, 14.64 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0° C. under nitrogen for 3 hours. After the reaction was terminated by adding purified water, the reaction mixture was extracted with DCM.
  • Step 2 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diyl bis(trifluoromethanesulfonate (4.6 g, 7.39 mmol) and diphenylmethaneimine (1.34 g, 7.39 mmol, 1.24 mLPd 2 (dba) obtained in Step 1 ) 3 (1.35 g, 1.48 mmol), Xantphos (1.71 g, 2.96 mmol), and Cs 2 CO 3 (7.22 g, 22.16 mmol) were dissolved in toluene (46 mL) and purged three times with nitrogen.
  • Step 3 3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate obtained in Step 2 (3 g, 4.59 mmol) was dissolved in THF (30 mL) and HCl (1 M, 30.00 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours.
  • Step 4 3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (800 mg, 1.63 mmol) obtained in Step 3 was mixed with BPD (829.87 mg, 3.27 mmol), potassium acetate (320.72 mg, 3.27 mmol) and Pd(dppf)Cl 2 (119.56 mg, 163.40 ⁇ mol) in toluene. Afterwards, nitrogen purge was performed three times. The reaction mixture was stirred at 110°C for 12 hours under nitrogen.
  • Step 1 Dissolve 4-Bromo-7-fluorobenzo[ d ]thiazol-2-amine (450 mg, 1.82 mmol) in THF (9 mL) and then dissolve Boc 2 O (476.97 mg, 2.19 mmol), diethylamine (353.07 mg, 2.73 mmol) and DMAP (4.45 mg, 36.42 ⁇ mol) were added and purged three times with nitrogen. The reaction mixture was stirred for 2 hours, then concentrated and purified by silica gel chromatography to produce tert -butyl (4-bromo-7-fluorobenzo[ d ]thiazol-2-yl)carbamate. (500 mg, 1.40 mmol, 77% yield) was obtained as a white solid.
  • Step 2 The compound tert -butyl (4-bromo-7-fluorobenzo[ d ]thiazol-2-yl)carbamate (250 mg, 720.04 ⁇ mol) obtained in Step 1 was dissolved in THF (2 mL) and then dissolved in n -BuLi (2.5 mL). M in THF, 351.38 ⁇ L) was added dropwise at -15 o C and stirred for 30 minutes. Triisopropyl borate (338.55 mg, 1.80 mmol) was added at -65°C and stirred for 30 minutes, then MeLi (1.6 M, 540.03 ⁇ L) was added at -65°C and nitrogen purged three times.
  • reaction mixture was reacted under nitrogen at 0 o C for one hour. After completion of the reaction, NH 4 Cl solution and ethyl acetate were added to extract the compound. Na 2 SO 4 was added to dry the water and the solvent was removed under reduced pressure. (2-(( tert -butoxycarbonyl)amino)-7-fluorobenzo[ b ]thiophen-4-yl)boronic acid (220 mg, unpurified mixture) was obtained as a white solid.
  • Step 1 4-Bromobenzo[ d ]thiazol-2-amine (1g, 4.36 mmol) was dissolved in THF (4 mL) and DCM (6 mL), and the temperature was lowered to 0°C. At 0°C, di- tert -butyl dicarbonate (1.1 mL, 4.8 mmol), TEA (1.16 mL, 8.73 mmol), and DMAP (53.3 mg, 436 ⁇ mol) were added and stirred for 2 hours. After the starting material was completely consumed, water was added to terminate the reaction, and the organic layer was extracted with ethyl acetate. After drying with anhydrous Na 2 SO 4 , it was filtered and concentrated.
  • Step 2 Dissolve tert -butyl (4-bromobenzo[ d ]thiazol-2-yl)carbamate (1.2 g, 3.65 mmol) obtained in Step 1 in 1,4-dioxane (10 mL), then add Potassium acetate (1.07 g) , 10.9 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.85 g, 7.29 mmol), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) ⁇ DCM complex (267 mg, 365 ⁇ mol) were added, the temperature was raised to 100°C, and the mixture was stirred for 24 hours.
  • Step 1 Dissolve 1-Bromo-5-fluoro-2-iodo-3-methylbenzene (3 g, 9.53 mmol) in DMF (60 mL) and add CuI (10.89 g, 57.16 mmol) and methyl 2,2-difluoro- 2-fluorosulfonyl-acetate (10.98 g, 57.16 mmol, 7.27 mL) was added. The reaction mixture was stirred at 60°C for 12 hours.
  • reaction residue was purified by silica gel chromatography to obtain 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (1.1 g, 4.28 mmol, 45% yield).
  • Step 2 Dissolve 1-Bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (1.7 g, 6.61 mmol) in THF (34 mL) and then dissolve LDA (2 M, 6.61 mL) under nitrogen - It was slowly added dropwise at 60 o C and stirred for 30 minutes. DMF (1.45 g, 19.84 mmol, 1.53 mL) was added dropwise to the reaction mixture and stirred at -60 o C for 1.5 hours.
  • Step 3 2-Bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (860 mg, 3.02 mmol) and NH 2 NH 2 ⁇ H 2 O (4.43 g, 86.72 mmol, 4.29 mL) were dissolved in DMSO ( After dissolving in 9 mL), nitrogen purge was performed three times. The reaction mixture was reacted at 60°C for 2 hours. After completion of the reaction, purified water (20 mL) was added dropwise to the reaction mixture and ethyl acetate (20 mL*3) was added to extract the organic layer, washed with saturated aqueous NaCl solution (30 mL*2), and dried over anhydrous MgSO 4 . .
  • Step 4 Dissolve 4-Bromo-6-methyl-5-(trifluoromethyl)-1 H -indazole (618 mg, 2.21 mmol) in DCM (12 mL) and then add TsOH ⁇ H 2 O (42.13 mg, 221.46 ⁇ mol). A solution of DHP (745.14 mg, 8.86 mmol) dissolved in acetonitrile (3 ml) was sequentially added and stirred at room temperature for 16 hours.
  • Step 5 Hypoboric acid (185.14 mg, 2.07 mmol), 4-bromo-6-methyl-1-(tetrahydro-2 H -pyran-2-yl)-5-(trifluoromethyl)-1 H -indazole (250 mg, 688.38 ⁇ mol) and cataCXium Pd G4 (50.20 mg, 68.84 ⁇ mol) were dissolved in MeOH (3 mL), and then DIEA (266.90 mg, 2.07 mmol) was slowly added dropwise under nitrogen. After degassing with nitrogen for 10 minutes, the mixture was stirred at 60°C for 40 minutes.
  • Step 1 Dissolve 4-Bromo-5-chloro-6-methyl-1 H -indazole (2 g, 8.15 mmol) in MeOH (25 mL), then add NaOH (4 M, 13.24 mL), I 2 (2.48 g, 9.78 mmol, 1.97 mL) was added dropwise at 0°C. It was stirred under nitrogen for 2 hours at room temperature. After completion of the reaction, purified water was added to the reaction mixture to terminate the reaction, and the organic layer was extracted by adding ethyl acetate and dried over anhydrous MgSO 4 .
  • Step 2 4-Bromo-5-chloro-3-iodo-6-methyl- 1H -indazole (200 mg, 538.50 ⁇ mol), p-TsOH (4.64 mg, 26.93 ⁇ mol), and DHP (90.59 mg, 1.08 mmol) were dissolved in DCM (2.5 mL), then degassed and purged with nitrogen three times, and then incubated at room temperature under nitrogen. It was stirred for 2 hours. After completion of the reaction, purified water was added to the reaction mixture to terminate the reaction, and the organic layer was extracted by adding ethyl acetate and dried over anhydrous MgSO 4 .
  • Step 3 4-Bromo-5-chloro-3-iodo-6-methyl-1-(tetrahydro- 2H -pyran-2-yl)-1H-indazole (1 g, 2.20 mmol), Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (89.64 mg, 109.77 ⁇ mol) was dissolved in DMF (10 mL), then dimethylzinc (1 M, 5.49 mL) was added under nitrogen and stirred at 80°C for 12 hours. After completion of the reaction, purified water was added to the reaction mixture to terminate the reaction, and the organic layer was extracted by adding ethyl acetate and dried over anhydrous MgSO 4 .
  • reaction residue was purified using silica gel chromatography and 4-bromo-5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1 H -indazole (320 mg, 931.19 ⁇ mol) , 42% yield) was obtained as a white solid.
  • Step 4 4-bromo-5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (320 mg, 651.83 ⁇ mol), hypoboric acid (175.31 mg, 1.96 mmol), DIEA (252.73 mg, 1.96 mmol), and cataCXium Pd G4 (47.54 mg, 65.18 ⁇ mol) were dissolved in MeOH (4 mL) and then degassed. After purging with nitrogen three times, the mixture was stirred at 60°C for 40 minutes.
  • Step 1 6-bromo- N , N -bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (110.67 mg, 190.78 ⁇ mol) and Su 2 Bu 6 (110.67 mg, 190.78 ⁇ mol) ) was dissolved in 1,4-dioxane (1 mL), and then Pd 2 (dba) 3 (5.55 mg, 6.06 ⁇ mol), tricyclohexylphosphane (3.40 mg, 12.11 ⁇ mol), and LiCl (12.84 mg, 302.83 ⁇ mol) were added. The reaction mixture was stirred at 110 °C for 16 hours.
  • N N -bis(4-methoxybenzyl)-4-methyl-6-(tributylstannyl)-5-(trifluoromethyl)pyridin-2-amine was purified by silica gel chloromatography. (25 mg, 32.25 ⁇ mol, 53.24% yield) was obtained as a colorless oil.
  • Step 1 6-Bromo-5-(trifluoromethyl)pyridin-2-amine (700 mg, 2.9 mmol) was dissolved in DMF (10 mL), and the temperature was lowered to 0 o C. Sodium hydride (290 mg, 7.26 mmol) was added at 0 o C and stirred for 30 minutes. After 30 minutes, 4-methoxybenzyl chloride (1.07 mL, 7.26 mmol) was added to the reaction mixture and stirred at room temperature for 4 hours. After completion of the reaction, the temperature was lowered to 0 o C, water was slowly added to terminate the reaction, and the organic layer was extracted with ethyl acetate. After drying with anhydrous MgSO 4 , it was concentrated under reduced pressure.
  • Step 2 6-bromo- N , N -bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2-amine (1.1 g, 2.29 mmol) obtained in Step 1 was added to 1,4-dioxane (10 mL). After dissolving, tricyclohexylphosphane (128 mg, 457 ⁇ mol), bis(tributylstannane) (3.48 mL, 6.86 mmol), Tris(dibenzylideneacetone)dipalladium(0) (209 mg, 229 ⁇ mol), and Lithium chloride (484 mg, 11.4 mmol) were added. Added it, raised the temperature to 110 o C and stirred for 5 hours.
  • Step 1 3-Bromo-4-(trifluoromethyl)aniline (500 mg, 2.08 mmol) was dissolved in DMF (10 mL), and the temperature was lowered to 0 o C. NaH (416 mg, 10.41 mmol) was added at 0 o C and stirred for 30 minutes. After 30 minutes, 4-methoxybenzyl chloride (1.4 mL, 10.41 mmol) was added to the reaction mixture and stirred at room temperature for 24 hours. After completion of the reaction, the reaction temperature was lowered to 0 o C, water was slowly added to terminate the reaction, and the organic layer was extracted with ethyl acetate. After drying with anhydrous Na 2 SO 4 , it was concentrated under reduced pressure.
  • Step 2 Dissolve 3-bromo- N , N -bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline (160 mg, 333 ⁇ mol) obtained in Step 1 in 1,4-dioxane (2 mL), then dissolve potassium acetate (98.1 mg, 999 ⁇ mol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2 Add -dioxaborolane (102 mg, 400 ⁇ mol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (24.4 mg, 33.3 ⁇ mol), raise the temperature to 90 o C, and stir for 24 hours.
  • Step 1 2,3,4,5-Tetrafluoroaniline (5g, 30.3 mmol,) was dissolved in acetonitrile (20 mL), then NBS (5.93 mg, 33.3 mmol) was added at room temperature and stirred at 60 o C for 2 hours. The reaction temperature was lowered to room temperature, the reaction was terminated with a saturated sodium thiosulfate aqueous solution, and then extracted with ethyl acetate. Purified by silica gel chromatography, 2-bromo-3,4,5,6-tetrafluoroaniline (5.5g, 22.5 mmol, 74% yield) was obtained as a brown solid. 1 H NMR (400 MHz, CDCl 3 , ppm): ⁇ 4.27 - 4.15 (m, 2H).
  • Step 2 2-bromo-3,4,5,6-tetrafluoroaniline (0.5 g, 2.05 mmol) obtained in Step 1 and B 2 pin 2 (1.30 g, 5.12 mmol), Pd(dppf)Cl 2 (149.95 mg, 204.93 ⁇ mol), potassium acetate (402.25 mg, 4.10 mmol) was added to 1,4-dioxane (5 mL), purged with nitrogen three times, and purified by silica gel chromatography for 2 hours under nitrogen.
  • Example 1 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol.
  • Step 1 Dissolve 6-bromo-1,3-dichloroimidazo[1',2':1,6]pyrido[3,2- d ]pyrimidine (2.4 g, 7.55 mmol) in DCM (48 mL), N -diisopropylamine (1.46 g, 11.32 mmol), tert -butyl (1 R ,5 S )-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.92 g, 9.06 mmol) were added and the reaction mixture was It was stirred at 25°C for 1 hour. The reaction mixture was diluted with purified water (80 mL) and extracted with DCM (50 mL*3).
  • Step 2 tert -butyl (1 R ,5 S )-3-(6-bromo-3-chloroimidazo[1',2':1,6]pyrido[3,2) obtained in Step 1 in THF (45 mL) - d ]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.44 g, 4.94 mmol) was dissolved and NaH (395.28 mg, 9.88 mmol) was added at 0°C.
  • Step 3 tert -butyl ( 1R , 5S )-3-(4-bromo-7-((( 2R , 7aS )-2-fluorotetrahydro-1H - pyrrolizin-7a( 5H )-yl obtained in step 2 )methoxy)imidazo[1,2- a ][1,5]naphthyridin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (470 mg, 821.57 ⁇ mol), 2-(8 -ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (355.14 mg, 985.89 ⁇ mol), cataCXium A Pd G3 (29.92 mg, 41.08 ⁇ mol) and Cs 2 CO 3 (535.37 mg, 1.64 mmol) were added to
  • reaction mixture was then stirred under nitrogen at 80° C. for 16 hours. After the starting material was completely consumed, the reaction mixture was concentrated under reduced pressure, the residue was diluted with water (10 mL), and the compound was extracted with ethyl acetate (5 mL*2). The organic layer was washed with saturated aqueous NaCl solution (5 mL*2), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by prep-TLC.
  • Step 4 tert -butyl (1 R ,5 S )-3-(6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(( ( 2R , 7aS )-2-fluorotetrahydro- 1H- pyrrolizin-7a( 5H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-1 -yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (65 mg, 84.43 ⁇ mol) was dissolved and then 4 N HCl in ethyl acetate solution (650 ⁇ L) was added.
  • the reaction mixture was stirred at 25 °C for 1 hour. After the starting material was completely consumed, the reaction mixture was concentrated under reduced pressure, the residue was diluted with saturated NaHCO 3 solution (10 mL), and the compound was extracted with ethyl acetate (5 mL*2). The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by Prep-HPLC.
  • Example 2 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Step 1 tert- Butyl (1 R ,5 S )-3-(6-bromo-3-(((2 R ,7a S )-2-fluorotetrahydro-1H-pyrrolizin-7a(5 H )-yl)methoxy )imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 243.30 ⁇ mol) , ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (149.64 mg , 291.96 ⁇ mol), cataCXium A Pd G3 (8.86 mg, 12.16 ⁇ mol) and Cs 2 CO 3 (158.
  • Step 2 tert -butyl ( 1R , 5S )-3-(6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl) in DMF (1.2 mL) -3-(((2 R ,7a S )-2-fluorotetrahydro-1H-pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 130.13 ⁇ mol) was dissolved and CsF (296.50 mg, 1.95 mmol, 71.97 ⁇ L) was added.
  • CsF 296.50 mg, 1.95 mmol, 71.97 ⁇ L
  • the reaction mixture was stirred at 40° C. for 16 hours.
  • the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL*3).
  • the organic matter was washed with saturated aqueous NaCl solution (10 mL*2), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a residue.
  • the residue was purified by prep-TLC.
  • Step 3 tert -butyl ( 1R , 5S )-3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-((( 2R ) in ACN (0.7 mL) ,7a S )-2-fluorotetrahydro-1H-pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-1-yl)- After dissolving 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 91.40 ⁇ mol), 4N HCl in dioxane (700 ⁇ L) was added under nitrogen at 0°C and stirred for 1 hour.
  • Example 3 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5,6-difluoronaphthalen-2-ol.
  • Step 1 tert -butyl (1 R ,5 S )-3-(6-bromo-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl) methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 262.20 ⁇ mol) ), 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (110.18 mg, 314.65 ⁇ mol), PdCl 2 (dtbpf) (17.09 mg, 26.22 ⁇ mol) and K 3 PO 4 (166.97 mg, 786.61 ⁇ mol) were added to 1,4-di
  • Step 2 tert -butyl ( 1R , 5S )-3-(6-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2) in ACN (1.3 mL) R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl )-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 171.09 ⁇ umol) was dissolved and HCl in dioxane (4 M, 1.30 mL) was added at 0 °C, then stirred at 0 °C for 1 hour.
  • reaction mixture was concentrated under reduced pressure.
  • the residue was diluted with saturated NaHCO 3 solution (15 mL) and the compound was extracted with ethyl acetate (10 mL*3).
  • the organic layer was washed with an aqueous NaCl solution, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Example 4 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol.
  • Step 1 Dissolve 6-bromo-1,3-dichloroimidazo[1',2':1,6]pyrido[3,2- d ]pyrimidine (2 g, 6.29 mmol) in DCM (40 mL) and add DIPEA (1.22 g, 9.44 mmol) and 1-(aminomethyl)- N , N -dimethylcyclobutan-1-amine (967.79 mg, 7.55 mmol) were added in that order. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water (80 mL) and extracted with DCM (50 mL*2).
  • Step 2 6-bromo-3-chloro -N -((1-(dimethylamino)cyclobutyl)methyl)imidazo[1',2':1,6]pyrido[3,2- d ] in THF (26 mL) After dissolving pyrimidin-1-amine (1.3 g, 3.56 mmol) and ((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methanol (2.27 g, 14.24 mmol) NaH (1.42 g, 35.59 mmol) was added at 0 °C. The reaction mixture was warmed to 25° C.
  • Step 3 6-bromo- N -((1-(dimethylamino)cyclobutyl)methyl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H obtained in Step 2 )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-1-amine (150 mg, 307.38 ⁇ mol), 2-(8-Ethyl-7-fluoro- 3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (132.87 mg, 368.85 ⁇ mol), PdCl 2 (dtbpf) (20.03 mg, 30.74 ⁇ mol), K 3 PO 4 (195.74 mg, 922.13 ⁇ mol) was dissolved in dioxane (2.4 mL) and water (0.6 mL), purged
  • reaction mixture was diluted with water (20 mL) and the compound was extracted with ethyl acetate (15 mL*3). The organic layer was washed with saturated aqueous NaCl solution (15 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step 4 N -((1-(dimethylamino)cyclobutyl)methyl)-6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- obtained in Step 3 in ACN (1 mL) 3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ] After dissolving pyrimidin-1-amine (100 mg, 145.81 ⁇ mol), HCl in dioxane (4 M, 0.5 mL) was added at 0°C and stirred for 1 hour.
  • Example 5 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5,6-difluoronaphthalen-2-ol.
  • Example 6 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H Synthesis of )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Step 1 6-bromo- N -((1-(dimethylamino)cyclobutyl)methyl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl) methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-1-amine (150 mg, 307.38 ⁇ mol), ((2-Fluoro-6-(methoxymethoxy)-8-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (189.05 mg, 368.85 ⁇ mol), PdCl 2 (dtbpf) (20.03 mg, 30.70 ⁇ mol) .), K 3 PO 4 (195.74 mg, 922.13 ⁇ mol) was added to dioxane (
  • reaction mixture was stirred under nitrogen at 80° C. for 1.5 hours. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and the compound was extracted with ethyl acetate (15 mL*3). The organic layer was washed with saturated aqueous NaCl solution (15 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography.
  • Step 2 N -((1-(dimethylamino)cyclobutyl)methyl)-6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen- obtained in Step 1 in DMF (1.5 mL) 1-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[ After dissolving 3,2- d ]pyrimidin-1-amine (145 mg, 173.01 ⁇ mol), CsF (394.20 mg, 2.60 mmol) was added, and the mixture was stirred at 40°C for 16 hours.
  • CsF 394.20 mg, 2.60 mmol
  • reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (15 mL*3).
  • the organic matter was washed with saturated aqueous NaCl solution (15 mL*2), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain a residue.
  • Step 3 Acetonitrile (0.8 mL) and N -((1-(dimethylamino)cyclobutyl)methyl)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen obtained in Step 2 in DCM (0.8 mL) -1-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido After dissolving [3,2- d ]pyrimidin-1-amine (80 mg, 117.34 ⁇ mol), HCl in dioxane (4 M, 800 ⁇ L) was added at 0 °C and stirred for 1 hour.
  • reaction mixture was concentrated under reduced pressure, the residue was diluted with saturated NaHCO 3 solution (15 mL), and the compound was extracted with ethyl acetate (10 mL*3). The organic layer was washed with saturated aqueous NaCl solution (10 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Example 7 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol synthesis.
  • Example 8 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((( R )-3-methylmorpholino)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Example 9 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy )Synthesis of imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Example 10 4-(3-((1-(((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-((1 R, 5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Example 11 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((( R )-2-methylmorpholino)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Example 12 4-(3-((1-(((1 S ,4 S )-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example 13 3-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-2,4,5,6-tetrafluoroaniline.
  • Step 1 ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1 in Step 1 of Example 2 It was synthesized in the same way using intermediate 26 instead of -yl)ethynyl)triisopropylsilane.
  • Step 2 tert -butyl ( 1R , 5S )-3-(6-(2-amino-3,4,5,6-tetrafluorophenyl)-3-((( 2R , 7aS ) obtained in Step 1 -2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8 -diazabicyclo[3.2.1]octane-8-carboxylate (75.00 mg, 107.04 ⁇ mol) was dissolved in acetonitrile, and then HCl in dioxane (4 M, 0.8 mL) was added dropwise.
  • Example 14 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.
  • Example 15 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-7-fluorobenzo[ d ]Synthesis of thiazol-2-amine.
  • Step 1 (2-(( tert -Butoxycarbonyl)amino)-7-fluorobenzo[ b ]thiophen-4-yl)boronic acid (220 mg, 563.88 ⁇ mol) and tert -butyl (1 R ,5 S )-8-(6-chloro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate ( After dissolving 280 mg, 489.45 ⁇ mol) in 1,4-dioxane (5 mL) and water (1 mL), K 3 PO 4 (311.68 mg, 1.47 mmol), Pd(amphos)Cl 2 (31.90 mg, 48.94
  • Step 2 tert -butyl (1 R ,5 S )-8-(6-(2-(( tert -butoxycarbonyl)amino)-7-fluorobenzo[ d ]thiazol-4-yl)-3- obtained in Step 1 ((( 2R , 7aS )-2-fluorotetrahydro- 1H -pyrrolizin-7a( 5H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2 -d ]pyrimidin -1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (227.62 mg, 323.42 ⁇ mol) was dissolved in ACN, then HCl in dioxane (4 M, 0.5 mL) was added and incubated at 0°C for 2 hours.
  • Example 16 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-((( R )-3-fluoropyrrolidin -1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol synthesis .
  • Example 17 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[ 3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Example 18 1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-6-(6-methyl-5-(trifluoromethyl)-1 H -indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidine.
  • Step 1 Intermediate 21 (210 mg, 640.06 ⁇ mol) and tert -butyl (1 R ,5 S )-8-(6-chloro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H - pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane -3-carboxylate (347.85 mg, 608.06 ⁇ mol) was dissolved in 1,4-dioxane (2.5 mL) and water (0.5 mL), then Cs 2 CO 3 (625.63 mg, 1.92 mmol) and cataCXium A Pd G4 (46.68 mg) , 64.01 ⁇ mol) is added.
  • Step 2 tert -butyl (1 R ,5 S )-8-(3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl) obtained in Step 1 methoxy)-6-(6-methyl-1-(tetrahydro-2 H -pyran-2-yl)-5-(trifluoromethyl)-1 H -indazol-4-yl)imidazo[1',2':1, 6]pyrido[3,2- d ]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (100 mg, 121.97 ⁇ mol) was dissolved in DCM (1 mL) and then dissolved in TFA ( Add 767.50 mg, 6.73 mmol).
  • Example 19 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-((( S )-3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Example 20 6-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine.
  • Step 1 tert -Butyl (1 R ,5 S )-3-(6-chloro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl) methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (62.28 mg, 108.86 ⁇ mol ), intermediate 23 (64 mg, 90.72 ⁇ mol), CuI (4.32 mg, 22.68 ⁇ mol), LiCl (9.61 mg, 226.80 ⁇ mol), cataCXium Pd G4 (16.54 mg, 22.68 ⁇ mol) with 1,4-dioxane (2 mL) and then purged three times with nitrogen.
  • reaction mixture was then stirred at 110 °C for 12 hours. After completion of the reaction, purification was performed using silica gel chromatography to obtain tert -butyl (1 R ,5 S )-8-(6-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2.
  • Step 3 tert -butyl (1 R ,5 S )-8-(6-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl obtained in Step 2 )-3-(((2 R ,7a S )-2-fluorotetrahydro-1H-pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- Dissolve d ]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (24 mg, 25.21 ⁇ mol) in dichloroethane (0.24 mL) and add TFA (368.40 mg, 3.23 mmol).
  • the reaction mixture was stirred at 60 °C for one hour. The reaction was terminated by adding saturated NaHCO 3 solution and extracted with ethyl acetate. The reaction mixture was purified by Prep-HPLC to obtain 6-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-4- Methyl-5-(trifluoromethyl)pyridin-2-amine (3.61 mg, 4.93 ⁇ mol, 20% yield) was obtained.
  • Example 21 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((( R )-2-methylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Example 22 1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidine.
  • Example 23 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example 24 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.
  • Example 25 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-7-fluorobenzo[ d ]Synthesis of thiazol-2-amine.
  • Example 26 1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-6-(6-methyl-5-(trifluoromethyl)-1 H -indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidine.
  • Example 27 1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidine.
  • Example 28 1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidine.
  • Example 29 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Example 30 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((( R )-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Example 31 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((( S )-3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Example 32 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 S ,7a R )-2-fluoro-6-methylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Example 33 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((( R )-2-methylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Example 34 6-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine.
  • Example 35 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl) Synthesis of methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol .
  • Example 36 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.
  • Example 37 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((( S )-2-(difluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Example 38 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine
  • Example 39 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2 S ,7a R )-2-fluoro-6-methylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]Synthesis of pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
  • Example 40 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((( R )-3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen Synthesis of -2-ol.
  • Example 41 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]Synthesis of quinazolin-6-yl)naphthalen-2-ol.
  • Step 1 Dissolve 6-Bromo-1,3-dichloro-8-methylfuro[3,2- f ]quinazoline (40.0 mg, 0.120 mmol) in DCM (3 mL), and tert- butyl (1 R ,5 S) at 0 o C. )-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30.7 mg, 0.145 mmol) and DIPEA (0.064 mL, 0.361 mmol) were sequentially added, and the reaction solution was stirred at the same temperature for 30 minutes. The reaction was terminated by adding purified water to the reaction mixture, and the organic layer was extracted by adding ethyl acetate and dried over anhydrous MgSO 4 .
  • Step 2 Dissolve ((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methanol (33.0 mg, 0.207 mmol) in THF (10 mL), NaH (78.8 mg , 0.207 mmol) was added and stirred for 30 minutes, then tert -butyl ( 1R , 5S )-3-(6-bromo-3-chloro-8-methylfuro[3,2 -f ] synthesized in step 1.
  • Step 3 tert -butyl ( 1R , 5S )-3-(6-bromo-3-((( 2R , 7aS )-2-fluorotetrahydro-1H-pyrrolizin-7a( 5H ) obtained from step 2 -yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (28.0 mg, 0.044 mmol), 2-(3 -(methoxymethoxy)naphtalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27.9 mg, 0.089 mmol), K 3 PO 4 (28.3 mg, 0.133 mmol) were dissolved in ethanol ( 1.50 mL), DMF (0.30 mL), and purified water (0.15 mL), cataCXium A Pd G3 (4.
  • Step 4 tert -butyl ( 1R , 5S )-3-(3-((( 2R , 7aS )-2-fluorotetrahydro-1H-pyrrolizin-7a(5H ) -yl)methoxy obtained from Step 3 )-6-(3-(methoxymethoxy)naphthalen-1-yl)-8-methylfuro[3,2- f ]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ( 30.0 mg, 0.041 mmol) was dissolved in DCM (1 mL), 4 N hydrochloric acid solution (0.50 mL) dissolved in 1,4-dioxane at 0 o C was added, and the reaction solution was stirred at room temperature for 30 minutes.
  • Example 42 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]Synthesis of quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Step 1 tert -Butyl (1 R ,5 S )-3-(6-bromo-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl) methoxy)-8-methylfuro[3,2- f ]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (51.0 mg, 0.081 mmol), ((2-Fluoro-6 -(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (62.2 mg, 0.121 mmol), K 3 PO 4 (51.5 mg, 0.243 mmol) was dissolved in ethanol (1.50 mL), DMF (0.30 mL), and purified water (0.15
  • Step 2 tert -butyl (1 R ,5 S )-3-(6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3 obtained from Step 1 -((( 2R , 7aS )-2-fluorotetrahydro- 1H- pyrrolizin-7a(5H ) -yl)methoxy)-8-methylfuro[3,2 -f ]quinazolin-1-yl)-3, Dissolve 8-diazabicyclo[3.2.1]octane-8-carboxylate (62.0 mg, 0.066 mmol) in THF (0.5 mL), and add 1 M TBAF (0.13 mL, 0.132 mmol) dissolved in THF at 0 o C.
  • Step 3 tert -butyl (1 R ,5 S )-3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-1-yl)-3,8-diazabicyclo[3.2 .1] Dissolve octane-8-carboxylate (50.0 mg, 0.064 mmol) in DCM (1 mL), add 4 N HCl solution (0.30 mL) dissolved in 1,4-dioxane at 0 °C, and cool the reaction solution to room temperature.
  • Example 43 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]Synthesis of quinazolin-6-yl)naphthalen-2-ol.
  • Step 1 tert -Butyl (1 R ,5 S )-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2- f ]quinazolin-1-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (60.0 mg, 0.114 mmol), 2-[3-(methoxymethoxy)naphtalene-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (53.8 mg, 0.171 mmol) and Cs 2 CO 3 (112 mg, 0.342 mmol) were dissolved in toluene (1.00 mL) and purified water (0.25 mL), and cataCXium A Pd G3 (8.3 mg, 0.011 mmol) was added to prepare the reaction solution.
  • Step 2 Dissolve ((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methanol (50.3 mg, 0.316 mmol) in THF (3.00 mL), NaH (12.6 mg , 0.316 mmol) was added and stirred for 30 minutes.
  • Step 3 tert -butyl ( 1R , 5S )-3-(5-fluoro-3-((( 2R , 7aS )-2-fluorotetrahydro-1H - pyrrolizin-7a( 5H ) obtained from step 2 )-yl)methoxy)-6-(3-(methoxymethoxy)naphthalen-1-yl)-8-methylfuro[3,2- f ]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane -8-Carboxylate (23.0 mg, 0.030 mmol) was dissolved in DCM (3.00 mL), 4 N hydrochloric acid solution (0.2 mL) dissolved in 1,4-dioxane was added at 0 °C, and the reaction solution was incubated at room temperature for 3 hours.
  • Example 44 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]Synthesis of quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Step 1 tert -Butyl (1 R ,5 S )-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2- f ]quinazolin-1-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.19 g, 2.26 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2- Dissolve dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.74 g, 3.39 mmol) and Cs 2 CO 3 (2.21 g, 6.79 mmol) in toluene (34.0 mL) and purified water (8.5 mL), and cataCXium A Pd G3 (165 mg, 0.226 mmol) was added and the reaction solution was stirred at 100 °C for
  • Step 3 Dissolve ((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methanol (1.05 g, 6.61 mmol) in THF (29 mL), NaH (265 mg , 6.61 mmol) was added and stirred for 30 minutes, then tert -butyl (1 R ,5 S )-3-(3-chloro-5-fluoro-6-(7-fluoro-3-methyl-) obtained from step 2.
  • the material obtained by concentrating the solvent was purified by silica gel chromatography to obtain a solid compound, tert -butyl (1 R ,5 S )-3-(5-fluoro-6-(7-fluoro-3-methyl-8-((triisopropylsilyl )ethynyl)naphthalen-1-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.524 mmol, 79% yield) was obtained.
  • Step 4 tert -butyl (1 R ,5 S )-3-(5-fluoro-6-(7-fluoro-3-methyl-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl) obtained from Step 3 -3-((( 2R , 7aS )-2-fluorotetrahydro- 1H- pyrrolizin-7a( 5H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-1-yl)- Dissolve 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.524 mmol) in THF (17.5 mL) and react by adding 1 M TBAF in THF (1.05 mL, 1.05 mmol) at 0°C.
  • Step 5 tert -butyl (1 R ,5 S )-3-(6-(8-ethynyl-7-fluoro-3-methylnaphthalen-1-yl)-5-fluoro-3-((((( 2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-1-yl)-3,8-diazabicyclo[ 3.2.1] Dissolve octane-8-carboxylate (20 mg, 0.025 mmol) in DCM (3 mL), add 4 N HCl in 1,4-dioxane (0.06 mL) at 0 o C, and cool the reaction solution at room temperature.
  • Example 45 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]Synthesis of quinazolin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol.
  • Example 46 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]Synthesis of quinazolin-6-yl)-5,6-difluoronaphthalen-2-ol.
  • Example 47 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]Synthesis of quinazolin-6-yl)naphthalen-2-ol.
  • Example 48 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]Synthesis of quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  • Example 49 3-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]Synthesis of quinazolin-6-yl)-4-(trifluoromethyl)aniline
  • Step 1 tert -Butyl (1 R ,5 S )-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2- f ]quinazolin-1-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 285 ⁇ mol), N , N -bis(4-methoxybenzyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)-4-(trifluoromethyl)aniline (228 mg, 428 ⁇ mol), cataCXium A Pd G3 (20.8 mg, 28.5 ⁇ mol) and Cs 2 CO 3 (279 mg, 856 ⁇ mol) were mixed with toluene (2 mL).
  • Step 2 Synthesize in the same manner as step 2 of Example 43 to obtain tert -butyl (1 R ,5 S )-3-(6-(5-(bis(4-methoxybenzyl)amino)-2-(trifluoromethyl)phenyl )-5-fluoro-3-((( 2R , 7aS )-2-fluorotetrahydro-1H - pyrrolizin-7a( 5H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin- 1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 51.6 ⁇ mol, 62% yield) was obtained.
  • LCMS (ES-API, m/z): [M+H] + 970.1.
  • Step 3 tert -butyl (1 R ,5 S )-3-(6-(5-(bis(4-methoxybenzyl)amino)-2-(trifluoromethyl)phenyl)-5-fluoro-3- obtained in Step 3 ((( 2R , 7aS )-2-fluorotetrahydro- 1H- pyrrolizin-7a( 5H )-yl)methoxy)-8-methylfuro[3,2 -f ]quinazolin-1-yl)-3,8 TFA (4 mL) was added to -diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 41.3 ⁇ mol), and stirred at room temperature for 9 hours.
  • Example 50 6-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]Synthesis of quinazolin-6-yl)-5-(trifluoromethyl)pyridin-2-amine.
  • Step 1 tert -Butyl (1 R ,5 S )-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2- f ]quinazolin-1-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 152 ⁇ mol), N , N -bis(4-methoxybenzyl)-6-(tributylstannyl)-5-(trifluoromethyl)pyridin-2-amine (126 mg, 183 ⁇ mol), tetrakis(triphenylphosphine)palladium(0) (35.2 mg, 30.4 ⁇ mol), Lithium chloride (19.3 mg, 456 ⁇ mol), Copper(I) iodide (5.8 mg, 30.4 ⁇ mol) in 1.4-dioxane (2 mL) After putting it in, degassing and nitrogen purge were repeated three times.
  • reaction mixture was then stirred under nitrogen at 130° C. for 8 hours. After the starting materials were completely consumed, the reaction temperature was lowered to room temperature, the palladium catalyst was removed through a celite filter, and the organic layer was extracted with ethyl acetate. After drying with anhydrous Na 2 SO 4 , it was concentrated under reduced pressure.
  • Step 2 Synthesize in the same manner as step 2 of Example 43 to obtain tert -butyl (1 R ,5 S )-3-(6-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin -2-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 30.9 ⁇ mol, 37% yield) was obtained.
  • LCMS (ES-API, m/z): [M+H] + 971.1.
  • Step 3 tert -butyl (1 R ,5 S )-3-(6-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-5- obtained in Step 2 fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1H-pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)- TFA (2 mL) was added to 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 41.3 ⁇ mol), and stirred at 40 o C for 9 hours.
  • Example 51 1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(5-chloro-6-methyl-1 H -indazol-4-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]Synthesis of quinazoline.
  • Step 1 tert -Butyl (1 R ,5 S )-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2- f ]quinazolin-1-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 190 ⁇ mol), 5-chloro-6-methyl-1-(tetrahydro-2 H -pyran-2-yl)-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H - indazole (107 mg, 285 ⁇ mol), Tetrakis(triphenylphosphine)palladium(0) (22 mg, 19 ⁇ mol) and Potassium phosphate tribasic ( 121 mg, 571 ⁇ mol) was added to 1,4-dioxane (2 mL) and water (0.5 mL), and then degassing and nitrogen purge were repeated three times.
  • reaction mixture was then stirred under nitrogen at 95°C for 30 minutes. After the starting materials were completely consumed, water was added to the reaction mixture to terminate the reaction, and the compound was extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step 2 Synthesize in the same manner as step 2 of Example 43 to obtain tert -butyl (1 R ,5 S )-3-(6-(5-chloro-6-methyl-1-(tetrahydro-2 H -pyran- 2-yl)-1 H -indazol-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8 -methylfuro[3,2- f ]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, 30.5 ⁇ mol, 10% yield) was obtained.
  • LCMS (ES-API, m/z): [M+H] + 819.4.
  • Step 3 tert -butyl (1 R ,5 S )-3-(6-(5-chloro-6-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H - obtained in Step 2 indazol-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, 30.5 ⁇ mol) was dissolved in DCM (1 mL), then dissolved in 4.0 M HCl in 1,4-dioxane ( Add 2 mL).
  • Example 52 6-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]Synthesis of quinazolin-6-yl)-4-methylpyridin-2-amine.
  • Example 53 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro Synthesis of -1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-iodo-4-methylpyridin-2-amine.
  • Example 54 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)benzo[ d ]Synthesis of thiazol-2-amine.
  • Step 1 tert -Butyl (1 R ,5 S )-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2- f ]quinazolin-1-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 190 ⁇ mol), intermediate 20 (107 mg, 285 ⁇ mol), [1,1'-Bis(di -tert- butylphosphino)ferrocene]dichloropalladium(II) (24.8 mg, 38 ⁇ mol) and Potassium phosphate tribasic (121 mg, 571 ⁇ mol) as 1,4 After adding -dioxane (2 mL) and water (0.5 mL), degassing and nitrogen purge were repeated three times.
  • the reaction mixture was then stirred under nitrogen at 90°C for 24 hours. After the starting material was completely consumed, the palladium catalyst was removed through a celite filter. After diluting the reaction mixture with water, the compound was extracted with ethyl acetate. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step 2 (( 2R , 7aS )-2-fluorotetrahydro-1H-pyrrolizin-7a( 5H )-yl)methanol (40.1 mg, 252 ⁇ mol), Sodium hydride (10.1 mg, 252 ⁇ mol) in THF (2mL) ) and stirred at room temperature for 30 minutes.
  • Step 3 tert -butyl (1 R ,5 S )-3-(6-(2-(( tert -butoxycarbonyl)amino)benzo[ d ]thiazol-4-yl)-5-fluoro-3 obtained in Step 2 -((( 2R , 7aS )-2-fluorotetrahydro- 1H- pyrrolizin-7a(5H ) -yl)methoxy)-8-methylfuro[3,2 -f ]quinazolin-1-yl)-3, Dissolve 8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 24.5 ⁇ mol) in DCM (1 mL), then add 4.0 M HCl in 1,4-dioxane (2 mL) and incubate at 50°C for 1 hour.
  • Example 55 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-7-fluorobenzo[ d ]Synthesis of thiazol-2-amine.

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Abstract

본 출원은 KRAS G12D 저해제로서의 신규한 3환 유도체 화합물 및 이의 용도에 관한 것으로, 본 출원의 일 예에 따른 화합물은 KRAS G12D 돌연변이 단백질의 활성을 억제하여 KRAS G12D 돌연변이에 의해 유발되는 질환의 예방 또는 치료에 사용될 수 있다.

Description

KRAS G12D 저해제로서 신규한 3환 화합물 및 이의 용도
본 출원은 신규한 3환 화합물, 이를 포함하는 약학적 조성물 및 약제로서의 이들의 용도에 관한 것이다.
Kristen rat sarcoma virus (KRAS)는 세포의 증식 및 분화에 있어 중요한 신호를 전달하는 RAS 패밀리 (NRAS, HRAS, KRAS) 에 속하는 단백질로써, 세포막 수용체로부터 신호를 전달받아 그 하위 신호 단백질들인 PI3K, Raf, MEK, ERK 등에 신호를 전달한다.
KRAS 단백질은 분자 스위치로써 내재적 뉴클레오타이드 교환을 통해 뉴클레오타이드 결합 부위 (nucleotide binding site)의 GDP가 GTP로 교환되어 하위 신호 전달 단백질로의 신호 전달이 일어나는 “활성화 (GTP-bound form, Turn-on) 상태”가 된다. 반대로 KRAS 단백질에 결합되어 있는 GTP가 GDP로 내재적 가수분해 되어 “비활성화 (GDP-bound form, Turn-off) 상태”가 되면 하위 신호 전달이 일어나지 않게 된다. 이때, 실제 세포 안에서는 구아닌 교환 인자 (GEF, Guanine Exchange Factor)에 의해 GDP에서 GTP로 교환이 촉진되며, GTP 분해 효소 활성 단백질 (GAP, GTPase activating Protein)에 의해 GTP가 GDP로 가수분해가 빠르게 증가된다.
KRAS 유전자 돌연변이는 많은 악성 종양에서 암세포 증식에 중요한 역할을 하는 것으로 밝혀졌으며, KRAS 유전자 돌연변이 암 환자 중 약 89%는 KRAS 유전자의 코돈 12의 글라이신 (KRAS G12)이 다른 아미노산으로 변형된 변이에 의해 일어난다. KRAS G12 돌연변이는 86%의 췌장 선암 (PDAC), 41%의 대장암 (CRC), 32%의 비소세포성 폐암 (NSCLC) 등에 나타나며, 전체 KRAS G12 변이 중 G12D (36%), G12V (23%), G12C (14%) 순으로 변이 빈도수가 보고 되고 있다. KRAS G12 돌연변이 단백질은 GAP에 의한 GTP의 가수분해를 저해하여 활성화 (GTP bound form) 상태를 유지시켜 줌에 따라, 지속적인 하위 신호 전달에 의해 빠르게 암세포의 증식 및 생존이 증가된다.
이전까지의 KRAS 저해제는 활성화 상태의 KRAS를 억제하기 위하여 GTP 결합에 대한 경쟁적 저해제를 만들었지만, 실제 세포 내에는 저해제의 농도보다 GTP가 상당히 많이 존재하기 때문에 많은 KRAS 저해제들이 실패하였다. 이러한 이유로 KRAS를 직접적으로 타깃하는 표적치료제 개발은 불가능 하다고 여겨졌고, KRAS 돌연변이 암을 억제하기 위한 대안으로 KRAS 단백질 이외의 PI3K, MEK, AKT, mTOR 등의 하위 신호 단백질을 저해하거나 KRAS 단백질 번역 후 변형 (Post-translation modification)을 억제하여 KRAS의 파네실트렌스퍼레이즈 (fanesyltransferase)를 저해하는 등의 간접적으로 KRAS 돌연변이 암세포의 활성을 억제하고자 하였으나 좋은 임상적 효과는 거두지 못하였다.
최근, KRAS G12C 돌연변이 단백질의 알로스테릭 (allosteric) 결합 포켓인 스위치-II (switch-II pocket)을 확인함에 따라 GDP 결합 상태의 KRAS G12C의 cysteine과 공유결합 (covalent binding)을 통해 KRAS의 활성을 억제하는 선택적 KRAS G12C 표적 저분자 물질인 소토라십 (Sotorasib, LUMAKRAS™)이 개발되었고, 비소세포성 폐암에 대한 FDA 승인을 받았다.
그러나, 아직까지 KRAS 돌연변이 중 가장 많은 비중을 차지하는 KRAS G12D 돌연변이를 타깃 하는 표적치료제의 개발은 미비한 실정으로 임상에서 아주 큰 미충족 수요 (unmet medical needs)로 남아있는 부분이다.
본 발명자들은 본 출원의 일 예에 따른 신규한 3환 화합물이 KRAS G12D 활성을 저해하는 효과를 가지는 것을 확인하였다. 이에, 본 출원의 일 목적은 우수한 KRAS G12D의 활성 억제 효과를 나타내는 화학식 1의 3환 고리 기반의 신규 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물, 또는 이들의 약학적으로 허용되는 염을 제공하기 위한 것이다.
본 출원의 다른 목적은 상기 3환 고리 기반의 신규 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물, 또는 이들의 약학적으로 허용되는 염을 유효성분으로 포함하는 약학적 조성물을 제공하는 것이다.
본 출원의 일 구현 예에 따르면, 하기 화학식 1의 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물, 또는 이들의 약학적으로 허용되는 염을 제공한다:
[화학식 1]
Figure PCTKR2023020084-appb-img-000001
상기 화학식 1에서,
A는
Figure PCTKR2023020084-appb-img-000002
,
Figure PCTKR2023020084-appb-img-000003
,
Figure PCTKR2023020084-appb-img-000004
, 또는
Figure PCTKR2023020084-appb-img-000005
이며;
X는 C 또는 N이며;
R1은 수소, 할로겐, C1-3알킬, 또는 C1-3알콕시이며;
L은 직접결합, O, 또는 NR6 이며;
R2는 C1-6알킬, C1-6알콕시, C1-6하이드록시알킬, C2-6알콕시알킬, C1-6할로알킬, Rx, -Z1-Rx, -Z1-Ry-Rx, -Z1-Ry-Z2-N(R15)2, -Z1-Ry-Z2-Rx, -N(R15)2, -Z1-N(R15)2, -Z1-C(O)N(R15)2, 또는 -Z1-OR15이며;
Rx 및 Ry는 서로 독립적으로 3원 내지 10원의 사이클로알킬, 3원 내지 10원의 헤테로사이클릴, 6원 내지 20원의 아릴, 또는 6원 내지 20원의 헤테로아릴이며, 선택적으로 하나 혹은 여러 개의 R7로 치환될 수 있고;
R7는 각각 H, 할로겐, 하이드록시, C1-4알킬, C2-4알케닐, C2-4알키닐, C1-4하이드록시알킬, C1-4할로알킬, C2-4할로알케닐, C2-4할로알키닐, C1-4알콕시, C1-4알킬-N(R16)2, =C-(R16)2, 사이아노, C(O)R16, C(=O)OR16, C(=O)N(R16)2, -NHC(O)-6원 내지 20원의 아릴, -N(R16)2, (C1-4알콕시)C1-4알킬-, 옥소, -OR16, -SR16, -(C1-4알킬)C(O)R16, 3원 내지 10원의 사이클로알킬, 3원 내지 10원의 헤테로사이클로알킬, 6원 내지 20원의 아릴, 6원 내지 20원의 헤테로아릴, -Z3-3원 내지 10원의 사이클로알킬, -Z3-3원 내지 10원의 헤테로사이클로알킬, -Z3-6원 내지 20원의 아릴, -Z3-6원 내지 20원의 헤테로아릴, -Z3-OC(O)N(R16)2, 또는 -Z3-OC(O)-3원 내지 10원의 헤테로사이클릴이며; 상기 R7는 1 내지 3개의 사이아노, 할로겐, 할로알킬, 아미노, -OR17, -SR17, 또는 -N(R17)2로 치환될 수 있으며;
Z1 내지 Z3는 서로 독립적으로 C1-4알킬이며; 선택적으로 하이드록시, C1-4하이드록시알킬, 또는 6원 내지 20원의 헤테로아릴로 치환될 수 있고;
R6, R15, R16, R17, R18, R19, R20 및 R21 는 서로 독립적으로 H 또는 C1-3알킬이며;
R3는 3원 내지 10원의 사이클로알킬, 3원 내지 10원의 헤테로사이클로알킬, 6원 내지 20원의 아릴, 또는 6원 내지 20원의 헤테로아릴이며, 선택적으로 하나 혹은 여러 개의 R8 로 치환될 수 있고;
R8은 H, 할로겐, 하이드록시, -N(R18)2, OR18, SH, S(C1-3알킬), S(=O)(C1-6알킬), S(=O)2(C1-6알킬), C(=O)(C1-6알킬), C(=O)OH, C(=O)N(R18)2, C1-4알킬, C2-4알케닐, C2-4알키닐, C1-3할로알킬, C1-3하이드록시알킬, C1-3알콕시알킬, C1-4알킬-N(R18)2, C1-3알콕시, C1-3할로알콕시, 사이아노알킬, 사이아노, 옥소, 3원 내지 10원의 사이클로알킬, 3원 내지 10원의 헤테로사이클로알킬, 6원 내지 20원의 아릴, 또는 6원 내지 20원의 헤테로아릴이며;
R4는
Figure PCTKR2023020084-appb-img-000006
,
Figure PCTKR2023020084-appb-img-000007
,
Figure PCTKR2023020084-appb-img-000008
또는 -NH-R9-R10이며;
R9는 직접결합 또는 C1-4알킬이며;
R10은 3원 내지 10원의 사이클로알킬 또는 3원 내지 10원의 헤테로사이클로알킬이며, 선택적으로 하나 혹은 여러개의 R11로 치환될 수 있고;
R11은 C1-3알킬, 하이드록시, N(R19)2, C1-3알킬-N(R19)2, C1-3사이아노알킬, 3원 내지 10원의 헤테로사이클릴이며;
R12는 H, C1-3알킬, OH, -N(R20)2, -CH2N(R20)2, 사이아노, 사이아노메틸, 또는 3원 내지 10원의 헤테로사이클릴이며;
R13는 H, 또는 -C(=O)R14이며;
R14는 C1-4알킬, C2-4알케닐, C2-4알키닐, -N(R6)2, -OR6, -SR6, 3원 내지 10원의 사이클로알킬, 3원 내지 10원의 사이클로알케닐, 3원 내지 10원의 사이클로알키닐, 3원 내지 10원의 헤테로사이클릴, 6원 내지 20원의 아릴, 또는 6원 내지 20원의 헤테로아릴이며;
n은 0 내지 4의 정수이며;
R5는 H, 할로겐, C1-6알킬, C1-3할로알킬, 3원 내지 6원의 사이클로알킬, 3원 내지 6원의 헤테로사이클로알킬, 사이아노, 사이아노C1-3알킬, 하이드록시, C1-3하이드록시알킬, C(O)(NR21)2, 6원 내지 20원의 아릴, C1-3알킬-3원 내지 6원의 사이클로알킬, C1-3알킬-3원 내지 6원의 헤테로사이클로알킬, C1-3알킬-6원 내지 20원의 아릴, 또는 C1-3알킬-6원 내지 20원의 헤테로아릴이다.
구체적으로, 상기 A는
Figure PCTKR2023020084-appb-img-000009
,
Figure PCTKR2023020084-appb-img-000010
, 또는
Figure PCTKR2023020084-appb-img-000011
일 수 있다.
구체적으로, 상기 R1은 수소, 할로겐, 또는 C1-3알킬일 수 있다.
구체적으로, 상기 L은 직접결합 또는 O 일 수 있다.
구체적으로, 상기 R2는 Rx, -Z1-Rx, -Z1-Ry-Rx, -Z1-Ry-Z2-N(R15)2, 또는 -Z1-Ry-Z2-Rx 일 수 있다.
구체적으로, 상기 Rx 및 상기 Ry는 서로 독립적으로 3원 내지 10원의 사이클로알킬 또는 3원 내지 10원의 헤테로사이클릴이며, 선택적으로 하나 혹은 여러 개의 R7로 치환될 수 있는 것일 수 있다.
더욱 구체적으로, 상기 Rx는 3원 내지 10원의 헤테로사이클릴이고, 상기 Ry는 3원 내지 10원의 사이클로알킬이며, 상기 Rx 및 상기 Ry는 선택적으로 하나 혹은 여러 개의 R7로 치환될 수 있는 것일 수 있다. 더욱 구체적으로, 상기 Rx는 N, O 및 S로 이루어지는 군에서 선택된 1 내지 3개의 헤테로원자를 포함하는 3원 내지 10원의 헤테로사이클, 또는 N 및 O로 이루어지는 군에서 선택된 1 내지 2개의 헤테로원자를 포함하는 3원 내지 10원의 헤테로사이클일 수 있다.
일 예로, 상기 Rx 및 Ry는 서로 독립적으로 3원 내지 5원의 사이클로알킬, 아제티디닐 (azetidinyl), 피롤리디닐, 피페리디닐, 몰포리닐, 2-옥사-5-아자바이사이클로[2.2.1]헵탄일 (2-oxa-5-azabicyclo[2.2.1]heptanyl), 피롤리지디닐(pyrrolizidinyl), 메틸렌피롤리지디닐 (methylenepyrrolizidinyl), 테트라하이드로-1’H,3’H-스피로[사이클로프로판-1,2'-피롤리지디닐] (tetrahydro-1’H,3’H-spiro[cyclopropane-1,2'-pyrrolizidinyl]), 6-아자스피로[2.5]옥탄일 (6-azaspiro[2.5]octanyl), 퀴놀리지디닐(quinolizidinyl), 인돌리닐, 벤즈이미다졸릴, 아자스피로옥탄일, 벤즈트리아졸릴(benztriazolyl), 티오잔티닐(thioxanthinyl), 카바졸릴(carbazolyl), 카르보리닐(carbolinyl), 또는 아크리디닐(acridinyl)이며, 선택적으로 하나 혹은 여러 개의 R7로 치환될 수 있는 것일 수 있다.
구체적 일 예로, 상기 Rx는 아제티디닐 (azetidinyl), 피롤리디닐, 피페리디닐, 몰포리닐, 2-옥사-5-아자바이사이클로[2.2.1]헵탄일 (2-oxa-5-azabicyclo[2.2.1]heptanyl), 피롤리지디닐(pyrrolizidinyl), 메틸렌피롤리지디닐 (methylenepyrrolizidinyl), 테트라하이드로-1’H,3’H-스피로[사이클로프로판-1,2'-피롤리지디닐] (tetrahydro-1’H,3’H-spiro[cyclopropane-1,2'-pyrrolizidinyl]), 또는 6-아자스피로[2.5]옥탄일 (6-azaspiro[2.5]octanyl)이고, 선택적으로 하나 혹은 여러 개의 R7로 치환될 수 있는 것일 수 있다.
구체적 일 예로, 상기 Ry는 3원 내지 5원의 사이클로알킬 (예를 들어, 사이클로프로필 또는 사이클로부틸)이고, 선택적으로 하나 혹은 여러 개의 R7로 치환될 수 있는 것일 수 있다.
일 예로, 상기 화학식 1에서 R2는 Rx, -Z1-Rx, -Z1-Ry-Rx, -Z1-Ry-Z2-N(R15)2, 또는 -Z1-Ry-Z2-Rx 이고, 상기 Rx는 3원 내지 10원의 헤테로사이클릴이고, 상기 Ry는 3원 내지 10원의 사이클로알킬이며, 상기 Rx 및 상기 Ry는 선택적으로 하나 혹은 여러 개의 R7로 치환될 수 있는 것일 수 있다.
구체적 일 예로, 상기 화학식 1에서 R2는 Rx, -Z1-Rx, -Z1-Ry-Rx, -Z1-Ry-Z2-N(R15)2, 또는 -Z1-Ry-Z2-Rx 이고, 상기 Rx는 아제티디닐 (azetidinyl), 피롤리디닐, 피페리디닐, 몰포리닐, 2-옥사-5-아자바이사이클로[2.2.1]헵탄일 (2-oxa-5-azabicyclo[2.2.1]heptanyl), 피롤리지디닐(pyrrolizidinyl), 메틸렌피롤리지디닐 (methylenepyrrolizidinyl), 테트라하이드로-1’H,3’H-스피로[사이클로프로판-1,2'-피롤리지디닐] (tetrahydro-1’H,3’H-spiro[cyclopropane-1,2'-pyrrolizidinyl]), 또는 6-아자스피로[2.5]옥탄일 (6-azaspiro[2.5]octanyl)이고, 상기 Ry는 3원 내지 5원의 사이클로알킬이고, 상기 Rx 및 상기 Ry는 선택적으로 하나 혹은 여러 개의 R7로 치환될 수 있는 것일 수 있다.
구체적 일 예로, 상기 화학식 1에서 R2는 아제티디닐 (azetidinyl), Z1-피롤리지디닐, Z1-테트라하이드로-1’H,3’H-스피로[사이클로프로판-1,2'-피롤리지디닐] (tetrahydro-1’H,3’H-spiro[cyclopropane-1,2'-pyrrolizidinyl]), 또는 Z1-Ry-Z2-Rx이며, 상기 Ry는 3원 내지 5원의 사이클로알킬 (예를 들어, 사이클로프로필 또는 사이클로부틸)이고, 상기 Rx는 3원 내지 10원의 헤테로사이클릴 (예를 들어, 피롤리디닐, 피페리디닐, 몰포리닐, 2-옥사-5-아자바이사이클로[2.2.1]헵탄일 (2-oxa-5-azabicyclo[2.2.1]heptanyl), 또는 6-아자스피로[2.5]옥탄일 (6-azaspiro[2.5]octanyl))일 수 있다.
구체적으로, 상기 R7는 각각 H, 할로겐, 하이드록시, C1-4알킬, C2-4알케닐, C2-4알키닐, C2-4하이드록시알킬, C1-4할로알킬, C2-4할로알케닐, C1-4알콕시, C1-4알킬-N(R16)2, =C-(R16)2, C(O)R16, C(=O)OR16, C(=O)N(R16)2, -NHC(O)아릴, -N(R16)2, (C1-4알콕시)C1-4알킬-, 옥소, -OR16, -SR16, -(C1-4알킬)C(O)R16, 3원 내지 10원의 사이클로알킬, 3원 내지 10원의 헤테로사이클로알킬, 6원 내지 20원의 아릴, 6원 내지 20원의 헤테로아릴, -Z3-3원 내지 10원의 사이클로알킬, -Z3-3원 내지 10원의 헤테로사이클로알킬, -Z3-6원 내지 20원의 아릴, -Z3-6원 내지 20원의 헤테로아릴, -Z3-OC(O)N(R16)2, 또는 -Z3-OC(O)-3원 내지 10원의 헤테로사이클릴이며; 1 내지 3개의 사이아노, 할로겐, 할로알킬 (예를 들어, C1-4할로알킬), 아미노, -OR17, -SR17, 또는 -N(R17)2로 치환될 수 있는 것일 수 있다.
일 예로, 상기 R7은 각각 H, 할로겐, C1-4알킬, C2-4알케닐, C2-4알키닐, C1-4할로알킬, C2-4할로알케닐, C2-4할로알키닐, C1-4알콕시, =C-(R16)2, -N(R16)2, 또는 (C1-4알콕시)C1-4알킬-이며, 1 내지 3개의 할로겐으로 치환될 수 있는 것일 수 있다.
일 예로, 상기 R7은 각각 H, 할로겐, C1-3알킬, C2-4알케닐, C2-4알키닐, C1-3할로알킬, C2-4할로알케닐, C2-4할로알키닐, C1-3알콕시, =C-(R16)2, -N(R16)2, 또는 (C1-3알콕시)C1-3알킬-이며, 1 내지 3개의 할로겐으로 치환될 수 있는 것일 수 있다.
구체적 일 예로, 상기 R7은 H, 할로겐, C1-4알킬, =CH2, =CF2, =CFH, -N(R16)2, C1-4알콕시, 또는 (C1-4알콕시)C1-4알킬-일 수 있다.
구체적으로, 상기 R3는 6원 내지 20원의 아릴, 또는 6원 내지 20원의 헤테로아릴이며, 선택적으로 하나 혹은 여러 개의 R8 로 치환될 수 있는 것일 수 있다.
구체적으로, 상기 R3은 페닐, 바이페닐, 나프틸, 톨루일, 나프탈렌일, 피리딘일, 안트라세닐, 인데닐, 인다닐, 퀴놀린일, 이소퀴놀린일, 벤즈이미다졸릴, 벤즈싸이아졸릴 (benzothiazolyl), 벤즈싸이오펜일 (benzothiophenyl), 벤즈퓨란일 (benzofuranyl), 또는 인다졸릴이며, 선택적으로 하나 혹은 여러 개의 R8 로 치환될 수 있는 것일 수 있다.
더욱 구체적으로, 상기 R3은 페닐, 나프틸, 나프탈렌일, 피리딘일, 퀴놀린일, 이소퀴놀린일, 벤즈싸이아졸릴 (benzothiazolyl), 벤즈싸이오펜일 (benzothiophenyl), 벤즈퓨란일 (benzofuranyl), 또는 인다졸릴이며, 선택적으로 하나 혹은 여러 개의 R8 로 치환될 수 있는 것일 수 있다.
구체적으로, 상기 R8은 H, 할로겐, 하이드록시, -N(R18)2, OR6, SH, S(C1-3알킬), S(=O)(C1-6알킬), S(=O)2(C1-6알킬), C(=O)(C1-6알킬), C(=O)OH, C(=O)N(R18)2, C1-4알킬, C2-4알케닐, C2-4알키닐, C1-3할로알킬, C1-3하이드록시알킬, C1-3알콕시알킬, C1-4알킬-N(R18)2, 사이아노, 옥소, 또는 3원 내지 10원의 사이클로알킬일 수 있다.
더욱 구체적으로, 상기 R8은 H, 할로겐, 하이드록시, -N(R18)2, C1-4알킬, C2-4알케닐, C2-4알키닐, C1-3할로알킬, C1-3하이드록시알킬, 또는 사이아노일 수 있다.
구체적으로, 상기 R10은 3원 내지 10원의 사이클로알킬이며, 선택적으로 하나 혹은 여러개의 R11로 치환될 수 있는 것일 수 있다.
구체적으로, 상기 R11은 C1-3알킬, 하이드록시, N(R19)2, C1-3알킬-N(R19)2, 또는 사이아노 C1-3알킬일 수 있다.
일 예로, 상기 화학식 1에서 R9는 C1-3알킬이고, R10은 3원 내지 5원의 사이클로알킬이고, R11은 N(R19)2 인 것일 수 있다.
구체적으로, 상기 R12는 H 일 수 있다.
구체적으로, 상기 R14는 3원 내지 10원의 헤테로사이클릴, N, O 및 S로 이루어지는 군에서 선택된 1 내지 2개의 헤테로원자를 포함하는 3원 내지 10원의 헤테로사이클릴, N, O 및 S로 이루어지는 군에서 선택된 1 내지 2개의 헤테로원자를 포함하는 3원 내지 5원의 헤테로사이클릴, 일 예로 옥시란 (oxirane)일 수 있다.
구체적으로, 상기 R5는 H 또는 C1-3알킬일 수 있다.
예를 들어, 상기 화학식 1에서 상기 L-R2는 하기 구조에서 선택된 것일 수 있다. 하기와 같은 구조를 가질 경우 KRAS G12D 저해 활성이 우수할 뿐만 아니라, 앞서 언급한 본 출원의 다양한 목적에 적합하다.
Figure PCTKR2023020084-appb-img-000012
예를 들어, 상기 화학식 1에서 상기 R3는 하기 구조에서 선택되는 것일 수 있다. 하기와 같은 구조를 가질 경우 KRAS G12D 저해 활성이 우수할 뿐만 아니라, 앞서 언급한 본 출원의 다양한 목적에 적합하다.
Figure PCTKR2023020084-appb-img-000013
예를 들어, 상기 화학식 1에서 상기 R4는 하기 구조에서 선택되는 것일 수 있다. 하기와 같은 구조를 가질 경우 KRAS G12D 저해 활성이 우수할 뿐만 아니라, 앞서 언급한 본 출원의 다양한 목적에 적합하다.
Figure PCTKR2023020084-appb-img-000014
본 출원의 앞서 언급한 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물, 또는 이들의 약학적으로 허용되는 염을 제공한다.
본 출원에 따른 화학식 1의 화합물의 예는 하기 실시예 1 내지 120에서 제조된 화합물들이다. 각 실시예 번호는 화합물 번호에 대응한다. 예를 들어, 실시예 90에서 제조된 최종 화합물의 번호는 화합물 90이다.
일 예로, 본 출원의 일 예에 따른 화학식 1의 화합물의 대표적인 것에는 다음의 표 1에 열거된 것을 포함하나, 이에 제한되는 것은 아니다.
실시예 화합물명
(1) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol
(2) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
(3) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5,6-difluoronaphthalen-2-ol
(4) 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5,6-difluoronaphthalen-2-ol.
(5) 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol.
(6) 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(7) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(8) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((R)-3-methylmorpholino)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(9) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(10) 4-(3-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(11) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((S)-3-methylmorpholino)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(12) 4-(3-((1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(13) 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-2,4,5,6-tetrafluoroaniline
(14) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.
(15) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-7-fluorobenzo[d]thiazol-2-amine.
(16) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(17) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(18) 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine.
(19) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(((S)-3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(20) 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine.
(21) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((R)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(22) 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine.
(23) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(24) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.
(25) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-7-fluorobenzo[d]thiazol-2-amine.
(26) 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine.
(27) 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine.
(28) 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine.
(29) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(30) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(31) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((S)-3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(32) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(33) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((R)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(34) 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine.
(35) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(36) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.
(37) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(38) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.
(39) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(40) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(41) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol.
(42) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(43) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol.
(44) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(45) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol.
(46) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5,6-difluoronaphthalen-2-ol.
(47) 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol.
(48) 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(49) 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-(trifluoromethyl)aniline.
(50) 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-(trifluoromethyl)pyridin-2-amine.
(51) 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(5-chloro-6-methyl-1H-indazol-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazoline.
(52) 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-methylpyridin-2-amine.
(53) 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-iodo-4-methylpyridin-2-amine.
(54) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)benzo[d]thiazol-2-amine.
(55) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazol-2-amine.
(56) 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-methyl-4-(trifluoromethyl)aniline.
(57) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.
(58) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.
(59) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(60) 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine.
(61) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-8-methyl-3-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)furo[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(62) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile.
(63) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile.
(64) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(65) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(66) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(67) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.
(68) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol.
(69) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(70) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol.
(71) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.
(72) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-(dimethylamino)azetidin-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(73) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(74) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.
(75) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(76) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.
(77) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile.
(78) 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline
(79) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(80) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(81) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.
(82) 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline.
(83) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol.
(84) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol.
(85) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol.
(86) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol.
(87) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(88) 4-(9-(2,5-diazabicyclo[2.2.2]octan-2-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(89) 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(5-chloro-3,6-dimethyl-1H-indazol-4-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline.
(90) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(91) 4-((R)-9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(92) 4-((S)-9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(93) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol.
(94) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(95) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol.
(96) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(97) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol.
(98) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(99) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine.
(100) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(101) 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline.
(102) (4-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazin-1-yl)(oxiran-2-yl)methanone.
(103) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(104) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile
(105) 4-(9-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
(106) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
(107) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol
(108) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine
(109) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol
(110) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-5-fluorobenzo[b]thiophene-3-carbonitrile.
(111) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-5,7-difluorobenzo[b]thiophene-3-carbonitrile.
(112) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile.
(113) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-aminobenzofuran-3-carbonitrile.
(114) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorobenzofuran-3-carbonitrile.
(115) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-5-fluorobenzofuran-3-carbonitrile.
(116) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine
(117) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(118) 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(5-ethynyl-6-fluoroisoquinolin-4-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline
(119) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
(120) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
본 출원에서 사용되는 모든 기술 용어는, 달리 정의되지 않는 이상, 본 출원의 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 또한, 본 명세서에는 예시적인 방법이나 시료가 기재되나, 이와 유사하거나 동등한 것들도 본 출원의 범주에 포함된다. 또한, 본 명세서에 기재된 수치는 명시하지 않아도 "약"의 의미를 포함하는 것으로 간주한다. 본 명세서에 참고문헌으로 기재되는 모든 간행물의 내용은 전체가 본 명세서에 참고로 통합된다.
상기 화학식 1에서, R1 내지 R21, Rx, 및 Ry 으로서 열거된 잔기는 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다.
별도로 기술되지 않는 한, 본원에서 "할로겐"은 단독으로 사용되는 경우 또는 그 밖에 추가적인 용어와의 조합으로 사용되는 경우 (예를 들면, 할로알킬), 불소, 염소, 브롬 또는 요오드를 지칭하며, 구체적으로는 불소, 염소이나, 이들로 제한되는 것은 아니다.
별도로 기술되지 않는 한, 본원에서 용어 “알콕시”는 알킬옥시, 예를 들면 1 내지 7개의 탄소 원자를 갖는 알킬옥시를 의미한다.
별도로 기술되지 않는 한, 본원에서 용어 "할로알킬"은 하나 이상의 수소가 동일하거나 상이한 할로겐으로 대체되는, 본원에 정의된 바와 같은 알킬을 의미한다. 할로알킬 그룹의 예로 -CH2Cl, -CH2CF3, -CH2CCl3, -CF3 등을 포함하나 이에 제한되는 것은 아니다.
별도로 기술되지 않는 한, 본원에서 용어 “하이드록시알킬”은 알킬 그룹 내의 하나 이상의 수소 원자가 하나 이상의 하이드록시(-OH), 예를 들면 2가 또는 3가 하이드록시로 치환되는 것을 포함한다.
별도로 기술되지 않는 한, 본원에서 용어 “아미노알킬”은 알킬 그룹 내의 하나 이상의 수소 원자가 하나 이상의 아미노(-NH2), 예를 들면 2가 또는 3가 아미노로 치환되는 것을 포함한다.
별도로 기술되지 않는 한, 본원에서 용어 "옥소"는 화학식 =O (즉, 이중 결합을 갖는 산소)의 기를 의미한다.
별도로 기술되지 않는 한, 본원에서 용어 "알킬"은 다른 언급이 없으면, 포화된, 직쇄형 또는 분지형의 1가의 탄화수소 라디칼을 지칭한다. 예를 들어, 상기 알킬은 C1-10알킬, C1-8알킬, C1-6알킬, C1-4알킬, 또는 C1-3알킬일 수 있다.
별도로 기술되지 않는 한, 본원에서 용어 "알켄일"은 다른 언급이 없으면, 적어도 하나의 탄소-탄소 이중결합을 함유하는 1가의 탄화수소 라디칼을 지칭하며, 각각의 이중결합은 E- 또는 Z-입체배치 형태를 가질 수 있다. 예를 들어, 상기 알켄일은 C2-10알켄일, C2-8알켄일, C2-6알켄일, 또는 C2-4알켄일일 수 있다.
별도로 기술되지 않는 한, 본원에서 용어 "알키닐"은 다른 언급이 없으면, 적어도 하나의 탄소-탄소 삼중 결합을 갖는 불포화된, 직쇄형 또는 분지형의 탄화수소 모이어티로부터 유래하는 1가 기를 지칭한다. 예를 들어, 상기 알키닐 C2-10알키닐, C2-8알키닐, C2-6알키닐, 또는 C2-4알키닐일 수 있다.
이러한 “알킬”, “알켄일” 및 “알키닐”은 단독으로 사용되는 경우 또는 그 밖에 추가적인 용어와의 조합으로 사용되는 경우 (예를 들면, 할로알킬) 직쇄형 또는 측쇄형일 수 있다. 각각의 정의에 따라, 알킬기 내에서 1 내지 10개, 1 내지 9개, 1 내지 8개, 1 내지 7개, 1 내지 6개, 1 내지 5개, 1 내지 4개, 또는 1 내지 3개의 탄소 원자를 갖는 포화된 지방족 탄화수소 군의 라디칼을 의미한다. 일반적인 알킬의 예는 메틸, 에틸, n-프로필, iso-프로필, n-부틸, iso-부틸, sec-부틸, tert-부틸, n-펜틸, iso-펜틸, neo-펜틸 및 tert-펜틸, 1-메틸펜틸, 2-메틸부틸, 1-에틸프로필, 1,2-다이메틸프로필, n-헥실, 3,3-디메틸부틸 및 이소헥실 등을 포함하나 이에 제한되는 것은 아니다. 알켄일기와 알카이닐기의 이중결합 및 삼중결합 각각은 임의의 위치에 치환할 수 있다. 알켄일 및 알키닐의 예는 에텐일, 프로프-1-엔일, 프로프-2-엔일, 부트-2-엔일, 2-메틸프로프-2-엔일, 3-메틸부트-2-엔일, 헥스-3-엔일, 헥스-4-엔일, 프로프-2-인일, 부트-2-인일, 부트-3-인일, 헥스-4-인일 또는 헥스-5-인일 등을 포함한 이에 제한되는 것은 아니다.
별도로 기술되지 않는 한, 본원에서 "사이클로알킬", “사이클로알켄일”, 또는 “사이클로알키닐”은 치환 또는 비치환될 수 있는 환상 알킬을 의미하며 불포화되거나 부분적 또는 전체적으로 포화된 (예를 들면 3 내지 24개의) 탄소 원자를 갖는 단일 또는 융합고리환을 이루는 탄화수소의 라디칼을 의미한다. 구체적으로 상기 사이클로알킬, 사이클로알켄일, 또는 사이클로알키닐은 3 내지 10개, 3 내지 8개, 3 내지 6개, 3 내지 5개, 4 내지 10개, 4 내지 8개, 4 내지 6개, 또는 4 내지 5개의 탄소 원자를 가질 수 있다. 상기 사이클로알킬은 카보사이클릴, 스피로카보사이클릴, 융합카보사이클릴, 가교카르보사이클릴을 들 수 있으나 이들로 제한되는 것은 아니다.
본원의 일 구체예에 따르면 상기 사이클로알킬은 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헥센일, 사이클로헵틸, 사이클로헵센일, 사이클로옥틸, 사이클로옥텐일, 2,5-사이클로헥사디엔일, 스파이로[3.5]노난, 스파이로[3.3]헵탄, 바이사이클로[1.1.1]펜탄, 바이사이클로[2.2.2]옥틸, 아다만트-1-일, 데카히드로나프틸, 옥소사이클로헥실, 디옥소사이클로헥실, 티오사이클로헥실, 2-옥소비사이클로[2.2.1]헵트-1-엔일, 벤젠, 나프탈렌일 수 있고 이들의 가능한 모든 이성질체들을 제한없이 포함할 수 있으나 이에 제한되지 않는다.
별도로 기술되지 않는 한, 본원에서 용어 "포화 또는 불포화 헤테로사이클릴"은 질소(N), 산소(O), 및 황(S)으로 구성된 군으로부터 선택되는 하나 이상의 헤테로 원자, 예를 들면 1 내지 8개의 헤테로 원자를 함유하는 불포화되거나 부분적으로 또는 전체적으로 포화된 단일 또는 융합고리환을 이루는 치환 또는 비치환될 수 있는, 3 내지 24원 탄화수소를 의미한다. 구체적으로, 상기 헤테로사이클릴은 1 내지 3개의 헤테로 원자를 갖는 3 내지 10원, 3 내지 8원, 3 내지 6원, 4 내지 10원, 4 내지 8원, 또는 4 내지 6원의 탄화수소 일 수 있다. 상기 헤테로사이클은 헤테로아릴, 헤테로사이클릴, 헤테로스피로카보사이클릴, 융합헤테로사이클릴, 가교헤테로사이클릴을 들 수 있으나 이들로 제한되는 것은 아니다.
본원의 일 구체 예에 따르면 상기 헤테로사이클릴은 피롤리디닐, 몰폴리닐, 피롤리지디닐(pyrrolizidinyl), 퀴놀리지디닐(quinolizidinyl), 아자스피로옥탄일, 피페리딘일, 피롤리딘일, 이미다졸린일, 피페라진일, 피페라진일-1-옥사이드, 몰포린일, 티아몰포린일, 테트라히드로퓨란일, 디아자바이사이클로옥탄일, 디아자스피로옥탄일, 테트라하이드로피리딘일, 다이하이드로피리딘일, 다이하이드로피란일, 테트라하이드로피란일, 2-옥사-6-아자스피로헵탄일, 아제티딘일, 옥사제판일, 2-옥사-5-아자바이사이클로[2.2.1]헵탄일, 피리딜, 테트라하이드로퓨란일, 8-아자바이사이클로[3.2.1]옥탄일, 2-아자스파이로[3.3]헵탄일, 2-옥사-7-아자스파이로[3.4]옥탄일, 2-아자바이사이클로[2.2.1]헵탄일, 3-옥사-8-아자바이사이클로[3.2.1]옥탄일, 피리미딘일, 피라졸일, 옥세탄 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다. 예컨대, C2-10헤테로사이클릴과 같은 경우, 탄소 수 표시 C2-10은 헤테로원자를 하나 이상 포함하는 3원 고리 이상의 고리 크기를 의미한다.
본 출원에서 용어 "아릴"은 다른 언급이 없으면, 치환 또는 비치환될 수 있는 방향족 그룹을 나타내며, 예를 들어 6 내지 20원일 수 있다. 예를 들어, 상기 아릴은 페닐, 바이페닐, 나프틸, 톨루일, 나프탈렌일, 안트라센일, 인데닐, 인다닐, 또는 이들의 가능한 모든 이성질체들을 제한없이 포함할 수 있다.
본 출원에서 용어 "헤테로아릴"은 다른 언급이 없으면 O, N 및 S 중에서 선택된 1개 이상, 예를 들어 1개 내지 4개, 1개 내지 3개, 또는 1개 내지 2개의 헤테로원자를 함유하는 모노사이클릭 또는 바이사이클릭 이상의 방향족 그룹을 의미하며, 예를 들어 6 내지 20원일 수 있다. 예를 들어, 모노사이클릭 헤테로아릴의 예로는 티아졸릴, 옥사졸릴, 티오펜일, 퓨란일, 피롤릴, 이미다졸릴, 이소옥사졸릴, 피라졸릴, 트리아졸릴, 티아디아졸릴, 테트라졸릴, 옥사디아졸릴, 피리딘일, 피리다진일, 피리미딘일, 피라진일, 퀴놀린일, 이소퀴놀린일, 벤즈이미다졸릴, 인다졸릴, 2-옥사-5-아자바이사이클로[2.2.1]헵탄일 또는 이와 유사한 그룹을 들 수 있으나, 이에 제한되는 것은 아니다. 예를 들어, 바이사이클릭 헤테로아릴의 예로는 피롤리지디닐(pyrrolizidinyl), 인돌릴, 인돌리닐, 벤조티오펜일, 벤조퓨란일, 벤즈이미다졸릴, 벤즈싸이아졸릴, 벤즈싸이오펜일, 벤즈옥사졸릴, 벤즈이속사졸릴, 벤즈티아졸릴, 벤즈티아디아졸릴, 벤즈트리아졸릴(benztriazolyl), 인다졸릴, 퀴놀린일, 이소퀴놀린일, 아자스피로옥탄일, 퓨린일, 퓨로피리딘일 또는 이와 유사한 그룹을 들 수 있으나, 이에 제한되는 것은 아니다. 예를 들어, 트리사이클릭 헤테로아릴의 예로는 티오잔티닐(thioxanthinyl), 카바졸릴(carbazolyl), 카르보리닐(carbolinyl), 아크리디닐(acridinyl) 또는 이와 유사한 그룹을 들 수 있으나, 이에 제한되는 것은 아니다.
본 출원에서 용어 "내지"를 이용하여 표시된 수치 범위는 용어 "내지" 전과 후에 기재되는 수치를 각각 하한 및 상한으로서 포함하는 범위를 말한다.
본 출원의 화합물은 비대칭 탄소 중심과 비대칭축 또는 비대칭 평면을 가질 수 있으므로 R 및 S 거울상체 (enantiomer)와 같이 실질적으로 순수한 거울상체뿐만 아니라 혼합 라세미체 (mixture racemate)를 포함한 모든 광학 및 입체 이성질체로서 존재할 수 있으며 이들 모든 이성질체 및 혼합물은 본 출원의 범위에 포함된다. 순수 거울상체와 관련하여, 화학식 1로 표현되는 이러한 거울상체 및 약학적으로 허용되는 이의 염의 광학적 순도는 바람직하게는 60 %ee 이상, 더욱 바람직하게는 95 %ee이상, 그리고 가장 바람직하게는 98 %ee이상이다.
상기 용어 "ee"는 광학 순도 (enantiomeric excess)를 의미한다. 예를 들어, 특정 화합물 내 하나의 거울상체는 다른 거울상체에 비해 많은 양으로 상기 화합물에 거울상체들의 혼합물로 존재한다. 거울상체가 풍부한 형태는 특정 화합물의 거울상체 혼합물 중 단일의 거울상체 농도가 상기 화합물의 다른 거울상체와 관련하여 50 % 이상인, 보다 전형적으로는 60 %, 70 %, 80 %, 또는 90 % 이상이거나, 또는 그 이상인 (예컨대, >95 %, >97 %, >99 %, >99.5 %) 특정 화합물의 거울상체 혼합물을 포함할 수 있다.
본 명세서에서는 편의상 달리 명시되지 않는 한, 화학식 1의 화합물은 화학식 1의 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 용매화물, 수화물, 및 이들의 약학적으로 허용되는 염을 모두 포함하는 의미로 사용된다.
본 명세서에서 용어 “동위원소 변형체”는 화합물을 구성하는 하나 이상의 원자에서의 비정상적인 비율의 동위원소를 포함하는 화합물을 일컫는다. 예를 들면, 화합물의 동위원소 변형체는 방사성 표지 될 수 있으며, 예를 들면 수소 원자는 수소, 중수소 및 삼중수소로부터 선택된 것일 수 있고, 탄소-13(13C), 질소-15(15N)등을 함유할 수 있다.
본 출원에 따른 화학식 1의 화합물, 이의 광학 이성질체, 입체 이성질체 또는 동위원소 변형체는 약학적으로 허용되는 염을 형성할 수 있다. 상기 약학적으로 허용 가능한 염으로는 산 또는 염기의 부가염 및 그의 입체화학적 이성질체 형태가 모두 포함된다. 상기 염에는 투여 대상인 객체에서 모 화합물 (parent compound)의 활성을 유지하며 바람직하지 못한 효과를 유발하지 않는 염이라면 어느 것이든 포함되는 것으로, 특별히 제한되는 것이 아니다. 그러한 염에는 무기염과 유기염이 포함되며, 예를 들어, 아세트산, 질산, 아스파트산, 술폰산, 설퓨릭산, 말레산, 글루탐산, 포름산, 숙신산, 인산, 프탈산, 탄닌산, 타르타르산, 히드로브롬산, 프로피온산, 벤젠술폰산, 벤조산, 스테아르산, 에실산, 락산, 비카르본산, 비설퓨릭산, 비타르타르산, 옥살산, 부틸산, 칼슘 이데트산, 캄실리산, 카르보닉산, 클로로벤조산, 시트르산, 이데트산, 톨루엔술폰산, 에디실린산, 에실린산, 퓨말산, 글루셉트산, 파모익산, 글루코닉산, 글리콜릴라르사닐산, 메틸니트릭산, 폴리갈라트록닉산, 헥실리소르시논산, 말론산, 히드라밤산, 히드로클로린산, 히드로요도익산, 하이드록시나프톨산, 이세티온산, 락토비오닉산, 만델산, 에스톨린산, 점액산, 나프실릭산, 뮤코닉산, p-니트로메탄설포닉산, 헥사믹산, 판토테닉산, 모노히드로겐인산, 디히드로겐인산, 살리실산, 술파민산, 술파닐린산, 메탄술폰산, 테오클릭산일 수 있다. 또한, 상기 염기성 염의 형태로는 예를 들어, 암모늄 염, 리튬 염, 소듐 염, 포타슘 염, 마그네슘 염 및 칼슘 염과 같은 알칼리 및 알칼리 토금속 염, 예를 들어, 벤자틴, N-메틸-D-글루카민, 하이드라바민 염과 같은 유기 염기를 갖는 염 및 예를 들어, 아르기닌, 리신과 같은 아미노산을 갖는 염을 포함한다. 또한, 상기 염 형태는 적당한 염기 또는 산으로 처리함으로써 유리 형태로 전환될 수도 있다. 용어, "부가염 (additional salt)"은 화학식 1의 화합물 및 이의 염이 형성할 수 있는 용매 화합물을 포함한다. 그러한 용매 화합물은 예를 들어, 수화물, 알콜화물이다.
본 명세서에서 사용된 용어와 약어들은 달리 정의되지 않는 한 그 본래의 의미를 갖는다.
본 출원은 또한 화학식 1의 화합물을 제조하는 방법을 제공한다. 이하에서는 본 출원에 대한 이해를 돕기 위해 화학식 1의 화합물의 제조 방법을 예시적인 반응식에 기초하여 설명한다. 그러나, 본 출원이 속한 기술 분야에서 통상의 지식을 가진 자라면 화학식 1의 구조를 바탕으로 공지의 화합물들 또는 이로부터 용이하게 제조할 수 있는 화합물들을 사용하여 다양한 방법에 의해 화학식 1의 화합물을 제조할 수 있으며, 이러한 방법들은 모두 본 출원의 범주에 포함되는 것으로 해석되어야 한다. 즉, 본 명세서에 기재되거나 선행기술에 개시된 여러 합성법들을 임의로 조합하여 화학식 1의 화합물을 제조할 수 있고, 따라서 상기 화학식 1의 화합물의 제조 방법과 관련된 하기의 설명은 예시적인 방법들을 제시하는 것에 지나지 않으며, 필요에 따라 단위 조작의 순서 등이 선택적으로 바뀔 수 있는 것으로서, 본 출원의 제조 방법의 범위가 이에 제한되는 것은 아니다.
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Figure PCTKR2023020084-appb-img-000015
단계 A: 상기 반응식 1의 화합물 1에 포스포릴 트리클로라이드와 N-에틸-N-아이소프로필프로판-2-아민을 넣고 열을 가해서 화합물 2를 얻는다.
단계 B: 상기 반응식 1의 화합물 2는 화학식 H-Y1-X-R1을 갖는 친핵체와 SNAR 반응을 거쳐 다이메틸클로라이드와 같은 용매 및 N-에틸-N-아이소프로필프로판-2-아민과 같은 염기의 존재 하에 화합물 3을 합성한다.
단계 C: 상기 반응식 1에서, 테트라하이드로퓨란과 같은 비극성 용매에서 수소화 나트륨와 같은 강한 염기를 사용하여 화학식 H-Y2-R2를 갖는 화합물 친핵체의 2-염소 치환기에 의해 치환기 -Y2-R2가 도입된다.
단계 D: 상기 반응식 1의 화합물 5를 합성하기 위해 단계 D에서 화합물 4와 보로닉 엑시드 또는 아릴 스타난과 스즈키 반응 또는 스틸리 반을 이용한다.
본 출원의 다른 측면에 따르면, 유효성분으로서 치료학적 유효량의 화학식 1의 화합물 또는 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염을 포함하는, KRAS G12D 변이 단백질과 관련된 질병의 예방 또는 치료용 약학적 조성물이 제공된다. 구체적으로, 상기 약학적 조성물은 KRAS G12D 돌연변이 단백질의 활성을 억제하여 KRAS G12D 변이 단백질과 관련된 질병을 예방 또는 치료하는 것일 수 있다.
본 출원의 일 예에 따른 화학식 1의 화합물 또는 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염은, GDP-/ GppNHp-KRAS G12D 돌연변이 단백질에 대하여 높은 결합능을 가지며, KRAS G12D 돌연변이로 유도된 extracellular signal-regulated kinases의 인산화 (Phospho-ERK, pERK)를 억제하여 KRAS G12D 돌연변이 특이적 억제제로 작용할 수 있다. 이에, 본 출원의 일 예는, 본 출원의 일 예에 따른 화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염을 포함하는, KRAS G12D 돌연변이 단백질 결합용 조성물에 관한 것이다. 또한, 본 출원의 일 예에 따른 화학식 1의 화합물 등은, KRAS G12D 돌연변이 단백질 관련 질병 또는 상태, 자세하게는 KRAS G12D 돌연변이 단백질에 의해 유발된 질병 또는 상태를 예방, 개선 또는 치료할 수 있다. 예를 들면, 본 출원에 따른 화학식 1의 화합물 등은, KRAS G12D 돌연변이 단백질의 억제제로서, KRAS G12D 돌연변이에 따른 암세포의 성장 신호를 효과적으로 억제할 수 있으며, 암의 예방 또는 치료용 약학적 조성물로 유용하게 사용할 수 있다.
본 출원의 다른 측면에 따르면, 유효성분으로서 치료학적 유효량의 화학식 1의 화합물 또는 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염을 포함하는, 암의 예방 또는 치료용 약학적 조성물이 제공된다.
또한 생체 내에서 목적한 바에 따라 화학식 1의 화합물로 전환되는 다양한 형태의 전구약물(prodrug)들도 본 출원의 범위에 포함된다. 상기 약학적 조성물은 약학적으로 허용 가능한 담체, 희석제 및 보조제로 구성된 군으로부터 선택되는 1종 이상의 첨가제를 더 포함할 수 있다.
본 명세서에서 “치료”란 발병 증상을 보이는 객체에 사용될 때 질병의 진행을 중단, 지연 또는 완화시키는 것을 의미한다.
본 명세서에서 “예방”이란 질병에 걸릴 가능성을 감소시키거나 가능성을 제거하는 것을 의미한다.
본 명세서에서 “약학적 조성물(pharmaceutical composition)”은 본 출원에 따른 활성 화합물에 추가하여 담체, 희석제, 부형제 등과 같은 다른 화학성분들을 포함할 수 있다. 따라서, 상기 약학적 조성물에는 필요에 따라 약학적으로 허용되는 담체, 희석제, 부형제, 또는 이들의 조합이 포함될 수 있다. 이러한 약학적 조성물은 생물체 내로 활성 화합물의 투여를 용이하게 한다. 화합물을 포함하는 약학적 조성물을 투여하는 다양한 기술이 알려져 있으며, 여기에는 경구, 주사, 에어로졸, 비경구, 및 국소 투여 등이 포함되지만 이들만으로 한정되는 것은 아니다. 또한, 상기 약학적 조성물은 멸균되거나, 방부제 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제를 더 포함할 수도 있고, 기타 치료적으로 유용한 물질을 더 포함할 수도 있으며, 혼합, 과립화 또는 코팅의 통상적인 방법에 따라 제제화될 수 있다.
본 명세서에서 “담체(carrier)”란 세포 또는 조직 내로 화합물의 투입을 용이하게 하는 화합물을 의미한다. 예를 들어, 디메틸설폭사이드(DMSO)는 생물체의 세포 또는 조직 내로 많은 유기 화합물의 투입을 용이하게 하는 통상의 담체이다.
본 명세서에서 “희석제(diluent)”란 대상 화합물의 생물학적 활성 형태를 안정화시킬 뿐만 아니라, 화합물을 용해시키는 물에서 희석되는 화합물로 정의된다. 완충액에 용해되어 있는 염은 당해 분야에서 희석제로 사용된다. 통상 사용되는 완충액은 인체 용액의 염 형태를 모방하고 있는 포스페이트 완충 식염수이다. 완충제 염은 낮은 농도에서 용액의 pH를 제어할 수 있기 때문에, 완충 희석제가 화합물의 생물학적 활성을 변형시키는 일은 드물다.
본 명세서에서 “약학적으로 허용되는(pharmaceutically acceptable)”이란, 화합물의 생물학적 활성과 물성들을 손상시키지 않는 성질을 의미한다.
또한, 상기 약학적 조성물은 KRAS G12D 변이 단백질과 관련된 질병의 예방 및/또는 치료용 조성물일 수 있다. 여기에서 상기 KRAS G12D 변이 단백질과 관련된 질병은, 예를 들면 암일 수 있고 기타 KRAS G12D 돌연변이와 관련된 것으로 알려진 임의의 질환을 포함할 수 있다.
상기 암은 혈관육종, 섬유육종, 횡문근육종, 지방육종, 점액종, 횡문근종, 섬유종, 지방종, 기형종; 편평세포암종, 미분화소세포암종, 미분화다세포암종, 샘암종, 폐포(세기관지성)암, 세기관지선종, 육종, 림프종, 연골과오종, 중피종, 식도암, 위암, 췌장암, 소장암, 대장암, 신장암, 방광암, 요도암, 전립선암, 고환암, 간암, 쓸개관암, 간모세포종, 간세포선종, 혈관종, 담낭암, 팽대부성 암, 골육종, 악성 섬유성 조직구종, 연골육종, 유잉육종, 악성 림프종(세망세포육종), 다발성골수종, 악성거대세포종, 골연골종, 양성연골종, 연골모세포종, 연골점액유사섬유종, 연골골종, 거대세포종, 두개골종, 두개혈관종, 두개육아종, 두개황색종, 두개 변형성 골염, 뇌수막종, 수막육종, 교모세포종, 별아교세포종, 수모세포종, 뇌실막세포종, 배아종, 핍지교종, 신경초종, 망막모세포종, 척수신경섬유종, 자궁내막암, 자궁경부암, 난소암, 혈액암, 급성 림프구성 백혈병, 만성 림프구성 백혈병, 급성 골수성 백혈병, 단핵구 백혈병, 만성 골수성 백혈병, 만성 림프구성 백혈병, 혼합 계통 백혈병, 호지킨 림프종, 비호지킨 림프종, 악성흑색종, 기저세포암, 건선암, 신경모세포종을 포함하지만 이에 한정되지 않는다.
상기 약학 조성물은 다양한 경구 투여 형태 또는 비경구 투여 형태로 제형화될 수 있다. 예를 들어, 정제, 환제, 경·연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭서제 (elixirs) 등의 임의의 경구 투여용 제형으로 될 수 있다. 이러한 경구 투여용 제형은 각 제형의 통상적인 구성에 따라 상기 유효 성분 외에, 예를 들어, 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신 등의 희석제나, 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜 등의 활택제 등의 약학적으로 허용 가능한 담체를 포함할 수 있다.
또한, 상기 경구 투여용 제형이 정제인 경우, 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 트라가칸스, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘 등의 결합제를 포함할 수 있고, 경우에 따라, 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제나, 비등 혼합물 및/또는 흡수제, 착색제, 향미제 또는 감미제 등을 추가로 포함할 수 있다.
상기 약학적 조성물은 비경구 투여 형태로 제형화될 수도 있는데, 이러한 경우 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사 등의 비경구 투여 방법에 의해 투여된다. 이 때, 상기 비경구 투여용 제형으로 제제화하기 위하여, 상기 약학적 조성물은 유효 성분, 즉, 화학식 1의 화합물 또는 광학 이성질체, 입체 이성질체, 동위원소 변형체 또는 이들의 약학적으로 허용 가능한 염이 안정제 또는 완충제와 함께 물에서 혼합되어 용액 또는 현탁액으로 제조되고, 이러한 용액 또는 현탁액이 앰플 또는 바이알의 단위 투여형으로 제조될 수 있다.
또한, 상기 약학적 조성물은 멸균되거나, 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제를 더 포함할 수도 있고, 기타 치료적으로 유용한 물질을 더 포함할 수도 있으며, 혼합, 과립화 또는 코팅의 통상적인 방법에 따라 제제화될 수 있다.
상기 유효 성분, 즉 상기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염은 사람을 포함하는 포유류에 대하여, 하루에 0.1 내지 500 ㎎/㎏(체중), 바람직하게는 0.5 내지 100 ㎎/㎏(체중)의 유효량으로 상기 약학적 조성물에 포함될 수 있고, 이러한 약학적 조성물이 1 일 1 회 또는 2 회 이상 분할되어 경구 또는 비경구적 경로를 통해 투여될 수 있다.
또한, 상기 약학 조성물은 본 출원의 일 예에 따른 화합물과, 적어도 하나 이상의 상이한 치료제를 추가적으로 포함하여 암을 치료하는데 사용될 수 있다. 본 출원의 일 예에 따른 화합물은 이와 상이한 치료제와 조합 사용되어 상승작용을 나타낼 수 있다. 용어 "상승작용적"은, 2개 이상의 단일 제제의 상가 효과(additive effect)보다 더 효과적인 치료적 조합을 지칭한다. 조합 치료법은 "상승작용"을 제공하고 "상승작용적"임을 입증하며, 즉, 활성 성분이 함께 사용될 때 달성되는 효과는 화합물을 별개로 사용하는 경우 비롯되는 효과의 합계보다 더 크다. 상승작용적 효과는 활성 성분이: (1) 조합된 단위 투여량 제형에서 공동-제형화되고 동시에 투여되거나 전달될 때; 또는 (2) 대체에 의해 별개의 제형으로서 전달될 때 얻어질 수 있다. 대체 치료법에서 전달될 때, 상승작용적 효과는 화합물이 예를 들어, 별개의 주사기에서 상이한 주사에 의해 순차적으로 투여되거나 전달될 때 얻어질 수 있다. 일반적으로, 대체 치료법 동안, 각각의 활성 성분의 유효 투여량은 순차적으로, 즉, 시간에서 일련으로 투여된다. 일부 구현예에서, 상승작용은 동일한 총 투여량에서 임의의 단일 성분의 동일한 용량과 비교하여 조합물의 더 낮은 독성에 의해 입증된다. 예를 들어, 화학식 1의 화합물이 이와 상이한 치료제와 공동 투여될 때, 상기 화학식 1의 화합물 및 상기 상이한 치료제를 포함하는 50:50 (w/w) 조합물의 독성은, 100% (w/w) 상기 화학식 1 화합물의 독성, 및/또는 100% (w/w) 상기 상이한 치료제의 독성보다 낮을 수 있으며, 여기서 조합물은 대략 동일한 수준 또는 그 이상의 효능을 갖는다. 즉, 화학식 1의 화합물 및 이와 상이한 치료제 조합의 독성이, 단일 성분의 독성보다 작으며, 조합의 효능이 단일 성분의 효능보다 더 큰 것이다. 또한, 화학식 1의 화합물 및 이와 상이한 치료제 조합하는 이유는, 독성을 감소시키고 더 큰 안전성을 부여하는 것뿐만 아니라 단일 제제 단독에 의해 부여되는 것보다 더 크게 효능을 증강시키는 것이다. 효능의 증가는 조합 치료법의 이익 중 하나이다.
상기 하나 이상의 치료제는 RTK/Ras-MAPK pathway 관련 단백질 저해제 (EGFR 저해제, FGFR 저해제, ALK 저해제, ROS 저해제, MET 저해제, RAF 저해제, ERK 저해제, MEK 저해제, SHP-2 저해제, PI3K 저해제, KRAS 저해제, KRAS-G12C 저해제, SOS1 저해제), DNA 손상 유도물질, EGFR antibody 또는 면역항암제를 포함하지만 이에 한정되지는 않는다.
일 예로 RTK/Ras-MAPK pathway 저해제는 EGFR 저해제 (엘로티닙 (Erlotinib), 게피티닙(Gefitinib), 아파티닙 (Afatinib) 또는 오시머티닙 (Osimertinib)), FGFR 저해제 (페미가티닙 (Pemigatinib) 또는 인피그라티닙 (BGJ398)), ALK/ROS/MET 저해제 (크리조티닙 (Crizotinib), 카보잔티닙 (Carbozantinib) 또는 포레티닙 (Foretinib)), RAF 저해제 (베무라페닙 (Vemurafenib), 다브라페닙 (Dabrafenib) 또는 벨바라페닙 (Belvarafenib)), ERK/MEK 저해제 (트라메티닙 (Trametinib) 또는 코비메티닙 (Cobimetinib)), SHP-2 저해제 (TNO155 및 RMC4630), PI3K 저해제 (AMG 511 및 부파리십 (bupalisib)), KRAS 저해제 및 KRAS-G12C 저해제 (소토라십(Sotorasib), 아다그라십 (Adagrasib) 및 디바라십 (Divarasib)이며, 이 중 하나 이상의 저해제를 포함하지만 이에 한정되지는 않는다.
일 예로 DNA 손상 유도 물질의 화합요법 물질은 알킬화제 (백금계 화합요법제: 시스플라틴 (Cisplatin), 카보플라틴 (Carboplatin), 옥살리플라틴 (Oxaliplatin)/ 니트로겐 머스타드 (Nitrogen mustard)계 약물: 메클로레타민 (Mechlorethamine, nitrogen mustard), 사이클로포스파마이드 (Cyclophosphamide), 이포스파마이드 (Ifosfamide), 멜팔란 (Melphalan), 클로람부실 (Chlorambucil)/ 니트로소우레아 (Nitrosourea)계 약물: 카무스틴 (Carmustine, BCNU), 로무스틴 (Lomustine, CCNU), 니무스틴 (Nimustine)/ 기타: 알트레타민 (Altretamine), 부설판 (Busulfan), 다카바진 (Dacarbazlne), 프로카바진 (Procarbazine), 테모졸로미드 (Temozolomide), 치오테파 (Thiotepa), 러비넥테딘 (Lurbinectedin) 등), 항대사물질 (플루오로우라실 (Fluorouracil, 5-FU), 카페시타빈 (Capecitabine), 시타라빈 (Cytarabine), 젬시타빈 (Gemcitabine), 메소트렉세이트 (Methotrexate), 메르캅토퓨린 (Mercaptopurine, 6-MP), 루코보린 (leucovorin), 페메트렉시드 (pemetrexed) 등), 토포아이소머라제 저해제 (에피포도필로톡신 (Epipodophyllotoxin) : 에토포사이드 (Etoposide), 테니포사이드 (Tenoposide)/ 캠프토테신 (Camptothecin) : 토포테칸 (Topotecan), 이리노테칸 (Irinotecan), SN-38/ 항생물질 (Antitumor Antibiotics) : 닥티노마이신 (Dactinomycin), 독소루비신 (Doxorubicin), 다우노루비신 (Daunorubicin), 마이토마이신 (Mitomycin), 블레오마이신 (Bleomycin) 등), 미세소관 저해제 (빈카알칼로이드 (Vinca Alkaloid): 빈블라스틴 (Vinblastine), 빈크리스틴 (Vincristine), 비노렐빈 (Vinorelvine)/ 탁산 (Taxane): 파클리탁셀 (Paclitaxel), 도세탁셀 (Docetaxel) 등), 호르몬 길항 약물 (타목시펜 (Tamoxifen), 플루타마이드 (Flutamide), 루프로라이드 (Leuprolide) 등) 등을 포함하지만 이에 한정되지는 않는다.
일 예로 EGFR antibody 는 세툭시맙 (cetuximab)을 포함하지만 이에 한정되지는 않는다.
일 예로 면역항암제는 AMG-404, 펨브롤리주맙(pembrolizumab) 또는 니볼루맙 (nivolumab) 등을 포함하지만 이에 한정되지는 않는다.
본 출원에 따르면, 우수한 KRAS G12D 억제 효과를 나타내는 3환 유도체 화합물, 또는 이의 광학 이성질체, 입체이성질체 또는 동위원소 변형체 또는 이들의 약학적으로 허용되는 염이 제공될 수 있다. 따라서 이러한 화합물 또는 이의 광학 이성질체, 입체 이성질체 또는 동위원소 변형체 또는 이들의 약학적으로 허용되는 염은 KRAS G12D 돌연변이 단백질과 관련된 질병, 예를 들면 암의 예방 또는 치료를 위해 효과적으로 사용될 수 있다.
또한 본 출원에 따른 화합물, 또는 이의 광학 이성질체, 입체 이성질체 또는 동위원소 변형체, 또는 이들의 약학적으로 허용되는 염은 우월한 효능 또는 개선된 약동학적 특성을 가질 수 있다.
이하에서 본 출원을 실시예를 통하여 보다 상세하게 설명한다. 그러나, 실시예는 본 출원을 예시적으로 설명하기 위한 것일 뿐 발명의 범위가 이에 의해서 한정되는 것은 아니다.
Intermediate 1: 6-bromo-1,3-dichloroimidazo[1',2':1,6]pyrido[3,2- d ]pyrimidine의 합성.
Figure PCTKR2023020084-appb-img-000016
단계 1: 6-Chloro-3-nitropicolinonitrile (10 g, 54.48 mmol)을 H2SO4 (276 g, 2.53 mol)에 녹이고 3.5시간 동안 70 ℃로 가열하였다. 반응 종료 후, 반응 혼합물을 20 ℃로 냉각한 후, 얼음물 (1200 mL)을 적가하고, 침전물을 여과, 물로 세척, 건조를 순서대로 한 후 감압 하에 농축하여 백색 고체의 6-chloro-3-nitropicolinamide (9.85 g, 비정제 화합물)를 얻었다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.54 (d, J = 8.8 Hz, 1H), 8.29 (brs, 1H), 8.03 (brs, 1H) 7.95 (d, J = 8.8 Hz, 1H).
단계 2: 6-chloro-3-nitropicolinamide (7.35 g, 36.46 mmol)의 용액을 에탄올 (30 mL)에 녹인 후 포화된 28% 암모니아 (27.30 g, 218.09 mmol) 용액을 적가하였다. 100 ℃에서 48시간 동안 실드 튜브 100 mL에서 반응하였다. 반응 종료 후 혼합물을 냉각하고 감압 하에 농축하여 잔류물을 얻었다. 잔류물을 Na2CO3 수용액 (100 mL)으로 희석하고 혼합물을 20 ℃에서 1시간 동안 교반한 다음 여과하고 필터 케이크를 물 (50 mL)로 세척하였다. 감압 하에 농축하여 잔류물을 얻었다. 노란색 고체의 6-amino-3-nitro-pyridine-2-carboxamide (4.85 g, 비정제 화합물)을 얻었다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.11 (d, J = 9.2 Hz, 1 H), 7.83 (brs, 1H), 7.57 (brs, 2H), 7.52 (brs, 1H), 6.50 (d, J = 9.2 Hz, 1 H).
단계 3: DMF (49 mL)에 6-amino-3-nitro-pyridine-2-carboxamide (4.85 g, 26.63 mmol)을 녹인 다음 NBS (5.69 g, 31.95 mmol)를 첨가한 후, 반응 혼합물을 25 ℃에서 4시간 동안 교반하였다. 반응 종료 후, 감압 하에서 용매의 대부분을 제거하고, 잔류물을 정제수 (100 mL)에 현탁하였다. 고체를 여과하고 감압 하에서 건조하였다. 생성물을 petroleum ether (45 mL) 및 ethyl acetate (40 mL)로 20 ℃에서 30분 동안 교반하고, 고체를 여과하고 감압 하에 건조하였다. 6-amino-3-nitropicolinamide (5.6 g, 21.13 mmol, 79.37% 수율)을 황색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 263.0; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.48 (s, 1H), 7.90 (brs, 2H), 7.65 (brs, 2H).
단계 4: Ethanol (59 mL) 과 증류수 (59 mL)에 6-amino-3-nitropicolinamide (5.9 g, 22.60 mmol)를 녹인 후 2-bromo-1,1-diethoxyethane (6.68 g, 33.90 mmol)과 HBr (9.14 g, 45.21 mmol)을 각각 20 ℃에서 적가하였다. 반응 혼합물을 100 ℃에서 16시간 동안 가열하였다. 반응 혼합물을 진공에서 농축하여 ethanol을 제거하고 잔류물의 pH를 NaHCO3 수용액을 이용하여 8로 조정하고, 고체를 침전시킨 다음, 여과하였다. 필터 케이크를 진공에서 농축하여 회색의 8-bromo-6-nitroimidazo[1,2-a]pyridine-5-carboxamide (5.28 g, 18.14 mmol, 80.26% 수율)을 얻었다. 결과는 LCMS와 HNMR로 확인하였다. LCMS (ES-API, m/z): [M+H]+= 287.0; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.55 (d, J = 10.0 Hz, 2 H), 8.34 (d, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1 H).
단계 5: Ethanol (90 mL) 및 증류수 (18 mL)에 8-bromo-6-nitroimidazo[1,2-a]pyridine-5-carboxamide (4.5 g, 15.79 mmol), Fe (3.53 g, 63.15 mmol) 및 NH4Cl (6.76 g, 126.29 mmol)을 넣고 85 ℃에서 16시간 동안 교반하였다. 반응 혼합물을 여과하고 필터 케이크를 800 mL EA/MeOH(10:1)로 세척하였다. 유기상을 합하여 잔류물을 얻었다. 그 다음 잔류물을 포화 탄산 수소 나트륨으로 세척하고 여과하고 필터 케이크를 감압 하에 농축하여 잔류물을 얻었다. 녹색 고체의 6-amino-8-bromoimidazo[1,2-a]pyridine-5-carboxamide (3.1 g, 비정제 화합물)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 254.9; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.21 - 7.61 (m, 3H), 7.57 - 7.20 (m, 2H), 6.02 - 5.40 (m, 2H).
단계 6: 1,4-Dioxane (100 mL)에 6-amino-8-bromoimidazo[1,2-a]pyridine-5-carboxamide (10.47 g, 35.28 mmol)를 녹인다. 생성된 현탁액을 질소 하에서 110 ℃, 16시간 동안 환류하였다. 출발 물질이 소모된 후 반응 용액을 20 ℃로 냉각하고, 증류수 (20 mL)을 첨가한 후 10분 동안 교반하여 반응을 종료하였다. 혼합물을 여과하고 고체를 ethyl acetate (200 mL)로 세척한 다음, 건조하였다. 노란색 고체의 6-bromoimidazo[1',2':1,6]pyrido[3,2-d]pyrimidine-1,3(2H,4H)-dione (10.7 g, 비정제 화합물)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 283.2; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 12.00 - 11.95 (m, 1H), 11.91 - 11.83 (m, 1H), 9.11 (d, J = 0.8 Hz, 1H), 8.02 - 7.94 (m, 1H), 7.84 - 7.74 (m, 1H)
단계 7: 250 mL 둥근 3구 병 플라스크 안에 POCl3 (117.84 g, 768.50 mmol)을 단계 6에서 얻은 6-bromoimidazo[1',2':1,6]pyrido[3,2-d]pyrimidine-1,3(2H,4H)-dione (5.4 g, 19.21 mmol)에 적가했다. 이어서 DIPEA (6.21 g, 48.03 mmol)을 천천히 적가하였다. 반응 혼합물을 질소로 충전한 후, 110 ℃에서 20시간 동안 교반하였다. 출발 물질이 완전히 소모된 후 용매와 대부분의 POCl3을 40 ℃에서 진공 하에 제거한 후, ethyl acetate (100 mL)를 첨가하고, 반응 혼합물을 포화 Na2CO3 용액으로 0 ℃에서 pH 7~8로 염기성화 하였다. 반응 혼합물을 ethyl acetate (200 mL*3)로 추출한 다음 유기층을 황산나트륨상에서 건조 및 여과하고, 농축하였다. 잔류물을 silica gel chromatography로 정제하였다. 6-bromo-1,3-dichloroimidazo[1',2':1,6]pyrido[3,2-d]pyrimidine (2.44 g, 7.24 mmol, 37.68% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 275.0; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 9.28 (d, J = 1.2 Hz, 1 H), 9.17 - 9.12 (m, 2 H), 8.12 - 8.07 (m, 1 H), 7.95 - 7.93 (m, 1 H), 7.92 - 7.90 (m, 2 H), 7.87 - 7.84 (m, 1 H).
Intermediate 2: 6-bromo-1,3-dichloro-8-methylfuro[3,2- f ]quinazoline의 합성.
Figure PCTKR2023020084-appb-img-000017
단계 1: 4-bromo-5-fluoro-2-nitrobezoic acid (50.0 g, 189 mmol)을 증류수 (600 mL)에 녹이고, 12 M KOH (63.8 g, 1.14 mol)을 첨가하고, 반응 용액을 80 oC에서 하루 동안 교반하였다. 반응 혼합물에 1 N HCl 수용액을 넣어 pH 3으로 만든 후, ethyl acetate를 가하여 유기층을 추출하고, 포화 NaCl 수용액으로 씻어 준 뒤, 무수 MgSO4로 건조하였다. 용매를 농축하여 4-bromo-5-hydroxy-2-nitrobenzoic acid (49.5 g, 189 mmol, 비정제 화합물)을 합성하였다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 13.7 (s, 1H), 12.1 (s, 1H), 8.27 (s, 1H), 7.14 (s, 1H).
단계 2: 단계 1에서 얻은 4-bromo-5-hydroxy-2-nitrobenzoic acid (49.5 g, 189 mmol)을 methanol (599 mL)에 녹이고, 0 oC에서 황산 (51.6 mL)을 첨가하여 반응 용액을 70 oC에서 하루 동안 교반하였다. 반응 혼합물에 증류수를 넣어 반응 종결 후, ethyl acetate를 가하여 유기층을 추출하고, 포화 NaCl 수용액으로 씻어준 뒤, 무수 MgSO4로 건조하였다. 용매를 농축하여 methyl 4-bromo-5-hydroxy-2-nitrobenzoate (52.2 g, 189 mmol, 비정제 화합물)을 합성하였다.
단계 3: 단계 2로부터 얻은 methyl 4-bromo-5-hydroxy-2-nitrobenzoate (52.2 g, 189 mmol)과 TEA (79.0 mL, 567 mmol)을 DCM (798 mL)에 녹이고, 0 ℃에서 acetyl chloride (20.2 mL, 283 mmol)를 첨가하여 반응 용액을 같은 온도에서 2시간 동안 교반하였다. 반응 혼합물에 정제수를 넣어 반응을 종결하고 DCM을 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. 용매를 농축하여 methyl 5-acetoxy-4-bromo-2-nitrobenzoate (60.1 g, 189 mmol, 비정제 화합물)을 합성하였다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.55 (s, 1H), 7.94 (s, 1H), 3.87 (s, 3H), 2.39 (s, 3H).
단계 4: 단계 3으로부터 얻은 methyl 5-acetoxy-4-bromo-2-nitrobenzoate (60.0 g, 189 mmol)을 ethanol (700 mL), 정제수 (300 mL), acetic acid (75.5 mL, 1.32 mol)에 녹이고, Fe (26.3 g, 472 mmol)을 천천히 첨가하였다. 반응 용액을 상온에서 3시간 동안 교반하였다. 반응 혼합물에 6 N KOH 수용액을 넣어 중화시킨 후, 용매를 제거하고, 필터하였다. 여액을 Ethyl acetate를 가하여 유기층을 추출하고, 포화 NaCl 수용액으로 씻어 준 뒤, 무수 MgSO4로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 고체 화합물로 methyl 5-acetoxy-2-amino-4-bromobenzoate (24.5 g, 85.0 mmol, 45% 수율)을 합성하였다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 7.50 (s, 1H), 7.13 (s, 1H), 6.76 (s, 2H), 3.79 (s, 3H), 2.26 (s, 3H).
단계 5: 단계 4로부터 얻은 methyl 5-acetoxy-2-amino-4-bromobenzoate (2.28 g, 7.91 mmol)을 MeOH (120 mL)에 녹이고, K2CO3 (2.19 g, 15.8 mmol)를 첨가하여 반응 용액을 상온에서 2시간 동안 교반하였다. 반응 혼합물에 1 N HCl 수용액을 첨가하여 산성화한 후, ethyl acetate로 유기층을 추출하고, 무수 MgSO4로 건조하였다. 용매를 농축하여 methyl 2-amino-4-bromo-5-hydroxybenzoate (1.95 g, 7.91 mmol, 비정제 화합물)을 합성하였다. 1H NMR (400 MHz, CD3OD, ppm): δ 8.36 (d, J = 1.2 Hz, 1H), 8.23 (d, J = 1.2 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 5.49 (s, 2H), 5.42 - 5.37 (m, 1H), 3.44 - 3.40 (m, 2H), 3.31 - 3.27 (m, 2H), 2.76 (s, 3H), 2.30 - 2.27 (m, 2H), 2.26 - 2.24 (m, 2H).
단계 6: 단계 5로부터 얻은 methyl 2-amino-4-bromo-5-hydroxybenzoate (1.95 g, 7.92 mmol)을 DMF (50 mL)에 녹이고, toluene에 녹여진 9.2 M 3-bromopropane (1.21 mL, 11.1 mmol)과 K2CO3 (2.19 g, 15.8 mmol)를 차례로 첨가하여 반응 용액을 상온에서 하루 동안 교반하였다. 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 포화 NaCl 수용액으로 씻어 준 뒤, 무수 MgSO4로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 고체 화합물로 methyl 2-amino-4-bromo-5-(prop-2-yn-1-yloxy)benzoate (1.66 g, 5.84 mmol, 74% 수율)을 합성하였다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 7.43 (s, 1H), 7.11 (s, 1H), 6.48 (s, 2H), 4.74 (d, J = 2.4 Hz, 2H), 3.80 (s, 3H), 3.58 (t, J = 2.3 Hz, 1H).
단계 7: 단계 6으로부터 얻은 methyl 2-amino-4-bromo-5-(prop-2-yn-1-yloxy)benzoate (1.66 g, 5.84 mmol)을 N,N-diethylaniline (10 mL)에 녹이고, CsF (1.33 g, 8.76 mmol)를 첨가하여 반응 용액을 가열 환류하여 1시간 동안 교반하였다. Ethyl acetate로 희석하고, 1 N 염산 수용액으로 2번 씻어 준 뒤, 무수 MgSO4로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 고체 methyl 5-amino-7-bromo-2-methylbenzofuran-4-carboxylate (1.41 g, 4.96 mmol, 85% 수율)을 합성하였다.
단계 8: 단계 7로부터 얻은 methyl 5-amino-7-bromo-2-methylbenzofuran-4-carboxylate (1.41 g, 4.96 mmol)을 THF (50 mL)에 녹이고, 0 ℃에서 trichloroacetyl isocyanate (0.651 mL, 5.46 mmol)을 첨가하여 반응 용액을 같은 온도에서 30분 동안 교반하였다. 용매를 농축하여 얻은 물질에 메탄올에 녹여진 7 N 암모니아 용액 (1.69 g, 99.0 mmol)을 첨가하고, 상온에서 하루 동안 교반하였다. Methanol로 필터하여 얻은 고체 6-bromo-8-methylfuro[3,2-f]quinazoline-1,3(2H,4H)-dione (1.23 g, 4.17 mmol, 84% 수율)을 합성하였다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.01 (s, 2H), 7.24 (d, J = 1.3 Hz, 1H), 7.22 (s, 1H), 2.54 (s, 3H).
단계 9: 단계 8로부터 얻은 6-bromo-8-methylfuro[3,2-f]quinazoline-1,3(2H,4H)-dione (1.22 g, 4.13 mmol)에 POCl3 (15.4 mL, 165 mmol)를 첨가하고, DIPEA (1.80 mL, 10.3 mmol)을 첨가하여 반응용액을 110 ℃에서 1.5시간 동안 교반하였다. 용매를 농축하고 반응 혼합물에 포화 NaHCO3 용액을 넣어 반응을 종결하고 ethyl acete를 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. 용매를 농축하여 얻은 물질을 DCM으로 필터하여 고체를 제거하고, 여액을 농축하여 silica gel chromatography로 정제하여 고체 6-bromo-1,3-dichloro-8-methylfuro[3,2-f]quinazoline (40.0 mg, 0.120 mmol, 3% 수율)을 합성하였다. LCMS (ES-API, m/z): [M+H]+= 329.9; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.23 (s, 1H), 7.70 (s, 1H), 2.68 (s, 3H).
Intermediate 3: 6-bromo-1,3-dichloro-5-fluoro-8-methyl-6a,9a-dihydrofuro[3,2- f ]quinazoline의 합성.
Figure PCTKR2023020084-appb-img-000018
단계 1: methyl 5-acetoxy-2-amino-4-bromobenzoate (20.0 g, 69.4 mmol)을 acetonitrile (1 L)에 녹이고, selectfluor (27.1 g, 76.4 mmol)를 첨가하고, 반응 용액을 80 ℃에서 하루 동안 교반하였다. 반응 혼합물에 포화 NaHCO3 수용액을 넣어 pH 8로 만든 후, ethyl acetate를 가하여 유기층을 추출하고, 포화 NaCl 수용액으로 씻어 준 뒤, 무수 MgSO4로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 고체 methyl 5-acetoxy-2-amino-4-bromo-3-fluorobenzoate (5.5 g, 18.0 mmol, 26% 수율)을 합성하였다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 7.45 (d, J = 2.0 Hz, 1H), 6.74 (s, 2H), 3.83 (s, 3H), 2.29 (s, 3H).
단계 2: 단계 1로부터 얻은 methyl 5-acetoxy-2-amino-4-bromo-3-fluorobenzoate (5.50 g, 18.0 mmol)을 methanol (275 mL)에 녹이고, K2CO3 (4.97 g, 35.9 mmol)를 첨가하여 반응용액을 상온에서 2시간 동안 교반하였다. 반응 혼합물에 1 N HCl 수용액을 첨가하여 산성화한 후, ethyl acetate로 유기층을 추출하고, 무수 MgSO4로 건조하였다. 용매를 농축하여 methyl 2-amino-4-bromo-3-fluoro-5-hydroxybenzoate (4.74 g, 18.0 mmol, 비정제 화합물)을 합성하였다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 9.86 (s, 1H), 7.19 (d, J = 2.1 Hz, 1H), 6.07 (s, 2H), 3.81 (s, 3H).
단계 3: 단계 2로부터 얻은 methyl 2-amino-4-bromo-3-fluoro-5-hydroxybenzoate (2.00 g, 7.57 mmol)을 DMF (47.8 mL)에 녹이고, toluene에 녹여진 9.2 M Propargyl bromide (1.15 mL, 10.6 mmol)과 K2CO3 (2.09 g, 15.1 mmol)를 차례로 첨가하여 반응 용액을 상온에서 하루 동안 교반하였다. 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 포화 NaCl 수용액으로 씻어 준 뒤, 무수 MgSO4로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 고체 methyl 2-amino-4-bromo-3-fluoro-5-(prop-2-yn-1-yloxy)benzoate (1.03 g, 3.41 mmol, 45% 수율)을 합성하였다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 7.34 (d, J = 2.0 Hz, 1H), 6.42 (s, 2H), 4.82 (s, 2H), 3.84 (s, 3H), 3.61 (t, J = 2.3 Hz, 1H).
단계 4: 단계 3으로부터 얻은 methyl 2-amino-4-bromo-3-fluoro-5-(prop-2-yn-1-yloxy)benzoate (1.02 g, 3.38 mmol)을 N,N-diethylaniline (10 mL)에 녹이고, CsF (769 mg, 5.06 mmol)를 첨가하여 반응 용액을 가열 환류하여 1시간 동안 교반하였다. Ethyl acetate로 희석하고, 1 N HCl 수용액으로 2번 씻어 준 뒤, 무수 MgSO4로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 고체 methyl 5-amino-7-bromo-6-fluoro-2-methylbenzofuran-4-carboxylate (910 mg, 3.01 mmol, 89% 수율)을 합성하였다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 6.91 (s, 1H), 6.67 (s, 2H), 3.89 (s, 3H), 2.45 (s, 3H).
단계 5: 단계 4로부터 얻은 methyl 5-amino-7-bromo-6-fluoro-2-methylbenzofuran-4-carboxylate (910 mg, 3.01 mmol)을 THF (30.3 mL)에 녹이고, 0 ℃에서 trichloroacetyl isocyante (0.395 mL, 3.31 mmol)을 첨가하여 반응용액을 같은 온도에서 30분 동안 교반하였다. 용매를 농축하여 얻은 물질에 7N NH4 in methanol (8.62 mL, 60.3 mmol)을 첨가하고, 상온에서 하루 동안 교반하였다. methanol로 필터하여 얻은 흰색 고체 6-bromo-5-fluoro-8-methylfuro[3,2-f]quinazoline-1,3(2H,4H)-dione (863 mg, 2.76 mmol, 91% 수율)을 합성하였다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 9.90 (s, 2H), 7.21 (s, 1H), 2.53 (s, 3H).
단계 6: 단계 5로부터 얻은 bromo-5-fluoro-8-methylfuro[3,2-f]quinazoline-1,3(2H,4H)-dione (750 mg, 2.40 mmol)에 POCl3 (8.93 mL, 95.80 mmol)를 첨가하고, DIPEA (1.04 mL, 5.99 mmol)을 첨가하여 반응용액을 110 ℃에서 7시간 동안 교반하였다. 반응 혼합물에 포화 NaHCO3 용액을 넣어 반응을 종결 후, ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. 용매를 농축하여 얻은 물질을 DCM으로 필터하여 흰색 고체로 얻고, 여액은 농축하여 silica gel chromatography로 정제하여 흰색 고체 6-bromo-1,3-dichloro-5-fluoro-8-methyl-6a,9a-dihydrofuro[3,2-f]quinazoline (707 mg, 2.02 mmol, 84% 수율)을 얻었다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 7.64 (s, 1H), 2.66 (s, 3H).
Intermediate 4: 4-bromo-7,9-dichloro-2-methyl-2 H -pyrazolo[4,3- f ]quinazoline의 합성.
Figure PCTKR2023020084-appb-img-000019
단계 1: THF (200 mL)에 7-bromo-5-nitro-1H-indazole (20 g, 82.6 mmol)을 녹인 후 NaH (8.3g, 124 mmol)를 0 ℃에서 첨가하고, 혼합물을 20 ℃에서 교반하였다. 20 ℃에서 30분 동안 교반한 후, MeI (35.2 g, 248 mmol)를 첨가하였다. 반응 혼합물을 질소 하에서 20 ℃, 1시간 동안 교반하였다. 반응 종료 후, 반응 혼합물에 정제수 (80 mL)를 첨가하고 ethyl acetate(50 mL*3)로 추출하였다. 합한 유기층을 소금물 (40 mL*3)로 세척하고 Na2SO4으로 건조하였다. 여과한 용액을 감압 하에 농축하여 잔류물을 얻었다. 잔류물을 hexane으로 20 ℃에서 30분 동안 교반하고, 고체를 여과하였다. 7-bromo-2-methyl-5-nitro-2H-indazole (20 g, 78.1 mmol, 94% 수율)를 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 257.1.
단계 2: Ethanol (120mL), THF (120 mL), 정제수 (40 mL)를 섞은 용액에 7-bromo-2-methyl-5-nitro-2H-indazole (20 g, 78.1 mmol), Fe (21.8 g, 391 mmol) 및 NH4Cl (5.01 g, 93.7 mmol)을 넣고 90 ℃에서 1시간 동안 교반하였다. 반응 혼합물을 셀라이트로 여과하여 잔류물을 얻었다. 잔류물을 silica gel chromatography로 정제하였다. 7-bromo-2-methly-2H-indazole-5-amine (7 g, 31 mmol, 40% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 227.1; 1H NMR (400 MHz, CDCl3, ppm): δ 7.73 (s, 1H), 6.85 (s,1H), 6.72 (s, 1H), 4.18 (s, 3H), 3.52 (br, 2H).
단계 3: 7-bromo-2-methly-2H-indazole-5-amine (6.67 g, 29.5 mmol), chloral hydrate (9.76 g, 29.5 mmol), Na2SO4 (33.5 g, 236 mmol)을 정제수 (70 mL)에 녹인 후 HCl (4 mL)을 천천히 적가 하고, 90 ℃에서 30분 동안 교반했다. 그 다음 N-chlorohydroxylamine (11.9 g, 177 mmol)을 넣고 90 ℃에서 1시간 동안 교반했다. 상온으로 반응 혼합물의 온도를 식힌 후 정제수 (70 mL)를 넣고 10 분간 교반했다. 고체를 침전시킨 다음, 여과하였다. 필터 케이크를 진공에서 농축하여 검은색 고체 N-(7-bromo-2-methyl-2H-indazole-5-yl)-2-(N-hydroxyamino)acetamide (8.77 g, 29.5 mmol, 100% 수율, 비정제 화합물)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 298.1.
단계 4: N-(7-bromo-2-methyl-2H-indazole-5-yl-2-(N-hydroxy imino)acetamide (9g, 30.3 mmol)에 진한 황산 (60 mL)을 천천히 적가하고 반응 혼합물을 90 ℃에서 30분 동안 교반했다. 반응 혼합물을 상온으로 식힌 뒤 얼음을 넣고 30분간 교반했다. 고체를 침전시킨 다음 고체를 여과하였다. 고체를 건조하여 검은색 4-bromo-2-mehtyl-2H,6H,7H,8H-pyrolo[3,2-e]indazole-7,8-dione (5.1g, 18.2 mmol, 60% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 281.1; 1H NMR (400 MHz, CD3OD, ppm): δ 8.30 (s, 1H), 8.14 (s, 1H), 7.74 (s, 1H), 7.61 (s, 1H), 4.24 (s, 3H).
단계 5: 4-bromo-2-mehtyl-2H,6H,7H,8H-pyrolo[3,2-e]indazole-7,8-dione (5.1 g, 18.2 mmol)을 2 N NaOH 수용액 (7.28 g, 182 mmol)에 녹인 후 H2O2 (3.1 g, 91 mmol)을 천천히 적가 한 후 1시간 동안 교반하였다. 0 ℃에서 반응 혼합물에 Acetic acid을 가하여 pH를 3으로 조정하고 침전된 고체를 여과하였다. 고체를 건조하여 검은색 5-amino-7-bromo-2-methyl-2H-indazole-4-carboxylic acid (3.08 g, 11.4 mmol, 63% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 271.1; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.81 (s, 1H), 8.58 (s, 1H), 7.25 (s, 1H), 4.19 (s, 3H).
단계 6: 5-amino-7-bromo-2-methyl-2H-indazole-4-carboxylic acid (962 mg, 3.56 mmol)을 methanol (14 mL) 과 toluene (42 mL)에 녹인 후 2 M (diazomethyl)trimethylsilane (488 mg, 4.27 mmol)을 0 ℃에서 천천히 적가했다. 상온으로 가열하여 5분간 교반하였다. 화합물을 ethyl acetate (200 mL*3)로 추출 한 다음 유기층을 Na2SO4로 건조 여과하고, 농축하였다. 잔류물을 silica gel chromatography로 정제하였다. methyl 5-amino-7-bromo-2-methyl-2H-indazole-4-carboxylate (283 mg, 0.996 mmol, 28% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 285.1; 1H NMR (400 MHz, CD3OD, ppm): δ 8.16 (s, 1H), 7.17 (s, 1H), 4.14 (s, 3H), 3.93 (s, 3 H).
단계 7: methyl 5-amino-7-bromo-2-methyl-2H-indazole-4-carboxylate (276 mg, 0.971 mmol)을 THF(13 mL)에 녹인 후 trichloroethanecarbonylisocyanate (220 mg, 1.17 mmol)을 0 ℃에서 적가 한 후 5분간 반응하였다. 감압하에서 용매의 대부분을 제거하고, 잔류물을 ether (10 mL)에 현탁하였다. 고체를 여과하고 감압하에서 건조시켰다. methyl 7-bromo-2-methyl-5[[(2,2,2-trichloroacetyl)carbamoyl]amino]-2H-indazole-4-carboxylate (459 mg, 0.971 mmol, 100% 수율)를 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 473.5.
단계 8: 7N NH4 in Methanol (100 mL)에 단계 7에서 얻은 methyl 7-bromo-2-methyl-5[[(2,2,2-trichloroacetyl)carbamoyl]amino]-2H-indazole-4-carboxylate (459 mg, 0.971 mmol)을 녹인다. 생성된 현탁액을 질소 하에서 110 ℃, 36시간 동안 환류하였다. 반응 종료 후 20 ℃로 냉각하고, 용매를 질소로 제거한 후, 혼합물을 여과하였다. 여과된 고체를 ether (200 mL)로 세척한 후, 건조하여 흰색 4-bromo-2-methyl-2H,6H,7H,8H,9H-pyrazolo[4,3-f]quinazoline-7,9-dione (287 mg, 100% 수율, 비정제 화합물)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 296.1; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.75 (s, 1H), 7.42 (s, 1H).
단계 9: POCl3 (5.9 g, 38.9 mmol)을 단계 8에서 얻은 4-bromo-2-methyl-2H,6H,7H,8H,9H-pyrazolo[4,3-f]quinazoline-7,9-dione (287 mg, 0.973 mmol)에 적가했다. 이어서 DIPEA (377 mg, 2.92 mmol)를 천천히 적가 하고, 혼합물을 질소로 충전한 후, 110 ℃에서 20시간 동안 교반하였다. 반응 종료 후, 용매와 대부분의 POCl3을 40 oC에서 진공 하에 제거하고, ethyl acetate (100 mL)를 첨가한 후, 혼합물을 포화 Na2CO3 용액으로 0 oC에서 pH 7~8로 염기성화 하였다. 화합물을 ethyl acetate (200 mL*3)로 추출한 다음 유기층을 Na2SO4로 건조 및 여과하고, 농축하였다. 잔류물을 silica gel chromatography로 정제하여 4-bromo-7,9-dichloro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (124 mg, 0.374 mmol, 38% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 333.0.
Intermediate 5: 4-bromo-7,9-dichloro-5-fluoro-2-methyl-2 H -pyrazolo[4,3-f]quinazoline의 합성
Figure PCTKR2023020084-appb-img-000020
단계 1: 7-Bromo-6-fluoro-2H-indazole (40.0 g, 186 mmol)을 ethyl acetate (500 mL)에 녹인 후 Me3OBF4 (41.3 g, 279 mmol)을 넣어 상온에서 12시간 동안 교반했다. 정제수 (500 mL)로 반응을 종결하고 ethyl acetate (500 mL*2)로 추출했다. 추출한 유기층을 포화 NaCl 수용액으로 세척하고 무수 Na2SO4 로 건조, 농축했다. Silica gel chromatography로 정제하여 노란색 고체인 7-bromo-6-fluoro-2-methyl-2H-indazole (37.3 g, 163 mmol, 88% 수율)을 얻었다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.54 (s, 1H), 7.78 (dd, J = 5.2, 8.8 Hz, 1H), 7.05 (t, J = 9.2 Hz, 1H), 4.19 (s, 3H).
단계 2: H2SO4 (370 mL)을 0 oC로 냉각한 후, 7-bromo-6-fluoro-2-methyl-2H-indazole (37.0 g, 162 mmol)을 적가했다. 반응 혼합물에 KNO3 (19.8 g, 1956 mmol)을 천천히 0 oC에서 적가하고 상온에서 12시간 동안 교반했다. 반응 확인 후 차가운 정제수로 반응을 종결하고 0 oC에서 NaHCO3 수용액으로 천천히 중성화했다. Ethyl acetate (500 mL*3)로 유기층을 추출하고, 포화 NaCl 수용액으로 세척했다. 유기층을 무수 Na2SO4로 건조, 농축하여 노란색 고체인 7-bromo-6-fluoro-2-methyl-5-nitro-2H-indazole (38.0 g, 139 mmol, 86% 수율)을 얻었다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.91 (s, 1H), 8.85 (d, J = 7.2 Hz, 1H), 4.26 (s, 3H).
단계 3: 7-bromo-6-fluoro-2-methyl-5-nitro-2H-indazole (38.0 g, 139 mmol)과 NH4Cl (59.3 g, 1.11 mol)을 EtOH (400 mL)과 H2O (200 mL)에 녹이고 Fe (62.0 g, 1.11 mol)을 적가하여 80 oC에서 2시간 동안 교반했다. 반응 확인후, 생성된 고체를 여과하고 EtOH로 세척하여 건조했다. 혼합물을 silica gel chromatography로 노란색 고체인 7-bromo-6-fluoro-2-methyl-2H-indazol-5-amine (30.0 g, 123 mmol, 89% 수율)을 얻었다.
단계 4: 2-((benzyloxy)imino)acetic acid (34.5 g, 193 mmol)을 DMF (245 mL)에 녹이고 HATU (54.9 g, 144 mmol), DIPEA (99.6 g, 770 mmol)과 7-bromo-6-fluoro-2-methyl-2H-indazol-5-amine (23.5 g, 96.3 mmol)을 적가했다. 반응 혼합액을 상온에서 2시간 동안 교반하고 차가운 정제수로 반응을 종결했다. Ethyl acetate(400 mL*2)로 유기층을 추출하고, 포화 NaCl 수용액으로 세척하여 무수 Na2SO4로 건조, 농축했다. petroleum ether/ EtOAc = 5: 1로 고체화하여 노란색 고체인 (E)-2-((benzyloxy)imino)-N-(7-bromo-6-fluoro-2-methyl-2H-indazol-5-yl)acetamide (35.5 g, 87.6 mmol, 91% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 407.0; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.10 (s, 1H), 8.54 (s, 1H), 8.12 (d, J = 7.2 Hz, 1H), 7.94 (s, 1H), 7.54 - 7.27 (m, 5H), 5.27 (s, 2H), 4.18 (s, 3H).
단계 5: (E)-2-((Benzyloxy)imino)-N-(7-bromo-6-fluoro-2-methyl-2H-indazol-5-yl)acetamide (34.0 g, 83.9 mmol)을 H2SO4 (680 mL)에 녹여 90 ℃에서 2시간 동안 교반했다. 반응 확인 후 냉각하여 차가운 정제수로 반응을 종결했다. Ethyl acetate (1.00 L*5)로 유기층을 추출하고 동결 건조했다. 이후 MeOH로 고체화하여 빨간색 고체인 4-bromo-5-fluoro-2-methyl-2,6-dihydropyrrolo[3,2-e]indazole-7,8-dione (11.0 g, 36.9 mmol, 44% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 320.1; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 11.42 (s, 1H), 8.63 (s, 1H), 4.18 (s, 3H).
단계 6: 4-bromo-5-fluoro-2-methyl-2,6-dihydropyrrolo[3,2-e]indazole-7,8-dione (10.5 g, 35.2 mmol)과 NaOH (14.1 g, 352 mmol)을 1,4-dioxane (200 mL)에 녹인다. 반응 혼합물에 H2O2 (20.5 g, 180 mmol)를 0 oC에서 적가하고 상온에서 1시간동안 교반했다. 반응 확인 후 Na2SO3 수용액(500 mL)으로 반응을 종결하고 감압 농축했다. 6 N HCl 수용액을 이용해 pH 4로 조정하고 생성된 노란색 고체를 여과하고 건조했다. 노란색 고체인 5-amino-7-bromo-6-fluoro-2-methyl-2H-indazole-4-carboxylic acid (8.80 g, 30.6 mmol, 86.7% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 287.9; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.26 (s, 1H), 4.09 (s, 3H).
단계 7: 5-Amino-7-bromo-6-fluoro-2-methyl-2H-indazole-4-carboxylic acid (9.00 g, 31.2 mmol)과 K2CO3 (8.64 g, 62.5 mmol)을 DMF (90.0 mL)에 녹이고 CH3I (5.10 g, 35.9 mmol)을 천천히 적가했다. 반응액을 상온에서 2시간 동안 교반했다. 반응 확인 후 NH4Cl 수용액 (500 mL)을 종결 하고 ethyl acetate (300 mL*3)로 유기층을 추출했다. 무수 Na2SO4로 건조, 농축하여 노란색 고체인 methyl 5-amino-7-bromo-6-fluoro-2-methyl-2H-indazole-4-carboxylate (10.0 g, 비정제혼합물)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 303.9; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.31 (s, 1H), 7.15 (s, 2H), 4.11 (s, 3H), 3.89 (s, 3H).
단계 8: Methyl 5-amino-7-bromo-6-fluoro-2-methyl-2H-indazole-4-carboxylate (9.70 g, 32.1 mmol)을 THF (100 mL)에 녹이고 2,2,2-trichloroacetyl isocyanate (12.1 g, 64.2 mmol)을 0 ℃에서 천천히 적가했다. 반응 혼합물을 상온에서 2시간 교반하고, 반응 확인 후 농축했다. 생성된 하얀색 고체를 NH3·H2O (91.0 g, 727 mmol)과 MeOH (100 mL)에 녹여 40 ℃에서 2시간 동안 교반했다. 반응액을 농축하고 MeOH (100 mL)로 고체화하여 노란색 고체인 4-bromo-5-fluoro-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-f]quinazoline-7,9(8H)-dione (9.10 g, 29.1 mmol, 90% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 314.8; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.72 (s, 1H), 4.19 (s, 3H).
단계 9: 4-bromo-5-fluoro-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-f]quinazoline-7,9(8H)-dione (8.10 g, 25.9 mmol)을 toluene (80.0 mL)에 녹이고 POCl3 (39.7 g, 259 mmol)과 DIPEA (7.36 g, 56.9 mmol)를 천천히 적가했다. 반응 혼합물을 115 ℃에서 40시간 동안 교반했다. 반응 확인 후 냉각하여 정제수로 반응을 ethyl acetate (500 mL*2)로 유기층을 추출했다. 추출한 유기층을 무수 Na2SO4로 건조, 농축하여 노란색 고체인 4-bromo-7,9-dichloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (9.00 g, 25.12 mmol, 97% 수율)를 얻었다. LCMS (ES-API, m/z): [M+H]+= 350.8; 1H NMR (400 MHz, CDCl3, ppm): δ 8.80 (s, 1H), 4.37 (s, 3H).
Intermediate 6: (1-(morpholinomethyl)cyclopropyl)methanol의 합성
Figure PCTKR2023020084-appb-img-000021
단계 1: 1-(Methoxycarbonyl)cyclopropane-1-carboxylic acid (1 g, 6.94 mmol)을 DCM (10 mL)에 녹인 후 oxalyl chloride (1.76 g, 13.88 mmol)와 DMF (50.72 mg, 694.00 μmol)를 0 oC에서 천천히 적가했다. 반응 혼합물은 상온에서 질소하에 3시간 동안 교반했다. methyl 1-(chlorocarbonyl)cyclopropane-1-carboxylate (1.1 g, 비정제혼합물)를 정제과정 없이 노란색 오일로 얻었다.
단계 2: 단계 1에서 얻은 methyl 1-(chlorocarbonyl)cyclopropane-1-carboxylate (1.1 g, 6.77 mmol)를 THF (22 mL)에 녹이고 TEA (1.37 g, 13.53 mmol)을 0 oC에서 적가했다. 그 후 morpholine (884.22 mg, 10.15 mmol)을 첨가 후 상온에서 16시간 동안 교반했다. 반응 종료 후 정제수를 첨가하여 ethyl acetate로 추출했다. Silica gel chromatography로 정제하여 methyl 1-(morpholine-4-carbonyl)cyclopropane-1-carboxylate (650 mg, 3.05 mmol, 45% 수율)을 노란색 오일로 얻었다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 3.74 (s, 3H), 3.71 - 3.63 (m, 6H), 3.53 - 3.49 (m, 2H), 1.53 - 1.48 (m, 2H), 1.36 - 1.32 (m, 2H).
단계 3: Methyl 1-(morpholine-4-carbonyl)cyclopropane-1-carboxylate (650 mg, 3.05 mmol)을 THF (13 mL)에 녹인 후 LAH (289.25 mg, 7.62 mmol)를 0 oC에서 적가하였다. 반응 혼합물은 상온에서 16시간 질소 하에서 교반하였다. 정제수를 천천히 넣어서 반응을 종료하고 포화 NaOH 수용액을 넣고 반응 혼합물을 여과 한 후 여액을 농축하였다. (1-(morpholinomethyl)cyclopropyl)methanol (520 mg, 비정제혼합물)를 노란색 오일로 얻었다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 3.75 - 3.69 (m, 4H), 3.58 - 3.52 (m, 2H), 2.75 - 2.53 (m, 4H), 2.51 - 2.43 (m, 2H), 0.55 - 0.49 (m, 2H), 0.40 - 0.34 (m, 2H).
Intermediate 7: (R) -(1-((3-methylmorpholino)methyl)cyclopropyl)methanol의 합성.
Figure PCTKR2023020084-appb-img-000022
(R)-3-methylmorpholine를 Intermediate 6과 동일한 방법으로 합성하여 (R)-(1-((3-methylmorpholino)methyl)cyclopropyl)methanol (843 mg, 70% 수율)을 무색의 오일로 얻었다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 0.18 - 0.25 (m, 1H), 0.26 - 0.34 (m, 1H), 0.47 - 0.54 (m, 1H), 0.73 (dt, J = 9.2, 4.8 Hz, 1H), 1.06 (d, J = 6.0 Hz, 3H), 1.76 - 1.85 (m, 1H), 2.25 - 2.32 (m, 1H), 2.41 - 2.51 (m, 1H), 3.12 (br d, J = 11.2 Hz, 1H), 3.19 - 3.40 (m, 3H), 3.59 - 3.74 (m, 3H), 3.80 (dt, J = 11.6, 3.2Hz, 1H), 3.96 (br d, J = 11.2Hz, 1H).
Intermediate 8: (1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methanol의 합성.
Figure PCTKR2023020084-appb-img-000023
1,1-difluoro-6-azaspiro[2.5]octane을 Intermediate 6과 동일한 방법으로 합성하여 (1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methanol (820 mg, 비정제혼합물)를 노란색 오일로 얻었다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 3.64 - 3.62 (m, 2H), 3.57 - 3.54 (m, 2H), 2.82 - 2.68 (m, 2H), 2.54 - 2.40 (m, 4H), 1.09 - 1.03 (m, 2H), 0.54 - 0.52 (m, 4H), 0.39 - 0.35 (m, 2H).
Intermediate 9: (1-(((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methanol의 합성.
Figure PCTKR2023020084-appb-img-000024
(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane를 Intermediate 6과 동일한 방법으로 합성하여 (1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methanol (470 mg, 비정제혼합물)을 노란색 오일로 얻었다. 1H NMR (400 MHz, CDCl3, ppm): δ 4.41 (s, 1H), 3.95 (d, J = 8.0 Hz, 1H), 3.69 - 3.80 (m, 2H), 3.64 (dd, J = 8.0, 1.6 Hz, 1H), 3.39 (d, J = 11.2 Hz, 1H), 3.06 (dd, J = 10.4, 1.6 Hz, 1H), 2.90 (d, J = 12.6 Hz, 1H), 2.55 - 2.64 (m, 2H), 1.73 - 1.82 (m, 2H), 0.51 - 0.60 (m, 1H), 0.41 - 0.49 (m, 2H), 0.25 - 0.35 (m, 1H).
Intermediate 10: ( R )-(1-((2-methylmorpholino)methyl)cyclopropyl)methanol의 합성.
Figure PCTKR2023020084-appb-img-000025
(R)-2-Methylmorpholine을 Intermediate 6과 동일한 방법으로 합성하여 (R)-(1-((2-methylmorpholino)methyl)cyclopropyl)methanol (760 mg, 비정제혼합물)를 노란색 오일로 얻었다. 1H NMR (400 MHz, CDCl3, ppm): δ 5.97 - 4.68 (m, 1H), 3.92 - 3.83 (m, 1H), 3.69 - 3.59 (m, 2H), 3.57 - 3.52 (m, 2H), 3.09 - 2.95 (m, 2H), 2.51 - 2.43 (m, 2H), 2.16 - 2.04 (m, 1H), 1.82 - 1.73 (m, 1H), 1.20 - 1.13 (m, 3H), 0.55 - 0.50 (m, 2H), 0.40 - 0.34 (m, 2H).
Intermediate 11: (1-(((1 S ,4 S )-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl) methanol의 합성.
Figure PCTKR2023020084-appb-img-000026
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane을 Intermediate 6과 동일한 방법으로 합성하여 (1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methanol (542 mg, 비정제혼합물)을 노란색 오일로 얻었다. LCMS (ES-API, m/z): [M+H]+= 200.2.
Intermediate 12: ( S )-(1-((3-fluoropiperidin-1-yl)methyl)cyclopropyl)methanol의 합성.
Figure PCTKR2023020084-appb-img-000027
(S)-3-fluoropiperidine을 Intermediate 6과 동일한 방법으로 합성하여 (S)-(1-((3-fluoropiperidin-1-yl)methyl)cyclopropyl)methanol (352 mg, 비정제혼합물)을 무색 오일로 얻었다. LCMS (ES-API, m/z): [M+H]+= 174.2; 1H NMR (400 MHz, CDCl3 , ppm): δ 5.52 - 4.95 (m, 1H), 4.77 - 4.56 (m, 1H), 3.63 (d, J = 11.2 Hz, 1H), 3.46 (d, J = 11.2 Hz, 1H), 2.90 - 2.64 (m, 2H), 2.58 (br d, J = 12.4 Hz, 2H), 2.51 - 2.36 (m, 2H), 1.94 - 1.75 (m, 2H), 1.73 - 1.66 (m, 1H), 1.55 (br dd, J = 3.6, 8.4 Hz, 1H), 0.60 - 0.48 (m, 2H), 0.40 - 0.31 (m, 2H).
Intermediate 13: (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanol의 합성.
Figure PCTKR2023020084-appb-img-000028
Pyrrolidine을 Intermediate 6과 동일한 방법으로 합성하여 (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanol (328 mg, 2.11 mmol, 67% 수율)를 노란색 오일로 얻었다. LCMS (ES-API, m/z): [M+H]+= 174.2; 1H NMR (400 MHz, CDCl3 , ppm): δ 6.25 - 5.82 (m, 1H), 3.56 (s, 2H), 2.65 - 2.58 (m, 6H), 1.77 (td, J = 3.2, 6.8 Hz, 4H), 0.52 - 0.47 (m, 2H), 0.40 - 0.34 (m, 2H).
Intermediate 14: ( R )-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol의 합성.
Figure PCTKR2023020084-appb-img-000029
(R)-3-Fluoropyrrolidine을 Intermediate 6과 동일한 방법으로 합성하여 (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol (837 mg, 비정제혼합물)을 무색의 오일로 얻었다. LCMS (ES-API, m/z): [M+H]+= 174.2; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 0.19 - 0.26 (m, 2 H), 0.33 - 0.43 (m, 2 H), 1.74 - 1.92 (m, 1 H), 1.99 - 2.19 (m, 1 H), 2.21 - 2.36 (m, 2 H), 2.39 - 2.45 (m, 1 H), 2.51 - 2.63 (m, 1 H), 2.73 - 2.90 (m, 2 H), 3.28 (br s, 1 H), 3.32 - 3.50 (m, 1 H), 4.47 (br s, 1 H), 5.01 - 5.29 (m, 1 H).
Intermediate 15: ( R )-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methanol의 합성.
Figure PCTKR2023020084-appb-img-000030
(R)-3-Fluoropyrrolidine을 Intermediate 6과 동일한 방법으로 합성하여 (R)-(1-((3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methanol (1.8 g, 비정제혼합물)을 노란색 고체로 얻었다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 5.82 - 4.99 (m, 2H), 3.80 (s, 2H), 3.03 - 2.66 (m, 5H), 2.59 - 2.47 (m, 1H), 2.18 - 1.92 (m, 3H), 1.90 - 1.77 (m, 5H).
Intermediate 16: ((2 S ,7a R )-2-fluoro-6-methylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methanol의 합성.
Figure PCTKR2023020084-appb-img-000031
단계 1: 1-(tert-Butyl) 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.5 g, 10.19 mmol)을 DCM (25 mL)에 녹인 후 imidazole (1.73 g, 25.48 mmol)을 넣고 0 oC에서 10분 동안 교반했다. 그 후 TBSCl (1.84 g, 12.23 mmol)을 천천히 넣어 주고 상온에서 12시간 교반했다. 반응을 종료한 후 silica gel chromatography로 정제하여 1-(tert-butyl) 2-methyl (2R,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (2.68 g, 7.31 mmol, 72% 수율)를 무색의 오일로 얻었다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 4.38 (br dd, J = 3.6, 8.4 Hz, 1H), 4.32 - 4.22 (m, 1H), 3.66 - 3.56 (m, 3H), 3.55 - 3.46 (m, 1H), 3.15 - 3.05 (m, 1H), 2.42 - 2.25 (m, 1H), 1.92 - 1.82 (m, 1H), 1.43 - 1.31 (m, 9H), 0.84 - 0.79 (m, 9H), 0.08 - 0.04 (m, 6H).
단계 2: 1-(tert-Butyl) 2-methyl (2R,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (2.18 g, 6.06 mmol)를 THF (21 mL)에 녹인 후 LiHMDS (1 M, 12.13 mL)를 -78 oC에서 질소 하에 첨가하였다. 반응 혼합물을 -78 oC에서 15분 동안 교반하였다. 그 후 3-chloro-2-(chloromethyl)prop-1-ene (1.89 g, 15.16 mmol)을 반응 혼합물에 넣고 상온에서 2시간 동안 교반하였다. 반응 종료 후 silica gel chromatography로 정제하여 1-(tert-butyl) 2-methyl (2R,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-1,2-dicarboxylate (2.62 g, 5.55 mmol, 91% 수율)을 노란색 오일로 얻었다. 1H NMR (400 MHz, CDCl3, ppm): δ 5.41 (d, J = 1.2 Hz, 1H), 5.16 - 5.06 (m, 1H), 4.49 - 4.20 (m, 1H), 4.14 - 4.00 (m, 2H), 3.78 - 3.69 (m, 3H), 3.69 - 3.53 (m, 1H), 3.37 - 3.01 (m, 2H), 2.83 - 2.60 (m, 1H), 2.36 - 2.17 (m, 1H), 2.16 - 2.06 (m, 1H), 1.50 - 1.39 (m, 9H), 0.91 - 0.83 (m, 9H), 0.09 - 0.00 (m, 6H).
단계 3: 1-(tert-butyl) 2-methyl (2R,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(2-(chloromethyl)allyl)pyrrolidine-1,2-dicarboxylate (4 g, 8.93 mmol)을 THF (40 mL)에 녹인 후 TBAF·3H2O (1 M, 10.71 mL)를 첨가하고 상온에서 12시간 교반했다. 반응 종료 후 silica gel chromatography로 반응 혼합물을 정제하였다. 1-(tert-butyl) 2-methyl (2R,4R)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.9 g, 7.82 mmol, 88% 수율)를 무색 오일로 얻었다. 1H NMR (400 MHz, CDCl3, ppm): δ 5.42 (s, 1H), 5.06 (s, 1H), 4.17 - 4.27 (m, 1H), 4.04 - 3.93 (m, 2H), 3.92 - 3.73 (m, 4H), 3.57 (d, J = 10.8 Hz, 1H), 3.44 - 3.24 (m, 2H), 2.60 (t, J = 13.6 Hz, 1H), 2.53 - 2.37 (m, 1H), 2.15 - 2.03 (m, 2H), 1.47 (s, 9H).
단계 4: 1-(tert-Butyl) 2-methyl (2R,4R)-2-(2-(chloromethyl)allyl)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.9 g, 8.69 mmol)를 DCM (30 mL)에 녹인 후 BAST (2.88 g, 13.03 mmol, 2.85 mL)를 -78 oC에서 천천히 적가했다. 반응 혼합물은 상온에서 12시간 동안 교반했다. 반응 종료 후 silica gel chromatography로 반응 혼합물을 정제하였다. 1-(tert-butyl) 2-methyl (2R,4S)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylate (1.82 g, 4.88 mmol, 56% 수율)를 옅은 노랑색 오일로 얻었다. 1H NMR (400 MHz, CDCl3, ppm): δ 5.45 - 5.32 (m, 1H), 5.30 - 5.05 (m, 2H), 4.18 - 4.11 (m, 2H), 4.07 - 3.74 (m, 2H), 3.74 - 3.64 (m, 3H), 3.38 - 3.15 (m, 1H), 2.85 (d, J = 14.4 Hz, 1H), 2.67 - 2.23 (m, 2H), 1.46 (s, 9H).
단계 5: 1-(tert-Butyl) 2-methyl (2R,4S)-2-(2-(chloromethyl)allyl)-4-fluoropyrrolidine-1,2-dicarboxylate (1.8 g, 5.36 mmol)를 DCM (15 mL)에 녹인 후 TFA (7.68 g, 67.31 mmol, 5 mL)를 0 oC에서 천천히 적가했다. 반응 혼합물은 상온에서 2시간 동안 교반했다. 출발물질이 사라진 것을 확인 후 7M NH4 in MeOH을 첨가하였다. 물을 넣어 반응을 종료한 후 DCM으로 추출하였다. Silicagel chromatography로 화합물을 정제하여 methyl (2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (950 mg, 4.29 mmol, 80% 수율)을 옅은 노란색 오일로 얻었다. LCMS (ES-API, m/z): [M+H]+= 236.0; 1H NMR (400 MHz, CDCl3, ppm): δ 5.38 - 5.13 (m, 1H), 4.94 (dt, J = 14.8, 2.0 Hz, 2H), 3.89 (br d, J = 13.6 Hz, 1H), 3.73 (s, 3H), 3.56 (br d, J = 14.0 Hz, 1H), 3.46 - 3.27 (m, 1H), 3.22 - 3.00 (m, 2H), 2.76 (br d, J = 16.0 Hz, 1H), 2.64 - 2.54 (m, 1H), 2.38 - 2.21 (m, 1H).
단계 6: Methyl (2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (940 mg, 4.72 mmol)을 THF (10 mL)에 녹인 후 LAH (2.5 M, 1.89 mL)를 0 oC에서 질소 하에 첨가하고 상온에서 2시간 교반하였다. 출발 물질이 소모되면 물과 15% aqueous NaOH로 반응을 종료했다. ((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (720 mg, 3.78 mmol, 80% 수율)를 흰색 오일로 얻었다. 1H NMR (400 MHz, CDCl3, ppm): δ 5.33 - 5.10 (m, 1 H), 4.97 - 4.85 (m, 2 H), 3.72 (br d, J = 14.0 Hz, 1 H), 3.53 (br d, J = 14.0 Hz, 1 H), 3.34 - 3.02 (m, 4 H), 2.68 (br d, J = 15.6 Hz, 1 H), 2.36 (dt, J = 15.6, 1.60 Hz, 1 H), 2.25 - 2.18 (m, 1 H), 2.17 - 2.02 (m, 2 H).
Intermediate 17: ((5 S ,7a S )-5-(methoxymethyl)-2-methylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methanol의 합성.
Figure PCTKR2023020084-appb-img-000032
단계 1,2: 1-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (40 g, 164.44 mmol)을 DCM (600 mL)에 녹인 후 DIBAL-H (1 M, 500 mL)을 -68 ℃에서 한방울씩 천천히 적가하고 30분 동안 교반했다. 그 이후 상온에서 2시간 동안 더 반응했다. 0 ℃에서 질소 하에 MeOH (200 mL)과 HCl 용액(2 M, 180 mL)을 넣고 20 oC에서 2 시간 동안 교반하였다. 반응 종료 후 반응 혼합물에 10% potassium sodium tartrate (500 mL)를 넣어 반응을 종결하고 ethyl acetae를 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. 반응 잔여물은 silica gel chromatography로 분리하여 tert-butyl (2S)-2-(hydroxymethyl)-5-methoxypyrrolidine-1-carboxylate (19 g, 82.15 mmol, 50% 수율)을 무색 오일로 얻었다. 1H NMR (400 MHz, CDCl3, ppm): δ 5.17 (brs, 1H), 4.03 - 4.06 (m, 1H), 3.75 - 3.77 (m, 1H), 3.52 - 3.56 (m, 1H), 3.48 (s, 1H), 3.33 (s, 3H), 1.77 - 2.05 (m, 5H), 1.49 (s, 9H).
단계 3: NaH (6.58 g, 164.44 mmol)를 DMF (190 mL)에 녹인 용액을 0 oC에서 tert-butyl (2S)-2-(hydroxymethyl)-5-methoxypyrrolidine-1-carboxylate (19 g, 82.15 mmol)에 넣은 후 15분 동안 교반하였다. 그런 다음 MeI (23.32 g, 164.30 mmol, 10.23 mL)를 0 oC에서 추가하고 20 oC에서 2시간 동안 교반하였다. 반응 종료 후 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetae를 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. silica gel chromatography로 정제하여 tert-butyl (5S)-2-methoxy-5-(methoxymethyl)pyrrolidine-1-carboxylate (10.7 g, 43.62 mmol, 53% 수율)를 노란색 오일로 얻었다. 1H NMR (400 MHz, CDCl3, ppm): δ 5.21 (brs, 1H), 3.97 (brs, 1H), 3.75 (brs, 1H), 3.38 (s, 3H), 3.30 (s, 3H), 2.07 - 2.18 (m, 1H), 1.71 - 2.01 (m, 3H), 1.49 (s, 9H).
단계 4: tert-Butyl (5S)-2-methoxy-5-(methoxymethyl)pyrrolidine-1-carboxylate (10.7 g, 43.62 mmol)을 DCM (100 mL)에 녹인 후 TMSOTf (969.44 mg, 4.36 mmol)를 0 oC에서 적가하고 15분간 교반 한 후 TMSCN (6.49 g, 65.43 mmol, 8.19 mL)을 천천히 적가 하고 0 ℃에서 2시간 동안 반응하였다. 반응 종료 후 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetae를 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. silica gel chromatography로 정제하여 tert-butyl (5S)-2-cyano-5-(methoxymethyl)pyrrolidine-1-carboxylate (6.3 g, 26.22 mmol, 60% 수율)을 노란색 오일로 얻었다. 1H NMR (400 MHz, CDCl3, ppm): δ 4.39 - 4.59 (m, 1H), 3.89 - 4.10 (m, 1H), 3.55 - 3.63 (m, 0.5H), 3.41 - 3.52 (m, 1.3H), 3.39 (s, 1.4H), 3.33 (s, 1.5H), 2.04 - 2.17 (m, 4H), 1.51 (s, 9H).
단계 5: tert-butyl (5S)-2-cyano-5-(methoxymethyl)pyrrolidine-1-carboxylate (3 g, 12.48 mmol)를 HCl/MeOH (2 M, 30.00 mL)에 넣고 20 oC에서 12시간 동안 반응했다. 반응 종료 후 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. 용매 제거 후 methyl (5S)-5-(methoxymethyl)pyrrolidine-2-carboxylate (1.5 g, 8.66 mmol, 69% 수율)을 노란색 오일로 얻었다. 1H NMR (400 MHz, CDCl3, ppm): δ 3.72 - 3.85 (m, 1H), 3.72 (s, 3H), 3.37 - 3.38 (m, 1H), 3.35 (s, 3H), 3.29 - 3.33 (m, 1H), 2.01 - 2.19 (m, 2H), 1.86 - 1.91 (m, 2H), 1.47 - 1.53 (m, 1H).
단계 6: Methyl (5S)-5-(methoxymethyl)pyrrolidine-2-carboxylate (1.5 g, 8.66 mmol) 와 Boc2O (1.89 g, 8.66 mmol)을 MeOH (30 mL)에 녹인 후 20 ℃에서 12시간 반응하였다. 반응 종료 후 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. 정제하여 1-(tert-butyl) 2-methyl (5S)-5-(methoxymethyl)pyrrolidine-1,2-dicarboxylate(2 g, 7.32 mmol, 84% 수율)을 노란색 오일로 얻었다. 1H NMR (400 MHz, CDCl3, ppm): δ 4.30 - 4.33 (m, 0.7H), 4.25 - 4.27 (s, 1H), 3.71 - 3.73 (m, 3H), 3.38 - 3.43 (m, 1H), 3.35 (d, J = 12Hz, 3H), 3.29 - 3.34 (m, 0.5H), 1.88 - 2.02 (m, 4H), 1.40 - 1.47 (m, 9H).
단계 7: 1-(tert-Butyl) 2-methyl (5S)-5-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (2.4 g, 8.78 mmol)을 THF (24 mL)에 녹인 후 LiHMDS (1 M, 17.56 mL)을 -68 oC에서 0.5시간 동안 교반하였다. (2.2 g, 17.56 mmol, 2.04 mL)을 반응에 넣고 상온에서 12시간 반응하였다. 반응 종료 후 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. 정제하여 1-(tert-butyl) 2-methyl (5S)-2-(2-(chloromethyl)allyl)-5-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (1.2 g, 2.95 mmol, 34% 수율)을 노란색 오일로 얻었다. 1H NMR (400 MHz, CDCl3, ppm): δ 5.34 - 5.43 (m, 1H), 5.05 - 5.12 (m, 1H), 4.01 - 4.11 (m, 3.4H), 3.73 (s, 3H), 3.37 (s, 3H), 3.27 - 3.35 (m, 2H), 3.11 - 3.25 (m, 1H), 2.62 - 2.77 (m, 1H) , 1.81 - 2.28 (m, 4H) , 1.40 - 1.52 (m, 9H).
단계 8: 1-(tert-Butyl) 2-methyl (5S)-2-(2-(chloromethyl)allyl)-5-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (600 mg, 1.66 mmol)을 DCM (6 mL)에 녹인 후 TFA (2.4 mL)를 0 ℃첨가하고 상온에서 2시간 동안 반응하였다. 반응 종료 후 농축하여 methyl (5S)-2-(2-(chloromethyl)allyl)-5-(methoxymethyl)pyrrolidine-2-carboxylate (434 mg, 비정제혼합물)을 갈색 오일로 얻었다. LCMS (ES-API, m/z): [M+H]+= 490.2.
단계 9: Methyl (5S)-2-(2-(chloromethyl)allyl)-5-(methoxymethyl)pyrrolidine-2-carboxylate (434 mg, 1.66 mmol)와 K2CO3 (458.32 mg, 3.32 mmol)를 MeOH (6 mL)에 녹인 후 상온에서 3시간 동안 교반하였다. 반응 종료 후 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetae를 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. 정제하여 methyl (5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (180 mg, 798.99 μmol, 48% 수율)을 노란색 오일로 얻었다. LCMS (ES-API, m/z): [M+H]+= 226.0; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 4.88 (br d, J = 10.4 Hz, 2H), 3.58 (s, 3H), 3.53 (br d, J = 14.8 Hz, 1H), 3.31 - 3.28 (m, 1H), 3.27 - 3.24 (m, 1H), 3.23 (s, 3H), 3.21 - 3.16 (m, 1H), 2.78 (s, 2H), 2.39 (br dd, J = 1.2, 16.0 Hz, 1H), 2.32 - 2.24 (m, 1H), 1.99 - 1.88 (m, 1H), 1.76 - 1.66 (m, 1H), 1.44 (br d, J = 9.2 Hz, 1H).
단계 10: Methyl (5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (234 mg, 1.04 mmol)을 THF (2.5 mL)에 녹인 후 LiAlH4 (2.5 M, 415.48 μL)을 0 ℃에서 첨가하고 상온에서 1시간 동안 교반했다. 반응 종료 후 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. 용매 제거 후 ((5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (190 mg, 963.13 μmol, 93% 수율)을 노란색 오일로 얻었다.
Intermediate 18: 6-fluoro-4-methyl-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000033
단계 1: 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (2.5 g, 6.97 mmol)을 DCM (17.5 mL)에 녹인 후 diethylamine (3.60 g, 27.89 mmol)과 Tf2O (4.13 g, 14.64 mmol)를 0 ℃에서 적가했다. 반응 혼합물을 질소 하에 0 ℃에서 3시간 동안 교반했다. 정제수를 넣어 반응을 종료한 후 DCM으로 반응 혼합물을 추출했다. Silica gel chromatography 정제하여 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diyl bis(trifluoromethanesulfonate (3.95 g, 6.34 mmol, 91 % 수율)를 노란색 고체로 얻었다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.55 (d, J = 2.4 Hz, 1H), 8.42 - 8.33 (m, 1H), 8.16 - 8.08 (m, 1H), 7.91 - 7.82 (m, 1H), 1.20 - 1.16 (m, 3H), 1.15 - 1.07 (m, 18H).
단계 2: 단계 1에서 얻은 7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diyl bis(trifluoromethanesulfonate (4.6 g, 7.39 mmol)와 diphenylmethaneimine (1.34 g, 7.39 mmol, 1.24 mLPd2(dba)3 (1.35 g, 1.48 mmol), Xantphos (1.71 g, 2.96 mmol), Cs2CO3 (7.22 g, 22.16 mmol)를 toluene (46 mL)에 녹인 후 질소로 3회 퍼지했다. 그 후 질소 하에서 100 ℃로 12시간 교반했다. 반응 종료 후 정제수를 넣고, ethyl acetate로 여러 번 추출했다. Silica gel chromatography을 하여 3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (3.5 g, 5.35 mmol, 72% 수율)을 갈색 고체로 얻었다. 1H NMR (400 MHz, DMSO-d 6, ppm): δ 7.96 - 7.90 (m, 1H), 7.75 - 7.67 (m, 3H), 7.54 (br s, 4H), 7.41 - 7.39 (m, 1H), 7.32 - 7.28 (m, 3H), 7.23 - 7.19 (m, 2H), 1.13 (br s, 21H).
단계 3: 단계 2에서 얻은 3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (3 g, 4.59 mmol)을 THF (30 mL)에 녹인 후 HCl (1 M, 30.00 mL)을 적가했다. 반응 혼합물을 상온에서 2시간 교반했다. 반응 종결 후 silica gel chromatography로 정제하여 3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (1.78 g, 3.35 mmol, 73 % 수율)를 얻었다. LCMS (ES-API, m/z): [M+H]+= 490.2; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 7.81 - 7.72 (m, 1H), 7.45 - 7.34 (m, 1H), 7.23 - 7.15 (m, 1H), 7.05 - 6.96 (m, 1H), 6.01 - 5.90 (m, 2H), 1.18 - 1.08 (m, 21H).
단계 4: 단계 3에서 얻은 3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (800 mg, 1.63 mmol)를 BPD (829.87 mg, 3.27 mmol), potassium acetate (320.72 mg, 3.27 mmol), Pd(dppf)Cl2 (119.56 mg, 163.40 μmol)과 함께 toluene에 녹인다. 그 후 질소 퍼지를 3회 하였다. 반응 혼합물을 질소 하에서 110 ℃, 12시간 교반했다. Silica gel chromatography 정제 후에 6-fluoro-4-methyl-5-((triisopropylsilyl)ethynyl)naphthalen-2-amine (360 mg, 671.26 μmol, 41% 수율)를 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 468.5; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 7.63 (dd, J = 6.0, 9.0 Hz, 1H), 7.33 - 7.24 (m, 1H), 7.23 - 7.19 (m, 1H), 6.91 - 6.85 (m, 1H), 5.54 - 5.44 (m, 2H), 1.36 - 1.29 (m, 12H), 1.13 - 1.07 (m, 21H).
Intermediate 19: (2-(( tert -butoxycarbonyl)amino)-7-fluorobenzo[ b ]thiophen-4-yl)boronic acid의 합성.
Figure PCTKR2023020084-appb-img-000034
단계 1: 4-Bromo-7-fluorobenzo[d]thiazol-2-amine (450 mg, 1.82 mmol)을 THF (9 mL) 에 녹인 후 Boc2O (476.97 mg, 2.19 mmol), diethylamine (353.07 mg, 2.73 mmol), DMAP (4.45 mg, 36.42 μmol)을 넣고 질소로 3회 퍼지하였다. 반응 혼합물을 2시간 동안 교반한 후, 농축하고 silica gel chromatography로 정제하여 tert-butyl (4-bromo-7-fluorobenzo[d]thiazol-2-yl)carbamate (500 mg, 1.40 mmol, 77% 수율)를 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 313.2; 1H NMR (400 MHz, CDCl3, ppm): δ 8.99 - 8.52 (m, 1H), 7.55 (dd, J = 4.8, 8.6 Hz, 1H), 6.91 (t, J = 8.6 Hz, 1H), 1.56 (s, 8H), 1.50 - 1.47 (m, 1H).
단계 2: 단계 1에서 얻은 화합물 tert-butyl (4-bromo-7-fluorobenzo[d]thiazol-2-yl)carbamate (250 mg, 720.04 μmol)를 THF (2 mL)에 녹인 후 n-BuLi (2.5 M in THF, 351.38 μL)을 -15 oC 에서 적가 하고 30분 동안 교반했다. Triisopropyl borate (338.55 mg, 1.80 mmol)를 -65 ℃에 넣고 30분 동안 교반한 다음 MeLi (1.6 M, 540.03 μL)을 -65 ℃에서 넣고 질소 퍼지 3회하였다. 반응 혼합물을 질소 하에서 0 oC, 한 시간 동안 반응했다. 반응 종결 후 NH4Cl 용액과 ethyl acetate를 첨가하여 화합물을 추출했다. Na2SO4을 넣어 물을 건조하고 감압하여 용매를 제거하여 (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[b]thiophen-4-yl)boronic acid (220 mg, 비정제혼합물)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 256.9; 1H NMR (400 MHz, CDCl3, ppm): δ 7.94 (dd, J = 6.0, 8.1 Hz, 1H), 7.06 (dd, J = 8.1, 9.5 Hz, 1H), 1.68 (s, 9H).
Intermediate 20: tert- butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[ d ]thiazol-2-yl)carbamate의 합성.
Figure PCTKR2023020084-appb-img-000035
단계 1: 4-Bromobenzo[d]thiazol-2-amine (1g, 4.36 mmol)을 THF (4 mL)와 DCM (6 mL)에 녹인 후, 0 ℃로 온도를 낮추었다. 0 ℃에서 di-tert-butyl dicarbonate (1.1 mL, 4.8 mmol), TEA (1.16 mL, 8.73 mmol), DMAP (53.3 mg, 436 μmol)을 넣고 2시간 동안 교반했다. 출발 물질이 완전히 소모된 후, 물을 넣어 반응을 종결하고유기층을 ethyl acetate로 추출하였다. 무수 Na2SO4으로 건조한 후, 여과하고 농축하였다. 잔류물을 silica gel chromatography (10% ethyl acetate/hexane)로 정제하여 tert-butyl (4-bromobenzo[d]thiazol-2-yl)carbamate (1.2 g, 3.65 mmol, 84% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 330.2.
단계 2: 단계 1에서 얻은 tert-butyl (4-bromobenzo[d]thiazol-2-yl)carbamate (1.2 g, 3.65 mmol) 을 1,4-dioxane (10 mL)에 녹인 후, Potassium acetate (1.07 g, 10.9 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.85 g, 7.29 mmol), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)·DCM complex (267 mg, 365 μmol)을 넣고 100 ℃로 온도를 올려서 24시간 동안 교반했다. 반응 종료 후, 상온으로 반응 온도를 낮추었다. Celite filter 로 팔라듐 촉매를 제거한 후, 유기층을 ethyl acetate로 추출하였다. 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatgraphy (10% ethyl acetate/hexane)로 정제하여 tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)carbamate (1.2 g, 3.19 mmol, 88% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 376.7.
Intermediate 21: (6-methyl-1-(tetrahydro-2 H -pyran-2-yl)-5-(trifluoromethyl)-1 H -indazol-4-yl)boronic acid의 합성.
Figure PCTKR2023020084-appb-img-000036
단계 1:　1-Bromo-5-fluoro-2-iodo-3-methylbenzene (3 g, 9.53 mmol)을　DMF (60 mL)에 녹인 후　CuI (10.89 g, 57.16 mmol)　와　methyl 2,2-difluoro-2-fluorosulfonyl-acetate (10.98 g, 57.16 mmol, 7.27 mL)를 첨가했다. 반응 혼합물을 60 ℃에서 12시간 교반했다. 반응 종료 후, 반응 혼합물에 정제수 (60 mL)를 적가하고 ethyl acetate (60 mL*3)를 가하여 유기층을 추출하고, 포화 NaCl 수용액 (150 mL*2)으로 씻어 준 뒤, 무수 MgSO4로 건조하였다. 얻어진 반응 잔여물을 silica gel chromatography로 정제하여 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (1.1 g, 4.28 mmol, 45% 수율)를 얻었다. 1H NMR (400 MHz, CDCl3, ppm): δ 7.33 (dd, J = 2.4, 7.6 Hz, 1H), 6.95 (dd, J = 2.4, 8.8 Hz, 1H), 2.54 (q, J = 3.6 Hz, 3H).
단계 2: 　1-Bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (1.7 g, 6.61 mmol)를 THF (34 mL)에 녹인 후　LDA (2 M, 6.61 mL)를 질소 하, -60 oC 에서 천천히 적가 하고 30분 동안 교반했다. 반응 혼합물에 DMF (1.45 g, 19.84 mmol, 1.53 mL)를 적가하고　-60 oC　에서 1.5시간 동안 교반했다.　반응 종료 후, 반응 혼합물에 포화 NH4Cl 수용액(40 mL)을 적가하고 ethyl acetate (40 mL*3)를 가하여 유기층을 추출하고, 포화 NaCl 수용액 (100 mL*2)으로 씻어 준 뒤, 무수 MgSO4로 건조하였다. 얻어진 반응 잔여물은 silica gel chromatography로 정제하여 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (860 mg, 3.02 mmol, 46% 수율)을 노란색 오일로 얻었다.　1H NMR (400 MHz, CDCl3, ppm): δ 10.35 (s, 1H), 7.08 (d, J = 10.5 Hz, 1H), 2.61 (q, J = 4.0 Hz, 3H).
단계 3: 2-Bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (860 mg, 3.02 mmol)과 NH2NH2·H2O (4.43 g, 86.72 mmol, 4.29 mL)을 DMSO (9 mL)에 녹인 후질소 퍼지를 3회 수행하였다. 반응 혼합물을 60 ℃에서 2시간 반응했다. 반응 종료 후, 반응 혼합물에 정제수 (20 mL)를 적가하고 ethyl acetate (20 mL*3)를 가하여 유기층을 추출하고, 포화 NaCl 수용액 (30 mL*2)으로 씻어 준 뒤, 무수 MgSO4로 건조하였다. 얻어진 반응 잔여물을 silica gel chromatography로 정제하여 4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (618 mg, 2.21 mmol, 73% 수율)를 노란색 오일로 얻었다. LCMS (ES-API, m/z): [M+H]+= 278.9; 1H NMR (400 MHz, CDCl3, ppm): δ 8.20 (s, 1H), 7.34 (s, 1H), 2.66 (q, J = 3.2 Hz, 3H).
단계 4: 4-Bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (618 mg, 2.21 mmol)를 DCM (12 mL)에 녹인 후 TsOH·H2O (42.13 mg, 221.46 μmol)을 넣고 순차적으로 acetonitrile (3 ml)에 DHP (745.14 mg, 8.86 mmol)에 녹인 용액을 넣어 주고 상온에서 16시간 교반했다. 반응 종료 후, 반응 혼합물에 정제수 (60 mL)를 적가하고 ethyl acetate (20mL*3)를 가하여 유기층을 추출하고, 포화 NaCl 수용액 (30 mL*2)으로 씻어 준 뒤, 무수 MgSO4로 건조하였다. 얻어진 반응 잔여물을 silica gel chromatography로 정제하여 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole (800 mg, 2.20 mmol, 99% 수율)를 옅은 노란색 오일로 얻었다. 1H NMR (400 MHz, CDCl3, ppm): δ 8.11 (s, 1H), 7.43 (s, 1H), 5.69 (dd, J = 2.8, 8.8 Hz, 1H), 4.05 - 3.96 (m, 1H), 3.81 - 3.70 (m, 1H), 2.67 (q, J = 3.2 Hz, 3H), 2.57 - 2.46 (m, 1H), 2.23 - 2.12 (m, 1H), 1.78 - 1.67 (m, 3H), 1.59 - 1.54 (m, 1H).
단계 5: Hypoboric acid (185.14 mg, 2.07 mmol),　4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole (250 mg, 688.38 μmol),　cataCXium Pd G4(50.20 mg, 68.84 μmol)　을 MeOH (3 mL)에 녹인 후 DIEA (266.90 mg, 2.07 mmol)를 질소 하에서 천천히 적가했다. 질소로 디게싱을 10분간 한 후 60 ℃에서 40분 동안 교반했다. 반응 종료 후 감압 하에 용매를 제거하고 (6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (210 mg, 비정제혼합물)을 검은색 고체로 얻었다.　 LCMS (ES-API, m/z): [M+H]+ = 245.1.
Intermediate 22: (5-chloro-3,6-dimethyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -indazol-4-yl)boronic acid의 합성.
Figure PCTKR2023020084-appb-img-000037
단계 1: 4-Bromo-5-chloro-6-methyl-1H-indazole (2 g, 8.15 mmol)을 MeOH (25 mL)에 녹인 후 NaOH (4 M, 13.24 mL), I2 (2.48 g, 9.78 mmol, 1.97 mL)를 0 ℃에서 적가했다. 상온에서 2시간 동안 질소 하에 교반했다. 반응 종료 후, 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. Silica gel chromatography로 정제하여 4-bromo-5-chloro-3-iodo-6-methyl-1H-indazole (2.9 g, 7.73 mmol, 95% 수율)를 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 372.8; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 14.24 - 13.32 (m, 1H), 7.60 (s, 1H), 2.50 (s, 3H).
단계 2: 4-Bromo-5-chloro-3-iodo-6-methyl-1H-indazole (200 mg, 538.50 μmol), p-TsOH (4.64 mg, 26.93 μmol), DHP (90.59 mg, 1.08 mmol)를 DCM (2.5 mL)에 녹인 후 디게싱과 질소 퍼지를 3회 한 다음 상온에서 질소 하에 2시간 교반하였다. 반응 종료 후, 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4으로 건조하였다. Ethyl acetate로 trituration을 하여 4-bromo-5-chloro-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (120 mg, 252.90 μmol, 47% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 454.9; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 7.88 (d, J = 0.6 Hz, 1H), 5.83 (dd, J = 2.5, 9.8 Hz, 1H), 3.93 - 3.82 (m, 1H), 3.74 (td, J = 6.9, 11.5 Hz, 1H), 2.54 (s, 3H), 2.41 - 2.21 (m, 1H), 2.10 - 1.90 (m, 2H), 1.81 - 1.64 (m, 1H), 1.64 - 1.49 (m, 2H).
단계 3: 4-Bromo-5-chloro-3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1 g, 2.20 mmol), Pd(dppf)Cl2·CH2Cl2 (89.64 mg, 109.77 μmol)을 DMF (10 mL)에 녹인 후 dimethylzinc (1 M, 5.49 mL)을 질소 하에 첨가하고 80 ℃에서 12시간 교반하였다.　반응 종료 후 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4으로 건조하였다. 반응 잔류물은 silica gel chromatography를 이용하여 정제하여 4-bromo-5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (320 mg, 931.19 μmol, 42% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 260.8; 1H NMR (400 MHz, CDCl3 , ppm): δ 7.34 (s, 1H), 5.55 (dd, J = 2.4, 9.6 Hz, 1H), 4.10 - 3.99 (m, 1H), 3.73 (dt, J = 2.4, 11.2 Hz, 1H), 2.74 (s, 3H), 2.55 (s, 3H), 2.54 - 2.46 (m, 1H), 2.20 - 2.10 (m, 1H), 2.01 (br dd, J = 3.2, 12.8 Hz, 1H), 1.82 - 1.70 (m, 2H), 1.69 - 1.62 (m, 1H).
단계 4: 4-bromo-5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (320 mg, 651.83 μmol), hypoboric acid (175.31 mg, 1.96 mmol),　DIEA (252.73 mg, 1.96 mmol),　cataCXium Pd G4 (47.54 mg, 65.18 μmol)를　MeOH (4 mL)에 녹인 후 디게싱을 하고 질소퍼지를 3번 해준 후 60 ℃에서 40분간 교반하였다. 반응 종료 후 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4으로 건조하였다. 반응 잔류물은 silica gel chromatography로 정제하여 (5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (200 mg, 582.04 μmol, 89% 수율)을 검은색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 309.0; 1H NMR (400 MHz, CDCl3 , ppm): δ 7.36 (s, 1H), 5.55 (dd, J = 2.4, 9.7 Hz, 1H), 5.33 - 5.12 (m, 1H), 4.09 - 4.02 (m, 1H), 3.77 - 3.72 (m, 1H), 3.70 (s, 1H), 2.53 (s, 3H), 2.50 - 2.49 (m, 3H), 2.18 - 2.10 (m, 1H), 2.01 (br d, J = 13.2 Hz, 2H), 1.81 - 1.71 (m, 3H).
Intermediate 23: N , N -bis(4-methoxybenzyl)-4-methyl-6-(tributylstannyl)-5-(trifluoromethyl)pyridin-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000038
단계 1: 6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (110.67 mg, 190.78 μmol)과 Su2Bu6 (110.67 mg, 190.78 μmol)을 1,4-dioxane (1 mL)에 녹인 후 Pd2(dba)3 (5.55 mg, 6.06 μmol) , tricyclohexylphosphane (3.40 mg, 12.11 μmol), LiCl (12.84 mg, 302.83 μmol)을 첨가했다. 반응 혼합물을 110 ℃에서 16시간 동안 교반했다. 반응 종료 후 silica gel chloromatography 정제하여 N,N-bis(4-methoxybenzyl)-4-methyl-6-(tributylstannyl)-5-(trifluoromethyl)pyridin-2-amine (25 mg, 32.25 μmol, 53.24% 수율)를 무색 오일로 얻었다. LCMS (ES-API, m/z): [M+H]+= 705.2; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 0.76 (t, J = 7.2 Hz, 9H), 0.87 (br t, J = 7.2 Hz, 2H), 0.96 - 1.03 (m, 5H), 1.14 - 1.22 (m, 6H), 1.39 - 1.47 (m, 5H), 2.24 (s, 3H), 3.71 (s, 6H), 4.72 (br s, 4H), 6.48 (s, 1H), 6.86 (d, J = 8.4 Hz, 4H), 7.12 (d, J = 8.4 Hz, 4H).
Intermediate 24: N , N -bis(4-methoxybenzyl)-6-(tributylstannyl)-5-(trifluoromethyl)pyridin-2-amine 의 합성.
Figure PCTKR2023020084-appb-img-000039
단계 1: 6-Bromo-5-(trifluoromethyl)pyridin-2-amine (700 mg, 2.9 mmol)을 DMF (10 mL)에 녹인 후, 0 oC로 온도를 낮추었다. 0 oC에서 Sodium hydride (290 mg, 7.26 mmol)를 넣고 30분 동안 교반하였다. 30분 후, 4-methoxybenzyl chloride (1.07 mL, 7.26 mmol)를 반응 혼합물에 넣어준 후, 상온에서 4시간 교반하였다. 반응 종료 후, 0 oC로 온도를 낮추고 천천히 물을 넣어 반응을 종결 시킨 후, 유기층을 ethyl acetate로 추출하였다. 무수 MgSO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography으로 정제하여 6-bromo-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2-amine (1.1 g, 2.29 mmol, 79% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 481.3.
단계 2: 단계 1에서 얻은 6-bromo-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-2-amine (1.1 g, 2.29 mmol) 을 1,4-dioxane (10 mL)에 녹인 후, tricyclohexylphosphane (128 mg, 457 μmol), bis(tributylstannane) (3.48 mL, 6.86 mmol), Tris(dibenzylideneacetone)dipalladium(0) (209 mg, 229 μmol), Lithium chloride (484 mg, 11.4 mmol)을 넣고 110 oC로 온도를 올려 5시간 동안 교반했다. 반응 종료 후, 상온으로 온도를 낮추었다. Celite filter 로 팔라듐 촉매를 제거한 후, 유기층을 ethyl acetate로 추출하였다. 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography로 정제하여 N,N-bis(4-methoxybenzyl)-6-(tributylstannyl)-5-(trifluoromethyl)pyridin-2-amine (160 mg, 231 mmol, 10% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 692.5.
Intermediate 25: N , N -bis(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000040
단계 1: 3-Bromo-4-(trifluoromethyl)aniline (500 mg, 2.08 mmol)을 DMF (10 mL)에 녹인 후, 0 oC로 온도를 낮추었다. 0 oC에서 NaH (416 mg, 10.41 mmol)를 넣고 30분 동안 교반했다. 30분 후, 4-methoxybenzyl chloride (1.4 mL, 10.41 mmol)를 반응 혼합물에 넣어준 후, 상온에서 24시간 교반했다. 반응 종료 후, 0 oC로 반응 온도를 낮추고 천천히 물을 넣어 반응을 종결 시킨 후, 유기층을 ethyl acetate로 추출하였다. 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography (5% ethyl acetate/hexane)로 정제하여 3-bromo-N,N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline (816 mg, 1.7 mmol, 85% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 481.3.
단계 2: 단계 1 에서 얻은 3-bromo-N,N-bis(4-methoxybenzyl)-4-(trifluoromethyl)aniline (160 mg, 333 μmol) 을 1,4-dioxane (2 mL)에 녹인 후, potassium acetate (98.1 mg, 999 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (102 mg, 400 μmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (24.4 mg, 33.3 μmol)을 넣고 90 oC로 온도를 올려서 24시간 동안 교반했다. 출발 물질이 완전히 소모된 후, 상온으로 반응 온도를 낮추었다. Celite filter 로 팔라듐 촉매를 제거한 후, 유기층을 ethyl acetate로 추출하였다. 무수 MgSO4으로 건조한 후, 감압하에 농축하였다. 잔류물을 silica gel chromatography로 정제하여 N,N-bis(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (175 mg, 333 mmol, 100% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 528.4
Intermediate 26: 2,3,4,5-tetrafluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline의 합성.
Figure PCTKR2023020084-appb-img-000041
단계 1: 2,3,4,5-Tetrafluoroaniline (5g, 30.3 mmol,)을 acetonitrile (20 mL)에 녹인 후, 상온에서 NBS (5.93 mg, 33.3 mmol)를 넣고 60 oC에서 2시간 교반하였다. 상온으로 반응 온도를 낮추고 sodium thiosulfate 포화수용액으로 반응을 종료시킨 후, ethyl acetate로 추출했다. Silica gel chromatography 정제하여 2-bromo-3,4,5,6-tetrafluoroaniline (5.5g, 22.5 mmol, 74% 수율)를 갈색 고체로 얻었다. 1H NMR (400 MHz, CDCl3, ppm): δ 4.27 - 4.15 (m, 2H).
단계 2: 단계 1에서 얻은 2-bromo-3,4,5,6-tetrafluoroaniline (0.5 g, 2.05 mmol와 B2pin2 (1.30 g, 5.12 mmol), Pd(dppf)Cl2 (149.95 mg, 204.93 μmol), potassium acetate (402.25 mg, 4.10 mmol)을 1,4-dioxane (5 mL)에 넣고 질소 퍼지 3회를 하였다. 그리고 질소 하에서 100 ℃, 2시간 반응했다. Silica gel chromatography 정제 후 2,3,4,5-tetrafluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 628.59 umol, 31% 수율)를 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 210.0; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 1.19 - 1.15 (m, 12H).
실시예 1: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000042
단계 1: DCM (48 mL)에 6-bromo-1,3-dichloroimidazo[1',2':1,6]pyrido[3,2-d]pyrimidine (2.4 g, 7.55 mmol)을 녹인 후 N,N-diisopropylamine (1.46 g, 11.32 mmol), tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.92 g, 9.06 mmol)를 첨가하고 반응 혼합물을 25 ℃에서 1시간 동안 교반하였다. 반응 혼합물을 정제수 (80 mL)로 희석하고 DCM (50 mL*3)으로 추출하였다. 유기물을 NaCl 수용액 (50 mL*2)으로 세척하고, Na2SO4으로 건조하고, 여과하고, 농축하여 잔류물을 얻었다. 생성물을 25 ℃에서 30분 동안 petroleum ether (50 mL) 및 EA (20 mL)로 교반한 다음, 고체를 여과하고 건조하였다. tert-Butyl (1R,5S)-3-(6-bromo-3-chloroimidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.44 g, 0.63 mmol, 88% 수율)을 황색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 494.1; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.28 (s, 1H), 7.82 - 7.69 (m, 2H), 4.17 - 4.09 (m, 2H), 3.84 - 3.70 (m, 2H), 3.65 - 3.51 (m, 2H), 1.71 - 1.60 (m, 2H), 1.58 - 1.49 (m, 2H), 1.48 - 1.43 (m, 9H).
단계 2: THF (45 mL)에 단계 1에서 얻은 tert-butyl (1R,5S)-3-(6-bromo-3-chloroimidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.44 g, 4.94 mmol)을 녹인 후 NaH (395.28 mg, 9.88 mmol)를 0 ℃에서 첨가하였다. 반응 혼합물을 실온에서 30분 동안 가열한 다음, THF (5 mL)에 ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (865.35 mg, 5.44 mmol)를 녹인 혼합물을 첨가하였다. 반응 혼합물을 질소하에 실온에서 16시간 동안 교반하였다. 반응 혼합물에 정제수를 첨가하고 ethyl acetate (50 mL*3)로 추출하였다. 합한 유기층을 NaCl 수용액 (40 mL*2)로 세척하고 Na2SO4으로 건조하였다. 여과한 용액을 감압 하에 농축하여 잔류물을 얻었다. 잔류물을 RP-HPLC (0.1% FA 조건)로 정제하였다. tert-Butyl (1R,5S)-3-(4-bromo-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1,2-a][1,5]naphthyridin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (920 mg, 1.58 mmol, 32% 수율)을 황색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 572.5; 1H NMR (400 MHz, DMSO-d 6, ppm): δ ppm 8.19 (s, 1 H), 7.69 - 7.65 (m, 1 H), 7.62 - 7.55 (m, 1 H), 5.39 - 5.16 (m, 1 H), 4.17 - 4.08 (m, 3 H), 3.83 - 3.69 (m, 2 H), 3.62 - 3.49 (m, 2 H), 3.12 - 2.98 (m, 4 H), 2.79 - 2.87 (m, 1 H), 2.10 - 2.15 (m, 1 H), 2.03 - 2.06 (m, 1 H), 1.73 - 1.88 (m, 4 H), 1.54 - 1.69 (m, 4 H), 1.42 - 1.48 (m, 9 H).
단계 3: 단계 2에서 얻은 tert-butyl (1R,5S)-3-(4-bromo-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1,2-a][1,5]naphthyridin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (470 mg, 821.57 μmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (355.14 mg, 985.89 μmol), cataCXium A Pd G3 (29.92 mg, 41.08 μmol) 및 Cs2CO3 (535.37 mg, 1.64 mmol)를 ethanol (9.4 mL)과 정제수 (0.9 mL)에 넣은 후 디게싱과 질소 퍼지를 3회 반복하였다. 그 다음 반응 혼합물을 질소 하에 80 ℃, 16시간 동안 교반하였다. 출발 물질이 완전히 소모된 후, 반응 혼합물을 감압 하에 농축하고 잔류물을 물 (10 mL)로 희석하고 화합물을 ethyl acetate (5 mL*2)로 추출하였다. 유기층을 포화 NaCl 수용액 (5 mL*2)로 세척하고, 무수 Na2SO4으로 건조 후, 감압하에 농축하였다. 잔류물을 prep-TLC로 정제하였다. tert-Butyl (1R,5S)-3-(6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (105 mg, 128.84 μmol, 16% 수율)을 황색 고체로 얻었다.
LCMS (ES-API, m/z): [M+H]+= 770.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.23 - 8.11 (m, 1H), 7.93 - 7.84 (m, 1H), 7.68 - 7.61 (m, 1H), 7.60 - 7.34 (m, 3H), 7.27 - 7.14 (m, 1H), 5.34 (s, 3H), 4.23 - 4.11 (m, 2H), 4.09 - 3.95 (m, 2H), 3.95 - 3.90 (m, 1H), 3.76 - 3.51 (m, 2H), 3.43 (s, 3H), 3.06 - 3.14 (m, 2H), 2.98 - 3.05 (m, 1H), 2.80 - 2.90 (m, 1H), 1.95 - 2.23 (m, 6H), 1.66 - 1.93 (m, 7H), 1.41 - 1.50 (m, 9H), 0.54 (br t, J = 6.4 Hz, 3H).
단계 4: DCM (1.3 mL)에 tert-butyl (1R,5S)-3-(6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (65 mg, 84.43 μmol)을 녹인 후 4 N HCl in ethyl acetate solution (650 μL)을 첨가하였다. 반응 혼합물을 25 ℃에서 1시간 동안 교반하였다. 출발 물질이 완전히 소모된 후, 반응 혼합물을 감압 하에 농축하고 잔류물을 포화 NaHCO3 용액 (10 mL)으로 희석하고 화합물을 ethyl acetate (5 mL*2)로 추출하였다. 유기층을 포화 NaCl 수용액으로 세척하고, 무수 Na2SO4으로 건조하고 농축하였다. 잔류물을 Prep-HPLC로 정제하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol (25.72 mg, 41.10 μmol, 49% 수율)를 회백색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 626.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 9.86 (s, 1H), 8.11 - 7.99 (m, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.68 - 7.52 (m, 1H), 7.51 - 7.42 (m, 1H), 7.42 - 7.24 (m, 3H), 7.08 - 7.02 (m, 1H), 5.42 - 5.17 (m, 1H), 4.12 (s, 3H), 3.78 - 3.59 (m, 1H), 3.57 - 3.38 (m, 3H), 3.15 - 3.07 (m, 2H), 3.02 (s, 1H), 2.88 - 2.79 (m, 1H), 2.44 - 2.37 (m, 1H), 2.24 - 2.08 (m, 2H), 2.09 - 1.96 (m, 3H), 1.92 - 1.67 (m, 5H), 1.59 - 1.45 (m, 1H), 1.42 - 1.15 (m, 1H), 0.50 (t, J = 6.8 Hz, 3H).
실시예 2: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성
Figure PCTKR2023020084-appb-img-000043
단계 1: tert-Butyl (1R,5S)-3-(6-bromo-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 243.30 μmol), ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (149.64 mg, 291.96 μmol), cataCXium A Pd G3 (8.86 mg, 12.16 μmol) 및 Cs2CO3 (158.54 mg, 486.60 μmol)을 ethanol (3 mL)과 물 (0.3 mL)에 넣은 후 디게싱과 질소 퍼지를 3회 반복하였다. 그 다음 혼합물을 질소 하에 80 ℃, 16시간 동안 교반하였다. 반응 종료 후 반응 혼합물을 감압 하에 농축하여 ethanol을 제거한 후, 미정제 잔류물을 정제수 (15 mL)로 희석하고, ethyl acetate (10 mL*2)로 추출하였다. 유기층을 포화 NaCl 수용액으로 세척하고, 무수 Na2SO4으로 건조한 후, 감압하에 농축하였다. 잔류물을 prep-TLC로 정제하였다. tert-butyl (1R,5S)-3-(6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 126.59 μmol, 52% 수율)을 황색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 922.5; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.22 - 7.97 (m, 2H), 7.77 - 7. 63 (m, 1H), 7.59 - 7. 47 (m, 2H), 7.46 - 7. 30 (m, 2H), 5.36 (s, 3H), 4.41 (brs, 1H), 4.32 - 4. 21 (m, 1H), 4.18- 3.99 (m, 2H), 3.97 - 3.78 (m, 1H), 3.43 (s, 3H), 3.14 - 3. 07 (m, 2H), 3.07 - 3.00 (m, 1H), 2.93 - 2. 79 (m, 2H), 2.31 - 2. 23 (m, 1H), 2.22 - 1.95 (m, 5H), 1.95 - 1. 62 (m, 6H), 1.46 (brs, 9H), 0.83 - 0. 62 (m, 18H), 0.46 - 0.26 (m, 3H).
단계 2: DMF (1.2 mL)에 tert-butyl (1R,5S)-3-(6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 130.13 μmol)을 녹인 후 CsF (296.50 mg, 1.95 mmol, 71.97 μL)를 첨가하였다. 반응 혼합물을 40 ℃에서 16시간 동안 교반하였다. 반응 혼합물을 물 (15 mL)로 희석하고 ethyl acetate(10 mL*3)로 추출하였다. 유기물을 포화 NaCl 수용액 (10 mL*2)로 세척, 무수 Na2SO4으로 건조한 후, 여과하고, 농축하여 잔류물을 얻었다. 잔류물을 prep-TLC로 정제하였다. tert-Butyl (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 91.17 μmol, 70% 수율)을 황색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 766.5; 1H NMR (400 MHz, CDCl3, ppm): δ 8.75 - 8. 36 (m, 1H), 7.85 (dd, J = 9.05, 5.75 Hz, 1H), 7.78 - 7. 61 (m, 1H), 7.56 (s, 1H), 7.51 (br d, J = 13.2 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.32 - 7. 26 (m, 2H), 5.51 - 5. 13 (m, 3H), 4.60 - 4. 11 (m, 4H), 3.66 - 3. 58 (m, 1H), 3.55 (s, 3H), 3.52 - 3. 46 (m, 2H), 3.38 - 3. 19 (m, 3H), 2.12 - 3. 99 (m, 1H), 2.63 - 2. 51 (m, 1H), 2.40 - 2. 09 (m, 5H), 2.06- 1.81 (m, 5H), 1.57- 1.48 (m, 9H).
단계 3: ACN (0.7 mL)에 tert-butyl (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 91.40 μmol)을 녹인 후 0 ℃, 질소 하에 4N HCl in dioxane (700 μL)을 첨가하고 1시간 동안 교반하였다. 출발 물질이 완전히 소모된 후, 반응 혼합물을 감압 하에 농축하고 잔류물을 포화 중탄산나트륨 (10 mL)으로 희석하고 화합물을 ethyl acetate (5 mL*4)로 추출하였다. 유기층을 소금물로 세척하고, 무수 Na2SO4으로 건조한 후, 감압하에 농축하였다. 잔류물을 분취하여 Prep-HPLC로 정제하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (27.37 mg, 43.79 umol, 48% 수율)을 백색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 622.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.33 - 9.92 (m, 1H), 8.55 - 8.36 (m, 1H), 7.99 - 7.93 (m, 1H), 7.61 - 7.47 (m, 1H), 7.47 - 7.34 (m, 3H), 7.33 - 7.26 (m, 1H), 7.20 (br s, 1H), 5.40 - 5.17 (m, 1H), 4.17 - 4.08 (m, 1H), 4.06 - 3.84 (m, 2H), 3.70 - 3.54 (m, 2H), 3.54 - 3.41 (m, 3H), 3.15 - 3.05 (m, 2H), 3.04 - 3.00 (m, 1H), 2.99 - 2.88 (m, 1H), 2.84 (br d, J = 7.2 Hz, 1H), 2.20 - 1.98 (m, 4H), 1.93 - 1.68 (m, 5H), 1.57 - 1.42 (m, 1H).
실시예 3: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5,6-difluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000044
단계 1: tert-butyl (1R,5S)-3-(6-bromo-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 262.20 μmol), 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (110.18 mg, 314.65 μmol), PdCl2(dtbpf) (17.09 mg, 26.22 μmol), K3PO4(166.97 mg, 786.61 μmol)을 1,4-dioxane (2.4 mL)과 물 (0.6 mL)에 넣은 후 디게싱과 질소 퍼지를 3회 반복하였다. 그다음 혼합물을 질소 하에서 80 ℃, 1시간 교반하였다. 출발 물질이 완전히 소모된 후, 반응 혼합물을 감압 하에 농축하고 잔류물을 물 (10 mL)로 희석하고 화합물을 ethyl acetate (5 mL*2)로 추출하였다. 유기층을 포화 NaCl 수용액 (5 mL*2)으로 세척하고, 무수 Na2SO4으로 건조한 후, 감압하에 농축하였다. 잔류물을 prep-TLC (DCM:MeOH=10:1)로 정제하여 tert-butyl (1R,5S)-3-(6-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 195.70 μmol, 75% 수율)을 황색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 760.2; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 7.68 (s, 1H), 7.57 - 7.34 (m, 4H), 7.27 - 7.16 (m, 2H), 5.33 - 5.12 (m, 3H), 4.69 (br d, J = 2.4 Hz, 2H), 4.46 - 4.10 (m, 4H), 3.62 (s, 1H), 3.46 - 3.42 (m, 3H), 3.39 (s, 3H), 3.37 - 3.28 (m, 1H), 3.26 - 3.15 (m, 2H), 3.13 - 3.06 (m, 1H), 2.97 - 2.86 (m, 1H), 2.27 - 2.04 (m, 4H), 1.94 - 1.83 (m, 3H), 1.47 - 1.37 (m, 9H).
단계 2: ACN (1.3 mL)에 tert-butyl (1R,5S)-3-(6-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (130 mg, 171.09 μumol)을 녹이고 HCl in dioxane (4 M, 1.30 mL)을 0 ℃에서 첨가한 후, 0 ℃에서 1시간 교반하였다. 출발 물질이 완전히 소모된 후, 반응 혼합물을 감압 하에 농축하였다. 잔류물을 포화 NaHCO3 용액 (15 mL)으로 희석하고 화합물을 ethyl acetate (10 mL*3)로 추출하였다. 유기층을 NaCl 수용액으로 세척하고, 무수 Na2SO4으로 건조한 뒤, 감압하에 농축하였다. 잔류물을 분취 후 RP-HPLC로 정제하여 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5,6-difluoronaphthalen-2-ol (14.11 mg, 22.48 μmol, 13% 수율)을 황록색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 616.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.21 (s, 1H), 8.07 - 7.96 (m, 1H), 7.74 - 7.59 (m, 1H), 7.58 - 7.42 (m, 2H), 7.42 - 7.32 (m, 2H), 7.21 (s, 1H), 5.39 - 5.18 (m, 1H), 4.12 (br d, J = 9.2 Hz, 1H), 4.03 (br s, 1H), 3.97 - 3.83 (m, 1H), 3.72 - 3.60 (m, 1H), 3.59 - 3.42 (m, 3H), 3.18 - 2.91 (m, 4H), 2.88 - 2.78 (m, 1H), 2.20 - 1.95 (m, 4H), 1.92 - 1.60 (m, 5H), 1.58 - 1.36 (m, 2H).
실시예 4: 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000045
단계 1: DCM (40 mL)에 6-bromo-1,3-dichloroimidazo[1',2':1,6]pyrido[3,2-d]pyrimidine (2 g, 6.29 mmol)을 녹이고 DIPEA (1.22 g, 9.44 mmol), 1-(aminomethyl)-N,N-dimethylcyclobutan-1-amine (967.79 mg, 7.55 mmol)을 순서대로 첨가하였다. 반응 혼합물은 25 ℃에서 1시간 교반하였다. 반응 혼합물을 물 (80 mL)로 희석하고 DCM (50 mL*2)으로 추출하였다. 유기물을 포화 NaCl 수용액 (50 mL*2)로 세척, 무수 Na2SO4으로 건조한 후 여과하고, 농축하여 잔류물을 얻었다. 생성물을 petroleum ether (15 mL) 및 ethyl acetate (45 mL)로 25 ℃에서 30분 교반한 후 여과 및 건조하였다. 6-Bromo-3-chloro-N-((1-(dimethylamino)cyclobutyl)methyl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (2.2 g, 5.33 mmol, 85% 수율)을 회백색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 365.0; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.57 - 8.48 (m, 1H), 7.90 (s, 1H), 7.77 - 7.75 (m, 1H), 7.74 - 7.64 (m, 1H), 3.79 (s, 2H), 2.27 (s, 6H), 2.21 - 2.10 (m, 2H), 1.91 - 1.65 (m, 4H).
단계 2: THF (26 mL)에 6-bromo-3-chloro-N-((1-(dimethylamino)cyclobutyl)methyl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (1.3 g, 3.56 mmol) 및 ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (2.27 g, 14.24 mmol)을 녹인 후 NaH (1.42 g, 35.59 mmol)을 0 ℃에서 넣었다. 반응 혼합물을 25 ℃로 가온하고 10분 동안 교반한 다음, 반응 혼합물을 질소 하에서 70 ℃, 16시간 동안 교반하였다. 혼합물을 포화 NH4Cl 수용액 (100 mL)에 붓고 ethyl acetate (50 mL*3)로 추출하였다. 합한 유기 층을 포화 NaCl 수용액 (50 mL*3)으로 세척, 건조한 후, 감압하에 농축하여 생성물을 수득하였다. 잔류물을 silica gel chromatography로 정제한 다음 Prep-HPLC를 사용하여 정제하였다. 6-Bromo-N-((1-(dimethylamino)cyclobutyl)methyl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (720 mg, 1.39 mmol, 39% 수율)를 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 488.2; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.42 (s, 1H), 7.83 (s, 1H), 7.66 - 7.54 (m, 1H), 7.40 - 7.20 (m, 1H), 5.38 - 5.14 (m, 1H), 4.15 - 3.95 (m, 2H), 3.85 - 3.72 (m, 2H), 3.15 - 3.05 (m, 2H), 3.04 - 2.98 (m, 1H), 2.88 - 2.78 (m, 1H), 2.29 - 2.22 (m, 6H), 2.19 - 2.11 (m, 3H), 2.06 - 2.02 (m, 1H), 2.01 - 1.94 (m, 1H), 1.88 - 1.64 (m, 7H).
단계 3: 단계 2에서 얻은 6-bromo-N-((1-(dimethylamino)cyclobutyl)methyl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (150 mg, 307.38 μmol), 2-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (132.87 mg, 368.85 μmol), PdCl2(dtbpf) (20.03 mg, 30.74 μmol), K3PO4(195.74 mg, 922.13 μmol)을 dioxane (2.4 mL) 및 물 (0.6 mL)에 녹이고 질소로 3회 퍼징한 다음, 혼합물을 질소 하에서 80℃, 1.5시간 동안 교반하였다. 반응 종료 후, 반응 혼합물을 물 (20 mL)로 희석하고 화합물을 ethyl acetate (15 mL*3)로 추출하였다. 유기층을 포화 NaCl 수용액 (15 mL)로 세척하고, 무수 Na2SO4으로 건조하고, 감압하에 농축하였다. 잔류물을 silica gel chromatography로 정제하여 N-((1-(dimethylamino)cyclobutyl)methyl)-6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (190 mg, 260.98 μmol, 85% 수율)을 황색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 488.2; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.15 (s, 1H), 7.69 - 7.66 (m, 2H), 7.52 - 7.51 (m, 2H), 7.27 - 7.23 (m, 1H), 7.21 - 7.18 (m, 1H), 6.98 - 6.94 (m, 1H), 5.30 - 5.26 (m, 3H), 4.31 - 4.30 (m, 1H), 4.13 - 4.12 (m, 1H), 3.85 - 3.84 (m, 2H), 3.51 (s, 3H), 3.29 - 3.21 (m, 3H), 3.04 - 2.96 (m, 1H), 2.46- 2.42 (m, 2H), 2.41 (s, 6H), 2.23 - 2.21 (m, 2H), 2.16 - 2.12 (m, 2H), 1.98 - 1.61 (m, 8H), 0.7 (t, J = 7.2 Hz, 3H).
단계 4: ACN (1 mL)에 단계 3에서 얻은 N-((1-(dimethylamino)cyclobutyl)methyl)-6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (100 mg, 145.81 μmol)을 녹인 후 HCl in dioxane (4 M, 0.5 mL)을 0 ℃에서 첨가하고 1시간 교반하였다. 반응 종료 후, 반응 혼합물을 감압 하에 농축하고 잔류물을 포화 NaHCO3 용액 (20 mL)으로 희석하고 화합물을 ethyl acetate(10 mL*3)로 추출하였다. 유기층을 포화 NaCl 수용액으로 세척, 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 분취 후 Prep-HPLC로 정제하였다. 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol (30.44 mg, 46.40 μmol 32% 수율)을 백색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 488.2; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 9.86 (br s, 1H), 8.39 (s, 1H), 7.75 (dd, J = 6.0, 9.2 Hz, 1H), 7.63 (s, 1H), 7.41 (s, 1H), 7.38 - 7.26 (m, 3H), 6.99 (d, J = 2.4 Hz, 1H), 5.40 - 5.17 (m, 1H), 4.16 - 4.01 (m, 2H), 3.92 (brs, 1H), 3.75 (brs, 1H), 3.16 - 2.97 (m, 3H), 2.88 - 2.79 (m, 1H), 2.47 - 2.40 (m, 1H), 2.29 (s, 6H), 2.24 - 2.11 (m, 3H), 2.10 - 1.96 (m, 3H), 1.93 - 1.67 (m, 7H), 0.60 (t, J = 7.2 Hz, 3H).
실시예 5: 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5,6-difluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000046
2-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
대신 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane을 사용하여 실시예 4와 동일한 방법으로 합성하였다. 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5,6-difluoronaphthalen-2-ol (46.13 mg, 72.23 μmol, 49% 수율)을 회색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 632.5; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.34 - 10.07 (m, 1H), 8.45 - 8.26 (m, 1H), 7.75 - 7.67 (m, 1H), 7.64 - 7.60 (m, 1H), 7.57 - 7.48 (m, 1H), 7.40 - 7.29 (m, 3H), 7.23 - 7.10 (m, 1H), 5.42 - 5.14 (m, 1H), 4.15 - 4.01 (m, 2H), 3.96 - 3.83 (m, 1H), 3.81 - 3.71 (m, 1H), 3.13 - 2.98 (m, 3H), 2.89 - 2.77 (m, 1H), 2.32 - 2.26 (m, 6H), 2.25 - 2.12 (m, 3H), 2.10 - 1.97 (m, 2H), 1.91 - 1.68 (m, 7H).
실시예 6: 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000047
단계 1: 6-bromo-N-((1-(dimethylamino)cyclobutyl)methyl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (150 mg, 307.38 μmol), ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (189.05 mg, 368.85 μmol), PdCl2(dtbpf) (20.03 mg, 30.70 μmol.), K3PO4(195.74 mg, 922.13 μmol)을 dioxane (2.4 mL) 및 물 (0.6 mL)에 넣고 질소로 3회 퍼지하였다. 반응 혼합물을 질소 하에서 80 ℃, 1.5시간 동안 교반하였다. 반응 종료 후 반응 혼합물을 물 (20 mL)로 희석하고 화합물을 ethyl acetate (15 mL*3)으로 추출하였다. 유기층을 포화 NaCl 수용액 (15mL)으로 세척하고, 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography로 정제하였다. N-((1-(dimethylamino)cyclobutyl)methyl)-6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (175 mg, 197.88 μmol, 64% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 838.6; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.14 - 8.05 (m, 1H), 7.83 - 7.74 (m, 1H), 7.71 - 7.65 (m, 1H), 7.54 - 7.48 (m, 2H), 7.31 - 7.29 (m, 1H), 7.27 - 7.23 (m, 1H), 6.98 - 6.86 (m, 1H), 5.29 (s, 3H), 4.38 - 4.26 (m, 1H), 4.21 - 4.10 (m, 1H), 3.94 - 3.74 (m, 2H), 3.52 (s, 3H), 3.38 - 3.16 (m, 3H), 3.09 - 2.93 (m, 1H), 2.45 (br d, J = 10.8 Hz, 2H), 2.37 (s, 6H), 2.30 - 2.20 (m, 2H), 2.01 - 1.79 (m, 8H), 0.79 - 0.74 (m, 18H), 0.51 (quin, J = 7.2 Hz, 3H).
단계 2: DMF (1.5 mL)에 단계 1에서 얻은 N-((1-(dimethylamino)cyclobutyl)methyl)-6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (145 mg, 173.01 μmol)을 녹인 후 CsF (394.20 mg, 2.60 mmol)를 첨가하고, 혼합물을 40 ℃에서 16시간 동안 교반하였다. 반응 혼합물을 물 (25 mL)로 희석하고 ethyl acetate (15 mL*3)으로 추출하였다. 유기물을 포화 NaCl 수용액 (15 mL*2)으로 세척하고, 무수 Na2SO4으로 건조하고, 여과하고, 농축하여 잔류물을 얻었다. 잔류물을 prep-TLC로 정제하여 N-((1-(dimethylamino)cyclobutyl)methyl)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (90 mg, 128.62 μmol, 74% 수율)을 황색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 838.6; 1H NMR (400 MHz, CDCl3, ppm): δ 8.20 - 8.09 (m, 1H), 7.88 - 7.78 (m, 1H), 7.71 - 7.66 (m, 1H), 7.58 - 7.52 (m, 1H), 7.49 - 7.45 (m, 1H), 7.39 - 7.34 (m, 1H), 7.29 - 7.28 (m, 1H), 7.26 - 7.24 (m, 1H), 7.07 - 6.92 (m, 1H), 5.41 - 5.36 (m, 1H), 5.31 - 5.29 (m, 1H), 5.28 - 5.22 (m, 1H), 4.37 - 4.27 (m, 1H), 4.25 - 4.10 (m, 1H), 3.85 (br d, J = 2.4 Hz, 2H), 3.54 (s, 3H), 3.40 - 3.19 (m, 3H), 3.02 (br s, 1H), 2.62 - 2.56 (m, 1H), 2.48 - 2.40 (m, 2H), 2.36 (s, 6H), 2.27 (br d, J = 12.0 Hz, 2H), 2.04 - 1.78 (m, 8H).
단계 3: Acetonitrile (0.8 mL) 및 DCM (0.8 mL)에 단계 2에서 얻은 N-((1-(dimethylamino)cyclobutyl)methyl)-6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-amine (80 mg, 117.34 μmol)을 녹인 후, 0 ℃에서 HCl in dioxane (4 M, 800 μL)을 첨가하고 1시간 동안 교반하였다. 출발 물질이 완전히 소모된 후, 반응 혼합물을 감압 하에 농축하고 잔류물을 포화 NaHCO3 용액(15 mL)으로 희석하여 화합물을 ethyl acetate (10 mL*3)로 추출하였다. 유기층을 포화 NaCl수용액 (10 mL)으로 세척하고, 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 Prep-HPLC로 정제하여 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (56.98 mg, 88.14 μmol, 75% 수율)을 회백색 고체로 얻었다.. LCMS (ES-API, m/z): [M+H]+= 838.6; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.34 - 9.88 (m, 1H), 8.32 (s, 1H), 7.95 (dd, J = 6.0, 9.2 Hz, 1H), 7.58 (s, 1H), 7.42 (t, J = 9.0 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.30 (s, 1H), 7.26 (br s, 1H), 7.17 (d, J = 2.0 Hz, 1H), 5.44 - 5.16 (m, 1H), 4.15 - 4.07 (m, 1H), 4.05 - 3.91 (m, 2H), 3.76 - 3.63 (m, 2H), 3.16 - 2.98 (m, 3H), 2.84 (br d, J = 6.0 Hz, 1H), 2.29 (s, 6H), 2.22 (br d, J = 9.6 Hz, 2H), 2.14 (br d, J = 5.6 Hz, 1H), 2.10 - 1.96 (m, 2H), 1.92 - 1.67 (m, 7H).
실시예 7: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000048
Intermediate 6을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (35 mg, 55.22 umol, 43% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 634.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.27 - 10.03 (m, 1H), 8.57 - 8.39 (m, 1H), 8.02 - 7.92 (m, 1H), 7.61 - 7.51 (m, 1H), 7.48 - 7.36 (m, 3H), 7.32 - 7.14 (m, 2H), 4.29 (s, 2H), 3.71 - 3.63 (m, 1H), 3.62 - 3.57 (m, 1H), 3.54 (br s, 4H), 3.51 - 3.48 (m, 1H), 3.47 - 3.42 (m, 1H), 3.25 - 3.13 (m, 1H), 3.03 - 2.88 (m, 1H), 2.45 - 2.29 (m, 6H), 2.26 - 2.05 (m, 1H), 1.98 - 1.68 (m, 2H), 1.64 - 1.35 (m, 2H), 0.71 - 0.60 (m, 2H), 0.47 - 0.39 (m, 2H).
실시예 8: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((( R )-3-methylmorpholino)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000049
Intermediate 7을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((R)-3-methylmorpholino)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (81.41 mg, 122.92 μmol, 51% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 648.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 0.31 - 0.39 (m, 1H), 0.46 - 0.61 (m, 2H), 0.62 - 0.73 (m, 1H), 0.84 (dd, J = 6.0, 3.2Hz, 3H), 1.36 - 1.66 (m, 3H), 1.68 - 1.93 (m, 2H), 2.03 - 2.19 (m, 2H), 2.21 - 2.35 (m, 2H), 2.83 - 3.08 (m, 3H), 3.39 - 3.55 (m, 6H), 3.61 - 3.72 (m, 2H), 3.79 - 4.11 (m, 2H), 4.45 - 4.73 (m, 1H), 7.15 - 7.24 (m, 1H), 7.26 - 7.43 (m, 3H), 7.43 - 7.59 (m, 1H), 7.96 (dd, J = 8.8, 6.0Hz, 2H), 9.87 - 10.22 (m, 1H).
실시예 9: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000050
Intermediate 8을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (66.62 mg, 94.29 μmol, 53% 수율)을 회백색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 694.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.25 - 10.00 (m, 1H), 8.52 - 8.40 (m, 1H), 8.05 - 7.90 (m, 1H), 7.57 - 7.51 (m, 1H), 7.46 - 7.35 (m, 3H), 7.32 - 7.26 (m, 1H), 7.24 - 7.17 (m, 1H), 4.35 - 4.24 (m, 2H), 4.06 - 3.92 (m, 1H), 3.72 - 3.40 (m, 4H), 3.01 - 2.87 (m, 1H), 2.47 - 2.38 (m, 4H), 2.38 - 2.33 (m, 2H), 2.27 - 2.04 (m, 1H), 1.92 - 1.71 (m, 2H), 1.64 - 1.41 (m, 6H), 1.24 - 1.12 (m, 2H), 0.71 - 0.60 (m, 2H), 0.43 (br s, 2H).
실시예 10: 4-(3-((1-(((1 R ,4 R )-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-((1 R, 5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000051
Intermediate 9를 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(3-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (39 mg, 59.19 μmol, 31% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 646.2; 1H NMR (400 MHz, DMSO-d 6 , ppm): δ 10.21 - 10.02 (m, 1H), 8.51 - 8.40 (m, 1H), 8.02 - 7.90 (m, 2H), 7.58 - 7.50 (m, 1H), 7.47 - 7.36 (m, 3H), 7.30 - 7.25 (m, 1H), 7.24 - 7.16 (m, 1H), 4.38 - 4.28 (m, 2H), 4.27 - 4.17 (m, 1H), 3.84 - 3.74 (m, 1H), 3.58 (br s, 1H), 3.53 - 3.45 (m, 4H), 3.44 - 3.39 (m, 2H), 2.89 (s, 1H), 2.88 - 2.82 (m, 1H), 2.65 - 2.57 (m, 2H), 2.44 - 2.36 (m, 1H), 2.24 - 2.05 (m, 1H), 1.94 - 1.70 (m, 2H), 1.70 - 1.63 (m, 1H), 1.57 - 1.46 (m, 2H), 0.62 - 0.55 (m, 2H), 0.53 - 0.45 (m, 1H), 0.44 - 0.38 (m, 1H).
실시예 11: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((( R )-2-methylmorpholino)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000052
Intermediate 10을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((R)-2-methylmorpholino)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (15 mg, 22.93 μmol, 20% 수율)를 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 648.5; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.23 - 9.97 (m, 1H), 8.54 - 8.37 (m, 1H), 8.03 - 7.89 (m, 1H), 7.58 - 7.15 (m, 5H), 4.36 - 4.21 (m, 2H), 4.05 - 3.93 (m, 1H), 3.84 - 3.61 (m, 2H), 3.60 - 3.52 (m, 1H), 3.51 - 3.35 (m, 5H), 2.99 - 2.72 (m, 2H), 2.43 - 2.23 (m, 4H), 2.16 - 2.06 (m, 1H), 2.03 - 1.89 (m, 1H), 1.88 - 1.75 (m, 1H), 1.73 - 1.59 (m, 1H), 1.58 - 1.39 (m, 2H), 1.05 - 0.95 (m, 3H), 0.71 - 0.59 (m, 2H), 0.46 - 0.38 (m, 2H).
실시예 12: 4-(3-((1-(((1 S ,4 S )-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성
Figure PCTKR2023020084-appb-img-000053
Intermediate 11을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(3-((1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (62 mg, 91.22 umol, 40% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 646.5; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.16 - 10.03 (m, 1H), 8.50 - 8.40 (m, 1H), 8.02 - 7.90 (m, 1H), 7.58 - 7.48 (m, 1H), 7.46 - 7.41 (m, 1H), 7.41 - 7.35 (m, 2H), 7.32 - 7.25 (m, 1H), 7.24 - 7.16 (m, 1H), 4.40 - 4.27 (m, 2H), 4.26 - 4.19 (m, 1H), 4.07 - 3.90 (m, 1H), 3.82 - 3.74 (m, 1H), 3.68 - 3.55 (m, 2H), 3.53 - 3.38 (m, 5H), 2.99 - 2.89 (m, 1H), 2.88 - 2.79 (m, 1H), 2.69 - 2.60 (m, 2H), 2.45 - 2.35 (m, 2H), 2.27 - 2.04 (m, 1H), 1.85 - 1.65 (m, 2H), 1.57 - 1.43 (m, 2H), 0.67 - 0.54 (m, 2H), 0.53 - 0.36 (m, 2H).
실시예 13: 3-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-2,4,5,6-tetrafluoroaniline의 합성.
Figure PCTKR2023020084-appb-img-000054
단계 1: 실시예 2의 단계 1에서 ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane 대신 intermediate 26을 사용하여 같은 방법으로 합성하였다. tert-butyl (1R,5S)-3-(6-(2-amino-3,4,5,6-tetrafluorophenyl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75 mg, 103.82 μmol, 27% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 701.4; 1H NMR (400 MHz, CDCl3, ppm): δ 8.68 - 8.53 (m, 1H), 7.83 - 7.72 (m, 1H), 7.69 - 7.63 (m, 1H), 7.59 - 7.49 (m, 1H), 5.39 - 5.21 (m, 2H), 4.36 - 4.28 (m, 1H), 4.23 (br d, J = 7.4 Hz, 3H), 4.17 - 4.09 (m, 1H), 3.88 - 3.54 (m, 2H), 3.45 - 3.36 (m, 1H), 3.26 (br s, 2H), 3.19 (br s, 1H), 3.05 - 2.95 (m, 1H), 2.37 - 2.11 (m, 5H), 2.02 - 1.80 (m, 7H), 1.55 - 1.47 (m, 9H).
단계 2: 단계 1에서 얻은 tert-butyl (1R,5S)-3-(6-(2-amino-3,4,5,6-tetrafluorophenyl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (75.00 mg, 107.04 μmol) 을 acetonitrile에 녹인 후 HCl in dioxane (4 M, 0.8 mL)을 적가했다. 반응 혼합물을 0 ℃에서 한 시간 동안 교반했다. 포화 NaHCO3 수용액을 첨가한 후 ethyl acetate로 추출했다. 비정제 화합물을 prep-HPLC로 정제하여 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-2,4,5,6-tetrafluoroaniline (15 mg, 24.98 μmol, 23% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 601.3; 1H NMR (400 MHz, CDCl3, ppm): δ 8.64 - 8.47 (m, 1H), 8.09 - 7.93 (m, 1H), 7.75 - 7.51 (m, 1H), 7.49 - 7.26 (m, 1H), 5.61 - 5.42 (m, 2H), 5.40 - 5.17 (m, 1H), 4.16 - 4.08 (m, 1H), 4.07 - 3.97 (m, 1H), 3.59 - 3.44 (m, 4H), 3.13 - 3.05 (m, 2H), 3.04 - 3.00 (m, 1H), 2.88 - 2.79 (m, 1H), 2.21 - 1.93 (m, 4H), 1.91 - 1.70 (m, 4H), 1.64 - 1.43 (m, 2H), 1.42 - 1.09 (m, 2H).
실시예 14: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000055
tert-Butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate와 intermediate 18을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (12.71 mg, 20.21 μmol, 15% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 621.5; 1H NMR (400 MHz, CDCl3, ppm): δ 8.78 - 8.59 (m, 1H), 7.80 - 7.69 (m, 1H), 7.48 (s, 1H), 7.35 - 7.26 (m, 2H), 7.10 - 7.00 (m, 2H), 5.67 - 5.53 (m, 2H), 5.40 - 5.16 (m, 1H), 4.22 (br dd, J = 4.4, 6.4 Hz, 1H), 4.14 - 4.07 (m, 1H), 4.05 - 3.97 (m, 1H), 3.91 (br s, 1H), 3.56 - 3.38 (m, 1H), 3.31 - 3.19 (m, 2H), 3.18 - 3.04 (m, 3H), 3.02 (s, 1H), 2.88 - 2.80 (m, 1H), 2.80 - 2.70 (m, 1H), 2.18 - 2.12 (m, 1H), 2.11 - 1.93 (m, 4H), 1.92 - 1.66 (m, 5H).
실시예 15: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-7-fluorobenzo[ d ]thiazol-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000056
단계 1: (2-((tert-Butoxycarbonyl)amino)-7-fluorobenzo[b]thiophen-4-yl)boronic acid (220 mg, 563.88 μmol)과 tert-butyl (1R,5S)-8-(6-chloro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (280 mg, 489.45 μmol)를 1,4-dioxane (5 mL)과 물 (1 mL)에 녹인 후 K3PO4 (311.68 mg, 1.47 mmol), Pd(amphos)Cl2 (31.90 mg, 48.94 μmol)을 넣고 질소 퍼지 3회를 하였다. 그 후 반응 혼합물을 80 ℃에서 12시간 교반하였다. 반응 종결 후 silica gel chromatography로 정제하여 tert-butyl (1R,5S)-8-(6-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (280 mg, 318.67 μmol, 65% 수율)를 얻었다. LCMS (ES-API, m/z): [M+H]+= 804.7; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 12.23 (br s, 1H), 9.05 - 8.51 (m, 1H), 8.17 (dd, J = 5.8, 8.6 Hz, 1H), 7.92 (s, 1H), 7.67 (s, 1H), 7.33 (t, J = 8.8 Hz, 1H), 5.39 - 5.19 (m, 1H), 4.28 (br d, J = 11.0 Hz, 2H), 4.17 - 4.12 (m, 1H), 4.06 (d, J = 9.8 Hz, 1H), 3.19 - 2.99 (m, 4H), 2.88 - 2.78 (m, 1H), 2.21 - 2.00 (m, 4H), 1.93 - 1.66 (m, 7H), 1.53 - 1.50 (m, 9H), 1.43 (br s, 9H).
단계 2: 단계 1에서 얻은 tert-butyl (1R,5S)-8-(6-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (227.62 mg, 323.42 μmol)을 ACN에 녹인 후 HCl in dioxane (4 M, 0.5 mL)을 넣고 0 ℃에서 2시간 교반하였다. 반응 종료 후 화합물을 Prep-HPLC로 정제하여 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-7-fluorobenzo[d]thiazol-2-amine (80 mg, 127.62 μmol, 39% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 604.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.93 - 8.61 (m, 1H), 8.07 - 7.96 (m, 3H), 7.92 (s, 1H), 7.67 (s, 1H), 7.08 (t, J = 8.9 Hz, 1H), 5.42 - 5.13 (m, 1H), 4.29 - 4.05 (m, 3H), 4.04 - 3.96 (m, 1H), 3.31 - 2.94 (m, 6H), 2.89 - 2.70 (m, 2H), 2.26 - 1.95 (m, 5H), 1.94 - 1.58 (m, 6H).
실시예 16: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-((( R )-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000057
Intermediate 14를 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (70.42 mg, 108.56 μmol, 56% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 636.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 0.45 (s, 2 H), 0.56 - 0.67 (m, 2 H), 0.68 - 0.88 (m, 1 H), 1.11 - 1.31 (m, 2 H), 1.74 - 1.93 (m, 3 H), 2.01 - 2.18 (m, 2 H), 2.28 - 2.34 (m, 1 H), 2.38 (br dd, J = 12.0, 9.07 Hz, 1 H), 2.57 (br d, J = 4.4 Hz, 1 H), 2.60 - 2.68 (m, 1 H), 2.73 - 2.82 (m, 2 H), 2.87 (br d, J = 11.2 Hz, 1 H), 3.08 - 3.28 (m, 2 H), 3.52 - 3.64 (m, 1 H), 3.83 - 3.98 (m, 1 H), 4.07 - 4.26 (m, 2 H), 4.27 - 4.33 (m, 1 H), 5.03 - 5.30 (m, 1 H), 7.21 (d, J = 2.4 Hz, 1 H), 7.35 (s, 1 H), 7.37 (d, J = 2.4 Hz, 1 H), 7.42 (t, J = 9.2 Hz, 1 H), 7.47 (s, 1 H), 7.96 (dd, J = 9.2, 6.00 Hz, 1 H), 8.30 - 8.93 (m, 1 H), 9.79 - 10.39 (m, 1 H).
실시예 17: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000058
Intermediate 13을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (20 mg, 32.05 μmol, 19% 수율)을 옅은 노랑색 고체로 얻었다.　LCMS (ES-API, m/z): [M+H]+= 618.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.18 - 10.08 (m, 1H), 8.78 - 8.60 (m, 1H), 7.96 (dd, J = 6..0, 9.2 Hz, 1H), 7.46 (br d, J = 9.2 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.35 (s, 1H), 7.21 (d, J = 2.4 Hz, 1H), 4.25 (s, 3H), 4.01 - 3.78 (m, 1H), 3.67 - 3.48 (m, 1H), 3.27 (br d, J = 12.4 Hz, 2H), 2.81 - 2.70 (m, 1H), 2.47 - 2.37 (m, 8H), 1.91 - 1.78 (m, 2H), 1.65 (br s, 5H), 0.62 - 0.59 (m, 2H), 0.45 - 0.41 (m, 2H).
실시예 18: 1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-6-(6-methyl-5-(trifluoromethyl)-1 H -indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidine의 합성.
Figure PCTKR2023020084-appb-img-000059
단계 1: Intermediate 21 (210 mg, 640.06 μmol) 과 tert-butyl (1R,5S)-8-(6-chloro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (347.85 mg, 608.06 μmol)을 1,4-dioxane (2.5 mL)과 물 (0.5 mL)에 녹인 후, Cs2CO3 (625.63 mg, 1.92 mmol)　와 cataCXium A Pd G4 (46.68 mg, 64.01 μmol)를 넣는다. 반응 혼합물을 질소 하에서 90 ℃로 두 시간 교반했다. 반응 종료 후 Prep-HPLC로 정제하여 tert-butyl (1R,5S)-8-(3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (279 mg, 309.66 μmol, 48% 수율)을 노란색 고체로 얻었다.　LCMS (ES-API, m/z): [M+H]+= 820.5 ; 1H NMR (400 MHz, CDCD3, ppm): δ 8.70 (br s, 1H), 7.67 (s, 1H), 7.63 - 7.59 (m, 1H), 7.54 (br s, 1H), 7.42 (d, J = 7.2 Hz, 1H), 5.82 - 5.66 (m, 1H), 5.42 - 5.16 (m, 1H), 4.63 - 4.37 (m, 1H), 4.34 - 4.17 (m, 2H), 4.10 - 3.99 (m, 2H), 3.97 - 3.88 (m, 1H), 3.85 - 3.68 (m, 2H), 3.61 - 3.37 (m, 2H), 3.32 - 3.11 (m, 3H), 3.07 - 2.95 (m, 1H), 2.73 (br s, 3H), 2.61 - 2.42 (m, 1H), 2.35 - 2.10 (m, 5H), 2.02 - 1.93 (m, 3H), 1.91 - 1.66 (m, 7H), 1.53 - 1.45 (m, 9H).
단계 2: 단계 1에서 얻은 tert-butyl (1R,5S)-8-(3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (100 mg, 121.97 μmol)　을 DCM (1 mL)에 녹인 후 TFA (767.50 mg, 6.73 mmol)을 넣는다. 반응 혼합물을 상온에서 한 시간 동안 반응했다. 반응 종료 후 반응 화합물을 Prep-HPLC로 정제하였다. 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine (25.17 mg, 38.80 μmol, 32% 수율)을 흰색 고체로 얻었다. 　LCMS (ES-API, m/z): [M+H]+= 636.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 13.52 - 13.32 (m, 1H), 9.05 - 8.48 (m, 1H), 7.74 - 7.63 (m, 2H), 7.59 - 7.51 (m, 1H), 7.34 (s, 1H), 5.37 - 5.18 (m, 1H), 4.17 (br s, 1H), 4.10 (s, 1H), 4.07 - 4.01 (m, 1H), 3.28 (s, 3H), 3.09 (br dd, J = 2.0, 8.0 Hz, 2H), 3.05 - 3.00 (m, 1H), 2.87 - 2.74 (m, 2H), 2.66 (br d, J = 1.6 Hz, 3H), 2.47 - 2.41 (m, 2H), 2.21 - 2.08 (m, 2H), 2.06 (br s, 3H), 1.90 - 1.70 (m, 5H).
실시예 19: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-((( S )-3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000060
Intermediate 12를 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(((S)-3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (23 mg, 35.05 μmol, 28% 수율)를 노란색 고체로 얻었다.　LCMS (ES-API, m/z): [M+H]+= 650.5; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.18 - 10.04 (m, 1H), 8.82 - 8.58 (m, 1H), 7.96 (dd, J = 6.0, 9.2 Hz, 1H), 7.48 (s, 1H), 7.42 (t, J = 9.2 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.22 (d, J = 2.4 Hz, 1H), 4.69 - 4.48 (m, 1H), 4.46 - 4.04 (m, 4H), 4.03 - 3.75 (m, 1H), 3.72 - 3.38 (m, 2H), 3.29 - 3.13 (m, 2H), 2.96 - 2.69 (m, 3H), 2.36 (br s, 3H), 2.28 - 2.15 (m, 2H), 2.13 - 1.94 (m, 1H), 1.93 - 1.73 (m, 3H), 1.71 - 1.62 (m, 1H), 1.54 - 1.34 (m, 2H), 0.65 (s, 2H), 0.43 (s, 2H).
실시예 20: 6-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000061
단계 1: tert-Butyl (1R,5S)-3-(6-chloro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (62.28 mg, 108.86 μmol), intermediate 23 (64 mg, 90.72 μmol), CuI (4.32 mg, 22.68 μmol), LiCl (9.61 mg, 226.80 μmol), cataCXium Pd G4 (16.54 mg, 22.68 μmol) 을 1,4-dioxane (2 mL)에 동시에 녹인 후 질소로 3회 퍼지하였다. 그 다음 반응 혼합물을 110 ℃에서 12시간 동안 교반하였다. 반응 종료 후 silica gel chromatography로 정제하여 tert-butyl (1R,5S)-8-(6-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (31 mg, 29.31 μmol, 32% 수율)를 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 952.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 1.41 (br s, 9 H), 1.56 - 1.62 (m, 6 H), 1.69 (br s, 4 H), 1.89 - 1.94 (m, 4 H), 2.39 (br s, 3 H), 2.77 - 2.88 (m, 2 H), 3.05 - 3.13 (m, 2 H), 3.73 (s, 6 H), 4.02 - 4.14 (m, 2 H), 4.16 - 4.32 (m, 2 H), 4.59 - 4.75 (m, 4 H), 5.13 - 5.39 (m, 1 H), 6.79 (s, 1 H), 6.87 (br d, J = 8.0 Hz, 4 H), 7.19 (d, J = 8.4 Hz, 5 H), 7.26 - 7.29 (m, 1 H), 7.64 - 7.69 (m, 1 H).
단계 3: 단계 2에서 얻은 tert-butyl (1R,5S)-8-(6-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (24 mg, 25.21 μmol)를 dichloroethane (0.24 mL)에 녹인 후 TFA (368.40 mg, 3.23 mmol)을 넣는다. 반응 혼합물을 60 ℃에서 한 시간 동안 교반했다. 포화 NaHCO3 용액을 넣어 반응을 종료하고 ethyl acetate로 추출했다. 반응 혼합물을 Prep-HPLC로 정제하여 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (3.61 mg, 4.93 μmol, 20% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 612.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 1.19 - 1.28 (m, 2 H), 1.70 - 1.87 (m, 4 H), 1.96 - 2.08 (m, 3 H), 2.09 - 2.24 (m, 2 H), 2.37 (s, 3 H), 2.71 - 2.86 (m, 2 H), 3.01 (s, 1 H), 3.08 (br d, J = 6.4 Hz, 2 H), 3.13 - 3.23 (m, 2 H), 3.23 - 3.28 (m, 2 H), 3.92 - 4.27 (m, 4 H), 5.11 - 5.42 (m, 1 H), 6.50 (s, 1 H), 6.73 (s, 2 H), 7.18 (s, 1 H), 7.59 (s, 1 H).
실시예 21: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((( R )-2-methylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000062
(R)-(2-Methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-3-(((R)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (32.76 mg, 122.23 μmol, 36% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 616.3; 1H NMR (400 MHz, MeOD, ppm): δ 8.87 - 8.62 (m, 1H), 7.82 (dd, J = 5.8, 9.1 Hz, 1H), 7.51 (s, 1H), 7.41 (s, 1H), 7.32 (d, J = 2.5 Hz, 1H), 7.29 - 7.21 (m, 2H), 5.00 (s, 2H), 4.53 - 4.23 (m, 4H), 3.78 (br d, J = 14.4 Hz, 1H), 3.55 - 3.34 (m, 2H), 3.25 - 3.15 (m, 1H), 3.09 - 2.58 (m, 6H), 2.51 (br d, J = 15.9 Hz, 1H), 2.26 - 1.80 (m, 8H), 1.36 - 1.21 (m, 2H).
실시예 22: 1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidine의 합성.
Figure PCTKR2023020084-appb-img-000063
((2-Fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane과 (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine (56.5 mg, 90.56 μmol, 50% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 618.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 1.67 - 1.73 (m, 1 H), 1.74 - 1.83 (m, 2 H), 1.83 - 1.92 (m, 2 H), 1.92 - 2.07 (m, 2 H), 2.08 - 2.27 (m, 1 H), 2.28 - 2.39 (m, 1 H), 2.52 - 2.65 (m, 3 H), 2.66 - 2.90 (m, 2 H), 3.01 (dt, J = 9.6, 4.91 Hz, 1 H), 3.08 - 3.32 (m, 3 H), 3.71 (br d, J = 14.8 Hz, 2 H), 3.93 (br dd, J = 2.8, 1.38 Hz, 1 H), 3.99 - 4.11 (m, 2 H), 4.20 (br d, J = 2.4 Hz, 1 H), 6.63 - 6.90 (m, 1 H), 7.39 (s, 1 H), 7.47 (br s, 1 H), 7.57 (t, J = 9.2 Hz, 1 H), 7.64 - 7.72 (m, 2 H), 8.15 - 8.24 (m, 2 H), 8.59 - 8.79 (m, 1 H).
실시예 23: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성
Figure PCTKR2023020084-appb-img-000064
(S,Z)-(2-(Fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (8 mg, 12.27 μmol, 13% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 634.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.12 (br s, 1H), 8.86 - 8.56 (m, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.49 (s, 1H), 7.43 (t, J = 9.2 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.22 (d, J = 2.0 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.90 - 6.63 (m, 1H), 5.61 (d, J = 7.6 Hz, 1H), 5.28 (br s, 2H), 4.20 (br s, 1H), 4.10 - 4.09 (m, 1H), 4.11 - 4.01 (m, 2H), 3.72 (br d, J = 15.2 Hz, 1H), 3.27 (br s, 3H), 3.11 - 2.90 (m, 2H), 2.85 - 2.70 (m, 1H), 2.63 - 2.53 (m, 3H), 2.40 - 2.30 (m, 1H), 2.12 - 1.94 (m, 2H), 1.92 - 1.68 (m, 5H).
실시예 24: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000065
((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane 대신 intermediate 18을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (38 mg, 59.51 μmol, 47% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 621.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.46 (s , 0.44H), 7.96 (s , 0.45H), 7.74 - 7.78 (m, 1H), 7.30 (d, J = 9.2Hz, 2H), 7.24 - 7.28 (m, 2H), 7.04 - 7.07 (m, 2H), 5.59 (s, 2H), 5.36 (d, J = 55.6Hz, 1H), 4.01 - 4.13 (m, 2H), 3.33 - 3.59 (m , 4H), 2.98 - 3.15 (m, 4H), 2.78 - 2.88 (m, 1H), 1.95 - 2.23 (m, 5H), 1.78 - 1.84 (m, 5H), 1.53 (brs, 1H).
실시예 25: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-7-fluorobenzo[ d ]thiazol-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000066
tert-Butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate을 사용하여 실시예 15와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-7-fluorobenzo[d]thiazol-2-amine (71.61 mg, 118.61 μmol, 53% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 604.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.53 (br d, J = 2.8 Hz, 1H), 8.07 - 7.94 (m, 4H), 7.93 - 7.55 (m, 2H), 7.06 (t, J = 8.8 Hz, 1H), 5.40 - 5.19 (m, 1H), 4.15 - 3.97 (m, 2H), 3.74 - 3.62 (m, 1H), 3.54 (br d, J = 13.2 Hz, 2H), 3.39 (br s, 1H), 3.15 - 2.99 (m, 4H), 2.89 - 2.80 (m, 1H), 2.21 - 1.96 (m, 4H), 1.91 - 1.72 (m, 4H), 1.65 - 1.41 (m, 3H).
실시예 26: 1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-6-(6-methyl-5-(trifluoromethyl)-1 H -indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidine의 합성.
Figure PCTKR2023020084-appb-img-000067
tert-Butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate을 사용하여 실시예 18과 동일한 방법으로 합성하였다. 1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine (25.36 mg, 39.89 μmol, 23% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 636.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 13.44 (br s, 1H), 8.58 (br s, 1H), 8.02 (br s, 1H), 7.74 - 7.63 (m, 2H), 7.51 - 7.24 (m, 2H), 5.41 - 5.15 (m, 1H), 4.18 - 3.97 (m, 2H), 3.81 - 3.37 (m, 5H), 3.16 - 3.00 (m, 4H), 2.89 - 2.78 (m, 1H), 2.66 (br d, J = 1.6 Hz, 3H), 2.23 - 1.95 (m, 4H), 1.94 - 1.71 (m, 4H), 1.63 - 1.47 (m, 2H), 1.29 - 1.21 (m, 1H).
실시예 27: 1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidine의 합성.
Figure PCTKR2023020084-appb-img-000068
((2-Fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane과 (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine (28 mg, 44.88 μmol, 40 % 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 618.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.45 (br d, J = 1.5 Hz, 1H), 8.26 - 8.12 (m, 2H), 7.97 (br s, 1H), 7.68 (br s, 2H), 7.60 - 7.54 (m, 1H), 7.41 (br d, J = 7.5 Hz, 2H), 6.89 - 6.61 (m, 1H), 4.12 - 3.99 (m, 2H), 3.97 - 3.86 (m, 1H), 3.77 - 3.63 (m, 2H), 3.61 - 3.47 (m, 2H), 3.43 (br s, 2H), 3.09 - 2.91 (m, 2H), 2.63 - 2.52 (m, 3H), 2.34 (br d, J = 14.4 Hz, 1H), 2.24 - 2.07 (m, 1H), 2.02 - 1.94 (m, 1H), 1.93 - 1.62 (m, 5H), 1.55 - 1.42 (m, 1H).
실시예 28: 1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidine의 합성.
Figure PCTKR2023020084-appb-img-000069
((2-Fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine (42.24 mg, 69.25 μmol, 49% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 606.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.4 (br s, 1H), 8.25 - 8.13 (m, 2H), 7.97 (br s, 1H), 7.67 (br d, J = 4.8 Hz, 2H), 7.60 - 7.51 (m, 1H), 7.51 - 7.26 (m, 2H), 5.38 - 5.20 (m, 1H), 4.17 - 3.98 (m, 2H), 3.98 - 3.70 (m, 1H), 3.70 - 3.37 (m, 4H), 3.31 - 3.24 (m, 2H), 3.20 - 2.90 (m, 4H), 2.89 - 2.79 (m, 1H), 2.25 - 1.96 (m, 4H), 1.92 - 1.40 (m, 6H).
실시예 29: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000070
(S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (50 mg, 78.11 μmol, 25% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 634.2; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.40 - 9.90 (m, 1H), 8.45 (br s, 1H), 7.96 (dd, J = 6.0, 9.1 Hz, 1H), 7.54 (br s, 1H), 7.50 - 7.25 (m, 4H), 7.21 (br s, 1H), 6.94 - 6.56 (m, 1H), 4.11 - 3.90 (m, 2H), 3.74 - 3.41 (m, 5H), 3.29 - 3.23 (m, 3H), 3.05 - 2.91 (m, 2H), 2.74 - 2.52 (m, 2H), 2.34 (br d, J = 15.1 Hz, 2H), 2.11 (br d, J = 1.1 Hz, 1H), 2.02 - 1.66 (m, 6H), 1.60 - 1.31 (m, 2H).
실시예 30: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((( R )-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000071
Intermediate 14를 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (22 mg, 33.92 μmol, 33% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 636.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.28 - 9.95 (m, 1H), 8.46 (br s, 1H), 7.97 (br dd, J = 6.1, 8.9 Hz, 1H), 7.54 (br d, J = 1.0 Hz, 1H), 7.47 - 7.35 (m, 3H), 7.33 - 7.26 (m, 1H), 7.21 (br s, 1H), 5.10 (br s, 1H), 4.39 - 4.13 (m, 2H), 4.04 - 3.92 (m, 1H), 3.75 - 3.54 (m, 2H), 3.51 - 3.43 (m, 2H), 2.90 - 2.78 (m, 2H), 2.68 - 2.60 (m, 1H), 2.43 - 2.27 (m, 3H), 2.26 - 1.96 (m, 3H), 1.93 - 1.69 (m, 3H), 1.55 - 1.41 (m, 1H), 1.31 - 1.22 (m, 1H), 0.64 (br s, 2H), 0.46 (br s, 2H).
실시예 31: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((( S )-3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000072
Intermediate 12를 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((S)-3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (22.27 mg, 33.86 μmol, 30% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 650.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.1 (s , 0.93H), 8.44 (s , 0.45H), 7.94 - 7.98 (m, 1H), 7.53 (s, 0.48H), 7.36 - 7.44 (m, 3H), 7.20 (d, J = 30.8Hz, 1.6H), 4.52 (d, J = 47.6Hz, 2H), 4.22 - 4.31 (m, 2H), 3.97 (brs, 0.48H), 3.47 - 3.65 (m , 4H), 2.63 - 3.03 (m, 2H), 2.22 - 2.36 (m, 6H), 1.60 - 1.88 (m, 4H), 1.33 - 1.58 (m, 4H), 0.65 (s, 2H), 0.42 (s, 2H).
실시예 32: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 S ,7a R )-2-fluoro-6-methylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000073
Intermediate 16를 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 634.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.83 - 9.19 (m, 1H), 8.45 (br s, 1H), 7.95 (dd, J = 6.0, 9.2 Hz, 1H), 7.59 - 7.25 (m, 4H), 7.20 (br s, 1H), 5.46 - 5.19 (m, 1H), 4.92 (br s, 2H), 4.15 - 3.79 (m, 2H), 3.74 - 3.55 (m, 4H), 3.30 - 3.11 (m, 5H), 3.09 - 2.90 (m, 2H), 2.62 (br s, 2H), 2.27 - 2.05 (m, 3H), 1.94 - 1.62 (m, 2H), 1.60 - 1.20 (m, 2H).
실시예 33: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((( R )-2-methylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000074
((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol 대신 (R)-(2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((R)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (15 mg, 48.73 μmol, 37% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 616.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.36 - 9.87 (m, 1H), 8.45 (br s, 1H), 7.96 (dd, J = 6.0, 9.1 Hz, 1H), 7.54 (br s, 1H), 7.46 - 7.25 (m, 4H), 7.20 (br s, 1H), 4.90 (br s, 2H), 4.07 - 3.93 (m, 2H), 3.72 - 3.40 (m, 6H), 3.20 (br d, J = 13.9 Hz, 2H), 3.05 - 2.89 (m, 2H), 2.69 - 2.53 (m, 2H), 2.37 (br d, J = 15.6 Hz, 1H), 2.25 - 2.05 (m, 1H), 1.98 (ddd, J = 4.4, 7.1, 11.7 Hz, 1H), 1.93 - 1.64 (m, 5H), 1.60 - 1.22 (m, 2H).
실시예 34: 6-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000075
tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 을 사용하여 실시예 20과 동일한 방법으로 합성하였다. 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (5.11 mg, 11.44 μmol, 14.5% 수율)을 회백색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 616.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.49 (br d, J = 1.2 Hz, 1H), 7.98 (br s, 1H), 7.75 - 7.46 (m, 1H), 7.27 - 7.07 (m, 1H), 6.70 (br s, 2H), 6.50 (s, 1H), 5.39 - 5.14 (m, 1H), 4.16 - 3.93 (m, 2H), 3.76 - 3.44 (m, 4H), 3.25 - 3.17 (m, 1H), 3.14 - 2.94 (m, 4H), 2.90 - 2.75 (m, 1H), 2.37 (br d, J = 1.6 Hz, 3H), 2.21 - 1.94 (m, 4H), 1.90 - 1.69 (m, 4H), 1.63 - 1.18 (m, 3H).
실시예 35: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000076
Intermediate 13을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (95.78 mg, 148.54 μmol, 42% 수율)를 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 618.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 9.81 - 10.39 (m, 1 H), 8.44 (br s, 1 H), 7.96 (dd, J = 9.2, 6.00 Hz, 1 H), 7.26 - 7.57 (m, 4 H), 7.21 (br s, 1 H), 4.26 (s, 2 H), 3.89 - 4.08 (m, 1 H), 3.54 - 3.75 (m, 2 H), 3.38 - 3.53 (m, 4 H), 2.82 - 3.06 (m, 1 H), 2.38 - 2.47 (m, 6 H), 1.70 - 2.26 (m, 3 H), 1.21 - 1.57 (m, 2 H), 0.61 (br s, 2 H), 0.43 (s, 2 H).
실시예 36: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000077
Intermediate 18과 (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol를 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (36.17 mg, 56.71 μmol, 28% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 633.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.45 (br s, 1H), 7.96 (br s, 1H), 7.81 - 7.72 (m, 1H), 7.59 - 7.39 (m, 1H), 7.37 - 7.23 (m, 2H), 7.12 - 7.01 (m, 2H), 6.91 - 6.63 (m, 1H), 5.59 (br s, 2H), 4.14 - 3.95 (m, 2H), 3.71 (d, J = 14.8 Hz, 1H), 3.67 - 3.38 (m, 4H), 3.28 (br s, 2H), 3.08 - 2.88 (m, 2H), 2.62 - 2.54 (m, 2H), 2.34 (br d, J = 14.8 Hz, 1H), 2.25 - 2.04 (m, 1H), 2.02 - 1.93 (m, 1H), 1.93 - 1.67 (m, 4H), 1.62 - 1.34 (m, 2H).
실시예 37: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((( S )-2-(difluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000078
(7aR)-2-(Difluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-methanol를 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (79.66 mg, 122.23 μmol, 36% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 652.2; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.25 - 9.94 (m, 1H), 8.45 (br s, 1H), 7.96 (dd, J = 6.0, 9.2 Hz, 1H), 7.58 - 7.26 (m, 4H), 7.20 (br s, 1H), 4.19 - 4.06 (m, 2H), 4.04 - 3.88 (m, 1H), 3.71 - 3.42 (m, 5H), 3.09 - 2.85 (m, 2H), 2.70 - 2.52 (m, 3H), 2.42 (br d, J = 16.0 Hz, 1H), 2.27 - 2.06 (m, 1H), 2.04 - 1.68 (m, 6H), 1.59 - 1.35 (m, 2H).
실시예 38: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine의 합성
Figure PCTKR2023020084-appb-img-000079
(S,Z)-(2-(Fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol과 intermediate 18을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (8 mg, 12.39 μmol, 18% 수율)을 노란색 고체로 얻었다.　LCMS (ES-API, m/z): [M+H]+= 633.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.76 - 8.55 (m, 1H), 7.68 (dd, J = 5.6, 9.2 Hz, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 7.19 (t, J = 8.9 Hz, 1H), 7.15 - 7.08 (m, 2H), 6.66 - 6.38 (m, 1H), 4.64 - 4.43 (m, 1H), 4.35 - 3.99 (m, 3H), 3.98 - 3.83 (m, 3H), 3.53 - 3.31 (m, 2H), 3.28 - 3.14 (m, 1H), 2.99 - 2.84 (m, 2H), 2.82 - 2.72 (m, 1H), 2.71 - 2.58 (m, 2H), 2.58 - 2.45 (m, 1H), 2.37 (br d, J = 13.2 Hz, 2H), 2.26 - 2.11 (m, 2H), 1.95 (br s, 3H), 1.83 (ddd, J = 4.8, 8.2, 12.4 Hz, 1H).
실시예 39: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2 S ,7a R )-2-fluoro-6-methylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성
Figure PCTKR2023020084-appb-img-000080
tert-Butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate과 intermediate 16를 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-3-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (45.18 mg, 70.58 μmol, 69% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 634.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.20 - 10.06 (m, 1H), 8.78 - 8.61 (m, 1H), 7.96 (dd, J = 6.0, 9.2 Hz, 1H), 7.71 (br s, 1H), 7.52 - 7.46 (m, 1H), 7.43 (t, J = 9.2 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.21 (s, 1H), 5.44 - 5.21 (m, 1H), 4.92 (br s, 2H), 4.34 - 4.12 (m, 1H), 4.09 - 4.00 (m, 2H), 3.98 - 3.79 (m, 1H), 3.68 (br d, J = 14.0 Hz, 1H), 3.48 (br d, J = 13.6 Hz, 2H), 3.29 - 3.12 (m, 3H), 3.11 - 2.96 (m, 1H), 2.89 - 2.66 (m, 2H), 2.63 (br s, 2H), 2.25 - 2.09 (m, 3H), 2.01 - 1.62 (m, 3H).
실시예 40: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((( R )-3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000081
Intermediate 15을 사용하여 실시예 2와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (132.88 mg, 201.04 μmol, 65% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 650.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.36 - 9.95 (m, 1H), 8.56 - 7.88 (m, 2H), 7.43 (s, 2H), 7.41 - 7.29 (m, 2H), 7.21 (br d, J = 5.2 Hz, 1H), 5.25 - 5.01 (m, 1H), 4.44 (br s, 2H), 4.05 - 3.90 (m, 1H), 3.72 - 3.63 (m, 1H), 3.59 (br s, 1H), 3.55 - 3.39 (m, 3H), 3.30 - 3.13 (m, 1H), 3.04 - 2.90 (m, 1H), 2.83 - 2.70 (m, 2H), 2.70 - 2.57 (m, 3H), 2.33 (br d, J = 2.0 Hz, 1H), 2.27 - 1.97 (m, 3H), 1.97 - 1.89 (m, 3H), 1.89 - 1.79 (m, 4H), 1.79 - 1.70 (m, 1H), 1.58 - 1.43 (m, 1H).
실시예 41: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)naphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000082
단계 1: 6-Bromo-1,3-dichloro-8-methylfuro[3,2-f]quinazoline (40.0 mg, 0.120 mmol)을 DCM (3 mL)에 녹이고, 0 oC에서 tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30.7 mg, 0.145 mmol)와 DIPEA (0.064 mL, 0.361 mmol)를 차례로 첨가하여 반응 용액을 같은 온도에서 30분 동안 교반하였다. 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4으로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 고체 tert-butyl (1R,5S)-3-(6-bromo-3-chloro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.098 mmol, 81.7% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 510.1.
단계 2: THF (10 mL)에 ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (33.0 mg, 0.207 mmol)을 녹이고, NaH (78.8 mg, 0.207 mmol)을 첨가하여 30분 동안 교반 후, 단계 1에서 합성한 tert-butyl (1R,5S)-3-(6-bromo-3-chloro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg, 0.098 mmol)을 THF (1 mL)에 녹인 용액에 천천히 첨가하여 반응 용액을 상온에서 7시간 동안 교반하였다. 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4으로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 고체 tert-butyl (1R,5S)-3-(6-bromo-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (51 mg, 0.081 mmol, 39% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 631.6.
단계 3: 단계 2로부터 얻은 tert-butyl (1R,5S)-3-(6-bromo-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (28.0 mg, 0.044 mmol), 2-(3-(methoxymethoxy)naphtalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27.9 mg, 0.089 mmol), K3PO4 (28.3 mg, 0.133 mmol)을 ethanol (1.50 mL), DMF (0.30 mL), 정제수 (0.15 mL)에 녹이고, cataCXium A Pd G3 (4.84 mg, 0.007 mmol)을 첨가하여 반응 용액을 80 oC에서 5분 동안 교반하였다. 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4으로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 고체 tert-butyl (1R,5S)-3-(3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(3-(methoxymethoxy)naphthalen-1-yl)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30.0 mg, 0.041 mmol, 93% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 738.9.
단계 4: 단계 3으로부터 얻은 tert-butyl (1R,5S)-3-(3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(3-(methoxymethoxy)naphthalen-1-yl)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30.0 mg, 0.041 mmol)을 DCM (1 mL)에 녹이고, 0 oC에서 1,4-dioxane에 녹여진 4 N 염산 용액 (0.50 mL)을 첨가하여 반응 용액을 상온에서 30분 동안 교반하였다. 용매를 농축하여 Prep-HPLC를 이용하여 정제한 후, 동결 건조하여 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol (17.0 mg, 0.029 mmol, 70% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 594.8; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 7.84 (d, J = 8.3 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.40 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.24 - 7.17 (m, 2H), 6.88 (s, 1H), 5.66 (s, 0.5H), 5.53 (s, 0.5H), 4.61 (s, 2H), 4.37 - 4.23 (m, 3H), 4.15 (s, 2H), 3.95 - 3.88 (m, 4H), 3.37 - 3.27 (m, 2H), 2.43 (s, 3H), 2.25 - 2.13 (m, 4H), 2.11 - 1.86 (m, 6H).
실시예 42: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000083
단계 1: tert-Butyl (1R,5S)-3-(6-bromo-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (51.0 mg, 0.081 mmol), ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (62.2 mg, 0.121 mmol), K3PO4 (51.5 mg, 0.243 mmol)을 ethanol (1.50 mL), DMF (0.30 mL), 정제수 (0.15 mL)에 녹이고, cataCXium A Pd G3 (8.82 mg, 0.012 mmol)을 첨가하여 반응 용액을 80 ℃에서 1시간 동안 교반하였다. 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4으로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 고체 화합물로 tert-butyl (1R,5S)-3-(6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (62.0 mg, 0.076 mmol, 81% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 937.4.
단계 2: 단계 1로부터 얻은 tert-butyl (1R,5S)-3-(6-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (62.0 mg, 0.066 mmol)을 THF (0.5 mL)에 녹이고, 0 oC에서 THF에 녹여진 1 M TBAF (0.13 mL, 0.132 mmol)를 첨가하여 반응 용액을 상온에서 20분 동안 교반하였다. 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4으로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 고체 화합물로 tert-butyl (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg, 0.064 mmol, 97% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 780.9.
단계 3: 단계 2로부터 얻은 tert-butyl (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50.0 mg, 0.064 mmol)을 DCM (1 mL)에 녹이고, 0 ℃에서 1,4-dioxane에 녹여진 4 N HCl 용액 (0.30 mL)을 첨가하여 반응용액을 상온에서 30분 동안 교반하였다. 용매를 농축하여 Prep-HPLC를 이용하여 정제한 후, 동결 건조하여 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (38.0 mg, 0.051 mmol, 79% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 636.9; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.00 (dd, J = 9.2, 6.0 Hz, 1H), 7.52 - 7.35 (m, 3H), 7.19 (d, J = 2.5 Hz, 1H), 6.82 (s, 1H), 5.66 (s, 0.5H), 5.53 (s, 0.5H), 4.64 (s, 2H), 4.36 - 4.24 (m, 1H), 4.22 - 4.10 (m, 3H), 3.97 - 3.82 (m, 4H), 3.35 - 3.26 (m, 2H), 2.41 (s, 3H), 2.36 - 2.30 (m, 2H), 2.27 - 2.13 (m, 3H), 2.11 - 2.04 (m, 1H), 2.04 -1.86 (m, 5H).
실시예 43: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)naphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000084
단계 1: tert-Butyl (1R,5S)-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60.0 mg, 0.114 mmol), 2-[3-(methoxymethoxy)naphtalene-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (53.8 mg, 0.171 mmol), Cs2CO3 (112 mg, 0.342 mmol)을 toluene (1.00 mL), 정제수 (0.25 mL)에 녹이고, cataCXium A Pd G3 (8.3 mg, 0.011 mmol)을 첨가하여 반응용액을 100 ℃에서 2시간 동안 교반하였다. 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4으로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 고체 tert-butyl (1R,5S)-3-(3-chloro-5-fluoro-6-(3-(methoxymethoxy)naphthalen-1-yl)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20.0 mg, 0.032 mmol, 28% 수율)을 합성하였다. LCMS (ES-API, m/z): [M+H]+= 634.3.
단계 2: THF (3.00 mL)에 ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (50.3 mg, 0.316 mmol)을 녹이고, NaH (12.6 mg, 0.316 mmol)을 첨가하여 30분 동안 교반했다. 단계 1로부터 얻은 tert-butyl (1R,5S)-3-(3-chloro-5-fluoro-6-(3-(methoxymethoxy)naphthalen-1-yl)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20.0 mg, 0.032 mmol)을 반응 용액에 첨가하여 반응용액을 70 ℃에서 하루 동안 교반하였다. 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4으로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 고체 tert-butyl (1R,5S)-3-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(3-(methoxymethoxy)naphthalen-1-yl)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (15.0 mg, 0.020 mmol, 63% 수율)을 합성하였다. LCMS (ES-API, m/z): [M+H]+= 756.6.
단계 3: 단계 2로부터 얻은 tert-butyl (1R,5S)-3-(5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(3-(methoxymethoxy)naphthalen-1-yl)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (23.0 mg, 0.030 mmol)을 DCM (3.00 mL)에 녹이고, 0 ℃에서 1,4-dioxane에 녹여진 4 N 염산 용액 (0.2 mL)을 첨가하여 반응용액을 상온에서 3시간 동안 교반하였다. 용매를 농축하여 Prep-HPLC를 이용하여 정제한 후, 동결 건조하여 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol (15.0 mg, 0.025 mmol, 65% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 612.8; 1H NMR (400 MHz, MeOD) δ=7.69 (d, J = 8.3 Hz, 1H), 7.33 (ddd, J = 8.1, 6.7, 1.2 Hz, 1H), 7.28 - 7.17 (m, 2H), 7.15 - 7.02 (m, 2H), 6.77 (d, J = 1.2 Hz, 1H), 5.54 (t, J = 3.7 Hz, 1, 0.5H), 5.41 (s, 0.5H), 4.64 (d, J = 1.6 Hz, 2H), 4.49 (t, J = 13.3 Hz, 2H), 4.08 (s, 2H), 4.02 - 3.71 (m, 5H), 3.37 (td, J = 10.7, 6.1 Hz, 1H), 3.25 (s, 1H), 2.77 - 2.18 (m, 9H), 2.18 - 1.85 (m, 6H).
실시예 44: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000085
단계 1: tert-Butyl (1R,5S)-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.19 g, 2.26 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.74 g, 3.39 mmol), Cs2CO3 (2.21 g, 6.79 mmol)을 toluene (34.0 mL), 정제수 (8.5 mL)에 녹이고, cataCXium A Pd G3 (165 mg, 0.226 mmol)을 첨가하여 반응 용액을 100 ℃에서 하루 동안 교반하였다. 반응 혼합물에 정제수를 넣어 반응을 종결하고 Ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4으로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 얻은 물질을 농축하여 hexane으로 녹인 후, 초음파 처리하여 생긴 고체를 필터하였다. 얻은 고체를 hexane으로 씻어서 고체 화합물로 tert-butyl (1R,5S)-3-(3-chloro-5-fluoro-6-(7-fluoro-3-methyl-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (640 mg, 0.770 mmol, 34% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 831.4; 1H NMR (400 MHz, CD3OD, ppm): δ 8.04 - 7.98 (m, 1H), 7.72 (d, J = 2.6 Hz, 1H), 7.44 (t, J = 8.9 Hz, 1H), 7.33 (d, J = 2.6 Hz, 1H), 6.88 (s, 1H), 5.38 (s, 2H), 4.66 - 4.62 (m, 1H), 4.45 - 4.42 (m, 1H), 4.29 - 4.26 (m, 1H), 4.04 - 3.99 (m, 1H), 3.75 - 3.71 (m, 1H), 3.54 (s, 3H), 2.45 (s, 3H), 1.91 - 1.82 (m, 2H), 1.56 (s, 9H), 1.37 - 1.29 (m, 3H), 0.80 (dd, J = 16.0, 7.5 Hz, 18H), 0.39 (p, J = 7.5 Hz, 3H).
단계 3: THF (29 mL)에 ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.05 g, 6.61 mmol)을 녹이고, NaH (265 mg, 6.61 mmol)을 첨가하여 30분 동안 교반 후, 단계 2로부터 얻은 tert-butyl (1R,5S)-3-(3-chloro-5-fluoro-6-(7-fluoro-3-methyl-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (550 mg, 0.661 mmol)을 THF (22.0 mL)에 녹인 용액에 천천히 첨가하여 반응 용액을 상온에서 3시간 동안 교반하였다. 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4으로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 고체 화합물로 tert-butyl (1R,5S)-3-(5-fluoro-6-(7-fluoro-3-methyl-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.524 mmol, 79% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 954.5; 1H NMR (400 MHz, CD3OD, ppm): δ 7.98 (dd, J = 9.1, 5.7 Hz, 1H), 7.68 (d, J = 2.6 Hz, 1H), 7.41 (t, J = 8.9 Hz, 1H), 7.30 (t, J = 2.8 Hz, 1H), 6.82 (s, 1H), 5.47 - 5.40 (m, 0.5H), 5.36 (s, 2H), 5.32 - 5.27 (m, 0.5H), 4.84 - 4.70 (m, 1H), 4.43 - 4.23 (m, 4H), 3.99 - 3.87 (m, 1H), 3.82 - 3.71 (m, 1H), 3.53 (s, 3H), 3.50 - 3.41 (m, 1H), 3.41 - 3.22 (m, 2H), 3.14 - 3.04 (m, 1H), 2.42 (s, 3H), 2.38 - 2.16 (m, 4H), 2.13 - 2.02 (m, 3H), 1.99 - 1.83 (m, 3H), 1.55 (s, 9H), 1.47 - 1.37 (m, 1H), 0.99 - 0.89 (m, 1H), 0.86 - 0.72 (m, 18H), 0.48 - 0.42 (m, 3H).
단계 4: 단계 3으로부터 얻은 tert-butyl (1R,5S)-3-(5-fluoro-6-(7-fluoro-3-methyl-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.524 mmol)을 THF (17.5 mL)에 녹이고, 0 ℃에서 1 M TBAF in THF (1.05 mL, 1.05 mmol)를 첨가하여 반응 용액을 상온에서 20분 동안 교반하였다. 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4으로 건조하였다. 용매를 농축하여 얻은 물질을 silica gel chromatography로 정제하여 고체 화합물로 tert-butyl (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-methylnaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280 mg, 0.351 mmol, 67% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 798.3; 1H NMR (400 MHz, CD3OD, ppm): δ 7.99 (dd, J = 9.2, 5.7 Hz, 1H), 7.70 (d, J = 2.6 Hz, 1H), 7.42 - 7.34 (m, 2H), 6.81 (d, J = 1.2 Hz, 1H), 5.45 - 5.40 (m, 1H), 5.38 (s, 2H), 5.32 - 5.26 (m, 1H), 4.54 - 4.27 (m, 5H), 4.27 - 4.09 (m, 1H), 3.81 - 3.69 (m, 1H), 3.69 - 3.59 (m, 1H), 3.55 (s, 3H), 3.33 (qd, J = 3.3, 2.2 Hz, 2H), 3.14 - 3.04 (m, 1H), 2.95 - 2.88 (m, 1H), 2.42 (s, 3H), 2.38 - 2.16 (m, 3H), 2.11 - 2.00 (m, 3H), 2.00 - 1.82 (m, 4H), 1.78 - 1.69 (m, 1H), 1.55 (s, 9H).
단계 5: 단계 4로부터 얻은 tert-butyl (1R,5S)-3-(6-(8-ethynyl-7-fluoro-3-methylnaphthalen-1-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.025 mmol)을 DCM (3 mL)에 녹이고, 0 oC에서 4 N HCl in 1,4-dioxane (0.06 mL)을 첨가하여 반응 용액을 상온에서 1시간 동안 교반하였다. 용매를 농축하여 Prep-HPLC를 이용하여 정제한 후, 동결 건조하여 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (6.2 mg, 0.008 mmol, 32% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 654.3; 1H NMR (400 MHz, CD3OD, ppm): δ 7.91 (dd, J = 9.2, 5.7 Hz, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.35 (t, J = 8.9 Hz, 1H), 7.22 (d, J = 2.6 Hz, 1H), 6.85 (s, 1H), 5.66 - 5.61 (m, 1H), 5.52 - 5.48 (m, 1H), 4.82 - 4.66 (m, 3H), 4.44 - 4.35 (m, 1H), 4.27 - 4.22 (m, 1H), 4.18 - 4.14 (m, 1H), 4.09 - 3.97 (m, 2H), 3.97 - 3.84 (m, 3H), 3.54 - 3.44 (m, 1H), 2.77 - 2.58 (m, 3H), 2.47 (s, 3H), 2.43 - 2.22 (m, 3H), 2.20 - 1.95 (m, 4H).
실시예 45: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000086
2-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane을 사용하여 실시예 43과 동일한 방법으로 합성하였다. Prep-HPLC로 정제하고 동결 건조하여 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol (10 mg, 61% 수율)을 합성하였다. LCMS (ES-API, m/z): [M+H]+= 657.29; 1H NMR (400 MHz, CD3OD, ppm): δ 7.74 (dd, J = 9.0, 5.9 Hz, 1H), 7.36 (d, J = 2.7 Hz, 1H), 7.29 (t, J = 9.4 Hz, 1H), 7.05 (d, J = 2.6 Hz, 1H), 6.89 (s, 1H), 5.66 (s, 0.5H), 5.53 (s, 0.5H), 4.80 - 4.68 (m, 2H), 4.63 (s, 1H), 4.48 (s, 1H), 4.21 (d, J = 23.7 Hz, 2H), 4.05 - 3.87 (m, 4H), 2.64 (d, J = 20.5 Hz, 1H), 2.46 (s, 3H), 2.38 (t, J = 8.7 Hz, 2H), 2.14 (d, J = 48.8 Hz, 5H), 0.59 (t, J = 7.3 Hz, 2H).
실시예 46: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-5,6-difluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000087
2-(7,8-Difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane을 사용하여 실시예 43과 동일한 방법으로 합성하였다. Prep-HPLC로 정제하고 동결 건조하여 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5,6-difluoronaphthalen-2-ol (14 mg, 57% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 647.25; 1H NMR (400 MHz, CD3OD, ppm): δ 7.74 (dd, J = 9.0, 5.9 Hz, 1H), 7.36 (d, J = 2.7 Hz, 1H), 7.29 (t, J = 9.4 Hz, 1H), 7.05 (d, J = 2.6 Hz, 1H), 6.89 (s, 1H), 5.66 (s, 0.5H), 5.53 (s, 0.5H), 4.79 - 4.69 (m, 2H), 4.64 (d, J = 13.2 Hz, 1H), 4.47 (m, 1H), 4.21 (d, J = 23.4 Hz, 2H), 3.96 (m, 4H), 3.56 - 3.42 (m, 1H), 2.87 - 2.55 (m, 3H), 2.46 (s, 3H), 2.39 (q, J = 8.5 Hz, 3H), 2.14 (d, J = 49.5 Hz, 6H), 0.59 (t, J = 7.3 Hz, 3H).
실시예 47: 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)naphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000088
1-(Aminomethyl)-N,N-dimethyl-cyclobutanamine를 사용하여 실시예 43과 동일한 방법으로 합성하였다. RP-HPLC로 정제하고 동결 건조하여 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol (14 mg, 75% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 627.30; 1H NMR (400 MHz, CD3OD, ppm): δ 7.81 (d, J = 8.3 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.39 - 7.32 (m, 2H), 7.30 - 7.15 (m, 3H) 5.61 (s, 0.5H), 5.48 (s, 0.5H), 4.85 - 4.67 (m, 7H), 4.53 - 4.31 (m, 2H), 4.08 - 3.77 (m, 3H), 3.46 (t, J = 8.6 Hz, 1H), 2.72 - 2.30 (m, 11H), 2.13 (p, J = 9.0 Hz, 2H), 2.02 (d, J = 6.5 Hz, 1H).
실시예 48: 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000089
1-(Aminomethyl)-N,N-dimethyl-cyclobutanamine를 사용하여 실시예 44과 동일한 방법으로 합성하였다. Prep-HPLC로 정제하고 동결 건조하여 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (9 mg, 75% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 669.29; 1H NMR (400 MHz, CD3OD, ppm): δ 7.92 (dd, J = 9.1, 5.8 Hz, 1H), 7.42 (d, J = 2.6 Hz, 1H), 7.40 - 7.30 (m, 2H), 7.22 (t, J = 2.2 Hz, 1H), 5.59 (s, 0.5H), 5.46 (s, 0.5H), 4.76 (qd, J = 13.3, 6.8 Hz, 5H), 4.41 (dt, J = 64.6, 15.7 Hz, 3H), 3.89 (d, J = 15.0 Hz, 3H), 3.57 - 3.43 (m, 2H), 3.02 (s, 5H), 2.97 (dd, J = 15.2, 1.1 Hz, 1H), 2.84 (s, 1H), 2.68 (s, 1H), 2.64 (s, 1H), 2.51 (s, 7H), 2.36 (s, 3H), 2.19 - 1.97 (m, 4H).
실시예 49: 3-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-4-(trifluoromethyl)aniline의 합성
Figure PCTKR2023020084-appb-img-000090
단계 1: tert-Butyl (1R,5S)-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 285 μmol), N,N-bis(4-methoxybenzyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (228 mg, 428 μmol), cataCXium A Pd G3 (20.8 mg, 28.5 μmol) 및 Cs2CO3 (279 mg, 856 μmol)를 toluene (2 mL)과 물 (0.5 mL)에 넣은 후 디게싱과 질소 퍼지를 3회 반복하였다. 그 다음 반응 혼합물을 질소 하에서 110 ℃, 5시간 동안 교반했다. 출발 물질이 완전히 소모된 후, 상온으로 반응 온도를 낮추고 celite filter 를 통하여 팔라듐 촉매를 제거한 후, 유기층을 ethyl acetate로 추출했다. 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography 로 정제하여 tert-butyl (1R,5S)-3-(6-(5-(bis(4-methoxybenzyl)amino)-2-(trifluoromethyl)phenyl)-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, 82.7 μmol, 29% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 946.3.
단계 2: 실시예 43의 단계 2와 동일한 방법으로 합성하여 tert-butyl (1R,5S)-3-(6-(5-(bis(4-methoxybenzyl)amino)-2-(trifluoromethyl)phenyl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 51.6 μmol, 62% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 970.1.
단계 3: 단계 3에서 얻은 tert-butyl (1R,5S)-3-(6-(5-(bis(4-methoxybenzyl)amino)-2-(trifluoromethyl)phenyl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 41.3 μmol)에 TFA (4mL)를 넣고, 상온에서 9시간 동안 교반했다. 출발 물질이 완전히 소모된 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography로 정제하여 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-(trifluoromethyl)aniline (19 mg, 25.9 μmol, 73% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 629.6; 1H NMR (400 MHz, MeOD) δ 7.55 (d, J = 8.7 Hz, 1H), 6.89 - 6.79 (m, 1H), 6.77 (d, J = 1.2 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 5.45 (s, 0.5H), 5.25 (s, 0.5H), 4.32 (d, J = 10.3 Hz, 2H), 4.24 (dd, J = 10.3, 2.6 Hz, 2H), 3.64 (q, J = 12.7 Hz, 2H), 3.54 (s, 2H), 3.31 - 3.13 (m, 3H), 3.03 (td, J = 9.6, 5.5 Hz, 1H), 2.46 (s, 4H), 2.35 - 2.13 (m, 3H), 2.01 (dq, J = 12.0, 6.5 Hz, 2H), 1.77 (s, 2H), 1.31 (s, 1H).
실시예 50: 6-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-5-(trifluoromethyl)pyridin-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000091
단계 1: tert-Butyl (1R,5S)-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 152 μmol), N,N-bis(4-methoxybenzyl)-6-(tributylstannyl)-5-(trifluoromethyl)pyridin-2-amine (126 mg, 183 μmol), tetrakis(triphenylphosphine)palladium(0) (35.2 mg, 30.4 μmol) 및 Lithium chloride (19.3 mg, 456 μmol), Copper(I) iodide (5.8 mg, 30.4 μmol) 를 1.4-dioxane (2 mL) 에 넣은 후 디게싱과 질소 퍼지를 3회 반복하였다. 그 다음 반응 혼합물을 질소 하에서 130 ℃, 8시간 동안 교반했다. 출발 물질이 완전히 소모된 후, 상온으로 반응 온도를 낮추고 celite filter 를 통하여 팔라듐 촉매를 제거하고 유기층을 Ethyl acetate로 추출했다. 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography로 정제하여 tert-butyl (1R,5S)-3-(6-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 47.2 μmol, 31% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 848.3.
단계 2: 실시예 43의 단계 2와 동일한 방법으로 합성하여 tert-butyl (1R,5S)-3-(6-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 30.9 μmol, 37% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 971.1.
단계 3: 단계 2에서 얻은 tert-butyl (1R,5S)-3-(6-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20mg, 41.3 μmol) 에 TFA (2mL)를 넣고, 40 oC에서 9시간 동안 교반했다. 출발 물질이 완전히 소모된 후, 감압하에 농축하였다. 잔류물을 Prep-HPLC (컬럼: Waters Xbridge C18 150*50mm* 10um; 이동상: [water(0.1% TFA)-acetonitrile]; B%: 30%)로 정제하여 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-(trifluoromethyl)pyridin-2-amine (7.5 mg, 11.9 μmol, 58% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 630.6; 1H NMR (400 MHz, MeOD) δ 7.94 (d, J = 8.9 Hz, 1H), 6.87 (d, J = 1.5 Hz, 1H), 5.67 (s, 0.5H), 5.54 (s, 0.5H), 4.79 - 4.68 (m, 2H), 4.56 (d, J = 15.5 Hz, 1H), 4.48 (s, 1H), 4.19 (s, 2H), 4.14 - 3.80 (m, 5H), 3.50 (td, J = 11.0, 6.1 Hz, 1H), 2.84 - 2.55 (m, 3H), 2.52 (s, 4H), 2.38 (dq, J = 11.4, 6.4 Hz, 2H), 2.08 (d, J= 8.3 Hz, 5H).
실시예 51: 1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(5-chloro-6-methyl-1 H -indazol-4-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazoline의 합성.
Figure PCTKR2023020084-appb-img-000092
단계 1: tert-Butyl (1R,5S)-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 190 μmol), 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (107 mg, 285 μmol), Tetrakis(triphenylphosphine)palladium(0) (22 mg, 19 μmol) 및 Potassium phosphate tribasic (121 mg, 571 μmol)를 1,4-dioxane (2 mL)과 물 (0.5 mL)에 넣은 후 디게싱과 질소 퍼지를 3회 반복하였다. 그 다음 반응 혼합물을 질소 하에서 95 ℃, 30분 동안 교반하였다. 출발 물질이 완전히 소모된 후, 반응 혼합물에 물을 넣어 반응을 종결시키고 화합물을 ethyl acetate로 추출하였다. 유기층을 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography로 정제하여 tert-butyl (1R,5S)-3-(3-chloro-6-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 86.3 μmol, 45% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 696.6.
단계 2: 실시예 43의 단계 2와 동일한 방법으로 합성하여 tert-butyl (1R,5S)-3-(6-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, 30.5 μmol, 10% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 819.4.
단계 3: 단계 2에서 얻은 tert-butyl (1R,5S)-3-(6-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (25 mg, 30.5 μmol) 을 DCM (1 mL)에 녹인 후, 4.0 M HCl in 1,4-dioxane (2 mL)를 넣는다. 상온에서 1시간 동안 교반했다. 출발 물질이 완전히 소모된 것을 확인한 후, 반응 혼합물을 감압하에 농축하였다. 잔류물을 Prep-HPLC (컬럼: Waters Xbridge C18 150*50mm* 10um; 이동상: [water(0.1% TFA)-acetonitrile]; B%: 25%)로 정제하여 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(5-chloro-6-methyl-1H-indazol-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazoline (6 mg, 9.46 μmol, 31% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 630.6; 1H NMR (400 MHz, MeOD) δ 7.72 (s, 1H), 7.53 (s, 1H), 6.90 (s, 1H), 5.66 (s, 0.5H), 5.53 (s, 0.5H), 4.75 (d, J= 2.8 Hz, 3H), 4.60 (t, J = 16.6 Hz, 2H), 4.20 (s, 2H), 4.13 - 3.84 (m, 7H), 2.90 - 2.57 (m, 7H), 2.47 (s, 5H), 2.38 (dq, J = 12.2, 6.4 Hz, 3H), 2.28 - 1.92 (m, 8H).
실시예 52: 6-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-4-methylpyridin-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000093
실시예 43과 동일한 방법으로 합성하여 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-methylpyridin-2-amine (23 mg, 42% 수율)를 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 690.7; 1H NMR (400 MHz, MeOD) δ 7.19 (s, 1H), 6.98 (d, J = 1.2 Hz, 1H), 6.91 (d, J = 1.2 Hz, 1H), 5.69 (s, 0.5H), 5.56 (s, 0.5H), 4.73 (s, 2H), 4.50 (t, J = 13.1 Hz, 3H), 4.18 (s, 2H), 3.95 (d, J = 15.3 Hz, 5H), 2.68 (s, 1H), 2.63 (s, 1H), 2.60 (s, 3H), 2.54 (d, J = 1.0 Hz, 4H), 2.48 (s, 1H), 2.39 (s, 2H), 2.22 (s, 1H), 2.06 (s, 4H), 1.33 (d, J = 17.7 Hz, 2H).
실시예 53: 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-iodo-4-methylpyridin-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000094
실시예 43과 동일한 방법으로 합성하여 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-iodo-4-methylpyridin-2-amine (12 mg, 23% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 816.6; 1H NMR (400 MHz, MeOD) δ 6.86 (s, 1H), 6.78 (s, 1H), 5.69 (s, 0.5H), 5.56 (s, 0.5H), 4.73 (s, 2H), 4.50 (t, J = 13.1 Hz, 3H), 4.18 (s, 2H), 3.95 (d, J = 15.3 Hz, 5H), 2.68 (s, 1H), 2.63 (s, 1H), 2.60 (s, 3H), 2.54 (d, J = 1.0 Hz, 4H), 2.48 (s, 1H), 2.39 (s, 2H), 2.22 (s, 1H), 2.06 (s, 4H), 1.33 (d, J = 17.7 Hz, 2H).
실시예 54: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)benzo[ d ]thiazol-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000095
단계 1: tert-Butyl (1R,5S)-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 190 μmol), intermediate 20 (107 mg, 285 μmol), [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (24.8 mg, 38 μmol) 및 Potassium phosphate tribasic (121 mg, 571 μmol)를 1,4-dioxane (2 mL)과 water (0.5 mL)에 넣은 후 디게싱과 질소 퍼지를 3회 반복하였다. 그 다음 반응 혼합물을 질소 하에서 90 ℃, 24시간 동안 교반하였다. 출발 물질이 완전히 소모된 후, celite 필터로 팔라듐 촉매를 제거하였다. 반응 혼합물을 물로 희석한 후, 화합물을 ethyl acetate로 추출하였다. 유기층을 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography (15% ethyl acetate/hexane)로 정제하여 tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (26 mg, 37.4 μmol, 20% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 696.2.
단계 2: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (40.1 mg, 252 μmol), Sodium hydride (10.1 mg, 252 μmol)를 THF (2mL)에 넣고 상온에서 30분 동안 교반했다. 30분 후, 단계 1에서 얻은 tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35 mg, 50.3 μmol)를 상온에서 반응 혼합물에 넣어준 후, 1시간 교반했다. 출발 물질이 완전히 소모된 후, 천천히 물을 넣어 반응을 종결시키고 유기층을 ethyl acetate로 추출하였다. 무수 황산나트륨으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography (5% methanol/DCM)로 정제하여 tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 24.5 μmol, 49% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 833.4
단계 3: 단계 2에서 얻은 tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 24.5 μmol) 을 DCM (1 mL)에 녹인 후, 4.0 M HCl in 1,4-dioxane (2 mL)를 넣고 50 ℃에서 1시간 동안 교반했다. 출발 물질이 완전히 소모된 후, 반응 혼합물을 감압 하에 농축하였다. 잔류물을 Prep-HPLC (컬럼: Waters Xbridge C18 150*50mm* 10um; 이동상: [water(0.1% TFA)-acetonitrile]; B%: 35%)로 정제하여 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)benzo[d]thiazol-2-amine (13 mg, 21.04 μmol, 86% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 618.7; 1H NMR (400 MHz, MeOD) δ 7.85 (dd, J = 7.9, 1.3 Hz, 1H), 7.45 (d, J = 7.5 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 6.85 (d, J = 1.2 Hz, 1H), 5.65 (s, 0.5H), 5.52 (s, 0.5H), 4.85 - 4.66 (m, 3H), 4.63 (s, 1H), 4.49 (d, J = 14.5 Hz, 1H), 4.19 (s, 2H), 4.12 - 3.77 (m, 4H), 2.79 - 2.53 (m, 3H), 2.51 (s, 2H), 2.44 - 2.31 (m, 2H), 2.12 (d, J = 44.9 Hz, 4H).
실시예 55: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-7-fluorobenzo[ d ]thiazol-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000096
Intermediate 19를 사용하여 실시예 54와 동일한 방법으로 합성하였다. 동결 건조하여 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazol-2-amine (26 mg, 31.4 μmol, 83% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 636.7; 1H NMR (400 MHz, MeOD) δ 7.47 (dd, J = 8.5, 5.4 Hz, 1H), 7.11 (t, J = 8.8 Hz, 1H), 6.85 (d, J = 1.3 Hz, 1H), 5.66 (s, 0.5H), 5.53 (s, 0.5H), 4.75 (t, J = 5.3 Hz, 2H), 4.72 - 4.57 (m, 2H), 4.49 (d, J = 14.4 Hz, 1H), 4.19 (s, 2H), 4.14 - 3.82 (m, 6H), 2.78 - 2.59 (m, 3H), 2.59 - 2.45 (m, 4H), 2.38 (dq, J = 11.7, 6.5 Hz, 3H), 2.22 - 2.13 (m, 2H), 2.04 (d, J = 9.6 Hz, 4H).
실시예 56: 3-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-5-methyl-4-(trifluoromethyl)aniline의 합성.
Figure PCTKR2023020084-appb-img-000097
N,N-Bis(4-methoxybenzyl)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline을 사용하여 실시예 51과 동일한 방법으로 합성하였다. Prep-HPLC로 정제하여 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-methyl-4-(trifluoromethyl)aniline (3.3 mg, 4.36 μmol, 6% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 642.7; 1H NMR (400 MHz, MeOD) δ 7.04 (s, 1H), 6.85 (d, J = 5.3 Hz, 2H), 5.67 (s, 0.5H), 5.54 (s, 0.5H), 4.92 (s, 1H), 4.82 - 4.62 (m, 3H), 4.53 (d, J = 14.1 Hz, 2H), 4.17 (s, 1H), 4.15 - 4.03 (m, 1H), 3.94 (t, J = 14.7 Hz, 3H), 3.54 (dd, J = 10.3, 5.6 Hz, 1H), 2.81 - 2.62 (m, 2H), 2.58 (s, 1H), 2.49 (q, J = 3.2 Hz, 2H), 2.40 (dt, J = 11.3, 6.3 Hz, 1H), 2.17 (s, 1H), 2.15 - 1.93 (m, 4H).
실시예 57: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000098
Intermediate 18을 사용하여 실시예 44와 동일한 방법으로 합성하였다. Prep-HPLC로 정제하고 동결 건조하여 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (26 mg, 39.8 μmol, 26% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 653.8; 1H NMR (400 MHz, DMSO-d 6, ppm) δ 7.73 (dd, J = 9.2, 6.0 Hz, 1H), 7.28 (t, J = 9.0 Hz, 1H), 7.09 - 6.94 (m, 2H), 6.76 (s, 1H), 5.58 (s, 2H), 5.29 (s, 0.5H), 5.15 (s, 0.5H), 4.11 - 3.84 (m, 3H), 3.37 (d, J = 22.7 Hz, 4H), 3.03 (d, J = 9.2 Hz, 1H), 2.95 (s, 1H), 2.76 (d, J = 7.1 Hz, 1H), 2.31 (s, 6H), 2.14 - 1.91 (m, 4H), 1.90 - 1.64 (m, 4H), 1.51 (s, 3H).
실시예 58: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-8-methylfuro[3,2- f ]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000099
Intermediate 18과 intermediate 8을 사용하여 실시예 44와 동일한 방법으로 합성하였다. 동결건조하여 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (70mg, 96.6 μmol, 58% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 724.8; 1H NMR (400 MHz, MeOD, ppm) δ 7.79 (dd, J = 9.2, 5.8 Hz, 1H), 7.32 - 7.23 (m, 2H), 7.15 (d, J = 2.4 Hz, 1H), 6.87 (s, 1H), 4.60 (dd, J = 44.9, 13.1 Hz, 2H), 4.50 - 4.32 (m, 2H), 4.20 (d, J = 21.3 Hz, 2H), 3.96 (dd, J = 32.0, 14.2 Hz, 3H), 2.91 (s, 1H), 2.46 (s, 3H), 2.28 (s, 2H), 2.10 (s, 4H), 1.33 (dt, J = 16.9, 8.3 Hz, 3H), 1.01 (s, 2H), 0.90 (d, J = 4.5 Hz, 2H).
실시예 59: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-8-methylfuro[3,2- f ]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000100
Intermediate 8을 사용하여 실시예 44와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol(16 mg, 22.1 mmol, 58% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 726.8; 1H NMR (400 MHz, CD3OD, ppm): δ 10.26 (d, J = 13.3 Hz, 1H), 8.06 - 7.98 (m, 1H), 7.54 - 7.43 (m, 1H), 7.21 (s, 1H), 6.79 (s, 1H), 4.31 (s, 1H), 4.15 (s, 4H), 3.77 (s, 2H), 3.52 (s, 1H), 2.41 (s, 3H), 1.57 (s, 1H), 1.47 (s, 2H), 1.18 (s, 1H), 0.89 (s, 1H), 0.80 (s, 1H), 0.66 (s, 1H), 0.43 (s, 1H).
실시예 60: 6-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine의 합성
Figure PCTKR2023020084-appb-img-000101
Intermediate 3을 사용하여 실시예 20과 동일한 방법으로 합성하였다. 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (9 mg, 13.9mmol, 46% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 644.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.49 (br d, J = 1.2 Hz, 1H), 7.98 (br s, 1H), 7.75 - 7.46 (m, 1H), 7.27 - 7.07 (m, 1H), 6.70 (br s, 2H), 6.50 (s, 1H), 5.39 - 5.14 (m, 1H), 4.16 - 3.93 (m, 2H), 3.76 - 3.44 (m, 4H), 3.25 - 3.17 (m, 1H), 3.14 - 2.94 (m, 4H), 2.90 - 2.75 (m, 1H), 2.37 (br d, J = 1.6 Hz, 3H), 2.21 - 1.94 (m, 4H), 1.90 - 1.69 (m, 4H), 1.63 - 1.18 (m, 3H).
실시예 61: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-8-methyl-3-(( S )-1-(( S )-1-methylpyrrolidin-2-yl)ethoxy)furo[3,2- f ]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000102
(S)-1-((S)-1-Methylpyrrolidin-2-yl)ethanol을 사용하여 실시예 44와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-8-methyl-3-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)furo[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (5 mg, 0.008 mmol, 36% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 738.7; 1H NMR (400 MHz, CD3OD, ppm): δ 7.90 (ddd, J = 8.2, 5.8, 2.0 Hz, 1H), 7.43 - 7.30 (m, 1H), 7.22 (d, J = 2.5 Hz, 1H), 6.85 (d, J = 5.1 Hz, 1H), 5.50 (s, 1H), 4.25 (s, 1H), 4.19 (s, 2H), 4.12 - 3.96 (m, 2H), 3.83 (d, J = 8.8 Hz, 2H), 3.72 (s, 2H), 3.64 (q, J = 7.2 Hz, 3H), 3.15 (s, 2H), 2.46 (s, 3H), 2.28 - 2.01 (m, 2H), 1.58 (d, J = 6.1 Hz, 3H).
실시예 62: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-2-amino-7-fluorobenzo[ b ]thiophene-3-carbonitrile의 합성.
Figure PCTKR2023020084-appb-img-000103
단계 1: tert-Butyl (1R,5S)-3-(6-bromo-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 571 μmol), tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (358 mg, 285 μmol), dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (81.6 mg, 393 μmol) 및 Cs2CO3 (558 mg, 1710 μmol)를 1,4-dioxane (4 mL)과 물 (1 mL)에 넣은 후 디게싱과 질소 퍼지를 3회 반복하였다. 그 다음 반응 혼합물을 질소 하에서 120 ℃, 6시간 동안 교반하였다. 출발 물질이 완전히 소모된 후, celite 필터로 팔라듐 촉매를 제거하였다. 반응 혼합물을 물로 희석한 후, 화합물을 ethyl acetate로 추출하였다. 유기층을 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography로 정제하여 tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (290 mg, 393 μmol, 69% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 738.2.
단계 2: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (111.5 mg, 700 μmol), NaH (28 mg, 700 μmol)를 THF (2 mL)에 넣고 상온에서 30분 동안 교반했다. 30분 후, tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 140 μmol)를 상온에서 반응 혼합물에 넣어준 후, 50 ℃에서 2시간 교반했다. 출발 물질이 완전히 소모된 후, 상온에서 천천히 물을 넣어 반응을 종결 시키고 유기층을 ethyl acetate로 추출하였다. 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography로 정제하여 tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 59.8 μmol, 43% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 836.9.
단계 3: 실시예 54의 단계 3과 동일한 방법으로 합성하여 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (17 mg, 25.8 μmol, 43 % 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 660.7; 1H NMR (400 MHz, MeOD) δ 7.40 (dd, J = 8.4, 5.1 Hz, 1H), 7.09 (t, J = 8.9 Hz, 1H), 6.79 (s, 1H), 5.41 (s, 0.5H), 5.28 (s, 0.5H), 4.55 - 4.06 (m, 4H), 3.80 - 3.46 (m, 3H), 3.28 (dd, J = 29.1, 19.7 Hz, 39H), 3.05 (d, J = 5.5 Hz, 1H), 2.54 - 1.62 (m, 11H), 1.31 (s, 1H).
실시예 63: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-2-amino-7-fluorobenzo[ b ]thiophene-3-carbonitrile의 합성.
Figure PCTKR2023020084-appb-img-000104
단계 1: ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (139 mg, 814 μmol), Sodium tert-butoxide (156 mg, 1,630 μmol) 를 THF (1mL) 과 DMF (3 mL)에 넣고 상온에서 30분 동안 교반했다. 30분 후, 실시예 62의 단계 2에서 얻은 tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-3-chloro-5-fluoro-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 271 μmol)를 상온에서 반응 혼합물에 넣어준 후, 2시간 동안 교반했다. 출발 물질이 완전히 소모된 후, 상온에서 천천히 물을 넣어 반응을 종결시키고 유기층을 Ethyl acetate로 추출하였다. 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography로 정제하여 tert-butyl (1R,5S)-3-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-5-fluoro-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, 126 μmol, 46% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 873.3.
단계 2: 실시예 54의 단계 3과 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (32 mg, 45.2 μmol, 39% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 672.7; 1H NMR (400 MHz, MeOD) δ 7.41 (dd, J = 8.4, 5.1 Hz, 1H), 7.11 (t, J = 8.9 Hz, 1H), 6.84 (d, J = 14.4 Hz, 1.5H), 6.65 (s, 0.5H), 4.68 - 4.39 (m, 2H), 4.21 (d, J = 64.5 Hz, 2H), 3.99 - 3.60 (m, 3H), 3.22 (q, J = 7.3 Hz, 2H), 3.14 - 2.79 (m, 3H), 2.62 (d, J = 15.9 Hz, 1H), 2.49 (s, 3H), 2.35 - 1.70 (m, 7H), 1.44 - 1.14 (m, 3H).
실시예 64: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000105
(S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol을 사용하여 실시예 44와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (32 mg, 0.048 mmol, 39% 수율)를 얻었다.
LCMS (ES-API, m/z): [M+H]+= 666.7; 1H NMR (400 MHz, CD3OD, ppm): δ 8.03 - 7.99(m, 1H), 7.51-7.44 (m, 1H), 7.22 (s, 1H), 6.87 (d, J = 2.6 Hz, 1H), 6.65 (s, 1H), 4.82 - 4.66 (m, 3H), 4.44 - 4.35 (m, 1H), 4.27 - 4.22 (m, 1H), 4.18 - 4.14 (m, 1H), 4.09 - 3.97 (m, 2H), 3.97 - 3.84 (m, 3H), 3.54 - 3.44 (m, 1H), 2.77 - 2.58 (m, 3H), 2.47 (s, 3H), 2.43 - 2.22 (m, 3H), 2.20 - 1.95 (m, 4H).
실시예 65: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2 S ,7a R )-2-fluoro-6-methylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성
Figure PCTKR2023020084-appb-img-000106
Intermediate 16을 사용하여 실시예 44와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (20 mg, 70% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 666.7; 1H NMR (400 MHz, CD3OD, ppm): δ 7.90 - 7.87(m, 1H), 7.38-7.31 (m, 1H), 7.21 (s, 1H), 6.78 (z, 1H), 6.65 (s, 1H), 4.82 - 4.66 (m, 3H), 4.44 - 4.35 (m, 1H), 4.27 - 4.22 (m, 1H), 4.18 - 4.14 (m, 1H), 4.09 - 3.97 (m, 2H), 3.97 - 3.84 (m, 3H), 3.54 - 3.44 (m, 1H), 2.77 - 2.58 (m, 3H), 2.43 (s, 3H), 2.43 - 2.22 (m, 3H), 2.20 - 1.95 (m, 4H).
실시예 66: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((( S )-2-(difluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-5-fluoro-8-methylfuro[3,2- f ]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000107
(7aR)-2-(difluoromethylene)tetrahydro-1H-pyrrolizine-7a(5H)-methanol을 사용하여 실시예 44와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (27 mg, 47% 수율)을 주황색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 684.2; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.28 (s, 1H), 8.01 (m, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.21 (s, 1H), 6.84 (s, 1H), 4.16 - 3.95 (m, 3H), 3.66 (m, 1H), 3.55 - 3.46 (m, 5H), 3.00 (m, 1H), 2.68 (s, 1H), 2.38 (s, 3H), 2.33 (s, 1H), 2.00 - 1.58 (m, 9H).
실시예 67: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methylfuro[3,2- f ]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine의 합성
Figure PCTKR2023020084-appb-img-000108
tert-Butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate을 사용하여 실시예 57과 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (50 mg, 62% 수율)를 갈색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 653.2; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 7.80 (m, 1H), 7.35 (t, J = 9.0 Hz, 1H), 7.08 (m, 2H), 6.85 (s, 1H), 5.65 (s, 2H), 5.36-5.22 (m, 1H), 4.43 (s, 2H), 4.06 (m, 2H), 3.41 (s, 1H), 3.21-3.03 (m, 5H), 2.84 (m, 1H), 2.68(m, 2H), 2.41 (s, 3H), 2.16 - 1.77 (m, 14H).
실시예 68: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)naphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000109
단계 1: DCM (48 mL)에 4-bromo-7,9-dichloro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (300 mg, 0.904 mmol)을 녹인 후 DIPEA (350 mg, 2.71 mmol, 0.501 mL)을 첨가한 다음 tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 1.08 mmol)를 첨가하였다. 반응 혼합물은 상온에서 1시간 동안 교반하였다. 반응 혼합물을 물 (80 mL)로 희석하고 DCM (50 mL*3)으로 추출하였다. 유기물을 포화 NaCl 수용액(50 mL*2)으로 세척하고, NaSO4으로 건조하고, 여과하고, 농축하여 잔류물을 얻었다. 생성물을 hexane에 침전 시킨 후, 여과하고, 여과된 고체를 건조하였다. tert-Butyl (1R,5S)-3-(4-bromo-7-chloro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (437 mg, 0.861 mmol, 95% 수율)을 옅은 베이지색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 508.8.
단계 2: ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (480 mg, 3.02 mmol)을 THF (15 mL)에 녹인 후 NaH (120.6 mg, 3.02 mmol)를 0 ℃에서 첨가하고, 혼합물을 상온에서 20분간 교반 후, 단계 1에서 얻은 tert-butyl (1R,5S)-3-(4-bromo-7-chloro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (123 mg, 0.302 mmol)을 THF (5 mL)에 녹인 용액에 천천히 첨가하고 상온에서 3시간 반응하였다. 반응 혼합물을 물 (20 mL)에 붓고 ethyl acetate (50 mL*2)로 추출하였다. 합한 유기층을 NaCl 수용액 (40 mL*2)으로 세척하고 Na2SO4으로 건조하였다. 여과한 용액을 감압 하에 농축하여 잔류물을 얻었다. 잔류물을 silica gel chromatography (5% DCM/MeOH)로 정제하였다. tert-butyl (1R,5S)-3-(4-bromo-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.283 mmol, 94% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 531.4.
단계 3: 단계 2에서 얻은 tert-butyl (1R,5S)-3-(4-bromo-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (53.5 mg, 84.8 μmol), 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (32 mg, 102μmol), cataCXium® A Pd G3 (9.2 mg, 12.7 μmol) 및 Cs2CO3 (54 mg, 255 μmol)를 toluene (1.5 mL)과 물 (0.15 mL)에 녹인 후 후 디게싱과 질소 퍼지를 3회 반복하였다. 그 다음 반응 혼합물을 질소 하에서 80 ℃, 1시간 동안 교반하였다. 출발 물질이 완전히 소모된 후, 반응 혼합물을 감압 하에 농축하고 잔류물을 물 (10 mL)로 희석하고 화합물을 ethyl acetate (5 mL*2)로 추출하였다. 유기층을 포화 NaCl 수용액 (5 mL*2)으로 세척하고, 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography (5% MeOH/DCM)로 정제하였다. tert-Butyl (1R,5S)-3-(7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-(methoxymethoxy)naphthalen-1-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 84.8 μmol, 64% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 738.9.
단계 4: DCM (1 mL)에 단계 3에서 얻은 tert-butyl (1R,5S)-3-(7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-(methoxymethoxy)naphthalen-1-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 54.2 μmol)을 녹인 후 HCl in dioxane (4 N, 0.3 mL)을 첨가하였다. 반응 혼합물을 상온에서 1시간 동안 교반하였다. 출발 물질이 완전히 소모된 후, 반응 혼합물을 감압 하에 농축하고 잔류물을 얻었다. 잔류물을 Prep-HPLC (컬럼: Waters Xbridge C18 150*50mm* 10um; 이동상: [water(0.1% TFA)-ACN]; B%: 40%)로 정제하였다. 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol (25 mg, 54.2 μmol, 78% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 594.7; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 7.84 (d, J = 8.3 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.40 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.24 - 7.17 (m, 2H), 6.88 (s, 1H), 5.66 (s, 0.5H), 5.53 (s, 0.5H), 4.61 (s, 2H), 4.37 - 4.23 (m, 3H), 4.15 (s, 2H), 3.95 - 3.88 (m, 4H), 3.37 - 3.27 (m, 2H), 2.43 (s, 3H), 2.25 - 2.13 (m, 4H), 2.11 - 1.86 (m, 6H).
실시예 69: 4-(9-((1 R ,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000110
단계 1: tert-Butyl (1R,5S)-3-(4-bromo-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (107 mg, 170 μmol), (2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (87 mg, 170 μmol), cataCXium A Pd G3 (18.5 mg, 25.5 μmol) 및 Cs2CO3 (108 mg, 509 μmol)를 toluene (1 mL)과 water (0.1 mL)에 넣은 후 디게싱과 질소 퍼지를 3회 반복하였다. 그다음 반응 혼합물을 질소 하에서 80 ℃, 3시간 동안 교반하였다. 출발 물질이 완전히 소모된 후, 반응 혼합물을 감압 하에 농축하고 잔류물을 정제수 (10mL)로 희석하고 화합물을 ethyl acetate (5 mL*2)로 추출하였다. 유기층을 포화 NaCl 수용액 (5 mL*2)으로 세척하고, 무수 Na2SO4으로 건조한 후, 감압하에 농축하였다. 잔류물을 silica gel chromatography(5% MeOH/DCM)로 정제하였다. tert-Butyl (1R,5S)-3-(4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 64.1 μmol, 38% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 937.2.
단계 2: 단계 1에서 얻은 tert-butyl (1R,5S)-3-(4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 64.1 μmol)을 THF (0.5 mL)에 녹인 후, TBAF (20.1 mg, 76.9 μmol)을 0℃에서 적가하였다. 출발 물질이 완전히 소모된 후, 반응 혼합물을 감압 하에 농축하고 잔류물을 정제수 (10 mL)로 희석하고 화합물을 ethyl acetate (5 mL*2)로 추출하였다. 유기층을 포화 NaCl 수용액 (5 mL*2)으로 세척하고, 무수 Na2SO4으로 건조한 후, 감압하에 농축하였다. 잔류물을 silica gel chromatography(MC: MeOH=20:1)로 정제하여 tert-butyl (1R,5S)-3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 64.1 μmol, 100% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 780.9.
단계 3: DCM (0.5 mL)에 단계 2에서 얻은 tert-butyl (1R,5S)-3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 53.4 μmol)을 녹인 후 4N HCl in dioxane(0.5 mL)을 첨가하였다. 반응 혼합물을 상온에서 1시간 동안 교반하였다. 출발 물질이 완전히 소모된 후, 반응 혼합물을 감압 하에 농축하고 잔류물을 얻었다. 잔류물을 Prep-HPLC (컬럼: Waters Xbridge C18 150*50mm* 10um; 이동상: [water(0.1% TFA)-아세토나이트릴]; B%: 25%)로 정제하였다. 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (25 mg, 39.3 μmol, 74% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 636.7; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.33 (s, 1H), 7.98 (dd, J = 9.2, 6.0 Hz, 1H), 7.45 (t, J = 9.0 Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H), 7.32 (s, 1H), 7.13 (d, J = 2.6 Hz, 1H), 5.67 (s, 0.5H), 5.54 (s, 0.5H), 4.64 - 4.54 (m, 2H), 4.39 (s, 1H), 4.20 - 4.13 (m, 2H), 4.10 (s, 3H), 3.94 - 3.81 (m, 3H), 3.69 - 3.60 (m, 3H), 3.44 (d, J = 4.2 Hz, 1H), 3.37 - 3.27 (m, 2H), 2.36 - 2.32 (m, 2H), 2.24 - 2.14 (m, 3H), 2.10 - 2.01 (m, 2H), 1.98 - 1.89 (m, 3H).
실시예 70: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000111
2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane을 사용하여 실시예 68과 동일하게 합성하였다. 잔류물을 Prep-HPLC로 정제하여 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol (16 mg, 25.8 μmol, 100% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 630.7; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.37 (s, 1H), 7.76 - 7.70 (m, 1H), 7.55 (q, J = 9.0 Hz, 1H), 7.40 (s, 1H), 7.37 (s, 1H), 7.13 (d, J = 2.3 Hz, 1H), 5.67 (s, 0.5H), 5.54 (s, 0.5H), 4.60 (s, 2H), 4.33 - 4.25 (m, 1H), 4.16 (s, 2H), 4.11 (s, 3H), 3.94 - 3.85 (m, 3H), 3.81 - 3.76 (m, 3H), 3.37 - 3.28 (m, 2H), 2.26 - 2.14 (m, 3H), 2.13 - 2.01 (m, 3H), 2.01 - 1.88 (m, 4H).
실시예 71: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine의 합성
Figure PCTKR2023020084-appb-img-000112
Intermediate 18를 사용하여 실시예 69와 동일한 방법으로 합성하였다. Prep-HPLC 정제 후 동결건조하여 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (60 mg, 94.5 μmol, 42% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 635.7; 1H NMR (400 MHz, DMSO-d 6) δ 8.28 (s, 1H), 7.75 (dd, J = 9.2, 6.0 Hz, 1H), 7.30 (t, J = 9.0 Hz, 1H), 7.16 (s, 1H), 7.01 (d, J = 2.9 Hz, 2H), 5.57 (s, 2H), 5.36 (s, 0.5H), 5.22 (s, 0.5H), 4.29 - 3.87 (m, 5H), 3.78 - 3.35 (m, 7H), 3.31 (s, 3H), 3.22 - 2.96 (m, 3H), 2.84 (q, J = 8.4 Hz, 1H), 2.21 - 1.70 (m, 7H), 1.58 (s, 3H).
실시예 72: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-(dimethylamino)azetidin-1-yl)-5-fluoro-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성
Figure PCTKR2023020084-appb-img-000113
4-Bromo-7,9-dichloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline과 N,N-dimethylazetidin-3-amine을 사용하여 실시예 68과 동일한 방법으로 합성하였다. Prep-HPLC 정제하고 동결 건조하여 노란색 고체인 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-(dimethylamino)azetidin-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (50.55 mg, 83.67 μmol, 43% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 595.3; 1H NMR (400 MHz, DMSO-d 6, ppm) δ 11.30 - 10.30 (m, 2H), 9.71 - 9.51 (m, 2H), 9.41 - 9.23 (m, 1H), 8.20 - 8.10 (m, 1H), 8.08 - 8.03 (m, 1H), 7.74 - 7.66 (m, 1H), 7.58 - 7.53 (m, 1H), 6.18 - 6.06 (m, 1H), 5.72 - 5.61 (m, 1H), 4.98 - 4.83 (m, 1H), 4.41 - 4.36 (m, 4H), 4.29 - 4.18 (m, 3H), 4.03 - 3.93 (m, 1H), 2.86 (s, 6H), 2.38 - 2.23 (m, 1H), 2.05 - 1.74 (m, 3H), 1.52 - 1.36 (m, 1H), 1.30 - 1.18 (m, 1H).
실시예 73: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000114
Intermediate 8을 사용하여 실시예 69과 동일한 방법으로 합성하였다. Prep-HPLC 정제하고 동결 건조하여 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (30 mg, 42.4 μmol, 45%)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 707.8; 1H NMR (400 MHz, DMSO-d 6, ppm) δ 10.05 (s, 1H), 8.28 (s, 1H), 7.96 (dd, J = 9.2, 6.0 Hz, 1H), 7.43 (t, J = 9.0 Hz, 1H), 7.35 (d, J = 2.6 Hz, 1H), 7.22 (s, 1H), 7.13 (d, J = 2.5 Hz, 1H), 4.27 (s, 2H), 4.06 (s, 2H), 3.85 - 3.55 (m, 3H), 3.42 (d, J = 14.8 Hz, 2H), 2.36 (q, J = 12.4 Hz, 7H), 1.99 (s, 1H), 1.83 - 1.28 (m, 7H), 1.29 - 1.04 (m, 3H), 0.64 (d, J = 4.9 Hz, 2H), 0.42 (s, 2H).
실시예 74: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000115
단계 1: (S,Z)-(2-(Fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (405 mg, 2.36 mmol), sodium tert-butoxide (454 mg, 4.73 mmol) 를 THF (3mL) 과 DMF (9 mL)에 넣고 상온에서 30분 동안 교반했다. 30분 후, tert-butyl (1R,5S)-3-(4-bromo-2,7-dimethyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 778 μmol)를 상온에서 반응 혼합물에 넣어준 후, 2시간 동안 교반했다. 출발 물질이 완전히 소모된 후, 상온에서 천천히 물을 넣어 반응을 종결 시키고 유기층을 ethyl acetate로 추출하였다. 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography (5% MeOH/DCM)로 정제하여 tert-butyl (1R,5S)-3-(4-bromo-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (470 mg, 731 μmol, 93% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 643.6.
단계 2: tert-Butyl (1R,5S)-3-(4-bromo-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 311 μmol), N-(6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)-1,1-diphenylmethanimine (295 mg, 467 μmol), cataCXium A Pd G3 (33.9 mg, 46.6 μmol) 및 Cesium carbonate (304 mg, 934 μmol)를 toluene (4 mL)과 water (1 mL)에 넣은 후 디게싱과 질소 퍼지를 3회 반복하였다. 그 다음 반응 혼합물을 질소 하에서 110 ℃, 24시간 동안 교반하였다. 출발 물질이 완전히 소모된 후, Palladium 촉매를 Celite 필터를 통해 제거했다. 잔류물을 물로 희석하고 화합물을 ethyl acetate로 추출하였다. 유기층을 무수 Na2SO4으로 건조한 후, 감압 하에 농축하였다. 잔류물을 silica gel chromatography (5% MeOH/DCM)로 정제하여 tert-butyl (1R,5S)-3-(4-(3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90 mg, 84.3 μmol, 27% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 1068.
단계 3: tert-Butyl (1R,5S)-3-(4-(3-((diphenylmethylene)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90 mg, 84.3 μmol)을 THF (2 mL)에 녹인 후, tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 126 μL, 126 μmol)을 0 ℃에서 적가했다. 반응 종료 후, 반응 혼합물을 물로 희석하고 ethyl acetate로 추출하여 감압하에 농축하였다. 잔류물을 silica gel chromatography (5% MeOH/DCM)로 정제하여 tert-butyl (1R,5S)-3-(4-(3-((diphenylmethylene)amino)-8-ethynyl-7-fluoronaphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 43.9 μmol, 52% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 912.1.
단계 4: tert-Butyl (1R,5S)-3-(4-(3-((diphenylmethylene)amino)-8-ethynyl-7-fluoronaphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (40 mg, 43.9 μmol)을 DCM (0.5 mL)에 녹인 후 4 N HCl in dioxane(1 mL)을 첨가하였다. 반응 혼합물을 상온에서 10분 동안 교반하였다. 출발 물질이 완전히 소모된 후, 반응 혼합물을 감압 하에 농축하고 잔류물을 얻었다. 잔류물을 silica gel chromatography(5% Methanol/DCM, 5% NH4OH)로 정제하여 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (18 mg, 27.8 μmol, 63% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 647.7; 1H NMR (400 MHz, MeOD) δ 8.31 (s, 1H), 7.76 (dd, J = 9.2, 5.8 Hz, 1H), 7.42 (s, 1H), 7.30 - 7.09 (m, 3H), 6.92 (s, 0.5H), 6.71 (s, 0.5H), 4.68 - 4.37 (m, 3H), 4.33 - 4.08 (m, 6H), 3.90 (d, J = 13.8 Hz, 2H), 3.78 (d, J = 14.1 Hz, 1H), 3.57 (s, 1H), 3.11 (s, 1H), 2.96 (d, J = 15.7 Hz, 1H), 2.87 (s, 1H), 2.70 (d, J = 15.7 Hz, 1H), 2.42 - 1.93 (m, 8H).
실시예 75: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000116
(S,Z)-(2-(Fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol을 사용하여 실시예 69와 동일한 방법으로 합성하였다. Prep-HPLC 정제 후 동결 건조하여 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (62 mg, 95.7 μmol, 84% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 648.7; 1H NMR (400 MHz, MeOD, ppm) δ 8.31 (s, 1H), 7.87 (dd, J = 9.2, 5.7 Hz, 1H), 7.41 (s, 1H), 7.38 - 7.24 (m, 2H), 7.20 (d, J = 2.6 Hz, 1H), 6.85 (s, 0.5H), 6.64 (s, 0.5H), 4.54 - 4.36 (m, 2H), 4.08 (d, J = 53.9 Hz, 6H), 3.87 (d, J = 13.7 Hz, 1H), 3.73 (t, J = 14.1 Hz, 2H), 3.48 - 3.30 (m, 16H), 3.02 - 2.77 (m, 3H), 2.59 (d, J = 15.6 Hz, 1H), 2.33 - 2.17 (m, 2H), 2.18 - 1.89 (m, 5H).
실시예 76: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000117
Intermediate 8을 사용하여 실시예 74과 동일한 방법으로 합성하였다. 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (30 mg, 42.4 μmol, 41% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 707.8; 1H NMR (400 MHz, MeOD, ppm) δ 8.33 (s, 1H), 7.81 (dd, J= 9.2, 5.8 Hz, 1H), 7.44 (s, 1H), 7.34 - 7.21 (m, 1H), 7.17 (d, J = 2.4 Hz, 1H), 4.66 - 4.42 (m, 2H), 4.19 (d, J= 20.4 Hz, 3H), 3.89 (dd, J = 41.4, 14.1 Hz, 2H), 2.91 (s, 1H), 2.22 (d, J = 67.0 Hz, 4H), 1.83 (d, J = 55.1 Hz, 2H), 1.51 - 1.26 (m, 2H), 0.99 (dd, J = 44.0, 5.8 Hz, 3H).
실시예 77: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-2-amino-7-fluorobenzo[ b ]thiophene-3-carbonitrile의 합성.
Figure PCTKR2023020084-appb-img-000118
Intermediate 4를 사용하여 실시예 62과 동일한 방법으로 합성하였다. 동결 건조하여 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (5.8 mg, 9.04 μmol, 11% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 707.8; 1H NMR (400 MHz, MeOD, ppm) δ 8.37 (s, 1H), 7.47 (s, 1H), 7.41 (dd, J = 8.3, 5.2 Hz, 1H), 7.08 (t, J = 8.9 Hz, 1H), 5.69 (s, 0.5H), 5.57 (s, 0.5H), 4.70 (d, J = 11.6 Hz, 3H), 4.38 - 3.74 (m, 9H), 3.50 (dq, J = 11.2, 5.9 Hz, 1H), 2.95 - 2.27 (m, 6H), 2.05 (d, J = 9.9 Hz, 5H), 1.86 (s, 2H), 1.57 (s, 2H), 1.46 - 1.25 (m, 3H).
실시예 78: 9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-7-((( S , Z )-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazoline의 합성
Figure PCTKR2023020084-appb-img-000119
Intermediate 4를 이용하여 실시예 27과 동일한 방법으로 합성하였다. 9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline (23 mg, 53% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 632.3; 1H NMR (400 MHz, MeOD, ppm): δ 8.27 (S, 1H), 8.13 - 8.09 (m, 1H), 7.67 - 7.61 (m, 1H), 7.44 - 7.39 (m, 1H), 7.38 (s, 1H), 6.79 (s, 0.5H), 6.58 (s, 0.5H), 4.34 - 4.12 (m, 3H), 4.09 (s, 3H), 4.06 (m, 1H), 3.92 - 3.88 (d, 1H), 3.69 - 3.50 (m, 5H), 3.21 - 3.19 (m, 1H), 2.96 (s, 1H), 2.81 - 2.74 (m, 2H), 2.51 - 2.47 (d, 1H), 2.20 - 2.17 (m, 1H), 2.06 - 1.84 (m, 8H).
실시예 79: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2 S ,7a R )-2-fluoro-6-methylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000120
Intermediate 16를 사용하여 실시예 32와 동일한 방법으로 합성하였다. 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (68 mg, 83% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 650.7; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.27 (s, 1H), 8.13 - 8.09 (m, 1H), 7.67 - 7.61 (m, 1H), 7.44 - 7.38 (m, 1H), 6.79 (s, 0.5H), 6.58 (s, 0.5H), 4.34 - 4.29 (m, 3H), 4.12 (s, 3H), 4.09 (m, 2H), 3.92 - 3.88 (d, 1H), 3.58 - 3.19 (m, 5H), 2.77 - 2.74 (m, 2H), 2.51 (d, 1H), 2.20 - 2.17 (m, 1H), 2.06 - 1.31 (m, 8H).
실시예 80: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000121
단계 1: 4-Bromo-7,9-dichloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (2 g, 5.71 mmol)를 ACN (30 mL)에 녹인 후 DIPEA (1.11 g, 8.57 mmol, 1.49 mL)과 tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (230 mg, 1.46 g, 6.86 mmol)를 첨가하였다. 반응 혼합물은 상온에서 1시간 동안 교반하였다. 반응 혼합물을 물 (40 mL)로 희석하고 ethyl acetate (30 mL*4)로 추출하였다. 유기물을 포화 NaCl 수용액 (50 mL*2)으로 세척하고, NaSO4으로 건조하고, 여과하고, 농축하여 잔류물을 얻었다. 생성물을 PE: EtOAc=2:1에 상온에서 30분 동안 교반하여 tert-butyl (1R,5S)-3-(4-bromo-7-chloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.1 g, 5.13 mmol, 90% 수율)을 분홍색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 527.1; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.69 (s, 1H), 4.24 (s, 3H), 4.21 (br d, J = 4.0 Hz, 2H), 4.13 - 4.02 (m, 2H), 3.59 (br d, J = 11.6 Hz, 2H), 1.69 - 1.54 (m, 4H), 1.46 (s, 9H).
단계 2: tert-Butyl (1R,5S)-3-(4-bromo-7-chloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 2.48 mmol)을 DMSO (30 mL)에 녹인 후 KF (865.15 mg, 14.89 mmol)와 ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (1.19 g, 7.45 mmol)과 18-crown-6 (2.30 g, 8.69 mmol)을 첨가했다. 반응 혼합물을 120 ℃에서 16시간 동안 반응했다. 출발 물질이 사라진 것을 확인하고 반응 혼합물에 물 (100 mL)로 희석하고 ethyl acetate(80 mL*4)으로 추출하였다. 유기물을 포화 NaCl 수용액 (50 mL*2)으로 세척하고, Na2SO4으로 건조하고, 여과하고, 농축하여 잔류물을 얻었다. 반응 혼합물은 silica gel chromatography (Eluent of 0~50% Ethyl acetate/Petroleum ether gradient)로 정제하여 tert-butyl (1R,5S)-3-(4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (545 mg, 689.09 μmol, 28% 수율)를 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 650.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.54 (s, 1H), 5.40 - 5.11 (m, 1H), 4.20 (s, 5H), 4.15 - 4.10 (m, 1H), 4.06 - 4.00 (m, 2H), 3.58 - 3.50 (m, 2H), 3.12 - 3.06 (m, 2H), 3.01 (s, 1H), 2.87 - 2.78 (m, 1H), 2.16 - 2.10 (m, 1H), 2.08 - 2.04 (m, 1H), 2.03 - 1.99 (m, 1H), 1.90 - 1.71 (m, 4H), 1.65 (br s, 4H), 1.45 (s, 9H).
단계 3: tert-butyl (1R,5S)-3-(4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 379.31 μmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (233.29 mg, 455.18 μmol), Pd(dtbpf)Cl2 (24.72 mg, 37.93 μmol), K3PO4 (241.55 mg, 1.14 mmol)을 1,4-dioxane (3 mL) 과 물 (0.75 mL)에 녹인 후 디게싱과 질소 퍼지를 3회 실시하였다. 반응 혼합물은 80 ℃에서 3시간 동안 반응하였다. 반응 종료 후 물 (10 mL)을 반응 혼합물에 넣고 ethyl acetate (10 mL*3)로 추출하였다. Silica gel chromatography 로 정제하여 tert-butyl (1R,5S)-3-(5-fluoro-4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (229 mg, 225.59 μmol, 59% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 954.5; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.42 (br s, 1H), 8.14 - 8.02 (m, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.54 (br t, J = 8.8 Hz, 1H), 7.28 (br d, J = 1.6 Hz, 1H), 5.35 (s, 2H), 5.22 (br s, 1H), 4.66 - 4.41 (m, 1H), 4.34 - 4.28 (m, 1H), 4.21 (br d, J = 4.8 Hz, 1H), 4.15 - 4.08 (m, 1H), 4.03 - 3.92 (m, 2H), 3.83 - 3.75 (m, 1H), 3.58 - 3.48 (m, 3H), 3.43 (s, 3H), 3.10 (br d, J = 6.8 Hz, 2H), 3.02 (br s, 1H), 2.88 - 2.80 (m, 1H), 2.28 - 2.15 (m, 2H), 2.10 - 2.00 (m, 2H), 1.86 - 1.73 (m, 4H), 1.47 (s, 9H), 1.28 - 1.20 (m, 2H), 0.88 - 0.80 (m, 4H), 0.69 - 0.60 (m, 18H).
단계 4: tert-Butyl (1R,5S)-3-(5-fluoro-4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (229 mg, 225.59 μmol)을 DMF (4 mL)에 녹인 후 CsF (514.02 mg, 3.38 mmol)를 넣고 상온에서 40분간 반응했다. 반응 종료 후 ethyl acetate (10 mL*4)와 포화 NaCl 수용액을 이용하여 추출하였다. Prep-TLC로 분리하여 tert-butyl (1R,5S)-3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (174 mg, 209.36 μmol, 93% 수율)을 주황색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 798.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.41 (s, 1H), 8.10 (dd, J = 6.0, 9.2 Hz, 1H), 7.74 (d, J = 2.8 Hz, 1H), 7.53 (t, J = 9.2 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 5.22 (br s, 3H), 4.27 (br s, 2H), 4.13 (br dd, J = 6.0, 10.4 Hz, 2H), 4.05 (s, 4H), 3.98 - 3.90 (m, 1H), 3.64 - 3.50 (m, 3H), 3.45 (s, 3H), 3.14 - 3.06 (m, 2H), 3.02 (br s, 1H), 2.88 - 2.80 (m, 1H), 2.15 (br dd, J = 4.4, 6.8 Hz, 1H), 2.09 - 2.00 (m, 2H), 1.89 - 1.67 (m, 7H), 1.47 (s, 9H).
단계 5: tert-Butyl (1R,5S)-3-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (174 mg, 209.36 μmol)에 HCl in 1.4-dioxane (2 M, 2.5 mL)을 넣고 0 ℃에서 한 시간 동안 반응했다. 반응 종료 후 prep-HPLC로 정제하여 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (47.05 mg, 71.26 μmol, 34% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 654.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.28 - 9.91 (m, 1H), 8.32 (s, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.44 (t, J = 9.2 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 5.39 - 5.18 (m, 1H), 4.11 (dd, J = 5.6, 10.4 Hz, 1H), 4.05 (s, 3H), 4.04 - 3.98 (m, 2H), 3.89 - 3.80 (m, 1H), 3.55 (br d, J = 13.2 Hz, 1H), 3.45 (br d, J = 8.0 Hz, 5H), 3.15 - 3.07 (m, 2H), 3.05 - 3.00 (m, 1H), 2.87 - 2.79 (m, 1H), 2.18 - 2.11 (m, 1H), 2.09 - 1.98 (m, 2H), 1.88 - 1.71 (m, 4H), 1.69 - 1.52 (m, 3H).
실시예 81: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000122
Intermediate 4를 사용하여 실시예 57과 동일한 방법으로 합성하였다. 얻어진 화합물을 prep-HPLC로 정제한 후, 동결 건조하여 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (75.99 mg, 115.06 μmol, 49% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 653.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.35 - 8.25 (m, 1H), 7.81 - 7.72 (m, 1H), 7.37 - 7.25 (m, 1H), 7.09 - 6.96 (m, 2H), 5.61 - 5.50 (m, 2H), 5.41 - 5.18 (m, 1H), 4.15 - 3.95 (m, 6H), 3.87 - 3.77 (m, 1H), 3.59 - 3.50 (m, 1H), 3.49 - 3.41 (m, 3H), 3.36 - 3.34 (m, 2H), 3.16 - 3.06 (m, 2H), 3.05 - 2.99 (m, 1H), 2.88 - 2.78 (m, 1H), 2.20 - 2.11 (m, 1H), 2.10 - 1.96 (m, 2H), 1.91 - 1.70 (m, 4H), 1.70 - 1.52 (m, 3H).
실시예 82: 9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazoline의 합성.
Figure PCTKR2023020084-appb-img-000123
((2-Fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane을 사용하여 실시예 80과 동일한 방법으로 합성하였다. 얻어진 화합물을 prep-HPLC로 정제한 후, 동결 건조하여 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline (32 mg, 49.38 μmol, 24% 수율)을 분홍색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 638.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.32 (s, 1H), 8.26 - 8.13 (m, 2H), 7.74 - 7.53 (m, 3H), 5.39 - 5.18 (m, 1H), 4.12 (dd, J = 6.0, 10.4 Hz, 1H), 4.07 - 3.98 (m, 5H), 3.87 (br d, J = 6.0 Hz, 1H), 3.59 - 3.43 (m, 5H), 3.21 - 2.96 (m, 4H), 2.89 - 2.78 (m, 1H), 2.22 - 2.12 (m, 1H), 1.99 (br s, 2H), 1.92 - 1.66 (m, 5H), 1.57 (br s, 2H).
실시예 83: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000124
2-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane을 사용하여 실시예 68과 동일한 방법으로 합성하였다. 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol (35 mg, 54.7 mmol, 86% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+= 640.7; 1H NMR (400 MHz, MeOD, ppm): δ 8.31 (s, 1H), 7.66 (dd, J = 9.2, 6.0 Hz, 1H), 7.39 (s, 1H), 7.28 - 7.16 (m, 1H), 7.05 (d, J = 2.7 Hz, 1H), 5.40 (s, 0.5H), 5.27 (s, 0.5H), 4.32 (d, J = 10.2 Hz, 2H), 4.23 (d, J = 10.3 Hz, 2H), 4.13 (s, 3H), 4.09 (s, 1H), 3.73 - 3.60 (m, 1H), 3.57 (s, 3H), 3.26 (s, 1H), 3.21 (s, 1H), 3.04 (s, 2H), 2.46 (s, 2H), 2.30 (s, 1H), 2.17 (s, 1H), 2.03 (s, 3H), 1.92 (d, J = 7.5 Hz, 1H), 1.79 (s, 2H), 0.64 (t, J = 7.2 Hz, 3H).
실시예 84: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000125
단계 1: tert-Butyl (1R,5S)-3-(4-bromo-7-chloro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.591 mmol), 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (310 mg, 0.886 mmol), cataCXium A Pd G3 (44 mg, 0.0591 mmol), Cs2CO3 (577 mg, 1.77 mmol)을 toluene (12 mL) 과 정제수 (3 mL)에 녹인 후 디게싱과 질소퍼지 3회를 하였다. 100 ℃, 3시간 교반 후 물을 넣어 반응 종료했다. Ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. Silica gel chromatography로 정제하여 갈색 오일의 tert-butyl (1R,5S)-3-(7-chloro-4-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (286 mg, 0.439 mmol, 74% 수율)를 얻었다. LCMS (ES-API, m/z): [M+H]+= 651.2.
단계 2: 단계 1에서 얻은 tert-Butyl (1R,5S)-3-(7-chloro-4-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (286mg, 0.439 mmol)을 THF (3 mL)과 DMF (3 mL)에 녹인 후 (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (376 mg, 2.2 mmol), sodium tert-butoxide (211 mg, 2.2 mmol)을 순서대로 첨가하고 40 ℃에서 3시간 교반했다. 반응 종료 후 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. silica gel chromatography로 정제하여 tert-butyl (1R,5S)-3-(4-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.191 mmol, 43% 수율)를 얻었다. LCMS (ES-API, m/z): [M+H]+= 785.9.
단계 3: tert-Butyl (1R,5S)-3-(4-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, 0.191 mmol)에 HCl in 1,4-dioxane (4 N, 2.5 mL)을 넣고 0 ℃에서 한 시간 동안 교반하였다. 반응 종료 후 prep-HPLC로 정제하여 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol (100 mg, 0.16 mmol, 82% 수율)를 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 642.7; 1H NMR (400 MHz, MeOD, ppm): δ 8.29 (s, 1H), 7.63 - 7.59 (m, 1H), 7.39 - 7.31 (m, 2H), 7.31 (s, 1H), 7.19 (s, 1H), 6.78 (s, 0.5H), 6.57 (s, 0.5H), 4.34 - 4.12 (m, 3H), 4.09 (s, 3H), 4.06 (m, 1H), 3.92 - 3.88 (d, 1H), 3.69 - 3.50 (m, 5H), 3.21 - 3.19 (m, 1H), 2.96 (s, 1H), 2.81 - 2.74 (m, 2H), 2.51 - 2.47 (d, 1H), 2.18 - 1.87 (m, 9H).
실시예 85: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000126
2-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane을 사용하여 실시예 84와 동일한 방법으로 합성하였다. 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol (33 mg, 0.049 mmol, 72% 수율)를 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 670.8; 1H NMR (400 MHz, MeOD, ppm): δ 8.33 (s, 1H), 7.70 (dd, J = 9.1, 6.0 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 7.24 (t, J = 9.3 Hz, 1H), 7.07 (d, J = 2.7 Hz, 1H), 6.78 (s, 0.5H), 6.56 (s, 0.5H), 4.35 - 4.26 (m, 3H), 4.13 (s, 5H), 3.89 (d, J = 15.1 Hz, 2H), 3.67 (d, J = 16.5 Hz, 2H), 3.59 (s, 4H), 3.47 (s, 2H), 3.32 (s, 2H), 2.50 (s, 2H), 1.92 (s, 2H), 1.80 (s, 3H), 1.31 (s, 2H), 0.68 (t, J = 7.3 Hz, 3H).
실시예 86: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000127
2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane을 사용하여 실시예 84와 동일한 방법으로 합성하였다. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol (46 mg, 0.069 mmol, 56% 수율)를 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 660.7; 1H NMR (400 MHz, MeOD, ppm): δ 8.31 (s, 1H), 7.62 (dd, J = 9.2, 4.8 Hz, 1H), 7.44 - 7.35 (m, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 6.78 (s, 0.5H), 6.57 (s, 0.5H), 4.38 - 4.27 (m, 2H), 4.22 (s, 2H), 4.14 (s, 3H), 3.89 (d, J = 15.0 Hz, 1H), 3.65 (dd, J = 12.9, 6.5 Hz, 2H), 3.59 (s, 2H), 3.49 (d, J = 14.2 Hz, 1H), 3.19 (dd, J = 10.4, 5.8 Hz, 1H), 2.85 - 2.69 (m, 2H), 2.48 (d, J = 15.2 Hz, 1H), 2.21 (s, 1H), 2.08 - 1.84 (m, 5H), 1.80 (s, 3H), 1.31 (s, 3H).
실시예 87: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000128
intermediate 8을 사용하여 실시예 80과 동일한 방법으로 합성하였다. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (26.26 mg, 35.82 μmol, 20% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 726.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.28 - 9.90 (m, 1H), 8.31 (s, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.44 (t, J = 9.2 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 4.30 (s, 2H), 4.10 (br d, J = 11.2 Hz, 1H), 4.05 (s, 3H), 3.83 (br d, J = 12.0 Hz, 1H), 3.57 (br d, J = 11.6 Hz, 2H), 3.48 (br s, 3H), 3.42 (s, 3H), 2.44 (br d, J = 1.2 Hz, 2H), 2.36 (br d, J = 9.6 Hz, 2H), 1.82 - 1.66 (m, 2H), 1.62 - 1.53 (m, 4H), 1.49 (br s, 2H), 1.17 (br t, J = 8.4 Hz, 2H), 0.64 (s, 2H), 0.41 (s, 2H).
실시예 88: 4-(9-(2,5-diazabicyclo[2.2.2]octan-2-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000129
tert-Butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate을 사용하여 실시예 80과 동일한 방법으로 합성하였다. 4-(9-(2,5-Diazabicyclo[2.2.2]octan-2-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (23.80 mg, 35.68 μmol, 18% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 654.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.72 - 9.56 (m, 1H), 8.33 (d, J = 9.2 Hz, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.44 (t, J = 8.8 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.20 - 7.07 (m, 1H), 5.40 - 5.17 (m, 1H), 4.34 (br d, J = 13.2 Hz, 1H), 4.16 - 4.08 (m, 1H), 4.06 (d, J = 4.4 Hz, 3H), 3.99 (br d, J = 10.4 Hz, 1H), 3.80 (br d, J = 10.4 Hz, 1H), 3.58 (br d, J = 11.2 Hz, 2H), 3.53 - 3.48 (m, 1H), 3.20 (br d, J = 9.2 Hz, 1H), 3.09 (br d, J = 9.2 Hz, 2H), 3.03 - 2.98 (m, 2H), 2.86 - 2.79 (m, 1H), 2.43 - 2.31 (m, 1H), 2.30 - 2.18 (m, 1H), 2.14 (br d, J = 5.6 Hz, 1H), 2.08 - 1.94 (m, 3H), 1.92 - 1.72 (m, 6H).
실시예 89: 9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(5-chloro-3,6-dimethyl-1 H -indazol-4-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazoline의 합성.
Figure PCTKR2023020084-appb-img-000130
단계 1: Intermediate 22 (100 mg, 324.08 μmol),　 tert-butyl (1R,5S)-3-(4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (199.67 mg, 307.87 μmol)　,　K3PO4 (206.37 mg, 972.23 μmol)　,　cataCXium A Pd G4 (21.12 mg, 32.41 μmol)　을 1,4-dioxane (1 mL)　과 물 (0.2 mL)에 녹인 후 디게싱과 질소 퍼지를 3회 시행하고 90 ℃에서 2시간 교반했다. 반응 종료 후 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetate를 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. 반응 잔여물은 prep-TLC로 정제하여 tert-butyl (1R,5S)-3-(4-(5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (87 mg, 99.19 μmol, 31% 수율)을 얻었다.　LCMS (ES-API, m/z): [M+H]+= 832.3.
단계 2: tert-Butyl (1R,5S)-3-(4-(5-chloro-3,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (77 mg, 92.51 μmol)를 DCM (1 mL)에 녹인 후 TFA (3.07 g, 26.92 mmol)를 적가하여 상온에서 한 시간 동안 교반하였다. 반응 종료 후 반응 혼합물에 정제수를 넣어 반응을 종결하고 ethyl acetae를 가하여 유기층을 추출하고, 무수 MgSO4로 건조하였다. 반응 잔여물은 prep-HPLC로 정제하여 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(5-chloro-3,6-dimethyl-1H-indazol-4-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline (15.36 mg, 23.63 μmol, 26% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 832.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 12.84 (br s, 1H), 8.39 (s, 1H), 7.58 (s, 1H), 5.38 - 5.19 (m, 1H), 4.17 - 4.10 (m, 1H), 4.06 (s, 2H), 4.09 - 4.00 (m, 1H), 4.05 - 4.00 (m, 1H), 3.92 - 3.84 (m, 1H), 3.59 (br d, J = 11.6 Hz, 1H), 3.53 - 3.43 (m, 3H), 3.16 - 3.05 (m, 2H), 3.04 - 2.98 (m, 1H), 2.87 - 2.79 (m, 1H), 2.52 (s, 4H), 2.22 - 2.12 (m, 1H), 2.09 - 1.97 (m, 2H), 1.89 - 1.72 (m, 4H), 1.58 (s, 6H).
실시예 90: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((( S )-2-(difluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-5-fluoro-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000131
(S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol을 사용하여 실시예 80과 동일한 방법으로 합성하였다. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (115.52 mg, 166.43 μmol, 53% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 684.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.22 - 9.95 (m, 1H), 8.32 (s, 1H), 7.97 (s, 1H), 7.48 - 7.40 (m, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 4.21 - 4.06 (m, 3H), 4.05 (s, 3H), 3.91 - 3.78 (m, 1H), 3.72 - 3.61 (m, 1H), 3.59 - 3.51 (m, 1H), 3.44 (m, 4H), 3.06 - 2.95 (m, 1H), 2.66 (br d, J = 15.6 Hz, 1H), 2.62 - 2.52 (m, 2H), 2.48 - 2.34 (m, 2H), 1.99 (m, 1H), 1.91 - 1.70 (m, 4H), 1.69 - 1.50 (m, 3H).
실시예 91: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((( S )-2-(difluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-5-fluoro-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 한 종류의 이성질체의 합성
Figure PCTKR2023020084-appb-img-000132
실시예 90의 화합물을 DAICEL CHIRALPAK AD (250mm*30mm, 10μm); 이동상: [CO2-ACN/i-PrOH (0.1% NH3·H2O)]; B%: 55%, 등용매이송 조건 (머무름시간: 1.160분)으로 분리하여 (ee% = 98.5%) 한 종류의 회전장애 이성질체 (126.94 mg, 182.88 μmol, 44% 수율)를 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 684.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.36 - 9.85 (m, 1H), 8.32 (s, 1H), 7.97 (dd, J = 6.0, 8.8 Hz, 1H), 7.44 (s, 1H), 7.40 - 7.36 (m, 1H), 7.16 (d, J = 2.4 Hz, 1H), 4.19 - 4.02 (m, 6H), 3.90 - 3.79 (m, 1H), 3.71 - 3.61 (m, 1H), 3.59 - 3.52 (m, 1H), 3.44 (br d, J = 12.0 Hz, 5H), 3.04 - 2.96 (m, 1H), 2.69 - 2.52 (m, 3H), 2.45 - 2.37 (m, 1H), 2.04 - 1.93 (m, 1H), 1.78 (br s, 4H), 1.56 (br s, 3H).
실시예 92: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((( S )-2-(difluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-5-fluoro-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 한 종류의 이성질체의 합성
Figure PCTKR2023020084-appb-img-000133
실시예 90의 화합물을 DAICEL CHIRALPAK AD (250mm*30mm, 10μm); 이동상: [CO2-ACN/i-PrOH (0.1% NH3·H2O)]; B%: 55%, 등용매이송 조건 (머무름시간: 1.605분)으로 분리하여 (ee% = 96.5%) 한 종류의 회전장애 이성질체 (98.73 mg, 141.7 μmol, 34% 수율)를 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 684.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.37 - 9.83 (m, 1H), 8.32 (s, 1H), 7.97 (dd, J = 6.0, 8.8 Hz, 1H), 7.51 - 7.35 (m, 2H), 7.16 (d, J = 2.4 Hz, 1H), 4.17 - 4.01 (m, 6H), 3.90 - 3.79 (m, 1H), 3.71 - 3.62 (m, 1H), 3.59 - 3.52 (m, 1H), 3.51 - 3.41 (m, 5H), 3.06 - 2.95 (m, 1H), 2.53 (br s, 3H), 2.43 (br s, 1H), 2.04 - 1.93 (m, 1H), 1.92 - 1.71 (m, 4H), 1.70 - 1.51 (m, 3H).
실시예 93: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000134
4-Bromo-7,9-dichloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline을 사용하여 실시예 83과 동일한 방법으로 합성하였다. 반응 잔여물을 Prep-HPLC로 정제하고 동결 건조하여 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol (40 mg, 0.061 mmol, 49% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 658.7; 1H NMR (400 MHz, MeOD, ppm): δ 8.33 (s, 1H), 7.72 (dd, J = 9.2, 5.8 Hz, 1H), 7.31 (s, 1H), 7.27 (t, J = 8.9 Hz, 1H), 7.06 (d, J = 2.6 Hz, 1H), 5.41 (s, 0.5H), 5.27 (s, 0.5H), 4.36 - 4.18 (m, 4H), 4.13 (s, 3H), 3.71 - 3.59 (m, 4H), 3.27 - 3.22 (m, 2H), 3.05 - 3.04 (m, 1H), 2.31 - 2.21 (m, 4H), 2.05 - 2.03 (m, 5H), 1.99 - 1.80 (m, 4H) 1.31 (m, 2H), 0.68 (m, 3H).
실시예 94: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-((( S , Z )-2-(fluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000135
(S,Z)-(2-(Fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol을 사용하여 실시예 80와 동일한 방법으로 합성하였다. Prep-HPLC로 정제하여 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (12 mg, 0.617 mmol, 29% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 666.7; 1H NMR (400 MHz, MeOD, ppm): δ 8.29 (s, 1H), 7.88 (dd, J = 9.2, 5.8 Hz, 1H), 7.36 (d, J = 2.6 Hz, 1H), 7.31 (t, J = 8.9 Hz, 1H), 7.22 (d, J = 2.6 Hz, 1H), 6.78 (s, 0.5H), 6.57 (s, 0.5H), 4.39 - 4.25 (m, 2H), 4.21 (t, J = 14.2 Hz, 2H), 4.13 (s, 3H), 3.90 (d, J = 15.1 Hz, 4H), 3.67 (d, J = 7.3 Hz, 2H), 3.52 (s, 2H), 2.85 - 2.70 (m, 2H), 2.48 (d, J = 15.2 Hz, 1H), 1.94 - 1.85 (m, 3H).
실시예 95: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000136
2-(7,8-Difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane을 사용하여 실시예 83과 동일한 방법으로 합성하였다. 반응 잔여물을 prep-HPLC로 정제하여 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol (56 mg, 0.086 mmol, 62% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 648.7; 1H NMR (400 MHz, MeOD, ppm): δ 8.31 (s, 1H), 7.62 (dd, J = 9.3, 4.8 Hz, 1H), 7.44 - 7.35 (m, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 5.41 (s, 0.5H), 5.28 (s, 0.5H), 4.35 (d, J = 10.4 Hz, 1H), 4.30 - 4.20 (m, 3H), 4.18 (s, 3H), 3.67 (s, 3H), 3.60 (s, 2H), 3.05 (q, J = 9.0 Hz, 1H), 2.42 (dd, J = 15.0, 4.7 Hz, 3H), 2.37 - 2.25 (m, 2H), 2.21 (dd, J = 18.9, 11.4 Hz, 2H), 2.03 (m, 2H), 1.94 - 1.84 (m, 4H).
실시예 96: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((5 S ,7a S )-5-(methoxymethyl)-2-methylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000137
Intermediate 17을 사용하여 실시예 80과 동일한 방법으로 합성하였다. 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (28.22 mg, 40.06 μmol, 34% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 692.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.20 - 9.99 (m, 1H), 8.32 (s, 1H), 7.97 (dd, J = 6.0, 9.2 Hz, 1H), 7.44 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.19 - 7.12 (m, 1H), 4.89 (br s, 2H), 4.12 - 4.00 (m, 5H), 3.93 (br dd, J = 6.0, 10.0 Hz, 1H), 3.89 - 3.81 (m, 1H), 3.60 - 3.48 (m, 5H), 3.48 - 3.42 (m, 2H), 3.28 - 3.19 (m, 6H), 2.94 - 2.84 (m, 1H), 2.62 - 2.54 (m, 1H), 2.33 (br d, J = 15.6 Hz, 1H), 2.12 - 2.04 (m, 1H), 1.96 (td, J = 2.8, 5.6 Hz, 1H), 1.82 - 1.73 (m, 1H), 1.73 - 1.55 (m, 5H).
실시예 97: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((( S )-2-(difluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-5-fluoro-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000138
(S)-(2-(Difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol을 사용하여 실시예 83과 동일한 방법으로 합성하였다. 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol (42 mg, 0.998 mmol, 61% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 688.7; 1H NMR (400 MHz, MeOD,, ppm): δ 8.33 (s, 1H), 7.70 (dd, J = 9.0, 5.9 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 7.24 (t, J = 9.4 Hz, 1H), 7.07 (d, J = 2.6 Hz, 1H), 4.40 (dd, J = 10.5, 5.1 Hz, 1H), 4.31 (dd, J = 10.5, 3.1 Hz, 2H), 4.25 (s, 1H), 4.13 (s, 3H), 3.84 (d, J = 14.4 Hz, 1H), 3.72 - 3.63 (m, 2H), 3.60 (s, 3H), 3.45 (d, J = 14.5 Hz, 1H), 3.22 - 3.15 (m, 1H), 2.86 (d, J = 16.2 Hz, 1H), 2.73 (d, J = 8.3 Hz, 1H), 2.54 (d, J = 16.0 Hz, 3H), 2.26 (s, 1H), 2.17 (d, J = 5.5 Hz, 1H), 2.00 (d, J = 17.7 Hz, 1H), 1.94 (s, 3H), 1.99 - 1.88 (m, 1H), 1.81 (s, 4H), 0.68 (t, J = 7.3 Hz, 3H).
실시예 98: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-((1-((( R )-3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000139
Intermediate 15를 사용하여 실시예 80과 동일한 방법으로 합성하였다. 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (5.24 mg, 7.46 μmol, 25% 수율)을 회백색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 682.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.23 - 9.97 (m, 1H), 7.44 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 5.24 - 5.01 (m, 1H), 4.48 - 4.37 (m, 2H), 4.14 - 4.01 (m, 4H), 3.86 (br d, J = 10.8 Hz, 1H), 3.56 (br d, J = 12.0 Hz, 1H), 3.47 (br d, J = 17.6 Hz, 4H), 2.81 - 2.61 (m, 5H), 2.42 - 2.29 (m, 1H), 2.05 - 1.83 (m, 7H), 1.80 - 1.52 (m, 5H), 1.23 (s, 1H).
실시예 99: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((( S )-2-(difluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-5-fluoro-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000140
(S)-(2-(Difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol을 사용하여 실시예 81과 동일한 방법으로 합성하였다. 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (45 mg, 65.91 μmol, 26% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 683.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.32 (s, 1H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.31 (t, J = 9.2 Hz, 1H), 7.06 - 7.00 (m, 2H), 5.57 (s, 2H), 4.17 - 4.03 (m, 7H), 3.87 - 3.77 (m, 1H), 3.70 - 3.62 (m, 1H), 3.56 (br d, J = 12.0 Hz, 1H), 3.49 - 3.44 (m, 3H), 3.06 - 2.97 (m, 1H), 2.70 - 2.56 (m, 3H), 2.41 (br d, J = 15.6 Hz, 1H), 2.04 - 1.67 (m, 6H), 1.66 - 1.52 (m, 3H).
실시예 100: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2 S ,7a R )-2-fluoro-6-methylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000141
Intermediate 16을 사용하여 실시예 80과 동일한 방법으로 합성하였다. 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (18 mg, 46% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 666.7; 1H NMR (400 MHz, MeOD, ppm): δ 8.29 (s, 1H), 7.88 (dd, J = 9.2, 5.7 Hz, 1H), 7.37 (d, J = 2.6 Hz, 1H), 7.31 (t, J = 8.9 Hz, 1H), 7.22 (d, J = 2.6 Hz, 1H), 5.45 (s, 0.5H), 5.31 (s, 0.5H), 5.01 (s, 2H), 4.36 - 4.18 (m, 3H), 4.13 (s, 3H), 3.82 (d, J = 13.5 Hz, 1H), 3.68 (t, J = 11.9 Hz, 3H), 3.45 (d, J = 15.1 Hz, 1H), 3.27 - 3.17 (m, 1H), 2.91 (d, J = 11.4 Hz, 1H), 2.80 (s, 2H), 2.32 (dd, J = 24.0, 14.7 Hz, 1H), 2.05 (d, J = 9.3 Hz, 1H), 1.92 (s, 1H), 1.86 (s, 3H), 0.91 (s, 3H).
실시예 101: 9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((( S )-2-(difluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-2-methyl-2 H -pyrazolo[4,3- f ]quinazoline의 합성.
Figure PCTKR2023020084-appb-img-000142
((2-Fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane과 (S)-(2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol을 사용하여 실시예 80과 동일한 방법으로 합성하였다. 9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (22 mg, 56% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 666.7; 1H NMR (400 MHz, MeOD, ppm): δ 8.31 (s, 1H), 8.17 - 8.09 (m, 1H), 7.73 - 7.61 (m, 1H), 7.43 (t, J = 8.9 Hz, 1H), 4.40 (dd, J = 10.6, 7.7 Hz, 1H), 4.32 (dd, J = 10.6, 6.8 Hz, 1H), 4.24 (d, J = 13.0 Hz, 2H), 4.12 (s, 3H), 3.86 (d, J = 14.5 Hz, 1H), 3.74 - 3.67 (m, 4H), 3.46 (s, 1H), 3.23 - 3.15 (m, 1H), 2.99 (s, 1H), 2.87 (d, J = 15.8 Hz, 1H), 2.75 (q, J = 8.2 Hz, 1H), 2.55 (d, J = 16.1 Hz, 1H), 2.04 (d, J = 9.2 Hz, 1H), 2.01 - 1.92 (m, 1H), 1.95 (s, 4H), 1.87 (s, 2H), 1.31 (s, 2H).
실시예 102: (4-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-9-yl)piperazin-1-yl)(oxiran-2-yl)methanone의 합성
Figure PCTKR2023020084-appb-img-000143
단계 1: 4-bromo-7,9-dichloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline (500 mg, 1.43 mmol, 1　당량)을 ACN (8 mL)에 녹여 DIPEA (369.29 mg, 2.86 mmol, 497.70 μL, 2　당량)과 tert-butyl piperazine-1-carboxylate (319.31 mg, 1.71 mmol, 1.2　당량)을 적가했다. 반응 혼합물을 상온에서 1시간동안 교반 후 여과하고 PE로 세척하여 진공 건조했다. 노란색 고체인 tert-butyl 4-(4-bromo-7-chloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate (570 mg, 비정제혼합물)을 얻었다. LCMS (ES-API, m/z): [M+H]+=501.0 ; HNMR (400 MHz, DMSO-d 6, ppm): δ 8.73 (s, 1H), 4.28 (s, 3H), 3.56 - 3.54 (m, 8H), 1.45 (s, 9H).
단계 2: tert-butyl 4-(4-bromo-7-chloro-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate을 사용하여 실시예 80의 단계 2와 같은 방법으로 합성하였다. 노란색 고체인 tert-butyl 4-(4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate (384 mg, 561.96 μmol, 74% 수율)을 얻었다. 　LCMS (ES-API, m/z): [M+H]+=624.0 ; HNMR (400 MHz, DMSO-d 6, ppm): δ 8.64 (s, 1H), 5.33 (d, J = 53.6 Hz, 1H) 4.29 (s, 3H), 4.20 - 4.07 (m, 2H), 3.63 (s, 3H), 3.55 - 3.50 (m, 4H),　3.15 - 3.06 (m, 3H),　2.93 - 2.77 (m, 2H), 2.20 - 2.03 (m, 3H), 1.93 - 1.83 (m, 3H), 1.48 (s, 9H).　
단계 3: tert-butyl 4-(4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate를 사용하여 실시예 80의 단계3과 동일한 방법으로 합성하였다. 노란색 고체인 tert-butyl 4-(5-fluoro-4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate (300 mg, 323.22 μmol, 59% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+=928.5.
단계 4: tert-butyl 4-(5-fluoro-4-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate을 사용하여 실시예 80의 단계 4와 동일한 방법으로 합성하였다. 노란색 고체인 tert-butyl 4-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate (310mg, 비정제혼합물)을 얻었다. LCMS (ES-API, m/z): [M+H]+=772.4.
단계 5: tert-butyl 4-(4-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazine-1-carboxylate을 사용하여 실시예 80의 단계 5와 동일한 방법으로 합성하였다. 노란색 고체인 5-ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(piperazin-1-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol (64 mg, 101.35 μmol, 46% 수율)을 얻었다. LCMS (ES-API, m/z): [M+H]+=628.3.
단계 6: potassium oxirane-2-carboxylate (19.29 mg, 152.95 μmol, 2.4 당량)을 DMF (0.5 mL)에 녹이고 HATU (29.08 mg, 76.47 μmol, 1.2 당량)을 적가했다. 5-ethynyl-6-fluoro-4-(5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-9-(piperazin-1-yl)-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol (40 mg, 63.73 μmol, 1 당량)과 DIPEA (24.71 mg, 191.19 μmol, 33.30 μL, 3 당량)을 반응 혼합물에 넣고 상온에서 1시간동안 교반했다. Prep-HPLC (neutral condition; column: Waters Xbridge 150*25mm* 5um;mobile phase: [water(10 mM NH4HCO3)-ACN]; gradient: 25%-55% B over 9 min)로 정제하여 노란색 고체인 (4-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazin-1-yl)(oxiran-2-yl)methanone (10.77 mg, 14.74 μmol, 12% 수율)를 얻었다. LCMS (ES-API, m/z): [M+H]+=698.4 ; HNMR (400 MHz, DMSO-d 6, ppm): δ 10.51 - 9.83 (m, 1H), 8.63 - 8.39 (m, 1H), 8.07 - 7.87 (m, 1H), 7.49 - 7.31 (m, 2H), 7.22 - 7.12 (m, 1H), 5.42 - 5.14 (m, 1H), 4.18 - 4.02 (m, 5H), 4.01 - 3.88 (m, 3H), 3.85 - 3.74 (m, 2H), 3.65 - 3.41 (m, 5H), 3.13 - 3.06 (m, 2H), 3.04 - 2.99 (m, 1H), 2.98 - 2.94 (m, 1H), 2.87 - 2.80 (m, 2H), 2.19 - 2.13 (m, 1H), 2.10 - 1.99 (m, 2H), 1.90 - 1.72 (m, 3H).
실시예 103: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성
Figure PCTKR2023020084-appb-img-000144
3-Boc-3,8-Diazabicyclo[3.2.1]octane을 사용하여 실시예 80과 동일하게 합성하였다. 4-(9-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (38 mg, 58.1 μmol, 71% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 654.3; 1H NMR (400 MHz, CD3OD, ppm): δ 8.28 (s, 1H), 7.88 (dd, J = 9.1, 5.8 Hz, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.31 (t, J = 8.9 Hz, 1H), 7.24 (d, J = 2.6 Hz, 1H), 5.42 (m, 0.5H), 5.29(m, 0.5H), 4.62 (m, 3H), 4.41-4.25 (m, 1H), 4.31(m, 1H), 4.15(s, 3H), 2.90-2.82 (m, 3H), 2.05-1.99 (m, 7H), 1.92 (m, 3H), 1.32(m, 6H).
실시예 104: 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-2-amino-7-fluorobenzo[ b ]thiophene-3-carbonitrile의 합성
Figure PCTKR2023020084-appb-img-000145
Intermediate 5를 사용하여 실시예 62와 같은 방법으로 합성하였다. 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (82 mg, 124.29 μmol, 76% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 660.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.34 (s, 1H), 7.99 - 7.88 (m, 2H), 7.38 (dd, J = 5.2, 8.4 Hz, 1H), 7.20 - 7.09 (m, 1H), 5.38 - 5.18 (m, 1H), 4.16 - 3.99 (m, 6H), 3.90 - 3.78 (m, 1H), 3.56 - 3.36 (m, 4H), 3.14 - 3.00 (m, 3H), 2.90 - 2.75 (m, 1H), 2.18 - 2.00 (m, 3H), 1.94 - 1.59 (m, 5H), 1.51 (br s, 3H).
실시예 105: 4-(9-((1 R ,4 R )-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000146
tert-Butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate을 사용하여 실시예 80과 동일한 방법으로 합성하였다. 4-(9-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (78 mg, 122.0 μmol, 77% 수율)을 미백색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 640.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.16 (s, 1H), 8.32 (d, J = 28.0 Hz, 1H), 7.99 - 7.96 (m, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.39 (m, 1H), 5.29 (d, J = 54.0 Hz, 1H), 4.86 (d, J = 55.2 Hz, 1H), 4.13-3.99 (m, 5H), 3.67-3.48 (m, 2H), 3.14-2.80 (m, 5H), 2.16-1.72 (m, 9H).
실시예 106: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((( S )-2-(difluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000147
(S)-(2-(Difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol 를 사용하여 실시예 2과 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (20 mg, 29.5 μmol, 15% 수율)을 백색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 652.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 10.12 (br d, J = 0.8 Hz, 1H), 8.81 - 8.55 (m, 1H), 7.97 (dd, J = 6.0, 9.1 Hz, 1H), 7.53 - 7.33 (m, 4H), 7.22 (s, 1H), 4.45 - 4.06 (m, 4H), 3.98 - 3.87 (m, 1H), 3.72 - 3.46 (m, 2H), 3.26 (br s, 1H), 3.05 - 2.97 (m, 1H), 2.84 - 2.55 (m, 4H), 2.43 (br d, J = 15.6 Hz, 2H), 2.18 - 1.73 (m, 8H).
실시예 107: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((( S )-2-(difluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000148
(S)-(2-(Difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol를 사용하여 실시예 1과 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol (15 mg, 22.12 μmol, 16% 수율)을 흰색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 656.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 8.79 - 8.59 (m, 1H), 7.70 - 7.64 (m, 1H), 7.60 (s, 1H), 7.56 - 7.53 (m, 1H), 7.52 - 7.47 (m, 3H), 7.22 (br d, J = 3.6 Hz, 5H), 5.27 (s, 3H), 4.26 (br d, J = 2.4 Hz, 6H), 3.99 - 3.78 (m, 3H), 3.50 (s, 6H), 3.44 - 3.24 (m, 4H), 2.97 - 2.63 (m, 3H), 1.53 - 1.47 (m, 9H), 0.67 - 0.56 (m, 5H).
실시예 108: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((( S )-2-(difluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine의 합성.
Figure PCTKR2023020084-appb-img-000149
(S)-(2-(Difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol를 실시예 14와 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-8-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (17.17 mg, 26.29 μmol, 17% 수율)을 노란색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 651.3; 1H NMR (400 MHz, DMSO-d 6, ppm): δ8.71 (br s, 1H), 7.81 - 7.71 (m, 1H), 7.53 - 7.46 (m, 1H), 7.37 - 7.26 (m, 2H), 7.11 - 7.02 (m, 2H), 5.75 - 5.48 (m, 2H), 4.49 - 4.05 (m, 4H), 4.02 - 3.86 (m, 1H), 3.74 - 3.61 (m, 1H), 3.56 - 3.44 (m, 1H), 3.38 - 3.34 (m, 2H), 3.04 - 2.54 (m, 6H), 2.47 - 2.38 (m, 1H), 2.34 - 1.65 (m, 9H).
실시예 109: 4-(1-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((( S )-2-(difluoromethylene)tetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2- d ]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol의 합성.
Figure PCTKR2023020084-appb-img-000150
(S)-(2-(Difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol를 사용하여 실시예 1과 동일한 방법으로 합성하였다. 4-(1-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol (11.65 mg, 17.61 μmol, 31% 수율)을 백색 고체로 얻었다. LCMS (ES-API, m/z): [M+H]+= 656.4; 1H NMR (400 MHz, DMSO-d 6, ppm): δ 9.83 (s, 1H), 8.69 - 8.40 (m, 1H), 8.13 - 7.95 (m, 1H), 7.75 (dd, J = 6.2, 8.8 Hz, 1H), 7.65 - 7.36 (m, 2H), 7.34 - 7.26 (m, 2H), 7.06 (s, 1H), 4.21 - 4.07 (m, 2H), 3.75 - 3.59 (m, 2H), 3.53 - 3.39 (m, 2H), 3.33 (br s, 2H), 3.03 - 2.97 (m, 1H), 2.68 - 2.54 (m, 3H), 2.48 - 2.37 (m, 3H), 2.10 - 1.92 (m, 3H), 1.88 - 1.72 (m, 4H), 1.58 - 1.48 (m, 1H), 1.38 - 1.17 (m, 2H), 0.51 (br t, J = 7.2 Hz, 3H).
실시예 110: 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-5-fluorobenzo[b]thiophene-3-carbonitrile.
Figure PCTKR2023020084-appb-img-000151
실시예 62의 합성법과 동일한 방법으로 상기 화합물을 합성한다.
실시예 111. 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-2-amino-5,7-difluorobenzo[ b ]thiophene-3-carbonitrile.
Figure PCTKR2023020084-appb-img-000152
실시예 62의 합성법과 동일한 방법으로 상기 화합물을 합성한다.
실시예 112. 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-2-amino-7-fluorothieno[3,2- c ]pyridine-3-carbonitrile.
Figure PCTKR2023020084-appb-img-000153
실시예 62의 합성법과 동일한 방법으로 상기 화합물을 합성한다.
실시예 113. 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-2-aminobenzofuran-3-carbonitrile.
Figure PCTKR2023020084-appb-img-000154
실시예 62의 합성법과 동일한 방법으로 상기 화합물을 합성한다.
실시예 114. 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-2-amino-7-fluorobenzofuran-3-carbonitrile.
Figure PCTKR2023020084-appb-img-000155
실시예 62의 합성법과 동일한 방법으로 상기 화합물을 합성한다.
실시예 115. 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-2-amino-5-fluorobenzofuran-3-carbonitrile.
Figure PCTKR2023020084-appb-img-000156
실시예 62의 합성법과 동일한 방법으로 상기 화합물을 합성한다.
실시예 116. 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine
Figure PCTKR2023020084-appb-img-000157
실시예 80의 합성법과 동일한 방법으로 상기 화합물을 합성한다.
실시예 117. 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2 R ,7a S )-2-methoxytetrahydro-1H-pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
Figure PCTKR2023020084-appb-img-000158
실시예 80의 합성법과 동일한 방법으로 상기 화합물을 합성한다.
실시예 118. 9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(5-ethynyl-6-fluoroisoquinolin-4-yl)-5-fluoro-7-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-2-methyl-2 H -pyrazolo[4,3- f ]quinazoline
Figure PCTKR2023020084-appb-img-000159
실시예 80의 합성법과 동일한 방법으로 상기 화합물을 합성한다.
실시예 119. 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((( R )-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
Figure PCTKR2023020084-appb-img-000160
실시예 80의 합성법과 동일한 방법으로 상기 화합물을 합성한다.
실시예 120. 4-(9-((1 R ,5 S )-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((1 S ,7a' S )-2,2-difluorodihydro-1' H ,3' H -spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5' H )-yl)methoxy)-5-fluoro-2-methyl-2 H -pyrazolo[4,3- f ]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
Figure PCTKR2023020084-appb-img-000161
실시예 80의 합성법과 동일한 방법으로 상기 화합물을 합성한다.
실험예 1: KRAS G12D 돌연변이 단백질에 대한 결합능 측정
본 출원의 일 예에 따른 화합물의 KRAS G12D 돌연변이 단백질에 대한 결합능을 시차 주사 형광측정법 (differential scanning fluorimetry, DSF)으로 확인하였다.
시차 주사 형광측정법은 단백질-화합물 결합에 따른 단백질의 안정성을 연구하기 위해 사용되는 방법으로, Real-time PCR (RT-PCR) 기기를 이용하여 실험할 수 있으며, 특정 단백질에 대한 저분자화합물들의 스크리닝 방법으로 사용되는 실험법 중 하나이다. 접힘 (folding) 상태의 단백질은 온도가 증가됨에 따라 풀림 (unfolding) 상태에 들어가게 되는데, 이때 단백질의 노출된 소수성 영역에 특정 염료 (SYPRO Orange)가 결합하게 되면 염료의 형광 (470nm 최대 흡수, 570nm 최대 형광 파장 방출) 세기 값이 측정된다. 단백질-화합물 결합은 화합물이 없을 때의 단백질 녹는점 (Tm)과 화합물이 있을 때의 Tm 값의 차이인 ΔTm으로 결정된다.
KRAS G12D 돌연변이 단백질에 대한 결합능 측정은 Applied biosystems사의 Protein Thermal Shift Dye kit (#4461146)를 활용하여 실험하였다. 실험에 사용된 GDP-KRAS G12D 돌연변이 단백질과 GppNHp-KRAS G12D 돌연변이 단백질은 Daegu Gyeongbuk Medical Innovation Foundation (DGMIF)에 재조합 단백질을 합성 의뢰하여 사용하였다. 화합물의 KRAS G12D 돌연변이 단백질 결합 분석은 다음의 분석 반응 레시피에 따라 진행되었다. 각 시험 샘플당 4 μg KRAS 단백질, 10 μM의 화합물, 2X SYPRO orange 염료가 사용되었으며, GDP-KRAS G12D 단백질 샘플에는 Protein Thermal Shift Dye kit 자체 버퍼를, GppNHp-KRAS G12D 단백질 샘플에는 50 mM HEPES (pH 7.5) 버퍼를 사용하였다.
단백질-화합물 결합 반응은 KRAS G12D 돌연변이 단백질에 화합물을 첨가하여 30분간 상온에서 반응 한 후에 2X SYPRO orange 염료를 첨가하였다. 최종적으로 Applied biosystem사의 QuantStudio1 (RT-PCR 장비)를 이용하여 25-99℃ (0.05℃/s)으로 온도를 증가시켰고, 580±10 nm (파장 흡수)/ 623±14 nm (파장 방출) 필터를 사용하여 ROX reporter로 형광 값을 측정하였다.
10 μM 화합물 농도에서 측정된 측정값을 Protein Thermal Shift Software 프로그램 (버전 v1.4, Thermo Fisher Science)을 사용하여 분석하고 화합물의 KRAS G12D 돌연변이 단백질 결합능 지표인 ΔTm (℃) 값을 산출하였다. 본 출원의 일 예에 따른 화합물의 KRAS G12D 돌연변이 단백질에 대한 DSF 측정 결과를 표 2에 나타내었다.
실시예 GDP-KRAS G12D (ΔTmD, ℃) GppNHp-KRAS G12D (ΔTmD, ℃)
1 10.05 4.27
2 9.91 5.61
3 6.05 1.90
4 1.90 0.57
5 4.27 1.60
6 1.01 1.31
7 8.57 3.24
8 9.02 3.39
9 8.87 3.39
10 9.00 2.79
11 9.74 2.49
12 9.61 2.65
13 0.28 -0.61
14 7.98 4.73
15 -0.01 0.28
16 9.01 4.27
17 9.45 4.71
18 2.35 1.01
19 7.68 3.82
20 -0.17 0.27
21 8.13 4.72
22 4.28 1.02
23 9.90 6.94
24 5.48 2.07
25 0.27 -0.17
26 4.12 1.01
27 4.27 0.71
28 3.53 0.27
29 12.01 6.82
30 8.12 2.81
31 7.82 2.22
32 9.05 4.04
33 7.42 3.59
34 0.13 -0.32
35 8.91 2.68
36 7.57 3.42
37 11.53 5.76
38 9.61 6.65
39 8.87 5.61
40 5.95 0.61
41 5.46 0.87
42 10.96 5.75
43 9.30 4.27
44 14.33 9.89
45 11.82 7.68
46 11.68 6.49
47 2.65 1.90
48 8.41 6.78
49 1.92 0.73
50 0.58 -0.31
51 4.73 1.32
52 0.30 0.00
53 -0.30 0.15
54 2.95 1.61
55 3.24 1.91
56 -0.75 -2.53
57 8.57 5.76
58 6.81 1.92
59 12.88 6.06
60 0.87 1.61
61 3.54 0.58
62 9.01 8.57
63 8.72 9.02
64 15.24 11.39
65 14.23 8.60
66 14.49 9.45
67 10.06 8.28
68 5.75 1.90
69 11.68 7.24
70 6.34 3.38
71 8.14 4.88
72 -0.29 0.00
73 11.97 5.60
74 7.82 5.30
75 13.74 9.60
76 5.17 1.47
77 1.76 2.35
78 5.46 1.17
79 10.98 7.13
80 14.81 11.13
81 10.04 6.66
82 7.52 3.26
83 10.06 5.76
84 8.13 4.13
85 15.24 12.43
86 13.07 10.69
87 14.94 8.86
88 6.35 5.31
89 2.80 0.42
90 16.27 11.38
91 -0.16 -0.45
92 17.61 13.02
93 14.20 8.72
94 17.46 12.28
95 11.83 7.54
96 15.09 10.64
97 14.20 8.42
98 11.43 5.79
99 11.13 7.27
100 14.50 8.92
101 7.99 2.55
103 14.80 11.59
106 10.21 6.65
107 8.91 4.32
108 8.47 5.36
109 10.51 4.28
표 2에 나타난 바와 같이, 본 출원에 따른 화합물은 GDP-/ GppNHp-KRAS G12D 돌연변이 단백질에 대하여 높은 결합능을 나타냄을 검증하였다.
실험예 2: KRAS G12D 돌연변이로 유도된 ERK 인산화 (pERK)에 대한 억제능 측정 (면역형광실험)
면역형광실험법 (Immunofluorescence)은 항원-항체 반응을 이용해 세포나 조직 내에 존재하는 물질을 확인하는 방법 중 하나로, 항체에 각종 형광 색소가 표시된 것을 사용해 특정 단백질의 유무를 확인할 수 있는 실험법이다. 특정 단백질을 식별하는 1차 항체가 선택적으로 항원결정부위와 결합한 후, 1차 항체에 대한 형광항체 (2차 항체)를 결합시키는 것이다.
본 출원의 일 예에 따른 화합물이 KRAS G12D 돌연변이로 유도된 extracellular signal-regulated kinases의 인산화 (Phospho-ERK, pERK)를 억제하는지 여부를 다음과 같이 확인하였다.
10% FBS 와 1% Penicillin-Streptomycin 이 포함되어 있는 RPMI-1640 배지에 AsPC-1 세포를 10,000 세포/웰의 농도로 384-웰 플레이트 (Perkinelmer, #6057300)에 분주시키고 16시간 동안 부착되도록 하였다. 세포가 플레이트에 부착이 되면 약물을 최대 농도 10 μM로 3배씩 희석하여 세포에 처리하였다. 약물 처리 3시간 후, 배지를 제거하고 50 μL의 4% 포름알데하이드 (바이오세상, #PC2031-050-00)를 20분 동안 처리하고 PBS (phosphate buffered saline) 50 μL로 3번 세정하였다.
세포에 항체가 투과할 수 있도록 0.3% Triton X-100 (Sigma, #T8787-250mL)이 포함된 PBS 50 μL 를 첨가하여 20분간 반응시킨 후 플레이트를 PBS 50 μL로 3번 세정하였다. 항체가 플레이트에 비특이적으로 결합하는 것을 차단하기 위해 2% BSA (sigma, #A7906-500G)와 0.01% Tween-20 (Sigma, #P1379-500mL)가 포함된 PBS (이하 PBS-T) 50 μL 를 첨가하여 실온에서 2시간 동안 반응하였다.
pERK를 검출하기 위해 1차 항체 (cell signaling, #9101)를 2% BSA가 포함된 PBS-T에 1:500으로 희석하여 50 μL 첨가 후 16시간 동안 4℃ 냉장고에 플레이트를 보관하여 반응시킨 후, PBS-T 50 μL로 3번 세정하였다. 1차 항체를 시각화하기 위해 2차 항체 즉 항 토끼-Alexa Fluor 488 (ThermoFisher, #A11008)을 2% BSA가 포함된 PBS-T에 1:1000으로 희석하여 50 μL 첨가한 후 1시간 동안 실온에서 반응 후, PBS-T 50 μL 로 3번 세정하였다. 그 다음, 세포의 핵을 시각화하기 위해 DAPI (Thermofisher, #62248, 1mg/mL)를 PBS-T에 1:1000 희석하여 50 μL씩 첨가하고 상온에서 10분간 반응한 후, PBS-T 50 μL로 3번 세정하였다. PBS-T 50 μL를 각 웰에 첨가하고 플레이트를 HCS 장비 (MOLECULAR DEVICES / ImageXpress Micro)를 통해 형광값을 판독하였다.
데이터 분석은 pERK (Thr202/Tyr204) 신호를 DAPI 신호로 정규화하고 DMSO 대조군 값의 퍼센트를 계산하였다. IC50 값은 GraphPad Prism 8.4.3 프로그램을 이용하여 용량 반응 곡선의 4개 파라미터 적합을 사용하여 보간법을 통해 50%으로 억제되는 농도를 계산하였다. 본 출원의 일 예에 따른 화합물의 KRAS G12D 돌연변이로 유도된 pERK 활성 억제 효능 계산 결과를 표 3에 기재하였다.
실시예 pERK IC50 (nM)
1 322
2 169
3 1419
5 953
6 2323
7 269
8 149
9 165
10 2104
11 174
12 1064
14 75
16 176
17 1169
21 196
23 25
29 15
37 12
38 15
39 76
41 899
42 64
43 953
44 12
45 70
46 45
47 7980
48 333
57 167
59 54
62 631
63 532
64 62
65 4
68 9016
69 169
70 735
71 512
73 49
74 143
75 20
79 22
80 35
81 81
83 100
85 7
86 29
87 4
88 484
90 5
93 16
94 18
95 82
96 20
표 3에 나타난 바와 같이, 본 출원의 일 예에 따른 화합물은 KRAS G12D 돌연변이로 유도된 pERK에 대한 높은 억제능을 나타냄을 검증하였다.
실험예 3: KRAS G12D 돌연변이 세포를 이용한 세포 생존능 검정 시험
KRAS G12D 돌연변이 췌장암 세포주인 AsPC-1 세포주를 한국세포주은행 (KCLB)에서 입수하여 100 파이 디쉬 혹은 T75 (75 cm2) 플라스크에서 RPMI1640 + 10% fetal bovine serum (FBS) + 1% Penicillin-Streptomycin 배지에서 유지하였으며 37°C에서 5% CO2로 배양하였다. 세포수는 Countess (invitrogen)를 사용하여 생존 세포 수를 계수하였다.
AsPC-1 세포가 플라스크에 85~100% confuence를 보일 때, 1X trypsin/EDTA 용액을 이용하여, 세포를 수확한 뒤, 3D 배양을 위한 96 well plate에 1000 cells/100 μL/well이 되도록 분주하였다. 다음 날, 화합물을 10 μM 혹은 50 μM부터 0.0001 μM 혹은 0.0006 μM 되도록 DMSO로 1/5씩 희석하여 세포가 분주된 plate에 1:1 (v/v)로 처리하였다.
세포 배양은 화합물 처리 후 5일째에 종료하였으며, 각 농도에서의 세포 생존능을 celltiter-glo 3D cell viability assay kit를 이용하여 측정하였다.
세포 생존능 검정은 DMSO 처리군을 100%로 정규화하고 화합물 처리 시 살아있는 세포 수를 퍼센트로 나타내었다.
세포 생존능 % = (시험물질 처리군 평균 RLU - 무처리군 평균 RLU)/(DMSO 처리균 평균 RLU - 무처리군 평균 RLU) X 100
데이터는 그래프패드 (GradpPad) 프리즘 9 (Graphpad software)를 사용하여 농도에 대한 생존능을 4-파라미터 s자 모양의 용량-반응과 함께 비선형 회귀 곡선 피트를 사용하여 모델링화하였다. 50% 성장저해 값 (IC50)은 생존율의 중간 지점을 교차하는 농도에 해당한다. 본 출원의 일 예에 따른 화합물의 KRAS G12D 돌연변이 세포 생존 저해능 결과를 표 4에 기재하였다.
실시예 AsPC-1 IC50 (nM)
1 364
2 226
7 109
8 50
9 50
11 140
12 975
14 53
16 94
23 24
29 19
37 29
38 12
39 91
41 1020
42 105
44 7
45 37
46 25
48 136
57 101
59 69
65 5
69 190
73 37
74 110
75 34
79 29
80 46
81 280
85 11
86 48
87 11
88 734
90 4
93 38
94 14
95 263
96 11
97 7
98 110
99 27
100 29
표 4에 나타난 바와 같이, 본 출원의 일 예에 따른 화합물은 KRAS G12D 돌연변이 세포의 세포 생존능을 억제하는 것을 검증하였다.
상기 결과를 통해, 본 출원의 일 예에 따른 화합물은 KRAS G12D 돌연변이에 따른 암세포 생존을 효과적으로 억제할 수 있으며, 암의 예방 또는 치료용 약학적 조성물로 유용하게 사용될 수 있다.

Claims (28)

  1. 하기 화학식 1의 화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염:
    [화학식 1]
    Figure PCTKR2023020084-appb-img-000162
    상기 화학식 1에서,
    A는
    Figure PCTKR2023020084-appb-img-000163
    ,
    Figure PCTKR2023020084-appb-img-000164
    ,
    Figure PCTKR2023020084-appb-img-000165
    , 또는
    Figure PCTKR2023020084-appb-img-000166
    이며;
    X는 C 또는 N이며;
    R1은 수소, 할로겐, C1-3알킬, 또는 C1-3알콕시이며;
    L은 직접결합, O, 또는 NR6 이며;
    R2는 C1-6알킬, C1-6알콕시, C1-6하이드록시알킬, C2-6알콕시알킬, C1-6할로알킬, Rx, -Z1-Rx, -Z1-Ry-Rx, -Z1-Ry-Z2-N(R15)2, -Z1-Ry-Z2-Rx, -N(R15)2, -Z1-N(R15)2, -Z1-C(O)N(R15)2, 또는 -Z1-OR15이며;
    Rx 및 Ry는 서로 독립적으로 3원 내지 10원의 사이클로알킬, 3원 내지 10원의 헤테로사이클릴, 6원 내지 20원의 아릴, 또는 6원 내지 20원의 헤테로아릴이며, 선택적으로 하나 혹은 여러 개의 R7로 치환될 수 있고;
    R7는 각각 H, 할로겐, 하이드록시, C1-4알킬, C2-4알케닐, C2-4알키닐, C1-4하이드록시알킬, C1-4할로알킬, C2-4할로알케닐, C2-4할로알키닐, C1-4알콕시, C1-4알킬-N(R16)2, =C-(R16)2, 사이아노, C(O)R16, C(=O)OR16, C(=O)N(R16)2, -NHC(O)-6원 내지 20원의 아릴, -N(R16)2, (C1-4알콕시)C1-4알킬-, 옥소, -OR16, -SR16, -(C1-4알킬)C(O)R16, 3원 내지 10원의 사이클로알킬, 3원 내지 10원의 헤테로사이클로알킬, 6원 내지 20원의 아릴, 6원 내지 20원의 헤테로아릴, -Z3-3원 내지 10원의 사이클로알킬, -Z3-3원 내지 10원의 헤테로사이클로알킬, -Z3-6원 내지 20원의 아릴, -Z3-6원 내지 20원의 헤테로아릴, -Z3-OC(O)N(R16)2, 또는 -Z3-OC(O)-3원 내지 10원의 헤테로사이클릴이며; 상기 R7는 1 내지 3개의 사이아노, 할로겐, 할로알킬, 아미노, -OR17, -SR17, 또는 -N(R17)2로 치환될 수 있으며;
    Z1 내지 Z3는 서로 독립적으로 C1-4알킬이며; 선택적으로 하이드록시, C1-4하이드록시알킬, 또는 6원 내지 20원의 헤테로아릴로 치환될 수 있고;
    R6, R15, R16, R17, R18, R19, R20 및 R21 는 서로 독립적으로 H 또는 C1-3알킬이며;
    R3는 3원 내지 10원의 사이클로알킬, 3원 내지 10원의 헤테로사이클로알킬, 6원 내지 20원의 아릴, 또는 6원 내지 20원의 헤테로아릴이며, 선택적으로 하나 혹은 여러 개의 R8 로 치환될 수 있고;
    R8은 H, 할로겐, 하이드록시, -N(R18)2, OR18, SH, S(C1-3알킬), S(=O)(C1-6알킬), S(=O)2(C1-6알킬), C(=O)(C1-6알킬), C(=O)OH, C(=O)N(R18)2, C1-4알킬, C2-4알케닐, C2-4알키닐, C1-3할로알킬, C1-3하이드록시알킬, C1-3알콕시알킬, C1-4알킬-N(R18)2, C1-3알콕시, C1-3할로알콕시, 사이아노알킬, 사이아노, 옥소, 3원 내지 10원의 사이클로알킬, 3원 내지 10원의 헤테로사이클로알킬, 6원 내지 20원의 아릴, 또는 6원 내지 20원의 헤테로아릴이며;
    R4는
    Figure PCTKR2023020084-appb-img-000167
    ,
    Figure PCTKR2023020084-appb-img-000168
    ,
    Figure PCTKR2023020084-appb-img-000169
    또는 -NH-R9-R10이며;
    R9는 직접결합 또는 C1-4알킬이며;
    R10은 3원 내지 10원의 사이클로알킬 또는 3원 내지 10원의 헤테로사이클로알킬이며, 선택적으로 하나 혹은 여러개의 R11로 치환될 수 있고;
    R11은 C1-3알킬, 하이드록시, N(R19)2, C1-3알킬-N(R19)2, C1-3사이아노알킬, 3원 내지 10원의 헤테로사이클릴이며;
    R12는 H, C1-3알킬, OH, -N(R20)2, -CH2N(R20)2, 사이아노, 사이아노메틸, 또는 3원 내지 10원의 헤테로사이클릴이며;
    R13는 H, 또는 -C(=O)R14이며;
    R14는 C1-4알킬, C2-4알케닐, C2-4알키닐, -N(R6)2, -OR6, -SR6, 3원 내지 10원의 사이클로알킬, 3원 내지 10원의 사이클로알케닐, 3원 내지 10원의 사이클로알키닐, 3원 내지 10원의 헤테로사이클릴, 6원 내지 20원의 아릴, 또는 6원 내지 20원의 헤테로아릴이며;
    n은 0 내지 4의 정수이며;
    R5는 H, 할로겐, C1-6알킬, C1-3할로알킬, 3원 내지 6원의 사이클로알킬, 3원 내지 6원의 헤테로사이클로알킬, 사이아노, 사이아노C1-3알킬, 하이드록시, C1-3하이드록시알킬, C(O)(NR21)2, 6원 내지 20원의 아릴, C1-3알킬-3원 내지 6원의 사이클로알킬, C1-3알킬-3원 내지 6원의 헤테로사이클로알킬, C1-3알킬-6원 내지 20원의 아릴, 또는 C1-3알킬-6원 내지 20원의 헤테로아릴이다.
  2. 제1항에 있어서,
    A는
    Figure PCTKR2023020084-appb-img-000170
    ,
    Figure PCTKR2023020084-appb-img-000171
    , 또는
    Figure PCTKR2023020084-appb-img-000172
    인,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염.
  3. 제1항에 있어서,
    R1은 수소, 할로겐, 또는 C1-3알킬인,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염.
  4. 제1항에 있어서,
    L은 직접결합 또는 O인,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염.
  5. 제1항에 있어서,
    Rx 및 Ry는 서로 독립적으로 3원 내지 10원의 사이클로알킬 또는 3원 내지 10원의 헤테로사이클릴이며, 선택적으로 하나 혹은 여러 개의 R7로 치환될 수 있는,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염.
  6. 제1항에 있어서,
    Rx는 3원 내지 10원의 헤테로사이클릴이고, Ry는 3원 내지 10원의 사이클로알킬이며, 상기 Rx 및 상기 Ry는 선택적으로 하나 혹은 여러 개의 R7로 치환될 수 있는,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염.
  7. 제1항에 있어서,
    R7는 각각 H, 할로겐, 하이드록시, C1-4알킬, C2-4알케닐, C2-4알키닐, C2-4하이드록시알킬, C1-4할로알킬, C2-4할로알케닐, C1-4알콕시, C1-4알킬-N(R16)2, =C-(R16)2, C(O)R16, C(=O)OR16, C(=O)N(R16)2, -NHC(O)아릴, -N(R16)2, (C1-4알콕시)C1-4알킬-, 옥소, -OR16, -SR16, -(C1-4알킬)C(O)R16, 3원 내지 10원의 사이클로알킬, 3원 내지 10원의 헤테로사이클로알킬, 6원 내지 20원의 아릴, 6원 내지 20원의 헤테로아릴, -Z3-3원 내지 10원의 사이클로알킬, -Z3-3원 내지 10원의 헤테로사이클로알킬, -Z3-6원 내지 20원의 아릴, -Z3-6원 내지 20원의 헤테로아릴, -Z3-OC(O)N(R16)2, 또는 -Z3-OC(O)-3원 내지 10원의 헤테로사이클릴이며; 1 내지 3개의 사이아노, 할로겐, 할로알킬, 아미노, -OR17, -SR17, 또는 -N(R17)2로 치환될 수 있는,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염.
  8. 제1항에 있어서,
    R3는 6원 내지 20원의 아릴, 또는 6원 내지 20원의 헤테로아릴이며, 선택적으로 하나 혹은 여러 개의 R8 로 치환될 수 있고.
    R8은 H, 할로겐, 하이드록시, -N(R18)2, OR6, SH, S(C1-3알킬), S(=O)(C1-6알킬), S(=O)2(C1-6알킬), C(=O)(C1-6알킬), C(=O)OH, C(=O)N(R18)2, C1-4알킬, C2-4알케닐, C2-4알키닐, C1-3할로알킬, C1-3하이드록시알킬, C1-3알콕시알킬, C1-4알킬-N(R18)2, 사이아노, 옥소, 또는 3원 내지 10원의 사이클로알킬인,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염.
  9. 제1항에 있어서,
    R10은 3원 내지 10원의 사이클로알킬이며, 선택적으로 하나 혹은 여러개의 R11로 치환될 수 있고;
    R11은 C1-3알킬, 하이드록시, N(R19)2, C1-3알킬-N(R19)2, 또는 사이아노 C1-3알킬인,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염.
  10. 제8항에 있어서,
    R3은 페닐, 바이페닐, 나프틸, 톨루일, 나프탈렌일, 피리딘일, 안트라세닐, 인데닐, 인다닐, 퀴놀린일, 이소퀴놀린일, 벤즈이미다졸릴, 벤즈싸이아졸릴 (benzothiazolyl), 벤즈싸이오펜일 (benzothiophenyl), 벤즈퓨란일 (benzofuranyl), 또는 인다졸릴이며, 선택적으로 하나 혹은 여러 개의 R8 로 치환될 수 있는 것인,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염.
  11. 제8항에 있어서,
    R3은 페닐, 나프틸, 나프탈렌일, 피리딘일, 퀴놀린일, 이소퀴놀린일, 벤즈싸이아졸릴 (benzothiazolyl), 벤즈싸이오펜일 (benzothiophenyl), 벤즈퓨란일 (benzofuranyl), 또는 인다졸릴이며, 선택적으로 하나 혹은 여러 개의 R8 로 치환될 수 있는 것이며,
    상기 R8은 H, 할로겐, 하이드록시, -N(R18)2, C1-4알킬, C2-4알케닐, C2-4알키닐, C1-3할로알킬, C1-3하이드록시알킬, 또는 사이아노인,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염.
  12. 제1항에 있어서,
    R9는 C1-3알킬이고,
    R10은 3원 내지 5원의 사이클로알킬이고,
    R11은 N(R19)2 인,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염.
  13. 제1항에 있어서,
    R12는 H인,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염.
  14. 제1항에 있어서,
    R5는 H 또는 C1-3알킬인,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염.
  15. 제5항에 있어서,
    상기 Rx 및 Ry는 서로 독립적으로 3원 내지 5원의 사이클로알킬, 아제티디닐 (azetidinyl), 피롤리디닐, 피페리디닐, 몰포리닐, 2-옥사-5-아자바이사이클로[2.2.1]헵탄일 (2-oxa-5-azabicyclo[2.2.1]heptanyl), 피롤리지디닐(pyrrolizidinyl), 메틸렌피롤리지디닐 (methylenepyrrolizidinyl), 테트라하이드로-1’H,3’H-스피로[사이클로프로판-1,2'-피롤리지디닐] (tetrahydro-1’H,3’H-spiro[cyclopropane-1,2'-pyrrolizidinyl]), 6-아자스피로[2.5]옥탄일 (6-azaspiro[2.5]octanyl), 퀴놀리지디닐(quinolizidinyl), 인돌리닐, 벤즈이미다졸릴, 아자스피로옥탄일, 벤즈트리아졸릴(benztriazolyl), 티오잔티닐(thioxanthinyl), 카바졸릴(carbazolyl), 카르보리닐(carbolinyl), 또는 아크리디닐(acridinyl)이며, 선택적으로 하나 혹은 여러 개의 R7로 치환될 수 있는 것인,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염.
  16. 제6항에 있어서,
    상기 R2는 Rx, -Z1-Rx, -Z1-Ry-Rx, -Z1-Ry-Z2-N(R15)2, 또는 -Z1-Ry-Z2-Rx 이고,
    상기 Rx는 아제티디닐 (azetidinyl), 피롤리디닐, 피페리디닐, 몰포리닐, 2-옥사-5-아자바이사이클로[2.2.1]헵탄일 (2-oxa-5-azabicyclo[2.2.1]heptanyl), 피롤리지디닐(pyrrolizidinyl), 메틸렌피롤리지디닐 (methylenepyrrolizidinyl), 테트라하이드로-1’H,3’H-스피로[사이클로프로판-1,2'-피롤리지디닐] (tetrahydro-1’H,3’H-spiro[cyclopropane-1,2'-pyrrolizidinyl]), 또는 6-아자스피로[2.5]옥탄일 (6-azaspiro[2.5]octanyl)이고,
    상기 Ry는 3원 내지 5원의 사이클로알킬이고,
    상기 Rx 및 상기 Ry는 선택적으로 하나 혹은 여러 개의 R7로 치환될 수 있으며,
    상기 R7은 각각 H, 할로겐, C1-4알킬, C2-4알케닐, C2-4알키닐, C1-4할로알킬, C2-4할로알케닐, C2-4할로알키닐, C1-4알콕시, =C-(R16)2, -N(R16)2, 또는 (C1-4알콕시)C1-4알킬-이며, 1 내지 3개의 할로겐으로 치환될 수 있는 것인,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염.
  17. 제1항에 있어서, 상기 화학식 1의 화합물은 하기 (1) 내지 (120)로 이루어지는 군에서 선택된 것인,
    화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염:
    (1) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol (2) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (3) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5,6-difluoronaphthalen-2-ol (4) 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5,6-difluoronaphthalen-2-ol. (5) 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol. (6) 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (7) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (8) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((R)-3-methylmorpholino)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (9) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (10) 4-(3-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (11) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((S)-3-methylmorpholino)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (12) 4-(3-((1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (13) 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-2,4,5,6-tetrafluoroaniline (14) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. (15) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-7-fluorobenzo[d]thiazol-2-amine. (16) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (17) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (18) 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine. (19) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(((S)-3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (20) 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine. (21) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((R)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (22) 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine. (23) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (24) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. (25) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-7-fluorobenzo[d]thiazol-2-amine. (26) 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(6-methyl-5-(trifluoromethyl)-1H-indazol-4-yl)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine. (27) 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine. (28) 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(8-ethynyl-7-fluoronaphthalen-1-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidine. (29) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (30) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (31) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((S)-3-fluoropiperidin-1-yl)methyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (32) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (33) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((R)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (34) 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine. (35) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (36) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. (37) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (38) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. (39) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (40) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (41) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol. (42) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (43) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol. (44) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (45) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol. (46) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5,6-difluoronaphthalen-2-ol. (47) 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)naphthalen-2-ol. (48) 4-(1-(((1-(dimethylamino)cyclobutyl)methyl)amino)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (49) 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-(trifluoromethyl)aniline. (50) 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-(trifluoromethyl)pyridin-2-amine. (51) 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(5-chloro-6-methyl-1H-indazol-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazoline. (52) 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-methylpyridin-2-amine. (53) 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-iodo-4-methylpyridin-2-amine. (54) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)benzo[d]thiazol-2-amine. (55) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazol-2-amine. (56) 3-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-methyl-4-(trifluoromethyl)aniline. (57) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. (58) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. (59) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (60) 6-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine. (61) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-8-methyl-3-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)furo[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (62) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile. (63) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile. (64) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (65) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-3-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (66) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (67) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methylfuro[3,2-f]quinazolin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. (68) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)naphthalen-2-ol. (69) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (70) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol. (71) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. (72) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(3-(dimethylamino)azetidin-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (73) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (74) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. (75) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (76) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. (77) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile. (78) 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline (79) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (80) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (81) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. (82) 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline. (83) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol. (84) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol. (85) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol. (86) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol. (87) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-((1-((1,1-difluoro-6-azaspiro[2.5]octan-6-yl)methyl)cyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (88) 4-(9-(2,5-diazabicyclo[2.2.2]octan-2-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (89) 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(5-chloro-3,6-dimethyl-1H-indazol-4-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline. (90) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (91) 4-((R)-9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (92) 4-((S)-9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (93) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol. (94) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (95) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5,6-difluoronaphthalen-2-ol. (96) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((5S,7aS)-5-(methoxymethyl)-2-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (97) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethyl-6-fluoronaphthalen-2-ol. (98) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclobutyl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (99) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine. (100) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2S,7aR)-2-fluoro-6-methylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (101) 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(8-ethynyl-7-fluoronaphthalen-1-yl)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazoline. (102) (4-(4-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-9-yl)piperazin-1-yl)(oxiran-2-yl)methanone. (103) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (104) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (105) 4-(9-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (106) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (107) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol (108) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (109) 4-(1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-3-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)imidazo[1',2':1,6]pyrido[3,2-d]pyrimidin-6-yl)-5-ethyl-6-fluoronaphthalen-2-ol (110) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-5-fluorobenzo[b]thiophene-3-carbonitrile. (111) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-5,7-difluorobenzo[b]thiophene-3-carbonitrile. (112) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile. (113) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-aminobenzofuran-3-carbonitrile. (114) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-7-fluorobenzofuran-3-carbonitrile. (115) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-2-amino-5-fluorobenzofuran-3-carbonitrile. (116) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-amine (117) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoro-7-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (118) 9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-(5-ethynyl-6-fluoroisoquinolin-4-yl)-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2-methyl-2H-pyrazolo[4,3-f]quinazoline (119) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol. (120) 4-(9-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(((1S,7a'S)-2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizin]-7a'(5'H)-yl)methoxy)-5-fluoro-2-methyl-2H-pyrazolo[4,3-f]quinazolin-4-yl)-5-ethynyl-6-fluoronaphthalen-2-ol.
  18. 제1항 내지 제17항 중 어느 한 항에 따른 화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염을 포함하는, 약학적 조성물.
  19. 제18항에 있어서, 약학적으로 허용되는 담체를 추가로 포함하는, 약학적 조성물.
  20. 제18항에 있어서, 상기 약학적 조성물은 KRAS G12D 변이 단백질의 길항제인, 약학적 조성물.
  21. 제18항에 있어서, 상기 약학적 조성물은 KRAS G12D 변이 단백질과 관련된 질병의 예방 또는 치료용인, 약학적 조성물.
  22. 제18항에 있어서, 상기 약학적 조성물은 암의 예방 또는 치료용인, 약학적 조성물.
  23. 제18항에 있어서, 상기 조성물은 경구 투여, 정맥 주사, 피하 주사, 근육 주사, 복강 주사, 내피 투여, 국소 투여, 비강내 투여, 폐내 투여, 및 직장내 투여로 이루어지는 군에서 선택된 1종 이상으로 투여되는 것인, 약학적 조성물.
  24. 제18항에 있어서, 상기 조성물은 정제, 환제, 경·연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 및 엘릭서제로 이루어지는 군에서 선택된 1종 이상으로 제형화된 것인, 약학적 조성물.
  25. 제18항에 있어서, 상기 약학적 조성물은 RTK/Ras-MAPK pathway 관련 단백질 저해제, DNA 손상 유도물질, EGFR antibody 및 면역항암제 치료제로 구성되는 군으로부터 선택되는 어느 하나 이상을 추가로 포함하는 것인, 약학적 조성물.
  26. 제25항에 있어서,
    상기 RTK/Ras-MAPK pathway 관련 단백질 저해제는 EGFR 저해제, FGFR 저해제, ALK 저해제, ROS 저해제, MET 저해제, RAF 저해제, ERK 저해제, MEK 저해제, SHP-2 저해제, PI3K 저해제, KRAS 저해제, KRAS-G12C 저해제 및 SOS1 저해제로 이루어진 군으로부터 선택되는 어느 하나 이상인 것인, 약학적 조성물.
  27. 제22항에 있어서,
    상기 암은 혈관육종, 섬유육종, 횡문근육종, 지방육종, 점액종, 횡문근종, 섬유종, 지방종, 기형종; 편평세포암종, 미분화소세포암종, 미분화다세포암종, 샘암종, 폐포(세기관지성)암, 세기관지선종, 육종, 림프종, 연골과오종, 중피종, 식도암, 위암, 췌장암, 소장암, 대장암, 신장암, 방광암, 요도암, 전립선암, 고환암, 간암, 쓸개관암, 간모세포종, 간세포선종, 혈관종, 담낭암, 팽대부성 암, 골육종, 악성 섬유성 조직구종, 연골육종, 유잉육종, 악성 림프종(세망세포육종), 다발성골수종, 악성거대세포종, 골연골종, 양성연골종, 연골모세포종, 연골점액유사섬유종, 연골골종, 거대세포종, 두개골종, 두개혈관종, 두개육아종, 두개황색종, 두개 변형성 골염, 뇌수막종, 수막육종, 교모세포종, 별아교세포종, 수모세포종, 뇌실막세포종, 배아종, 핍지교종, 신경초종, 망막모세포종, 척수신경섬유종, 자궁내막암, 자궁경부암, 난소암, 혈액암, 급성 림프구성 백혈병, 만성 림프구성 백혈병, 급성 골수성 백혈병, 단핵구 백혈병, 만성 골수성 백혈병, 만성 림프구성 백혈병, 혼합 계통 백혈병, 호지킨 림프종, 비호지킨 림프종, 악성흑색종, 기저세포암, 건선암, 신경모세포종으로 이루어지는 군에서 선택된 1종 이상인, 약학적 조성물.
  28. 제1항 내지 제17항 중 어느 한 항에 따른 화합물, 이의 광학 이성질체, 입체 이성질체, 라세미체, 동위원소 변형체, 용매화물, 수화물, 또는 이들의 약학적으로 허용되는 염을 포함하는, KRAS G12D 돌연변이 단백질 결합용 조성물.
PCT/KR2023/020084 2022-12-07 2023-12-07 Kras g12d 저해제로서 신규한 3환 화합물 및 이의 용도 WO2024123102A1 (ko)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
US20130330765A1 (en) * 2009-03-12 2013-12-12 Genentech, Inc. Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents for the treatment of hematopoietic malignancies
US20180155348A1 (en) * 2016-09-29 2018-06-07 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
WO2020259513A1 (en) * 2019-06-24 2020-12-30 Guangdong Newopp Biopharmaceuticals Co., Ltd. Heterocyclic compounds as inhibitors of kras g12c
WO2021041671A1 (en) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Kras g12d inhibitors
CN112574224A (zh) * 2019-09-30 2021-03-30 上海迪诺医药科技有限公司 Kras g12c抑制剂及其应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130330765A1 (en) * 2009-03-12 2013-12-12 Genentech, Inc. Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents for the treatment of hematopoietic malignancies
US20180155348A1 (en) * 2016-09-29 2018-06-07 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
WO2020259513A1 (en) * 2019-06-24 2020-12-30 Guangdong Newopp Biopharmaceuticals Co., Ltd. Heterocyclic compounds as inhibitors of kras g12c
WO2021041671A1 (en) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Kras g12d inhibitors
CN112574224A (zh) * 2019-09-30 2021-03-30 上海迪诺医药科技有限公司 Kras g12c抑制剂及其应用

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