WO2025253326A1 - Nouveaux composés tricycliques et leur utilisation en tant qu'inhibiteurs de kras - Google Patents

Nouveaux composés tricycliques et leur utilisation en tant qu'inhibiteurs de kras

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Publication number
WO2025253326A1
WO2025253326A1 PCT/IB2025/055788 IB2025055788W WO2025253326A1 WO 2025253326 A1 WO2025253326 A1 WO 2025253326A1 IB 2025055788 W IB2025055788 W IB 2025055788W WO 2025253326 A1 WO2025253326 A1 WO 2025253326A1
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Prior art keywords
methyl
methoxy
luoro
ethynyl
quinazol
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Pending
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PCT/IB2025/055788
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English (en)
Korean (ko)
Inventor
송지영
박천응
장은성
조경희
정회윤
조민창
문미진
기소영
고일규
홍범진
조현호
임선아
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SK Biopharmaceuticals Co Ltd
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SK Biopharmaceuticals Co Ltd
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Priority claimed from KR1020250037604A external-priority patent/KR20250174461A/ko
Application filed by SK Biopharmaceuticals Co Ltd filed Critical SK Biopharmaceuticals Co Ltd
Publication of WO2025253326A1 publication Critical patent/WO2025253326A1/fr
Pending legal-status Critical Current
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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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the present application relates to a novel tricyclic compound, a pharmaceutical composition comprising the same, and their use as a medicament.
  • KRAS Kristen rat sarcoma virus
  • the KRAS protein acts as a molecular switch, and through endogenous nucleotide exchange, GDP at the nucleotide binding site is exchanged for GTP, and the signal transmission to the downstream signaling protein occurs in the “activated (GTP-bound form, Turn-on) state.” Conversely, when the GTP bound to the KRAS protein is endogenously hydrolyzed to GDP, and the “inactivated (GDP-bound form, Turn-off) state,” the downstream signal transmission does not occur. At this time, in an actual cell, the exchange of GDP to GTP is promoted by the guanine exchange factor (GEF), and the hydrolysis of GTP to GDP is rapidly increased by the GTPase activating protein (GAP).
  • GEF guanine exchange factor
  • KRAS gene mutations have been shown to play an important role in cancer cell proliferation in many malignant tumors, and about 89% of KRAS gene mutant cancer patients are caused by mutations in which glycine in codon 12 of the KRAS gene (KRAS G12) is changed to another amino acid.
  • KRAS G12 mutations appear in 86% of pancreatic adenocarcinomas (PDAC), 41% of colorectal cancers (CRC), and 32% of non-small cell lung cancers (NSCLC), and the frequency of mutations among all KRAS G12 mutations is reported to be in the order of G12D (36%), G12V (23%), and G12C (14%).
  • KRAS G12 mutant protein maintains the activated (GTP-bound form) state by inhibiting GTP hydrolysis by GAP, thereby rapidly increasing cancer cell proliferation and survival through continuous downstream signaling.
  • Previous KRAS inhibitors were designed to inhibit activated KRAS by competitively binding to GTP.
  • many KRAS inhibitors failed because GTP exists significantly more than the inhibitor concentration in cells. For this reason, the development of targeted therapies directly targeting KRAS was considered impossible.
  • downstream signaling proteins such as PI3K, MEK, AKT, and mTOR other than KRAS protein, or to inhibit posttranslational modification of KRAS protein to inhibit farnesyltransferase of KRAS.
  • KRAS G12D mutation which accounts for the most common KRAS mutation, occurs at a high frequency in various cancers, such as about 34% of pancreatic adenocarcinoma, 10-12% of colorectal cancer, 4% of lung adenocarcinoma, 11% of cholangiocarcinoma, and 5% of endometrial cancer.
  • most of the development of targeted therapies remains in the research or preclinical stage, leaving it as a very large unmet medical need.
  • KRAS G12C inhibitors that have been recently reported, it was confirmed that patients who received KRAS G12C inhibitors acquired new KRAS mutations, including G12D/R/V/W, G13D, Q61N, R68S, H95D/Q/R, and Y96C, as resistance mechanisms. In addition, a resistance mechanism in which the expression of the KRAS G12C gene is increased has also been reported. To overcome this, pan-KRAS inhibitors that can simultaneously inhibit various KRAS mutations rather than being limited to a single KRAS mutation are also being developed, and a development trend to overcome this resistance mechanism through combination therapy among KRAS inhibitors is also being confirmed.
  • one object of the present application is to provide a novel compound based on a tricyclic ring of Chemical Formula 1 or Chemical Formula 2, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, which exhibits an excellent activity inhibitory effect on KRAS mutants.
  • Another object of the present application is to provide a novel compound based on the tricyclic ring, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a pharmaceutically acceptable salt as an active ingredient is provided.
  • a compound of the following chemical formula 1, an optical isomer, a stereoisomer, an isotopic variant, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof is provided:
  • Ri is hydrogen, halogen, Ci-3 alkyl, or Ci-3 alkoxy
  • L is a direct bond, 0, or NR 6 ;
  • R2 is C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C2-6 alkoxyalkyl, C1-6 haloalkyl, R X , — Zl— R X , — Zl— Ry— R X , — Zl— Ry— Z2— N(R15)2, — Zl— Ry— Z2— N(R15)2, — Zl— Ry— Z2— Rx , — N(R15)2, — Z1- N(R15)2, -Z1-C(O)N(R15)2, or - Zl- 0R15 ;
  • Rx and Ry are independently a 3- to 10-membered cycloalkyl, a 3- to 12-membered heterocyclyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl, which may be optionally substituted with one or more R7;
  • R15 is independently in each case H, C1-6 alkyl, C1-6 haloalkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocycloalkyl; wherein said cycloalkyl or said heterocycloalkyl may be substituted with 1 to 4 halogens or Ci- 6 alkoxy;
  • R16 is independently H, halogen, or Ci-6 alkyl in each case
  • Zi to Z3 are independently Ci-4 alkyl; optionally substituted with D, hydroxy, Ci-4 hydroxyalkyl, or 6- to 20-membered heteroaryl;
  • R 6 , R14, R17, R18, R20, R22, R23, R24 and R25 are each independently H or C1-6 alkyl;
  • R3 is a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 6- to 20-membered aryl, or a 6- to 20-membered heteroaryl, which may be optionally substituted with one or more R8;
  • Y1 is H, halogen, C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl- C1-4 alkyl, 6- to 20-membered aryl, 6- to 20-membered aryl- C1-4 alkyl, 6- to 20-membered heteroaryl, 6- to 20-membered heteroaryl-Ci-4 alkyl, 3- to 6-membered heterocycle, or 3- to 6-membered heterocycle-Ci-4 alkyl, which may be optionally substituted with one or more R21;
  • Y2 is H, CD 3 , C1-4 alkyl, or Ci-4 haloalkyl; or Yi and Y2 are linked to form a 3- to 10-membered heterocycloalkyl, or a 3- to 10-membered heterocycloalkenyl, which may be optionally substituted with one or more R9;
  • R9 is in each case independently H, hydroxy, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkenyl, -NH-R17, -N(R17)2, C1-3 alkyl - N(R17)2, oxo, -I (C1-3 alkyl), - (C1-3 alkyl)- OH, -(C1-3 alkyl)- 0-(Ci-3 alkyl), -(C1-3 alkyl)- 0-(Ci-3 haloalkyl), -C(O)OH, - C(0)0(Ci-3 alkyl), -C(0)NH 2 , -C(
  • Rio is independently in each case H, Ci-3 alkyl, hydroxy, halogen, - N(R22)2, -CH 2 N(R 22 )2, oxo, - o- (C1-3 alkyl), - (C1-3 alkyl)- OH, -C(O)OH, - C(0)0(Ci-3 alkyl), - C(0)N(R22)2, cyano, C1-3 cyanoalkyl, or 3- to 10-membered heterocyclyl;
  • R19 is independently H, C1-6 alkyl, or C1-6 haloalkyl in each case;
  • R12 is independently in each case D, halogen, hydroxy, C1-3 alkyl, C1-
  • 3-haloalkyl C1-3hydroxyalkyl, C1-3alkenyl, C1-3alkynyl, C1-3alkyl-0-R20, C1-3alkyl-0-C1-
  • R13 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-3 alkyl-0- C1-6 alkyl, - N(R23)2, - OR23, -SR23, 3 to 10 membered cycloalkyl, 3 to
  • R5 is H, halogen, Ci-6 alkyl, Ci-3 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, cyano, cyano Ci-3 alkyl, hydroxy, Ci-3 hydroxyalkyl, C(0)(NR25)2, 6-20 membered aryl, - Ci-3 alkyl- 3-6 membered cycloalkyl, - Ci-3 alkyl- 3-6 membered heterocycloalkyl, - Ci-3 alkyl- 6-20 membered aryl, - Ci-3 alkyl- 0- Ci-3 alkyl- 6-20 membered aryl, or - Ci-3 alkyl- 6-20 membered heteroaryl.
  • Yi may not be cycloalkyl, cycloalkyl-alkyl-, heterocycloalkyl, and heterocycloalkyl-alkyl-.
  • Yi is H, halogen, Ci-4 alkyl, 6- to 20-membered aryl, 6- to 20-membered aryl-Ci-4 alkyl-, 6- to 20-membered heteroaryl, or 6- to 20-membered heteroaryl-C1-4 alkyl-, and may be optionally substituted with one or more R21.
  • Rn is shown, R12 is independently in each case D, halogen, Ci-
  • 3-haloalkyl C1-3hydroxyalkyl, C1-3alkenyl, C1-3alkynyl, C1-3alkyl-0-R20, C1-3alkyl-0-C1-
  • Rx is pyridinyl, piperazinyl, diazepanyl, oxaazabicyclohexanyl, oxaazabicyclooctanyl, oxaazabicyclononanyl, azabicyclohexanyl, azabicycloheptanyl
  • R5 may be - Ci-3alkyl- 0- Ci-3alkyl- 6- to 20-membered aryl.
  • Rii is cycloalkyl or heterocycloalkyl
  • Co-2 alkyl- 3-6 membered cycloalkyl, Co-2 alkyl- 3-6 membered heterocycloalkyl, Co-2 alkyl- 6-20 membered Aryl, or Co-2 alkyl- may be substituted with 6- to 20-membered heteroaryl; Or
  • Rii is alkyl
  • Rii is Ci-4 alkyl
  • 3-haloalkyl, hydroxy C1-3 alkyl, - 0- C1-3 alkyl, C1-3 alkyl- 0- C1-3 alkyl, or N(R19)2 may be substituted.
  • R13 is C5-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C5-6 haloalkyl, C1-6 cyanoalkyl, C1-3 alkyl- 0- C1-6 alkyl, - SR23, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-20 membered aryl, 6-20 membered heteroaryl, or - C1-6 alkyl- 3-10 membered cycloalkyl; 3-membered cycloalkyl is optionally substituted with one or more D, hydroxy, halogen, C1-3 alkyl
  • the Ri may be hydrogen, halogen, or Ci-3 alkoxy.
  • the Ri may be hydrogen or halogen.
  • the L may be a direct bond or 0.
  • the R2 may be Ci-6 alkyl, Rx, -Zi-Rx, -Zi-Ry-Rx, -Zi- Ry -Z 2 -N(Ri 5 ) 2 , - Zi- Ry- Z2- Rx, or - Zi- N(Ri 5 ) 2 .
  • the R2 may be Ci-6 alkyl, Rx, -Z1- Rx, - Zi- Ry- Z2- N(Ri 5 ) 2 , - ZI- Ry- Z2- RX, or - Zi- N(Ri 5 ) 2 .
  • Rx and Ry are independently a 3- to 10-membered cycloalkyl, a 3- to 12-membered heterocyclyl, or a 6- to 20-membered heteroaryl, which may be optionally substituted with one or more R7s.
  • Rx is a 3- to 12-membered heterocyclyl, or a 6- to 20-membered heteroaryl
  • Ry is a 3- to 10-membered cycloalkyl
  • Rx and Ry may be optionally substituted with one or more R7s.
  • Rx is a 3- to 12-membered monocyclic, bicyclic or tricyclic heterocyclyl, or a 6- to 20-membered monocyclic heteroaryl, and may be optionally substituted with one or more R7s.
  • Rx and Ry are independently 3- to 5-membered cycloalkyl, pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, diazepanyl, morphol inyl, pyrrol izidinyl, methylenepyrrol izidinyl, oxaazabicyclohexanyl, oxaazabicycloheptanyl, oxaazabicyclooctanyl , oxaazabicyclononanyl, azabicyclohexanyl, azabicycloheptanyl, azaspiroheptanyl, azaspiroctanyl, oxaazaspiroheptanyl, oxaazaspirooctanyl, oxaazaspirooctanyl, oxaazaspirononanyl, oxaazaspirodecanyl, oxa
  • Rx and Ry are independently 3- to 5-membered cycloalkyl, pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl , diazepanyl, morpholinyl, oxazabicyclo [2.2. 1 ]heptanyl ( oxaaz ab i eye lo[2.2.1] hept any 1 ), oxaazabicyclo [3. 1.1]heptanyl (oxaazabicyclo [3.1. Uheptanyl), oxaazabicyclo [4.1. 0]heptanyl (oxaazabicyclo [4.1.
  • the Rx is pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, diazepanyl, morpholinyl, 1-azabicyclo[3.2.heptanyl], 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2—oxa— 5—azabicyclo[2.2.2]octanyl ab i eye lo[2.2.2] oct any 1 ), 3 —oxa— 8— azabicyclo [3.2.1]octanyl ( 3— oxa— 8— az ab i eye lo[3.2.1] oct any 1 ), 8 -oxa- ⁇ -3- azabicyclo [3.2.1]octanyl ( 8— oxa— 3— az ab i eye lo[3.2.1] oct any 1 ), 6 -oxa- 1- azabicyclo [3.3.
  • the Ry is a 3- to 5-membered It may be cycloalkyl, and may be optionally substituted with one or more R7.
  • Ry may be a 3- to 5-membered cycloalkyl, and may be optionally substituted with halogen or Ci-4 haloalkyl.
  • H D
  • halogen hydroxy, C1-4 alkyl, C2-4 alkenyl, C2-4 alky
  • the R3 is a 6- to 20-membered monocyclic or bicyclic aryl, or a 6- to 20-membered monocyclic or bicyclic heteroaryl, which may be optionally substituted with one or more R8 . More specifically, the R3 is phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, pyridinyl, anthracenyl, indenyl, dihydroindenyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzthiazolyl
  • Rn is Ci-6 alkyl, optionally one or more halogen, hydroxy, cyano, halo C1-3 alkyl (e.g., CF3), - C(0)N(R19)2, - S- C1-3 alkyl, - S(0)2- C1-3 alkyl, - 0- C(O)N(R19)2, - o- C1-3 alkyl, - 0-halo C1-3 alkyl, - 0- CD3, - 0-(Ci-3 alkyl)- 0-C1-3 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl (e.g., azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran (tetrahydropyran), or oxaspiro [3.4]octane
  • azetidine oxe
  • a 3- to 10-membered heterocycloalkenyl e.g., dihydroimidazole
  • a 5- to 6-membered heteroaryl e.g., furan or imidazole
  • the Y1 is C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4 alkyl-, 3-6 membered heterocycle, or 3-6 membered heterocycle-C1-4 alkyl-, and may be optionally substituted with one or more R21.
  • the Y2 may be C1-4 alkyl, or C1-4 haloalkyl.
  • the Y1 and Y2 are connected to piperidine, pyrrolidine, piperazine, azepane, azetidine, morpholine, oxazepane, dihydropyridine.
  • R9 may be independently H, hydroxy, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkenyl, - NH- R17, -N(R17)2, C1-3 alkyl - N(R17)2, oxo, - 0- (C1-3 alkyl), - (C1-3 alkyl)- OH, -(C1-3 alkyl)- 0-(Ci-3 alkyl), - (C1-3 alkyl)- 0- (C1-
  • 3-haloalkyl 3-haloalkyl), -C(O)OH, - C(0)0(Ci-3alkyl), -C(0)NH 2 , -C(O)N(R17)2, cyano, C1-3cyanoalkyl, 3- to 10-membered heterocyclyl, 6- to 20-membered aryl, or 6- to 20-membered heteroaryl.
  • two identical or different R9s can form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycle at the same atom, thereby forming a spiro ring with the ring formed by connecting Yi and Y2, and can be optionally substituted by one or more halogens, hydroxy, oxo, C1-3 alkyl, C1-3 haloalkyl, or -0- C1-3 alkyl.
  • the ring structure formed by connecting Yi and Y2 is substituted by multiple R9s
  • two identical or different R9s can be linked at adjacent atoms to form a 3- to 6-membered heterocycloalkyl, thereby forming a fused ring with the ring formed by connecting Yi and Y2, and can be optionally substituted by one or more Rio.
  • the Rio can be independently H, Ci-3 alkyl, halogen, or - C(0)N(R22)2 in each case.
  • the R5 can be H, C1-3 alkyl, C1-3 hydroxyalkyl, or - C1-3 alkyl- 0- C1-3 alkyl- 6- to 20-membered aryl.
  • the L- R2 can be selected from the following structures. When it has the following structure, not only is the KRAS G12D inhibitory activity excellent, but it is also suitable for various purposes of the present application mentioned above.
  • R3 may be selected from the following structures.
  • R4 may be selected from the following structures.
  • the KRAS G12D inhibitory activity excellent, but it is also suitable for various purposes of the present application mentioned above.
  • the present application provides compounds, optical isomers, stereoisomers, isotopic variants, hydrates, solvates, or pharmaceutically acceptable salts thereof, as mentioned above.
  • Examples of compounds of formula 1 according to the present application are compounds prepared in Examples 1 to 506 below. Each example number corresponds to a compound number. For example, the number of the final compound prepared in Example 90 is Compound 90.
  • representative examples of compounds of formula 1 according to an example of the present application include, but are not limited to, those listed below:
  • haloalkyl refers to alkyl, as defined herein, wherein one or more hydrogens are replaced by the same or different halogens.
  • haloalkyl groups include, but are not limited to, -CH2CI, -CH2CF3, -CH2CCI3, -CF2H , -CF3 , and the like.
  • hydroxyalkyl as used herein includes alkyl groups in which one or more hydrogen atoms are replaced by one or more hydroxyl (- 0H), for example, divalent or trivalent hydroxy.
  • aminoalkyl as used herein includes alkyl groups in which one or more hydrogen atoms are replaced by one or more amino (- NH2), for example, divalent or trivalent amino.
  • alkyl refers to a saturated, straight-chain or branched monovalent hydrocarbon radical, unless otherwise stated.
  • the alkyl can be C1-10 alkyl, C1-8 alkyl, C1-6 alkyl, C1-4 alkyl, or C1-3 alkyl.
  • alkenyl refers to a monovalent hydrocarbon radical containing at least one carbon-carbon double bond, each of which may have an E- or Z-configuration.
  • the alkenyl may be C2-10 alkenyl, C2-8 alkenyl, C2-6 alkenyl, or C2-4 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 C2-10 alkynyl, C2-8 alkynyl, C2-6 alkynyl, or C2-4 alkynyl.
  • alkyl alkenyl and alkynyl, when used alone or in combination with other additional terms (e.g., haloalkyl), may be straight-chain or branched. According to each definition, there may be 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, or 1 to It refers to a radical of a saturated aliphatic hydrocarbon group having three carbon atoms.
  • alkyl are methyl, ethyl, ⁇ propyl, ⁇ propyl, ⁇ butyl, Examples thereof include, but are not limited to, hexamethyl-butyl, hexamethyl-butyl, hexamethyl-pent ...
  • alkenyl and alkynyl include, but are not limited to, ethenyl, prop-1-enyl, prop-2-enyl, but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, hex-3-enyl, hex-4-enyl, prop-2-ynyl, but-2-ynyl, but-3-ynyl, hex-4-ynyl, or hex-5-ynyl.
  • cycloalkyl means a cyclic alkyl which may be substituted or unsubstituted and which is a radical of a hydrocarbon group forming a single or fused cyclic ring having unsaturated or partially or fully saturated (e.g., from 3 to 24) carbon atoms.
  • the cycloalkyl, cycloalkenyl, or cycloalkynyl may have 3 to 10, 3 to 8, 3 to 6, 3 to 5, 4 to 10, 4 to 8, 4 to 6, or 4 to 5 carbon atoms.
  • the cycloalkyl may include, but is not limited to, carbocyclyl, spirocarbocyclyl, fused carbocyclyl, and bridged carbocyclyl.
  • the cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclohepsenyl, 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, dioxocyclohexyl, thiocyclohexy
  • saturated or unsaturated heterocyclyl means a substituted or unsubstituted 3 to 24 membered hydrocarbon group containing one or more heteroatoms selected from the group consisting of nitrogen (N), oxygen (0), and sulfur (S), for example, 1 to 8 heteroatoms, forming an unsaturated or partially or fully saturated single or fused cyclic ring.
  • the heterocyclyl may be a 3 to 10 membered, 3 to 8 membered, 3 to 6 membered, 4 to 10 membered, 4 to 8 membered, or 4 to 6 membered hydrocarbon group having 1 to 3 heteroatoms.
  • Heterocycles include, but are not limited to, heteroaryl, heterocyclyl, heterospirocarbocyclyl, fused heterocyclyl, and bridged heterocyclyl.
  • the heterocyclyl is pyrrolidinyl, morpholinyl, pyrrol izidinyl, quinol izidinyl, azaspirooctanyl, piperidinyl, pyrrolidinyl, imidazolinyl, piperazinyl, piperazinyl-1-oxide, morpholinyl, thiamorpholinyl, tetrahydrofuranyl, diazabicyclooctanyl, diazaspirooctanyl, tetrahydropyridinyl, dihydropyridinyl, dihydropyranyl, tetrahydropyranyl, 2-oxa-6-azaspiroheptanyl, azetidinyl, o
  • the carbon number designation C2-10 means a ring size of at least a 3-membered ring containing at least one heteroatom.
  • aryl in the present application, unless otherwise stated, represents an aromatic group which may be substituted or unsubstituted, and may be, for example, 6 to 20 membered.
  • the aryl may include, without limitation, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, indenyl, indanyl, or all possible isomers thereof.
  • heteroaryl in the present application, unless otherwise stated, means a monocyclic or bicyclic or higher aromatic group containing one or more heteroatoms selected from 0, N, and S, for example, 1 to 4, 1 to 3, or 1 to 2, and may be, for example, 6 to 20 membered.
  • examples of monocyclic heteroaryl include, but are not limited to, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, 2-oxa-5-azabicyclo [2.2.1]heptanyl or similar groups.
  • bicyclic heteroaryls include pyrrolizidinyl, indolyl, indolinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzthiazolyl, benzthiophenyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, indazolyl, quinolinyl, isoquinolinyl
  • tricyclic heteroaryl include, but are not limited to, azaspirooctanyl, purinyl, furopyridinyl, or similar groups.
  • examples of tricyclic heteroaryl include, but are not limited to, thioxanthinyl, carbazolyl, carbonyl, acridinyl, or similar groups.
  • the numerical range indicated using the term “to” in this application refers to a range that includes the numerical values described before and after the term “to” as the lower limit and the upper limit, respectively. Since the compounds of the present application may have an asymmetric carbon center and an asymmetric axis or an asymmetric plane, they may exist as all optical and stereoisomers, including substantially pure enantiomers such as the R and S enantiomers, as well as mixed racemates, and all of these isomers and mixtures are included in the scope of the present application.
  • the optical purity of such enantiomers and pharmaceutically acceptable salts thereof represented by Formula 1 or Formula 2 is preferably at least 60 %ee, more preferably at least 95 %ee, and most preferably at least 98 %ee.
  • ee refers to enantiomeric excess. For example, one enantiomer in a particular compound is present in a mixture of enantiomers in an amount greater than that of the other enantiomer in the compound.
  • An enantiomeric enriched form can include an enantiomeric mixture of a particular compound in which the concentration of a single enantiomer in the enantiomeric mixture of the particular compound is at least 50%, more typically at least 60%, 70%, 80%, or 90%, or greater (e.g., >95%, >97%, >99%, >99.5%) with respect to the other enantiomers of the compound.
  • the compound of formula 1 or formula 2 is used to mean all compounds of formula 1 or formula 2, optical isomers, stereoisomers, isotopic variants, solvates, hydrates, and pharmaceutically acceptable salts thereof.
  • isotopic variant refers to a compound that contains an unusual ratio of isotopes at one or more atoms constituting the compound.
  • an isotopic variant of a compound may be radiolabeled, for example, the hydrogen atoms may be selected from hydrogen, deuterium and tritium, and may contain carbon-13 ( 13 C), nitrogen-15 ( 15 N), etc.
  • the compound of formula 1 or formula 2 according to the present application, optical isomers, stereoisomers or isotopic variants thereof may form pharmaceutically acceptable salts.
  • the pharmaceutically acceptable salts described above include acid or base addition salts and their stereochemically isomeric forms.
  • the salts include, but are not limited to, any salt that retains the activity of the parent compound in the subject being administered and does not cause undesirable effects.
  • Such salts include inorganic and organic salts, for example, 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, 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, camsylic acid, carbonic acid, chlorobenzoic acid, citric acid, idetic acid, toluenesulfonic acid, edicilinic acid, esylinic acid, fumaric acid,
  • the basic salt form includes, for example, alkali and alkaline earth metal salts such as ammonium salt, lithium salt, sodium salt, potassium salt, magnesium salt and calcium salt, salts with organic bases such as benzathine, >methyl-Z>glucamine, hydrabamine salt and salts with amino acids such as arginine and lysine.
  • the salt form can also be converted into the free form by treatment with a suitable base or acid.
  • additional salt includes a solvate which the compound of formula 1 or formula 2 and its salt can form. Such solvate is, for example, a hydrate, an alcoholate.
  • the present application also provides a process for preparing a compound of formula 1 or formula 2.
  • a method for preparing a compound of Chemical Formula 1 or Chemical Formula 2 will be described based on an exemplary reaction scheme to help understanding the present application.
  • a person having ordinary skill in the art to which the present application pertains can prepare a compound of Chemical Formula 1 or Chemical Formula 2 by various methods using known compounds or compounds that can be easily prepared therefrom based on the structure of Chemical Formula 1 or Chemical Formula 2, and all such methods should be interpreted as being included in the scope of the present application. That is, by arbitrarily combining various synthetic methods described in the present specification or disclosed in the prior art.
  • Step A Compound 2 is obtained by adding phosphoryl trichloride and >ethyl->isopropylpropan-2-amine to compound 1 and heating.
  • Step B Compound 2 undergoes an SNAR reaction with a nucleophile having the formula H- Ri to synthesize compound 3 in the presence of a solvent such as dimethyl chloride and a base such as >ethyl->isopropylpropan-2-amine.
  • Step C Using a strong base such as sodium hydride in a nonpolar solvent such as tetrahydrofuran, the substituent -Y- R2 is introduced by the 2-chlorine substituent of the nucleophile of the compound having the formula H- Y- R2.
  • Step D In order to synthesize compound 5, the Suzuki reaction or Stilley reaction is used with compound 4 in step 1 and boronic acid or aryl stannane.
  • a pharmaceutical composition for preventing or treating a disease associated with a KRAS mutant protein comprising G12D comprising a therapeutically effective amount of a compound of formula 1 or formula 2 or an optical isomer, stereoisomer, racemate, isotope variant, solvate, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition may prevent or treat a disease associated with a KRAS mutant protein comprising G12D by inhibiting the activity of the KRAS mutant protein comprising G12D.
  • a compound of chemical formula 1 or 2 or an optical isomer, stereoisomer, racemate, isotope variant, solvate, hydrate, or a pharmaceutically acceptable salt thereof has a high binding ability to GDP-/GppNHp-KRAS mutant protein and can act as a KRAS mutation-specific inhibitor including G12D by inhibiting phosphorylation of extracellular signal-regulated kinases (Phospho-ERK, pERK) induced by KRAS mutation.
  • Phospho-ERK, pERK extracellular signal-regulated kinases
  • an example of the present application is a compound according to an example of the present application, an optical isomer, stereoisomer, racemate, isotope variant, or ...
  • the compound of Chemical Formula 1 or Chemical Formula 2 according to an example of the present application can prevent, improve, or treat a disease or condition related to a KRAS mutant protein including G12D, specifically, a disease or condition caused by a KRAS mutant protein including KRAS G12D.
  • the compound of Chemical Formula 1 or Chemical Formula 2 according to the present application can effectively suppress growth signals of cancer cells due to KRAS mutations as an inhibitor of a KRAS mutant protein including G12D, and can be usefully used as a pharmaceutical composition for preventing or treating cancer.
  • a pharmaceutical composition for preventing or treating cancer which comprises a therapeutically effective amount of a compound of Formula 1 or Formula 2 or an optical isomer, stereoisomer, racemate, isotopic variant, solvate, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient.
  • various forms of prodrugs that are converted into the compound of Formula 1 or Formula 2 in vivo as desired are also included in the scope of the present application.
  • the pharmaceutical composition may further comprise 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 on a subject exhibiting symptoms of the disease.
  • a “pharmaceutical composition” may include other chemical components such as carriers, diluents, excipients, etc. in addition to the active compound according to the present application. Accordingly, the pharmaceutical composition may contain pharmaceutically acceptable carriers, diluents, excipients, or a combination thereof, as needed. Such pharmaceutical compositions facilitate administration of the active compound into a living organism. Various techniques for administering pharmaceutical compositions containing the 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 auxiliary agents such as preservatives, stabilizers, wetting agents, emulsifying agents, salts for osmotic pressure control, and/or buffers, and may further contain other therapeutically useful substances, and may be formulated according to conventional methods of mixing, granulating, or coating.
  • carrier refers to a compound that facilitates the introduction of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • the term "diluent” refers to a compound that not only stabilizes the biologically active form of the target compound but also dilutes in water to dissolve the compound. Salts dissolved in buffers are used as diluents in the art. A commonly used buffer is phosphate-buffered saline, which mimics the salt form of human body fluids. Because buffer salts can control the pH of a solution at low concentrations, buffered diluents rarely alter the biological activity of a compound. As used herein, “pharmaceutically acceptable” refers to a property that does not impair the biological activity and physical properties of a compound.
  • the pharmaceutical composition may be a composition for the prevention and/or treatment of diseases associated with KRAS mutant proteins, including G12D.
  • the disease associated with the KRAS mutant protein including the G12D may be, for example, cancer and may include any disease known to be associated with other KRAS mutations.
  • the cancer may include angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; Squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic multicellular carcinoma, adenocarcinoma, alveolar (bronchiolar) cancer, bronchiolar adenoma, sarcoma, lymphoma, chondromatosis, mesothelioma, esophageal cancer, stomach cancer, pancreatic cancer, small intestine cancer, colon cancer, kidney cancer, bladder cancer, urethral cancer, prostate cancer, testicular cancer, liver cancer, biliary tract cancer, hepatoblastoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampullary carcinoma, osteosarcoma, malignant fibrous histiocytoma
  • the pharmaceutical composition may be formulated into various oral dosage forms or parenteral dosage forms.
  • it can be in any oral dosage form such as tablets, pills, hard/soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, etc.
  • These oral dosage forms may contain the active ingredient according to the usual composition of each dosage form.
  • it may contain pharmaceutically acceptable carriers such as diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, or lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol.
  • the oral administration dosage form when it is a tablet, it may contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and, if desired, disintegrants such as starch, agar, alginic acid or its sodium salt, effervescent mixtures and/or absorbents, coloring agents, flavoring agents or sweeteners.
  • the pharmaceutical composition may be formulated as a parenteral dosage form, in which case it is administered by parenteral administration methods such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the active ingredient i.e., the compound of Chemical Formula 1 or Chemical Formula 2 or an optical isomer, stereoisomer, isotopic variant, or a pharmaceutically acceptable salt thereof, is mixed in water with a stabilizer or buffer to prepare a solution or suspension, and such a solution or suspension can be prepared in a unit dosage form of an ampoule or vial.
  • the pharmaceutical composition may be sterilized, or may further include auxiliary agents such as preservatives, stabilizers, wetting agents or emulsifying promoters, salts for osmotic pressure control, and/or buffers, and may further include other therapeutically useful substances, and may be formulated according to conventional methods of mixing, granulating, or coating.
  • auxiliary agents such as preservatives, stabilizers, wetting agents or emulsifying promoters, salts for osmotic pressure control, and/or buffers, and may further include other therapeutically useful substances, and may be formulated according to conventional methods of mixing, granulating, or coating.
  • the above active ingredient i.e., the compound of Chemical Formula 1 or Chemical Formula 2 or a pharmaceutically acceptable salt thereof, may be included in the pharmaceutical composition in an effective amount of 0.1 to 500 mg/kg (body weight) per day, preferably 0.5 to 100 mg/kg (body weight) for mammals including humans, and such pharmaceutical composition may be administered orally or parenterally once a
  • the pharmaceutical composition may be used to treat cancer by additionally containing the compound according to an example of the present application and at least one or more different therapeutic agents.
  • the compound according to an example of the present application may exhibit synergistic effects when used in combination with different therapeutic agents.
  • the term “synergistic” refers to a therapeutic combination that is more effective than the additive effect of two or more single agents.
  • Combination therapy provides “synergistic” and demonstrates “synergistic", i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects resulting from the use of the compounds separately.
  • the synergistic effect is achieved when the active ingredients are: (1) co-formulated in a combined unit dosage form; When administered or delivered simultaneously; or (2) when delivered as separate formulations by substitution.
  • synergistic effect can 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 ingredient at the same total dosage.
  • the toxicity of a 50:50 (w/w) combination comprising the compound of Formula 1 or Formula 2 and the different therapeutic agent can be less than the toxicity of 100% (w/w) of the compound of Formula 1 or Formula 2, and/or the toxicity of 100% (w/w) of the different therapeutic agent, wherein the combination has about the same or greater efficacy. That is, the toxicity of the combination of the compound of Chemical Formula 1 or Chemical Formula 2 and a different therapeutic agent is less than the toxicity of the individual components, and the efficacy of the combination is greater than the efficacy of the individual components.
  • the purpose of combining the compound of Chemical Formula 1 or Chemical Formula 2 and a different therapeutic agent is not only to reduce toxicity and provide greater safety, but also to enhance efficacy to a greater extent than that provided by either agent alone. Increased efficacy is one of the benefits of combination therapy.
  • the one or more therapeutic agents may include, but are not limited to, one or more additional combinations selected from the group consisting of RTK/Ras-MAPK pathway-related protein inhibitors (EGFR inhibitors, FGFR inhibitors, ALK inhibitors, ROS inhibitors, MET inhibitors, RAF inhibitors, ERK inhibitors, MEK inhibitors, SHP-2 inhibitors, PI3K inhibitors, KRAS inhibitors, KRAS-G12C inhibitors, S0S1 inhibitors), DNA damage inducers, EGFR antibody inhibitors, and immuno-oncology therapeutic agents.
  • RTK/Ras-MAPK pathway-related protein inhibitors EGFR inhibitors, FGFR inhibitors, ALK inhibitors, ROS inhibitors, MET inhibitors, RAF inhibitors, ERK inhibitors, MEK inhibitors, SHP-2 inhibitors, PI3K inhibitors, KRAS inhibitors, KRAS-G12C inhibitors, S0S1 inhibitors
  • DNA damage inducers EGFR antibody inhibitors
  • RTK/Ras-MAPK pathway inhibitors including EGFR inhibitors (e.g., gefitinib, erlotinib, or lapatinib), FGFR inhibitors (e.g., pemigatinib or infigratinib (BGJ398)), ALK/ROS/MET inhibitors (e.g., crizotinib, cabozantinib, or foretinib), RAF inhibitors (e.g., vemurafenib, dabrafenib, or belvarafenib), ERK/MEK inhibitors (e.g., trametinib or cobimetinib), SHP-2 inhibitors (e.g., TN0155 and RMC4630), PI3K inhibitors (e.g., AMG 511 and bupalisib), KRAS inhibitors and KRAS-G12C inhibitors (e.g., soto
  • chemotherapy agents that induce DNA damage are alkylating agents (platinum chemotherapy agents: cisplatin, carboplatin, oxaliplatin/ nitrogen mustard drugs: mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil/ nitrosourea drugs: carmustine (BCNU), lomustine (CCNU), nimustine/ others: altretamine, busulfan , dacarbazine, Procarbazine, Temozolomide, Thiotepa, Lurbinectedin, etc.), antimetabolites (Fluorouracil (1,5-FU), Capecitabine, Cytarabine, Gemcitabine, Methotrexate, Mercaptopurine (6-MP), Leucovorin, Pemetrexed, etc.), Topoisomerase inhibitors (Epipodophyllotoxin: Etoposide), Teniphosa 0
  • Examples of the one or more therapeutic agents include, but are not limited to, EGFR antibody inhibitors include, but are not limited to, cetuximab, panitumumab, zalutumumab, nimotuzumab, and matuzumab.
  • Examples of the one or more therapeutic agents include, but are not limited to, immunotherapy agents include, but are not limited to, AMG-404, pembrolizumab, or nivolumab.
  • a tricyclic derivative compound, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, which exhibits an excellent inhibitory effect on a KRAS mutant protein can be provided. Therefore, such a compound, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof, can be effectively used for the prevention or treatment of a disease related to a KRAS mutant protein including G12D, such as cancer.
  • the compound according to the present application, or an optical isomer, stereoisomer, or isotopic variant thereof, or a pharmaceutically acceptable salt thereof can have superior efficacy or improved pharmacokinetic properties.
  • Step 1 7-Bromo-5-nitro-L6Hndazole (20 g, 82.6 mmol) was dissolved in THF (200 mL), and NaH (8.3 g, 124 mmol) was added at 0 °C under nitrogen, and the mixture was stirred at room temperature for 30 minutes. Mel (35.2 g, 248 mmol) was added to the reaction mixture, and the mixture was stirred for an additional hour. The reaction was quenched by adding purified water, and the mixture was extracted with Toyo.
  • Step 2 7-Bromo-2-methyl-5-nitro-2-Hndazole (20 g, 78.1 mmol), Fe (21.8 g, 391 mmol), and NH4C1 (5.01 g, 93.7 mmol) were dissolved in ethanol (120 mL), THF (120 mL), and purified water. (40 mL) was dissolved in the mixed solution and stirred at 90 °C for 1 hour. The reaction mixture was filtered through Celite, concentrated, and purified by silica gel column chromatography to obtain 7-bromo-2-methly-2-month-indazole-5-amine (7 g, 40% yield) as a yellow solid.
  • Step 3 7—Bromo—2—methly—27 ⁇ —indazole—5—amine (6.67 g, 29.5 mmol), chloral hydrate (9.76 g, 29.5 mmol), and Na2SC)4 (33.5 g, 236 mmol) were dissolved in purified water (70 mL), and then HC1 aqueous solution (4 mL) was slowly added and stirred at 90 °C for 30 minutes. 7-bromo-11-methyl-2-hydroxy-1-amine (11.9 g, 177 mmol) was added to the reaction mixture and stirred at 90 °C for an additional hour. Purified water was added to the reaction mixture to quench the reaction, and the solid was filtered.
  • Step 5 4-Bromo-2-methy-2 ⁇ 7, QH, 7 H, 8 ⁇ -pyrolo[3, 2- e]indazole- 7,8-dione (5.1 g, 18.2 mmol) was dissolved in 2 # NaOH aqueous solution (7.28 g, 182 mmol), then H 2 0 2 (3.1 g, 91 mmol) was slowly added and stirred for 1 hour.
  • Step 6 5— Amino— 7— bromo— 2— methyl— 2— indazole— 4— carboxylic acid (962 mg, 3.56 mmol) was dissolved in methanol (14 mL) / toluene (42 mL), and 2 M (diazomethyl )trimethylsilane (488 mg, 4.27 mmol) was slowly added at 0 °C and stirred at room temperature for 5 minutes. Distilled water was added to the compound to terminate the reaction, and EA (200 mL*3) was extracted.
  • Step 7 Methyl 5— amino— 7— bromo— 2— methyl— 2-dimethyl- 2 -indazole— 4— carboxylate (276 mg, 0.971 mmol) was dissolved in THF (13 111 L), and trichloroethanecarbonyl isocyanate (220 mg, 1.17 mmol) was added at 0 °C and stirred for 5 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ether. The solid was filtered to obtain methyl 7-bromo-2-methyl- 5[ [(2,2,2-tri ch lor oacetyl) carbamoyl ] ami no] -2j ⁇ -indazole-4-car boxy late (459 mg, 100% yield).
  • Step 9 4-Bromo-2-methyl ⁇ 2H, QH, TH, 8H, 9 ⁇ 2 -pyr azo lo [4, 3 — /] qu i micho 1 i ne-7, 9-di one (287 mg, 0.973 mmol) was slowly added POCls (5.9 g, 38.9 mmol) and DI PEA (377 mg, 2.92 mmol) and stirred at 110 °C for 20 h under nitrogen. The reaction mixture was concentrated under reduced pressure, and after adding Toyo, the pH was adjusted to 7-8 with saturated Na 2 CO 3 solution at 0 °C.
  • Step 1 7-Bromo-6-f luoro-2-methyl-Hndazole (40.0 g, 186 mmol) was dissolved in EA (500 mL), and Me 3 0BF 4 (41.3 g, 279 mmol) was added. The mixture was stirred at room temperature for 12 hours. Purified water was added to the reaction mixture to quench the reaction, and extraction was performed using a distilled water bath.
  • Step 2 After cooling H 2 S0 4 (370 mL) to 0 °C, 7-bromo-6-fluoro-2-methyl-2-indazole (37.0 g, 162 mmol) and KNO 3 (19.8 g, 1,956 mmol) were slowly added at 0 °C and stirred at room temperature for 12 hours. Cold purified water was added to the reaction mixture to terminate the reaction, and saturated NaHC0 3 aqueous solution was slowly added at 0 °C to adjust the pH.
  • Step 3 7-Bromo-6-fluoro-2-methyl-5-nitro-2-hydroxyl-indazol- 5- amine (30.0 g, 89% yield) was obtained as a yellow solid by dissolving 7-Bromo-6-fluoro-2-methyl-2-nitro-2-hydroxyl-indazol-5-amine (38.0 g, 139 mmol) and NH4C1 (59.3 g, 1.11 mol) in EtOH (400 mD/IfeO (200 mL). Fe (62.0 g, 1.11 mol) was added and stirred at 80 °C for 2 h.
  • Step 4 2-((Benzyl oxy) imino)acetic acid (34.5 g, 193 mmol) in DMF (245 111 L) and HATU (54.9 g, 144 mmol), DI PEA (99.6 g, 770 mmol), 7— bromo— 6— f luoro— 2— methyl- 2j ⁇ indazol- 5-amine (23.5 g, 96.3 mmol) were added dropwise.
  • Step 5 G?)— 2— (( Benzy 1 oxy ) imino) ⁇ N ⁇ ( 7— br omo— 6 -f 1 uor 0— 2— me t hy 1 ⁇ 2H ⁇ indazol-5- )acetamide (34.0 g, 83.9 mmol) was dissolved in H2SO4 (680 mL) and stirred at 90 °C for 2 hours. The mixture was cooled to room temperature and the reaction was quenched by adding cold purified water. The organic layer was extracted with EA (1.0 L*5) and freeze-dried.
  • Step 6 4-Bromo-5 -f 1 uor 0— 2— me t hy 1 — 2 , 6— di hydr opyr rolo[3,2— e]indazole— 7,8— di one (10.5 g, 35.2 mmol) and NaOH (14.1 g, 352 mmol) were dissolved in 1,4-dioxane (200 mL), then H 2 O 2 (20.5 g, 180 mmol) was added at 0 °C and stirred at room temperature for 1 hour. The reaction mixture was quenched by adding aqueous Na 2 SO 3 solution, and concentrated under reduced pressure to remove 1,4-dioxane.
  • Step 7 5— Amino— 7— bromo— 6— f luoro— 2— methyl— 2 -butyl-2-indazole— 4— carboxylic acid (9.00 g, 31.2 mmol) O ⁇ K 2 C0 3 (8.64 g, 62.5 mmol) was dissolved in DMF (90.0 mL), then CH 3 I (5.10 g, 35.9 mmol) was slowly added and stirred at room temperature for 2 hours. Saturated NH 4 Cl aqueous solution was added to the reaction mixture to terminate the reaction, and the organic layer was extracted with a distilled water.
  • Step 8 Methyl 5— amino— 7— bromo— 6— f luoro— 2— methyl— 2- ⁇ 2 - indazole— 4— carboxylate (9.70 g, 32.1 mmol) was dissolved in THF (100111 L), and 2, 2, 2-tri chloroacetyl isocyanate (12.1 g, 64.2 mmol) was slowly added at 0 °C and stirred at room temperature for 2 hours. The reaction mixture was concentrated and dissolved in NH 3 • H2O (91.0 g, 727 mmol) and MeOH (100 mL), and stirred at 40 °C for an additional 2 h.
  • Step 9 4-Bromo-5 -f 1 uor o— 2— me t hy 1 -2 , 6-di hydr o— 7 ⁇ 2 - pyr azo 1 o [ 4 , 3 — /] qu i micho 1 i ne- 7, 9(8 ⁇ ) -dione (8.10 g, 25.9 mmol) was dissolved in toluene (80.0 mL), then POC1 3 (39.7 g, 259 mmol) and DI PEA (7.36 g, 56.9 mmol) were slowly added, and the mixture was stirred at 115 °C for 40 hours.
  • the reaction mixture was cooled to room temperature, purified water was added to terminate the reaction, and the organic layer was extracted with a distilled water.
  • the extracted organic layer was dried over anhydrous NH2S04, filtered, and concentrated to obtain 4— bromo— 7 ,9— di ch loro— 5— fl uor o— 2— me t hy 1 — 2 ⁇ 2 - py r az o 1 o [ 4 , 3 — /] qu i mich o 1 i ne (9.00 g, 97% yield) as a yellow solid.
  • Step 2 2-(7-Bromo-5-nitro-2-Hndazol-2-yl)ethan-1-ol (6.96 g, 24.3 mmol) was dissolved in a mixture of THF (37.4 mL), H 2 0 (12.5 mL), and EtOH (37.4 mL). Then, Fe (6.79 g, 122 mmol) and NH 4 Cl (1.56 g, 29.2 mmol) were added and stirred at 90 °C for 1 hour. The reaction mixture was filtered through celite, and the solvent was concentrated to give 2-(5-amino-7-bromo-2-yl)ethan-1-ol.
  • Step 4 ( ⁇ )-2-( (Benzyl oxy ) imino) ⁇ N ⁇ ( 7- bromo- 2- ( 2-hydroxye thyl ) - 2H- i ndazo 1-5- yl )acetamide (8.46 g, 20.3 mmol) was dissolved in H 2 SO 4 (40.6 mL) and stirred at 90 °C for 30 minutes. The resulting solid was filtered, and the organic layer was extracted by adding ethanol and purified water to the filtrate.
  • Step 5 4-Bromo-2-(2-hydr oxyethyl)-2, 6-di hydr opyr rolo[3,2— e]indazole— 7,8— di one (5.0 g, 16.1 mmol) was dissolved in MeOH (150 mL), then ZerZ' butyl hydroperoxide (2.91 g, 32.2 mmol) and Cs 2 C0 3 (7.88 g, 24.2 mmol) were added and stirred at 70 °C for 2 hours. The reaction mixture was filtered and concentrated, and purified water was added to the obtained residue.
  • Step 6 To a suspension of NaH (229 mg, 9.55 mmol) in THF (10 mL), methyl 5—amino—7—bromo—2—(2—hydroxyethyl )—2-butyl- 2 -indazole—4—carboxylate (1.00 g, 3.18 mmol) and (bromomethyl )benzene (544 mg, 3.18 mmol) dissolved in THF (10 mL) were slowly added and stirred at 70 °C for 2 hours. Purified water was added to the reaction mixture to terminate the reaction and Toyo Extracted.
  • Step 7 Methyl 5-amino- 2- (2- (benzyloxy)ethyl )- 7- bromo- 2-butyl-indazole- 4-carboxylate (390 mg, 965 ⁇ mol) was dissolved in THF (10 mL), 2,2,2-trichloro-1- isocyanato-l-ethanone (273 mg, 1.45 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was depressurized to remove the solvent, and an excess of 7 N NH 3 solution dissolved in MeOH was added and stirred at room temperature for 12 hours. The residue obtained by concentrating the reaction mixture was added to purified water and stirred at room temperature for 30 minutes.
  • Step 2 Methyl 5— acetoxy— 2— amino— 4— bromo— 3 -f luorobenzoate (5.50 g, 18.0 mmol) was dissolved in methanol (275 mL), and K2CO3 (4.97 g, 35.9 mmol) was added and stirred at room temperature for 2 hours.
  • the reaction mixture was acidified by adding 1 N aqueous HC1 solution, and the organic layer was extracted with distilled water and dried over MgS04. The solvent was concentrated to obtain methyl 2-amino-4-bromo-3-fluoro-5-nitrobenzoate (4.74 g, crude compound).
  • Step 5 Methyl 5— amino— 7— bromo— 6— f luoro— 2— methylbenzofuran— 4— carboxylate (910 mg, 3.01 mmol) was dissolved in THF (30.3 mL), trichloroacetyl isocyante (0.40 mL, 3.31 mmol) was added at 0 °C, and the mixture was stirred for 30 minutes. NHjMeOH (7 N, 8.62 mL, 60.3 mmol) was added to the residue obtained by concentrating the reaction solvent, and the mixture was stirred at room temperature for 1 day.
  • Step 6 Bromo-5-fluoro-8-methylfuro[3,2- /]quinazoline-l,3(2'7, 460- dione (750 mg, 2.40 mmol) was added POCls (8.93 mL, 95.80 mmol), DI PEA (1.04 mL, 5.99 mmol) and stirred at 110 °C for 7 hours. Saturated NaHC0 3 aqueous solution was added to the reaction mixture to terminate the reaction and extract the toyo. The organic layer was dried over anhydrous MgS0 4, filtered and concentrated under reduced pressure, and then filtered with DCM to obtain a solid.
  • Step 2 2-amino-3-bromo-5-nitrophenol (25 g, 107.29 mmol) obtained in Step 1 was dissolved in toluene (250 111 L), 1,1,1-triethoxyethane (87.02 g, 536.44 mmol) was added, and the mixture was stirred at 100 °C for 12 hours. Ice water (250 mL) was added to the reaction mixture, and the reaction was stopped by stirring for 10 minutes, and then extracted with Toyo. The organic layer was purified with anhydrous NH2S04.
  • Step 3 4-bromo-2-methyl-6-nitrobenzo[(y]oxazole (12.5 g, 48.63 mmol) obtained in Step 2 was dissolved in THF (250 mL) was stirred at room temperature until completely dissolved.
  • the H 2 back pressure controller was adjusted to 1 MPa.
  • the solution was pumped into the fixed bed at a flow rate of 0.4 mL/min, and the flow rate of the resulting product was 20 mL/min and collected after 3.3 min.
  • Step 4 4-Bromo-2-methylbenzo[(y]oxazol-6-amine (11 g, 48.45 mmol) obtained in Step 3 was dissolved in a mixed solution of THF (165 mL) and MeOH (165 mL), cooled to 5 °C, TS0H-H 2 0 (921.52 mg, 4.84 mmol) and NIS (15.26 g, 67.82 mmol) were added, and stirred at room temperature for 1 hour. To the reaction mixture, NaHC0 3 aqueous solution (200 mL), EA (10 mL), and purified water (100 mL) were added to terminate the reaction, and extraction was performed with a filtrate.
  • Step 5 4-bromo-7-iodo-2-methylbenzo[(y]oxazole-6-amine (6.5 g, 18.42 mmol), TEA (5.59 g, 55.25 nmol), Pd(dppf KlrOfeCh (1.50 g, 1.84 mmol) obtained in Step 4 were dissolved in MeOH (135 mL) and stirred at 50 °C for 12 h under carbon monoxide. The reaction mixture was filtered and concentrated, and then purified by silica gel column chromatography to obtain methyl 6— amino— 4— bromo— 2— methylbenzo[(y]oxazole— 7— carboxylate (1.07 g, 18.2% yield) as a yellow solid.
  • Step 6 Methyl 6-amino-4-bromo-2-methylbenzo[(y]oxazole-7- obtained in Step 5 After dissolving carboxylate (1.21 g, 4.24 mmol) in THF (12 mL), 2, 2, 2-tri chloroacetyl isocyanate (1.60 g, 8.49 mmol) was slowly added at 0 °C under nitrogen, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain a white solid (1.8 g, crude compound).
  • Step 7 4-Bromo-2-niethyloxazok)[5,4-/]quinazol ine-7,9-diol (1.2 g, 4.05 mmol) obtained in Step 6 was dissolved in POC1 3 (19.74 g, 128.74 mmol), then DI PEA (1.05 g, 8.11 mmol) was slowly added at room temperature under nitrogen, and the mixture was stirred at 120 °C for 4 hours. The reaction mixture was cooled to room temperature, concentrated, dissolved in ethanol, and then slowly added with stirring to a solution of NaHC0 3 .
  • Step 2 6-Chloro-3-nitropicol inamide (7.35 g, 36.46 mmol) was dissolved in ethanol (30111 L). After dissolving, a saturated 28% ammonia solution (27.30 g, 218.09 mmol) was added and stirred in a sealed tube at 100 °C for 48 hours. The reaction mixture was cooled and concentrated under reduced pressure, and then an NH2C03 aqueous solution was added and stirred at room temperature for 1 hour to terminate the reaction. The resulting solid was filtered, washed with distilled water, and dried to obtain 6-amino-3-nitro-pyridine-2-carboxamide (4.85 g, crude compound) as a yellow solid.
  • Step 3 6— Amino— 3— nitro— pyridine— 2— carboxamide (4.85 g, 26.63 mmol) was dissolved in DMF (49 mL), NBS (5.69 g, 31.95 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, purified water was added to stop the reaction, and the resulting solid was filtered and dried.
  • Step 4 6-Am ino-3-nitr op i col inamide (5.9 g, 22.60 mmol) was dissolved in ethanol (59 mL) and distilled water (59 mL), and 2-bromo-l, 1-diethoxyethane (6.68 g, 33.90 mmol) and HBr (9.14 g, 45.21 mmol) were added at room temperature, and the mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated to remove ethanol, and the pH was adjusted to 8 by adding aqueous NaHC0 3 solution.
  • Step 5 8—Bromo—6—nitroimidazo[l, 2—a]pyridine—5—carboxamide (4.5 g, 15.79 mmol), Fe (3.53 g, 63.15 mmol), and NEUC1 (6.76 g, 126.29 mmol) were dissolved in a mixture of ethanol (90 mL) and water (18 mL), and stirred at 85 °C for 16 hours. The reaction mixture was filtered, and the solid was washed with EA/MeOH (10:1).
  • Step 6 6— Amino— 8— bromoimidazo[l, 2— a]pyridine— 5— carboxamide (10.47 g, 35.28 mmol) was added to 1,4-dioxane (100 mL), and the resulting suspension was stirred at 110 °C for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, purified water was added, and the mixture was stirred for 10 minutes. The reaction was completed by stirring. The resulting solid was filtered, washed with distilled water and dried to obtain 6-bromoimidazo[l ',2':l,6]pyrido[3,2—(f]pyrimidine—l,3(2j7, 460— dione (10.7 g, crude compound) as a yellow solid.
  • Step 7 In Step 6 To the obtained 6-bromoimidazo[r,2':l,6]pyrido[3,2-(f]pyrimidine-1,3(2 ⁇ ,4 ⁇ )-dione (5.4 g, 19.2 mmol), POC1 3 (117.8 g, 768.5 mmol) and DI PEA (6.2 g, 48.0 mmol) were slowly added and stirred at 110 °C for 20 h under nitrogen. The reaction mixture was concentrated under reduced pressure at 40 °C, and after adding Toyo, the pH was adjusted to 7-8 with saturated Na 2 CO 3 solution at 0 °C.
  • Step 2 4-bromo-5 -f luoro-2-methy Ibenzo[d ⁇ oxazo 1 e (4.2 g, 18.26 mmol) obtained in Step 1 was dissolved in H 2 SO 4 (21 mL) and pumped into the flow reactor 1 (FLR1, PFA, coil reactor, 3.175(1/8”) mm, 20.036 mL, 80 °C) by pump 1 (SI, Pl, 3.649 mL/min), and HN0 3 (3.5 g) was pumped into the flow reactor 1 by pump 2 (S2, P2, 0.358 mL/min).
  • the residence time in the flow reactor 1 was 5 min for FLR1, and the reaction mixture was collected in a bottle containing 20 mL of purified water at 0 °C for 15 min by operating pumps 1 and 2 simultaneously.
  • the reaction mixture was Ice water (100 mL) was added, and the resulting solid was filtered, washed with purified water (200 mL), and dried.
  • the product was purified by silica gel column chromatography aphy to obtain 4-bromo-5-f 1 uor 0— 2— me t hy 1 — 6— nitrobenzo[(/] oxazole (3.1 g, 62.0% yield) as a yellow solid.
  • LCMS (ES-API , m/z): [M+H] + 275.0;
  • Step 3 4-bromo-5-f luoro-2-methyl-6-nitrobenzo[(y]oxazole (3.1 g, 11.27 mmol) obtained in Step 2 was dissolved in EtOH (250 mL) and purified water (30 mL), and then Fe (2.52 g, 45.09 mmol) and NH 4 C1 (4.82 g, 90.17 mmol) were added and stirred at 50 °C for 2 h. The reaction mixture was filtered and concentrated, and then extracted with aqueous NaHC0 3 solution and distilled water.
  • Step 4 4-bromo-5-f luoro-2-methylbenzo[(y]oxazol-6-amine (2.6 g, 10.61 mmol) obtained in Step 3 was dissolved in a mixed solution of THF (39 mL) and MeOH (39 mL), then Ts0H-H 2 0 (201.82 mg, 1.06 mmol) and NIS (3.58 g, 15.92 mmol) were added at 0 °C and stirred at room temperature. The mixture was stirred for 40 minutes. The reaction was terminated by adding aqueous NaHC0 3 solution and purified water to the reaction mixture, and extracted with a distilled water.
  • Step 5 4-bromo-5 -f 1 uor o-7 - iodo-2-meth y 1 benzo
  • [ d ⁇ oxazo 1 -6- amine (3.9 g, 10.41 mmol), TEA (3.83 g, 37.85 mmol), Pd(dppf KlrCIfeCh (1.154 g, 1.56 mmol) obtained in Step 4 were dissolved in a mixed solution of MeOH (39 mL), 1,4-di oxane (19.5 mL), and DMF (19.5 mL), and stirred at 50 °C for 12 h under carbon monoxide.
  • Step 6 After dissolving methyl 6-amino-4-bromo-5-f luoro-2-methylbenzo[(y]oxazole-7-carboxylate (550 mg, 1.81 mmol) obtained in Step 5 in THF (5.5111 L), 2, 2, 2-tri chloroacetyl isocyanate (683.77 mg, 3.63 mmol) was slowly added at 0 °C under nitrogen, and the mixture was stirred at room temperature. The reaction mixture was concentrated and stirred for 1 hour.
  • Step 7 4-bromo-5 -f 1 uor o-2-methy 1 oxazo 10 [ 5 , 4 -/] qu i micho 1 i ne- 7,9-diol (380 mg, 1.21 mmol) obtained in Step 6 was dissolved in POC1 3 (6.5 g, 42.17 mmol), then DI PEA (312.7 mg, 2.42 mmol) was slowly added at room temperature and stirred at 120 °C for 4 hours under nitrogen. The reaction mixture was cooled to room temperature and concentrated to remove P0C13, dissolved in Toyo, and then NaHC0 3 aqueous solution was slowly added with stirring.
  • Step 2 Dissolve the ⁇ -butyl (L?,5S)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4 g, 8.80 mmol) and TMEDA (4.1 g, 35.20 mmol) obtained in Step 1 in THF (40 mL), then slowly add —BuLi (1.3 M, 27.07 mL) at -50 °C under nitrogen, and stir for 2.5 h. Ethyl formate (1.96 g, 26.40 mmol) was added to the reaction mixture, and the mixture was stirred for an additional 2 h at -20 °C.
  • the reaction was quenched by adding NH4C1 aqueous solution to the reaction mixture at 0 °C, and the mixture was extracted with a distilled water.
  • the organic layer was dried over anhydrous Na2S04, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain tert ⁇ butyl l-formyl-3-tr ity 1-3 ,8-di azabi cyclo [3.2.1] octane-8-car boxy late (2.4 g, 48.0% yield) as a white solid.
  • Step 4 AcOH (17 mL) was added to ⁇ -butyl 3-trityl-l-vinyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (840 mg, 1.75 mmol) obtained in Step 3, and the mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure to obtain ⁇ -butyl 1-viny 1 -3 , 8-diazabicyclo[3.2.1 ]octane-8-carboxy 1 at e (416 mg, 100% yield, crude compound) as a yellow solid.
  • Step 2 Preparation of ⁇ -butyl 3-trityl-1-vinyl-3,8- obtained in Step 1
  • Diazabicyclo[3.2.1]octane- 8-carboxylate (960 mg, 2.00 mmol) was dissolved in MeOH (10 mL), Pd/C (96 mg, 10% purity) was added under nitrogen, and the mixture was degassed and purged with hydrogen three times, followed by stirring under hydrogen (15 Psi) at room temperature for 2 h.
  • the reaction mixture was filtered and concentrated under reduced pressure to obtain ⁇ -butyl 1-ethyl- 3-trityl- 3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (930 mg, crude compound) as a white solid.
  • Step 1 ZerZ ⁇ butyl l-/brmyl-3-trityl-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (1.4 g, 2.90 mmol) obtained in Step 2 of Intermediate 8 was dissolved in MeOH (10 mL), then NaBH 4 (384.12 mg, 10.15 mmol) was added and stirred at 0 °C for 1 h under nitrogen.
  • Step 3 AcOH (13 mL) was added to ⁇ -butyl l-(methoxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (650 mg, 1.30 mmol) obtained in Step 2, and the mixture was stirred at room temperature for 12 h.
  • reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain ZerZ" butyl l-(methoxymethy 1 )-3 , 8-diazabicyclo[3.2.1]octane- 8-carboxylate (313 mg, 75.9% yield) as a white solid.
  • Step 2 ZerZ obtained in Step 1 was dissolved in DCM (5 mL) and purified water (5 mL) to form butyl l-(hydroxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1 g, 2.06 mmol), then KOAc (1.24 g, 12.59 mmol) and (bromo(difluoro)methyl 1)-trimethylsilane (1.72 g, 8.46 mmol) were slowly added at 0 °C and stirred at room temperature for 12 hours. The reaction mixture was quenched by adding saturated NaHC0 3 aqueous solution and extracted with DCM.
  • Step 3 8-diazabicyclo[3.2.1]octane-8-carboxylate (620 mg, 1.16 mmol) obtained in Step 2 was dissolved in DCM (6.2 mL), AcOH (13.01 g, 216.61 mmol) was added, and the mixture was stirred at room temperature for 12 h. After concentrating the reaction mixture, purified water and acetic acid were added to extract the aqueous layer.
  • Step 1 ZerZ obtained in Step 1 of Intermediate 8 was dissolved in THF (5 mL) of butyl (17?,5S)-3-trityl-3,8-diazabicyclo[3.2.1]octane— 8— carboxylate (0.5 g, 1.10 mmol) and TMEDA (511.26 mg, 4.40 mmol). —BuLi (1.3 M, 3.38 mL) was added under nitrogen at -50 °C and stirred for 2.5 h.
  • step 2 ZerZ obtained in step 1 was dissolved in DMSO (30 mL) to obtain 1-(4-(( Z'erZ'-butyldimethylsilyl)oxy)-l- hydr oxybutyl )-3-tri ty 1-3 ,8-di azabi cyclo [3.2.1] octane-8-carboxylate (2.9 g, 3.53 mmol) and stirred at room temperature for 16 hours. Purified water (100 mL) was added to the reaction mixture to terminate the reaction and extracted with a solvent.
  • Step 3 After dissolving ⁇ -butyl l-(l,4-dihydroxybutyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane— 8— carboxylate (1.59 g, 2.93 mmol) obtained in Step 2 in pyridine (16 mL), benzenesulfonyl chloride (1.55 g, 8.79 mmol) was added and stirred at room temperature for 16 hours. 1 #HC1 solution (50 mL) was added to the reaction mixture to terminate the reaction and extracted with distilled water. The organic layer was dried over anhydrous NH2S04, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography.
  • Step 4 AcOH (5 mL) was added to ZerZ ⁇ butyl l—(G?)—tetrahydrofuran—2—yl)—3—trityl — 3 , 8-di az ab i eye 1 o [ 3.2.1 ] oct ane-8-car boxy late (300 mg, 457.41 umol) obtained in Step 3, and the mixture was stirred at 30 °C for 16 hours. Purified water (10 mL) was added to the reaction mixture to terminate the reaction, and the aqueous layer was extracted by adding distilled water.
  • tert-butyl (1 ⁇ ,5S)-3-trityl-3,8- di az ab i eye 1 o [ 3.2.1 ] oct ane-8-car boxy 1 at e 800 mg, 1.66 mmol obtained in step 1 was added in THF (8 mL). Dissolve and add, and stir for 1 hour at 0 °C under nitrogen, and then for 12 hours at room temperature. The reaction was terminated by adding purified water (50 mL) at 0 °C, and extracted with distilled water.
  • Step 2 ZerZ ⁇ butyl G?)-l-(2-methoxyvinyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (0.74 g, 1.45 mmol) obtained in Step 1 was dissolved in MeOH (15 mL), Pd/C (1.54 g, 1.45 mmol) was added, and the mixture was stirred at room temperature for 2 h under hydrogen.
  • reaction mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain ZerZ ⁇ butyl l-(2-methoxyethy 1 )-3-tri ty 1-3 , 8-diazabicyclo[3.2.1]octane- 8-carboxylate (0.76 g, crude mixture) as a yellow oil.
  • Step 3 AcOH (10 mL) was added to ⁇ -butyl l-(2-methoxyethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (760 mg, 1.48 mmol) obtained in Step 2, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove AcOH, purified water was added, and washed with distilled water.
  • Step 1 ZerZ ⁇ butyl (17?,5S)-3-trityl-3,8- diazabicyclo[3.2.1]octane— 8— carboxylate (1.2 g, 2.49 mmol) obtained in Step 2 of Intermediate 8 was dissolved in THF (12 mL), and MeMgBr (3 M, 4.14 mL) was added at 0 °C under nitrogen, and stirred for 1 hour. The reaction was terminated by adding saturated NH 4 Cl aqueous solution, and extraction was performed with a distilled water.
  • Step 2 ZerZ obtained in Step 1 was dissolved in DMF (4 mL) butyl l-(l-hydroxyethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane- 8-carboxylate (470 mg, 942.54 ⁇ mol), and Mel (176.03 uL, 2.83 mmol) and NaH (45.24 mg, 1.13 mmol) were slowly added sequentially, and the mixture was stirred at 0 °C for 1 hour. The reaction was terminated by adding NH 4 Cl aqueous solution to the reaction mixture, and the mixture was extracted with distilled water.
  • Step 3 AcOH (7 mL) was added to ⁇ -butyl l-(l-methoxyethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (660 mg, 1.29 mmol) obtained in Step 2. and stirred at room temperature for 16 hours. Purified water was added to the reaction mixture to quench the reaction and washed with EA. After adjusting the pH of the aqueous layer to 8-9, it was extracted with EA, and the organic layer was washed with a saturated NaCl aqueous solution and dried over anhydrous Na2S04.
  • step 2 ZerZ" butyl l-(hydroxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (700 mg, 1.44 mmol) obtained in step 1 was dissolved in DMF (7 mL), and then EtI (346.58 uL, 4.33 mmol) and NaH (69.32 mg, 1.73 mmol) were sequentially added slowly and stirred at 0 °C for 1 hour. NH 4 Cl aqueous solution was added to the reaction mixture to terminate the reaction, and then extracted with a distilled water bath.
  • Step 3 To the ⁇ -butyl l-(ethoxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (730 mg, 1.42 mmol) obtained in Step 2, AcOH (7.3 111 L) was added and stirred at room temperature for 16 hours. Purified water was added to the reaction mixture to terminate the reaction, and then extraction was performed with a distilled water bath. The organic layer was dried over anhydrous NH2S04, filtered and concentrated under reduced pressure to give ter'-butyl 1-(ethoxymethyl)-3,8-diazabi eye lo[3.2.1]octane-8-carboxylate (350 mg, crude mixture) as a yellow oil.
  • Step 1 ZerZ ⁇ Butyl 3- formylpiperidine-1-carboxylate (8 g, 37.51 mmol) was dissolved in DCM (80 mL), and CH 3 I (15.97 g, 112.53 mmol) and r-BuOK (6.31 g, 56.27 mmol) were added sequentially at 0 °C under nitrogen, and the mixture was stirred at room temperature for 3 h. Distilled water was added to the reaction mixture to stop the reaction, and the mixture was extracted with distilled water.
  • Step 2 ZerZ obtained in Step 1 was dissolved in DCM (40 mL) and DAST (8.94 g, 55.43 mmol) was added at -15 °C under nitrogen and stirred for 1 hour.
  • reaction mixture was quenched by adding saturated NaHC0 3 aqueous solution and extracted with distilled water.
  • organic layer was washed with saturated NaCl aqueous solution, dried over NH2S04, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain tert-butyl 3-(difluoromethyl)-3-methylpiperidine-1-carboxylate (1.8 g, crude) as a colorless oil.
  • Step 3 ZerZ' butyl 3- (difluoromethyl)-3- methylpiperidine-1-carboxylate (600 mg, 2.41 mmol) obtained in Step 2 was dissolved in DCM (4 mL), and HCl/l,4-dioxane (2 M, 8.00 mL) was added at room temperature and stirred for 1 hour.
  • Step 2 To prepare (L?, 5S)-3-methyl-3,8- diazabicyclo [3.2.1]octane-8-carboxy 1 at e (1 g, 4.42 mmol) obtained in Step 1, dissolved in DCM (10 mL), TFA (10.00 mL) was added, and the mixture was stirred at room temperature for 30 min.
  • Step 2 Ethyl formate (977.71 mg, 13.20 mmol) was dissolved in TMEDA (2.05 g, 17.60 mmol) in THF (30 mL), and —BuLi (1.3 M, 13.54 mL) was slowly added at -50 °C under nitrogen, and the mixture was stirred at -50 °C for 2.5 h.
  • Step 3 ZerZ ⁇ butyl (IS, 57?)-2-formyl-8-tri tyl-3 , 8-diazabicyclo[3.2.1]octane- 3-carboxylate (1.29 g, 2.67 mmol) obtained in Step 2 was dissolved in EtOH (13 mL), and then NaBH 4 (252.81 mg, 6.68 mmol) was added at 0 °C under nitrogen, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding saturated NH 4 Cl aqueous solution (25 mL), and extracted with EA (25 mL*3).
  • Step 4 AcOH (4.5 mL) was added to ZerZ ⁇ butyl (IS, 57?) -2- (hydr oxymethyl )-8-tri ty 1-3 , 8-diazabicyclo[3.2.1]octane— 3— carboxylate (450 mg, 928.55 u niol) obtained in Step 3, and the mixture was stirred at room temperature for 12 h. After completion of the reaction, the mixture was dried under reduced pressure to obtain tert-butyl (IS, 57?) -2 - ( hydr oxymethy 1 )-3 , 8-di azabi eye lo[3.2.1] octane-3-carboxylate
  • Step 1 ZerZ ⁇ Butyl (17?, 5 S) -3, 8-di az ab i eye 1 o [3.2. 1 ] oct ane-8-car boxy late (10 g, After dissolving 47.11 mmol) in THF (100 mL), K 2 C0 3 (19.53 g, 141.32 mmol) was added and CH 3 I (19.99 g, 140.85 mmol) was slowly added dropwise at room temperature for 1 hour. The reaction mixture was stirred at room temperature for 3 hours.
  • Step 2 After ter'-butyl (17?, 5S)-3-methy 1-3, 8-diazabicyclo[3.2.1]octane— 8— carboxylate (5.2 g, 22.98 mmol) and rutheniumoxide hydrate (712.83 mg, 4.60 mmol) obtained in Step 1 were dissolved in EA (265 mL), and then NaICU aqueous solution (10% wt, 265.49 mL) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 16 hours. This was repeated in another batch.
  • Step 3 To (1 ⁇ ,5S)-3-methyl-2,4-dioxo-3,8-diazabicyclo[3.2.1]octane— 8— carboxylate (3.2 g, 12.58 mmol) obtained in Step 2, HCl/l,4-di oxane (2 M, 90 mL) was added at room temperature and stirred for 12 hours.
  • Step 4 (17?, 5 S) -3-methoxy 1 -3 , 8-di az ab i eye 10 [ 3.2.1 ] octane-2 , 4- dione (2.0 g, 10.49 mmol) and PhCHO (3.34 g, 31.48 mmol) obtained in Step 3 were dissolved in DCM (20 mL), and then NaBH(0Ac) 3 (6.67 g, 31.48 mmol) was added. AcOH (6.30 mg, 104.92 umol) was added. The mixture was stirred at room temperature for 2 hours. Saturated NaHC0 3 (10 mL) was added to the reaction mixture to terminate the reaction, and the mixture was extracted with DCM (10 mL*3).
  • Step 5 (17?, 5S)-8-benzy 1 -3-methyl-3,8- diazabicyclo[3.2.1] octane-2,4-di one (2 g, 8.19 mmol) obtained in Step 4 was dissolved in THF (40111L), and then LiAlD4 (2 M, 24.56 mL) was slowly added at 0 °C under nitrogen.
  • reaction mixture was stirred at room temperature for 30 minutes, then heated to 66 °C and stirred for an additional 8 hours.
  • Water (1.86 mL), 15% NaOH aqueous solution (1.86 mL), and water (5.58 mL) were sequentially added to the reaction mixture at 0 °C to terminate the reaction, and then concentrated under reduced pressure to obtain (1 ⁇ ,5S)-8-benzyl-3-methyl- 3,8-diazabicyclo[3.2.1].
  • l]octane- 2, 2,4,4- ( ⁇ (1.66 g, 92.2% yield) was obtained as a yellow oil, and the deuterated ratio test confirmed that the ratio of the 4D label product was 93.7% and the 3D label product was 6.1%.
  • Step 6 (17?, 5 S) -8-benzy 1 -3-methyl-3,8- diazabicyclo[3.2.1]octane- 2,2,4,4- ( ⁇ (800 mg, 3.63 mmol) obtained in Step 5 was dissolved in EtOH (20 111 L), and wet Pd/C (772.75 mg, 726.13 umol) and HC00NH 4 (1.14 g, 18.15 mmol) were sequentially added at room temperature, and stirred at 90 °C for 3 hours under nitrogen. The reaction mixture was cooled to room temperature, filtered with EtOH (10 mL), and the resulting solid was washed with EtOH (10 mL*3).
  • HC 1 /1, 4-di oxane (2 M, 10 mL) was added to the filtrate at room temperature. The mixture was stirred for 2 hours. After concentrating under reduced pressure, the reaction mixture was dissolved in water (10 mL) and washed with MTBE (10 mL*2). The aqueous layer was basified by slowly adding a NaOH aqueous solution (15% wt.) at room temperature, and then extracted with DCM (20 mL*3). The resulting organic layer was dried over Na2S04 and filtered. HC 1 /1, 4-dioxane (2 M, 20 mL) was added to the resulting filtrate, and the mixture was stirred at room temperature for 1 hour.
  • Step 2 To prepare the ⁇ / ⁇ -butyl (L?, 5S)- 3- (methyl- ⁇ )-3,8- diazabicyclo[3.2.1] octane-8-carboxy 1 at e (600 mg, 2.62 mmol) obtained in Step 1, TFA (4.61 g, 40.40 mmol) was added and stirred at 20 °C for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain (1 ⁇ , 5S)-3- (Methyl- sesame)- 3,8- diazabicyclo[3.2.1] octane (636 mg, crude) as a white solid.
  • LCMS (ES-API , m/z): [M+H]+ 130.2.
  • MeMgBr (3 M, 3.88 mL) was added at -65 °C and stirred for an additional 2 hours. Distilled water was added to the reaction mixture to stop the reaction, and extraction was performed with a distilled water bath. The organic layer was dried over anhydrous NH2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give ter'-butyl (IS, 57?)-2,2,3-tri imethy 1-3,8-diazabicyclo [3.2.1]octane-8-carboxylate (477 mg, 57.9% yield) as a pale yellow oil.
  • Step 2 ter'-butyl (lS,57?)-2,2,3-trimethyl-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (477 mg, 1.88 mmol) obtained in Step 1 was dissolved in DCM (4.2 111 L), and TFA (1.92 g, 16.8 mmol) was added at room temperature, followed by stirring for 2 hours. The reaction mixture was concentrated under reduced pressure, and TFA was removed together with MeCN (10 mL).
  • reaction mixture was washed with i-Pr 2 0 (10 mL), filtered, and concentrated under reduced pressure to obtain (15,5 ⁇ )-2,2,3-trimethyl-3,8-diazabicyclo[3.2.1]octane (589 mg, crude) as a yellow oil.
  • Step 2 ZerZ ⁇ butyl 2- (methoxymeth y 1 ene) -6-azasp ir 0 [ 3.5 ] nonane- 6-car boxy late (2.25 g, 8.42 mmol) obtained in Step 1 was dissolved in MeCN (22 mL) and H2O (5.5 mL), and TFA (1.38 g, 12.12 mmol) was added and stirred at 20 °C for 2 hours.
  • reaction mixture was quenched by adding saturated NaHC0 3 aqueous solution, extracted with distilled water, and concentrated under reduced pressure to obtain ter'— butyl 2-formy 1 -6-azasp ir 0 [ 3.5 ] nonane-6-car boxy 1 at e (1.77 g, crude) as a yellow oil.
  • Step 3 ZerZ ⁇ butyl 2-f ormy 1 -6-azasp ir 0 [ 3.5 ] nonane-6-carboxylate (1.77 g, 6.99 mmol) obtained in Step 2 was dissolved in DCM (18 mL), and DAST (2.25 g, 13.97 mmol) was added at 0 °C and stirred for 2 hours. Saturated NaHC0 3 aqueous solution was added to the reaction mixture to stop the reaction, and the mixture was extracted with DCM and washed with saturated NaCl aqueous solution.
  • Step 4 ZerZ ⁇ butyl 2- (difluoromethyl)- 6- azaspiro[3.5]nonane- 6- carboxylate (1.22 g, 4.43 mmol) obtained in Step 3 was dissolved in DCM (12 mL), then HCl/l, 4-di oxane (2 M, 24.40 mL) was added and stirred at room temperature for 30 minutes.
  • Step 2 After dissolving diethyl 4-chloro-1-pyrazole-3,5-dicarboxylate (3.88 g, 15.73 mmol) obtained in Step 1 in DMF (24 mL), ⁇ / ⁇ —butyl (3-bromopropyl )carbamate (5.62 g, 23.60 mmol), CS2CO3 (25.63 g, 78.65 mmol) KI (130.57 mg, 786.55 Limol) were added and stirred at room temperature for 16 hours. Distilled water was added to the reaction mixture to stop the reaction, and then the mixture was extracted with distilled water.
  • Step 3 Diethyl 1- (3- (( ⁇ / ⁇ - butoxycarbonyl ) ami no)pr opy 1 )-4-chloro— 1 ⁇ — pyr azole— 3,5— dicarboxy late (3.11 g, 7.70 mmol) obtained in Step 2 was dissolved in 1,4-dioxane (15 mL), then HC1/ 1,4-dioxane (2 M, 45 mL) was added and stirred at room temperature for 3 h.
  • Step 4 Diethyl 1-(3-aminopropyl)-4-chloro-1-month-pyrazole-3,5-dicarboxylate hydrochloride (2.6 g, 7.64 mmol) obtained in Step 3 was dissolved in MeOH (50 mL), TEA (3.87 g, 38.21 mmol) was added, and the mixture was stirred at 80 °C for 16 hours.
  • reaction mixture was concentrated under reduced pressure to remove methanol, dissolved in distilled water, and washed with distilled water.
  • the organic layer was dried over Na2SC)4, filtered, and concentrated under reduced pressure to obtain ethyl 3-chloro-4-oxo-5,6,7,8-tetrahydro-4-month—pyrazolo[l,5— ⁇ ][1,4]diazepine—2—carboxylate and methyl 3—chloro—4—oxo—
  • Step 5 A mixture of ethyl 3-chloro-4-oxo-5,6,7,8-tetrahydro-4-month-pyrazolo[l,5 — ⁇ ] [1,4] di azepine— 2— carboxylate and methyl 3— chloro— 4— oxo— 5,6,7,8— tetrahydro— 4-month-pyrazolo[l,5 — ⁇ ] [l,4]diazepine— 2— carboxylate obtained in Step 4 (1.80 g, 3.62 mmol) was dissolved in THF (26 mL), and BH 3 -Me 2 S (10 M, 1.57 mL) was added at 0 °C under nitrogen, stirred at room temperature for 2 hours, and then stirred at
  • Step 6 A mixture of ethyl 3-chloro- 5, 6, 7, 8-tetrahydro- 4-pyrazolo[1,5- a ⁇ [1,4] diazepine— 2-carboxylate and methyl 3— chloro— 5, 6, 7, 8— tetrahydro— 4-pyrazolo[l ,5 — ⁇ ] [1 ,4] diazepine— 2-carboxylate (861 mg, 3.53 mmol) obtained in Step 5 was dissolved in DCM (10 mL), and DMAP (43.16 mg, 353.32 ymol), TEA (1.07 g, 10.60 mmol) and BOC 2 O (1.70 g, 7.77 mmol) were sequentially added and stirred at room temperature for 2 hours.
  • Step 8 ZerZ ⁇ butyl 3-chloro-2-(dimethylcarbamoyl)-7,8-dihydro- 4j ⁇ -pyrazolo[l,5— a] [l,4]diazepine— 5(6-way O-carboxylate (113 mg, 329.62 umol) obtained in Step 7 was dissolved in 1,4-dioxane (1 mL). After dissolving, HCl/l,4-dioxane (2 M, 1 mL) was added and stirred at room temperature for 1 hour.
  • reaction mixture was After cooling to room temperature and evaporation under reduced pressure, the residue was purified by silica gel column chromatography to obtain ethyl 2,2-difluoro-5'-oxodihydro-1'-, 3'-spiro[cyclopropane-1,2'-pyrrolizine]-7a'(5'-butyl 0—carboxylate (4.80 g, 48.4% yield) in the form of a racemic mixture as a yellow solid.
  • Step 2 Ethyl 2,2-difluoro-5'-oxodihydro- 1' ⁇ , 3' ⁇ " spiro[cyclopropane— 1,2'— pyrrolizine]— 7a'(5' ⁇ 0— carboxylate (3.0 g, 11.6 mmol) obtained in Step 1 was dissolved in THF (30 mL), LAH (2.5 M, 27.8 mL) was added at 0 °C under nitrogen, and stirred at 60 °C for 2 hours. To the reaction mixture, H 2 0 (2.6 mL), 15% aq. NaOH (2.6 mL), H2O (7.9 mL) were sequentially added to terminate the reaction and extracted with distilled water.
  • Step 3 (2,2- difluorodihydro- 1'month, 3'month- spiro[cyclopropane- 1,2'-pyrrolizin]- 7a'(5' ⁇ 0- yl)methanol (1.9 g, 9.35 mmol) obtained in Step 2 was dissolved in DMF (10 mL) and TBDPSC1 (3.08 g, 11.2 mmol) and imidazole (1.27 g, 18.7 mmol) were added and stirred at room temperature for 18 h.
  • Step 4 Racemic mixture of 7a'-((( ter /"-but y 1 di pheny 1 si ly 1 )oxy)methy 1 )-2 , 2- dif luorotetrahydro— 1' ⁇ , 3' ⁇ — spiro[cyclopropane—l,2'-pyrrolizine] (1.20 g) was separated into chiral isomers using SFC (column: DAICEL CHIRALPAK IC (250 mm*50 mm, 10 ym); mobile phase: [CO2—EtOH(Ol% NH3H2O)]: B%: 12%, isocratic elution mode).
  • MeOH MeOH
  • KHF 2 (2.10 g, 26.9 mmol) was added and stirred at room temperature for 18 h.
  • reaction mixture was reduced in pressure to remove MeOH and purified by silica gel column chromatography to give ((L?, 7a' ⁇ ?)— 2,2— difluorodihydro— 1' ⁇ , 3 ' ⁇ 2 - spiro[cyclopropane— 1,2'-pyrrol i z in]- 7a'(5' ⁇ )-yl)methanol (185 mg, 67.8% yield) as a colorless oil.
  • Step 2 1-(ZerZ ⁇ butyl)2-methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-1,2-dicarboxylate (1.9 g, 5.80 mmol) obtained in Step 1 was dissolved in DCM (19111L), and then TFA (5.83 g, 51.16 mmol) was added at room temperature and stirred for 2 hours. Reaction The mixture was depressurized to remove DCM and methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-2-carboxylate TFA was obtained as a yellow solid.
  • Step 3 Methyl 2-(2-chloroethyl)-4,4-difluoropyrrolidine-2-carboxylate (2.2 g, 6.44 mmol), the TFA salt obtained in Step 2, was dissolved in MeCN (33 111 L), and K 2 CO 3 (2.67 g, 19.32 mmol) was added at room temperature.
  • Step 4 Methyl 3,3-difluoro-l-azabicyclo[3.2.i heptane-5-carboxylate] (790 mg, 4.13 mmol) obtained in Step 3 was dissolved in THF (16 mL), and then LAH (2.5 M, 4.96 mL) was slowly added dropwise under nitrogen at 0 °C, and stirred at room temperature for 12 hours.
  • Step 2 5-( ⁇ / ⁇ -butyl ) 6-methyl (6S)-1 , 1-di f luoro-5- azasp i ro [ 2.4] heptane-5,6-dicarboxylate (5 g, 17.17 mmol) and HMPA (4.00 g, 22.31 mmol) obtained in Step 1 were dissolved in THF (125 mL), and Li HMDS (1 M, 22.31 mL) was added at -40 °C under nitrogen and stirred for 1 hour. Then, 1-bromo-2-chloroethane (12.31 g, 85.83 mmol) was added at -40 °C, and the reaction mixture was stirred at room temperature for 12 hours.
  • the reaction was quenched by adding saturated NH 4 Cl aqueous solution to the reaction mixture, and then extracted with distilled water. The organic layer was washed with saturated NaCl aqueous solution, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain 5-( ⁇ / ⁇ - butyl ) 6-methyl 6-(2-chloroethyl)— 1,1— dif luoro— 5— azaspiro [2.4] heptane— 5,6— di carboxylate (2.17 g, 35.8% yield) as a yellow oil.
  • Step 3 5-( ⁇ / ⁇ -butyl ) 6 -methyl 6-(2-chloroethyl )-1 , 1- dif luoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (2.17 g, 6.14 mmol) obtained in Step 2 was dissolved in DCM (22 mL), TFA (7.70 g, 67.54 mmol) was added at room temperature, and the mixture was stirred for 1 hour.
  • Step 4 Methyl 6— (2— chloroethyl )— 1 , 1— di f luoro— 5— azaspiro[2.4]heptane-6-carboxylate (1.56 g, 6.15 mmol) obtained in Step 3 was dissolved in MeCN (85 mL), and TEA (3.11 g, 30.75 mmol) was added at room temperature, followed by stirring at 85 °C for 6 h.
  • reaction mixture was concentrated under reduced pressure and purified through silica gel column chromatography to obtain methyl 2 ' ,2 ' — di f luoro— 1— azaspiro[bi cyclo [3.2.0]heptane— 3 , 1 ' -eye 1 opr opane ] -5 - carboxylate (351 mg, 26.3% yield) was obtained as a yellow oil.
  • Step 5 Methyl 2',2'-difluoro-l- azaspiro[bicyclo[3.2.0]heptane— 3,1'— cyclopropane]— 5— carboxylate (350 mg, 1.61 mmol) obtained in Step 4 was dissolved in THF (20 mL), LAH (2.5 M, 1.29 mL) was added at 0 °C under nitrogen, and the mixture was stirred at room temperature for 30 minutes. Saturated Na 2 SO 4 aqueous solution was added to the reaction mixture at 0 °C to terminate the reaction, and the mixture was extracted with Toyo.

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Abstract

La présente invention concerne un nouveau composé dérivé tricyclique en tant qu'inhibiteur de protéine mutante KRAS, et son utilisation. Le composé selon un mode de réalisation de la présente invention inhibe l'activité d'une protéine mutante KRAS et peut ainsi être utilisé dans la prévention ou le traitement de maladies induites par la mutation KRAS.
PCT/IB2025/055788 2024-06-05 2025-06-05 Nouveaux composés tricycliques et leur utilisation en tant qu'inhibiteurs de kras Pending WO2025253326A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2024-0074009 2024-06-05
KR20240074009 2024-06-05
KR1020250037604A KR20250174461A (ko) 2024-06-05 2025-03-24 Kras 저해제로서 신규한 3환 화합물 및 이의 용도
KR10-2025-0037604 2025-03-24

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040229890A1 (en) * 2003-05-15 2004-11-18 Berthel Steven Joseph Diaminopyrroloquinazolines compounds as protein tyrosine phosphatase inhibitors
WO2004101568A1 (fr) * 2003-05-15 2004-11-25 F. Hoffmann-La Roche Ag Composes de diaminopyrroloquinazoline en tant qu'inhibiteurs de proteine tyrosine phosphatases
US20180155348A1 (en) * 2016-09-29 2018-06-07 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
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

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040229890A1 (en) * 2003-05-15 2004-11-18 Berthel Steven Joseph Diaminopyrroloquinazolines compounds as protein tyrosine phosphatase inhibitors
WO2004101568A1 (fr) * 2003-05-15 2004-11-25 F. Hoffmann-La Roche Ag Composes de diaminopyrroloquinazoline en tant qu'inhibiteurs de proteine tyrosine phosphatases
US20180155348A1 (en) * 2016-09-29 2018-06-07 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
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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