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WO2021084765A1 - Dérivés de 4-aminobut-2-enamide et sels de ces derniers - Google Patents

Dérivés de 4-aminobut-2-enamide et sels de ces derniers Download PDF

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Publication number
WO2021084765A1
WO2021084765A1 PCT/JP2019/049075 JP2019049075W WO2021084765A1 WO 2021084765 A1 WO2021084765 A1 WO 2021084765A1 JP 2019049075 W JP2019049075 W JP 2019049075W WO 2021084765 A1 WO2021084765 A1 WO 2021084765A1
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unsubstituted
substituted
ring
represented
alkyl
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Inventor
Kazuaki Shibata
Tetsuya Sugimoto
Yuki Kataoka
Yuichi Kawai
Hiroki ASAKURA
Naoki Egashira
Tomohiro Yamamoto
Tatsuya Suzuki
Takeshi Sagara
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Taiho Pharmaceutical Co Ltd
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Taiho Pharmaceutical Co Ltd
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Priority to CN202411574064.2A priority Critical patent/CN119424423A/zh
Priority to CN202080087842.9A priority patent/CN115551500A/zh
Priority to JP2022553421A priority patent/JP2023515235A/ja
Priority to EP20819899.4A priority patent/EP4051266A1/fr
Priority to PCT/JP2020/041642 priority patent/WO2021085653A1/fr
Priority to US17/773,215 priority patent/US20230023023A1/en
Priority to TW109137912A priority patent/TW202128632A/zh
Publication of WO2021084765A1 publication Critical patent/WO2021084765A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to 4-aminobut-2-enamide derivatives and pharmaceutically acceptable salts thereof having inhibitory activity against active form of KRAS G12C mutation, and relates to a pharmaceutical composition comprising the same as an active ingredient.
  • RAS which is a small monomeric GTP-binding protein having a molecular weight of about 21 kDa, acts as a molecular on/off switch.
  • RAS can bind to GTP by binding to proteins of a guanine nucleotide exchange factor (GEF) (e.g., SOS1), which forces the release of a bound nucleotide, and releasing GDP.
  • GEF guanine nucleotide exchange factor
  • SOS1 guanine nucleotide exchange factor
  • RAS also possesses enzymatic activity with which it cleaves the terminal phosphate of the nucleotide and converts it to GDP.
  • the rate of conversion is usually slow, but can be dramatically sped up by a protein of the GTPase- activating protein (GAP) class, such as RasGAP.
  • GAP GTPase- activating protein
  • the mainly known members of the RAS subfamily include
  • Non-patent Literature (NPL) 1 Non-patent Literature 1
  • KRAS mutations are historically thought to exist in a constitutively active state (GTP-bound) in cancer cells.
  • GTP-bound constitutively active state
  • KRAS G12C mutation has basal GTPase activity.
  • K-Ras has a pocket structure to which a medical agent can bind.
  • Switch 1 has threonine-35 and Switch 2 has glycine-60, and these amino acids respectively form a hydrogen bond with g-phosphoric acid of GTP, and then keep Switch 1 and Switch 2 in an active form.
  • ARS-853 binds to the cysteine of the G12C mutant of inactive KRAS (GDP), thus preventing conversion of inactive KRAS (GDP) to active KRAS (GTP), inhibiting downstream signaling, and inducing apoptosis in cancer cells with KRAS G12C mutation (Patent Literature (PTL) 1 and NPL 2). It has also been reported that ARS-1620 with a quinazoline backbone exerts antitumor action in tumor-bearing mice expressing KRAS G12C mutation by improving metabolic stability in mice (PTL 2 and NPL 3).
  • NPL 1 Nature Reviews Drug Discovery 13 (11), 828-51, 2014
  • NPL 2 Cancer Discov. 6 (3), 316-29, 2016
  • NPL 3 Cell. 172 (3), 578-89, 2018
  • NPL 4 Science. 351 (6273), 604-8, 2016
  • KRAS upstream inputs to KRAS protein or aberration of GAP function will be cancer-type or patients specific.
  • appropriate treatment by GDP form KRAS G12C mutation inhibitors such as ARS-853 and ARS-1620 may require a precise understanding of tumor-specific signaling vulnerabilities upstream or downstream of KRAS pathway.
  • inhibitors for GDP form KRAS G12C mutation will need to select the effective patient population and likely have to choose the strategies of drug combination, based on the vulnerabilities of KRAS upstream/downstream signaling.
  • inhibitors against active form of KRAS G12C mutation are expected to have therapeutic opportunities toward wider G12C positive patients even as a single agent, with almost no effect from KRAS upstream status.
  • the present invention relates to the following inventions.
  • An antitumor agent comprising a compound or a pharmaceutically acceptable salt thereof that covalently binds to GTP-bound KRAS G12C as an active ingredient.
  • A is a chemical moiety capable of interacting with a region between Switch 2 and a3-Helix;
  • LI is a linker
  • L2 is a linker
  • G is an electrophilic chemical moiety capable of forming a covalent bond with cysteine 12 of GTP-bound
  • J is a chemical moiety capable of interacting with GTP.
  • G is represented by the following formula:
  • D is a single ring having at least one amino group which binds to carbonyl between D and E to form amide, wherein the single ring is unsubstituted or substituted with substituent other than said amino, or D is substituted or unsubstituted fused ring;
  • E is a ring system selected from a substituted or unsubstituted single ring or a substituted or unsubstituted fused ring;
  • Ri is hydrogen or substituted or unsubstituted C1-C6 alkyl; R 2 and R 3 join together to form a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or
  • R2 and R3 are independently represented, and R2 is hydrogen; or Cl- C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1- CIO alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • R3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • Ra represents independently halogen, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted Cl- C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or a substituted or
  • E is an unsaturated 6-membered ring which is unsubstituted or substituted with R 4 , wherein Ei, E2, E 3 and E 4 represent independently C, CH, CH2, N or NH;
  • R4 is halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl; m is an integer of 0 to 4.
  • R 5 is halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl; two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A' or ring A'' when the number of R 6 is two or more; or
  • R 6 may independently represents halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted Cl- C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl; n is an integer of 0 to 5; and p is 0, 1, or 2.
  • R 7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted Cl- C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl;
  • R 8 is halogen or substituted or unsubstituted C1-C10 alkyl; q and r represent independently 0, 1, or 2.
  • R 6 may be independently halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy.
  • R 2 is C1-C10 alkyl which is unsubstituted or substituted with Ra, C3-C10 cycloalkyl which is unsubstituted or substituted with Ra, or a 4- to 10-membered saturated heterocyclic group which is unsubstituted or substituted with Ra.
  • D is a fused ring represented by ring D and ring D'
  • ring D' is a saturated or unsaturated 5-membered ring forming a fused ring containing Di, D2 and D 7 with ring D
  • Di' and 02' represent independently C, CH, CH2, N, NH or S,
  • R 7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl or substituted or unsubstituted C1-C10 alkoxy.
  • (21) The antitumor agent according to (20), wherein R7 is halogen or substituted or unsubstituted C1-C10 alkyl.
  • A is a ring system selected from a substituted or unsubstituted single ring or a substituted or unsubstituted fused ring;
  • D is a single ring having at least one amino group which binds to carbonyl between D and E to form amide, wherein the single ring is unsubstituted or substituted with substituent other than said amino, or D is substituted or unsubstituted fused ring;
  • E is a ring system selected from a substituted or unsubstituted single ring or a substituted or unsubstituted fused ring;
  • Ri is hydrogen or substituted or unsubstituted C1-C6 alkyl
  • R2 and R3 join together to form a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or
  • R2 and R3 are independently represented, and R2 is hydrogen; or Cl- C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, Cl- C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • R3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • Ra represents independently halogen, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkyla ino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted Cl- CIO alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or a substituted or
  • R4 is halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl; m is an integer of 0 to 4; or a pharmaceutically acceptable salt thereof.
  • R 5 is halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl; two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A' or ring A when the number of R 6 is two or more; or
  • R 6 may independently represents halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted Cl- C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl; n is an integer of 0 to 5; and p is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.
  • R 7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted Cl- C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl;
  • Rs is halogen or substituted or unsubstituted C1-C10 alkyl; q and r represent independently 0, 1, or 2; or a pharmaceutically acceptable salt thereof.
  • R 6 may be independently halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy; or a pharmaceutically acceptable salt thereof.
  • D is a fused ring represented by ring D and ring D'
  • ring D' is a saturated or an unsaturated 5-membered ring forming a fused ring containing Di, D2 and D7with ring D
  • Di' and D2' represents independently C, CH, CH2, N, NH or S,
  • R7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl or substituted or unsubstituted C1-C10 alkoxy; or a pharmaceutically acceptable salt thereof.
  • a medicament comprising the compound or pharmaceutically acceptable salt thereof of any of (22) to (39).
  • a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of any of (22) to (39).
  • An anti-tumor agent comprising the compound or pharmaceutically acceptable salt thereof of any of (22) to (39) as an active ingredient.
  • An anti-tumor agent for oral administration comprising the compound or pharmaceutically acceptable salt thereof of any of (22) to (39) as an active ingredient.
  • (50) A method for treating tumor, comprising administrating a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of any of (22) to (39) to a subject in need thereof.
  • the antitumor agent of (52), wherein the cancer is one or more selected from the group consisting of a carcinoma, squamous carcinoma, adenocarcinoma, sarcoma, leukemia, neuroma, melanoma, and lymphoma.
  • squamous carcinoma is a cancer of uterine cervix, tarsus, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx or esophagus.
  • An antitumor agent comprising a compound or a pharmaceutically acceptable salt thereof of any one of (22) to (39), and one or more other antitumor agents as an active ingredient.
  • An antitumor agent comprising a compound or a pharmaceutically acceptable salt thereof of any one of (22) to (39) as an active ingredient, which is administered in combination with one or more other antitumor agents.
  • (61) The combination of a compound according to any one of (22) to (39) or a salt thereof and one or more other antitumor agents for use in the treatment of tumors.
  • a method for treating tumor comprising administrating a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of any of (22) to
  • a method for treating tumor comprising administrating a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of any of (22) to
  • a method for treating tumor comprising administrating a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof that covalently binds to GTP-bound KRAS G12C to a subject in need thereof.
  • G is represented by the following formula: (69)
  • the antitumor agent according to any of (1),(2) or (68),wherein LI is represented by D with -C( 0)-, L2 is represented by E with -NRi- and J is represented by -CHR 2 '-
  • NR2R3 in the formula A-L1-L2-G-J, and the compound is represented by Formula (vii): wherein A is a ring system selected from a substituted or unsubstituted single ring or a substituted or unsubstituted fused ring;
  • D is a single ring having at least one amino group which binds to carbonyl between D and E to form amide, wherein the single ring is unsubstituted or substituted with substituent other than said amino, or D is substituted or unsubstituted fused ring;
  • E is a ring system selected from a substituted or unsubstituted single ring or a substituted or unsubstituted fused ring;
  • Ri is hydrogen or substituted or unsubstituted C1-C6 alkyl;
  • R2and R3or R2and R2' join together to form a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or R2, R2'and R3are independently represented, and R2 is hydrogen; or Cl-ClO alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • R 2 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; and R 3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • Ra represents independently halogen, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted Cl- C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or a substituted or
  • E is an unsaturated 6-membered ring which is unsubstituted or substituted with R 4 , wherein Ei, E 2 , E 3 and E4 represent independently C, CH, CH 2 , N or NH;
  • R 4 is halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted Cl-ClO alkylsulfonyl; m is an integer of 0 to 4.
  • R 5 is halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl; two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A' or ring A'' when the number of ]3 ⁇ 4 is two or more; or
  • R 6 may independently represents halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted Cl- C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl; n is an integer of 0 to 5; and p is 0, 1, or 2.
  • R 7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted Cl- C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl;
  • Rs is halogen or substituted or unsubstituted C1-C10 alkyl; q and r represent independently 0, 1, or 2.
  • R 6 may be independently halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy.
  • R 2 and R 2 ' join together to form a 4- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or R2, and R2' are independently represented, and R2 is C1-C10 alkyl which is unsubstituted or substituted with Ra, C3-C10 cycloalkyl which is unsubstituted or substituted with Ra, or a 4- to 10-membered saturated heterocyclic group which is unsubstituted or substituted with Ra.
  • D is a fused ring represented by ring D and ring D'
  • ring D' is a saturated or unsaturated 5-membered ring forming a fused ring containing Di, D 2 and D 7 with ring D
  • Di' and D 2 ' represent independently C, CH, CH 2 , N, NH or S,
  • R 7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl or substituted or unsubstituted C1-C10 alkoxy.
  • A is a ring system selected from a substituted or unsubstituted single ring or a substituted or unsubstituted fused ring;
  • D is a single ring having at least one amino group which binds to carbonyl between D and E to form amide, wherein the single ring is unsubstituted or substituted with substituent other than said amino, or D is substituted or unsubstituted fused ring;
  • E is a ring system selected from a substituted or unsubstituted single ring or a substituted or unsubstituted fused ring;
  • Ri is hydrogen or substituted or unsubstituted C1-C6 alkyl
  • Ra represents independently halogen, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted Cl- C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or a substituted or
  • E is an unsaturated 6-membered ring which is unsubstituted or substituted with R 4 , wherein Ei, E 2 , E 3 and E 4 represent independently C, CH, CH 2 , N or NH;
  • R 4 is halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl; m is an integer of 0 to 4; or a pharmaceutically acceptable salt thereof.
  • R 6 may independently represents halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted Cl- C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl; n is an integer of 0 to 5; and p is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.
  • R7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted Cl- C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl; Rs is halogen or substituted or unsubstituted C1-C10 alkyl; q and r represent independently 0, 1, or 2; or a pharmaceutically acceptable salt thereof.
  • R 6 may be independently halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy; or a pharmaceutically acceptable salt thereof.
  • R2, and R2 ' are independently represented, and R2 is C1-C10 alkyl which is unsubstituted or substituted with Ra, C3-C10 cycloalkyl which is unsubstituted or substituted with Ra, a 4- to 10-membered saturated heterocyclic group which is unsubstituted or substituted with Ra; or a pharmaceutically acceptable salt thereof.
  • D is a fused ring represented by ring D and ring D'
  • ring D' is a saturated or an unsaturated 5-membered ring forming a fused ring containing Di,D 2 and D 7 with ring D
  • Di' and D 2 ' represents independently C, CH, CH 2 , N, NH or S,
  • R 7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl or substituted or unsubstituted C1-C10 alkoxy; or a pharmaceutically acceptable salt thereof.
  • R7 is halogen or substituted or unsubstituted C1-C10 alkyl; or a pharmaceutically acceptable salt thereof.
  • (115)A method for treating tumor comprising administrating a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of any of (87) to (104) to a subject in need thereof.
  • an antitumor agent comprising a compound or a pharmaceutically acceptable salt thereof of any one of (87) to (104), and one or more other antitumor agents as an active ingredient.
  • an antitumor agent comprising a compound or a pharmaceutically acceptable salt thereof of any one of (87) to (104) as an active ingredient, which is administered in combination with one or more other antitumor agents.
  • (122)A method for treating tumor comprising administrating a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of any of (87) to (104), and one or more other antitumor agents to a subject in need thereof.
  • a method for treating tumor comprising administrating a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of any of (87) to (104) , which is administered in combination with one or more other antitumor agents to a subject in need thereof.
  • a compound or a salt thereof according to an embodiment of the present invention binds to the mutant cysteine (G12C) of active form of KRAS.
  • a compound or a salt thereof according to a preferred embodiment of the present invention impairs the KRAS function in KRAS G12C mutation-positive cancer cells, thereby showing antitumor action; and can be used as an anti-cancer agent.
  • Figure 1 illustrates 2D interaction diagram for the binding site of the compound of Example 19. Residues are annotated with their 3-letter amino acid code.
  • Figure 1 was generated by the ligand interaction tool within the Molecular Operating Environment (MOE, version 2019.0101) (Molecular Operating Environment; C.C.G., I., 1255 University St., Suite 1600, Montreal, Quebec, Canada, H3B 3X3.).
  • MOE Molecular Operating Environment
  • Figure 2 illustrates cocrystal structure of Example 19 and Gppcp-bound K-Ras4B G12C, focused on covalent binding between the chemical moiety G of Example 19 and cysteine 12 of K-Ras4B G12C, and hydrogen bond (shown as black dashed lines) between the chemical moiety J of Example 19 and the g-phosphate group of Gppcp.
  • Figure 2 was created with the molecular visualization system, PyMOL (version 2.2.0) (Schrodinger).
  • examples of the "substituent” include hydrogen, halogen, cyano, nitro, amino, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkenyl, unsaturated hydrocarbon, alkoxy, haloalkoxy, cycloalkoxy, cycloalkyl-alkoxy, aralkyl, aralkyloxy, alkylthio, cycloalkyl-alkylthio, alkoxyalkyl, mono- or dialkylamino, cycloalkyl-alkylamino, aromatic hydrocarbon, acyl, alkylcarbonyl, acyloxy, arylcarbonyl, oxo, carboxy, alkoxycarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aralkyloxycarbonyl, carbamoyl, sul
  • halogen include chlorine, bromine, fluorine, and iodine, with chlorine, fluorine, and bromine being preferable, and chlorine and fluorine being more preferable.
  • alkyl refers to a linear or branched saturated hydrocarbon group. Examples include C1-C10 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl, isopentyl, and hexyl.
  • the "alkyl” is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.
  • alkenyl refers to a linear or branched unsaturated hydrocarbon group containing at least one double bound (e.g., one to two double bonds, and preferably one double bond). Examples include C2-C6 alkenyl, such as vinyl, allyl,
  • alkynyl refers to linear or branched unsaturated hydrocarbon containing at least one triple bond (e.g., one or two triple bonds, and preferably one triple bond).
  • Examples include C2-C6 alkynyl groups, such as ethynyl, 1- or 2-propynyl, 1-, 2-, or 3-butynyl, and l-methyl-2-propynyl, with ethynyl and 2-propynyl being preferable.
  • haloalkyl refers to alkyl mentioned above having at least one halogen atom (preferably having 1 to 10, and more preferably 1 to 3 halogen atoms).
  • examples include C1-C10 haloalkyl, such as fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,1,1- trifluoroethyl, monofluoro-n-propyl, 1,1,1-trifluoro-n-propyl, perfluoro-n-propyl, and perfluoroisopropyl, with trifluoromethyl, difluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, and 1,1,1- trifluoroethyl being preferable.
  • hydroxyalkyl refers to alkyl mentioned above having at least one hydroxy group (preferably having 1 to 10, and more preferably 1 to 2 hydroxy groups). Examples include C1-C6 hydroxyalkyl, such as hydroxymethyl, hydroxyethyl,
  • cycloalkyl refers to monocyclic or polycyclic saturated hydrocarbon, including bicyclic, tricyclic, bridged and spirocyclic hydrocarbon. Examples include C3-C10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclodecyl, [2.2.0]bicyclohexyl,
  • cycloalkenyl refers to monocyclic or polycyclic unsaturated hydrocarbon containing at least one carbon-carbon double bond (e.g., one to two carbon-carbon double bonds, and preferably one carbon-carbon double bond).
  • Examples include C4-C10 cycloalkenyl, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclodecenyl, with cyclopropenyl, cyclobutenyl, and cyclopentenyl being preferable, and cyclobutenyl and cyclopentenyl being particularly preferable.
  • the "unsaturated hydrocarbon” refers to linear or branched unsaturated hydrocarbon containing at least one carbon-carbon double bond or triple bond.
  • examples include C2-C10 unsaturated hydrocarbon, such as vinyl, allyl, methylvinyl, 1- propenyl, butenyl, pentenyl, hexenyl, ethynyl, and 2-propynyl, with C2-C4 linear or branched hydrocarbon containing at least one carbon-carbon double bond or triple bond being preferable, and vinyl, allyl, and 1-propenyl being more preferable.
  • alkoxy refers to oxy having alkyl mentioned above.
  • examples include C1-C10 alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, and hexyloxy, with methoxy, ethoxy and n-propoxy being preferable, and methoxy and ethoxy being more preferable.
  • haloalkoxy refers to alkoxy mentioned above having at least one halogen atom (preferably having 1 to 13, and more preferably 1 to 3 halogen atoms).
  • halogen atoms preferably having 1 to 13, and more preferably 1 to 3 halogen atoms.
  • Examples include C1-C10 haloalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, fluoroethoxy, 1,1,1- trifluoroethoxy, monofluoro-n-propoxy, perfluoro-n-propoxy, and perfluoro-isopropoxy.
  • cycloalkoxy refers to oxy having cycloalkyl mentioned above.
  • examples include C3-C10 cycloalkoxy, such as cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy, with cyclobutoxy, cyclopentyloxy, and cyclohexyloxy being preferable.
  • cycloalkyl-alkoxy refers to alkoxy mentioned above having at least one cycloalkyl group mentioned above.
  • examples include C3-C10 cycloalkyl-Cl-CIO alkoxy, such as cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, and cycloheptylmethoxy, with cyclohexylmethoxy being preferable.
  • aralkyl refers to alkyl mentioned above substituted with aromatic hydrocarbon mentioned above. Examples include C7-C16 aralkyl, such as benzyl, phenylethyl, phenylpropyl, naphthylmethyl, and naphthylethyl, with benzyl being preferable.
  • aralkyloxy refers to oxy having aralkyl mentioned above. Examples include C7-C20 aralkyloxy, such as benzyloxy, phenethyloxy, naphthylmethyloxy, and fluorenylmethyloxy.
  • alkylthio refers to thioxy having alkyl mentioned above. Examples include C1-C10 alkylthio, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio, and hexylthio.
  • cycloalkyl-alkylthio refers to alkylthio mentioned above having at least one cycloalkyl group mentioned above.
  • examples include C3-C10 cycloalkyl-Cl-CIO alkylthio, such as cyclopropylmethylthio, cyclobutylmethylthio, cyclopentylmethylthio, cyclohexylmethylthio, and cycloheptylmethylthio.
  • alkoxyalkyl refers to alkyl mentioned above having at least one alkoxy group mentioned above.
  • examples include C1-C10 alkoxy-Cl-ClO alkyl, such as methoxymethyl, ethoxyethyl, methoxyethyl, and methoxypropyl, with methothymethyl being preferable.
  • alkylamino refers to amino having one or two alkyl groups mentioned above. Specific examples include C1-C10 alkylamino, such as methylamino, ethylamino, dimethylamino, diethylamino, and ethylmethylamino, with methylamino, dimethylamino, and diethylamino being preferable.
  • the "monoalkylamino” refers to amino having one alkyl group mentioned above. Examples include C1-C10 monoalkylamino, such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, n- pentylamino, isopentylamino, and hexylamino, with methylamino and ethylamino being preferable.
  • C1-C10 monoalkylamino such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, n- pentylamino, isopentylamino, and hexylamino, with methylamino and ethyla
  • dialkylamino refers to amino having two alkyl groups mentioned above.
  • Examples include C1-C10 dialkylamino, which has two alkyls each having 1 to 10 carbon atoms, such as dimethylamino, diethylamino, di (n-propyl)amino, diisopropylamino, di(n-butyl)amino, diisobutylamino, di(tert- butyl)amino, di(n-pentyl)amino, diisopentylamino, dihexylamino, methylethylamino, and methylisopropylamino, with dimethylamino and diethylamino being preferable.
  • cycloalkyl-alkylamino refers to alkylamino mentioned above having cycloalkyl mentioned above in which cycloalkyl is attached to the alkyl moiety of alkylamino.
  • examples include C3-C10 cycloalkyl-Cl-CIO alkylamino, such as cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino, cycloheptylmethylamino, and cyclohexyldimethylamino, with cyclohexyldimethylamino being preferable.
  • aromatic hydrocarbon refers to monocyclic or polycyclic aromatic hydrocarbon as being an unsaturated bond-containing ring substituent containing carbon and hydrogen, the monocyclic or polycyclic aromatic hydrocarbon containing 4e+2 number of electrons (e is an integer of 1 or more) in the cyclic n electron system. Examples include phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, and the like, and phenyl being preferable.
  • acyl refers to alkylcarbonyl or arylcarbonyl.
  • alkylcarbonyl refers to carbonyl having alkyl mentioned above.
  • examples include C1-C10 alkylcarbonyl, such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert- butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, and hexylcarbonyl, with methylcarbonyl being preferable.
  • C1-C10 alkylcarbonyl refers to (C1-C10 alkyl)carbonyl.
  • acyloxy refers to acyl having carbonyloxy mentioned above. Examples include C1-C10 acyloxy, such as alkylcarbonyloxy or arylcarbonyloxy.
  • arylcarbonyl refers to carbonyl having aromatic hydrocarbon mentioned above.
  • examples include (C6— C20 aryl)carbonyl, such as phenylcarbonyl, naphthylcarbonyl, fluorenylcarbonyl, anthrylcarbonyl, biphenylylcarbonyl, tetrahydronaphthylcarbonyl, chromanylcarbonyl, 2,3-dihydro-l,4- dioxanaphthalenylcarbonyl, indanylcarbonyl, and phenanthrylcarbonyl.
  • alkoxycarbonyl refers to carbonyl having alkoxy mentioned above.
  • examples include (C1-C10 alkoxy)carbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, and hexyloxycarbonyl, with tert- butoxycarbonyl being preferable.
  • alkylcarbonyloxy refers to oxy having alkylcarbonyl mentioned above.
  • Examples include (C1-C10 alkyl)carbonyloxy, such as methylcarbonyloxy, ethylcarbonyloxy, n- propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy, and hexylcarbonyloxy, with tert- butylcarbonyloxy being preferable.
  • arylcarbonyloxy refers to oxy having arylcarbonyl mentioned above.
  • Examples include (C6-C13 aryl)carbonyloxy, such as phenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy, anthrylcarbonyloxy, biphenylylcarbonyloxy, tetrahydronaphthylcarbonyloxy, chromanylcarbonyloxy, 2,3-dihydro- 1,4-dioxanaphthalenylcarbonyloxy, indanylcarbonyloxy, and phenanthrylcarbonyloxy.
  • aralkyloxycarbonyl refers to carbonyl having aralkyloxy mentioned above. Examples include (C6- C20 aralkyl)oxycarbonyl, such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethyloxycarbonyl, and fluorenylmethyloxycarbonyl.
  • saturated heterocyclic group refers to a monocyclic or polycyclic saturated heterocyclic group containing at least one heteroatom (preferably having 1 to 5, and more preferably 1 to 3 heteroatoms) selected from nitrogen, oxygen, and sulfur.
  • a monocyclic or polycyclic saturated heterocyclic group includes monocyclic, bicyclic, tricyclic, bridged and spirocyclic saturated heterocyclic group.
  • Examples include aziridinyl, azetidinyl, imidazolidinyl, morpholino, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, thiazolidinyl, oxazolidinyl, and the like, with azetidinyl, pyrrolidinyl, and piperidinyl being preferable, and azetidinyl and pyrrolidinyl being more preferable.
  • the "partially saturated heterocyclic group” refers to a monocyclic or polycyclic partially saturated heterocyclic group containing at least one heteroatom (preferably having 1 to 5, and more preferably 1 to 3 heteroatoms) selected from nitrogen, oxygen, and sulfur.
  • a monocyclic or polycyclic partially saturated heterocyclic group includes monocyclic, bicyclic, tricyclic, bridged and spirocyclic partially saturated heterocyclic group.
  • Examples include indoline, 1,3- dihydroisobenzofuran, 2,3-dihydro-lH-benzo[d]imidazole, 1,3- benzodioxole and the like, with indoline, 2,3-dihydro-lH- benzo[d]imidazole and 1,3-benzodioxole being preferable, and indoline, 1,3-benzodioxole being more preferable.
  • the "unsaturated heterocyclic group” refers to a monocyclic or polycyclic, completely unsaturated heterocyclic group containing at least one heteroatom (preferably containing 1 to 5, and more preferably 1 to 3 heteroatoms) selected from nitrogen, oxygen, and sulfur.
  • a monocyclic or polycyclic unsaturated heterocyclic group includes monocyclic, bicyclic, tricyclic, bridged and spirocyclic unsaturated heterocyclic group.
  • Examples include imidazolyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, triazolopyridyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, furanyl, benzofuranyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalyl, methylenedioxyphenyl, ethylenedioxyphenyl, dihydrobenzofuranyl, imidazopyridinyl, indazolyl, and the like, with
  • CA-CB used in the description of a group indicates that the group has A to B number of carbon atoms.
  • C1-C6 alkyl refers to alkyl having 1 to 6 carbon atoms
  • C6-C14 aromatic hydrocarbon oxy refers to oxy to which C6-C14 aromatic hydrocarbon is bonded.
  • A- to B-membered indicates that the number of atoms (number of ring members) that constitute a ring is A to B. More specifically, "4- to 10-membered saturated heterocyclic group” refers to a saturated heterocyclic group containing 4 to 10 ring members.
  • C means carbon
  • N means nitrogen
  • S means sulfur
  • 0 means oxygen
  • a linker in the formula A-Ll- L2-G-J refers to a divalent linker.
  • single ring refers to a substituted or unsubstituted ring having a single cyclic structure, and may refer to a substituted or unsubstituted monocyclic ring.
  • examples of a single ring include substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C6-C10 aromatic hydrocarbon, a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group, a substituted or unsubstituted 4- to 10-membered partially saturated heterocyclic group or a substituted or unsubstituted 4- to 10-membered unsaturated heterocyclic group.
  • fused ring refers to a substituted or unsubstituted group formed with two or more rings, in which two or more rings share two or more atoms.
  • examples of a fused ring include a fused ring formed by two or more rings selected from a substituted or unsubstituted C4-C10 hydrocarbon ring, a substituted or unsubstituted C7-C10 aromatic hydrocarbon ring, a substituted or unsubstituted 7- to 10- membered saturated heterocyclic ring, a substituted or unsubstituted 7- to 10-membered partially saturated heterocyclic ring and a substituted or unsubstituted 7- to 10-membered unsaturated heterocyclic ring.
  • an antitumor agent of the present invention comprises a compound or a pharmaceutically acceptable salt thereof that covalently binds to GTP-bound KRAS G12C as an active ingredient, and the compound has the following formula:
  • A is a chemical moiety capable of interacting with a region between Switch 2 and a3-Helix;
  • LI is a linker
  • L2 is a linker; J is a chemical moiety capable of interacting with GTP; and G is an electrophilic chemical moiety capable of forming a covalent bond with cysteine 12 of GTP-bound KRAS G12C.
  • G is represented by the following formula:
  • an antitumor agent of the present invention comprises a compound or a pharmaceutically acceptable salt thereof that covalently binds to GTP-bound KRAS G12C as an active ingredient, and the compound has the following formula: A-L1-L2-G-J wherein,
  • A is a chemical moiety capable of interacting with a region between Switch 2 and a3-Helix;
  • LI is a linker
  • L2 is a linker
  • G-J is represented by the following formula:
  • G-J is represented by the following formula: u , y refers to the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.
  • the term "chemical moiety capable of interacting with a region between Switch 2 and a3-Helix" in moiety A refers to a chemical moiety which can interect with a region between Switch 2 (residue 60 to 76) and of3-helix (residue 86 to 103) of K-Ras.
  • the moiety A interacting with the region via hydrogen bond, van der Waals force, covalent bond, ionic bond or hydrophobic interaction.
  • a region between Switch 2 and a3-Helix denotes a region formed by one or more amino acids selected from methionine-67, arginine-68, aspartic acid-69, aspartic acid-70, glutamine-71, methionine-72, arginine- 73, threonine-75, histidine-95, tyrosine-96, glutamine-99, isoleucine-100, lysine-101, arginine-102 and valine-103, and preferably a region formed by one or more amino acids selected from arginine-68, aspartic acid-69, methionine-72, glutamine-99, isoleucine-100 and valine-103.
  • K-Ras protein may comprise an amino acid seguence, for example, at least 50%, at least 85%, at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or 100% identical to one of SEQ ID Nos: 1 and 2.
  • the term "a chemical moiety capable of interacting with a region between Switch 2 and a3-Helix" in moiety A of a compound of the present invention can be determined by conducting an X-ray structural analysis on a cocrystal of the compound of the present invention and GTP-bound KRAS G12C and identifying the moiety which interacts with at least one amino acid moiety which exists in a region between Switch 2 and a3-Helix of the GTP-bound KRAS G12C.
  • Such an X-ray structural analysis may be conducted by using the ligand interaction tool within the Molecular Operating Environment.
  • the at least one amino acid moiety which interacts with the compound is selected from methionine-67, arginine-68, aspartic acid-69, aspartic acid-70, glutamine-71, methionine-72, arginine-73, threonine-75, histidine- 95, tyrosine-96, glutamine-99, isoleucine-100, lysine-101, arginine-102 and valine-103, and preferably is selected from arginine-68, aspartic acid-69, methionine-72, glutamine-99, isoleucine-100 and valine-103.
  • a chemical moiety capable of interacting with a region between Switch 2 and a3-Helix may be a ring system selected from a substituted or unsubstituted single ring or a substituted or unsubstituted fused ring.
  • an electrophilic chemical moiety capable of forming a covalent bond with a GTP-bound K-Ras G12C in moiety G represents an chemical moiety which can react electrophilically with a mutation at the 12th amino acid (cysteine —12 residue) of GTP-bound K-Ras to form a covalent bond.
  • moiety J represents a chemical moiety that can interact with GTP bound to K-ras.
  • the chemical moiety interacts with g-phosphoric acid placed at a terminal of the GTP, and preferably interacts with the g-phosphoric acid via hydrogen bond, covalent bond or ionic bond.
  • moiety J is -NR 2 R 3 and may directly bind to moiety G or bind to moiety G via -CH2- or -0RP3 ⁇ 4'-, and in a more preferred embodiment, moiety J is -CHR2'-NR2R 3 .
  • C1-C6 alkyl represented by Ri may be C2-C6 alkyl, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl or C1-C2 alkyl, and is preferably methyl, ethyl, or tert-butyl, more preferably methyl or ethyl, and particularly preferably methyl.
  • Ri is hydrogen or substituted or unsubstituted C1-C3 alkyl.
  • Ri is preferably hydrogen, methyl, ethyl, or tert-butyl.
  • Ri is more preferably hydrogen or methyl.
  • Ri is most preferably hydrogen.
  • R2and R3 may join together to form a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra, and R2' is hydrogen or C1-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra.
  • the "4- to 10-membered saturated heterocyclic group" in the "a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-3 substituents independently represented by Ra" formed with R2 and R3 is preferably a 4- to 8- membered, 5- to 8-membered, 5- to 7-membered or 5- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents, and more preferably pyrrolidinyl, piperidinyl, piperazinyl.
  • the "substituted with Ra" in the "a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" formed with R2 and R3 preferably means substitution with halogen, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsubstit
  • the "4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" formed with R2and R3 is preferably pyrrolidinyl, piperidinyl, or piperazinyl.
  • the "4- to 10-membered saturated heterocyclic group" in the "a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-3 substituents independently represented by Ra" formed with R2 and R2' is preferably a 4- to 8- membered, 5- to 8-membered, 5- to 7-membered or 5- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents, and more preferably pyrrolidinyl, piperidinyl, piperazinyl.
  • the "substituted with Ra" in the "a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" formed with R2 and R2 preferably means substitution with halogen, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsubstit
  • the "4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" formed with R2and R2' is preferably pyrrolidinyl, piperidinyl, or piperazinyl.
  • ⁇ 1 ⁇ 2, R ⁇ ' and R3 may be are independently represented, and in the compound represented by any one of Formula (i) to (xii) of the present invention,
  • R2 is hydrogen; or C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • R2 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • R3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra.
  • the "C1-C10 alkyl” represented by R2 may be C2-C6 alkyl, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl or C1-C2 alkyl, and is preferably methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n- pentyl, and more preferably methyl, ethyl, n-propyl, isopropyl, n- butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl (C3-C6 alkyl). [0075]
  • R2 which may substitute “C1-C10 alkyl” represented by R2 may be, for example, the substituents mentioned above, and is preferably halogen, cyano, hydroxy, C3-C7 cycloalkyl, or a 4- to 10-membered saturated heterocyclic group and more preferably hydroxy.
  • the "C1-C10 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" represented by R2 is preferably C1-C6 alkyl, 1,2-dihydroxyisopropyl, 2- hydroxypropyl, more preferably C1-C6 alkyl, still more preferably methyl, ethyl, isopropyl or tert-butyl, and most preferably tert- butyl.
  • the "C2-C10 alkenyl” represented by R2 may be C2-C6 alkenyl, C3-C6 alkenyl, C4-C6 alkenyl, C5-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl or C2-C3 alkenyl, and is preferably vinyl, 1-propenyl, allyl, or isopropenyl, and more preferably vinyl or isopropenyl.
  • R2 which may substitute “C2-C10 alkenyl” represented by R2 may be, for example, the substituents mentioned above, and is preferably halogen, cyano, C1-C6 alkyl, or hydroxy, more preferably chlorine, fluorine, or methyl, and more preferably fluorine.
  • C2-C10 alkenyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" represented by R2 is preferably C2-C6 alkenyl that may contain halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl, or 1-(trifluoromethyl)vinyl, and more preferably vinyl or 1- (trifluoromethyl)vinyl.
  • the "C2-C10 alkynyl" represented by R2 may be C2-C6 alkynyl, C3-C6 alkynyl, C4-C6 alkynyl, C5-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl or C2-C3 alkynyl, and is preferably ethynyl or 1- propynyl.
  • Ra which may substitute "C2-C10 alkynyl” represented by R2 may be, for example, the substituents mentioned above, and is preferably halogen or hydroxy, and more preferably fluorine or chlorine.
  • C2-C10 alkynyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" represented by R2 is preferably ethynyl, 1-chloroethynyl, or 1- propynyl.
  • the "C3-C10 cycloalkyl" represented by R2 may be C3-C8 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, C5-C6 cycloalkyl, C3-C6 cycloalkyl or C4-C6 alkynyl, and is preferably monocyclic or bicyclic C3-C10 cycloalkyl, and more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or bicyclo[3.1.0]hexanyl, and more preferably cyclohexyl.
  • Ra which may substitute “C3-C10 cycloalkyl” represented by R2 may be, the substituents mentioned above, and is preferably hydroxy, halogen, C2-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, saturated heterocyclic group, and more preferably fluorine, chlorine, hydroxy, methyl, ethyl, n-propyl, methoxy, ethoxy, difluoromethoxy, dimethylamino, diethylamino, isopropylamino, trifluoromethyl, dioxolane.
  • C3-C10 cycloalkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" represented by R2 is preferably C3-C10 cycloalkyl that may be substituted with hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, saturated heterocyclic group, preferably C3-C6 cycloalkyl that may be substituted with hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 monoalkylamino, C1-C3 dialkylamino, saturated heterocyclic group, and more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohe
  • C1-C10 alkoxy which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" represented by R2 is preferably methoxy, ethoxy.
  • C6-C10 aromatic hydrocarbon which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" represented by R2 is preferably phenyl.
  • the "4- to 10-membered saturated heterocyclic group" represented by R2 may be 4- to 8-membered, 5- to 8-membered, 5- to
  • 7-membered or 5- to 6-membered saturated heterocyclic group is preferably a monocyclic or bicyclic 4- to 10-membered saturated heterocyclic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably a monocyclic 4- to 8-membered saturated heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably pyrolidinyl, piperidinyl, piperadinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, 8- oxabicyclo[3,2,1]octanyl, 8-methyl-1,4-dioxaspiro ⁇ 4,5 ⁇ decane thianyl, and more preferably, piperidinyl, piperadinyl, 2- ethyltetrahydropyranyl, or tetrahydropyranyl.
  • Ra which may substitute "4- to 10-membered saturated heterocyclic group” represented by R2 may be the substituents mentioned above, or is preferably halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, Cl- C6 monoalkylamino, C1-C6 dialkylamino, C1-C6 alkylsulfonyl, C1-C6 alkylcarbonyl, and more preferably fluorine, chlorine, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, difluoromethoxy, dimethylamino, diethylamino, isopropylamino, trifluoromethyl, dioxolane, methoxycarbonyl, or ethylcarboxyl, and most preferably methyl, dimethylamino
  • the "4- to 10-membered saturated heterocyclic group which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" represented by R2 is preferably a monocyclic 4- to 8-membered saturated heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, substituted with at least one substituent selected from halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, C1-C6 alkylsulfonyl, and C1-C6 alkylcarbonyl, and more preferably N- isopropyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, 2-methyl- 4-tetrahydropyranyl, l-methyl-4-tetrahydropyranyl, 2,2-d
  • the "4- to 10-membered partially saturated heterocyclic group which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" represented by R2 is preferably a monocyclic or bicyclic 4- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 7-membered or 5- to 6-membered partially saturated heterocyclic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably a monocyclic 4- to 7-membered partially saturated heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and preferably 4H-pyranyl, indoline, 1,3-dihydroisobenzofuran, 2,3- dihydro-lH-benzo[d]imidazole, 1,3-benzodioxole.
  • the "4- to 10-membered unsaturated heterocyclic group which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" represented by R2 is preferably a monocyclic or bicyclic 4- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 7-membered or 5- to 6-membered unsaturated heterocyclic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably a monocyclic 5- to 7-membered unsaturated heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably pyridyl, imidazolyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrazyl, pyrimidin
  • R2 is preferably C1-C6 alkyl, C3-C10 cycloalkyl, a 4- to 10-membered saturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra.
  • R2 is more preferably C3-C6 alkyl, cycloalkyl, a 6- to 10-membered saturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra.
  • the Ra which may substitute R2 is preferably halogen, cyano, hydroxy, C1-C10 alkylamino, C1-C10 alkoxy, C1-C10 alkylsulfonyl, C3-C7 cycloalkyl, or a 4- to 10-membered saturated heterocyclic group.
  • the Ra which may substitute R2 is more preferably hydroxy, dimethylamino, methoxy, methylsulfonyl.
  • R2 which is unsubstituted or substituted with Ra is preferably methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl, 4- methoxycyclohexyl, 4-ethoxycyclohexyl, 4-diethylaminocyclohexyl, 4-dimethylaminocyclohexyl, 4-difluoromethoxycyclohexyl, 4,4- difluorocyclohexyl, difluoro-bicyclo[3.1.0]hexane, 4- dioxaspiro[4.5]decane, N-isopropyl-4-piperidinyl, N- methylsulfonyl-4-piperidinyl, 2-methyl-4-tetrahydropyranyl, 1- methyl-4-tetrahydropyranyl, 2,2-di
  • R2 is more preferably methyl, ethyl, isopropyl, tert- butyl, cyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl, 4- ethoxycyclohexyl, 4-diethylaminocyclohexyl, N-isopropyl-4- pyperidinyl, l-methyl-4-tetrahydropyranyl, 2- ethyltetrahydropyranyl, or 3,5-dimethyltetrahydropyranyl.
  • R2 is most preferably tert-butyl, cyclohexyl, 4- hydroxycyclohexyl, 4-methoxycyclohexyl, 4-diethylaminocyclohexyl.
  • the "C1-C6 alkyl” in the "C1-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" in R2' is preferably methyl, ethyl, isopropyl, or tert-butyl, more preferably methyl or ethyl, and most preferably methyl.
  • C1-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" in R2' is preferably methyl, ethyl, isopropyl, or tert-butyl, more preferably methyl or ethyl, and most preferably methyl.
  • Ra which may substitute "C1-C10 alkyl” represented by R2' may be, for example, the substituents mentioned above, and is preferably halogen, cyano, hydroxy, C3-C7 cycloalkyl, or a 4- to 10-membered saturated heterocyclic group and more preferably hydroxy.
  • R2' is preferably hydrogen or C1-C6 alkyl.
  • R2' is more preferably hydrogen, methyl, ethyl, isopropyl, or tert-butyl.
  • R 2 is most preferably hydrogen.
  • C1-C6 alkyl represented by R3 is preferably methyl, ethyl, isopropyl, or tert-butyl, more preferably methyl or ethyl, and most preferably methyl.
  • R3 which may substitute “C1-C10 alkyl” represented by R3 may be, for example, the substituents mentioned above, and is preferably halogen, cyano, hydroxy, C3-C7 cycloalkyl, or a 4- to 10-membered saturated heterocyclic group and more preferably hydroxy.
  • R 3 is more preferably hydrogen or methyl, ethyl, isopropyl, or tert-butyl.
  • R 3 is more preferably hydrogen or methyl.
  • R 3 is most preferably hydrogen.
  • R 2 and R 3 may be are independently represented, and in the compound represented by any one of Formula (i) to (xii) of the present invention, R 2 and R 2' join together to form a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra,
  • R 3 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra.
  • the "4- to 10-membered saturated heterocyclic group" in the "a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-3 substituents independently represented by Ra" formed with R 2 and R 2' is preferably a 4- to 8- membered, 5- to 8-membered, 5- to 7-membered or 5- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents, and more preferably pyrrolidinyl, piperidinyl, piperazinyl.
  • the "substituted with Ra" in the "a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" formed with R2 and R2 ' preferably means substitution with halogen, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 alkylsulfonyl, substituted or unsub
  • the "4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra" formed with R2and R2' is preferably pyrrolidinyl, piperidinyl, or piperazinyl.
  • C1-C6 alkyl represented by R3 is preferably methyl, ethyl, isopropyl, or tert-butyl, more preferably methyl or ethyl, and most preferably methyl.
  • R3 which may substitute “C1-C10 alkyl” represented by R3 may be, for example, the substituents mentioned above, and is preferably halogen, cyano, hydroxy, C3-C7 cycloalkyl, or a 4- to 10-membered saturated heterocyclic group and more preferably hydroxy.
  • R3 is more preferably hydrogen or methyl, ethyl, isopropyl, or tert-butyl.
  • R3 is more preferably hydrogen or methyl.
  • R 3 is most preferably hydrogen.
  • R4 represents cyano, hydroxy, halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted Cl- C10 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 sulfonyl.
  • halogen represented by R4 is preferably chlorine, bromine, fluorine, and iodine, with chlorine, fluorine, and bromine being preferable, and chlorine and fluorine being more preferable, and fluorine being most preferable.
  • the "C1-C10 alkyl" in the "substituted or unsubstituted C1-C10 alkyl” represented by R4 is preferably methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n- pentyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl (C3-C6 alkyl), and still more preferably methyl.
  • the "substituent" in the "substituted or unsubstituted C1-C10 alkyl” represented by R4 may be, for example, the substituents mentioned above, and is preferably halogen, cyano, hydroxy or C3-C7 cycloalkyl, and more preferably hydroxy.
  • the "substituted or unsubstituted C1-C10 alkyl" represented by R 4 is preferably C1-C6 alkyl, hydroxymethyl, 2- hydroxyethyl, 1,2-dihydroxyisopropyl, 2-hydroxypropyl, and more preferably C1-C3 alkyl, still more preferably methyl, isopropyl, tert-butyl, hydroxymethyl or 2-hydroxyethyl, and most preferably methyl.
  • C2-C10 alkenyl in the "substituted or unsubstituted C2-C10 alkenyl” represented by R 4 is preferably vinyl, 1-propenyl, allyl, or isopropenyl, and more preferably vinyl or isopropenyl.
  • the "substituent" in the "substituted or unsubstituted C2-C10 alkenyl” represented by R 4 may be, for example, the substituents mentioned above, and is preferably halogen, cyano, or hydroxy, more preferably chlorine or fluorine, and more preferably fluorine.
  • the "substituted or unsubstituted C2-C10 alkenyl" represented by R 4 is preferably C2-C6 alkenyl that may contain halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl, or 1-(trifluoromethyl)vinyl, and more preferably vinyl or 1- (trifluoromethyl)vinyl.
  • C2-C10 alkynyl in the "substituted or unsubstituted C2-C10 alkynyl” represented by R 4 is preferably ethynyl or 1-propynyl.
  • the substituent in the "substituted or unsubstituted C2- C10 alkynyl" represented by R 4 may be, for example, the substituents mentioned above, and is preferably halogen ' or hydroxy, and more preferably fluorine or chlorine.
  • the "substituted or unsubstituted C2-C10 alkynyl" represented by R 4 is preferably ethynyl or 1-propynyl.
  • C3-C10 cycloalkyl in the "substituted or unsubstituted C3-C10 cycloalkyl” represented by R4 is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and more preferably cyclopropyl.
  • the "substituted or unsubstituted C1-C10 haloalkyl" represented by FU is preferably fluoromethyl, difluoromethyl, trifluoromethyl.
  • the "substituted or unsubstituted C1-C10 alkoxyl" represented by R4 is preferably methoxy, ethoxy, 1-fluoromethoxy.
  • the "substituted or unsubstituted C1-C10 acyl" represented by R4 is preferably formyl, acetyl, propionyl.
  • the "substituted or unsubstituted C1-C10 alkoxycarbonyl" represented by R4 is preferably methoxycarbonyl, ethoxycarbonyl.
  • the "substituted or unsubstituted C1-C10 alkylsulfonyl" represented by R4 is preferably methoxysulfonyl, ethoxysulfonyl.
  • R4 is preferably halogen, cyano or a substituted or unsubstituted C1-C6 alkyl.
  • R4 is more preferably halogen, cyano or C1-C3 alkyl.
  • R4 is more preferably halogen, or cyano.
  • R4 is most preferably fluorine or cyano.
  • R5 represents cyano, hydroxy, halogen, amino, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 or C2-C6 alkenyl, substituted or unsubstituted C2-C10 or C2-C6 alkynyl, substituted or unsubstituted C1-C10 or C2-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted Cl- C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkyl sulfonyl.
  • halogen represented by Rs is preferably chlorine, bromine, fluorine, and iodine, with chlorine, fluorine, and bromine being preferable, and chlorine and fluorine being more preferable, and chlorine being most preferable.
  • C1-C10 alkyl in the "substituted or unsubstituted C1-C10 alkyl” represented by Rs is preferably methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n- pentyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl (C3-C6 alkyl), and still more preferably methyl.
  • the "substituent" in the "substituted or unsubstituted C1-C10 alkyl” represented by Rs may be, for example, the substituents mentioned above, and is preferably halogen, cyano, hydroxy or C3-C7 cycloalkyl, and more preferably fluorine.
  • the "substituted or unsubstituted C1-C10 alkyl" represented by Rs is preferably C1-C6 alkyl, more preferably methyl.
  • C2-C10 alkenyl in the "substituted or unsubstituted C2-C10 alkenyl” represented by Rsis preferably vinyl, 1-propenyl, allyl, or isopropenyl, and more preferably vinyl or isopropenyl.
  • the "substituent" in the "substituted or unsubstituted C2-C10 alkenyl” represented by Rs may be, for example, the substituents mentioned above, and is preferably halogen, cyano, or hydroxy, more preferably chlorine or fluorine, and more preferably fluorine.
  • the "substituted or unsubstituted C2-C10 alkenyl" represented by R 5 is preferably C2-C6 alkenyl that may contain halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl, or 1-(trifluoromethyl)vinyl, and more preferably vinyl or 1- (trifluoromethyl)vinyl.
  • C2-C10 alkynyl in the "substituted or unsubstituted C2-C10 alkynyl” represented by R 5 is preferably ethynyl or 1-propynyl.
  • the substituent in the "substituted or unsubstituted C2- C10 alkynyl" represented by R 5 may be, for example, the substituents mentioned above, and is preferably halogen or hydroxy, and more preferably fluorine or chlorine.
  • the "substituted or unsubstituted C2-C10 alkynyl" represented by R 5 is preferably ethynyl or 1-propynyl.
  • the "substituted or unsubstituted C1-C10 haloalkyl" represented by R5 is preferably fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl or 1,1-difluoroethyl, and more preferably fluoromethyl, difluoromethyl or trifluoromethyl.
  • the "substituted or unsubstituted C1-C10 alkoxyl" represented by R5 is preferably methoxy, ethoxy, 1-fluoromethoxy.
  • the "substituted or unsubstituted C1-C10 acyl" represented by R 5 is preferably formyl, acetyl, propionyl.
  • the "substituted or unsubstituted C1-C10 alkoxycarbonyl” represented by R 5 is preferably methoxycarbonyl, ethoxycarbonyl.
  • the "substituted or unsubstituted C1-C10 alkyl sulfonyl” represented by R 5 is preferably methoxysulfonyl, ethoxysulfonyl.
  • R5 is more preferably halogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 alkoxy, or substituted or unsubstituted C1-C6 haloalkyl.
  • R5 is more preferably halogen, C1-C6 alkyl which is unsubstituted or substituted with fluorine, C1-C6 alkoxy which is unsubstituted or substituted with fluorine, or C1-C6 haloalkyl which is unsubstituted or substituted with fluorine.
  • R 5 is more preferably chlorine, fluorine, methyl, tert- butyl, fluoromethyl, fluoroethyl, difluoromethyl, or trifluoromethyl.
  • R 5 is most preferably chlorine or trifluoromethyl.
  • two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A' or ring A when the number of R 6 is two or more; or
  • R 6 may independently represents cyano, hydroxy, halogen, amino, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 or C2-C6 alkenyl, substituted or unsubstituted C2-C10 or C2-C6 alkynyl, substituted or unsubstituted C1-C10 or Cl- C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or . unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl.
  • the "C3-C10 hydrocarbon ring" which may be formed with two R 6 is preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and more preferably cyclopentyl.
  • the "4- to 10-membered saturated heterocyclic ring" which may be formed with two R 6 is preferably 4- to 10-membered ring which contains nitrogen, and more preferably pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, and more preferably pyrrolidinyl, or tetrahydrofuranyl.
  • halogen represented by R 6 is preferably chlorine, bromine, fluorine, and iodine, with chlorine, fluorine, and bromine being preferable, and chlorine and fluorine being more preferable.
  • the "C1-C10 alkyl" in the "substituted or unsubstituted Cl-CIO alkyl” represented by R 6 is preferably methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n- pentyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl (C3-C6 alkyl), and still more preferably methyl or ethyl.
  • the "substituent" in the "substituted or unsubstituted C1-C10 alkyl” represented by R 6 may be, for example, the substituents mentioned above, and is preferably halogen, cyano, hydroxy or C1-C6 alkoxy, and more preferably methoxy.
  • the "substituted or unsubstituted C1-C10 alkyl" represented by R 6 is preferably C1-C6 alkyl, 1,2-dihydroxyisopropyl, 2-hydroxypropyl, methoxymethyl, ethoxymethyl, more preferably Cl- C3 alkyl, still more preferably methyl, ethyl, methoxymethyl or ethoxymethyl and most preferably methyl, or methoxymethyl.
  • C2-C10 alkenyl in the "substituted or unsubstituted C2-C10 alkenyl” represented by R 6 is preferably vinyl, 1-propenyl, allyl, or isopropenyl, and more preferably vinyl or isopropenyl.
  • the "substituent" in the "substituted or unsubstituted C2-C10 alkenyl” represented by R 6 may be, for example, the substituents mentioned above, and is preferably halogen, cyano, or hydroxy, more preferably chlorine or fluorine, and more preferably fluorine.
  • the "substituted or unsubstituted C2-C10 alkenyl" represented by R 6 is preferably C2-C6 alkenyl that may contain halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl, or 1-(trifluoromethyl)vinyl, and more preferably vinyl or 1- (trifluoromethyl)vinyl.
  • C2-C10 alkynyl in the "substituted or unsubstituted C2-C10 alkynyl” represented by R 6 is preferably ethynyl or 1-propynyl.
  • the substituent in the "substituted or unsubstituted C2- C10 alkynyl" represented by R 6 may be, for example, the substituents mentioned above, and is preferably halogen or hydroxy, and more preferably fluorine or chlorine.
  • the "substituted or unsubstituted C2-C10 alkynyl" represented by R 6 is preferably ethynyl or 1-propynyl.
  • the "substituted or unsubstituted C1-C10 haloalkyl" represented by R 6 is preferably C1-C6 haloalkyl, and more preferably, fluoromethyl, difluoromethyl, trifluoromethyl.
  • the "substituted or unsubstituted C1-C10 alkoxyl" represented by R 6 is preferably methoxy, ethoxy, 1-fluoromethoxy.
  • the "substituted or unsubstituted C1-C10 acyl" represented by R 6 is preferably formyl, acetyl, propionyl.
  • the "substituted or unsubstituted C1-C10 alkoxycarbonyl" represented by R 6 is preferably methoxycarbonyl, ethoxycarbonyl.
  • the "substituted or unsubstituted C1-C10 alkylsulfonyl" represented by f3 ⁇ 4 6 is preferably methoxysulfonyl, ethoxysulfonyl.
  • R 6 is more preferably halogen or substituted or unsubstituted Cl-C6alkyl, or two R 6 may join together to form a C3- C10 hydrocarbon ring, a 4- to 10-membered saturated heterocyclic ring.
  • R 6 is more preferably halogen or methyl, ethyl, methoxymethyl, may join together to form cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl.
  • R 6 is most preferably methyl, ethyl, may join together to form cyclopentyl, pyrrolidinyl.
  • R 7 represents cyano, hydroxy, halogen, amino, substituted or unsubstituted Cl- C10 alkyl, substituted or unsubstituted C2-C10 or C2-C6 alkenyl, substituted or unsubstituted C2-C10 or C2-C6 alkynyl, substituted or unsubstituted C1-C10 or C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl.
  • halogen represented by R7 is preferably chlorine, bromine, fluorine, and iodine, with chlorine, fluorine, and bromine being preferable, and chlorine and fluorine being more preferable.
  • the "C1-C10 alkyl" in the "substituted or unsubstituted C1-C10 alkyl” represented by R 7 is preferably methyl, ethyl, n- propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n- pentyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl (C3-C6 alkyl), and still more preferably methyl, ethyl, or tert-butyl.
  • the "substituent" in the "substituted or unsubstituted C1-C10 alkyl” represented by Fb may be, for example, the substituents mentioned above, and is preferably halogen, cyano, hydroxy or C3-C7 cycloalkyl, and more preferably hydroxy.
  • the "substituted or unsubstituted C1-C10 alkyl" represented by R7 is preferably C1-C6 alkyl, 1,2-dihydroxyisopropyl, 2-hydroxypropyl, more preferably C3-C6 alkyl, still more preferably methyl, ethyl, isopropyl or tert-butyl, and most preferably methyl.
  • C2-C10 alkenyl in the "substituted or unsubstituted C2-C10 alkenyl” represented by R7 is preferably vinyl, 1-propenyl, allyl, or isopropenyl, and more preferably vinyl or isopropenyl.
  • the "substituent" in the "substituted or unsubstituted C2-C10 alkenyl” represented by R7 may be, for example, the substituents mentioned above, and is preferably halogen, cyano, or hydroxy, more preferably chlorine or fluorine, and more preferably fluorine.
  • the "substituted or unsubstituted C2-C10 alkenyl" represented by R7 is preferably C2-C6 alkenyl that may contain halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl, or 1-(trifluoromethyl)vinyl, and more preferably vinyl or 1- (trifluoromethyl)vinyl.
  • C2-C10 alkynyl in the "substituted or unsubstituted C2-C10 alkynyl” represented by R7 is preferably ethynyl or 1-propynyl.
  • the substituent in the "substituted or unsubstituted C2- C10 alkynyl" represented by R7 may be, for example, the substituents mentioned above, and is preferably halogen or hydroxy, and more preferably fluorine or chlorine.
  • the "substituted or unsubstituted C2-C10 alkynyl" represented by R 7 is preferably ethynyl or 1-propynyl.
  • C3-C10 cycloalkyl in the "substituted or unsubstituted C3-C10 cycloalkyl” represented by R7 is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and more preferably cyclohexyl.
  • the "substituted or unsubstituted C1-C10 haloalkyl" represented by R7 is preferably fluoromethyl, difluoromethyl, trifluoromethyl.
  • the "substituted or unsubstituted C1-C10 alkoxyl" represented by R7 is preferably methoxy, ethoxy, 1-fluoromethoxy.
  • the "substituted or unsubstituted C1-C10 acyl" represented by R 7 is preferably formyl, acetyl, propionyl.
  • the "substituted or unsubstituted C1-C10 alkoxycarbonyl” represented by R7 is preferably methoxycarbonyl, ethoxycarbonyl.
  • the "substituted or unsubstituted C1-C10 sulfonyl” represented by R7 is preferably methoxysulfonyl, ethoxysulfonyl.
  • R7 is preferably halogen or a substituted or unsubstituted C1-C6 alkyl.
  • R7 is more preferably halogen or C1-C3 alkyl.
  • R 7 is most preferably fluorine or methyl.
  • R represents halogen or substituted or unsubstituted C1-C6 alkyl.
  • the "halogen” represented by Rs is preferably chlorine, bromine, fluorine, and iodine, with chlorine, fluorine, and bromine being preferable, and chlorine and fluorine being more preferable.
  • C1-C6 alkyl in the "substituted or unsubstituted C1-C6 alkyl” represented by Rs is preferably methyl, ethyl, n- propyl, or isopropyl, more preferably methyl or ethyl, and particularly preferably methyl.
  • the substituent in the "substituted or unsubstituted Cl- C6 alkyl" represented by Rs may be, for example, the substituents mentioned above, and is preferably, halogen, cyano, or hydroxy, and more preferably fluorine, chlorine, cyano, or hydroxy.
  • the "substituted or unsubstituted C1-C6 alkyl" represented by Rs is preferably C1-C6 alkyl, more preferably methyl, ethyl, or tert-butyl, more preferably methyl or ethyl, and particularly preferably methyl.
  • Rs is preferably halogen, or substituted or unsubstituted C1-C6 alkyl.
  • Rs is more preferably halogen or C1-C6 alkyl.
  • Rs is most preferably fluorine or methyl.
  • A represents a chemical moiety capable of interacting with a region between Switch 2 and a3-Helix, and more preferably A represents ring system, ring A which is a substituted or unsubstituted single ring or a substituted or unsubstituted fused ring, more preferably A represents ring A which is a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted C6-C10 aromatic hydrocarbon, a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group, or a substituted or unsubstituted 4- to 10-membered partially saturated heterocyclic group or a substituted or unsubstituted 4- to 10- membered unsaturated heterocyclic group.
  • ring A' forms a fused ring with ring A containing A 3 and A 4 , and Ai and As are C, CH, or CH 2 .
  • a 2 in ring A represents C.
  • ring A and ring A' jointly represent benzimidazolyl, benzothiazolyl, indazolyl, benzodioxanyl, imidazopyridinyl, and more preferably, benzoimidazolyl.
  • LI represents a linker. More preferably, LI is a combination of a substituted or unsubstituted single ring or a substituted or unsubstituted fused ring with -
  • D is a single ring having at least one amino group which binds to carbonyl between D and E to form amide, wherein the single ring is unsubstituted or substituted with substituent other than said amino, or D is substituted or unsubstituted fused ring, more preferably a substituted or unsubstituted C6-C10 aromatic hydrocarbon, or a substituted or unsubstituted 4- to 10-membered partially saturated heterocyclic group, or a substituted or unsubstituted 4- to 10- membered unsaturated heterocyclic group.
  • D represents a single ring having at least one amino group which binds to carbonyl between D and E to form amide, wherein the single ring is unsubstituted or substituted with substituent other than said amino, or D is substituted or unsubstituted fused ring, more preferably a substituted or unsubstituted C6-C10 aromatic hydrocarbon, or a substituted or unsubstituted 4- to 10-membered partially saturated heterocyclic group, or a substituted or unsubstituted 4- to 10-membered unsaturated heterocyclic group. [0217] More preferably, in the compound represented by Formula
  • D when D is a single ring, D' is absent, and the single ring is represented by ring D, which is an unsaturated 6-membered ring which is unsubstituted or substituted with R 7 , wherein Direpresents N or NH, and D 2 , D 3 , D 4 ,
  • D 5 , ⁇ z and D 7 represent independently C, CH, CH 2 , N or NH; when D is a fused ring, the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted with R 7 , wherein Di, D 2 , D 3 , D 4 , D 5 , Ob and D 7 represent independently C, CH, Cfa, N or NH, and ring D' is a saturated or unsaturated ring which is unsubstituted or substituted with Rs and forms a fused ring with ring D containing
  • D 6 in ring D is C.
  • D 3 , D 4 and D 5 are C.
  • D is fused ring represented by ring D and ring D'
  • ring D' is a saturated or an unsaturated 5-membered ring forming a fused ring containing Di, D 2 and D 7 with ring D
  • Di' and D 2 ' represent independently C, CH, C3 ⁇ 4, N, NH or S.
  • Di' and D2' represent independently C, CH, C3 ⁇ 4, N or NH.
  • D and ring D' jointly represents indole, indolizine, imidazopyridine, indoline or benzothiophene, still more preferably indole, indolizine, imidazopyridine or indoline.
  • L2 represents a linker, and more preferably a combination of a substituted or unsubstituted single ring or a substituted or unsubstituted fused ring with -NRi-, more preferably
  • E represents a ring system, and more preferably a ring system selected from a substituted or unsubstituted single ring or a substituted or unsubstituted fused ring.
  • E represents 6- membered ring, more preferably a substituted or unsubstituted C6- C10 aromatic hydrocarbon, a substituted or unsubstituted 4- to 10- membered partially saturated heterocyclic group, or a substituted or unsubstituted 4- to 10-membered unsaturated heterocyclic group.
  • Ei,E 2 ,E 3 ,E 4 in E represent independently C, CH, C3 ⁇ 4, N or NH, and E is a saturated or unsaturated 6-membered ring.
  • E represents phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl, and preferably phenyl or pyridinyl.
  • m represents an integer of 0 to 4 and more preferably 0, 1 or 2, and more preferably 1.
  • n represents an integer of 0 to 5 and more preferably 1, 2 or 3, and more preferably 1.
  • q represents 0, 1 or 2 and more preferably 0.
  • r represents 0, 1 or 2 and more preferably 0.
  • G represents an electrophilic chemical moiety capable of forming a covalent bond with cysteine
  • J represents a chemical moiety capable of interacting with GTP and more preferably
  • A is selected from:
  • D is selected from: [0236]
  • E is selected from: T ,
  • -NR2R3 is selected from: Embodiment A
  • the compound represented by Formula (iv) or a pharmaceutically acceptable salt thereof is provided, where when A is a single ring, A' and A are absent, and the single ring is represented by ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted with R5, wherein Ai, A2, A3, A4 and As represent independently C, CH, CH2, N or NH; when A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A'', wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted with R5, wherein Ai, A2, A3, A4 and As represent independently C, CH, C3 ⁇ 4, N or NH, and ring A' or A'' is a saturated or unsaturated ring which is unsubstituted or substituted with R 6 and forms a fused ring with ring A containing A 3 and A 4 or A 4
  • Ri is hydrogen or substituted or unsubstituted C1-C6 alkyl
  • R 2 and R 3 may join together to form a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or
  • R 2 and R 3 may be independently represented, and R 2 is hydrogen; or C1-C10 alkyl, C2-C10 or C2-C6 alkenyl, C2-C10 or C2-C6 alkynyl, C3- C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • R 3 is hydrogen orCl-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • R is halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 or C1-C6 alkyl, substituted or unsubstituted C2-C10 or C2-C6 alkenyl, substituted or unsubstituted C2-C10 or C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted Cl- C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl;
  • R 5 is halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl; two F 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A' or ring A'' when the number of ]3 ⁇ 4 is two or more; R 6 may independently represents halogen, cyano, amino,
  • R7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C10 or C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl;
  • R 8 is halogen or substituted or unsubstituted C1-C10 alkyl
  • Ra represents independently halogen, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted Cl- C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or a substituted or
  • the compound represented by Formula (iv) or a pharmaceutically acceptable salt thereof is provided, where when A is a single ring, A' and A'' are absent, and the single ring is represented by ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted with Rs, wherein Ai and As represent C, CH, or CH2, and A2, A3 and A4 represent independently C, CH, CH2, N or NH; when A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring ⁇ '', wherein ring A is an unsaturated
  • 6-membered ring which is unsubstituted or substituted with Rs, wherein Aiand Asrepresent C, CH, or C3 ⁇ 4, and A 2 , A 3 and A4represent independently C, CH, C3 ⁇ 4, N or NH, and ring A' or A'' is a saturated or unsaturated ring which is unsubstituted or substituted with R6 and forms a fused ring with ring A containing A 3 and A 4 or A4 and As; when D is a single ring, D' is absent, and the single ring is represented by ring D, which is an unsaturated 6-membered ring which is unsubstituted or substituted with R 7 , wherein Direpresents N or NH, D 6 represents C, CH, or C3 ⁇ 4, and D 2 , D 3 , D 4 , Ds and D 7 represent independently C, CH, C3 ⁇ 4, N or NH; when D is a fused ring, the fused ring is represented by ring D and
  • E is an unsaturated 6-membered ring which is unsubstituted or substituted with R4, wherein Ei, E2, E3 and E4 represent independently C, CH, CH2, N or NH;
  • R2 and R3 are independently represented, and R2 is hydrogen; or Cl- C10 alkyl, C2-C10 or C2-C6 alkenyl, C2-C10 or C2-C6 alkynyl, C3- C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • R3 is hydrogen orCl-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • R4 is halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 or C1-C6 alkyl, substituted or unsubstituted C2-C10 or C2-C6 alkenyl, substituted or unsubstituted C2-C10 or C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted Cl- C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl;
  • R 6 is halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl; two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A' or ring A'' when the number of R 6 is two or more; R 6 may independently represent halogen, cyano, amino, hydroxy,
  • R7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C10 or C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl;
  • R8 is halogen or substituted or unsubstituted C1-C10 alkyl
  • Ra represents independently halogen, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted Cl- C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or a substituted or
  • A is a fused ring, and the fused ring is represented by ring A and ring A' or ring A and ring A'', wherein ring A is an unsaturated
  • 6-membered ring which is unsubstituted or substituted with Rs, wherein Ai and As represent C, CH, or CH2, and A2, A3and A4 represent independently C, CH, CH2, N or NH, and ring A' or A'' is an unsaturated 5-membered ring which is unsubstituted or substituted with R 6 and forms a fused ring with ring A containing A3 and A4 or A4 and As, and Ai', A2' and A3' represent independently C, CH, CH2, N, NH, 0 or S; when D is a single ring, D' is absent, and the single ring is represented by ring D, which is an unsaturated 6-membered ring which is unsubstituted or substituted with R7, wherein Direpresents N or NH, D 6 represents C, CH, or C3 ⁇ 4, and D2, D3, D4, D5 and D7 represent independently C, CH, C3 ⁇ 4, N or NH; when D is a fused
  • E is an unsaturated b-membered ring which is unsubstituted or substituted with R 4 , wherein Ei, E2, E3 and E4 represent independently C, CH, CH2, N or NH;
  • R 2 and R 3 are independently represented, and R 2 is C1-C10 alkyl, C3- C10 cycloalkyl or a 4- to 10-membered saturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • R 3 is hydrogen orCl-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • R4 is halogen, cyano or substituted or unsubstituted C1-C10 alkyl
  • Rs is halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy
  • two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A' or ring ⁇ '' when the number of R 6 is two or more
  • R 6 may independently represent halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted Cl- C10 alkoxy;
  • Fb is halogen
  • Re is halogen or substituted or unsubstituted C1-C10 alkyl
  • Ra represents independently halogen, hydroxy, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy or substituted or unsubstituted Cl-ClO alkylsulfonyl; m is an integer of 0 to 2; n is an integer of 0 to 3; and p, q and r represent independently 0, 1, or 2.
  • A is a fused ring, and the fused ring is represented by ring A and ring A' or ring A and ring A'', wherein ring A is an unsaturated
  • 6-membered ring which is unsubstituted or substituted with Rs, wherein Ai, A 2 and As represent C, CH, or CH 2 , and A 3 and A 4 represent independently C, CH, C3 ⁇ 4, N or NH, and ring A' or A'' is an unsaturated 5-membered ring which is unsubstituted or substituted with R 6 and forms a fused ring with ring A containing A 3 and A or A 4 and As, and Ai' and A 3 ' represent independently C, CH, C3 ⁇ 4, N, NH, O or S, and A 2 ' represents C; when D is a single ring, D' is absent, and the single ring is represented by ring D, which is an unsaturated 6-membered ring which is unsubstituted or substituted with R 7 , wherein Direpresents N or NH, D 6 represents C, CH, or C3 ⁇ 4, and D 2 , D 3 , D 4 , Ds and D 7 represent independently C, CH
  • E is an unsaturated 6-membered ring which is unsubstituted or substituted with R4, wherein Ei, E2, E3 and E4 represent independently C, CH, CH2, N or NH;
  • R2 and R3 are independently represented, and R2 is C3-C10 cycloalkyl or a 4- to 10-membered saturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • R 3 is hydrogen
  • R4 is halogen, cyano or substituted or unsubstituted C1-C10 alkyl
  • Rs is halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy
  • two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A' or ring A when the number of R 6 is two or more
  • R 6 may independently represent substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted Cl-CIO alkoxy;
  • R 7 is halogen
  • Rs is halogen or substituted or unsubstituted C1-C6 alkyl
  • Ra represents independently halogen, hydroxy, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy or substituted or unsubstituted C1-C10 alkylsulfonyl; m is an integer of 0 to 1; n is an integer of 0 to 2; and p, q and r represent independently 0, 1, or 2.
  • the compound represented by Formula (iv) or a pharmaceutically acceptable salt thereof is provided, where D is a fused ring, and the fused ring is represented by ring A and ring A' or ring A and ring A' ', wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted with Rs, wherein Ai, A 2 and A 5 represent C, CH, or CH 2 , and A 3 and A 4 represent independently C, CH, CH 2 , N or NH, and ring A' or A' ' is an unsaturated 5-membered ring which is unsubstituted or substituted with R 6 and forms a fused ring with ring A containing A 3 and A 4 or A 4 and As, and Ai' and 3' represent independently C, CH, C3 ⁇ 4, N, NH, O or S, and A2' represents C;
  • D is a fused ring, and the fused ring is represented by ring D and ring D' , wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted with R 7 , wherein Di, D 2 , D 3 , D 4 , D 5 , D 6 and D 7 represent independently C, CH, C3 ⁇ 4, N or NH, and ring D' is a saturated or unsaturated 5-membered ring which is unsubstituted or substituted with Rsand forms a fused ring with ring D containing Di, D 2 and D 7 and Di' and D 2 ' represent independently C, CH, C3 ⁇ 4, N, NH or S;
  • E is an unsaturated 6-membered ring which is unsubstituted or substituted with R 4 , wherein Ei, E2, E3 and E4 represent independently C, CH, C3 ⁇ 4, N or NH;
  • Ri is hydrogen;
  • R2 and R 3 are independently represented, and R2 is C3-C10 cycloalkyl or a 4- to 10-membered saturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • R 3 is hydrogen;
  • R4 is halogen, cyano or substituted or unsubstituted C1-C10 alkyl
  • Rs is halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy
  • two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A' or ring A'' when the number of R 6 is two or more
  • R 6 may independently represents substituted or unsubstituted Cl- C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy;
  • R 7 is halogen; Rs is halogen or substituted or unsubstituted C1-C6 alkyl; the number of Ra is one or two and each Ra represents independently halogen, hydroxy, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy or substituted or unsubstituted C1-C10 alkylsulfonyl; m is an integer of 0 to 1; n is an integer of 0 to 2; and p, q and r represent independently 0, 1, or 2.
  • the compound represented by Formula (x) or a pharmaceutically acceptable salt thereof is provided, where when A is a single ring, A' and A'' are absent, and the single ring is represented by ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted with Rs, wherein Ai, A2, A3, A4 and As represent independently C, CH, CH2, N or NH; when A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A'', wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted with R5, wherein Ai, A2, A3, A4 and A5 represent independently C, CH, CH2, N or NH, and ring A' or A'' is a saturated or unsaturated ring which is unsubstituted or substituted with R 6 and forms a fused ring with ring A containing A3 and A or A and A
  • E is an unsaturated 6-membered ring which is unsubstituted or substituted with R4, wherein Ei, E2, E3 and E4 represent independently C, CH, CH2, N or NH;
  • Ri is hydrogen or substituted or unsubstituted C1-C6 alkyl
  • R2and R3or R2and R2' may join together to form a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or R2, R2' and R3may be independently represented, and R2 is hydrogen; or C1-C10 alkyl, C2-C10 or C2-C6 alkenyl, C2-C10 or C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; R2 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; and R3 is hydrogen orCl
  • R4 is halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 or C1-C6 alkyl, substituted or unsubstituted C2-C10 or C2-C6 alkenyl, substituted or unsubstituted C2-C10 or C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted Cl- C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl;
  • R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A' or ring A'' when the number of ]3 ⁇ 4 is two or more;
  • Re may independently represents halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl;
  • two R 6 may join together to form a C
  • R7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C10 or C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl;
  • R 8 is halogen or substituted or unsubstituted C1-C10 alkyl
  • Ra represents independently halogen, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted Cl- C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or a substituted or
  • the compound represented by Formula (x) or a pharmaceutically acceptable salt thereof is provided, where when A is a single ring, A' and A'' are absent, and the single ring is represented by ring A, which is an unsaturated 6-membered ring which is unsubstituted or substituted with R 5 , wherein Ai and A 5 represent C, CH, or CH 2 , and A 2 , A 3 and A 4 represent independently C, CH, CH 2 , N or NH; when A is a fused ring, the fused ring is represented by ring A and ring A' or ring A and ring A'', wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted with R 5 , wherein Aiand As represent C, CH, or C3 ⁇ 4, and A 2 , A 3 and A 4 represent independently C, CH, C3 ⁇ 4, N or NH, and ring A' or A'' is a saturated or uns
  • E is an unsaturated 6-membered ring which is unsubstituted or substituted with R 4 , wherein Ei, E 2 , E 3 and E4 represent independently C, CH, C3 ⁇ 4, N or NH;
  • R 2 and R 2 ' may join together to form a 4- to 10-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; or R 2 , R 2 'and R 3 are independently represented, and R 2 is hydrogen; or C1-C10 alkyl, C2-C10 or C2-C6 alkenyl, C2-C10 or C2-C6 alkynyl, C3- C10 cycloalkyl, C1-C10 alkoxy, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, a 4- to 10-membered partially saturated heterocyclic group or a 4- to 10-membered unsaturated heterocyclic group, each of which is unsubstituted or substituted with 1-2-substituents independently represented by Ra; R 2 is hydrogen or C1-C6 alkyl which is unsubstituted or substituted with 1-2 substituents independently represented by Ra; and R3 is hydrogen orC
  • R 4 is halogen, cyano, hydroxy, substituted or unsubstituted C1-C10 or C1-C6 alkyl, substituted or unsubstituted C2-C10 or C2-C6 alkenyl, substituted or unsubstituted C2-C10 or C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted Cl- C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl;
  • R 5 is halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl, or substituted or unsubstituted C1-C10 alkylsulfonyl; two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A' or ring A'' when the number of R 6 is two or more; R 6 may independently represent halogen, cyano, amino, hydroxy,
  • R7 is halogen, cyano, hydroxy, amino, carboxamide, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C10 or C1-C6 haloalkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or substituted or unsubstituted C1-C10 alkylsulfonyl;
  • R 8 is halogen or substituted or unsubstituted C1-C10 alkyl
  • Ra represents independently halogen, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 haloalkyl, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C1-C10 haloalkoxy, substituted or unsubstituted Cl- C10 alkylsulfonyl, substituted or unsubstituted C1-C10 acyl, substituted or unsubstituted C1-C10 alkoxycarbonyl or a substituted or
  • A is a fused ring, and the fused ring is represented by ring A and ring A' or ring A and ring A'', wherein ring A is an unsaturated
  • 6-membered ring which is unsubstituted or substituted with R5, wherein Aiand As represent C, CH, or CH2, and A ⁇ , A3and A4 represent independently C, CH, CH2, N or NH, and ring A' or A'' is an unsaturated 5-membered ring which is uhsubstituted or substituted with R 6 and forms a fused ring with ring A containing A3 and A4 or D4 and A5, and Ai', A2' and A3' represent independently C, CH, CH2, N, NH, 0 or S; when D is a single ring, D' is absent, and the single ring is represented by ring D, which is an unsaturated b-membered ring which is unsubstituted or substituted with R7, wherein Direpresents N or NH, D 6 represents C, CH, or C3 ⁇ 4, and D2, D3, D4, D5 and D7 represent independently C, CH, C3 ⁇ 4, N or NH;
  • E is an unsaturated b-membered ring which is unsubstituted or substituted with R4, wherein Ei, E2, E3 and E4 represent independently C, CH, C3 ⁇ 4, N or NH;
  • R2 and R2' join together to form a 4- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra, or
  • R2 is C1-C10 alkyl which is unsubstituted or substituted with Ra, C3-C10 cycloalkyl which is unsubstituted or substituted with Ra, or a 4- to 10- membered saturated heterocyclic group which is unsubstituted or substituted with Ra;
  • R2' is hydrogen orC1-C3 alkyl
  • R3 is hydrogen orCl-C3 alkyl
  • R4 is halogen, cyano or substituted or unsubstituted C1-C10 alkyl
  • R5 is halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy
  • two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A' or ring A'' when the number of R 6 is two or more
  • R 6 may independently represent halogen, cyano, amino, hydroxy, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted Cl- C10 alkoxy;
  • R 7 is halogen
  • R 8 is halogen or substituted or unsubstituted C1-C10 alkyl
  • Ra represents independently halogen, hydroxy, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy or substituted or unsubstituted C1-C10 alkylsulfonyl; m is an integer of 0 to 2; n is an integer of 0 to 3; and p, q and r represent independently 0, 1, or 2.
  • A is a fused ring, and the fused ring is represented by ring A and ring A' or ring A and ring A' ', wherein ring A is an unsaturated
  • 6-membered ring which is unsubstituted or substituted with Rs, wherein Ai, A 2 and As represent C, CH, or CH 2 , and A 3 and A4 represent independently C, CH, C3 ⁇ 4, N or NH, and ring A' or A'' is an unsaturated 5-membered ring which is unsubstituted or substituted with R 6 and forms a fused ring with ring A containing A 3 and A 4 or A 4 and As, and Ai' and A3' represent independently C, CH, C3 ⁇ 4, N, NH, 0 or S, and A2' represents C; when D is a single ring, D' is absent, and the single ring is represented by ring D, which is an unsaturated 6-membered ring which is unsubstituted or substituted with R 7 , wherein Direpresents N or NH, D6 represents C, CH, or C3 ⁇ 4, and D 2 , D 3 , D 4 , D 5 and D 7 represent independently C, CH
  • E is an unsaturated 6-membered ring which is unsubstituted or substituted with R4, wherein Ei, E2, E3 and E4 represent independently C, CH, CH2, N or NH;
  • R2 and R2' join together to form a 4- to 6-membered saturated heterocyclic ring which is unsubstituted or substituted with 1-2 substituents independently represented by Ra, or
  • R2, R2'and R3 are independently represented, and R2 is C3-C10 cycloalkyl or a 4- to 10-membered saturated heterocyclic group, each of which is unsubstituted or substituted with 1-2 substituents independently represented by Ra;
  • R2' is hydrogen or C1-C3 alkyl
  • R 3 is hydrogen
  • R4 is halogen, cyano or substituted or unsubstituted C1-C10 alkyl
  • Rs is halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy
  • two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A' or ring A'' when the number of R 6 is two or more
  • R 6 may independently represent substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy;
  • R 7 is halogen
  • Rs is halogen or substituted or unsubstituted C1-C6 alkyl
  • Ra represents independently halogen, hydroxy, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy or substituted or unsubstituted C1-C10 alkylsulfonyl; m is an integer of 0 to 1; n is an integer of 0 to 2; and p, q and r represent independently 0, 1, or 2. [0247]
  • A is a fused ring, and the fused ring is represented by ring A and ring A' or ring A and ring A'', wherein ring A is an unsaturated 6-membered ring which is unsubstituted or substituted with Rs, wherein Ai, A 2 and A 5 represent C, CH, or CH 2 , and A 3 and A 4 represent independently C, CH, CH 2 , N or NH, and ring A' or A'' is an unsaturated 5-membered ring which is unsubstituted or substituted with R 6 and forms a fused ring with ring A containing A 3 and A 4 or A4 and A 5 , and Ai' and A 3 ' represent independently C, CH, C3 ⁇ 4, N, NH, 0 or S, and A ⁇ ' represents C;
  • D is a fused ring, and the fused ring is represented by ring D and ring D', wherein ring D is an unsaturated 6-membered ring which is unsubstituted or substituted with R 7 , wherein Di, D 2 , D 3 , D 4 , D 5 , D6 and D 7 represent independently C, CH, C3 ⁇ 4, N or NH, and ring D' is a saturated or unsaturated 5-membered ring which is unsubstituted or substituted with Rsand forms a fused ring with ring D containing Di, D 2 and D 7 and Di' and D 2 ' represent independently C, CH, C3 ⁇ 4, N, NH or S;
  • E is an unsaturated 6-membered ring which is unsubstituted or substituted with R 4 , wherein Ei, E 2 , E 3 and E 4 represent independently C, CH, C3 ⁇ 4, N or NH;
  • R 2 and R 2 ' join together to form a 4- to 6-membered saturated heterocyclic ring, or R 3 is hydrogen;
  • R 4 is halogen, cyano or substituted or unsubstituted C1-C10 alkyl;
  • Rs is halogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy;
  • two R 6 may join together to form a C3-C10 hydrocarbon ring or a 4- to 10-membered saturated heterocyclic ring sharing two adjacent atoms with ring A' or ring A' ' when the number of R 6 is two or more;
  • R 6 may independently represents substituted or unsubstituted Cl- C10 alkyl, substituted or unsubstituted C1-C6 haloalkyl or substituted or unsubstituted C1-C10 alkoxy;
  • R 7 is halogen;
  • R 8 is halogen or substituted or unsubstituted C1-C6 alkyl;
  • the number of Ra is one or two and each Ra represents independently halogen, hydroxy, substituted or unsubstituted C1-C10 monoalkylamino, substituted or unsubstituted C1-C10 dialkylamino, substituted or unsubstituted C1-C10 alkoxy or substituted or unsubstituted C1-C10 alkylsulfonyl;
  • m is an integer of 0 to 1;
  • n is an integer of 0 to 2; and
  • p, q and r represent independently 0, 1, or 2.
  • a compound of the invention is selected from the followings:
  • the compound represented by Formula (I) or (vii) of the present invention can be produced, for example, through the following production methods or the methods described in the Examples. However, the production methods for the compound represented by Formula (I), (I'), (i) or (vii) of the present invention are not limited to these reaction examples.
  • the reaction product obtained in each step can be subjected to the subsequent step after, or without, isolation and purification by known separation and purification methods, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • a protecting group that can be easily converted to the functional group can be introduced if it is effective in each step, or so as to change the order of the steps.
  • the protecting group used here may be the protecting groups etc. used in the method disclosed in the document "Protective Groups in Organic Synthesis," 5th edition, Greene and Wuts, John Wiley & Sons Inc., 2014.
  • the protecting group may be appropriately selected according to the reaction conditions of each step. After introducing a protecting group and performing reaction, the protecting group is optionally removed to thus yield a desired compound.
  • the "mole” refers to a unit denoting
  • L a represents halogen
  • each R' independently represents hydrogen or substituted or unsubstituted alkyl
  • two R' may together form a 5- to 10-membered ring
  • other symbols are as defined in embodiment A.
  • This step is a step of obtaining a compound represented by the general formula (IV) by a cross-coupling reaction of a compound represented by the general formula (II) with an arylboronic acid or arylboronic acid ester, or unsaturated heterocyclic boronic acid or unsaturated heterocyclic boronic acid ester (III), each of which may be a commercially available product or can be produced by a known method, when L a in the compound represented by the general formula (II) has a leaving group such as halogen.
  • the compound represented by the general formula (II) may be a commercially available product or can be produced in accordance with a known method.
  • This step can be usually carried out in accordance with a known method (e.g., Chemical Reviews, Vol. 95, p. 2457, 1995), and can be carried out, for example, in the presence of a transition metal catalyst and a base, in a solvent which does not adversely affect the reaction.
  • a known method e.g., Chemical Reviews, Vol. 95, p. 2457, 1995
  • the arylboronic acid or arylboronic acid ester, or unsaturated heterocyclic boronic acid or unsaturated heterocyclic boronic acid ester can be used in an amount of 1 to 10 moles, and preferably of the order of 1 to 3 moles, based on 1 mole of the compound of the general formula (II).
  • a palladium catalyst e.g., palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, and dichlorobis(triphenylphosphine)palladium
  • a nickel catalyst e.g., nickel chloride
  • a ligand e.g., triphenylphosphine and tri-tert-butylphosphine
  • a metal oxide e.g., copper oxide and silver oxide
  • the amount of the transition metal catalyst to be used is usually about 0.0001 to 1 mole, and preferably of the order of 0.01 to 0.5 moles, based on 1 mole of the compound of the general formula (II).
  • the amount of the ligand to be used is usually about 0.0001 to 4 moles, and preferably of the order of 0.01 to 2 moles, based on 1 mole of the compound of the general formula (II).
  • the amount of the co-catalyst to be used is usually about 0.0001 to 4 moles, and preferably of the order of 0.01 to 2 moles, based on 1 mole of the compound of the general formula (II).
  • the base examples include organic amines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N- methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, and N,N-dimethylaniline), alkaline metal salts (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide), metal hydrides (e.g., potassium hydride and sodium hydride), alkaline metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide), and alkaline metal disilazides (e.g., lithium disilazide, sodium disilazide, and potassium disilazide).
  • the solvent is only required not to adversely affect the reaction.
  • the solvent include hydrocarbons (e.g., benzene, toluene, and xylene), halogenated hydrocarbons (e.g., chloroform and 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., 1,2-dimethoxyethane and THF), alcohols (e.g., methanol and ethanol), aprotic polar solvents (e.g., DMF, dimethyl sulfoxide, and hexamethylphosphoramide), water, and mixtures thereof.
  • hydrocarbons e.g., benzene, toluene, and xylene
  • halogenated hydrocarbons e.g., chloroform and 1,2-dichloroethane
  • nitriles e.g., acetonitrile
  • ethers e.g., 1,
  • the reaction time is 0.1 to 100 hours, and preferably 0.5 to 24 hours.
  • the reaction temperature is 0°C to the boiling point of the solvent, and preferably 0°C to 150°C.
  • the compound of the general formula (IV) thus obtained may be isolated and purified by a known separation purification means, or may be subjected to the subsequent step without such isolation and purification.
  • This step is a step of obtaining a compound represented by the general formula (VI) by an amidation reaction between the amine represented by the general formula (IV) and a carboxylic acid (V), which may be a commercially available product or can be produced by a known method.
  • This step is carried out using 0.5 to 10 moles of, and preferably 1 to 3 moles of the carboxylic acid (V), based on 1 mole of the compound represented by the general formula (IV).
  • an appropriate condensing agent as an amidation reagent is added, and the mixture is stirred under cooling to under heating, preferably -20°C to 80°C, usually for 1 minute to 1 week.
  • condensing agent examples include, but are not particularly limited to, N,N'-dicyclohexylcarbodiimide, N,N'- diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazol-l-yloxy-tris-
  • solvent examples include, but are not particularly limited to, toluene, methylene chloride, chloroform, THF, 1,4- dioxane, DMF, N,N-dimethylacetamide, NMP, 2-propanol, ethanol, methanol, water, and mixtures thereof.
  • An additive such as 1-hydroxybenzotriazole and a base also may be added, as required.
  • the base include, but are not particularly limited to, inorganic bases, such as sodium carbonate, potassium carbonate, and sodium hydrogen carbonate, or organic bases, such as triethylamine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine, or mixtures thereof.
  • the compound represented by the general formula (VI) thus obtained may be used for production of a compound represented by the general formula (I) after or without isolation and purification by a known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • a known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • This step is a step of obtaining a compound represented by the general formula (VIII) by subjecting the compound represented by the general formula (IV) and a carboxylic acid represented by the general formula (VII), which may be a commercially available product or can be produced by a known method, to an amidation reaction.
  • This step can be carried out in the same manner as Step
  • This step is a step of producing a compound represented by the general formula (VI) by reducing the compound represented by the general formula (VIII).
  • This step can be carried out in a solvent that does not adversely affect the reaction, for example, acetonitrile, ethyl acetate, THF, methanol, ethanol, DMF, DMA, or NMP by use of a hydrogen source, such as hydrogen, formic acid, ammonium formate, or cyclohexadiene, and with palladium/carbon or palladium hydroxide/carbon as a catalyst.
  • a hydrogen source such as hydrogen, formic acid, ammonium formate, or cyclohexadiene
  • This step is usually carried out using 0.01 to 5 moles of, and preferably 0.05 to 1 mole of the catalyst, based on 1 mole of the compound represented by the general formula (VIII).
  • the reaction temperature is usually room temperature to the reflux temperature of the solvent.
  • the reaction time is usually 1 hour to 24 hours.
  • the compound represented by the general formula (VI) thus obtained may be used for production of the compound represented by the general formula (I) after or without isolation and purification by a known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • a known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • L b represents halogen
  • L c represents a hydroxy group or chlorine atom or bromine atom
  • other symbols are as defined in embodiment A.
  • the acid halide may be a commercially available product or can be produced in accordance with a known method.
  • a base also may be added, as reguired.
  • the base include organic amines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 1,8- diazabicyclo[5,4,0]undec-7-ene, pyridine, and N,N-dimethylaniline), alkaline metal salts (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide), metal hydrides (e.g., potassium hydride and sodium hydride), and alkaline metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide).
  • the amount of the base to be used is usually 1 to 100 moles, and preferably of the order of 1 to 10 moles,
  • the solvent to be used in the reaction is only reguired not to adversely affect the reaction.
  • the solvent include alcohols (e.g., methanol), hydrocarbons (e.g., benzene, toluene, and xylene), halogenated hydrocarbons (e.g., methylene chloride, chloroform, and 1,2-dichloroethane), nitriles (e.g., acetonitrile), ethers (e.g., 1,2-dimethoxyethane and THF), aprotic polar solvents (e.g., DMF, dimethyl sulfoxide, and hexamethylphosphoramide), and mixtures thereof.
  • alcohols e.g., methanol
  • hydrocarbons e.g., benzene, toluene, and xylene
  • halogenated hydrocarbons e.g., methylene chloride, chloroform, and 1,2-dichloroethane
  • the reaction time is 0.1 to 100 hours, and preferably 0.5 to 24 hours.
  • the reaction temperature is 0°C to the boiling point of the solvent, and preferably 0°C to 100°C.
  • This step is a step of obtaining a compound represented by the general formula (VI) by a coupling reaction of the compound represented by the general formula (XI) with an arylboronic acid or arylboronic acid ester, dr with unsaturated heterocyclic boronic acid or unsaturated heterocyclic boronic acid ester (XII), each of which may be a commercially available product or can be produced by a known method, when L b in the compound represented by the general formula (XI) has a leaving group such as halogen.
  • This step can be carried out in the same manner as Step
  • This step is a step of obtaining a compound represented by the general formula (XIV) by means of an amidation reaction between the compound represented by the general formula (VI) and a carboxylic acid (XIII). This step can be carried out in the same manner as Step
  • This step is a step of producing the compound of the present invention represented by the general formula (I) by allowing the compound represented by the general formula (XIV) to react with an amine represented by the general formula (XV).
  • the amine represented by the general formula (XV) may be used in an amount of 1 to 20 moles, and preferably of 1 to 10 moles, based on 1 mole of the compound represented by the general formula (XIV).
  • a base may be added to the reaction described above, as required.
  • the base include organic bases, such as triethylamine, N,N-diisopropylethylamine, pyridine, lutidine, collidine, 4-dimethylaminopyridine, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and butyl lithium or inorganic bases, such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, and potassium phosphate.
  • the amount of the base to be added 1 to 100 moles, and preferably 1 to 20 moles may be used, based on 1 mole of the compound represented by the general formula (XIV).
  • An inorganic salt also may be added, as required.
  • the inorganic salt include sodium iodide and potassium iodide.
  • the amount of the inorganic salt to be used is usually 1 to 100 moles, and preferably of the order of 1 to 10 moles, based on 1 mole of the compound represented by the general formula (XIV).
  • the reaction solvent is not particularly limited as long as the solvent does not adversely affect the reaction.
  • DMF dimethyl sulfoxide
  • THF 1,4-dioxane
  • N-methylpyrrolidine-2-one 1,4-dioxane
  • acetonitrile may be used singly or in admixture.
  • the reaction time is 0.1 to 100 hours, and preferably 0.5 to 24 hours.
  • the reaction temperature is 0°C to the boiling point of the solvent, and preferably 0 to 100°C.
  • the compound of the present invention represented by the general formula (I) thus obtained may be isolated and purified by a known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • L d represents a fluorine atom or amino group or NHRi
  • L e represents halogen, and other symbols are as defined in embodiment D.
  • This step is a method of obtaining a compound represented by the general formula (XVII) by means of a bromination reaction of a compound represented by the general formula (XVI), which may be a commercially available product or can be produced by a known method.
  • This step may be carried out in a solvent that does not adversely affect the reaction, for example, acetonitrile, ethyl acetate, dichloromethane, chloroform, 1,4-dioxane, or ethanol by use of a bromine source, such as bromine or copper(II) bromide. Iodine as an additive also may be used, as required.
  • a bromine source such as bromine or copper(II) bromide.
  • Iodine as an additive also may be used, as required.
  • usually 1 to 100 moles of, and preferably of the order of 1 to 10 moles of a bromine source may be usually used, based on 1 mole of the compound represented by the general formula (XVI).
  • the reaction temperature is usually room temperature to the reflux temperature of the solvent.
  • the reaction time is usually 1 hour to 24 hours.
  • the compound represented by the general formula (XVII) thus obtained may be subjected to the subsequent step after or without isolation and purification by a known separation and purification means.
  • This step is a step of obtaining a compound represented by the general formula (XVIII) by means of a nucleophilic substitution reaction of a substituted pyridine, which may be a commercially available product or can be produced by a known method, with the compound represented by the general formula (XVII), followed by an intramolecular cyclization reaction.
  • D2 is N
  • Di' and D2' are C, CH or CH2
  • L d is a fluorine atom
  • a solvent that does not adversely affect the reaction such as THF and ethanol
  • 0.5 to 10 moles of, and preferably of the order of 1 to 5 moles of 2-methylpyridine having substituents L e and R7 may be usually used, based on 1 mole of the compound represented by the general formula (XVII).
  • the 2- methylpyridine may be a commercially available product or can be produced in accordance with a known method.
  • the reaction temperature is usually room temperature to the reflux temperature of the solvent.
  • the reaction time is usually 1 hour to of the order of 4 days.
  • the pyridinium salt thus obtained may be subjected to the subsequent reaction after or without isolation and purification by a known separation and purification means.
  • the base examples include organic amines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 1,8- diazabicyclo[5,4,0]undec-7-ene, pyridine, and N,N-dimethylaniline), alkaline metal salts (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide), metal hydrides (e.g., potassium hydride and sodium hydride), and alkaline metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide).
  • the amount of the base to be used is usually 1 to 100 moles, and preferably of the order of 1 to 10 moles, based on 1 mole of the pyridinium salt.
  • the solvent to be used in the reaction is only required not to adversely affect the reaction.
  • the solvent include aprotic polar solvents (e.g., DMF, dimethyl sulfoxide, and hexamethylphosphoramide).
  • the reaction time is 0.1 to 100 hours, and preferably 0.5 to 24 hours.
  • the reaction temperature is 0°C to the boiling point of the solvent, and preferably 0°C to 100°C.
  • the compound represented by the general formula (XVIII) thus obtained may be used for production of the compound (I') of the present invention after or without isolation and purification by a known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • D2 and D2' are N or NH and Di' is C, CH, or CH2
  • a solvent that does not adversely affect the reaction such as DMF and ethanol
  • usually 0.5 to 10 moles of, and preferably of the order of 1 to 5 moles of (E)-N,N-dimethyl-N'-(pyridin-2- yl)formimidamide having substituents L e and R7 can be used, based on 1 mole of the compound represented by the general formula (XVII).
  • the (E)-N,N-dimethyl-N'-(pyridin-2-yl)formimidamide may be a commercially available product or can be produced in accordance with a known method.A base also may be added, as required.
  • Examples of the base include organic amines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, 1,8- diazabicyclo[5,4,0]undec-7-ene, pyridine, and N,N-dimethylaniline) and alkaline metal salts (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide).
  • the reaction temperature is usually room temperature to the reflux temperature of the solvent.
  • the reaction time is usually 1 hour to 24 hours.
  • the compound represented by the general formula (XVIII) thus obtained may be used for production of the compound (I') of the present invention after or without isolation and purification by a known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • L f represents a hydroxy group, chlorine atom, or bromine atom, and other symbols are as defined in embodiment A.
  • This step is a step of obtaining a compound represented by the general formula (XXI) by a Friedel-Crafts reaction between a compound represented by the general formula (XIX), which may be a commercially available product or can be produced by a known method, and a compound represented by the general formula (XX).
  • this step can be carried out in a solvent that does not adversely affect the reaction, such as dichloromethane, THF, and 1,4-dioxane by use of trifluoroacetic anhydride, phosphoric acid or the like.
  • a base also may be added, as required. Examples of the base include organic amines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N- methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, and N,N-dimethylaniline).
  • reaction temperature is usually room temperature to the reflux temperature of the solvent.
  • reaction time is usually 1 hour to 3 days.
  • this step can be carried out in a solvent that does not adversely affect the reaction, such as dichloromethane, THF, and 1,4-dioxane, in the presence of a Lewis acid such as aluminum chloride or an organic amine (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N- methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, and N,N-dimethylaniline).
  • a Lewis acid such as aluminum chloride or an organic amine (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine, N- methylmorpholine, 1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, and N,N-dimethylaniline).
  • reaction temperature is usually 0°C to the reflux temperature of the solvent.
  • reaction time is usually 1 hour to 24 hours.
  • the compound represented by the general formula (XXI) thus obtained can be subjected to the subsequent reaction after or without isolation and purification by a known separation and purification means.
  • This step is a method of obtaining a compound represented by the general formula (XXII) by an aromatic electrophilic substitution reaction of an amine, when L d is a fluorine atom.
  • a solvent that does not adversely affect the reaction such as THF, 1,4-dioxane, and 1,2- dimethoxyethane
  • alkylamine R1-NH2
  • XXI alkylamine
  • the reaction temperature is usually room temperature to the reflux temperature of the solvent.
  • the reaction time is usually 1 hour to 24 hours.
  • This step is a step of obtaining a compound represented by the general formula (XXIII) by a cross-coupling reaction of a compound represented by the general formula (XXII) with an arylboronic acid or arylboronic acid ester, or with unsaturated heterocyclic boronic acid or unsaturated heterocyclic boronic acid ester (XII), each of which may be a commercially available product or can be produced by a known method, when L e in the compound represented by the general formula (XXII) has a leaving group such as halogen.
  • This step can be carried out in the same manner as Step
  • This step is a step of obtaining a compound represented by the general formula (XXIV) by an amidation reaction between the compound represented by the general formula (XXIII) and a carboxylic acid (XIII).
  • This step can be carried out in the same manner as Step
  • This step is a step of producing a compound of the present invention represented by the general formula (I') by allowing the compound represented by the general formula (XXIV) to react with an amine represented by the general formula (XV).
  • This step can be carried out in the same manner as Step
  • L g represents halogen
  • L h represents chlorine or bromine
  • L ⁇ represents halogen
  • other symbols are as defined in embodiment A.
  • the reaction solvent that may be used is not particularly limited as long as the solvent does not participate the reaction. Examples of the solvent include ethers, such as THF and 1,4-dioxane, hydrocarbons such as benzene and toluene, and mixtures thereof.
  • Examples of the strong base which may be used include, but are not particularly limited to, butyl lithium, lithium diisopropylamide, lithium 2,2,6,6- tetramethylpiperidide, 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex, and isopropylmagnesium chloride lithium chloride complex.
  • the compound represented by the general formula (XXVII) thus obtained can be used for production of the compound of the present invention after or without isolation and purification by a known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • a known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • any of the isomers and mixtures thereof are included within the scope of the compound of the present invention unless otherwise specified.
  • the compound of the present invention has optical isomers, racemic mixtures and the optical isomers separated from a racemic mixture are also included within the scope of the compound of the present invention unless otherwise specified.
  • the compound or a salt thereof according to one embodiment of the present invention may be in the form of amorphous or crystals. Single crystals and polymorphic mixtures are included within the scope of the compound or a salt thereof of the present invention. Such crystals can be produced by crystallization according to a crystallization method known in the art.
  • the compound or a salt thereof of the present invention may be a solvate (e.g., a hydrate) or a non-solvate.
  • the salts of the compound according to one embodiment of the present invention refer to any pharmaceutically acceptable salts; examples include base addition salts and acid addition salts [0312]
  • the compound or a salt thereof according to one embodiment of the present invention also encompass prodrugs thereof
  • a prodrug refers to a compound that can be converted to the compound or a salt thereof of the present invention through a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, i.e., a compound that can be converted to the compound or a salt thereof of the present invention by enzymatic oxidation, reduction, hydrolysis, or the like; or a compound that can be converted to the compound or a salt thereof of the present invention by hydrolysis or the like with gastric acid or the like.
  • the prodrug may be compounds that can be converted to the compound or a salt thereof of the present invention under physiological conditions, such as those described in Iyakuhin no Kaihatsu, "Development of Pharmaceuticals," Vol. 7, Molecular Design, published in 1990 by Hirokawa Shoten Co., pp. 163-198.
  • the "effective amount" of the compound according to an embodiment of the present invention refers to an amount of the compound which is sufficient to achieve a biological response or therapeutic response of a subject, such as causing reduction or prevention of an activity of enzyme or protein; or improving a symptom, alleviating a medical state, delaying or retarding progression of disorder, or preventing a disease (therapeutically effective amount).
  • the "subject" includes a mammal and a nonmammal.
  • a mammal include, but not limited to, a human, a chimpanzee, an anthropoid, a monkey, a cow, a horse, a sheep, a goat, a pig, a rabbit, a dog, a cat, a rat, a mouse, a Cavia porcellus, a hedgehog, a kangaroo, a mole, a boar, a bear, a tiger and a lion.
  • a nonmammal include, but not limited to, birds, fishes and reptiles.
  • the subject is a human, and may be a human who has been diagnosed to need a treatment for the symptom, the medical state or disease as disclosed herein.
  • a medicament, a pharmaceutical composition or a pharmaceutical preparation comprising the compound or pharmaceutically acceptable salt thereof of the present invention may be provided.
  • an anti-tumor agent comprising the compound or pharmaceutically acceptable salt thereof of the present invention as an active ingredient may be provided.
  • a pharmaceutically acceptable carrier can be added, if required, thereby forming a suitable dosage form according to prevention and treatment purposes.
  • the dosage form include oral preparations, injections, suppositories, ointments, inhalations, patches, and the like.
  • Such dosage forms can be formed by methods conventionally known to a person skilled in the art.
  • various conventional organic or inorganic carrier materials used as preparation materials may be blended as an excipient, binder, disintegrant, lubricant, or colorant in solid preparations; or as a solvent, solubilizing agent, suspending agent, isotonizing agent, buffer, or soothing agent in liquid preparations.
  • pharmaceutical preparation additives such as antiseptics, antioxidants, colorants, sweeteners, and stabilizers, may also be used, if required.
  • a medicament, a pharmaceutical composition or a pharmaceutical preparation for oral administration or an oral solid preparation comprising the compound or pharmaceutically acceptable salt thereof of the present invention may be provided.
  • an anti-tumor agent for oral administration comprising the compound or pharmaceutically acceptable salt thereof of the present invention as an active ingredient may be provided.
  • Oral solid preparations or a medicament, a pharmaceutical composition, an anti-tumor agent or a pharmaceutical preparation for oral administration are prepared as follows. After an excipient is added optionally with a binder, disintegrant, lubricant, colorant, taste-masking or flavoring agent, etc. to the compound or a salt thereof of the present invention, the resulting mixture is formulated into tablets, coated tablets, granules, powders, capsules, or the like by ordinary methods.
  • a pH regulator, a buffer, a stabilizer, an isotonizing agent, a local anesthetic, and the like may be added to the compound of the present invention; and the mixture may be formulated into a subcutaneous, intramuscular, or intravenous injection according to an ordinary method.
  • the amount of the compound according to one embodiment of the present invention to be incorporated in each of such dosage unit forms depends on the condition of the patient to whom the compound is administered, the dosage form, etc. In general, for an oral agent, the amount of the compound is preferably about 0.05 to 1000 mg per dosage unit form. For an injection, the amount of the compound is preferably about 0.01 to 500 mg per dosage unit form, and for a suppository, the amount of the compound is preferably about 1 to 1000 mg per dosage unit form.
  • the daily dose of the medicine in such a dosage form varies depending on the condition, body weight, age, sex, etc. of ⁇ the patient, and cannot be unconditionally determined.
  • the daily dose for an adult (body weight: 50 kg) of the compound of the present invention may be generally about 0.05 to 5000 mg, and preferably 0.1 to 1000 mg.
  • the compound or a salt thereof according to one embodiment of the present invention has excellent KRAS inhibitory activity against KRAS G12C mutation-positive cancer cells. Therefore, the compound or a salt thereof according to one embodiment of the present invention is useful as an antitumor agent against KRAS G12C mutation-positive cancer cells, and has the advantage of having fewer side effects.
  • the compound or a salt thereof according to one embodiment of the present invention inhibits the KRAS function and is useful as a pharmaceutical preparation for preventing and treating KRAS- associated signaling-related diseases.
  • use of a compound or pharmaceutically acceptable salt thereof of the present invention for manufacturing a pharmaceutical composition may be provided.
  • use of a compound or pharmaceutically acceptable salt thereof of the present invention for manufacturing an anti-tumor agent may be provided.
  • use of a compound or pharmaceutically acceptable salt thereof of the present invention for manufacturing an anti-tumor agent for oral administration may be provided.
  • a compound or pharmaceutically acceptable salt thereof of the present invention for use as medicament may be provided.
  • a compound or pharmaceutically acceptable salt thereof of the present invention for use in the prevention and/or treatment of tumor may be provided.
  • a compound or pharmaceutically acceptable salt thereof of the present invention for use in the prevention and/or treatment of tumor by oral administration may be provided.
  • a method for preventing and/or treating tumor comprising administrating a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of the present invention to a subject in need thereof.
  • an antitumor agent which is administered to a subject in need thereof in combination with a pharmaceutically effective amount of one or more other antitumor drugs may be provided.
  • KRAS is involved in various signaling transduction as RAS-associated signaling; KRAS mainly activates, but is not limited to, RAF, PI3K, RAL-GEF, and the like.
  • the diseases include diseases whose incidence can be reduced, and whose symptoms can be remitted, relieved, and/or completely cured by deleting, suppressing, and/or inhibiting their functions. Examples of such diseases include, but are not limited to, tumors, cancers, autoimmune diseases, macroglobulinemia, and the like.
  • cancers targeted in the present invention include, but are not particularly limited to, head and neck cancer, digestive organ cancer (esophageal cancer, stomach cancer, duodenal cancer, liver cancer, biliary cancer (e.g., gallbladder and bile duct cancer), pancreatic cancer, colorectal cancer (e.g., colon cancer, and rectal cancer), etc.), lung cancer (e.g., non-small-cell lung cancer, small-cell lung cancer, and mesothelioma), breast cancer, genital cancer (ovarian cancer, uterine cancer (e.g., cervical cancer and endometrial cancer), etc.), urological cancer (e.g., kidney cancer, bladder cancer, prostate cancer, and testicular tumor), hematopoietic tumor (e.g., leukemia, lymphoma, malignant lymphoma, and multiple myeloma), sarcoma (e.g., osteosarcoma, and soft-tissue sarcoma),
  • Preferable examples include lung cancer, pancreatic cancer, rectal cancer, colon cancer and colorectal cancer.
  • squamous carcinoma is a cancer of uterine cervix, tarsus, conjunctiva, vagina, lung, oral cavity, skin, bladder, tongue, larynx or esophagus.
  • adenocarcinoma is a cancer of prostate, small intestine, endometrium, uterine cervix, large intestine, lung, pancreas, esophagus, rectum, uterus, stomach, breast or ovary.
  • tumor is rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, lung cancer, breast cancer or leukemia.
  • a subject suffering from any of the disease selected from the above does not have to have K-Ras G12C mutant protein. In a preferred embodiment, a subject suffering from any of the disease selected from the above has K-Ras G12C mutant protein.
  • an antitumor agent comprising a compound or a pharmaceutically acceptable salt thereof of the present invention, and one or more other antitumor agents as an active ingredient may be provided.
  • an antitumor agent comprising a compound or a pharmaceutically acceptable salt thereof of the present invention as an active ingredient, which is administered in combination with one or more other antitumor agents may be provided.
  • use of the compound of the present invention or a salt thereof and one or more other antitumor agents for the manufacture of an antitumor agent may be provided.
  • use of the compound of the present invention or a salt thereof for the manufacture of an antitumor agent, which is administered in combination with one or more other antitumor agents may be provided.
  • the combination of a compound of the present invention or a salt thereof and one or more other antitumor agents for use in the treatment of tumors may be provided.
  • the compound or pharmaceutically acceptable salt thereof of the present invention for use in the treatment of tumor, which is administered in combination with one or more other antitumor agents may be provided.
  • a method for treating tumor comprising administrating a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of the present invention, and one or more other antitumor agents to a subject in need thereof may be provided.
  • a method for treating tumor comprising administrating a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of the present invention, which is administered in combination with one or more other antitumor agents to a subject in need thereof may be provided.
  • use of a compound or pharmaceutically acceptable salt thereof that covalently binds to GTP-bound KRAS G12C for manufacturing of an anti-tumor agent may be provided.
  • a compound or pharmaceutically acceptable salt thereof that covalently binds to GTP-bound KRAS G12C for use in the treatment of tumor may be provided.
  • a method for treating tumor comprising administrating a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof that covalently binds to GTP-bound KRAS G12C to a subject in need thereof may be provided.
  • a method for modulating an activity of Ras protein including human K-Ras G12C mutant protein which comprises contacting the Ras protein with an effective amount of the compound of the present invention.
  • the activity to be modulated includes GTPase activity, nucleotide exchange, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, Ras, e.g., K-Ras, localization in a cell, post- translational processing of Ras, e.g., K-Ras, and posttranslation modification of Ras, e.g., K-Ras, and preferably include K-Ras localization in a cell, post-translational processing of K-Ras, and posttranslation modification of K-Ras.
  • the "modulating" may be increasing or decreasing the activity of the Ras, e.g., K-Ras
  • Ras e.g., K-Ras
  • protein exists in a living cell, such as a living cell which forms a part of a living object.
  • the reagents used in the Examples are commercially available products unless indicated otherwise. Prepacked columns manufactured by Shoko Scientific Co., Ltd., or Biotage were used in silica gel column chromatography and basic silica gel column chromatography. An AL400 spectrometer (400 MHz; JEOL Ltd. (JEOL)) or Mercury 400 (400 MHz; Varian) spectrometer was used for NMR spectra. For a deuterated solvent containing tetramethylsilane, tetramethylsilane was used as the internal reference. For other cases, measurement was performed using an NMR solvent as the internal reference. All d values are indicated in ppm. Microwave reaction was performed using an Initiator (trademark) manufactured by Biotage.
  • CD30D deuterated methanol
  • Boc tert-butoxycarbonyl group
  • Step 2 Crude N-methyl-2-nitro-5-(trifluoromethyl)aniline obtained in step 1 and N-bromosuccinimide (5.11 g) were added to acetic acid (80 ml).After the mixture was refluxed for 1 hour, the mixture was cooled to room temperature and poured into water. The resulting solid was collected by filtration, thereby obtaining crude 4-bromo- N-methyl-2-nitro-5-(trifluoromethyl)aniline (6.63 g).
  • Step 3 A suspension of crude 4-bromo-N-methyl-2-nitro-5- (trifluoromethyl)aniline (6.63 g) obtained in step 2 and iron powder (6.19 g) in a 2M ammonium chloride aqueous solution (55 mL), THF (110 mL), and methanol (110 mL) was stirred at 70°C for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting mixture was diluted with water and ethyl acetate, followed by filtrating off the insoluble matter. The organic layer was separated and washed with a saturated sodium chloride solution, followed by drying over sodium sulfate.
  • Step 4 Concentrated hydrochloric acid (300 pL) was added to a suspension of 4-bromo-Nl-methyl-5-(trifluoromethyl)benzene-1,2- diamine (5.25 g) obtained in step 3 in 1,1,1-triethoxypropane (30 mL), followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (hexane:ethyl acetate), thereby obtaining 5-bromo-2-ethyl-l-methyl-6- (trifluoromethyl)-IH-benzo[d]imidazole (5.22 g). [0336]
  • Step 5 A suspension of 5-bromo-2-ethyl-l-methyl-6-
  • Step 6 1-Hydroxybenzotriazole monohydrate (1.12 g), 4-amino-3- cyano-benzoic acid (1.35 g), triethylamine (1.2 mL), and WSC hydrochloride (1.60 g) were added to a solution of 3-(2-ethyl-l- methyl-6-(trifluoromethyl)-IH-benzo[d]imidazol-5-yl)aniline (1.77 g) obtained in step 5 in DMF (55 mL). A reaction was performed at room temperature overnight.Water was added to the reaction mixture, and extraction was performed with ethyl acetate, followed by washing the organic layer with a saturated sodium chloride solution.
  • Step 7 (E)-4-chlorobut-2-enoic acid (745 mg), 1-propanephosphonic acid anhydride cyclic trimer (a 1.7M THF solution, 4.8 mL), and triethylamine (860 pL) were added to a solution of 4-amino-3-cyano- N-(3-(2-ethyl-l-methyl-6-(trifluoromethyl)-IH-benzo[d]imidazol-5- yl)phenyl)benzamide (1.91 g) obtained in step 6 in DMF (21 mL). A reaction was performed at room temperature for 2 hours.
  • Step 8 (lr,4r)-4-methoxycyclohexan-l-amine hydrochloride (28.5 mg), potassium carbonate (47.6 mg), and potassium iodide (34.3 mg) were added to a solution of (E)-4-(4-chlorobut-2-enamido)-3-cyano- N-(3-(2-ethyl-l-methyl-6-(trifluoromethyl)-IH-benzo[d]imidazol-5- yl)phenyl)benzamide (39.0 mg) obtained in step 7 in DMF (690 pL). A reaction was performed at room temperature for 2 hours.
  • N,2-dimethylpropan-2-amine (660 pL), potassium carbonate (220 mg), and potassium iodide (132 mg) were added to a solution of (E)-4-(4-chlorobut-2-enamido)-3-cyano-N-(3-(2-ethyl-l-methyl- 6-(trifluoromethyl)-IH-benzo[d]imidazol-5-yl)phenyl)benzamide (150 mg) obtained in Example 1 (step 7) in DMF (1.0 mL). A reaction was performed at room temperature for 2 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate, followed by washing the organic layer with a saturated sodium chloride solution.
  • Step 1 Bis(pinacolato)diboron (1.52 g) was added to a suspension of 6-bromo-7-methyl-2,3-dihydro-lH-benzo[d]pyrrolo[1,2- a]imidazole (1.00 g), potassium acetate (1.17g), [1,1'-
  • Step 2 A suspension of 4-amino-3-cyanobenzoic acid (500 mg) and thionyl chloride (2.5 mL) was heated at 100°C for 15 min. Then the excessive thionyl chloride was evaporated under reduced pressure. Toluene was added to the obtained residue again to dissolve the residue, followed by evaporating the solvent under reduced pressure The residue was dissolved in dichloromethane (5.0 mL), and 6- bromopyridin-2-amine (800 mg) and triethylamine (1.3 mL) were added thereto, followed by stirring at 50°C for 1 hour.
  • Step 3 A 2M sodium carbonate aqueous solution (340 pL) was added to a suspension of 7-methyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2,3-dihydro-lH-benzo[d]pyrrolo[1,2-a]imidazole (151 mg) obtained in step 1, 4-amino-N-(6-bromopyridin-2-yl)-3- cyanobenzamide (107 mg) obtained in step 2, and Xphos Pd G2 (26.6 mg) in 1,4-dioxane (1.5 mL), followed by stirring at 100°C for 2 hours.
  • Step 4 Triethylamine (170 pL) was added to a solution of 4-amino- 3-cyano-N-(6-(7-methyl-2,3-dihydro-lH-benzo[d]pyrrolo[1,2- a]imidazol-6-yl)pyridin-2-yl)benzamide (127 mg) obtained in step 3, (E)-4-chlorobut-2-enoic acid (56.4 mg) and 1-propanephosphonic acid anhydride cyclic trimer (48% in DMF, 390 pL) in DMF (1.5 mL), followed by stirring at room temperature for 1.5 hours. Ethyl acetate and a sodium hydrogen carbonate aqueous solution were added to the reaction mixture.
  • Step 5 Potassium carbonate (56.8 mg) was added to a suspension of (E)-4-(4-chlorobut-2-enamido)-3-cyano-N-(6-(7-methyl-2,3-dihydro- IH-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)pyridin-2-yl)benzamide (30.0 mg) obtained in step 4, (lr,4r)-4-methoxycyclohexan-l-amine hydrochloride (24.3 mg), and potassium iodide (29.2 mg) in DMF (400 pL), followed by stirring at room temperature for 2 hours.
  • Step 1 Dibromocopper (37.6 g) was added to a solution of 5-acetyl- 2-fluorobenzonitrile (25.0 g) in ethyl acetate (380 mL), followed by stirring at 70°C for 6 hours. Another dibromocopper (37.6 g) was added to the reaction mixture, followed by stirring at 70°C for 2 hours. The reaction mixture was filtered through celite, followed by washing with saturated sodium bicarbonate water and brine. After the organic layer was dried over sodium sulfate and concentrated, diisopropyl ether was added to the obtained residue, followed by stirring at ambient temperature for 30 minutes. The precipitated solid was collected via filtration, thereby obtaining 5-(2- bromoacetyl)-2-fluorobenzonitrile (32.0 g). [0347]
  • Step 2 3-bromo-2-methylpyridine (30 mL) was added to a solution of 5-(2-bromoacetyl)-2-fluorobenzonitrile (32.0 g) obtained in step 1 in THF (130 mL), and the mixture was stirred at 85°C for 4 days. Heptane was added to the reaction mixture at ambient temperature, and stirred for 30 minutes. The precipitated solid was collected via filtration, thereby obtaining 3-bromo-l-(2-(3-cyano-4- fluorophenyl)-2-oxoethyl)-2-methylpyridin-l-ium bromide (55.0 g). [0348]
  • Step 3 A mixture of DMF (41 mL) and dimethyl sulfate (50 mL) was stirred at 80°C for 3 hours. After cooling the mixture to room temperature, the mixture was added to a solution of 3-bromo-l-(2- (3-cyano-4-fluorophenyl)-2-oxoethyl)-2-methylpyridin-l-ium bromide (14.6 g) obtained in step 2 in DMF (44 mL) at room temperature. After stirring at room temperature for 30 minutes, N,N-diisopropylethylamine (61 mL) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. Water (230 mL) was added to the reaction mixture, followed by collecting the precipitated solid.
  • Step 4 A 28% ammonia aqueous solution (70 mL) was added to a solution of 5-(8-bromoindolizine-3-carbonyl)-2-fluorobenzonitrile (9.69 g) obtained in step 3 in 1,4-dioxane (60 mL) and 1,2- dimethoxyethane (10 mL), and the mixture was stirred at 115°C overnight. After cooling to room temperature, water (200 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours, followed by collecting the precipitated solid. The solid was dried in vacuo at 60°C overnight, and ethyl acetate was added to the solid.
  • Step 5 Methylamine (ca. 7% in THF, 53 mL) was added to l-bromo-4- fluoro-2-methyl-5-nitrobenzene (5.00 g), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the residue. The organic layer was separated and washed with a saturated sodium chloride solution, followed by drying over sodium sulfate. The solvent was evaporated under reduced pressure, thereby obtaining crude 4-bromo-N,5-dimethyl-2-nitroaniline (5.45 g). [0351]
  • Step 6 A suspension of crude 4-bromo-N,5-dimethyl-2-nitroaniline (5.45 g) obtained in step 5, iron powder (5.97 g), and ammonium chloride (5.71 g) in methanol(100 mL), THF (100 mL) and water (50 mL) was stirred at 85°C for 2 hours. The insoluble matter was filtered off, followed by evaporating the solvent under reduced pressure. The residue was diluted with ethyl acetate, and washed with water and a saturated sodium chloride solution, followed by drying over sodium sulfate. The solvent was evaporated under reduced pressure, thereby obtaining crude 4-bromo-N 1 ,5- dimethylbenzene-1,2-diamine (4.80 g).
  • Step 7 Concentrated hydrochloric acid (250 pL) was added to a suspension of crude 4-bromo-N 1 ,5-dimethylbenzene-l,2-diamine (4.80 g) obtained in step 6 in triethyl orthoformate (50 mL), followed by stirring at room temperature overnight. Ethyl acetate was added to the reaction mixture, followed by collecting the precipitate and washing with a mixture solvent of hexane-ethyl acetate (3:1), thereby obtaining 5-bromo-l,6-dimethyl-lH-benzo[d]imidazole (2.56 g) ⁇
  • Step 8 A suspension of 5-bromo-l,6-dimethyl-lH-benzo[d]imidazole (2.00 g) obtained in step 7, [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (726 mg), bis(pinacolato)diboron (3.38 g), and potassium acetate (2.62g) in DMSO (30 mL) was heated to 100°C for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate, water and celite were added thereto, followed by stirring for 10 min.

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Abstract

La présente invention concerne un agent antitumoral comprenant un composé ou un sel pharmaceutiquement acceptable de celui-ci qui se lie de manière covalente au KRASG12C lié à GTP en tant que principe actif.
PCT/JP2019/049075 2019-10-31 2019-12-06 Dérivés de 4-aminobut-2-enamide et sels de ces derniers Ceased WO2021084765A1 (fr)

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US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
WO2022232320A1 (fr) * 2021-04-27 2022-11-03 Merck Sharp & Dohme Corp. Inhibiteurs à petites molécules de mutant de kras g12c
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11697657B2 (en) 2019-10-28 2023-07-11 Merck Sharp & Dohme Llc Small molecule inhibitors of KRAS G12C mutant
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US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
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US12065430B2 (en) 2018-10-26 2024-08-20 Taiho Pharmaceutical Co., Ltd. Indazole compound or salt thereof
WO2024175999A2 (fr) 2023-02-23 2024-08-29 Dunad Therapeutics Ltd. Dérivés de benzènesulfonamide et leurs utilisations
US12162893B2 (en) 2020-09-23 2024-12-10 Erasca, Inc. Tricyclic pyridones and pyrimidones
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US12398154B2 (en) 2020-12-15 2025-08-26 Mirati Therapeutics, Inc. Azaquinazoline pan-KRas inhibitors
US12421253B2 (en) 2020-12-16 2025-09-23 Mirati Therapeutics, Inc. Tetrahydropyridopyrimidine pan-KRas inhibitors
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
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US12466840B2 (en) 2023-10-20 2025-11-11 Merck Sharp & Dohme Llc Small molecule inhibitors of KRAS proteins

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