WO2022018875A1 - Composition pharmaceutique contenant un dérivé d'arylamide pour traiter ou prévenir des maladies à prolifération cellulaire - Google Patents

Composition pharmaceutique contenant un dérivé d'arylamide pour traiter ou prévenir des maladies à prolifération cellulaire Download PDF

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WO2022018875A1
WO2022018875A1 PCT/JP2020/028575 JP2020028575W WO2022018875A1 WO 2022018875 A1 WO2022018875 A1 WO 2022018875A1 JP 2020028575 W JP2020028575 W JP 2020028575W WO 2022018875 A1 WO2022018875 A1 WO 2022018875A1
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fluoro
methyl
compound
difluoro
iodoanilino
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PCT/JP2020/028575
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English (en)
Japanese (ja)
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義明 一色
史郎 渡辺
正樹 富澤
樹人 羽田
一夫 服部
健一 川崎
郁美 兵藤
紀裕 青木
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中外製薬株式会社
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Priority to PCT/JP2020/028575 priority Critical patent/WO2022018875A1/fr
Priority to JP2022538564A priority patent/JPWO2022018875A1/ja
Priority to KR1020210095267A priority patent/KR102550455B1/ko
Priority to JP2021121960A priority patent/JP7168734B2/ja
Publication of WO2022018875A1 publication Critical patent/WO2022018875A1/fr
Priority to JP2022172687A priority patent/JP2023011759A/ja
Priority to KR1020230081877A priority patent/KR20230098762A9/ko

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • 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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • A61K31/695—Silicon compounds
    • 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 disclosure is effective for arylamide derivatives having RAF / MEK complex stabilizing activity and / or MEK inhibitory activity and useful for the treatment or prevention of cell proliferative diseases, particularly cancer, and such arylamide derivatives.
  • the present invention relates to a RAF / MEK complex stabilizer or a MEK inhibitor contained as an ingredient.
  • the present disclosure also relates to pharmaceutical compositions for the treatment or prevention of cell proliferation diseases, particularly cancer, which contain such an arylamide derivative as an active ingredient.
  • MEK Mitogen-activated protein kinase kinase
  • MAPK MAPK signaling pathway
  • PD0325901, CH4987655, trametinib, cobimetinib, selumetinib and the like have been reported as MEK inhibitors (see Patent Document 1 and Non-Patent Document 2), and cancers having a RAF mutation alone or in combination with a RAF inhibitor. For example, it has been reported to have a clinical effect on malignant melanoma having a BRAF mutation (see Non-Patent Documents 3 and 4).
  • CH51267666 (see Patent Document 2 and Non-Patent Documents 7 and 8), which is known not only as a MEK inhibitor but also as a stabilizer for the RAF / MEK complex, is clinically used for non-small cell lung cancer having a RAS mutation. It has been reported to show the above effect (see Non-Patent Document 9). It has also been reported that CH5126766 stabilizes the RAF / MEK complex and suppresses the enhancement of MEK phosphorylation (feedback activation of the MAPK signal pathway) (see Non-Patent Document 10) (see Non-Patent Document 7). And 8). This feedback activation is also considered to be one of the reasons why the clinical effect of MEK inhibitors on cancers having RAS mutations is not always sufficient (see Non-Patent Document 10).
  • the present disclosure discloses a novel compound having RAF / MEK complex stabilizing activity and / or MEK inhibitory activity and useful for the treatment or prevention of cell proliferation diseases, particularly cancer, or cell proliferation diseases, in particular. It is an object of the present invention to provide a novel RAF / MEK complex stabilizer or MEK inhibitor useful for the treatment or prevention of diseases.
  • CH4987655 which is a known MEK inhibitor
  • CH51267666 which is a known RAF / MEK complex stabilizer
  • CH4987655 shows comparable MEK inhibitory activity in non-cellular lines but slower dissociation from MEK when compared to another MEK inhibitor, PD0325901. Then, in the cynomolgus monkey peripheral blood showed strong MEK inhibitory activity than PD0325901 (low IC 50 of), to realize a MEK inhibitor longer lasting. They are believed to be due to a characteristic substituent containing a 3-oxo- [1,2] oxadinane ring structure present at the 5'position of the benzamide skeleton of CH4987655 (Bioorg. Med. Chem. See Let.2011, vol.21, no.6, p.1795-1801).
  • CH5126766 forms a complex with MEK in a characteristic structure. That is, when CH51267666 binds to MEK, the MEK activation segment moves, and accordingly, Asn221 and Ser222 of MEK are placed in spatially different locations than when PD0325089 (enantiomer of PD0325901) binds.
  • the sulfamide group of CH5126766 has a hydrogen bond with Asn221 of MEK directly and with Ser222 via water. Since Ser222 is one of the two amino acids phosphorylated by RAF, the RAF / MEK complex stabilizing action of CH5126766 and the enhancing action of MEK phosphorylation (feedback activation of the MAPK signal pathway) are such. It is believed to be due to the complex structure (see Cancer Cell. 2014, vol. 25, no. 5, p. 697-710 (Non-Patent Document 8)).
  • CH4987655 when bound to MEK, results in a spatial arrangement of Asn221 and Ser222 similar to CH51267666. It is also similar to CH5126766 in that it interacts with Asn221. Although CH4987655 has a weak effect of suppressing the enhancement of MEK phosphorylation, it is considered that this is due to such a complex structure (Cancer Cell. 2014, vol. 25, no. 5,). See p. 679-710 (Non-Patent Document 8)).
  • CH4987655 differs from CH5126766 in that it is distant from Ser222 and does not interact with it, and its interaction with Asn221 is weak via the 3-oxo- [1,2] oxadinane ring structure. On the other hand, CH5126766 does not interact with Lys97, unlike MEK inhibitors such as CH4987655 and PD0325901.
  • Hypothesis 1 By introducing a chemical structure capable of hydrogen-bonding with Lys97 into CH5126766, the RAF / MEK complex stabilizing activity and MEK phosphorylation enhancement (feedback activation of MAPK signal pathway) inhibitory activity of CH51267666 are maintained. At the same time, MEK inhibitory activity equivalent to that of CH4987655 can be obtained.
  • Hypothesis 2 If a chemical structure capable of forming a strong hydrogen bond with Asn221 and Ser222 is introduced into CH4987655, the RAF / MEK complex stabilizing activity equivalent to that of CH5126766 and MEK phosphorus are maintained while maintaining the MEK inhibitory activity of CH4987665. It is possible to obtain the activity of suppressing the enhancement of oxidation (activation of feedback of the MAPK signal pathway).
  • HCT-116 and Colo-205 are human cancer cells having a RAS mutation and a BRAF mutation, respectively.
  • compound AA-2 did not acquire the expected profile.
  • compound AA-1 showed remarkable MEK1 inhibitory activity, BRAF inhibitory activity, HCT-116 growth inhibitory activity and Colo-205 proliferation inhibitory activity.
  • the present inventor has a specific arylamide derivative having RAF / MEK complex stabilizing activity and / or MEK inhibitory activity, and cell proliferation diseases, particularly It has been found to be useful for the treatment or prevention of cancer.
  • (A1) A compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.
  • Ring A has the following general formulas (2), (3), (4) or (5) (where, the bonds with *, ** and *** are -NH-, -CONH- and -CONH-, respectively. It is a group represented by -CH 2-bonded to-) and is represented by.
  • R 2 is a hydrogen atom, a halogen atom or a C1 ⁇ 6 alkyl group
  • R 8 and R 8 is substituted with a hydrogen atom and a C1 to 6 alkyl group (the C1 to 6 alkyl group is substituted with a halogen atom, a hydroxy group, a C1 to 6 alkoxy group, a C3 to 6 cycloalkyl group or a C3 to 6 heterocycloalkyl group).
  • a monocyclic or bicyclic C3 to 6 cycloalkyl group (the C3 to 6 cycloalkyl group may be substituted with a C1 to 6 alkyl group or a C1 to 6 alkoxy group) or. It is a monocyclic or bicyclic C3-6 heterocycloalkyl group.
  • R 3 represents a hydrogen atom, C1 ⁇ 6 alkyl group (said C1 ⁇ 6 alkyl group is a halogen atom may be substituted with a hydroxy group or a C1 ⁇ 6 alkoxy group.), C3 ⁇ 6 cycloalkyl group (said C3 The ⁇ 6 cycloalkyl group may be substituted with a halogen atom or a C1 to 6 alkyl group) or a C1 to 6 alkoxy group (the C1 to 6 alkoxy group is substituted with a halogen atom, a hydroxy group or a C1 to 6 alkoxy group).
  • R 5 is a halogen atom or a C1 ⁇ 6 alkyl group
  • R 6 is a hydrogen atom, a halogen atom or a C1 to 6 alkyl group
  • R 4 is a hydrogen atom, a halogen atom, a C1 to 6 alkyl group, a C2 to 7 alkenyl group, a C2 to 7 alkynyl group, and a C3 to 6 cycloalkyl group.
  • R 7 is a hydrogen atom or a C1-6 alkyl group.
  • R 9 is a hydrogen atom, a halogen atom or a C1-6 alkyl group.
  • Ring A is a group represented by the general formula (2) or (4).
  • R 8 is a hydrogen atom, a C1 to 6 alkyl group (the C1 to 6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1 to 6 alkoxy group) or a monocyclic C3 to 6 cycloalkyl. It is a group (the C3 to 6 cycloalkyl group may be substituted with a C1 to 6 alkyl group).
  • R 3 is a hydrogen atom, a C1 to 6 alkyl group, a C3 to 6 cycloalkyl group or a C1 to 6 alkoxy group (the C1 to 6 alkoxy group may be substituted with a hydroxy group).
  • R 6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group, and R 4 is a halogen atom or a cyclopropyl group.
  • R 7 is a hydrogen atom or a methyl group, The compound, salt or solvate according to (A1).
  • R 2 is a hydrogen atom, a halogen atom or a C1 ⁇ 6 alkyl group
  • R 8 and R 8 is a hydrogen atom, a C1 to 6 alkyl group (the C1 to 6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1 to 6 alkoxy group) or a monocyclic C3 to 6 cycloalkyl. It is a group (the C3 to 6 cycloalkyl group may be substituted with a C1 to 6 alkyl group).
  • R 3 is a hydrogen atom, a C1 to 6 alkyl group, a C3 to 6 cycloalkyl group or a C1 to 6 alkoxy group (the C1 to 6 alkoxy group may be substituted with a hydroxy group).
  • R 5 is a halogen atom or a C1 ⁇ 6 alkyl group
  • R 6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group
  • R 4 is a halogen atom or a cyclopropyl group.
  • R 2 is a hydrogen atom or a halogen atom
  • R 8 is a C1 to 6 alkyl group (the C1 to 6 alkyl group may be substituted with a halogen atom or a C1 to 6 alkoxy group) or a monocyclic C3 to 6 cycloalkyl group (the C3 to 6).
  • the cycloalkyl group may be substituted with a C1-6 alkyl group).
  • R 3 is a hydrogen atom, a C1 to 6 alkyl group, a C3 to 6 cycloalkyl group or a C1 to 6 alkoxy group (the C1 to 6 alkoxy group may be substituted with a hydroxy group).
  • R 5 is a halogen atom
  • R 6 is a hydrogen atom and R 4 is a halogen atom or a cyclopropyl group.
  • R 2 is a hydrogen atom or a fluorine atom.
  • R 8 is a C1 to 4 alkyl group (the C1 to 4 alkyl group may be substituted with a fluorine atom or a C1 to 4 alkoxy group) or a cyclopropyl group (the cyclopropyl group is a C1 to 4 alkyl group). It may be replaced.
  • R 3 is a hydrogen atom, a C1 to 4 alkyl group, a cyclopropyl group or a C1 to 4 alkoxy group (the C1 to 4 alkoxy group may be substituted with a hydroxy group).
  • R 5 is a fluorine atom
  • R 6 is a hydrogen atom and R 4 is an iodine atom or a cyclopropyl group.
  • R 2 is a fluorine atom
  • R 3 is a hydrogen atom or a cyclopropyl group and is
  • R 5 is a fluorine atom
  • R 6 is a hydrogen atom and
  • R 4 is an iodine atom or a cyclopropyl group.
  • the present disclosure also provides the agents according to (A7) to (A10) below.
  • the compound, salt or solvate described in (A7) below includes the compound, salt or solvate described in (A1) to (A6).
  • (A7) A stabilizer for a RAF / MEK complex containing a compound represented by the following general formula (11) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or salt as an active ingredient.
  • Ring A has the following general formulas (2), (3), (4) or (5) (where, the bonds with *, ** and *** are -NH-, -CONH- and -CONH-, respectively. -X 7 -.
  • R 2 is a hydrogen atom, a halogen atom or a C1 ⁇ 6 alkyl group
  • X 7 is-(CH 2 ) m -or -O- and m is 1, 2 or 3.
  • R 3 represents a hydrogen atom
  • C1 ⁇ 6 alkyl group (said C1 ⁇ 6 alkyl group is a halogen atom may be substituted with a hydroxy group or a C1 ⁇ 6 alkoxy group.)
  • C3 ⁇ 6 cycloalkyl group (said C3 The ⁇ 6 cycloalkyl group may be substituted with a halogen atom or a C1 to 6 alkyl group) or a C1 to 6 alkoxy group (the C1 to 6 alkoxy group is substituted with a halogen atom, a hydroxy group or a C1 to 6 alkoxy group).
  • R 5 is a hydrogen atom, a halogen atom or a C1 ⁇ 6 alkyl group
  • R 6 is a hydrogen atom, a halogen atom or a C1 to 6 alkyl group
  • R 4 is a hydrogen atom, a halogen atom, a C1 to 6 alkyl group, a C2 to 7 alkenyl group, a C2 to 7 alkynyl group, and a C3 to 6 cycloalkyl group.
  • R 6 and R 4 forms a together with the carbon atom bonded unsaturated heterocyclic 5-membered ring
  • R 7 is a hydrogen atom or a C1-6 alkyl group
  • R 9 is a hydrogen atom, a halogen atom or a C1-6 alkyl group.
  • Ring A is a group represented by the general formula (2) or (4).
  • X 7 is -CH 2-
  • R 8 is a hydrogen atom, a C1 to 6 alkyl group (the C1 to 6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1 to 6 alkoxy group) or a monocyclic C3 to 6 cycloalkyl. It is a group (the C3 to 6 cycloalkyl group may be substituted with a C1 to 6 alkyl group).
  • R 3 is a hydrogen atom, a C1 to 6 alkyl group, a C3 to 6 cycloalkyl group or a C1 to 6 alkoxy group (the C1 to 6 alkoxy group may be substituted with a hydroxy group).
  • R 5 is a halogen atom or a C1 ⁇ 6 alkyl group
  • R 6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group
  • R 4 is a halogen atom or a cyclopropyl group.
  • R 7 is a hydrogen atom or a methyl group, The stabilizer for the RAF / MEK complex according to (A7).
  • R 2 is a hydrogen atom, a halogen atom or a C1 ⁇ 6 alkyl group
  • R 8 and R 8 is a hydrogen atom, a C1 to 6 alkyl group (the C1 to 6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1 to 6 alkoxy group) or a monocyclic C3 to 6 cycloalkyl. It is a group (the C3 to 6 cycloalkyl group may be substituted with a C1 to 6 alkyl group).
  • R 3 is a hydrogen atom, a C1 to 6 alkyl group, a C3 to 6 cycloalkyl group or a C1 to 6 alkoxy group (the C1 to 6 alkoxy group may be substituted with a hydroxy group).
  • R 5 is a halogen atom or a C1 ⁇ 6 alkyl group
  • R 6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group
  • R 4 is a halogen atom or a cyclopropyl group.
  • R 2 is a hydrogen atom or a halogen atom
  • R 8 is a C1 to 6 alkyl group (the C1 to 6 alkyl group may be substituted with a halogen atom or a C1 to 6 alkoxy group) or a monocyclic C3 to 6 cycloalkyl group (the C3 to 6).
  • the cycloalkyl group may be substituted with a C1-6 alkyl group).
  • R 3 is a hydrogen atom, a C1 to 6 alkyl group, a C3 to 6 cycloalkyl group or a C1 to 6 alkoxy group (the C1 to 6 alkoxy group may be substituted with a hydroxy group).
  • R 5 is a halogen atom
  • R 6 is a hydrogen atom
  • R 4 is a halogen atom or a cyclopropyl group.
  • the present disclosure also provides the compounds, salts or solvates described in (A11)-(A15) below.
  • the compound, salt or solvate described in (A7) includes the compounds, salts or solvates described in the following (A11) to (A15).
  • (A11) N-Cyclopropyl-3,4-difluoro-2- (2-fluoro-4-iodoanilino) -5-[[3-fluoro-2- (methylsulfamoylamino) pyridin-4-yl] methyl] benzamide
  • Compound A-2 2- (2-Fluoro-4-iodoanilino) -5-[[3-Fluoro-2- (methylsulfamoylamino) pyridin-4-yl] methyl] -1-methyl-6-oxopyridine-3-carboxamide
  • Compound J-1 2- (4-Cyclopropyl-2-fluoroanilino) -3,4-
  • the compounds, salts or solvates according to (A1) to (A15) have high RAF / MEK complex stabilizing activity and have cell proliferation diseases, especially cancer (more specifically, for example, RAS mutations). It can be used as an active ingredient of a therapeutic or prophylactic agent for cancer). That is, the present disclosure also provides a pharmaceutical composition containing the compound, salt or solvate according to any one of (A1) to (A15) as an active ingredient. Further, a pharmaceutical composition for treating or preventing a cell proliferation disease, particularly cancer, containing the compound, salt or solvate according to any one of (A1) to (A15) as an active ingredient is provided.
  • the present disclosure also provides the compounds, salts or solvates described in (B1)-(B3) below and the agents described in (B4) below.
  • (B1) A compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.
  • Ring A has the following general formulas (2), (3) or (4) (where, the bonds with *, ** and *** are -NH-, -CONH- and -CH 2-, respectively. It is a group represented by) and is bonded to.
  • R 2 is a hydrogen atom, a halogen atom or a C1 ⁇ 4 alkyl group
  • R 8 and R 8 may be substituted with a C1 to 4 alkyl group (the C1 to 4 alkyl group may be substituted with a halogen atom, a hydroxy group, a C1 to 4 alkoxy group, a C3 to 6 cycloalkyl group or a C3 to 6 heterocycloalkyl group. ) Or a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-4 alkyl group).
  • R 3 is a hydrogen atom, a C3 ⁇ 6 cycloalkyl group or a C1 ⁇ 6 alkoxy group
  • R 5 is a halogen atom
  • R 6 is a hydrogen atom
  • R 4 is a halogen atom or a C3-6 cycloalkyl group
  • R 7 is a C1-4 alkyl group
  • R 9 is a hydrogen atom.
  • (B4) A MEK inhibitor containing the compound, salt or solvate according to any one of (B1) to (B3) as an active ingredient.
  • the compounds, salts or solvates according to (B1) to (B3) have high MEK inhibitory activity and treat cell proliferation diseases, particularly cancers (more specifically, cancers having a RAF mutation, for example). Alternatively, it can be used as an active ingredient of a preventive agent. That is, the present disclosure also provides a pharmaceutical composition containing the compound, salt or solvate according to any one of (B1) to (B3) as an active ingredient. Further, a pharmaceutical composition for treating or preventing a cell proliferation disease, particularly cancer, containing the compound, salt or solvate according to any one of (B1) to (B3) as an active ingredient is provided.
  • Novel RAF / MEK complex stabilizers or MEK inhibitors useful for treatment or prevention are provided.
  • the present disclosure also provides a novel pharmaceutical composition for the treatment or prevention of cell proliferation diseases, particularly cancer, which contains a compound having RAF / MEK complex stabilizing activity and / or MEK inhibitory activity as an active ingredient.
  • FIG. 1 shows a powder X-ray diffraction pattern of sample A-1a (FormI).
  • FIG. 2 shows a powder X-ray diffraction pattern of sample A-1b.
  • FIG. 3 shows a powder X-ray diffraction pattern of sample A-1c.
  • FIG. 4 shows MEK1 added to the surface of the sensor chip on which RAF1 is immobilized together with the test compound (ref-2, ref-3, ref-4, A-1, ref-1, ref-5 or B-1). It is a sensorgram showing the time course of the binding amount of.
  • FIG. 5 shows MEK1 added to the surface of the sensor chip on which RAF1 is immobilized together with the test compound (A-2, A-25, J-1, E-1, M-1, N-1 or H-3).
  • FIG. 6 shows the amount of MEK1 bound to the surface of the sensor chip on which RAF1 is immobilized together with the test compound (I-1, H-4, L-1, P-1, E-7 or A-27). It is a sensorgram showing the transition over time.
  • FIG. 7 shows MEK1 added to the surface of the sensor chip on which RAF1 is immobilized together with the test compound (A-33, A-18, N-2, A-20, A-8, E-13 or H-1). It is a sensorgram showing the time course of the binding amount of.
  • FIG. 6 shows the amount of MEK1 bound to the surface of the sensor chip on which RAF1 is immobilized together with the test compound (I-1, H-4, L-1, P-1, E-7 or A-27). It is a sensorgram showing the transition over time.
  • FIG. 7 shows MEK1 added to the surface of the sensor chip on which RAF1 is immobilized together with the test compound (A-33, A-18, N-2, A-20, A-8, E-13 or H-1).
  • FIG. 8 shows MEK1 added to the surface of the sensor chip on which RAF1 is immobilized together with the test compound (P-2, A-41, E-9, A-6, J-14, A-31 or A-34). It is a sensorgram showing the time course of the binding amount of.
  • FIG. 9 shows MEK1 added to the surface of the sensor chip on which RAF1 is immobilized together with the test compound (A-35, A-30, D-4, A-15, J-8, J-5 or A-4). It is a sensorgram showing the time course of the binding amount of.
  • FIG. 10 is a sensorgram showing the time course of the binding amount of MEK1 added together with the test compound (A-13, E-23 or J-10) on the surface of the sensor chip on which RAF1 is immobilized.
  • FIG. 9 shows MEK1 added to the surface of the sensor chip on which RAF1 is immobilized together with the test compound (P-2, A-41, E-9, A-6, J-14, A-31 or A-34). It is
  • FIG. 11 is a sensorgram showing the change over time in the amount of MEK1 bound to the surface of the sensor chip on which RAF1 is immobilized together with the test compound (ref-4, A-1, P-2 or A-6).
  • FIG. 12 shows the results of Western blotting of proteins (p-MEK, MEK, p-ERK, and ERK) extracted from A549 cells cultured in the presence of the test substance (ref-5 or compound A-1). It is an electrophoretic image.
  • FIG. 13 is a graph showing changes over time in tumor volume (mean ⁇ standard deviation) in nude mice subcutaneously transplanted with the human lung cancer cell line Calu-6.
  • the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the C1 to 6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms.
  • the C2 to 7 alkenyl group means a linear or branched alkenyl group having 2 to 7 carbon atoms.
  • examples thereof include a vinyl group, an allyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a pentanyl group, a pentadienyl group, a hexenyl group, a hexadienyl group, a heptenyl group, a heptadienyl group and a heptatrienyl group.
  • the C2-7 alkynyl group means a linear or branched alkynyl group having 2 to 7 carbon atoms.
  • the group is mentioned.
  • the C1 to 6 alkoxy group means an alkyloxy group having a linear or branched alkyl group having 1 to 6 carbon atoms. Examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentoxy group and an n-hexoxy group.
  • the C1 to 6 alkylthio group means an alkylthio group having a linear or branched alkyl group having 1 to 6 carbon atoms. Examples thereof include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, a sec-butylthio group, a tert-butylthio group, an n-pentylthio group and an n-hexylthio group.
  • the C3 to 6 cycloalkyl group means a cyclic alkyl group having 3 to 6 atoms constituting the ring. It may be monocyclic or bicyclic, but unless otherwise specified, it means monocyclic. Examples of the monocyclic type include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. Examples of the bicyclic type include a bicyclo [1.1.1] pentanyl group and a bicyclo [2.1.1] hexyl group.
  • the C3 to 6 heterocycloalkyl group means a C3 to 6 cycloalkyl group in which at least one of the carbon atoms constituting the ring is replaced with a nitrogen atom, an oxygen atom or a sulfur atom. It may be monocyclic or bicyclic, but unless otherwise specified, it means monocyclic. Examples of the monocyclic group include a tetrahydrofuranyl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group and a morpholinyl group. Examples of the bicyclic type include an oxabicyclo [3.1.0] hexane-6-yl group and an azabicyclo [2.1.1] hexanyl group.
  • the unsaturated hetero 5-membered ring means an unsaturated 5-membered ring containing at least one hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples include furan, thiophene, pyrrole, imidazole and thiazole.
  • pharmaceutically acceptable salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate; methanesulfonate, benzenesulfonic acid.
  • inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate; methanesulfonate, benzenesulfonic acid.
  • Toluene sulfonate and other sulfonates formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandel Carborates such as acid salts, benzoates, salicylates, fluoroacetates, trifluoroacetates, tartrates, propionates, glutarates; lithium salts, sodium salts, potassium salts, cesium salts, rubidium salts, etc.
  • Alkali metal salts such as magnesium salts, calcium salts; and ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, tetraalkylammonium salts and the like.
  • alkali metal salts such as lithium salt, sodium salt, potassium salt, cesium salt and rubidium salt are preferable, and sodium salt and potassium salt are more preferable.
  • the pharmaceutically acceptable solvate is, for example, a solvate with water, alcohol (eg, methanol, ethanol, 1-propanol or 2-propanol), acetone, dimethylformamide or dimethylacetamide. .. It may be a solvate with a single solvent or a solvate with a plurality of solvents. Preferred solvates include, for example, hydrates.
  • the first aspect of the present disclosure provides a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.
  • Ring A has the following general formulas (2), (3), (4) or (5) (where, the bonds with *, ** and *** are -NH-, -CONH- and -CONH-, respectively. It is a group represented by -CH 2-bonded to-) and is represented by.
  • R 2 is a hydrogen atom, a halogen atom or a C1 ⁇ 6 alkyl group
  • R 8 and R 8 is substituted with a hydrogen atom and a C1 to 6 alkyl group (the C1 to 6 alkyl group is substituted with a halogen atom, a hydroxy group, a C1 to 6 alkoxy group, a C3 to 6 cycloalkyl group or a C3 to 6 heterocycloalkyl group).
  • a monocyclic or bicyclic C3 to 6 cycloalkyl group (the C3 to 6 cycloalkyl group may be substituted with a C1 to 6 alkyl group or a C1 to 6 alkoxy group) or. It is a monocyclic or bicyclic C3-6 heterocycloalkyl group.
  • R 3 represents a hydrogen atom, C1 ⁇ 6 alkyl group (said C1 ⁇ 6 alkyl group is a halogen atom may be substituted with a hydroxy group or a C1 ⁇ 6 alkoxy group.), C3 ⁇ 6 cycloalkyl group (said C3 The ⁇ 6 cycloalkyl group may be substituted with a halogen atom or a C1 to 6 alkyl group) or a C1 to 6 alkoxy group (the C1 to 6 alkoxy group is substituted with a halogen atom, a hydroxy group or a C1 to 6 alkoxy group).
  • R 5 is a halogen atom or a C1 ⁇ 6 alkyl group
  • R 6 is a hydrogen atom, a halogen atom or a C1 to 6 alkyl group
  • R 4 is a hydrogen atom, a halogen atom, a C1 to 6 alkyl group, a C2 to 7 alkenyl group, a C2 to 7 alkynyl group, and a C3 to 6 cycloalkyl group.
  • R 7 is a hydrogen atom or a C1-6 alkyl group.
  • R 9 is a hydrogen atom, a halogen atom or a C1-6 alkyl group.
  • the compound, salt or solvate of the first embodiment has high RAF / MEK complex stabilizing activity and is used to treat cell proliferation diseases, especially cancers (more specifically, for example, cancers having RAS mutations). Or it can be used for prevention. In addition, many of them have high MEK inhibitory activity, for example, and such compounds, salts or solvates are also suitable for cancers having, for example, RAF mutations.
  • Ring A is preferably a group represented by the general formula (2) or (4), and more preferably a group represented by the general formula (2).
  • R 2 is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, more preferably a fluorine atom.
  • R 8 is preferably a hydrogen atom, C1 ⁇ 6 alkyl group (said C1 ⁇ 6 alkyl group is a halogen atom, a hydroxyl group or a C1 ⁇ 6 alkoxy group may be substituted.) Or C3 ⁇ monocyclic 6 It is a cycloalkyl group (the C3 to 6 cycloalkyl group may be substituted with a C1 to 6 alkyl group), more preferably a C1 to 6 alkyl group (the C1 to 6 alkyl group is a halogen atom or C1 to C1 to).
  • a C1-4 alkyl group (the C1-4 alkyl group may be substituted with a fluorine atom or a C1-4 alkoxy group) or a cyclopropyl group (the cyclopropyl group is substituted with a C1-4 alkyl group). It may be.), And more preferably it is a C1-4 alkyl group.
  • R 3 is preferably a hydrogen atom, C1 ⁇ 6 alkyl group, C3 ⁇ 6 cycloalkyl group or a C1 ⁇ 6 alkoxy group (said C1 ⁇ 6 alkoxy group may be substituted with a hydroxy group.), More It is preferably a hydrogen atom, a C1 to 4 alkyl group, a cyclopropyl group or a C1 to 4 alkoxy group (the C1 to 4 alkoxy group may be substituted with a hydroxy group), and more preferably a hydrogen atom or a cyclopropyl group. It is a group.
  • R 5 is preferably a halogen atom, more preferably a fluorine atom.
  • R 6 is preferably a hydrogen atom, a halogen atom or a C1 to 6 alkyl group, and more preferably a hydrogen atom.
  • R 4 is preferably a halogen atom or a cyclopropyl group, more preferably an iodine atom or a cyclopropyl group.
  • R 7 is preferably a hydrogen atom or a methyl group.
  • the compound represented by the general formula (1) is preferably, for example, a compound represented by the following general formula (6).
  • R 2 is a hydrogen atom, a halogen atom or a C1 ⁇ 6 alkyl group
  • R 8 and R 8 is a hydrogen atom, a C1 to 6 alkyl group (the C1 to 6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1 to 6 alkoxy group) or a monocyclic C3 to 6 cycloalkyl. It is a group (the C3 to 6 cycloalkyl group may be substituted with a C1 to 6 alkyl group).
  • R 3 is a hydrogen atom, a C1 to 6 alkyl group, a C3 to 6 cycloalkyl group or a C1 to 6 alkoxy group (the C1 to 6 alkoxy group may be substituted with a hydroxy group).
  • R 5 is a halogen atom or a C1 ⁇ 6 alkyl group
  • R 6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group
  • R 4 is a halogen atom or a cyclopropyl group.
  • Examples of the compound represented by the general formula (1) include, for example. N-Cyclopropyl-3,4-difluoro-2- (2-fluoro-4-iodoanilino) -5-[[3-fluoro-2- (methylsulfamoylamino) pyridin-4-yl] methyl] benzamide ( Compound A-2), 2- (2-Fluoro-4-iodoanilino) -5-[[3-Fluoro-2- (methylsulfamoylamino) pyridin-4-yl] methyl] -1-methyl-6-oxopyridine-3-carboxamide (Compound J-1), 2- (4-Cyclopropyl-2-fluoroanilino) -3,4-difluoro-5-[[3-fluoro-2- (methylsulfamoylamino) pyridin-4-yl] methyl] benzamide (Compound A) -1), N-Cyclo
  • N-Cyclopropyl-3,4-difluoro-2- (2-fluoro-4-iodoanilino) -5-[[3-fluoro-2- (methylsulfamoylamino) pyridin-4-yl] methyl] benzamide Compound A-2
  • Compound J-1 2- (4-Cyclopropyl-2-fluoroanilino) -3,4-difluoro-5-[[3-fluoro-2- (methylsulfamoylamino) pyridin-4-
  • the second aspect of the present disclosure is a RAF / containing a compound represented by the following general formula (11) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or salt as an active ingredient.
  • a stabilizer for the MEK complex is provided.
  • R 2 is a hydrogen atom, a halogen atom or a C1 ⁇ 6 alkyl group
  • X 7 is-(CH 2 ) m -or -O- and m is 1, 2 or 3.
  • a monocyclic or bicyclic C3 to 6 cycloalkyl group (the C3 to 6 cycloalkyl group may be substituted with a C1 to 6 alkyl group or a C1 to 6 alkoxy group) or. It is a monocyclic or bicyclic C3-6 heterocycloalkyl group.
  • R 3 represents a hydrogen atom, C1 ⁇ 6 alkyl group (said C1 ⁇ 6 alkyl group is a halogen atom may be substituted with a hydroxy group or a C1 ⁇ 6 alkoxy group.), C3 ⁇ 6 cycloalkyl group (said C3 The ⁇ 6 cycloalkyl group may be substituted with a halogen atom or a C1 to 6 alkyl group) or a C1 to 6 alkoxy group (the C1 to 6 alkoxy group is substituted with a halogen atom, a hydroxy group or a C1 to 6 alkoxy group).
  • R 5 is a hydrogen atom, a halogen atom or a C1 ⁇ 6 alkyl group
  • R 6 is a hydrogen atom, a halogen atom or a C1 to 6 alkyl group
  • R 4 is a hydrogen atom, a halogen atom, a C1 to 6 alkyl group, a C2 to 7 alkenyl group, a C2 to 7 alkynyl group, and a C3 to 6 cycloalkyl group.
  • R 6 and R 4 forms a together with the carbon atom bonded unsaturated heterocyclic 5-membered ring
  • R 7 is a hydrogen atom or a C1-6 alkyl group
  • R 9 is a hydrogen atom, a halogen atom or a C1-6 alkyl group.
  • the compound, salt or solvate of the second embodiment has high RAF / MEK complex stabilizing activity and is used to treat cell proliferation diseases, especially cancers (more specifically, cancers having RAS mutations, for example). Or it can be used for prevention. In addition, many of them have high MEK inhibitory activity, for example, and such compounds, salts or solvates are also suitable for cancers having, for example, RAF mutations.
  • Ring A is preferably a group represented by the general formula (2) or (4), and more preferably a group represented by the general formula (2).
  • R 2 is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, more preferably a fluorine atom.
  • X 7 is preferably -CH 2- .
  • R 8 is preferably a hydrogen atom, C1 ⁇ 6 alkyl group (said C1 ⁇ 6 alkyl group is a halogen atom, a hydroxyl group or a C1 ⁇ 6 alkoxy group may be substituted.) Or C3 ⁇ monocyclic 6 It is a cycloalkyl group (the C3 to 6 cycloalkyl group may be substituted with a C1 to 6 alkyl group), more preferably a C1 to 6 alkyl group (the C1 to 6 alkyl group is a halogen atom or C1 to C1 to).
  • a C1-4 alkyl group (the C1-4 alkyl group may be substituted with a fluorine atom or a C1-4 alkoxy group) or a cyclopropyl group (the cyclopropyl group is substituted with a C1-4 alkyl group). It may be.), And more preferably it is a C1-4 alkyl group.
  • R 3 is preferably a hydrogen atom, C1 ⁇ 6 alkyl group, C3 ⁇ 6 cycloalkyl group or a C1 ⁇ 6 alkoxy group (said C1 ⁇ 6 alkoxy group may be substituted with a hydroxy group.), More It is preferably a hydrogen atom, a C1 to 4 alkyl group, a cyclopropyl group or a C1 to 4 alkoxy group (the C1 to 4 alkoxy group may be substituted with a hydroxy group), and more preferably a hydrogen atom or a cyclopropyl group. It is a group.
  • R 5 is preferably a halogen atom or a C1 ⁇ 6 alkyl group, more preferably a halogen atom, more preferably a fluorine atom.
  • R 6 is preferably a hydrogen atom, a halogen atom or a C1 to 6 alkyl group, and more preferably a hydrogen atom.
  • R 4 is preferably a halogen atom or a cyclopropyl group, more preferably an iodine atom or a cyclopropyl group.
  • R 7 is preferably a hydrogen atom or a methyl group.
  • the compound represented by the general formula (11) is preferably, for example, a compound represented by the following general formula (6).
  • R 2 is a hydrogen atom, a halogen atom or a C1 ⁇ 6 alkyl group
  • R 8 and R 8 is a hydrogen atom, a C1 to 6 alkyl group (the C1 to 6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1 to 6 alkoxy group) or a monocyclic C3 to 6 cycloalkyl. It is a group (the C3 to 6 cycloalkyl group may be substituted with a C1 to 6 alkyl group).
  • R 3 is a hydrogen atom, a C1 to 6 alkyl group, a C3 to 6 cycloalkyl group or a C1 to 6 alkoxy group (the C1 to 6 alkoxy group may be substituted with a hydroxy group).
  • R 5 is a halogen atom or a C1 ⁇ 6 alkyl group
  • R 6 is a hydrogen atom, a halogen atom or a C1-6 alkyl group
  • R 4 is a halogen atom or a cyclopropyl group.
  • Examples of the compound represented by the general formula (11) include, for example. N-Cyclopropyl-3,4-difluoro-2- (2-fluoro-4-iodoanilino) -5-[[3-fluoro-2- (methylsulfamoylamino) pyridin-4-yl] methyl] benzamide ( Compound A-2), 2- (2-Fluoro-4-iodoanilino) -5-[[3-Fluoro-2- (methylsulfamoylamino) pyridin-4-yl] methyl] -1-methyl-6-oxopyridine-3-carboxamide (Compound J-1), 2- (4-Cyclopropyl-2-fluoroanilino) -3,4-difluoro-5-[[3-fluoro-2- (methylsulfamoylamino) pyridin-4-yl] methyl] benzamide (Compound A) -1), N-Cy
  • N-Cyclopropyl-3,4-difluoro-2- (2-fluoro-4-iodoanilino) -5-[[3-fluoro-2- (methylsulfamoylamino) pyridin-4-yl] methyl] benzamide Compound A-2
  • Compound J-1 2- (4-Cyclopropyl-2-fluoroanilino) -3,4-difluoro-5-[[3-fluoro-2- (methylsulfamoylamino) pyridin-4-
  • a third aspect of the present disclosure provides a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.
  • a fourth aspect of the present disclosure provides a MEK inhibitor containing such a compound, salt or solvate as an active ingredient.
  • Ring A has the following general formulas (2), (3) or (4) (where, the bonds with *, ** and *** are -NH-, -CONH- and -CH 2-, respectively. It is a group represented by) and is bonded to.
  • R 2 is a hydrogen atom, a halogen atom or a C1 ⁇ 4 alkyl group
  • R 8 and R 8 may be substituted with a C1 to 4 alkyl group (the C1 to 4 alkyl group may be substituted with a halogen atom, a hydroxy group, a C1 to 4 alkoxy group, a C3 to 6 cycloalkyl group or a C3 to 6 heterocycloalkyl group. ) Or a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-4 alkyl group).
  • R 3 is a hydrogen atom, a C3 ⁇ 6 cycloalkyl group or a C1 ⁇ 6 alkoxy group
  • R 5 is a halogen atom
  • R 6 is a hydrogen atom
  • R 4 is a halogen atom or a C3-6 cycloalkyl group
  • R 7 is a C1-4 alkyl group
  • R 9 is a hydrogen atom.
  • the compound, salt or solvate of the third or fourth aspect has high MEK inhibitory activity and is used to treat or prevent cell proliferation diseases, especially cancers (more specifically, for example, cancers having RAF mutations). Can be used for.
  • Examples of the compound of the third or fourth aspect include, for example, in terms of MEK inhibitory activity and metabolic stability, for example.
  • 2- (4-Cyclopropyl-2-fluoroanilino) -3,4-difluoro-5-[[3-fluoro-2- (methylsulfamoylamino) pyridin-4-yl] methyl] benzamide (Compound A) -1), (+/-) -3,4-difluoro-5-[[3-Fluoro-2- (2-hydroxypropylsulfamoylamino) pyridin-4-yl] methyl] -2- (2-fluoro-4-yl] Iodoanilino) Benzamide (Compound A-17), 3,4-Difluoro-2- (2-fluoro-4-iodoanilino) -5-[[3-fluoro-2- (oxetane-3-ylmethylsulfamoylamino)
  • Boc tert-butoxycarbonyl COMU: (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate
  • DBU diazabicycloundecene
  • DCC N, N'- Dicyclohexylcarbodiimide
  • DCM dichloromethane
  • DIPEA N, N-diisopropylethylamine
  • DMA N, N-dimethylacetamide
  • DMF N, N-dimethylformamide
  • DMSO dimethylsulfoxide
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • EDC HCl 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
  • EtOH Ethanol HATU: O- (7-azabenzotrifluoride
  • R a represents, for example, 4-methylphenyl group or a 2-nitrophenyl group
  • R b represents an example Boc group or a 2,4-dimethoxybenzyl group.
  • Step 1-1 The presence of S N Ar reaction base with aniline derivatives 1b and fluorobenzene derivatives 1a, reacting the aniline derivative 1b fluorobenzene derivative 1a.
  • the base include an organic lithium reagent, and lithium bis (trimethylsilyl) amide and lithium diisopropylamide are preferable.
  • the solvent include polar aprotic solvents such as THF, 1,4-dioxane, and NMP, and THF is preferable.
  • Step 1-2 Methylation of the benzoic acid derivative 1c
  • the benzoic acid derivative 1c is reacted with the methylation reagent.
  • the methylation reagent include a diazomethane derivative, and diazomethyltrimethylsilane is preferable.
  • the solvent include alcohol, a non-polar solvent and a mixed solvent thereof, and a mixed solvent of toluene and methanol and a mixed solvent of THF and methanol are preferable.
  • Step 1-3 Hydrazonization of the aldehyde derivative 1d
  • the aldehyde derivative 1d is reacted with arylsulfonyl hydrazide.
  • arylsulfonyl hydrazide include methylbenzenesulfonyl hydrazide and nitrobenzenesulfonyl hydrazide, with 4-methylbenzenesulfonyl hydrazide and 2-nitrobenzenesulfonyl hydrazide being preferred.
  • the solvent include polar solvents such as alcohol, and methanol and ethanol are preferable.
  • Step 1-4 Coupling of hydrazone derivative 1e and arylboronic acid derivative 1f
  • the hydrazone derivative 1e is reacted with the arylboronic acid derivative 1f in the presence of a base.
  • the base include carbonates and amines, and potassium carbonate and DIPEA are preferable.
  • the solvent include polar solvents such as 1,4-dioxane, DMF, NMP, and THF, and 1,4-dioxane is preferable.
  • the reaction temperature is preferably 80 ° C. or higher.
  • Step 1-5 Deprotection of 1 g of Methyl benzoate derivative
  • the protecting group R b is desorbed by placing 1 g of the methyl benzoate derivative under acidic conditions.
  • the acid include sulfuric acid, hydrochloric acid, methanesulfonic acid and trifluoroacetic acid, and trifluoroacetic acid is preferable.
  • the solvent include alcohol and non-polar solvents such as DCM, and DCM is preferable.
  • Step 1-6 Hydrolysis of the ester derivative 1h
  • the ester derivative 1h is reacted with the hydroxide.
  • the hydroxide include lithium hydroxide, potassium hydroxide and sodium hydroxide, and lithium hydroxide is preferable.
  • the solvent include alcohol, a polar solvent such as THF, water, and a mixed solvent thereof, and an aqueous solution of THF is preferable.
  • Step 1-7 Amidation of Benzoic Acid Derivative 1i
  • the benzoic acid derivative 1i is reacted with the corresponding amine or amine hydrochloride.
  • the corresponding amine or amine hydrochloride may have a Boc group.
  • the condensing agent include DCC, EDC or EDC / HCl, HATU, COMU, and propylphosphonic acid anhydride (cyclic trimmer), and for example, HOOBt or HOAt may be further added as appropriate.
  • a combination of EDC or EDC / HCl and HOOBt, or HATU is used.
  • a base such as DIPEA or triethylamine may be used in addition to the condensing agent, and DIPEA is preferable as the base.
  • the solvent include polar solvents such as DMF, DMA, NMP, methanol and ethanol, and mixed solvents thereof, and DMF is preferable.
  • Step 1-8 Sulfamides or sulfonamides of amine derivatives 1j, 1ja or 1jb Sulfamides: In the presence of a base, the amine derivative 1j, 1ja or 1jb is reacted with the corresponding sulfamoyl chloride or sulfamic acid 4-nitrophenyl.
  • the corresponding sulfamoyl chloride or sulfamic acid 4-nitrophenyl may have a Boc group.
  • the base include amines, with pyridine, triethylamine, DIPEA and imidazole being preferred.
  • the solvent examples include polar solvents such as DMF, DMA, NMP, THF, 1,4-dioxane, acetonitrile and pyridine, non-polar solvents such as dichloromethane and dichloroethane, and mixed solvents thereof. THF and dichloromethane are preferred.
  • the amine derivative 1j, 1ja or 1jb is reacted with the corresponding sulfonyl chloride.
  • the base include amines, with pyridine, triethylamine, DIPEA and imidazole being preferred.
  • the solvent include polar solvents such as DMF, DMA, NMP, THF, 1,4-dioxane, acetonitrile and pyridine, non-polar solvents such as dichloromethane and dichloroethane, and mixed solvents thereof, and dichloromethane and pyridine are used. preferable.
  • Step 1-9-1 If R 1 or R 3 sulfamide or removal of Boc sulfamide or sulfonamide derivatives of sulfonamide derivatives 1k1 1k1 has a Boc group, desorbed the Boc group by placing the compound 1k1 acidic conditions.
  • the acid include sulfuric acid, hydrochloric acid, methanesulfonic acid and trifluoroacetic acid.
  • de-Bocization may be performed by generating an acid in alcohol, for example, chlorotrimethylsilane (TMSCl).
  • TMSCl chlorotrimethylsilane
  • the solvent include alcohol and non-polar solvents such as DCM.
  • TMSCl chlorotrimethylsilane
  • the solvent include alcohol and non-polar solvents such as DCM.
  • the combination of the acid and the solvent for example, a combination of TMSCl and 2,2,2-trifluoroethanol or a combination of trifluoroacetic acid and DCM is preferable.
  • Step 1-9-2 Alkylation of sulfamide or sulfonamide derivatives 1k1, if alkenylation, is R 4 or R 5 alkynyl reduction or thioether sulfamide or sulfonamide derivatives 1k1 is a halogen, for example alkylation in the following way, alkenylation, alkynylation or Thioetherification can be performed.
  • Method 1 Alkylation or alkenylation by Suzuki-Miyaura cross-coupling: In the presence of Pd, compound 1k1 is reacted with the corresponding boronic acid, boronic acid ester or borate.
  • boronic acid boronic acid ester or borate.
  • the base include inorganic salts such as carbonate and hydroxide, and amines such as triethylamine and DIPEA, and sodium carbonate, potassium carbonate and triethylamine are preferable.
  • the solvent examples include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, methanol, ethanol, 2-propanol, and water, and mixed solvents thereof, which include THF and 2-propanol.
  • a mixed solvent and a mixed solvent of THF and water are preferable.
  • Pd and ligand include Chem. Rev. 1995, vol. 95, no. 7, p. 2457, ACC. Chem. Res. , Vol. 40, p. 275, and ACC. Chem. Res. , Vol. 41, p.
  • the ones described in 1461 are mentioned, and PdCl 2 (PPh 3 ) 2 , Pd (PPh 3 ) 4 , and [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride are preferable.
  • the reaction temperature is preferably 80 ° C. or higher.
  • Method 2 Alkylation or alkenylation by Negishi cross-coupling: In the presence of Pd or Ni, compound 1k1 is reacted with the corresponding organozinc reagent.
  • organozinc reagent for example, Tetrahedron. 1992, vol. 48, no. 44, p. 9577 or Aldrichimica Acta. 2005, vol. 38, p. It can be carried out by the method described in 71.
  • the solvent include polar solvents such as THF, 1,4-dioxane, DMF, DMA, and NMP, and mixed solvents thereof, and THF is preferable.
  • Pd and Ni include Tetrahedron. 1992, vol. 48, no. 44, p. 9577 and Aldrichimica Acta. 2005, vol.
  • Method 3 Alkynylation by Sonogashira cross-coupling: In the presence of Pd and Cu, compound 1k1 is reacted with the corresponding alkyne.
  • the corresponding alkyne may have a silyl group and may be, for example, trimethylsilylacetylene.
  • the base include amines such as triethylamine, DIPEA, DBU and piperidine, and inorganic bases such as NaOAc, and triethylamine and DIPEA are preferable.
  • Examples of the Pd catalyst include PdCl 2 (PPh 3 ) 2 , Pd (PPh 3 ) 4 , [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, Pd (OAc) 2 , and Pd. 2 (dba) 3 is mentioned, with PdCl 2 (PPh 3 ) 2 , Pd (PPh 3 ) 4 , and [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride being preferred.
  • Examples of Cu include copper iodide, copper bromide and copper chloride, and copper iodide is preferable.
  • Examples of the solvent include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, DMSO, methanol, ethanol and 2-propanol, and mixed solvents thereof, and THF is preferable.
  • Method 4 In the presence of Pd, compound 1k1 is reacted with the corresponding mercaptan or mercaptan salt.
  • the base include amines such as triethylamine, DIPEA, DBU and piperidine, and triethylamine and DIPEA are preferable.
  • the Pd catalyst include 0-valent Pd complexes typified by Pd (PPh 3 ) 4 , and [(4,5-bis (diphenylphosphino) -9,9-dimethylxanthene) -2- ( 2'-amino-1,1'biphenyl)] palladium (II) methanesulfonate is preferred.
  • solvent examples include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, DMSO, methanol, ethanol and 2-propanol, and mixed solvents thereof, and 1,4-dioxane is preferable. ..
  • Step 1-10 Bromination or chlorination of the amine derivative 1j
  • R 4 or R 5 of the amine derivative 1j is halogen
  • bromination or chlorination can be performed by reacting compound 1j with copper bromide or copper chloride.
  • the solvent include polar solvents such as THF, 1,4-dioxane, DMF, DMA, and NMP, and DMF is preferable.
  • Step 1-11 TBS conversion of the amine derivative 1j
  • TBS conversion can be performed by reacting compound 1j with tert-butyldimethylchlorosilane (TBSCl) in the presence of a base.
  • the base include bases such as triethylamine, DIPEA, and imidazole, and triethylamine is preferable.
  • the solvent include polar solvents such as THF, 1,4-dioxane, DMF, DMA, and NMP, and DMF is preferable.
  • Step 1-12-1 If de-TBS sulfamide or where R 3 of the sulfonamide derivatives 1k2 sulfamide or sulfonamide derivatives 1k2 has a TBS group, desorbed the TBS group by reacting the compound 1k2 and tetrabutylammonium fluoride.
  • the solvent include polar solvents such as THF, 1,4-dioxane and DMF, and THF is preferable.
  • Step 1-12-2 If R 4 or R 5 desilylation sulfamide or sulfonamide derivative 1k2 sulfamide or sulfonamide derivatives 1k2 has a silyl group, desorbed silyl group by reacting the compound 1k2 with a base.
  • the base include carbonate, and potassium carbonate is preferable.
  • the solvent include alcohols such as methanol and ethanol, and methanol is preferable.
  • Step 2-1 Sulfamide formation or sulfonamide formation of the amine derivative 1h is carried out in the same manner as in Step 1-8.
  • Step 2-2 Hydrolysis of the ester derivative 2a is carried out in the same manner as in Step 1-6.
  • Step 2-3 The amidation of the benzoic acid derivative 2b is carried out in the same manner as in Step 1-7. Prior to amidation, optionally, deBocification, alkylation, alkenylation, alkynylation, thioetherification, bromination or chlorination of the benzoic acid derivative 2b is performed in steps 1-9-1, 1-9-2 or It may be carried out in the same manner as 1-10.
  • Step 3-1 Hydrazonization of the aldehyde derivative 1c is carried out in the same manner as in Step 1-3.
  • Process 3-2 The amidation of the benzoic acid derivative 3a is carried out in the same manner as in Step 1-7.
  • Step 3-3 Coupling of the hydrazone derivative 3b with the arylboronic acid derivative 1f, desorption of the protecting group Rb , and sulfamide formation or sulfonamide formation of the amine derivative were carried out in this order in steps 1-4, 1-5 and 1-8, respectively. Do the same.
  • Step 4-1 Alkylation of compound 4a
  • compound 4a is reacted with compound 4b.
  • the base include phosphates and metal alkoxides such as sodium tert-butoxide, with tripotassium phosphate being preferred.
  • potassium iodide or tetrabutylammonium iodide may be added in order to accelerate the reaction, and tetrabutylammonium iodide is preferable as such an additive.
  • the solvent include polar solvents such as NMP and 1,3-dimethyl-2-imidazolidinone, and 1,3-dimethyl-2-imidazolidinone is preferable.
  • the reaction temperature is preferably 40 ° C. or higher.
  • the starting compound or reagent may form a salt or solvate as long as the desired reaction is not inhibited.
  • the compound of the present disclosure When the compound of the present disclosure is obtained as a free form, it can be converted into a pharmaceutically acceptable salt or solvate form according to a conventional method. Further, when the compound of the present disclosure is obtained in the form of a pharmaceutically acceptable salt or solvate, it can be converted into a free form according to a conventional method.
  • Isolation or purification of the compounds, salts or solvates of the present disclosure can be performed, for example, by distillation, recrystallization or chromatography. Also, if isomers (eg, enantiomers, diastereomers or constitutive isomers) are present, their isolation or purification may be, for example, recrystallization, diastereomeric salt method, enzymatic splitting method or chromatography (eg, eg). It can be performed using thin layer chromatography, column chromatography, high performance liquid chromatography or gas chromatography).
  • isomers eg, enantiomers, diastereomers or constitutive isomers
  • isolation or purification may be, for example, recrystallization, diastereomeric salt method, enzymatic splitting method or chromatography (eg, eg). It can be performed using thin layer chromatography, column chromatography, high performance liquid chromatography or gas chromatography).
  • the present disclosure provides a pharmaceutical composition containing the compound, salt or solvate of any one of the first to fourth aspects as an active ingredient.
  • the pharmaceutical compositions of the present disclosure may consist of the compounds, salts or solvates of the present disclosure, as well as other pharmaceutically acceptable ingredients such as excipients, lubricants (coatings). Agents), binders, disintegrants, stabilizers, flavoring agents, bases, dispersants, diluents, surfactants, and emulsifiers, even those containing at least one component selected from the group. good.
  • the present disclosure discloses a cell proliferation disease, particularly a drug for treating or preventing cancer, which contains the compound, salt or solvate of any one of the first to fourth aspects as an active ingredient.
  • the composition is provided.
  • the pharmaceutical compositions for the treatment or prevention of cell proliferative disorders of the present disclosure may consist of the compounds, salts or solvates of the present disclosure, as well as other pharmaceutically acceptable components such as, for example. At least one selected from the group consisting of excipients, lubricants (coatings), binders, disintegrants, stabilizers, flavoring agents, bases, dispersants, diluents, surfactants, and emulsifiers. It may contain the component of.
  • excipients examples include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and calcium hydrogen phosphate.
  • lubricant examples include ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, shellac, talc, carnauba wax, and paraffin.
  • binder examples include polyvinylpyrrolidone and macrogol, as well as compounds similar to the above-mentioned excipients.
  • disintegrant examples include chemically modified starches and celluloses such as croscarmellose sodium, carboxymethyl starch sodium, and crosslinked polyvinylpyrrolidone, as well as compounds similar to the above-mentioned excipients.
  • the stabilizer examples include paraoxybenzoic acid esters such as methylparaben and propylparaben; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.
  • flavoring agent examples include commonly used sweeteners, acidulants and flavors.
  • Examples of the base include fats such as pork fat; vegetable oils such as olive oil and sesame oil; higher alcohols such as stearyl alcohol and cetanol; animal oils; lanolinic acid; petrolatum; paraffin; bentonite; glycerin; and glycol oil. ..
  • Dispersants include, for example, cellulose derivatives (eg, gum arabic, tragant, and methylcellulose), polyester stearate, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, and sorbitan fatty acid esters. ..
  • solvent or diluent in the liquid preparation examples include phenol, chlorocresol, purified water, and distilled water.
  • surfactant or emulsifier examples include polysorbate 80, polyoxyl 40 stearate, and lauromacrogol.
  • the subject to which the compound, salt or solvate of the present disclosure is administered is an animal, preferably a mammal (eg, mouse, rat, rabbit, dog, monkey (eg, cynomolgus monkey) or human), particularly preferably a human.
  • a mammal eg, mouse, rat, rabbit, dog, monkey (eg, cynomolgus monkey) or human
  • Humans may be adults (18 years or older) or children (under 18 years). Children are preferably, for example, 6 months or older.
  • the dose and the administration interval depend on the degree of symptoms, the age and weight of the subject to be administered, the presence or absence of concomitant drugs, the administration method, and the like. It can be determined as appropriate.
  • the administration subject is a human
  • an amount of 0.00001 to 5000 mg, preferably 0.01 to 100 mg per 1 kg of body weight is usually administered once every 1 day to 3 weeks.
  • the above dose may be administered in 2 to 4 divided doses.
  • Examples of the administration method to the subject include systemic administration such as oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intracisional administration, intravaginal administration, intraperitoneal administration, intravesical administration, and inhalation administration. And topical administration with an ointment, gel or cream, but oral administration is preferred.
  • the compound, salt or solvate of the present disclosure is usually used by being formulated into a certain formulation (dosage form).
  • formulations include, for example, tablets, capsules, granules, powders, fine granules, pills, and aqueous or non-aqueous solutions and suspensions. Solutions and suspensions can be packed and stored in containers suitable for subdivision into individual doses.
  • the above-mentioned various formulations can be produced by a well-known method by mixing the compound, salt or solvate of the present disclosure with a pharmaceutically acceptable additive.
  • additives include, for example, the above-mentioned excipients, lubricants (coatings), binders, disintegrants, stabilizers, flavoring agents, bases, dispersants, diluents, surfactants, etc. And emulsifiers.
  • the preferable content ratio of the compound, salt or solvate of the present disclosure in the pharmaceutical product varies depending on the dosage form, but is usually 0.01 to 100% by weight based on the total weight of the pharmaceutical product.
  • Cell proliferation diseases treated or prevented using the compounds, salts or solvates of the present disclosure include cancer, rheumatism and inflammation, which are preferred cancers.
  • cancer examples include leukemia (acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.), malignant lymphoma (Hodgkin's disease, non-Hodgkin's lymphoma, etc.), multiple myeloma, and myelodystrophy.
  • Blood and lymph cancers such as plastic syndrome; cancers of the central nervous system such as brain tumors and gliomas; as well as head and neck cancers (pharyngeal cancer, laryngeal cancer, tongue cancer, etc.), esophageal cancer, gastric cancer, colon cancer (cementitis) Cancer, colon cancer, rectal cancer, etc.), lung cancer (small cell cancer, non-small cell cancer, etc.), thyroid cancer, breast cancer, cholecyst cancer, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer, uterine cancer (endometrial cancer, Cervical cancer, etc.), testis cancer, renal cell cancer, bladder cancer, renal pelvis / urinary tract cancer, malignant melanoma, skin cancer (basal cell cancer, spinous cell cancer, extramammary Paget's disease, Mercel cell cancer, sweat adenocarcinoma)
  • solid cancers such as apocrine adenocarcinoma or ecculin adenocarcino
  • Cancer may have a gene mutation, no gene mutation, or it may be unknown whether it is either.
  • genes that cause mutations include EGFR, FGFR, ALK, ROS1, PI3K, BRAF, HRAS, KRAS and NRAS.
  • the cancer for example, a cancer having a RAS mutation is preferable, and for example, a solid cancer having a KRAS mutation (particularly non-small cell lung cancer) is particularly preferable. preferable. In one embodiment, it is also used for cancers having RAF mutations, particularly cancers having RAF mutations and RAS mutations.
  • a cancer having a RAF mutation is preferable, and for example, a solid cancer having a BRAF mutation (particularly malignant melanoma) is particularly preferable. ..
  • the mass spectrometric data includes a single quadrupole mass spectrometer (LCMS-2020) with ultra-high performance liquid chromatography (Nexera UC) manufactured by Shimadzu Corporation or an accuracy ultra-high performance liquid chromatography (UPLC or UPLC I-Class) manufactured by Waters. Obtained using a single quadrupole mass spectrometer (SQD or SQD2).
  • LCMS-2020 single quadrupole mass spectrometer
  • UPLC or UPLC I-Class ultra-high performance liquid chromatography
  • the microwave reaction was carried out using an Initiator manufactured by Biotage. A snap cap reaction vial was used for the microwave reaction.
  • room temperature means a temperature of about 20 ° C to about 25 ° C.
  • production example of compound A-1 means production example A-1-1
  • production example of compound a9 means production example a9-1.
  • Tetrakis (triphenylphosphine) palladium (0) (11.2 mg, 9.68 ⁇ mol) and 0.5 M cyclopropyl zinc bromide (1.94 mL, 0.969 mmol) were added to an anhydrous THF solution (1.9 mL) of 194 mmol). The mixture was stirred at room temperature for 2.5 hours under a nitrogen atmosphere. Ethyl acetate (5 mL) was added to the reaction mixture, and the mixture was filtered through Celite and washed with ethyl acetate (3 mL).
  • Tris (dibenzylideneacetone) dipalladium (0) (14.9 g, 16.3 mmol) and toluene (540 mL) were added, and the mixture was further degassed under reduced pressure and replaced with nitrogen.
  • the mixture was heated to an outside temperature of 120 ° C. under a nitrogen atmosphere and stirred for 7 hours.
  • the outside temperature was cooled to room temperature, the reaction mixture was filtered and washed with toluene (450 mL).
  • Activated carbon (9.00 g, 749 mmol) was added to the filtrate, and the mixture was stirred at room temperature for 1 hour.
  • sample A-1b To compound A-1 (53.6 mg), a 20% sodium ethoxide ethanol solution (0.054 mL) and methyl isobutyl ketone (0.161 mL) were added, and the mixture was stirred at room temperature for 30 minutes. Methyl isobutyl ketone (0.161 mL) was then added and stirred at 60 ° C. for 4 days. Then, DMSO (0.054 mL) was added, and the mixture was stirred at 60 ° C. for 5 hours to obtain a sodium salt (25.6 mg) of compound A-1 as powdery crystals (Sample A-1b).
  • sample A-1c DMSO (4.26 mL) and 2M aqueous sodium hydroxide solution (1.07 mL) were added to compound A-1 (1.02 g). The solution was lyophilized at ⁇ 20 ° C. for 4 days and then vacuum dried at room temperature for 3 days. 1-Pentanol (10.0 mL) was added to the obtained solid, and the mixture was stirred at 80 ° C. for 10 minutes. Then, the mixture was stirred at room temperature for 6 hours to obtain a sodium salt (0.966 g) of compound A-1 as powdery crystals (Sample A-1c).
  • Sample A-1a (FormI)
  • Sample A-1b and Sample A-1c were subjected to powder X-ray diffraction measurement under the following conditions.
  • Measuring device SmartLab, D / Tex Ultra detector (manufactured by Rigaku)
  • Anti-cathode Cu Tube voltage: 45kV Tube current: 200mA Sampling width: 0.02 °
  • FIGS. 1 to 3 The results of powder X-ray diffraction measurement are shown in FIGS. 1 to 3.
  • FIG. 1 shows a powder X-ray diffraction pattern of sample A-1a (FormI).
  • FIG. 2 shows a powder X-ray diffraction pattern of sample A-1b.
  • FIG. 3 shows a powder X-ray diffraction pattern of sample A-1c.
  • the horizontal axis (X-axis) represents the diffraction angle 2 ⁇ (°)
  • the vertical axis (Y-axis) represents the diffraction intensity.
  • Measuring device Dionex ICS-1600, AS-AP (manufactured by Thermo Fisher Scientific) Column: Dionex IonPac CG16 (5 x 50 mm) / CS16 (5 x 250 mm) (manufactured by Thermo Fisher Scientific) Eluent: 30 mmol / L methanesulfonic acid solution Suppressor: Dionex CERS-500 4 mm, 88 mA (manufactured by Thermo Fisher Scientific) Column temperature: 40 ° C Eluent flow rate: 1.00 mL / min Sample injection volume: 10 ⁇ L Detector: Electrical conductivity detector Sample treatment: Sample A-1a is suspended in a 20 mmol / L methanesulfonic acid solution at a concentration of 0.5 mg / mL, shaken for 17 hours and stirred to extract sodium ions, and the supernatant is obtained. Was measured.
  • Compound B-8 3,4-Difluoro-2- (2-fluoro-4-iodoanilino) -5-[[3-fluoro-2- (propylsulfonylamino) pyridin-4-yl] methyl] benzamide 5-[(2-Amino-3-fluoropyridin-4-yl) methyl] -3,4-difluoro-2- (2-) under the same conditions as in the production examples of Compound A-25, Compound b2 and Compound a8.
  • the title compound was synthesized from methyl benzoate (compound a6) and the corresponding sulfonyl chloride.
  • Compound B-12 2- (2-Chloro-4-iodoanilino) -N-cyclopropyl-5-[[2- (cyclopropylsulfamoylamino) -3-fluoropyridin-4-yl] methyl] -3,4-difluorobenzamide 5-[(2-Amino-3-fluoropyridin-4-yl) methyl] -2- (2-chloro-4-iodoanilino) under the same conditions as in the production examples of Compound A-1, Compound b2 and Compound a8.
  • Compound B-13 2- (2-Chloro-4-iodoanilino) -5-[[2- (cyclopropylsulfamoylamino) -3-fluoropyridin-4-yl] methyl] -3,4-difluoro-N-[(2) -Methylpropane-2-yl) oxy] benzamide 5-[(2-Amino-3-fluoropyridin-4-yl) methyl] -2- (2-chloro-4-iodoanilino) under the same conditions as in the production examples of Compound A-1, Compound b2 and Compound a8.
  • Compound B-16 5-[[2- (Ethylsulfonylamino) -3-fluoropyridin-4-yl] methyl] -3,4-difluoro-2- (2-fluoro-4-iodoanilino) -N-methoxybenzamide 5-[(2-Amino-3-fluoropyridin-4-yl) methyl] -3,4-difluoro-2- (2-) under the same conditions as in the production examples of Compound A-25, Compound b2 and Compound a12. The title compound was synthesized from methyl benzoate (compound a6) and the corresponding sulfonyl chloride.
  • Lithium hydroxide monohydrate (7.9 mg, 0.19 mmol) was added to a mixed solution of THF (0.7 mL) and water (0.3 mL) of 038 mmol), and the mixture was stirred at room temperature for 2 hours.
  • the reaction mixture was concentrated under reduced pressure, 1 M hydrochloric acid (0.76 mL) was added, and the mixture was further concentrated under reduced pressure.
  • HOOBt (9.3 mg, 0.057 mmol) and EDC ⁇ HCl (10.9 mg, 0.057 mmol) were added to an anhydrous DMF solution (0.3 mL) of the obtained mixture, and the mixture was stirred at room temperature for 3 hours.
  • reaction mixture was added to a THF solution (9.0 mL) of 2,3,4-trifluorobenzoic acid (1.50 g, 8.52 mmol) at ⁇ 78 ° C., stirred for 10 minutes, then anhydrous DMF (0.759 mL, 0.759 mL,). 9.80 mmol) was added, and the mixture was stirred at 0 ° C. for 2 hours.
  • a THF solution (30 mL) of benzo [b] thiophenone-5-amine (1.65 g, 11.1 mmol) was cooled to ⁇ 78 ° C.
  • reaction mixture was added to an anhydrous THF solution (15 mL) of 1,2,3-trifluoro-4-[(4-methoxyphenyl) methoxy] benzene (compound h9, 3.00 g, 11.2 mmol) at ⁇ 78 ° C.
  • the mixture was stirred for 3 hours and then for 30 minutes while injecting carbon dioxide gas.
  • 1M Hydrochloric acid 60 mL was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, the desiccant was removed, and the mixture was concentrated under reduced pressure.
  • the title compound was synthesized from iodoanilino) -5-methyl-6-oxopyridine-3-carboxylate (compound p10). However, a 1M aqueous sodium hydroxide solution was used instead of the lithium hydroxide monohydrate used in the production example of compound b2, and the corresponding amine was used instead of the 7M ammonia MeOH solution used in the production example of compound K-10. .. LCMS m / z: 634 [M + H] + HPLC retention time: 0.67 minutes (analysis condition C)
  • reaction mixture was washed with 1M hydrochloric acid and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to give the title compound (4.0 g, 33%) as a white solid.
  • RAF1 (Carna Biosciences) fused with GST tags was immobilized on the surface of Sensor Chip CM5 (GE Healthcare) using Anti-GST Antibody (GE Healthcare). Then, a running buffer (blank), a 40 nM MEK1 solution, or a mixed solution of 40 nM MEK1 and a 3 ⁇ M test compound was flowed on the surface of the sensor chip for 120 seconds, and then a running buffer was flowed. As MEK1, MEK1 Recombinant Humanprotein, Inactive (Thermo Fisher Scientific) was used.
  • the obtained sensorgram (a graph showing the change over time in the amount of MEK1 bound to the immobilized RAF1) was double-referenced (double-referencing) with Biacore Insight Software, and further, RAF1 was used with TIBCO Spotfire.
  • the sensorgram was normalized by the amount of immobilization. Normalized sensorgrams are shown in FIGS. 4-11. On each sensor gram, the experiment ID, the channel number in Viacore, and the compound number are written in order (however, "no compound” indicates that the test compound does not exist).
  • the horizontal axis (X-axis) represents the time (seconds) after the start of addition of the sample solution
  • the vertical axis (Y-axis) represents the normalized MEK1 binding amount.
  • A549 cells were seeded in 12-well plates so that the number of cells per well was 400,000, and in a 5% carbon dioxide incubator at 37 ° C., using Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (manufactured by Sigma). It was cultured. The next day, the test compound (0.3 ⁇ M ref-5 or 0.05 ⁇ M compound A-1) or DMSO was added to the medium, and after culturing for 30 minutes or 2 hours, the cells were collected with a cell scraper and solubilized. The extracted protein was separated by SDS-PAGE and transferred to a PVDF membrane.
  • FIG. 12 is an electrophoretic image showing the result of Western blotting.
  • Phospho-MEK1 / 2 Ser217 / 221
  • MEK1 / 2 antibody Phospho-ERK1 / 2 (Thr202 / Tyr204) antibody
  • ERK1 / 2 antibody all manufactured by Cell Signaling Technology.
  • HRP-labeled secondary antibody manufactured by Cell Signaling Technology
  • FIG. 12 is an electrophoretic image showing the result of Western blotting.
  • "p-MEK” and "p-ERK” represent phosphorylated MEK and phosphorylated ERK, respectively.
  • test compounds CRAF (Thermo Fisher), MEK1 (Thermo Fisher) and ERK2 (Carna Biosciences) were mixed in a buffer containing ATP and reacted at 30 ° C. for 60 minutes. Then, FAM-labeled Erktide (manufactured by Molecular Devices) was added and reacted at 30 ° C. for 45 minutes. Further, IMAP (registered trademark) Progressive Binding Reagent (manufactured by Molecular Devices) was added, and the mixture was reacted at room temperature for 15 minutes. After the reaction, the fluorescent polarized light was measured with a fluorescent plate reader, and the 50% inhibition concentration (IC 50 ) was calculated based on the inhibition rate for the control group containing no test compound. The results are shown in Table 3.
  • test compounds BRAF (manufactured by Eurofin) and MEK1 (manufactured by Thermo Fisher) were mixed in a buffer containing ATP and reacted at 30 ° C. for 90 minutes. Then, LANCE® Eu-Phospho-MEK1 / 2 (Ser217 / 221) antibody (manufactured by PerkinElmer) was added and reacted at room temperature for 60 minutes. After the reaction, the fluorescence resonance energy transfer was measured with a fluorescent plate reader, and the 50% inhibition concentration (IC 50 ) was calculated based on the inhibition rate for the control group containing no test compound. The results are shown in Table 3.
  • test compound was serially diluted with DMSO, then diluted 25-fold with Ca 2+ , Mg 2+ -free phosphate buffered saline, and 5 ⁇ L per well was dispensed into a 96-well plate.
  • reaction solution 50 ⁇ L was added to acetonitrile (100 ⁇ L) to stop the metabolic reaction.
  • a 1 ⁇ M warfarin aqueous solution 50 ⁇ L was added as an internal standard to each reaction solution in which the metabolic reaction was stopped.
  • the reaction solution is filtered and LC / MS / MS (LC: NEXTERA manufactured by SHIMADZU; MS: 4000 Qtrap manufactured by ABSicex; column: Ascentis Express C18 HPLC column (5 cm ⁇ 2.1 mm, 2.7 ⁇ m); ionization method: electrospray ionization method. ) was used for analysis.
  • a human lung cancer cell line Calu-6 having a KRAS mutation was subcutaneously injected into a cell suspension on the ventral side of a nude mouse (CANN. Cg-Foxn1nu / CrlCrlj, female, 5 weeks old, Charles River) with a 26G injection needle. It was transplanted into mice by injection. At 17 days after transplantation when the tumor volume reached about 200 mm 3 , the mice were divided into 5 groups (8 animals in each group) according to the dose of the test compound, and the administration of the test compound was started.
  • mice in group 4 For mice in group 4 (A-1 administration group), 0.0625 mg / kg, 0.25 mg each time using 10% DMSO / 10% Cremophor EL / 15% PEG400 / 15% HPCD as a solvent (vehicle). / Kg, 1 mg / kg or 4 mg / kg of compound A-1 was orally administered. Only the above solvent was orally administered to the remaining 1 group (solvent control group) of mice. Administration of the test compound or solvent was performed once a day for 10 days.
  • Tumor volumes were measured 20 days, 24 days and 27 days after transplantation.
  • the tumor volume was calculated according to the following formula after measuring the major axis and the minor axis of the tumor using a caliper.
  • the results are shown in FIG.
  • FIG. 13 is a graph showing changes over time in tumor volume (mean ⁇ standard deviation).
  • the horizontal axis (X-axis) represents the number of days after transplantation, and the vertical axis (Y-axis) represents the tumor volume.
  • Tumor volume (mm 3 ) 1/2 x major axis (mm) x minor axis (mm) x minor axis (mm)
  • the compounds, salts or solvates of the present disclosure, RAF / MEK complex stabilizers, MEK inhibitors, pharmaceutical compositions, and pharmaceutical compositions for the treatment or prevention of cell proliferation disorders are described in cell proliferation disorders, in particular. It can be used for the treatment or prevention of illness.

Abstract

La présente divulgation concerne, par exemple, une composition pharmaceutique destiné à traiter ou prévenir des maladies à prolifération cellulaire, la composition pharmaceutique destinée à traiter ou prévenir des maladies à prolifération cellulaire contenant, en tant que principe actif, un composé représenté par la formule générale (6) suivante [dans laquelle X1, X2, X3 et X4 représentent indépendamment -CR2=, ou -N=, R 2 représente, par exemple, un atome d'halogène, R1 représente, par exemple, -S(=O)2-NH-R8, R8 représente, par exemple, un groupe alkyle en C1-6, R3 représente, par exemple, un atome d'hydrogène, R5 représente, par exemple, un atome d'halogène, R6 représente, par exemple, un atome d'hydrogène et R4 représente, par exemple, un groupe cyclopropyle] ou un sel de qualité pharmaceutique de celui-ci, ou un solvate de qualité pharmaceutique d'un composé ou d'un sel susmentionné.
PCT/JP2020/028575 2020-07-22 2020-07-22 Composition pharmaceutique contenant un dérivé d'arylamide pour traiter ou prévenir des maladies à prolifération cellulaire WO2022018875A1 (fr)

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KR1020210095267A KR102550455B1 (ko) 2020-07-22 2021-07-21 아릴 아마이드 유도체를 포함하는 세포 증식성 질환의 치료 또는 예방용 의약 조성물
JP2021121960A JP7168734B2 (ja) 2020-07-22 2021-07-26 アリールアミド誘導体を含む細胞増殖性疾患の治療又は予防用医薬組成物
JP2022172687A JP2023011759A (ja) 2020-07-22 2022-10-27 アリールアミド誘導体を含む細胞増殖性疾患の治療又は予防用医薬組成物
KR1020230081877A KR20230098762A9 (ko) 2020-07-22 2023-06-26 아릴 아마이드 유도체를 포함하는 세포 증식성 질환의 치료 또는 예방용 의약 조성물

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WO2024010925A3 (fr) * 2022-07-08 2024-03-21 Nested Therapeutics, Inc. Inhibiteurs de protéine kinase activée par mitogène (mek)

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JPWO2022018875A1 (fr) 2022-01-27
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