JP2023011759A - Arylamide derivative-containing pharmaceutical composition for treating or preventing cell proliferation diseases - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel pharmaceutical composition that contains, as an active ingredient, a compound with RAF/MEK complex stabilization activity and/or MEK inhibitory activity for treating or preventing cell proliferation diseases, particularly cancer.

SOLUTION: The present invention provides a pharmaceutical composition for treating or preventing cell proliferation diseases, comprising a compound represented by e.g. the general formula (6) [where X₁, X₂, X₃ and X₄ each independently represent -CR₂= or -N=], a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt as an active ingredient.

SELECTED DRAWING: None

COPYRIGHT: (C)2023,JPO&INPIT

Description

The present disclosure provides arylamide derivatives that have RAF/MEK complex stabilizing activity and/or MEK inhibitory activity and are useful for the treatment or prevention of cell proliferative diseases, particularly cancer, and such arylamide derivatives are effective. It relates to a RAF/MEK complex stabilizer or MEK inhibitor contained as an ingredient. The present disclosure also relates to a pharmaceutical composition for treating or preventing cell proliferative diseases, particularly cancer, containing such an arylamide derivative as an active ingredient.

MEK (mitogen-activated protein kinase kinase) is a serine-threonine kinase in the MAPK signaling pathway, and is known to transmit intracellular signals and be deeply involved in cell growth (see Non-Patent Document 1). ). As MEK inhibitors, PD0325901, CH4987655, trametinib, cobimetinib, selumetinib, etc. have been reported (see Patent Document 1 and Non-Patent Document 2). , for example, has been reported to show clinical efficacy against malignant melanoma with BRAF mutation (see Non-Patent Documents 3 and 4).

On the other hand, it is known that some MEK inhibitors are not necessarily clinically effective against RAS-mutated cancers, such as RAS-mutated non-small cell lung cancer. In fact, it has been reported that selumetinib and trametinib had poor efficacy in clinical trials of non-small cell lung cancer with KRAS mutations (see Non-Patent Documents 5 and 6).

CH5126766 (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 of the RAF/MEK complex, has been clinically demonstrated in non-small cell lung cancer with RAS mutations. It has been reported that the above effects are exhibited (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 signaling pathway) (see Non-Patent Document 10) (Non-Patent Document 7). and 8). This feedback activation is considered to be one of the reasons why the clinical effects of MEK inhibitors against cancers with RAS mutations are not necessarily sufficient (see Non-Patent Document 10).

WO2006/011466 WO2007/091736

Nature. 2018, vol. 15, p. 709-720 Molecules. 2017, vol. 22, e1551 N. Engl. J. Med. 2012, vol. 367, p. 107-114 N. Engl. J. Med. 2012, vol. 367, p. 1694-1703 JAMA. 2017, vol. 317, no. 18, p. 1844-1853 Ann. Oncol. 2015, vol. 26, no. 5, p. 894-901 Cancer Res. 2013, vol. 73, no. 13, p. 4050-4060 Cancer Cell. 2014, vol. 25, no. 5, p. 697-710 J. Clin. Oncol. 2017, vol. 35, no. 15, suppl. , 2506 Nat. Rev. Clin. Oncol. 2014, vol. 11, p. 385-400

Although some RAF/MEK complex stabilizers or MEK inhibitors are known to be useful in the treatment or prevention of cell proliferative disorders, particularly cancer, there are still insufficient to meet diverse consumer needs. The reality is that we cannot say that there are alternatives.

Therefore, the present disclosure provides novel compounds that have RAF/MEK complex stabilizing activity and/or MEK inhibitory activity and are useful for the treatment or prevention of cell proliferative diseases, particularly cancer, or cell proliferative diseases, particularly cancer. An object of the present invention is to provide a novel RAF/MEK complex stabilizer or MEK inhibitor useful for the treatment or prevention of cancer. In addition, the present disclosure provides a novel pharmaceutical composition for treating or preventing cell proliferative diseases, particularly cancer, containing a compound having RAF/MEK complex stabilizing activity and/or MEK inhibitory activity as an active ingredient. for the purpose.

In order to create novel compounds as described above, the present inventor focused on CH4987655 below, which is a known MEK inhibitor, and CH5126766, below, which is a known RAF/MEK complex stabilizer.

CH4987655 exhibits comparable MEK inhibitory activity in non-cell systems but slower disengagement from MEK when compared to another MEK inhibitor, PD0325901. And, in cynomolgus monkey peripheral blood, it exhibits stronger MEK inhibitory activity (lower _IC50 ) than PD0325901, and achieves longer-lasting MEK inhibition. They are believed to be attributed to characteristic substituents, including the 3-oxo-[1,2]oxazinane ring structure, present at the 5′ position of the benzamide backbone of CH4987655 (Bioorg. Med. Chem. Lett.2011, vol.21, no.6, p.1795-1801).

CH5126766 forms a unique structural complex with MEK. Thus, when CH5126766 binds to MEK, the MEK activation segment is translocated, with Asn221 and Ser222 of MEK being spatially positioned differently than when PD0325089 (an enantiomer of PD0325901) is bound. In the conjugate, the sulfamide group of CH5126766 hydrogen bonds directly to Asn221 of MEK and to Ser222 via water. Since Ser222 is one of the two amino acids phosphorylated by RAF, the effects of CH5126766 on stabilizing the RAF/MEK complex and enhancing MEK phosphorylation (feedback activation of the MAPK signaling pathway) suppressing effects of such It is believed that this is due to the complex structure (Cancer Cell. 2014, vol. 25, no. 5, p. 697-710 (see Non-Patent Document 8)).

CH4987655, when bound to MEK, results in a spatial arrangement of Asn221 and Ser222 similar to CH5126766. 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 believed that this is due to such a complex structure (Cancer Cell. 2014, vol. 25, no. 5, pp. 697-710 (see Non-Patent Document 8)).

CH4987655 differs from CH5126766 in that it does not interact remotely with Ser222 and interacts weakly with Asn221 via the 3-oxo-[1,2]oxazinane ring structure. On the other hand, CH5126766 does not interact with Lys97 unlike MEK inhibitors such as CH4987655 and PD0325901.

The inventor made the following two hypotheses based on the above analysis.
(Hypothesis 1) If a chemical structure capable of hydrogen bonding with Lys97 is introduced into CH5126766, the RAF/MEK complex stabilizing activity of CH5126766 and the enhancement of MEK phosphorylation (feedback activation of the MAPK signaling pathway) suppressing activity are maintained. While, MEK inhibitory activity equivalent to CH4987655 can be acquired.
(Hypothesis 2) If a chemical structure capable of forming a strong hydrogen bond with Asn221 and Ser222 is introduced into CH4987655, the MEK inhibitory activity possessed by CH4987655 is maintained, while the RAF/MEK complex stabilizing activity and MEK phosphorylation activity equivalent to those of CH5126766 are maintained. Suppressive activity for enhancing oxidation (feedback activation of MAPK signaling pathway) can be acquired.

In the complex of CH4987655 and MEK, the hydroxamate structure of CH4987655 interacts with Lys97 of MEK. Therefore, based on hypothesis 1, the following compound AA-2 was produced by introducing a substituent having a hydroxamate structure into the structure of CH5126766.

In the complex of CH5126766 and MEK, the sulfamide structure of CH5126766 interacts with Asn221 and Ser222 of MEK. Therefore, based on Hypothesis 2, the following compound AA-1 was produced in which a sulfamide structure was introduced at the terminal site of the structure corresponding to the 5' side chain of CH4987655.

MEK1 inhibitory activity (IC ₅₀ ), BRAF inhibitory activity (IC ₅₀ ), HCT-116 growth inhibitory activity (IC ₅₀ ) and/or Colo-205 growth inhibitory activity (IC ₅₀ ) for compound AA-2 and compound AA-1 was measured in the same manner as in Test Examples 3, 4 or 5 described later (HCT-116 and Colo-205 were obtained from ATCC). The results are shown in Table 1 below. HCT-116 and Colo-205 are human cancer cells with RAS and BRAF mutations, respectively.

As evident from Table 1, compound AA-2 did not acquire the expected profile. On the other hand, compound AA-1 showed significant MEK1 inhibitory activity, BRAF inhibitory activity, HCT-116 growth inhibitory activity and Colo-205 growth inhibitory activity.

As a result of intensive studies using compound AA-1 as a lead compound, the present inventors have found that a specific arylamide derivative has RAF/MEK complex stabilizing activity and/or MEK inhibitory activity, cell proliferative diseases, particularly We have found that it is useful for the treatment or prevention of cancer.

［式中、
環Ａは、下記一般式（２）、（３）、（４）又は（５）（ここで、＊、＊＊及び＊＊＊が付された結合手はそれぞれ－ＮＨ－、－ＣＯＮＨ－及び－ＣＨ_２－に結合している。）で表される基であり、

Ｘ_１、Ｘ_２、Ｘ_３、Ｘ_４、Ｘ_５及びＸ_６は各々独立して－ＣＲ_２＝又は－Ｎ＝であり、
Ｒ_２は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、
Ｒ_１は－Ｓ（＝Ｏ）_２－ＮＨ－Ｒ_８又は－Ｓ（＝Ｏ）_２－Ｒ_８であり、
Ｒ_８は、水素原子、Ｃ１～６アルキル基（当該Ｃ１～６アルキル基はハロゲン原子、ヒドロキシ基、Ｃ１～６アルコキシ基、Ｃ３～６シクロアルキル基又はＣ３～６ヘテロシクロアルキル基で置換されていてもよい。）、単環式若しくは二環式のＣ３～６シクロアルキル基（当該Ｃ３～６シクロアルキル基はＣ１～６アルキル基又はＣ１～６アルコキシ基で置換されていてもよい。）又は単環式若しくは二環式のＣ３～６ヘテロシクロアルキル基であり、
Ｒ_３は、水素原子、Ｃ１～６アルキル基（当該Ｃ１～６アルキル基はハロゲン原子、ヒドロキシ基又はＣ１～６アルコキシ基で置換されていてもよい。）、Ｃ３～６シクロアルキル基（当該Ｃ３～６シクロアルキル基はハロゲン原子又はＣ１～６アルキル基で置換されていてもよい。）又はＣ１～６アルコキシ基（当該Ｃ１～６アルコキシ基はハロゲン原子、ヒドロキシ基又はＣ１～６アルコキシ基で置換されていてもよい。）であり、
Ｒ_５はハロゲン原子又はＣ１～６アルキル基であり、
Ｒ_６は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、Ｒ_４は水素原子、ハロゲン原子、Ｃ１～６アルキル基、Ｃ２～７アルケニル基、Ｃ２～７アルキニル基、Ｃ３～６シクロアルキル基又はＣ１～６アルキルチオ基であるか、又はＲ_６及びＲ_４は、それらが結合している炭素原子と一緒になって不飽和ヘテロ５員環を形成しており、
Ｒ_７は水素原子又はＣ１～６アルキル基であり、
Ｒ_９は水素原子、ハロゲン原子又はＣ１～６アルキル基である。］ The present disclosure provides compounds, salts or solvates described in (A1) to (A6) below.
(A1)
A compound represented by the following general formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.

[In the formula,
Ring A is represented by the following general formula (2), (3), (4) or (5) (wherein the bonds marked with *, ** and *** are -NH-, -CONH- and -CH ₂ -.) is a group represented by

X ₁ , X ₂ , X ₃ , X ₄ , X ₅ and X ₆ are each independently -CR ₂ = or -N=;
R ₂ is a hydrogen atom, a halogen atom or a C1-6 alkyl group,
R ₁ is -S(=O) ₂ -NH-R ₈ or -S(=O) ₂ -R ₈ ;
R ₈ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group is substituted with a halogen atom, a hydroxy group, a C1-6 alkoxy group, a C3-6 cycloalkyl group or a C3-6 heterocycloalkyl group; ), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group,
R ₃ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3 ~6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group) or a C1-6 alkoxy group (the C1-6 alkoxy group is substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group ) and
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, and R ₄ is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group or a C1-6 alkylthio group, or R ₆ and R ₄ together with the carbon atom to which they are attached form an unsaturated hetero 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. ]

(A2)
Ring A is a group represented by general formula (2) or (4),
R ₈ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group),
R ₃ is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group);
R ₆ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, R ₄ is a halogen atom or a cyclopropyl group,
_R7 is a hydrogen atom or a methyl group,
The compound, salt or solvate according to (A1).

［式中、
Ｘ_１、Ｘ_２、Ｘ_３及びＸ_４は各々独立して－ＣＲ_２＝又は－Ｎ＝であり、
Ｒ_２は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、
Ｒ_１は－Ｓ（＝Ｏ）_２－ＮＨ－Ｒ_８又は－Ｓ（＝Ｏ）_２－Ｒ_８であり、
Ｒ_８は、水素原子、Ｃ１～６アルキル基（当該Ｃ１～６アルキル基はハロゲン原子、ヒドロキシ基又はＣ１～６アルコキシ基で置換されていてもよい。）又は単環式のＣ３～６シクロアルキル基（当該Ｃ３～６シクロアルキル基はＣ１～６アルキル基で置換されていてもよい。）であり、
Ｒ_３は、水素原子、Ｃ１～６アルキル基、Ｃ３～６シクロアルキル基又はＣ１～６アルコキシ基（当該Ｃ１～６アルコキシ基はヒドロキシ基で置換されていてもよい。）であり、
Ｒ_５はハロゲン原子又はＣ１～６アルキル基であり、
Ｒ_６は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、Ｒ_４はハロゲン原子又はシクロプロピル基である。］ (A3)
The compound, salt or solvate according to (A1), wherein the compound represented by the general formula (1) is a compound represented by the following general formula (6).

[In the formula,
X ₁ , X ₂ , X ₃ and X ₄ are each independently -CR ₂ = or -N=;
R ₂ is a hydrogen atom, a halogen atom or a C1-6 alkyl group,
R ₁ is -S(=O) ₂ -NH-R ₈ or -S(=O) ₂ -R ₈ ;
R ₈ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group),
R ₃ is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 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, and R ₄ is a halogen atom or a cyclopropyl group. ]

(A4)
R ₂ is a hydrogen atom or a halogen atom,
R ₈ is a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 The cycloalkyl group may be substituted with a C1-6 alkyl group.)
R ₃ is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group);
_R5 is a halogen atom,
R ₆ is a hydrogen atom and R ₄ is a halogen atom or a cyclopropyl group,
The compound, salt or solvate according to any one of (A1) to (A3).

(A5)
R ₂ is a hydrogen atom or a fluorine atom,
R ₈ is 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 a C1-4 alkyl group; It may be substituted.)
R ₃ is a hydrogen atom, a C1-4 alkyl group, a cyclopropyl group or a C1-4 alkoxy group (the C1-4 alkoxy group may be substituted with a hydroxy group);
_R5 is a fluorine atom,
R ₆ is a hydrogen atom and R ₄ is an iodine atom or a cyclopropyl group,
The compound, salt or solvate according to any one of (A1) to (A3).

(A6)
_R2 is a fluorine atom,
R ₁ is -S(=O) ₂ -NH-R ₈ ,
R ₈ is a C1-4 alkyl group,
R ₃ is a hydrogen atom or a cyclopropyl group,
_R5 is a fluorine atom,
R ₆ is a hydrogen atom and R ₄ is an iodine atom or a cyclopropyl group,
The compound, salt or solvate according to any one of (A1) to (A3).

［式中、
環Ａは、下記一般式（２）、（３）、（４）又は（５）（ここで、＊、＊＊及び＊＊＊が付された結合手はそれぞれ－ＮＨ－、－ＣＯＮＨ－及び－Ｘ_７－に結合している。）で表される基であり、

Ｘ_１、Ｘ_２、Ｘ_３、Ｘ_４、Ｘ_５及びＸ_６は各々独立して－ＣＲ_２＝又は－Ｎ＝であり、
Ｒ_２は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、
Ｘ_７は－（ＣＨ_２）_ｍ－又は－Ｏ－であり、ｍは１、２又は３であり、
Ｒ_１は－Ｓ（＝Ｏ）_２－ＮＨ－Ｒ_８又は－Ｓ（＝Ｏ）_２－Ｒ_８であり、
Ｒ_８は、水素原子、Ｃ１～６アルキル基（当該Ｃ１～６アルキル基はハロゲン原子、ヒドロキシ基、Ｃ１～６アルコキシ基、Ｃ３～６シクロアルキル基又はＣ３～６ヘテロシクロアルキル基で置換されていてもよい。）、単環式若しくは二環式のＣ３～６シクロアルキル基（当該Ｃ３～６シクロアルキル基はＣ１～６アルキル基又はＣ１～６アルコキシ基で置換されていてもよい。）又は単環式若しくは二環式のＣ３～６ヘテロシクロアルキル基であり、
Ｒ_３は、水素原子、Ｃ１～６アルキル基（当該Ｃ１～６アルキル基はハロゲン原子、ヒドロキシ基又はＣ１～６アルコキシ基で置換されていてもよい。）、Ｃ３～６シクロアルキル基（当該Ｃ３～６シクロアルキル基はハロゲン原子又はＣ１～６アルキル基で置換されていてもよい。）又はＣ１～６アルコキシ基（当該Ｃ１～６アルコキシ基はハロゲン原子、ヒドロキシ基又はＣ１～６アルコキシ基で置換されていてもよい。）であり、
Ｒ_５は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、
Ｒ_６は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、Ｒ_４は水素原子、ハロゲン原子、Ｃ１～６アルキル基、Ｃ２～７アルケニル基、Ｃ２～７アルキニル基、Ｃ３～６シクロアルキル基又はＣ１～６アルキルチオ基であるか、又はＲ_６及びＲ_４は、それらが結合している炭素原子と一緒になって不飽和ヘテロ５員環を形成しており、
Ｒ_７は水素原子又はＣ１～６アルキル基であり、
Ｒ_９は水素原子、ハロゲン原子又はＣ１～６アルキル基である。］ The present disclosure also provides agents described in (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 the RAF/MEK complex containing, as an active ingredient, a compound represented by the following general formula (11), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.

[In the formula,
Ring A is represented by the following general formula (2), (3), (4) or (5) (wherein the bonds marked with *, ** and *** are -NH-, -CONH- and -X ₇ -.) is a group represented by

X ₁ , X ₂ , X ₃ , X ₄ , X ₅ and X ₆ are each independently -CR ₂ = or -N=;
R ₂ is a hydrogen atom, a halogen atom or a C1-6 alkyl group,
X ₇ is -(CH ₂ ) _m - or -O-, m is 1, 2 or 3,
R ₁ is -S(=O) ₂ -NH-R ₈ or -S(=O) ₂ -R ₈ ;
R ₈ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group is substituted with a halogen atom, a hydroxy group, a C1-6 alkoxy group, a C3-6 cycloalkyl group or a C3-6 heterocycloalkyl group; ), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group,
R ₃ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3 ~6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group) or a C1-6 alkoxy group (the C1-6 alkoxy group is substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group ) and
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 C1-6 alkyl group, R ₄ is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group or a C1-6 alkylthio group, or R ₆ and R ₄ together with the carbon atom to which they are attached form an unsaturated hetero 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. ]

(A8)
Ring A is a group represented by general formula (2) or (4),
X ₇ is -CH ₂ -,
R ₈ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group),
R ₃ is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 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,
_R7 is a hydrogen atom or a methyl group,
A stabilizer for the RAF/MEK complex according to (A7).

［式中、
Ｘ_１、Ｘ_２、Ｘ_３及びＸ_４は各々独立して－ＣＲ_２＝又は－Ｎ＝であり、
Ｒ_２は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、
Ｒ_１は－Ｓ（＝Ｏ）_２－ＮＨ－Ｒ_８又は－Ｓ（＝Ｏ）_２－Ｒ_８であり、
Ｒ_８は、水素原子、Ｃ１～６アルキル基（当該Ｃ１～６アルキル基はハロゲン原子、ヒドロキシ基又はＣ１～６アルコキシ基で置換されていてもよい。）又は単環式のＣ３～６シクロアルキル基（当該Ｃ３～６シクロアルキル基はＣ１～６アルキル基で置換されていてもよい。）であり、
Ｒ_３は、水素原子、Ｃ１～６アルキル基、Ｃ３～６シクロアルキル基又はＣ１～６アルコキシ基（当該Ｃ１～６アルコキシ基はヒドロキシ基で置換されていてもよい。）であり、
Ｒ_５はハロゲン原子又はＣ１～６アルキル基であり、
Ｒ_６は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、Ｒ_４はハロゲン原子又はシクロプロピル基である。］ (A9)
The RAF/MEK complex stabilizer according to (A7), wherein the compound represented by the general formula (11) is a compound represented by the following general formula (6).

[In the formula,
X ₁ , X ₂ , X ₃ and X ₄ are each independently -CR ₂ = or -N=;
R ₂ is a hydrogen atom, a halogen atom or a C1-6 alkyl group,
R ₁ is -S(=O) ₂ -NH-R ₈ or -S(=O) ₂ -R ₈ ;
R ₈ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group),
R ₃ is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 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, and R ₄ is a halogen atom or a cyclopropyl group. ]

(A10)
R ₂ is a hydrogen atom or a halogen atom,
R ₈ is a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 The cycloalkyl group may be substituted with a C1-6 alkyl group.)
R ₃ is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group);
_R5 is a halogen atom,
R ₆ is a hydrogen atom and R ₄ is a halogen atom or a cyclopropyl group,
The RAF/MEK complex stabilizer according to any one of (A7) to (A9).

The present disclosure also provides compounds, salts or solvates according to (A11) to (A15) below. The compound, salt or solvate described in (A7) includes the compound, salt or solvate described in (A11) to (A15) below.
(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-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -1),
N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide ( Compound A-4),
N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino ) benzamide (compound A-6),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2- methylpropan-2-yl)oxy]benzamide (compound A-8),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide (compound A-13),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25) ,
5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30 ),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -31),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -33),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -34),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41) ,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxy ethoxy)benzamide (compound B-1),
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound D-4),
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound E-1),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (Compound E-7),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide (Compound E-13),
4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound I-1),
N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxo pyridine-3-carboxamide (compound J-5),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]- N-methoxybenzamide (compound A-15),
3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide (Compound A -18),
2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A- 20),
2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A- 27),
2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide (Compound E-9),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide (Compound E-23),
2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound H-1),
3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl ] benzamide (compound H-3),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]oxybenzamide (Compound H-4),
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine -3-carboxamide (compound J-8),
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropane -2-yl)oxy]-6-oxopyridine-3-carboxamide (compound J-10),
5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (compound J-14),
5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide (Compound L-1),
5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide (Compound M-1),
5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-1),
5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-2),
4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (Compound P-1), and 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6- Oxopyridine-3-carboxamide (compound P-2)
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

(A12)
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-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide ( Compound A-4),
N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino ) benzamide (compound A-6),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2- methylpropan-2-yl)oxy]benzamide (compound A-8),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide (compound A-13),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25) ,
5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30 ),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -31),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -33),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -34),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41) ,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxy ethoxy)benzamide (compound B-1),
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound D-4),
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound E-1),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (Compound E-7),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide (Compound E-13),
4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound I-1), and N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxo Pyridine-3-carboxamide (compound J-5)
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

(A13)
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), and 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4- yl]methyl]benzamide (compound A-1)
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

(A14)
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

(A15)
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -1) or a sodium or potassium salt thereof or a pharmaceutically acceptable solvate of said compound or salt.

The compounds, salts or solvates according to (A1) to (A15) have high RAF/MEK complex stabilizing activity, cell proliferative diseases, especially cancer (more specifically, for example, RAS mutation cancer) can be used as an active ingredient of a therapeutic or preventive agent. 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. There is also provided a pharmaceutical composition for treating or preventing cell proliferative diseases, particularly cancer, containing the compound, salt or solvate according to any one of (A1) to (A15) as an active ingredient.

［式中、
環Ａは、下記一般式（２）、（３）又は（４）（ここで、＊、＊＊及び＊＊＊が付された結合手はそれぞれ－ＮＨ－、－ＣＯＮＨ－及び－ＣＨ_２－に結合している。）で表される基であり、

Ｘ_１、Ｘ_２、Ｘ_３、Ｘ_４及びＸ_５は各々独立して－ＣＲ_２＝又は－Ｎ＝であり、
Ｒ_２は水素原子、ハロゲン原子又はＣ１～４アルキル基であり、
Ｒ_１は－Ｓ（＝Ｏ）_２－ＮＨ－Ｒ_８又は－Ｓ（＝Ｏ）_２－Ｒ_８であり、
Ｒ_８は、Ｃ１～４アルキル基（当該Ｃ１～４アルキル基はハロゲン原子、ヒドロキシ基、Ｃ１～４アルコキシ基、Ｃ３～６シクロアルキル基又はＣ３～６ヘテロシクロアルキル基で置換されていてもよい。）又はＣ３～６シクロアルキル基（当該Ｃ３～６シクロアルキル基はＣ１～４アルキル基で置換されていてもよい。）であり、
Ｒ_３は、水素原子、Ｃ３～６シクロアルキル基又はＣ１～６アルコキシ基であり、
Ｒ_５はハロゲン原子であり、
Ｒ_６は水素原子であり、Ｒ_４はハロゲン原子又はＣ３～６シクロアルキル基であり、
Ｒ_７はＣ１～４アルキル基であり、
Ｒ_９は水素原子である。］ The present disclosure also provides the compounds, salts or solvates described in (B1) to (B3) below and the agent described in (B4) below.
(B1)
A compound represented by the following general formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.

[In the formula,
Ring A is represented by the following general formula (2), (3) or (4) (wherein the bonds marked with *, ** and *** are -NH-, -CONH- and -CH ₂ - It is a group represented by

X ₁ , X ₂ , X ₃ , X ₄ and X ₅ are each independently -CR ₂ = or -N=;
R ₂ is a hydrogen atom, a halogen atom or a C1-4 alkyl group,
R ₁ is -S(=O) ₂ -NH-R ₈ or -S(=O) ₂ -R ₈ ;
R ₈ is a C1-4 alkyl group (the C1-4 alkyl group may be substituted with a halogen atom, a hydroxy group, a C1-4 alkoxy group, a C3-6 cycloalkyl group or a C3-6 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,
_R5 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,
_R9 is a hydrogen atom. ]

(B2)
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- iodoanilino)benzamide (Compound A-17),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(oxetan-3-ylmethylsulfamoylamino)pyridin-4-yl]methyl]benzamide ( Compound A-21),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25) ,
5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30 ),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -33),
5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-40) ,
3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A -42),
5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound B- 16),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound C-3),
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropane -2-yl)oxy]-6-oxopyridine-3-carboxamide (compound J-10),
5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide (Compound L-1),
5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-1),
1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (compound P-2),
1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-N-methoxy-5-methyl-6-oxopyridine-3 - carboxamide (compound P-5), and N-cyclopropyl-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl] Methyl]-5-methyl-6-oxopyridine-3-carboxamide (compound P-6)
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

(B3)
(+/-)-3,4-difluoro-5-[[3-fluoro-2-(2-hydroxypropylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4- iodoanilino)benzamide (Compound A-17),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(oxetan-3-ylmethylsulfamoylamino)pyridin-4-yl]methyl]benzamide ( Compound A-21),
5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-40) ,
3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A -42),
5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound B- 16),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound C-3),
1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-N-methoxy-5-methyl-6-oxopyridine-3 - carboxamide (compound P-5), and N-cyclopropyl-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl] Methyl]-5-methyl-6-oxopyridine-3-carboxamide (compound P-6)
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

(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 are used for the treatment of cell proliferative diseases, especially cancers (more specifically cancers with RAF mutations, 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. Also provided is a pharmaceutical composition for treating or preventing cell proliferative diseases, particularly cancer, containing the compound, salt or solvate according to any one of (B1) to (B3) as an active ingredient.

According to the present disclosure, novel compounds having RAF/MEK complex stabilizing activity and/or MEK inhibitory activity and useful for the treatment or prevention of cell proliferative diseases, particularly cancer, or cell proliferative diseases, particularly cancer Novel RAF/MEK complex stabilizers or MEK inhibitors useful for therapy or prophylaxis are provided. In addition, the present disclosure provides a novel pharmaceutical composition for treating or preventing cell proliferative diseases, particularly cancer, containing a compound having RAF/MEK complex stabilizing activity and/or MEK inhibitory activity as an active ingredient. be.

FIG. 1 shows the powder X-ray diffraction pattern of sample A-1a (Form I). FIG. 2 shows the powder X-ray diffraction pattern of sample A-1b. FIG. 3 shows the powder X-ray diffraction pattern of sample A-1c. FIG. 4 shows MEK1 added together with a test compound (ref-2, ref-3, ref-4, A-1, ref-1, ref-5 or B-1) on the RAF1-immobilized sensor chip surface. is a sensorgram showing the time course of the binding amount of . FIG. 5 shows MEK1 added together with a test compound (A-2, A-25, J-1, E-1, M-1, N-1 or H-3) on the RAF1-immobilized sensor chip surface. is a sensorgram showing the time course of the binding amount of . FIG. 6 shows the binding amount of MEK1 added together with a test compound (I-1, H-4, L-1, P-1, E-7 or A-27) to the RAF1-immobilized sensor chip surface. It is a sensorgram which shows a time-dependent transition. FIG. 7 shows MEK1 added together with a test compound (A-33, A-18, N-2, A-20, A-8, E-13 or H-1) on the RAF1-immobilized sensor chip surface. is a sensorgram showing the time course of the binding amount of . FIG. 8 shows MEK1 added together with a test compound (P-2, A-41, E-9, A-6, J-14, A-31 or A-34) on the RAF1-immobilized sensor chip surface. is a sensorgram showing the time course of the binding amount of . FIG. 9 shows MEK1 added together with a test compound (A-35, A-30, D-4, A-15, J-8, J-5 or A-4) on the RAF1-immobilized sensor chip surface. is a sensorgram showing the time course of the binding amount of . FIG. 10 is a sensorgram showing changes over time in the binding amount of MEK1 added to the RAF1-immobilized sensor chip surface together with a test compound (A-13, E-23 or J-10). FIG. 11 is a sensorgram showing changes over time in the binding amount of MEK1 added together with a test compound (ref-4, A-1, P-2 or A-6) to the sensor chip surface on which RAF1 is immobilized. be. Figure 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 test compounds (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 implanted with human lung cancer cell line Calu-6.

Illustrative embodiments of the present disclosure are described below.

In the present disclosure, halogen atom means fluorine atom, chlorine atom, bromine atom or iodine atom.

In the present disclosure, a C1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, 1-methylpropyl group, n-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 1,2-dimethylpropyl group, 1-ethylpropyl group, n-hexyl group, 1-methylpentyl group, 2- methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2, 3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl and 2-ethylbutyl groups are included.

In the present disclosure, a C2-7 alkenyl group means a linear or branched alkenyl group having 2 to 7 carbon atoms. Examples include vinyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, heptadienyl and heptatrienyl groups.

In the present disclosure, a C2-7 alkynyl group means a linear or branched alkynyl group having 2 to 7 carbon atoms. For example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentynyl, pentadiynyl, hexynyl, hexadiynyl, heptynyl, heptadynyl and heptatriinyl groups.

In the present disclosure, a C1-6 alkoxy group means an alkyloxy group having a linear or branched alkyl group with 1-6 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy groups.

In the present disclosure, a C1-6 alkylthio group means an alkylthio group having a linear or branched alkyl group with 1-6 carbon atoms. Examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n-pentylthio and n-hexylthio.

In the present disclosure, a C3-6 cycloalkyl group means a cyclic alkyl group having 3 to 6 atoms constituting the ring. It can be monocyclic or bicyclic, but monocyclic is meant unless otherwise stated. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. Bicyclic ones include, for example, a bicyclo[1.1.1]pentanyl group and a bicyclo[2.1.1]hexyl group.

In the present disclosure, a C3-6 heterocycloalkyl group means a C3-6 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 can be monocyclic or bicyclic, but monocyclic is meant unless otherwise stated. Monocyclic groups include, for example, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups. Bicyclic ones include, for example, the oxabicyclo[3.1.0]hexan-6-yl group and the azabicyclo[2.1.1]hexanyl group.

In the present disclosure, unsaturated hetero 5-membered ring means an unsaturated 5-membered ring containing at least one heteroatom selected from nitrogen, oxygen and sulfur atoms. Examples include furan, thiophene, pyrrole, imidazole and thiazole.

In the present disclosure, pharmaceutically acceptable salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate; , toluenesulfonate; formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandel carboxylates such as acid salts, benzoates, salicylates, fluoroacetates, trifluoroacetates, tartrates, propionates, glutarate; lithium salts, sodium salts, potassium salts, cesium salts, rubidium salts, etc. alkaline earth metal salts such as magnesium salts and calcium salts; and ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts and tetraalkylammonium salts. Among them, alkali metal salts such as lithium salts, sodium salts, potassium salts, cesium salts and rubidium salts are preferred, and sodium salts and potassium salts are more preferred.

In the present disclosure, pharmaceutically acceptable solvates are solvates with, for example, water, alcohols (such as methanol, ethanol, 1-propanol or 2-propanol), acetone, dimethylformamide or dimethylacetamide. . It may be a solvate with a single solvent or a solvate with multiple solvents. Preferred solvates include, for example, hydrates.

［式中、
環Ａは、下記一般式（２）、（３）、（４）又は（５）（ここで、＊、＊＊及び＊＊＊が付された結合手はそれぞれ－ＮＨ－、－ＣＯＮＨ－及び－ＣＨ_２－に結合している。）で表される基であり、

Ｘ_１、Ｘ_２、Ｘ_３、Ｘ_４、Ｘ_５及びＸ_６は各々独立して－ＣＲ_２＝又は－Ｎ＝であり、
Ｒ_２は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、
Ｒ_１は－Ｓ（＝Ｏ）_２－ＮＨ－Ｒ_８又は－Ｓ（＝Ｏ）_２－Ｒ_８であり、
Ｒ_８は、水素原子、Ｃ１～６アルキル基（当該Ｃ１～６アルキル基はハロゲン原子、ヒドロキシ基、Ｃ１～６アルコキシ基、Ｃ３～６シクロアルキル基又はＣ３～６ヘテロシクロアルキル基で置換されていてもよい。）、単環式若しくは二環式のＣ３～６シクロアルキル基（当該Ｃ３～６シクロアルキル基はＣ１～６アルキル基又はＣ１～６アルコキシ基で置換されていてもよい。）又は単環式若しくは二環式のＣ３～６ヘテロシクロアルキル基であり、
Ｒ_３は、水素原子、Ｃ１～６アルキル基（当該Ｃ１～６アルキル基はハロゲン原子、ヒドロキシ基又はＣ１～６アルコキシ基で置換されていてもよい。）、Ｃ３～６シクロアルキル基（当該Ｃ３～６シクロアルキル基はハロゲン原子又はＣ１～６アルキル基で置換されていてもよい。）又はＣ１～６アルコキシ基（当該Ｃ１～６アルコキシ基はハロゲン原子、ヒドロキシ基又はＣ１～６アルコキシ基で置換されていてもよい。）であり、
Ｒ_５はハロゲン原子又はＣ１～６アルキル基であり、
Ｒ_６は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、Ｒ_４は水素原子、ハロゲン原子、Ｃ１～６アルキル基、Ｃ２～７アルケニル基、Ｃ２～７アルキニル基、Ｃ３～６シクロアルキル基又はＣ１～６アルキルチオ基であるか、又はＲ_６及びＲ_４は、それらが結合している炭素原子と一緒になって不飽和ヘテロ５員環を形成しており、
Ｒ_７は水素原子又はＣ１～６アルキル基であり、
Ｒ_９は水素原子、ハロゲン原子又はＣ１～６アルキル基である。］ A first aspect of the present disclosure provides a compound represented by the following general formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.

[In the formula,
Ring A is represented by the following general formula (2), (3), (4) or (5) (wherein the bonds marked with *, ** and *** are -NH-, -CONH- and -CH ₂ -.) is a group represented by

X ₁ , X ₂ , X ₃ , X ₄ , X ₅ and X ₆ are each independently -CR ₂ = or -N=;
R ₂ is a hydrogen atom, a halogen atom or a C1-6 alkyl group,
R ₁ is -S(=O) ₂ -NH-R ₈ or -S(=O) ₂ -R ₈ ;
R ₈ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group is substituted with a halogen atom, a hydroxy group, a C1-6 alkoxy group, a C3-6 cycloalkyl group or a C3-6 heterocycloalkyl group; ), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group,
R ₃ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3 ~6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group) or a C1-6 alkoxy group (the C1-6 alkoxy group is substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group ) and
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 hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group or a C1-6 alkylthio group, or R ₆ and R ₄ together with the carbon atom to which they are attached form an unsaturated hetero 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. ]

Compounds, salts or solvates of the first aspect have high RAF/MEK complex stabilizing activity and are useful in the treatment of cell proliferative diseases, particularly cancers (more particularly cancers with RAS mutations, for example). Or it can be used for prophylaxis. Many also have, for example, high MEK inhibitory activity, and such compounds, salts or solvates are also suitable, for example, for cancers with RAF mutations.

Ring A is preferably a group represented by general formula (2) or (4), more preferably a group represented by general formula (2).
R ₂ is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, still more preferably a fluorine atom.
R ₁ is preferably -S(=O) ₂ -NH-R ₈ .
R ₈ is preferably a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group) or a monocyclic C3-6 A cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), more preferably a C1-6 alkyl group (the C1-6 alkyl group is a halogen atom or a C1- 6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), and Preferably, 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 may be substituted with a C1-4 alkyl group). ), more preferably a C1-4 alkyl group.
R ₃ is preferably a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group), and more It is preferably a hydrogen atom, a C1-4 alkyl group, a cyclopropyl group or a C1-4 alkoxy group (the C1-4 alkoxy group may be substituted with a hydroxy group), more preferably a hydrogen atom or cyclopropyl is the base.
_R5 is preferably a halogen atom, more preferably a fluorine atom.
R ₆ is preferably a hydrogen atom, a halogen atom or a C1-6 alkyl group, 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.
_R7 is preferably a hydrogen atom or a methyl group.

［式中、
Ｘ_１、Ｘ_２、Ｘ_３及びＸ_４は各々独立して－ＣＲ_２＝又は－Ｎ＝であり、
Ｒ_２は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、
Ｒ_１は－Ｓ（＝Ｏ）_２－ＮＨ－Ｒ_８又は－Ｓ（＝Ｏ）_２－Ｒ_８であり、
Ｒ_８は、水素原子、Ｃ１～６アルキル基（当該Ｃ１～６アルキル基はハロゲン原子、ヒドロキシ基又はＣ１～６アルコキシ基で置換されていてもよい。）又は単環式のＣ３～６シクロアルキル基（当該Ｃ３～６シクロアルキル基はＣ１～６アルキル基で置換されていてもよい。）であり、
Ｒ_３は、水素原子、Ｃ１～６アルキル基、Ｃ３～６シクロアルキル基又はＣ１～６アルコキシ基（当該Ｃ１～６アルコキシ基はヒドロキシ基で置換されていてもよい。）であり、
Ｒ_５はハロゲン原子又はＣ１～６アルキル基であり、
Ｒ_６は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、Ｒ_４はハロゲン原子又はシクロプロピル基である。］ The compound represented by general formula (1) is preferably, for example, a compound represented by general formula (6) below.

[In the formula,
X ₁ , X ₂ , X ₃ and X ₄ are each independently -CR ₂ = or -N=;
R ₂ is a hydrogen atom, a halogen atom or a C1-6 alkyl group,
R ₁ is -S(=O) ₂ -NH-R ₈ or -S(=O) ₂ -R ₈ ;
R ₈ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group),
R ₃ is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 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, and R ₄ is a halogen atom or a cyclopropyl group. ]

As the compound represented by the general formula (1), 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-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide ( Compound A-4),
N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino ) benzamide (compound A-6),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2- methylpropan-2-yl)oxy]benzamide (compound A-8),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide (compound A-13),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25) ,
5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30 ),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -31),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -33),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -34),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41) ,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxy ethoxy)benzamide (compound B-1),
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound D-4),
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound E-1),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (Compound E-7),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide (Compound E-13),
4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound I-1),
N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxo pyridine-3-carboxamide (compound J-5),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]- N-methoxybenzamide (compound A-15),
3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide (Compound A -18),
2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A- 20),
2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A- 27),
2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide (Compound E-9),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide (Compound E-23),
2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound H-1),
3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl ] benzamide (compound H-3),
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine -3-carboxamide (compound J-8),
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropane -2-yl)oxy]-6-oxopyridine-3-carboxamide (compound J-10),
5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (compound J-14),
5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide (Compound L-1),
5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide (Compound M-1),
5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-1),
5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-2),
4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (Compound P-1), and 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6- Oxopyridine-3-carboxamide (compound P-2)
is mentioned.

Among those compounds, for example in terms of MEK inhibitory activity, RAF inhibitory activity, cell growth inhibitory activity and/or metabolic stability, e.g.
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-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide ( Compound A-4),
N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino ) benzamide (compound A-6),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2- methylpropan-2-yl)oxy]benzamide (compound A-8),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide (compound A-13),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25) ,
5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30 ),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -31),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -33),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -34),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41) ,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxy ethoxy)benzamide (compound B-1),
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound D-4),
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound E-1),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (Compound E-7),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide (Compound E-13),
4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound I-1), and N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxo Pyridine-3-carboxamide (compound J-5)
is preferred,
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), and 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4- yl]methyl]benzamide (compound A-1)
is more preferred,
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -1)
is particularly preferred.
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A The pharmaceutically acceptable salt of -1) is preferably sodium salt or potassium salt.

［式中、
環Ａは、下記一般式（２）、（３）、（４）又は（５）（ここで、＊、＊＊及び＊＊＊が付された結合手はそれぞれ－ＮＨ－、－ＣＯＮＨ－及び－Ｘ_７－に結合している。）で表される基であり、

Ｘ_１、Ｘ_２、Ｘ_３、Ｘ_４、Ｘ_５及びＸ_６は各々独立して－ＣＲ_２＝又は－Ｎ＝であり、
Ｒ_２は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、
Ｘ_７は－（ＣＨ_２）_ｍ－又は－Ｏ－であり、ｍは１、２又は３であり、
Ｒ_１は－Ｓ（＝Ｏ）_２－ＮＨ－Ｒ_８又は－Ｓ（＝Ｏ）_２－Ｒ_８であり、
Ｒ_８は、水素原子、Ｃ１～６アルキル基（当該Ｃ１～６アルキル基はハロゲン原子、ヒドロキシ基、Ｃ１～６アルコキシ基、Ｃ３～６シクロアルキル基又はＣ３～６ヘテロシクロアルキル基で置換されていてもよい。）、単環式若しくは二環式のＣ３～６シクロアルキル基（当該Ｃ３～６シクロアルキル基はＣ１～６アルキル基又はＣ１～６アルコキシ基で置換されていてもよい。）又は単環式若しくは二環式のＣ３～６ヘテロシクロアルキル基であり、
Ｒ_３は、水素原子、Ｃ１～６アルキル基（当該Ｃ１～６アルキル基はハロゲン原子、ヒドロキシ基又はＣ１～６アルコキシ基で置換されていてもよい。）、Ｃ３～６シクロアルキル基（当該Ｃ３～６シクロアルキル基はハロゲン原子又はＣ１～６アルキル基で置換されていてもよい。）又はＣ１～６アルコキシ基（当該Ｃ１～６アルコキシ基はハロゲン原子、ヒドロキシ基又はＣ１～６アルコキシ基で置換されていてもよい。）であり、
Ｒ_５は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、
Ｒ_６は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、Ｒ_４は水素原子、ハロゲン原子、Ｃ１～６アルキル基、Ｃ２～７アルケニル基、Ｃ２～７アルキニル基、Ｃ３～６シクロアルキル基又はＣ１～６アルキルチオ基であるか、又はＲ_６及びＲ_４は、それらが結合している炭素原子と一緒になって不飽和ヘテロ５員環を形成しており、
Ｒ_７は水素原子又はＣ１～６アルキル基であり、
Ｒ_９は水素原子、ハロゲン原子又はＣ１～６アルキル基である。］ A second aspect of the present disclosure is 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 RAF / Kind Code: A1 A stabilizer for the MEK complex is provided.

[In the formula,
Ring A is represented by the following general formula (2), (3), (4) or (5) (wherein the bonds marked with *, ** and *** are -NH-, -CONH- and -X ₇ -.) is a group represented by

X ₁ , X ₂ , X ₃ , X ₄ , X ₅ and X ₆ are each independently -CR ₂ = or -N=;
R ₂ is a hydrogen atom, a halogen atom or a C1-6 alkyl group,
X ₇ is -(CH ₂ ) _m - or -O-, m is 1, 2 or 3,
R ₁ is -S(=O) ₂ -NH-R ₈ or -S(=O) ₂ -R ₈ ;
R ₈ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group is substituted with a halogen atom, a hydroxy group, a C1-6 alkoxy group, a C3-6 cycloalkyl group or a C3-6 heterocycloalkyl group; ), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group,
R ₃ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3 ~6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group) or a C1-6 alkoxy group (the C1-6 alkoxy group is substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group ) and
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 C1-6 alkyl group, R ₄ is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group or a C1-6 alkylthio group, or R ₆ and R ₄ together with the carbon atom to which they are attached form an unsaturated hetero 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. ]

Compounds, salts or solvates of the second aspect have high RAF/MEK complex stabilizing activity and are used for the treatment of cell proliferative diseases, especially cancers (more particularly cancers with RAS mutations, for example) Or it can be used for prophylaxis. Many also have, for example, high MEK inhibitory activity, and such compounds, salts or solvates are also suitable, for example, for cancers with RAF mutations.

Ring A is preferably a group represented by general formula (2) or (4), more preferably a group represented by general formula (2).
R ₂ is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, still more preferably a fluorine atom.
X ₇ is preferably -CH ₂ -.
R ₁ is preferably -S(=O) ₂ -NH-R ₈ .
R ₈ is preferably a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group) or a monocyclic C3-6 A cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), more preferably a C1-6 alkyl group (the C1-6 alkyl group is a halogen atom or a C1- 6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), and Preferably, 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 may be substituted with a C1-4 alkyl group). ), more preferably a C1-4 alkyl group.
R ₃ is preferably a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group), and more It is preferably a hydrogen atom, a C1-4 alkyl group, a cyclopropyl group or a C1-4 alkoxy group (the C1-4 alkoxy group may be substituted with a hydroxy group), more preferably a hydrogen atom or cyclopropyl is the base.
R ₅ is preferably a halogen atom or a C1-6 alkyl group, more preferably a halogen atom, still more preferably a fluorine atom.
R ₆ is preferably a hydrogen atom, a halogen atom or a C1-6 alkyl group, 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.
_R7 is preferably a hydrogen atom or a methyl group.

［式中、
Ｘ_１、Ｘ_２、Ｘ_３及びＸ_４は各々独立して－ＣＲ_２＝又は－Ｎ＝であり、
Ｒ_２は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、
Ｒ_１は－Ｓ（＝Ｏ）_２－ＮＨ－Ｒ_８又は－Ｓ（＝Ｏ）_２－Ｒ_８であり、
Ｒ_８は、水素原子、Ｃ１～６アルキル基（当該Ｃ１～６アルキル基はハロゲン原子、ヒドロキシ基又はＣ１～６アルコキシ基で置換されていてもよい。）又は単環式のＣ３～６シクロアルキル基（当該Ｃ３～６シクロアルキル基はＣ１～６アルキル基で置換されていてもよい。）であり、
Ｒ_３は、水素原子、Ｃ１～６アルキル基、Ｃ３～６シクロアルキル基又はＣ１～６アルコキシ基（当該Ｃ１～６アルコキシ基はヒドロキシ基で置換されていてもよい。）であり、
Ｒ_５はハロゲン原子又はＣ１～６アルキル基であり、
Ｒ_６は水素原子、ハロゲン原子又はＣ１～６アルキル基であり、Ｒ_４はハロゲン原子又はシクロプロピル基である。］ The compound represented by general formula (11) is preferably, for example, a compound represented by general formula (6) below.

[In the formula,
X ₁ , X ₂ , X ₃ and X ₄ are each independently -CR ₂ = or -N=;
R ₂ is a hydrogen atom, a halogen atom or a C1-6 alkyl group,
R ₁ is -S(=O) ₂ -NH-R ₈ or -S(=O) ₂ -R ₈ ;
R ₈ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group),
R ₃ is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 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, and R ₄ is a halogen atom or a cyclopropyl group. ]

As the compound represented by the general formula (11), 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-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide ( Compound A-4),
N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino ) benzamide (compound A-6),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2- methylpropan-2-yl)oxy]benzamide (compound A-8),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide (compound A-13),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25) ,
5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30 ),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -31),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -33),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -34),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41) ,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxy ethoxy)benzamide (compound B-1),
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound D-4),
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound E-1),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (Compound E-7),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide (Compound E-13),
4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound I-1),
N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxo pyridine-3-carboxamide (compound J-5),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]- N-methoxybenzamide (compound A-15),
3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide (Compound A -18),
2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A- 20),
2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A- 27),
2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide (Compound E-9),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide (Compound E-23),
2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound H-1),
3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl ] benzamide (compound H-3),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]oxybenzamide (Compound H-4),
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine -3-carboxamide (compound J-8),
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropane -2-yl)oxy]-6-oxopyridine-3-carboxamide (compound J-10),
5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide (compound J-14),
5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide (Compound L-1),
5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide (Compound M-1),
5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-1),
5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-2),
4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide (Compound P-1), and 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6- Oxopyridine-3-carboxamide (compound P-2)
are mentioned.

Among those compounds, for example in terms of MEK inhibitory activity, RAF inhibitory activity, cell growth inhibitory activity and/or metabolic stability, e.g.
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-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide ( Compound A-4),
N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino ) benzamide (compound A-6),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2- methylpropan-2-yl)oxy]benzamide (compound A-8),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide (compound A-13),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25) ,
5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30 ),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -31),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -33),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -34),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide (Compound A-35),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-41) ,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxy ethoxy)benzamide (compound B-1),
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound D-4),
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound E-1),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide (Compound E-7),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide (Compound E-13),
4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound I-1), and N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxo Pyridine-3-carboxamide (compound J-5)
is preferred,
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), and 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4- yl]methyl]benzamide (compound A-1)
is more preferred,
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -1)
is particularly preferred.
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A The pharmaceutically acceptable salt of -1) is preferably sodium salt or potassium salt.

［式中、
環Ａは、下記一般式（２）、（３）又は（４）（ここで、＊、＊＊及び＊＊＊が付された結合手はそれぞれ－ＮＨ－、－ＣＯＮＨ－及び－ＣＨ_２－に結合している。）で表される基であり、

Ｘ_１、Ｘ_２、Ｘ_３、Ｘ_４及びＸ_５は各々独立して－ＣＲ_２＝又は－Ｎ＝であり、
Ｒ_２は水素原子、ハロゲン原子又はＣ１～４アルキル基であり、
Ｒ_１は－Ｓ（＝Ｏ）_２－ＮＨ－Ｒ_８又は－Ｓ（＝Ｏ）_２－Ｒ_８であり、
Ｒ_８は、Ｃ１～４アルキル基（当該Ｃ１～４アルキル基はハロゲン原子、ヒドロキシ基、Ｃ１～４アルコキシ基、Ｃ３～６シクロアルキル基又はＣ３～６ヘテロシクロアルキル基で置換されていてもよい。）又はＣ３～６シクロアルキル基（当該Ｃ３～６シクロアルキル基はＣ１～４アルキル基で置換されていてもよい。）であり、
Ｒ_３は、水素原子、Ｃ３～６シクロアルキル基又はＣ１～６アルコキシ基であり、
Ｒ_５はハロゲン原子であり、
Ｒ_６は水素原子であり、Ｒ_４はハロゲン原子又はＣ３～６シクロアルキル基であり、
Ｒ_７はＣ１～４アルキル基であり、
Ｒ_９は水素原子である。］ A third aspect of the present disclosure provides a compound represented by the following general formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.
A fourth aspect of the present disclosure provides MEK inhibitors containing such compounds, salts or solvates as active ingredients.

[In the formula,
Ring A is represented by the following general formula (2), (3) or (4) (wherein the bonds marked with *, ** and *** are -NH-, -CONH- and -CH ₂ - It is a group represented by

X ₁ , X ₂ , X ₃ , X ₄ and X ₅ are each independently -CR ₂ = or -N=;
R ₂ is a hydrogen atom, a halogen atom or a C1-4 alkyl group,
R ₁ is -S(=O) ₂ -NH-R ₈ or -S(=O) ₂ -R ₈ ;
R ₈ is a C1-4 alkyl group (the C1-4 alkyl group may be substituted with a halogen atom, a hydroxy group, a C1-4 alkoxy group, a C3-6 cycloalkyl group or a C3-6 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,
_R5 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,
_R9 is a hydrogen atom. ]

The compound, salt or solvate of the third or fourth aspect has high MEK inhibitory activity and is used for the treatment or prevention of cell proliferative diseases, especially cancer (more specifically cancer with RAF mutation, for example). can be used for

Compounds of the third or fourth aspect, 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- iodoanilino)benzamide (Compound A-17),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(oxetan-3-ylmethylsulfamoylamino)pyridin-4-yl]methyl]benzamide ( Compound A-21),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A-25) ,
5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-30 ),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound A -33),
5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound A-40) ,
3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide (Compound A -42),
5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide (Compound B- 16),
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound C-3),
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropane -2-yl)oxy]-6-oxopyridine-3-carboxamide (compound J-10),
5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide (Compound L-1),
5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide (Compound N-1),
1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide (compound P-2),
1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-N-methoxy-5-methyl-6-oxopyridine-3 - carboxamide (compound P-5), and N-cyclopropyl-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl] Methyl]-5-methyl-6-oxopyridine-3-carboxamide (compound P-6)
is preferred.

Examples of abbreviations used herein along with their meanings are listed below.
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-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl Uronium hexafluorophosphate HOAt: 1-hydroxy-7-azabenzotriazole HOOBt: 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine LDA: lithium diisopropylamide MeOH: methanol NMP: N-methyl-2-pyrrolidone TBS: tert-butyldimethylsilyl TFA: trifluoroacetic acid THF: tetrahydrofuran Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Examples of preferred methods for producing the compounds of the present disclosure are now described. Hereinafter, the definitions of X ₁ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₇ are as described above unless the context dictates otherwise. R _a represents, for example, a 4-methylphenyl group or a 2-nitrophenyl group, and R _b represents, for example, a Boc group or a 2,4-dimethoxybenzyl group.

(General manufacturing method-1)
In general production method-1, among the compounds represented by general formula (6), X ₂ , X ₃ and X ₄ (X ₂ , X ₃ and X ₄ may be the same or different) are It is a preferred method for preparing compounds wherein -CR ₂ = and R ₆ is a hydrogen atom.

Step 1-1:
_SN Ar Reaction of Aniline Derivative 1b and Fluorobenzene Derivative 1a In the presence of a base, the aniline derivative 1b is reacted with the fluorobenzene derivative 1a. Examples of bases include organolithium reagents, with lithium bis(trimethylsilyl)amide and lithium diisopropylamide being preferred. Examples of the solvent include polar aprotic solvents such as THF, 1,4-dioxane and NMP, with THF being preferred.

Step 1-2:
Methylation of Benzoic Acid Derivative 1c Benzoic acid derivative 1c is reacted with a methylating reagent. Examples of methylation reagents include diazomethane derivatives, and diazomethyltrimethylsilane is preferred. Examples of the solvent include alcohols, nonpolar solvents, and mixed solvents thereof, and preferred are mixed solvents of toluene and methanol and mixed solvents of THF and methanol.

Step 1-3:
Hydrazonation of Aldehyde Derivative 1d Aldehyde derivative 1d is reacted with an arylsulfonyl hydrazide. Arylsulfonyl hydrazides include, for example, methylbenzenesulfonyl hydrazide and nitrobenzenesulfonyl hydrazide, with 4-methylbenzenesulfonyl hydrazide and 2-nitrobenzenesulfonyl hydrazide being preferred. Solvents include, for example, polar solvents such as alcohols, with methanol and ethanol being preferred.

Step 1-4:
Coupling of Hydrazone Derivative 1e and Arylboronic Acid Derivative 1f In the presence of a base, the hydrazone derivative 1e is reacted with the arylboronic acid derivative 1f. Bases include, for example, carbonates and amines, with potassium carbonate and DIPEA being preferred. Examples of the solvent include polar solvents such as 1,4-dioxane, DMF, NMP and THF, with 1,4-dioxane being preferred. The reaction temperature is preferably 80°C or higher.

Step 1-5:
Deprotection of 1 g of Methyl Benzoate Derivative 1 g of methyl benzoate derivative is subjected to acidic conditions to remove the protecting group _Rb . Acids include, for example, sulfuric acid, hydrochloric acid, methanesulfonic acid and trifluoroacetic acid, with trifluoroacetic acid being preferred. Solvents include, for example, alcohols and non-polar solvents such as DCM, with DCM being preferred.

Step 1-6:
Hydrolysis of Ester Derivative 1h Ester derivative 1h is reacted with a hydroxide. Examples of hydroxides include lithium hydroxide, potassium hydroxide and sodium hydroxide, with lithium hydroxide being preferred. Examples of the solvent include polar solvents such as alcohols and THF, water, and mixed solvents thereof, preferably an aqueous THF solution.

Step 1-7:
Amidation of benzoic acid derivative 1i Benzoic acid derivative 1i is reacted with the corresponding amine or amine hydrochloride in the presence of a condensing agent. The corresponding amine or amine hydrochloride may have a Boc group. Condensing agents include, for example, DCC, EDC or EDC.HCl, HATU, COMU, and propylphosphonic anhydride (cyclic trimer), and optionally, for example, HOOBt or HOAt may be further added. Preferably, for example, a combination of EDC or EDC.HCl and HOOBt, or HATU is used. In addition to the condensing agent, a base such as DIPEA or triethylamine may optionally be used, with DIPEA being preferred as the base. Examples of the solvent include polar solvents such as DMF, DMA, NMP, methanol and ethanol, and mixed solvents thereof, with DMF being preferred.

Step 1-8:
Sulfamidation or Sulfamidation of Amine Derivatives 1j, 1ja or 1jb Sulfamidation:
Amine derivatives 1j, 1ja or 1jb are reacted with the corresponding sulfamoyl chloride or 4-nitrophenyl sulfamate in the presence of a base. The corresponding sulfamoyl chloride or 4-nitrophenyl sulfamate may have a Boc group. Examples of bases include amines, preferably pyridine, triethylamine, DIPEA and imidazole. Examples of the solvent include polar solvents such as DMF, DMA, NMP, THF, 1,4-dioxane, acetonitrile and pyridine, nonpolar solvents such as dichloromethane and dichloroethane, and mixed solvents thereof. DMF, DMA, THF and dichloromethane are preferred.

Sulfonamidation:
Amine derivative 1j, 1ja or 1jb is reacted with the corresponding sulfonyl chloride in the presence of a base. Examples of bases include amines, preferably pyridine, triethylamine, DIPEA and imidazole. Examples of the solvent include polar solvents such as DMF, DMA, NMP, THF, 1,4-dioxane, acetonitrile and pyridine, nonpolar solvents such as dichloromethane and dichloroethane, and mixed solvents thereof, and dichloromethane and pyridine. preferable.

Step 1-9-1:
De-Boc Removal of Sulfamide or Sulfonamide Derivative 1k1 When _R1 or R3 of sulfamide or sulfonamide derivative _1k1 has a Boc group, the Boc group is removed by subjecting compound 1k1 to acidic conditions. Acids include, for example, sulfuric acid, hydrochloric acid, methanesulfonic acid and trifluoroacetic acid. Alternatively, Boc may be removed by generating an acid with, for example, chlorotrimethylsilane (TMSCl) in alcohol. Solvents include, for example, alcohols and non-polar solvents such as DCM. As a combination of acid and 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, alkenylation, alkynylation or thioetherification of sulfamide or sulfonamide derivatives 1k1 When R ₄ or R ₅ of sulfamide or sulfonamide derivatives 1k1 is halogen, for example alkylation, alkenylation, alkynylation or Thioetherification can be carried out.

Method 1 (alkylation or alkenylation by Suzuki-Miyaura cross-coupling):
Compound 1k1 is reacted with the corresponding boronic acid, boronate ester or borate in the presence of Pd. For example, Chem. Rev. 1995, vol. 95, no. 7, p. 2457 or ACC. Chem. Res. , vol. 40, p. 275 can be used. Examples of bases include inorganic salts such as carbonates and hydroxides, and amines such as triethylamine and DIPEA, with sodium carbonate, potassium carbonate and triethylamine being preferred. Examples of the solvent include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, methanol, ethanol, 2-propanol, water, and mixed solvents thereof. A mixed solvent and a mixed solvent of THF and water are preferred. As Pd and ligands, for example, Chem. Rev. 1995, vol. 95, no. 7, p. 2457, ACC. Chem. Res. , vol. 40, p. 275, and ACC. Chem. Res. , vol. 41, p. 1461, with PdCl ₂ (PPh ₃ ) ₂ , Pd(PPh ₃ ) ₄ and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride being preferred. The reaction temperature is preferably 80° C. or higher.

Method 2 (Alkylation or alkenylation by Negishi cross-coupling):
Compound 1k1 is reacted with the corresponding organozinc reagent in the presence of Pd or Ni. For example, Tetrahedron. 1992, vol. 48, no. 44, p. 9577 or Aldrichimica Acta. 2005, vol. 38, p. 71 can be used. Examples of the solvent include polar solvents such as THF, 1,4-dioxane, DMF, DMA and NMP, and mixed solvents thereof, with THF being preferred. As Pd and Ni, for example, Tetrahedron. 1992, vol. 48, no. 44, p. 9577 and Aldrichimica Acta. 2005, vol. 38, p. 71, and PdCl ₂ (PPh ₃ ) ₂ , Pd(PPh ₃ ) ₄ , and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, PdCl ₂ (PPh ₃ ) ₂ , Pd(PPh ₃ ) ₄ and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are preferred.

Method 3 (alkynylation via Sonogashira cross-coupling):
Compound 1k1 is reacted with the corresponding alkyne in the presence of Pd and Cu. For example, Chem. Soc. Rev. 2011, vol. 40, p. 5048 can be implemented. The corresponding alkyne may have a silyl group, eg trimethylsilylacetylene. Bases include, for example, amines such as triethylamine, DIPEA, DBU, piperidine, and inorganic bases such as NaOAc, with triethylamine and DIPEA being preferred. Pd catalysts include, for example, PdCl ₂ (PPh ₃ ) ₂ , Pd(PPh ₃ ) ₄ , [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc) ₂ , and Pd(OAc) 2 . ₂ (dba) ₃ , 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, with copper iodide being preferred. 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, preferably THF.

Method 4 (Thioetherification):
Compound 1k1 is reacted with the corresponding mercaptan or mercaptan salt in the presence of Pd. Examples of bases include amines such as triethylamine, DIPEA, DBU, piperidine, etc. Triethylamine and DIPEA are preferred. Pd catalysts include, for example, zerovalent Pd complexes such as Pd(PPh ₃ ) ₄ and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′ -amino-1,1′-biphenyl)]palladium(II) methanesulfonate is preferred. Examples of the solvent include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, DMSO, methanol, ethanol, 2-propanol, and mixed solvents thereof, preferably 1,4-dioxane. .

Step 1-10:
Bromination or Chlorination of Amine Derivative 1j When R ₄ or R ₅ of amine derivative 1j is a halogen, bromination or chlorination can be carried out by reacting compound 1j with copper bromide or copper chloride. Examples of the solvent include polar solvents such as THF, 1,4-dioxane, DMF, DMA and NMP, with DMF being preferred.

Step 1-11:
TBS Conversion of Amine Derivative 1j When R ₃ of amine derivative 1j has a hydroxy group, TBS conversion can be performed by reacting compound 1j with tert-butyldimethylchlorosilane (TBSCl) in the presence of a base. Examples of the base include bases such as triethylamine, DIPEA, and imidazole, with triethylamine being preferred. Examples of the solvent include polar solvents such as THF, 1,4-dioxane, DMF, DMA and NMP, with DMF being preferred.

Step 1-12-1:
DeTBS of Sulfamide or Sulfonamide Derivatives 1k2 If R3 of sulfamide or sulfonamide derivatives 1k2 has a TBS group _, the TBS group is removed by reacting compound 1k2 with tetrabutylammonium fluoride. Examples of the solvent include polar solvents such as THF, 1,4-dioxane and DMF, with THF being preferred.

Step 1-12-2:
Desilylation of Sulfamide or Sulfonamide Derivatives 1k2 If R ₄ or R ₅ of the sulfamide or sulfonamide derivative 1k2 has a silyl group, the silyl group is removed by reacting the compound 1k2 with a base. Examples of the base include carbonates, and potassium carbonate is preferred. Examples of solvents include alcohols such as methanol and ethanol, with methanol being preferred.

(General manufacturing method -2)
General Preparation-2 is another preferred method for preparing compound 1k1.

Step 2-1:
Sulfamidation or sulfonamidation of amine derivative 1h is carried out analogously to step 1-8.
Step 2-2:
Hydrolysis of the ester derivative 2a is carried out analogously to step 1-6.
Step 2-3:
Amidation of the benzoic acid derivative 2b is carried out in the same manner as in step 1-7. Prior to the amidation, the benzoic acid derivative 2b is optionally de-Boc'ed, alkylated, alkenylated, alkynylated, thioetherified, brominated or chlorinated in steps 1-9-1, 1-9-2 or It may be carried out in the same manner as in 1-10.

(General manufacturing method -3)
General Preparation-3 is another preferred method for preparing compound 1k1.

Step 3-1:
The hydrazonation of aldehyde derivative 1c is carried out analogously to step 1-3.
Step 3-2:
Amidation of benzoic acid derivative 3a is carried out in the same manner as in step 1-7.
Step 3-3:
Coupling of hydrazone derivative 3b with arylboronic acid derivative 1f, removal of protecting group _Rb , and sulfamidation or sulfonamidation of amine derivative are carried out in this order in steps 1-4, 1-5 and 1-8, respectively. Do the same.

(General manufacturing method-4)
In general production method-4, in the compound represented by general formula (1), ring A is a group represented by general formula (4), X ₁ is -N=, and X ₂ is -CF= is a preferred method of constructing the skeleton of compounds in which R ₆ and R ₉ are hydrogen atoms.

Step 4-1:
Alkylation of Compound 4a Compound 4a is reacted with compound 4b in the presence of a base. Examples of bases include phosphates and metal alkoxides such as sodium tert-butoxide, with tripotassium phosphate being preferred. Also, potassium iodide or tetrabutylammonium iodide, for example, may be added to accelerate the reaction, and tetrabutylammonium iodide is preferred as such an additive. Examples of the solvent include polar solvents such as NMP and 1,3-dimethyl-2-imidazolidinone, with 1,3-dimethyl-2-imidazolidinone being preferred. The reaction temperature is preferably 40° C. or higher.

In the preparation of the compounds of the present disclosure, starting compounds or reagents may form salts or solvates as long as the desired reaction is not inhibited.

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 conventional methods. In addition, when the compound of the present disclosure is obtained in the form of a pharmaceutically acceptable salt or solvate, it can be converted into the free form according to a conventional method.

Isolation or purification of a compound, salt or solvate of the disclosure can be accomplished using, for example, distillation, recrystallization or chromatography. Also, if isomers (e.g., enantiomers, diastereomers or conformers) exist, their isolation or purification can be accomplished, for example, by recrystallization, diastereomeric salt methods, enzymatic resolution methods or chromatography (e.g., thin layer chromatography, column chromatography, high performance liquid chromatography or gas chromatography).

In one aspect, the disclosure provides a pharmaceutical composition comprising a 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 a compound, salt or solvate 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 at least one component selected from the group consisting of emulsifiers. good.

In another aspect, the present disclosure provides a medicament for treating or preventing cell proliferative diseases, particularly cancer, containing the compound, salt, or solvate of any one of the first to fourth aspects as an active ingredient. A composition is provided. The pharmaceutical composition for treating or preventing a cell proliferative disease of the present disclosure may consist of a compound, salt or solvate of the present disclosure, or other pharmaceutically acceptable ingredients such as At least one selected from the group consisting of excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, bases, dispersants, diluents, surfactants, and emulsifiers It may contain a component of.

Excipients include, for example, starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and calcium hydrogen phosphate.

Lubricants (coating agents) include, for example, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, talc, carnauba wax, and paraffin.

Binders include, for example, polyvinylpyrrolidone, macrogol, and the same compounds as the excipients described above.

Examples of disintegrants include chemically modified starches and celluloses such as croscarmellose sodium, carboxymethyl starch sodium, crosslinked polyvinylpyrrolidone, and the same compounds as the above excipients.

Stabilizers include, for example, paraoxybenzoic acid esters such as methylparaben and propylparaben; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

Flavoring agents include, for example, commonly used sweeteners, acidulants and flavors.

Examples of bases include fats such as lard; vegetable oils such as olive oil and sesame oil; higher alcohols such as stearyl alcohol and cetanol; animal oils; .

Dispersants include, for example, cellulose derivatives (eg, gum arabic, tragacanth, and methylcellulose), stearic polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, and sorbitan fatty acid esters. .

Solvents or diluents in liquid formulations include, for example, phenol, chlorocresol, purified water, and distilled water.

Surfactants or emulsifiers include, for example, polysorbate 80, polyoxyl 40 stearate, and lauromacrogol.

Subjects to which the compounds, salts or solvates of the present disclosure are administered are animals, preferably mammals (e.g. mice, rats, rabbits, dogs, monkeys (e.g. cynomolgus monkeys) or humans), particularly preferably humans. is. A human may be an adult (18 years of age or older) or a child (under 18 years of age). Children are preferably, for example, 6 months or older.

When the compound, salt or solvate of the present disclosure is used for the treatment or prevention of a cell proliferative disease, the dosage and administration interval may vary depending on the severity of symptoms, age and body weight of the subject, presence or absence of concomitant drugs, administration method, etc. can be determined as appropriate. For example, when the subject of administration is a human, the dose is usually 0.00001 to 5000 mg, preferably 0.01 to 100 mg per kg of body weight, once a day to once every three weeks. When administered daily, the above amount may be divided and administered in 2 to 4 doses.

Examples of administration methods to subjects include systemic administration such as oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intracisternal administration, intravaginal administration, intraperitoneal administration, intravesical administration, and inhalation administration; and topical administration via ointments, gels or creams, although oral administration is preferred.

The compounds, salts, or solvates of the present disclosure are usually used after being formulated into certain formulations (dosage forms). Such formulations include, for example, tablets, capsules, granules, powders, granules, pills, and aqueous or non-aqueous solutions and suspensions. Solutions and suspensions can be filled and stored in suitable containers for subdivision into individual doses.

The various formulations described above can be produced by well-known methods by mixing the compound, salt or solvate of the present disclosure with pharmaceutically acceptable excipients. Such additives include, for example, the aforementioned excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, bases, dispersants, diluents, surfactants, and emulsifiers.

A preferable content ratio of the compound, salt or solvate of the present disclosure in the formulation varies depending on the dosage form, but is usually 0.01 to 100% by weight based on the total weight of the formulation.

Cell proliferative diseases treated or prevented using the compounds, salts or solvates of the present disclosure include cancer, rheumatism and inflammation, preferably cancer.

Cancers include, for example, leukemia (acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, etc.), malignant lymphoma (Hodgkin's disease, non-Hodgkin's lymphoma, etc.), multiple myeloma, and myeloma. cancers of the blood and lymph, such as dysplastic syndrome; cancers of the central nervous system, such as brain tumors and gliomas; cancer, colon cancer, rectal cancer, etc.), lung cancer (small cell cancer, non-small cell cancer, etc.), thyroid cancer, breast cancer, gallbladder cancer, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer, uterine cancer (endometrial cancer, cervical cancer, etc.), testicular cancer, renal cell carcinoma, bladder cancer, renal pelvic/ureteral cancer, malignant melanoma, skin cancer (basal cell carcinoma, squamous cell carcinoma, extramammary Paget's disease, Merkel cell carcinoma, sweat gland carcinoma ( Examples include solid cancers such as apocrine adenocarcinoma or eccrine adenocarcinoma), sebaceous adenocarcinoma, trichomepithelioma, and the like. Cancers include, for example, cancers of mammals (eg, mice, rats, rabbits, dogs, monkeys (eg, cynomolgus monkeys) or humans), particularly human cancers.

A cancer may have a genetic mutation, may not have a genetic mutation, or may be unknown. Examples of mutated genes include EGFR, FGFR, ALK, ROS1, PI3K, BRAF, HRAS, KRAS and NRAS.

When the compound, salt or solvate of the first or second aspect is used, the cancer is preferably, for example, a cancer having RAS mutations, particularly solid cancer having KRAS mutations (particularly non-small cell lung cancer). preferable. In one embodiment, it is also used in cancers with RAF mutations, particularly RAF and RAS mutations.
When the compound, salt or solvate of the third or fourth aspect is used, the cancer is preferably, for example, a cancer having RAF mutations, and particularly preferably a solid cancer having BRAF mutations (particularly malignant melanoma). .

Hereinafter, the present disclosure will be described in more detail based on examples (manufacturing examples and test examples), but the present disclosure is not limited to the following examples.

[Manufacturing example]
NMR analysis was performed using AVANCE III HD400 (400 MHz) manufactured by BRUKER. NMR data are reported in parts per million (δ) and are referenced to the deuterium lock signal from the sample solvent.

Mass spectral data was obtained with a single quadrupole mass spectrometer (LCMS-2020) with an ultra-performance liquid chromatography (Nexera UC) manufactured by Shimadzu Corporation or with an Acquity ultra-performance liquid chromatography (UPLC or UPLC I-Class) manufactured by Waters. Data were obtained using a single quadrupole mass spectrometer (SQD or SQD2).

High-performance liquid chromatography was performed using any one of analytical conditions A to G shown in Table 2 below. In Table 2 below, "TFA" means trifluoroacetic acid, "FA" means formic acid, and "AA" means ammonium acetate.

Microwave reactions were performed using a Biotage Initiator. Snap-cap reaction vials were used for microwave reactions.

Commercially available reagents were used without further purification.
All non-aqueous reactions were carried out in anhydrous solvents.
Vacuum concentration or solvent distillation was performed using a rotary evaporator.

As used herein, "room temperature" means a temperature of about 20°C to about 25°C.

In the following Production Examples, "Production Example of Compound A-1" means Production Example A-1-1, and "Production Example of Compound a9" means Production Example a9-1.

３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）－５－ホルミル安息香酸（５．５０ｇ、１３．１ｍｍｏｌ）のトルエン（４４ｍＬ）及びＭｅＯＨ（１１ｍＬ）混合懸濁液を０℃に冷却し、１０％ジアゾメチルトリメチルシランヘキサン溶液（２１．８ｍＬ、１３．１ｍｍｏｌ）を加え、室温で６４時間攪拌した。反応混合物に酢酸（０．７４８ｍＬ）を加え、減圧濃縮した。得られた残渣をトリチュレーション（ヘキサン／酢酸エチル）で精製して、表題化合物（５．０１ｇ、８８％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４３６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．００分（分析条件Ｄ） Compound a1:
Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-formylbenzoate

A mixed suspension of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid (5.50 g, 13.1 mmol) in toluene (44 mL) and MeOH (11 mL) was cooled to 0° C., 10% diazomethyltrimethylsilane hexane solution (21.8 mL, 13.1 mmol) was added, and the mixture was stirred at room temperature for 64 hours. Acetic acid (0.748 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was purified by trituration (hexane/ethyl acetate) to give the title compound (5.01 g, 88%) as a colorless solid.
LCMS m/z: 436 [M+H] ⁺
HPLC retention time: 1.00 minutes (analysis condition D)

３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－ホルミル安息香酸メチル（化合物ａ１、５．００ｇ、１１．５ｍｍｏｌ）のＥｔＯＨ（１００ｍＬ）懸濁液に４－メチルベンゼンスルホニルヒドラジド（２．１４ｇ、１１．５ｍｍｏｌ）を加え、室温で３時間攪拌した。反応混合物を減圧濃縮した後、ヘキサン（１５０ｍＬ）を加えた。０℃に冷却し、ろ過後、ヘキサン（３０ｍＬ）で洗浄して、表題化合物（７．０５ｇ、ｑｕａｎｔ．）を固体として得た。
ＬＣＭＳ ｍ／ｚ： ６０４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０６分（分析条件Ｄ） Compound a2:
Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate

A suspension of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-formylbenzoate (compound a1, 5.00 g, 11.5 mmol) in EtOH (100 mL) was added with 4-methylbenzenesulfonyl Hydrazide (2.14 g, 11.5 mmol) was added and stirred at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, hexane (150 mL) was added. After cooling to 0° C., filtering and washing with hexane (30 mL), the title compound (7.05 g, quant.) was obtained as a solid.
LCMS m/z: 604 [M+H] ⁺
HPLC retention time: 1.06 minutes (analysis condition D)

２，３－ジフルオロ－４－ヨードピリジン（２．０９ｇ、８．６７ｍｍｏｌ）のＮＭＰ（３２ｍＬ）溶液にトリエチルアミン（３．６３ｍＬ、２６．０ｍｍｏｌ）及び１－（２，４－ジメトキシフェニル）メタンアミン（３．２６ｍＬ、２１．７ｍｍｏｌ）を加え、１００℃で１．５時間攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を１３％食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、乾燥剤をろ去後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製して、表題化合物（３．２０ｇ、９５％）を油状物質として得た。
ＬＣＭＳ ｍ／ｚ： ３８９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９４分（分析条件Ｃ） Compound a3:
N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridin-2-amine

Triethylamine (3.63 mL, 26.0 mmol) and 1-(2,4-dimethoxyphenyl)methanamine (3 .26 mL, 21.7 mmol) was added and stirred at 100° C. for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 13% brine, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.20 g, 95%) as an oil.
LCMS m/z: 389 [M+H] ⁺
HPLC retention time: 0.94 minutes (analysis condition C)

Ｎ－（２，４－ジメトキシベンジル）－３－フルオロ－４－ヨードピリジン－２－アミン（化合物ａ３、２．７０ｇ、６．９６ｍｍｏｌ）、［１，１－ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン付加物（５６８ｍｇ、０．６９６ｍｍｏｌ）、酢酸カリウム（２．０５ｇ、２０．９ｍｍｏｌ）及びビス（ピナコラト）ジボロン（２．６５ｇ、１０．４ｍｍｏｌ）の１，４－ジオキサン溶液（２７ｍＬ）を窒素雰囲気下、９０℃で５時間、次いで１１０℃で１９時間攪拌した。反応混合物を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（２．０７ｇ、９７％）を油状物質として得た。
ＬＣＭＳ ｍ／ｚ： ３０７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．４４分（分析条件Ｃ） Compound a4:
[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid

N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridin-2-amine (compound a3, 2.70 g, 6.96 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloro Palladium(II) dichloromethane adduct (568 mg, 0.696 mmol), potassium acetate (2.05 g, 20.9 mmol) and bis(pinacolato)diboron (2.65 g, 10.4 mmol) in 1,4-dioxane (27 mL) ) was stirred at 90° C. for 5 hours and then at 110° C. for 19 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (2.07 g, 97%) as an oil. obtained as a substance.
LCMS m/z: 307 [M+H] ⁺
HPLC retention time: 0.44 minutes (analytical condition C)

３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［（Ｅ）－［（４－メチルフェニル）スルホニルヒドラジニリデン］メチル］安息香酸メチル（化合物ａ２、１．３０ｇ、２．１６ｍｍｏｌ）、［２－［（２，４－ジメトキシフェニル）メチルアミノ］－３－フルオロピリジン－４－イル］ボロン酸（化合物ａ４、１．９８ｇ、６．４６ｍｍｏｌ）及び炭酸カリウム（３５７ｍｇ、２．５９ｍｍｏｌ）の１，４－ジオキサン懸濁液（５９ｍＬ）を窒素雰囲気下、１００℃で２．５時間、次いで１１０℃で３時間攪拌した。反応混合物に酢酸エチルを加え、水及び１３％食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥させ、乾燥剤をろ去後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製して、表題化合物（５２４ｍｇ、３６％）を泡状物質として得た。
ＬＣＭＳ ｍ／ｚ： ６８２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０３分（分析条件Ｄ） Compound a5:
5-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid methyl

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate (compound a2, 1.30 g, 2.16 mmol), [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4, 1.98 g, 6.46 mmol) and potassium carbonate (357 mg, 2.59 mmol) in 1,4-dioxane (59 mL) was stirred under a nitrogen atmosphere at 100° C. for 2.5 hours and then at 110° C. for 3 hours. Ethyl acetate was added to the reaction mixture and washed with water and 13% brine. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (524 mg, 36%) as a foam.
LCMS m/z: 682 [M+H] ⁺
HPLC retention time: 1.03 minutes (analysis condition D)

５－［［２－［（２，４－ジメトキシフェニル）メチルアミノ］－３－フルオロピリジン－４－イル］メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ａ５、５２３ｍｇ、０．７６８ｍｍｏｌ）のＤＣＭ溶液（１６ｍＬ）を０℃に冷却し、トリフルオロ酢酸（１５．７ｍＬ）を加え、室温で１時間攪拌した。反応混合物を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィー（０．０５％トリフルオロ酢酸水溶液／０．０５％トリフルオロ酢酸アセトニトリル溶液）で精製して、表題化合物（３２１ｍｇ、７９％）を油状物質として得た。
ＬＣＭＳ ｍ／ｚ： ５３２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．５５分（分析条件Ｄ） Compound a6:
Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate

5-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid A DCM solution (16 mL) of methyl (compound a5, 523 mg, 0.768 mmol) was cooled to 0° C., trifluoroacetic acid (15.7 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.05% trifluoroacetic acid aqueous solution/0.05% trifluoroacetic acid acetonitrile solution) to give the title compound (321 mg, 79%). was obtained as an oil.
LCMS m/z: 532 [M+H] ⁺
HPLC retention time: 0.55 minutes (analytical condition D)

５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ａ６、４．００ｇ、７．５３ｍｍｏｌ）のＴＨＦ（６４ｍＬ）及び水（３２ｍＬ）混合溶液を０℃に冷却し、水酸化リチウム一水和物（９４８ｍｇ、２２．６ｍｍｏｌ）を加え、室温で３．５時間攪拌した。０℃に冷却後、反応混合物に５Ｍ塩酸（１５．１ｍＬ）を加え、減圧濃縮した。得られた残渣を水及びＴＢＭＥで洗浄して、表題化合物（４．２０ｇ、ｑｕａｎｔ．）を紫色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５１８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６８分（分析条件Ｃ） Compound a7:
5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a6, 4.00 g, 7. 53 mmol) in THF (64 mL) and water (32 mL) was cooled to 0° C., lithium hydroxide monohydrate (948 mg, 22.6 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. After cooling to 0° C., 5M hydrochloric acid (15.1 mL) was added to the reaction mixture and concentrated under reduced pressure. The resulting residue was washed with water and TBME to give the title compound (4.20 g, quant.) as a purple solid.
LCMS m/z: 518 [M+H] ⁺
HPLC retention time: 0.68 minutes (analytical condition C)

５－（（２－アミノ－３－フルオロピリジン－４－イル）メチル）－３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）安息香酸塩酸塩（化合物ａ７、２００ｍｇ、０．３６１ｍｍｏｌ）の無水ＤＭＦ溶液（３．６ｍＬ）を０℃に冷却し、ＨＯＯＢｔ（６７．８ｍｇ、０．４１５ｍｍｏｌ）及びＥＤＣ・ＨＣｌ（８０．０ｍｇ、０．４１５ｍｍｏｌ）を加え、室温で１．５時間攪拌した。さらにＨＯＯＢｔ（８．８ｍｇ、０．０５４ｍｍｏｌ）及びＥＤＣ・ＨＣｌ（１０．４ｍｇ、０．０５４ｍｍｏｌ）を加え、室温で１時間攪拌した後、０℃で７ＭアンモニアＭｅＯＨ溶液（０．１０３ｍＬ、０．７２２ｍｍｏｌ）及びＤＩＰＥＡ（０．１８９ｍＬ、１．０８ｍｍｏｌ）を加え、室温で３０分間攪拌した。反応混合物に水及び飽和炭酸水素ナトリウム水溶液を１：１で加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥させ、乾燥剤をろ去後、減圧濃縮した。得られた残渣を酢酸エチル（１ｍＬ）に溶解させ、ヘキサン（１０ｍＬ）を加えた。得られた固体をろ取し、ヘキサンで洗浄して、表題化合物（１６２ｍｇ、８７％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５１７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６４分（分析条件Ｃ） Compound a8:
5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (compound a7, 200 mg , 0.361 mmol) in anhydrous DMF (3.6 mL) was cooled to 0° C., HOOBt (67.8 mg, 0.415 mmol) and EDC.HCl (80.0 mg, 0.415 mmol) were added, and 1 Stirred for .5 hours. Further, HOOBt (8.8 mg, 0.054 mmol) and EDC.HCl (10.4 mg, 0.054 mmol) were added and stirred at room temperature for 1 hour. ) and DIPEA (0.189 mL, 1.08 mmol) were added and stirred at room temperature for 30 minutes. Water and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture at a ratio of 1:1, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (1 mL) and hexane (10 mL) was added. The resulting solid was collected by filtration and washed with hexane to give the title compound (162 mg, 87%) as a colorless solid.
LCMS m/z: 517 [M+H] ⁺
HPLC retention time: 0.64 minutes (analytical condition C)

製造例ａ９－１：
５－（（２－アミノ－３－フルオロピリジン－４－イル）メチル）－３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）ベンズアミド（化合物ａ８、１００ｍｇ、０．１９４ｍｍｏｌ）の無水ＴＨＦ溶液（１．９ｍＬ）にテトラキス（トリフェニルホスフィン）パラジウム（０）（１１．２ｍｇ、９．６８μｍｏｌ）及び０．５Ｍシクロプロピル亜鉛ブロミド（１．９４ｍＬ、０．９６９ｍｍｏｌ）を加え、窒素雰囲気下、室温で２．５時間攪拌した。反応混合物に酢酸エチル（５ｍＬ）を加え、セライトろ過後、酢酸エチル（３ｍＬ）で洗浄した。ろ液を水及び飽和食塩水で洗浄し、有機層を無水硫酸ナトリウムで乾燥させ、乾燥剤をろ去後、減圧濃縮した。得られた残渣にジクロロメタン／ヘキサン（１／１０、１１ｍＬ）を加え、固体をろ取し、ヘキサン（３ｍＬ）で洗浄して、化合物ａ９（６３．４ｍｇ、７６％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４３１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６１分（分析条件Ｃ） Compound a9:
5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzamide

Production Example a9-1:
5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (Compound a8, 100 mg, 0. 194 mmol) in anhydrous THF (1.9 mL) was added tetrakis(triphenylphosphine)palladium(0) (11.2 mg, 9.68 μmol) and 0.5 M cyclopropylzinc bromide (1.94 mL, 0.969 mmol). , under a nitrogen atmosphere, at room temperature for 2.5 hours. Ethyl acetate (5 mL) was added to the reaction mixture, filtered through celite, and washed with ethyl acetate (3 mL). The filtrate was washed with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and concentrated under reduced pressure. Dichloromethane/hexane (1/10, 11 mL) was added to the resulting residue, the solid was collected by filtration and washed with hexane (3 mL) to give compound a9 (63.4 mg, 76%) as a colorless solid.
LCMS m/z: 431 [M+H] ⁺
HPLC retention time: 0.61 minutes (analysis condition C)

４－ニトロフェノール（５．００ｇ、３５．９ｍｍｏｌ）及びトリエチルアミン（１１．３ｍＬ、８１．０ｍｍｏｌ）のジクロロメタン溶液（６０ｍＬ）を－７８℃に冷却し、メチルスルファモイルクロリド（５．８２ｇ、４４．９ｍｍｏｌ）のジクロロメタン溶液（１５ｍＬ）を加え、－７８℃で１．５時間攪拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）及び逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（５．５１ｇ、６６％）を無色固体として得た。
ＨＰＬＣ保持時間： ０．６３分（分析条件Ｃ）
^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３） δ： ８．３１（２Ｈ，ｍ），７．４６（２Ｈ，ｍ），４．６８（１Ｈ，ｍ），３．００（３Ｈ，ｄ，Ｊ＝５．４Ｈｚ）． Compound r1:
4-nitrophenyl methylsulfamate

A dichloromethane solution (60 mL) of 4-nitrophenol (5.00 g, 35.9 mmol) and triethylamine (11.3 mL, 81.0 mmol) was cooled to −78° C. and methylsulfamoyl chloride (5.82 g, 44.0 mmol) was added. 9 mmol) in dichloromethane (15 mL) was added, and the mixture was stirred at -78°C for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) and reversed-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title The compound (5.51 g, 66%) was obtained as a colorless solid.
HPLC retention time: 0.63 minutes (analysis condition C)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.31 (2H, m), 7.46 (2H, m), 4.68 (1H, m), 3.00 (3H, d, J = 5 .4 Hz).

製造例Ａ－１－１：
５－（（２－アミノ－３－フルオロピリジン－４－イル）メチル）－２－（（４－シクロプロピル－２－フルオロフェニル）アミノ）－３，４－ジフルオロベンズアミド（化合物ａ９、２．４７ｇ、５．７４ｍｍｏｌ）を無水ＤＭＦ（２８．７ｍＬ）に溶解させ、ピリジン（２．７８ｍＬ、３４．４ｍｍｏｌ）及びメチルスルファミン酸 ４－ニトロフェニル（化合物ｒ１、４．００ｇ、１７．２ｍｍｏｌ）を加え、４０℃で２．５時間攪拌した。反応混合物を室温まで冷却し、水（２４．７ｍＬ）を加えた。アセトニトリル（３ｍＬ）及び水（１９．８ｍＬ）を加え、１０分間攪拌した後、固体をろ取した。得られた固体を水／アセトニトリル（１／１、４９．４ｍＬ）で洗浄して、化合物Ａ－１（２．５６ｇ、８５％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５２４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１３分（分析条件Ａ） Compound A-1:
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

Production Example A-1-1:
5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzamide (compound a9, 2.47 g , 5.74 mmol) was dissolved in anhydrous DMF (28.7 mL), pyridine (2.78 mL, 34.4 mmol) and 4-nitrophenyl methylsulfamate (compound r1, 4.00 g, 17.2 mmol) were added, Stirred at 40° C. for 2.5 hours. The reaction mixture was cooled to room temperature and water (24.7 mL) was added. After adding acetonitrile (3 mL) and water (19.8 mL) and stirring for 10 minutes, the solid was collected by filtration. The solid obtained was washed with water/acetonitrile (1/1, 49.4 mL) to give compound A-1 (2.56 g, 85%) as a colorless solid.
LCMS m/z: 524 [M+H] ⁺
HPLC retention time: 1.13 minutes (analytical condition A)

５－（（２－アミノ－３－フルオロピリジン－４－イル）メチル）－３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）安息香酸塩酸塩（化合物ａ７、１００ｍｇ、０．１９３ｍｍｏｌ）を無水ＤＭＦ（１ｍＬ）に溶解させ、室温でＨＯＯＢｔ（６３．１ｍｇ、０．３８７ｍｍｏｌ）及びＥＤＣ・ＨＣｌ（７４．１ｍｇ、０．３８７ｍｍｏｌ）を加えた。室温で３時間攪拌した後、アミノシクロプロパン（３３．１ｍｇ、０．５８０ｍｍｏｌ）及びＤＩＰＥＡ（０．１０１ｍＬ、０．５８０ｍｍｏｌ）を加え、室温で１時間攪拌した。反応混合物を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（１０３ｍｇ、９６％）を褐色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５５７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７３分（分析条件Ｃ） Compound a10:
5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (compound a7, 100 mg , 0.193 mmol) was dissolved in anhydrous DMF (1 mL) and HOOBt (63.1 mg, 0.387 mmol) and EDC.HCl (74.1 mg, 0.387 mmol) were added at room temperature. After stirring for 3 hours at room temperature, aminocyclopropane (33.1 mg, 0.580 mmol) and DIPEA (0.101 mL, 0.580 mmol) were added and stirred for 1 hour at room temperature. The reaction mixture was purified by reverse phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (103 mg, 96%) as a brown solid.
LCMS m/z: 557 [M+H] ⁺
HPLC retention time: 0.73 minutes (analysis condition C)

化合物Ａ－１の製造例と同様の条件で、５－（（２－アミノ－３－フルオロピリジン－４－イル）メチル）－Ｎ－シクロプロピル－３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）ベンズアミド（化合物ａ１０）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６５０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６５分（分析条件Ｂ） Compound A-2:
N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2- The title compound was synthesized from fluoro-4-iodophenyl)amino)benzamide (compound a10).
LCMS m/z: 650 [M+H] ⁺
HPLC retention time: 1.65 minutes (Analysis condition B)

４－ニトロフェノール（１２．０ｇ、８６ｍｍｏｌ）及びピリジン（６．９８ｍＬ、８６ｍｍｏｌ）のＥｔ_２Ｏ懸濁液（９６ｍＬ）を－７８℃に冷却し、塩化スルフリル（６．９８ｍＬ、８６ｍｍｏｌ）のＥｔ_２Ｏ溶液（９６ｍＬ）を１０分かけて加え、室温で６．５時間攪拌した。反応混合物をろ過し、Ｅｔ_２Ｏ（１５ｍＬ）で洗浄した後、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／ＤＣＭ）で精製して、表題化合物（１９．８ｇ、９７％）を黄色油状物質として得た。
ＨＰＬＣ保持時間： ０．７７分（分析条件Ｃ）
^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３） δ： ８．４１（２Ｈ，ｍ），７．６１（２Ｈ，ｍ）． Compound r2:
1-chlorosulfonyloxy-4-nitrobenzene

An Et ₂ O suspension (96 mL) of 4-nitrophenol (12.0 g, 86 mmol) and pyridine (6.98 mL, 86 mmol) was cooled to −78° C. and sulfuryl chloride (6.98 mL, 86 mmol) in Et ₂ O solution (96 mL) was added over 10 minutes and stirred at room temperature for 6.5 hours. After filtering the reaction mixture and washing with Et ₂ O (15 mL), the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/DCM) to give the title compound (19.8 g, 97%) as a yellow oil.
HPLC retention time: 0.77 minutes (analytical condition C)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.41 (2H, m), 7.61 (2H, m).

１－クロロスルホニルオキシ－４－ニトロベンゼン（化合物ｒ２、１．７８ｇ、７．４８ｍｍｏｌ）のＤＣＭ溶液（３６ｍＬ）を－７８℃に冷却し、２，４－ジメトキシベンジルアミン（１．００ｇ、５．９８ｍｍｏｌ）、４－ニトロフェノール（１．０４ｇ、７．４８ｍｍｏｌ）及びトリエチルアミン（５．００ｍＬ、３５．９ｍｍｏｌ）のＤＣＭ溶液（５３ｍＬ）を１０分かけて加え、室温で４時間攪拌した。反応混合物を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）及びシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製して、表題化合物（１．２８ｇ、５８％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ３６７［Ｍ－Ｈ］^－
ＨＰＬＣ保持時間： ０．８１分（分析条件Ｃ） Compound r3:
4-nitrophenyl N-[(2,4-dimethoxyphenyl)methyl]sulfamate

A DCM solution (36 mL) of 1-chlorosulfonyloxy-4-nitrobenzene (compound r2, 1.78 g, 7.48 mmol) was cooled to −78° C. and treated with 2,4-dimethoxybenzylamine (1.00 g, 5.98 mmol). ), 4-nitrophenol (1.04 g, 7.48 mmol) and triethylamine (5.00 mL, 35.9 mmol) in DCM (53 mL) were added over 10 minutes and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) and silica gel column chromatography (hexane/ethyl acetate) to give the title The compound (1.28 g, 58%) was obtained as a colorless solid.
LCMS m/z: 367 [MH] ^-
HPLC retention time: 0.81 minutes (analytical condition C)

化合物ａ６の製造例と同様の条件で、Ｎ－［（２，４－ジメトキシフェニル）メチル］スルファミン酸 ４－ニトロフェニル（化合物ｒ３）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ２１７［Ｍ－Ｈ］^－
ＨＰＬＣ保持時間： ０．５３分（分析条件Ｃ） Compound r4:
4-nitrophenyl sulfamate

The title compound was synthesized from 4-nitrophenyl N-[(2,4-dimethoxyphenyl)methyl]sulfamate (compound r3) under the same conditions as in the production example of compound a6.
LCMS m/z: 217 [MH] ^-
HPLC retention time: 0.53 minutes (analysis condition C)

化合物ｒ３の製造例と同様の条件で、１－クロロスルホニルオキシ－４－ニトロベンゼン（化合物ｒ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ２４５［Ｍ－Ｈ］^－
ＨＰＬＣ保持時間： ０．６８分（分析条件Ｃ） Compound r5:
4-Nitrophenyl N-ethylsulfamate

The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the production example of compound r3.
LCMS m/z: 245 [MH] ^-
HPLC retention time: 0.68 minutes (analytical condition C)

化合物ｒ３の製造例と同様の条件で、１－クロロスルホニルオキシ－４－ニトロベンゼン（化合物ｒ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ２５７［Ｍ－Ｈ］^－
ＨＰＬＣ保持時間： ０．７０分（分析条件Ｃ） Compound r6:
4-nitrophenyl N-cyclopropylsulfamate

The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the production example of compound r3.
LCMS m/z: 257 [MH] ^-
HPLC retention time: 0.70 minutes (analysis condition C)

化合物ｒ３の製造例と同様の条件で、１－クロロスルホニルオキシ－４－ニトロベンゼン（化合物ｒ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ２６３［Ｍ－Ｈ］^－
ＨＰＬＣ保持時間： ０．６５分（分析条件Ｃ） Compound r7:
4-nitrophenyl N-(2-fluoroethyl)sulfamate

The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the production example of compound r3.
LCMS m/z: 263 [MH] ^-
HPLC retention time: 0.65 minutes (analytical condition C)

化合物ｒ３の製造例と同様の条件で、１－クロロスルホニルオキシ－４－ニトロベンゼン（化合物ｒ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ３８９［Ｍ－Ｈ］^－
ＨＰＬＣ保持時間： １．０３分（分析条件Ｃ） Compound r11:
4-nitrophenyl N-[2-[tert-butyl(dimethyl)silyl]oxypropyl]sulfamate

The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the production example of compound r3.
LCMS m/z: 389 [MH] ^-
HPLC retention time: 1.03 minutes (analysis condition C)

化合物ｒ３の製造例と同様の条件で、１－クロロスルホニルオキシ－４－ニトロベンゼン（化合物ｒ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ２７７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６４分（分析条件Ｃ） Compound r8:
4-nitrophenyl N-(2-methoxyethyl)sulfamate

The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the production example of compound r3.
LCMS m/z: 277 [M+H] ⁺
HPLC retention time: 0.64 minutes (analytical condition C)

化合物ｒ３の製造例と同様の条件で、１－クロロスルホニルオキシ－４－ニトロベンゼン（化合物ｒ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ２８７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７８分（分析条件Ｃ） Compound r9:
4-nitrophenyl N-(1-methylcyclobutyl)sulfamate

The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the production example of compound r3.
LCMS m/z: 287 [M+H] ⁺
HPLC retention time: 0.78 minutes (analytical condition C)

化合物ｒ３の製造例と同様の条件で、１－クロロスルホニルオキシ－４－ニトロベンゼン（化合物ｒ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ３０３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６７分（分析条件Ｃ） Compound r10:
4-nitrophenyl N-[1-(methoxymethyl)cyclopropyl]sulfamate

The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the production example of compound r3.
LCMS m/z: 303 [M+H] ⁺
HPLC retention time: 0.67 minutes (analytical condition C)

化合物ｒ３の製造例と同様の条件で、１－クロロスルホニルオキシ－４－ニトロベンゼン（化合物ｒ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ２６１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７２分（分析条件Ｃ） Compound r12:
4-nitrophenyl N-propylsulfamate

The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the production example of compound r3.
LCMS m/z: 261 [M+H] ⁺
HPLC retention time: 0.72 minutes (analysis condition C)

化合物ｒ３の製造例と同様の条件で、１－クロロスルホニルオキシ－４－ニトロベンゼン（化合物ｒ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ２８９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．５９分（分析条件Ｃ） Compound r13:
4-nitrophenyl N-(oxetan-3-ylmethyl)sulfamate

The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the production example of compound r3.
LCMS m/z: 289 [M+H] ⁺
HPLC retention time: 0.59 minutes (analysis condition C)

化合物ｒ３の製造例と同様の条件で、１－クロロスルホニルオキシ－４－ニトロベンゼン（化合物ｒ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ３０１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６３分（分析条件Ｃ） Compound r14:
4-nitrophenyl N-(3-oxabicyclo[3.1.0]hexan-6-yl)sulfamate

The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the production example of compound r3.
LCMS m/z: 301 [M+H] ⁺
HPLC retention time: 0.63 minutes (analysis condition C)

化合物ｒ３の製造例と同様の条件で、１－クロロスルホニルオキシ－４－ニトロベンゼン（化合物ｒ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ２７３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７３分（分析条件Ｃ） Compound r15:
4-Nitrophenyl N-(1-methylcyclopropyl)sulfamate

The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the production example of compound r3.
LCMS m/z: 273 [M+H] ⁺
HPLC retention time: 0.73 minutes (analysis condition C)

化合物ｒ３の製造例と同様の条件で、１－クロロスルホニルオキシ－４－ニトロベンゼン（化合物ｒ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ３０３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６７分（分析条件Ｃ） Compound r16:
4-Nitrophenyl N-[[(2R)-oxolan-2-yl]methyl]sulfamate

The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the production example of compound r3.
LCMS m/z: 303 [M+H] ⁺
HPLC retention time: 0.67 minutes (analytical condition C)

化合物ｒ３の製造例と同様の条件で、１－クロロスルホニルオキシ－４－ニトロベンゼン（化合物ｒ２）及び対応するアミンより表題化合物を合成した。
ＨＰＬＣ保持時間： ０．７６分（分析条件Ｃ）
^１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ_６） δ： ８．５９（１Ｈ，ｓ），８．３４（２Ｈ，ｍ），７．５８（２Ｈ，ｍ），３．３０（２Ｈ，ｓ），３．２７（３Ｈ，ｓ），１．２８（６Ｈ，ｓ）． Compound r17:
4-nitrophenyl N-(1-methoxy-2-methylpropan-2-yl)sulfamate

The title compound was synthesized from 1-chlorosulfonyloxy-4-nitrobenzene (compound r2) and the corresponding amine under the same conditions as in the production example of compound r3.
HPLC retention time: 0.76 minutes (analytical condition C)
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 8.59 (1H, s), 8.34 (2H, m), 7.58 (2H, m), 3.30 (2H, s), 3.27 (3H, s), 1.28 (6H, s).

化合物Ａ－１の製造例と同様の条件で、５－（（２－アミノ－３－フルオロピリジン－４－イル）メチル）－Ｎ－シクロプロピル－３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）ベンズアミド（化合物ａ１０）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６３６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．５８分（分析条件Ｂ） Compound A-3:
N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(sulfamoylamino)pyridin-4-yl]methyl]benzamide

5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2- The title compound was synthesized from fluoro-4-iodophenyl)amino)benzamide (compound a10) and the corresponding 4-nitrophenyl sulfamate.
LCMS m/z: 636 [M+H] ⁺
HPLC retention time: 1.58 minutes (analysis condition B)

化合物Ａ－１の製造例と同様の条件で、５－（（２－アミノ－３－フルオロピリジン－４－イル）メチル）－Ｎ－シクロプロピル－３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）ベンズアミド（化合物ａ１０）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６６４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７０分（分析条件Ｂ） Compound A-4:
N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2- The title compound was synthesized from fluoro-4-iodophenyl)amino)benzamide (compound a10) and the corresponding 4-nitrophenyl sulfamate.
LCMS m/z: 664 [M+H] ⁺
HPLC retention time: 1.70 minutes (analysis condition B)

化合物Ａ－１の製造例と同様の条件で、５－（（２－アミノ－３－フルオロピリジン－４－イル）メチル）－Ｎ－シクロプロピル－３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）ベンズアミド（化合物ａ１０）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６７６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７０分（分析条件Ｂ） Compound A-5:
N-cyclopropyl-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2- The title compound was synthesized from fluoro-4-iodophenyl)amino)benzamide (compound a10) and the corresponding 4-nitrophenyl sulfamate.
LCMS m/z: 676 [M+H] ⁺
HPLC retention time: 1.70 minutes (analysis condition B)

化合物Ａ－１の製造例と同様の条件で、５－（（２－アミノ－３－フルオロピリジン－４－イル）メチル）－Ｎ－シクロプロピル－３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）ベンズアミド（化合物ａ１０）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６８２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６６分（分析条件Ｂ） Compound A-6:
N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino ) benzamide

5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-cyclopropyl-3,4-difluoro-2-((2- The title compound was synthesized from fluoro-4-iodophenyl)amino)benzamide (compound a10) and the corresponding 4-nitrophenyl sulfamate.
LCMS m/z: 682 [M+H] ⁺
HPLC retention time: 1.66 minutes (Analysis condition B)

化合物ａ１０及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸塩酸塩（化合物ａ７）より表題化合物を合成した。但し、化合物ａ１０の製造例で用いたアミノシクロプロパンの代わりに２ＭメチルアミンＴＨＦ溶液を用いた。
ＬＣＭＳ ｍ／ｚ： ６２４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６２分（分析条件Ｂ） Compound A-7:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methylbenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4 -Iodoanilino)benzoic acid hydrochloride (compound a7) to synthesize the title compound. However, a 2M methylamine THF solution was used in place of the aminocyclopropane used in the production example of compound a10.
LCMS m/z: 624 [M+H] ⁺
HPLC retention time: 1.62 minutes (analysis condition B)

５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸塩酸塩（化合物ａ７、１００ｍｇ、０．１８１ｍｍｏｌ）を無水ＤＭＦ（０．９ｍＬ）に溶解させ、ＨＯＯＢｔ（５８．９ｍｇ、０．３６１ｍｍｏｌ）及びＥＤＣ・ＨＣｌ（６９．２ｍｇ、０．３６１ｍｍｏｌ）を加え、室温で３．５時間攪拌した。その後、ｔｅｒｔ－ブトキシアミン塩酸塩（６８．１ｍｇ、０．５４２ｍｍｏｌ）及びＤＩＰＥＡ（０．９５ｍＬ、０．５４２ｍｍｏｌ）を加え、室温で１．５時間攪拌した。反応混合物を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（８９ｍｇ、８４％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５８９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７７分（分析条件Ｃ） Compound a12:
5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-(tert-butoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid hydrochloride (Compound a7, 100 mg, 0.181 mmol ) was dissolved in anhydrous DMF (0.9 mL), HOOBt (58.9 mg, 0.361 mmol) and EDC.HCl (69.2 mg, 0.361 mmol) were added, and the mixture was stirred at room temperature for 3.5 hours. After that, tert-butoxyamine hydrochloride (68.1 mg, 0.542 mmol) and DIPEA (0.95 mL, 0.542 mmol) were added and stirred at room temperature for 1.5 hours. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (89 mg, 84%) as a colorless solid.
LCMS m/z: 589 [M+H] ⁺
HPLC retention time: 0.77 minutes (analytical condition C)

化合物Ａ－１の製造例と同様の条件で、５－（（２－アミノ－３－フルオロピリジン－４－イル）メチル）－Ｎ－（ｔｅｒｔ－ブトキシ）－３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）ベンズアミド（化合物ａ１２）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６８２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６９分（分析条件Ｂ） Compound A-8:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2- Methylpropan-2-yl)oxy]benzamide

5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-(tert-butoxy)-3,4-difluoro-2-( The title compound was synthesized from (2-fluoro-4-iodophenyl)amino)benzamide (compound a12).
LCMS m/z: 682 [M+H] ⁺
HPLC retention time: 1.69 minutes (analysis condition B)

化合物Ａ－１の製造例と同様の条件で、５－（（２－アミノ－３－フルオロピリジン－４－イル）メチル）－Ｎ－（ｔｅｒｔ－ブトキシ）－３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）ベンズアミド（化合物ａ１２）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ７２６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７１分（分析条件Ｂ） Compound A-9:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]-N-[ (2-methylpropan-2-yl)oxy]benzamide

5-((2-amino-3-fluoropyridin-4-yl)methyl)-N-(tert-butoxy)-3,4-difluoro-2-( The title compound was synthesized from (2-fluoro-4-iodophenyl)amino)benzamide (compound a12) and the corresponding 4-nitrophenyl sulfamate.
LCMS m/z: 726 [M+H] ⁺
HPLC retention time: 1.71 minutes (analysis condition B)

化合物ａ１２及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸塩酸塩（化合物ａ７）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６６８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２４分（分析条件Ａ） Compound A-10:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-propane-2- yloxybenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4 -iodoanilino)benzoic acid hydrochloride (compound a7) and the corresponding amine to synthesize the title compound.
LCMS m/z: 668 [M+H] ⁺
HPLC retention time: 1.24 minutes (analytical condition A)

化合物ａ１２及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸塩酸塩（化合物ａ７）及び対応するアミンより表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ７１２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２６分（分析条件Ａ） Compound A-11:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]-N-propane -2-yloxybenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4 -iodoanilino)benzoic acid hydrochloride (compound a7) and the corresponding amine to synthesize the title compound. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 712 [M+H] ⁺
HPLC retention time: 1.26 minutes (analytical condition A)

化合物ａ１２及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸塩酸塩（化合物ａ７）及び対応するアミンより表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ７２２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．８１分（分析条件Ｂ） Compound A-12:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]- N-propan-2-yloxybenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4 -iodoanilino)benzoic acid hydrochloride (compound a7) and the corresponding amine to synthesize the title compound. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 722 [M+H] ⁺
HPLC retention time: 1.81 minutes (analysis condition B)

化合物ａ１２及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸塩酸塩（化合物ａ７）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６４０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１６分（分析条件Ａ） Compound A-13:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4 -iodoanilino)benzoic acid hydrochloride (compound a7) and the corresponding amine to synthesize the title compound.
LCMS m/z: 640 [M+H] ⁺
HPLC retention time: 1.16 minutes (analytical condition A)

化合物ａ１２及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸塩酸塩（化合物ａ７）及び対応するアミンより表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６８４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１８分（分析条件Ａ） Compound A-14:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4 -iodoanilino)benzoic acid hydrochloride (compound a7) and the corresponding amine to synthesize the title compound. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 684 [M+H] ⁺
HPLC retention time: 1.18 minutes (analytical condition A)

化合物ａ１２及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸塩酸塩（化合物ａ７）及び対応するアミンより表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６９４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７２分（分析条件Ｂ） Compound A-15:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]- N-Methoxybenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4 -iodoanilino)benzoic acid hydrochloride (compound a7) and the corresponding amine to synthesize the title compound. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 694 [M+H] ⁺
HPLC retention time: 1.72 minutes (analysis condition B)

化合物ａ１２及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸塩酸塩（化合物ａ７）及び対応するアミンより表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６８０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２０分（分析条件Ａ） Compound A-16:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[[1-(methoxymethyl)cyclopropyl]sulfamoylamino]pyridin-4-yl] methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4 -iodoanilino)benzoic acid hydrochloride (compound a7) and the corresponding amine to synthesize the title compound. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 680 [M+H] ⁺
HPLC retention time: 1.20 minutes (analytical condition A)

化合物ａ１２及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸塩酸塩（化合物ａ７）及び対応するアミンより表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ７６８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１２分（分析条件Ｃ） Compound a15:
5-[[2-[2-[tert-butyl(dimethyl)silyl]oxypropylsulfamoylamino]-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro -4-iodoanilino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4 -iodoanilino)benzoic acid hydrochloride (compound a7) and the corresponding amine to synthesize the title compound. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 768 [M+H] ⁺
HPLC retention time: 1.12 minutes (analytical condition C)

５－［［２－［２－［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシプロピルスルファモイルアミノ］－３－フルオロピリジン－４－イル］メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ１５、６０．０ｍｇ、０．７８ｍｍｏｌ）をＭｅＯＨ（０．４ｍＬ）に溶解させ、（－）－１０－カンファースルホン酸（２７．２ｍｇ、０．１１７ｍｍｏｌ）を加え、室温で１時間攪拌した。反応混合物を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（３８ｍｇ、７４％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ６５４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１０分（分析条件Ａ） Compound A-17:
(+/-)-3,4-difluoro-5-[[3-fluoro-2-(2-hydroxypropylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4- iodoanilino)benzamide (racemic)

5-[[2-[2-[tert-butyl(dimethyl)silyl]oxypropylsulfamoylamino]-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro -4-iodoanilino)benzamide (compound a15, 60.0 mg, 0.78 mmol) was dissolved in MeOH (0.4 mL) and (−)-10-camphorsulfonic acid (27.2 mg, 0.117 mmol) was added, Stir at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (38 mg, 74%) as a colorless solid. Obtained.
LCMS m/z: 654 [M+H] ⁺
HPLC retention time: 1.10 minutes (analytical condition A)

５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８、３０．０ｍｇ、０．０５８ｍｍｏｌ）を無水１，４－ジオキサン（０．３ｍＬ）に溶解させ、メチルメルカプタンナトリウム（１２．２ｍｇ、０．１７４ｍｍｏｌ）、ＤＩＰＥＡ（３０．４μＬ、０．１７４ｍｍｏｌ）及び［（４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン）－２－（２’－アミノ－１，１’－ビフェニル）］パラジウム（ＩＩ）メタンスルホン酸塩（１１．２ｍｇ、０．０１２ｍｍｏｌ）を加え、窒素雰囲気下、室温で３０分間攪拌した。反応混合物を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（１５ｍｇ、５９％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４３７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６０分（分析条件Ｃ） Compound a16:
5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-methylsulfanylanilino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 30.0 mg, 0.058 mmol) was dissolved in anhydrous 1,4-dioxane (0.3 mL) and sodium methyl mercaptan (12.2 mg, 0.174 mmol), DIPEA (30.4 μL, 0.174 mmol) and [(4,5-bis(diphenylphosphine) Phino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (11.2 mg, 0.012 mmol) was added and , and stirred at room temperature for 30 minutes. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (15 mg, 59%) as a colorless solid.
LCMS m/z: 437 [M+H] ⁺
HPLC retention time: 0.60 minutes (analysis condition C)

化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－メチルスルファニルアニリノ）ベンズアミド（化合物ａ１６）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５３０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０９分（分析条件Ａ） Compound A-18:
3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-methylsulfanyl The title compound was synthesized from anilino)benzamide (compound a16).
LCMS m/z: 530 [M+H] ⁺
HPLC retention time: 1.09 minutes (analysis condition A)

５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８、５００ｍｇ、０．９６９ｍｍｏｌ）を脱気した２－プロパノール（１２ｍＬ）及び無水ＴＨＦ（２ｍＬ）に溶解させ、カリウムビニルトリフルオロボラート（１４３ｍｇ、１．０７ｍｍｏｌ）、トリエチルアミン（０．４０５ｍＬ、２．９１ｍｍｏｌ）及び［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド ジクロロメタン付加物（７９．０ｍｇ、０．０９７ｍｍｏｌ）を加え、窒素雰囲気下、８０℃で２時間攪拌した。反応混合物をセライトろ過し、固形物を酢酸エチル及びＭｅＯＨで洗浄した。ろ液を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（３４３ｍｇ、８５％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４１７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６０分（分析条件Ｃ） Compound a17:
5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinylphenyl)amino)benzamide

5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 500 mg, 0.969 mmol) was removed. Potassium vinyltrifluoroborate (143 mg, 1.07 mmol), triethylamine (0.405 mL, 2.91 mmol) and [1,1′-bis( Diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (79.0 mg, 0.097 mmol) was added and stirred at 80° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was filtered through celite and the solid was washed with ethyl acetate and MeOH. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (343 mg, 85%) as a colorless solid. Obtained.
LCMS m/z: 417 [M+H] ⁺
HPLC retention time: 0.60 minutes (analysis condition C)

化合物Ａ－１の製造例と同様の条件で、５－（（２－アミノ－３－フルオロピリジン－４－イル）メチル）－３，４－ジフルオロ－２－（（２－フルオロ－４－ビニルフェニル）アミノ）ベンズアミド（化合物ａ１７）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５１０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１１分（分析条件Ａ） Compound A-19:
2-(4-ethenyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-vinyl The title compound was synthesized from phenyl)amino)benzamide (compound a17).
LCMS m/z: 510 [M+H] ⁺
HPLC retention time: 1.11 minutes (analytical condition A)

５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８、２．６７ｇ、５．１７ｍｍｏｌ）の無水ＴＨＦ溶液（２６ｍＬ）にトリエチルアミン（３１．７ｍＬ、２２８ｍｍｏｌ）、トリメチルシリルアセチレン（１．４３ｍＬ、１０．３ｍｍｏｌ）、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロリド（３６３ｍｇ、０．５１７ｍｍｏｌ）及びヨウ化銅（Ｉ）（２９６ｍｇ、１．５５ｍｍｏｌ）を加え、室温で３時間攪拌した。反応混合物を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（２．５７ｇ、８３％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４８７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８４分（分析条件Ｇ） Compound a18:
5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 2.67 g, 5.17 mmol) in anhydrous THF (26 mL), triethylamine (31.7 mL, 228 mmol), trimethylsilylacetylene (1.43 mL, 10.3 mmol), bis(triphenylphosphine)palladium(II) dichloride (363 mg, 0.517 mmol) and iodide Copper (I) (296 mg, 1.55 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (2.57 g, 83%) as a colorless Obtained as a solid.
LCMS m/z: 487 [M+H] ⁺
HPLC retention time: 0.84 minutes (analytical condition G)

５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－［２－フルオロ－４－（２－トリメチルシリルエチニル）アニリノ］ベンズアミド（化合物ａ１８、２０．０ｍｇ、０．０４１ｍｍｏｌ）のＭｅＯＨ溶液（０．４１１ｍＬ）に炭酸カリウム（１７．０ｍｇ、０．１２３ｍｍｏｌ）を加え、室温で１．５時間攪拌した。反応混合物を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（１４ｍｇ、８２％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４１５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６０分（分析条件Ｇ） Compound a19:
5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-ethynyl-2-fluoroanilino)-3,4-difluorobenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide (compound a18, 20. 0 mg, 0.041 mmol) in MeOH (0.411 mL) was added potassium carbonate (17.0 mg, 0.123 mmol) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (14 mg, 82%) as a colorless solid. Obtained.
LCMS m/z: 415 [M+H] ⁺
HPLC retention time: 0.60 minutes (analysis condition G)

化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（４－エチニル－２－フルオロアニリノ）－３，４－ジフルオロベンズアミド（化合物ａ１９）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５３６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１８分（分析条件Ａ） Compound A-20:
2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide

Under the same conditions as in the Production Example of Compound A-1, 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-ethynyl-2-fluoroanilino)-3,4 -difluorobenzamide (compound a19) and the corresponding 4-nitrophenyl sulfamate to synthesize the title compound.
LCMS m/z: 536 [M+H] ⁺
HPLC retention time: 1.18 minutes (analytical condition A)

化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。但し、ピリジンの代わりにイミダゾールを用いた。
ＬＣＭＳ ｍ／ｚ： ６６６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１１分（分析条件Ａ） Compound A-21:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(oxetan-3-ylmethylsulfamoylamino)pyridin-4-yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in Production Example of Compound A-1 The title compound was synthesized from benzamide (compound a8) and the corresponding 4-nitrophenyl sulfamate. However, imidazole was used instead of pyridine.
LCMS m/z: 666 [M+H] ⁺
HPLC retention time: 1.11 minutes (analytical condition A)

化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。但し、ピリジンの代わりにイミダゾールを用いた。
ＬＣＭＳ ｍ／ｚ： ６７８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１６分（分析条件Ａ） Compound A-22:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(3-oxabicyclo[3.1.0]hexane-6-ylsulfamoylamino)pyridine -4-yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in Production Example of Compound A-1 The title compound was synthesized from benzamide (compound a8) and the corresponding 4-nitrophenyl sulfamate. However, imidazole was used instead of pyridine.
LCMS m/z: 678 [M+H] ⁺
HPLC retention time: 1.16 minutes (analytical condition A)

化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。但し、ピリジンの代わりにイミダゾールを、無水ＤＭＦの代わりに無水ＴＨＦを用いた。
ＬＣＭＳ ｍ／ｚ： ６５０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２５分（分析条件Ａ） Compound A-23:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclopropyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-1 The title compound was synthesized from benzamide (compound a8) and the corresponding 4-nitrophenyl sulfamate. However, imidazole was used instead of pyridine, and anhydrous THF was used instead of anhydrous DMF.
LCMS m/z: 650 [M+H] ⁺
HPLC retention time: 1.25 minutes (analytical condition A)

化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。但し、ピリジンの代わりにイミダゾールを、無水ＤＭＦの代わりに無水ＴＨＦを用いた。
ＬＣＭＳ ｍ／ｚ： ６８２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２７分（分析条件Ａ） Compound A-24:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methoxy-2-methylpropan-2-yl)sulfamoylamino]pyridine- 4-yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-1 The title compound was synthesized from benzamide (compound a8) and the corresponding 4-nitrophenyl sulfamate. However, imidazole was used instead of pyridine, and anhydrous THF was used instead of anhydrous DMF.
LCMS m/z: 682 [M+H] ⁺
HPLC retention time: 1.27 minutes (analytical condition A)

５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８、１０．０ｍｇ、０．０１９ｍｍｏｌ）を無水ＤＭＡ（０．１ｍＬ）に溶解させ、０℃でピリジン（２．３μＬ、０．０２９ｍｍｏｌ）及びメチルスルファモイルクロリド（２．５μＬ、０．０２９ｍｍｏｌ）を加え、室温で１時間攪拌した。反応混合物を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（１０．２ｍｇ、８６％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ６１０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１５分（分析条件Ａ） Compound A-25:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 10.0 mg, 0.019 mmol) was dissolved in anhydrous DMA (0.1 mL), pyridine (2.3 μL, 0.029 mmol) and methylsulfamoyl chloride (2.5 μL, 0.029 mmol) were added at 0° C., and stirred at room temperature for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (10.2 mg, 86%) as a colorless solid.
LCMS m/z: 610 [M+H] ⁺
HPLC retention time: 1.15 minutes (analytical condition A)

スルフリルクロリド（０．１０２ｍＬ、１．２５ｍｍｏｌ）を無水アセトニトリル（１．５ｍＬ）に溶解させ、０℃でビシクロ［１．１．１］ペンタン－１－アミン塩酸塩（５０．０ｍｇ、０．４１８ｍｍｏｌ）を加え、窒素雰囲気下、８０℃で１６時間攪拌した。反応混合物を減圧濃縮して表題化合物の粗生成物を得た。 Compound s2:
N-(1-bicyclo[1.1.1]pentanyl)sulfamoyl chloride

Sulfuryl chloride (0.102 mL, 1.25 mmol) was dissolved in anhydrous acetonitrile (1.5 mL) at 0° C. to bicyclo[1.1.1]pentan-1-amine hydrochloride (50.0 mg, 0.418 mmol). was added and stirred at 80° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the crude title compound.

化合物ｓ２の製造例と同様の条件で、対応するアミンより表題化合物を合成した。但し、トリエチルアミンも添加した。 Compound s3:
N-(oxan-4-yl)sulfamoyl chloride

The title compound was synthesized from the corresponding amine under the same conditions as in the production example of compound s2. However, triethylamine was also added.

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファモイルクロリドより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６６２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２７分（分析条件Ａ） Compound A-28:
5-[[2-(1-bicyclo[1.1.1]pentanylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4 - iodoanilino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from the benzamide (compound a8) and the corresponding sulfamoyl chloride.
LCMS m/z: 662 [M+H] ⁺
HPLC retention time: 1.27 minutes (analytical condition A)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファモイルクロリドより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６８０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１６分（分析条件Ａ） Compound A-29:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(oxan-4-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from the benzamide (compound a8) and the corresponding sulfamoyl chloride.
LCMS m/z: 680 [M+H] ⁺
HPLC retention time: 1.16 minutes (analytical condition A)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファモイルクロリドより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６３６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２１分（分析条件Ａ） Compound A-30:
5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from the benzamide (compound a8) and the corresponding sulfamoyl chloride.
LCMS m/z: 636 [M+H] ⁺
HPLC retention time: 1.21 minutes (analytical condition A)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファモイルクロリドより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６３８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２４分（分析条件Ａ） Compound A-31:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from the benzamide (compound a8) and the corresponding sulfamoyl chloride.
LCMS m/z: 638 [M+H] ⁺
HPLC retention time: 1.24 minutes (analytical condition A)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファモイルクロリドより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６５０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２６分（分析条件Ａ） Compound A-32:
5-[[2-(Cyclobutylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from the benzamide (compound a8) and the corresponding sulfamoyl chloride.
LCMS m/z: 650 [M+H] ⁺
HPLC retention time: 1.26 minutes (analytical condition A)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファモイルクロリドより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６５４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１７分（分析条件Ａ） Compound A-33:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from the benzamide (compound a8) and the corresponding sulfamoyl chloride.
LCMS m/z: 654 [M+H] ⁺
HPLC retention time: 1.17 minutes (analytical condition A)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファモイルクロリドより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６５２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．３１分（分析条件Ａ） Compound A-34:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from the benzamide (compound a8) and the corresponding sulfamoyl chloride.
LCMS m/z: 652 [M+H] ⁺
HPLC retention time: 1.31 minutes (analytical condition A)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファモイルクロリドより表題化合物を合成した。但し、反応は０℃で行った。
ＬＣＭＳ ｍ／ｚ： ６６４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．３０分（分析条件Ａ） Compound A-35:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from the benzamide (compound a8) and the corresponding sulfamoyl chloride. However, the reaction was carried out at 0°C.
LCMS m/z: 664 [M+H] ⁺
HPLC retention time: 1.30 minutes (analytical condition A)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファモイルクロリドより表題化合物を合成した。但し、反応は０℃で行った。
ＬＣＭＳ ｍ／ｚ： ６５０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２６分（分析条件Ａ） Compound A-36:
5-[[2-(Cyclopropylmethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from the benzamide (compound a8) and the corresponding sulfamoyl chloride. However, the reaction was carried out at 0°C.
LCMS m/z: 650 [M+H] ⁺
HPLC retention time: 1.26 minutes (analytical condition A)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファモイルクロリドより表題化合物を合成した。但し、反応は０℃で行った。
ＬＣＭＳ ｍ／ｚ： ６５２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２８分（分析条件Ａ） Compound A-37:
5-[[2-(tert-butylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from the benzamide (compound a8) and the corresponding sulfamoyl chloride. However, the reaction was carried out at 0°C.
LCMS m/z: 652 [M+H] ⁺
HPLC retention time: 1.28 minutes (analytical condition A)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルホニルクロリドより表題化合物を合成した。但し、溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６０９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２０分（分析条件Ａ） Compound A-38:
5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from the benzamide (compound a8) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent.
LCMS m/z: 609 [M+H] ⁺
HPLC retention time: 1.20 minutes (analytical condition A)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－Ｎ－シクロプロピル－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ１０）及び対応するスルホニルクロリドより表題化合物を合成した。但し、溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６４９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６８分（分析条件Ｂ） Compound A-39:
N-Cyclopropyl-5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-N-cyclopropyl-3,4-difluoro-2-(2-fluoro The title compound was synthesized from 4-iodoanilino)benzamide (compound a10) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent.
LCMS m/z: 649 [M+H] ⁺
HPLC retention time: 1.68 minutes (analysis condition B)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファモイルクロリドより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６２４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２０分（分析条件Ａ） Compound A-40:
5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from the benzamide (compound a8) and the corresponding sulfamoyl chloride.
LCMS m/z: 624 [M+H] ⁺
HPLC retention time: 1.20 minutes (analytical condition A)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファモイルクロリドより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６３８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２５分（分析条件Ａ） Compound A-41:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from the benzamide (compound a8) and the corresponding sulfamoyl chloride.
LCMS m/z: 638 [M+H] ⁺
HPLC retention time: 1.25 minutes (analytical condition A)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８）及び対応するスルファモイルクロリドより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６４２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１７分（分析条件Ａ） Compound A-42:
3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from the benzamide (compound a8) and the corresponding sulfamoyl chloride.
LCMS m/z: 642 [M+H] ⁺
HPLC retention time: 1.17 minutes (analytical condition A)

３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［３－フルオロ－２－（メチルスルファモイルアミノ）ピリジン－４－イル］メチル］ベンズアミド（化合物Ａ－２５、１０．０ｍｇ、０．０１６ｍｍｏｌ）を無水ＴＨＦ（０．１ｍＬ）に溶解させ、トリエチルアミン（０．１００ｍＬ、０．７１７ｍｍｏｌ）、トリメチルシリルアセチレン（４．１μＬ、０．０３３ｍｍｏｌ）、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド ジクロロメタン付加物（１．２ｍｇ、１．６μｍｏｌ）及びヨウ化銅（Ｉ）（０．９ｍｇ、５μｍｏｌ）を加え、室温で２４時間攪拌した。反応混合物を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（１２．４ｍｇ）を油状物質として得た。
ＬＣＭＳ ｍ／ｚ： ５８０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９５分（分析条件Ｃ） Compound a20:
3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound A-25, 10.0 mg, 0.016 mmol) was dissolved in anhydrous THF (0.1 mL), triethylamine (0.100 mL, 0.717 mmol), trimethylsilylacetylene (4.1 μL, 0.033 mmol), [1,1′-bis (Diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (1.2 mg, 1.6 μmol) and copper(I) iodide (0.9 mg, 5 μmol) were added and stirred at room temperature for 24 hours. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (12.4 mg) as an oil.
LCMS m/z: 580 [M+H] ⁺
HPLC retention time: 0.95 minutes (analytical condition C)

３，４－ジフルオロ－５－［［３－フルオロ－２－（メチルスルファモイルアミノ）ピリジン－４－イル］メチル］－２－［２－フルオロ－４－（２－トリメチルシリルエチニル）アニリノ］ベンズアミド（化合物ａ２０、１１．０ｍｇ、０．０１９ｍｍｏｌ）をＭｅＯＨ（０．２ｍＬ）に溶解させ、炭酸カリウム（７．９ｍｇ、０．０５７ｍｍｏｌ）を加え、室温で１．５時間攪拌した。反応混合物を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（５．０ｍｇ、５２％）を固体として得た。
ＬＣＭＳ ｍ／ｚ： ５０８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０５分（分析条件Ａ） Compound A-26:
2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-[2-fluoro-4-(2-trimethylsilylethynyl)anilino]benzamide (Compound a20, 11.0 mg, 0.019 mmol) was dissolved in MeOH (0.2 mL), potassium carbonate (7.9 mg, 0.057 mmol) was added and stirred at room temperature for 1.5 hours. The reaction mixture was purified by reverse phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (5.0 mg, 52%) as a solid.
LCMS m/z: 508 [M+H] ⁺
HPLC retention time: 1.05 minutes (analysis condition A)

５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８、６０．０ｍｇ、０．１１６ｍｍｏｌ）を無水ＤＭＦ（１．２ｍＬ）に溶解させ、臭化銅（Ｉ）（８３．０ｍｇ、０．５８１ｍｍｏｌ）を加え、１００℃で２４時間攪拌した。反応混合物を分取ＨＰＬＣ（ＴＳＫ－ｇｅｌ ＯＤＳ ８０ＴＳ ５μｍ、２０×２５０ｍｍ ｃｏｌｕｍｎ（ＴＯＳＯＨ）、０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（３５．６ｍｇ）を固体として得た。
ＬＣＭＳ ｍ／ｚ： ４６９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６１分（分析条件Ｃ） Compound a21:
5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-bromo-2-fluoroanilino)-3,4-difluorobenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 60.0 mg, 0.116 mmol) was dissolved in anhydrous DMF (1.2 mL), copper (I) bromide (83.0 mg, 0.581 mmol) was added and stirred at 100° C. for 24 hours. The reaction mixture was purified by preparative HPLC (TSK-gel ODS 80TS 5 μm, 20×250 mm column (TOSOH), 0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (35.6 mg). Obtained as a solid.
LCMS m/z: 469 [M+H] ⁺
HPLC retention time: 0.61 minutes (analysis condition C)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（４－ブロモ－２－フルオロアニリノ）－３，４－ジフルオロベンズアミド（化合物ａ２１）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５６２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１３分（分析条件Ａ） Compound A-27:
2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

Under the same conditions as in the Production Example of Compound A-25, 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-bromo-2-fluoroanilino)-3,4 The title compound was synthesized from -difluorobenzamide (compound a21).
LCMS m/z: 562 [M+H] ⁺
HPLC retention time: 1.13 minutes (analytical condition A)

５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ８、１０２ｍｇ、０．１９８ｍｍｏｌ）を無水ＴＨＦ（２ｍＬ）に溶解させ、窒素雰囲気下、０℃でピリジン（０．１６０ｍＬ、１．９８ｍｍｏｌ）及びメタンスルフィン酸クロリド（０．１００ｍＬ、０．７１７ｍｍｏｌ）を加えた。この溶液に０℃で次亜塩素酸ｔｅｒｔ－ブチル（４４．６μＬ、０．３９５ｍｍｏｌ）を加え、１分間攪拌した後、さらに次亜塩素酸ｔｅｒｔ－ブチル（４４．６μＬ、０．３９５ｍｍｏｌ）を加えた。２ＭメチルアミンＴＨＦ溶液（１．９８ｍＬ、３．９５ｍｍｏｌ）を加え、攪拌した後、反応混合物を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（４５．９ｍｇ、３８％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ６０８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．００分（分析条件Ａ） Compound A-43:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[[methyl-(methylamino)-oxo-λ6-sulfanylidene]amino]pyridin-4-yl ]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a8, 102 mg, 0.198 mmol) was Dissolve in THF (2 mL) and add pyridine (0.160 mL, 1.98 mmol) and methanesulfinyl chloride (0.100 mL, 0.717 mmol) at 0° C. under a nitrogen atmosphere. To this solution was added tert-butyl hypochlorite (44.6 μL, 0.395 mmol) at 0° C., stirred for 1 minute, and then tert-butyl hypochlorite (44.6 μL, 0.395 mmol) was added. rice field. After adding 2M methylamine THF solution (1.98 mL, 3.95 mmol) and stirring, the reaction mixture was purified by reverse phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution), The title compound (45.9 mg, 38%) was obtained as a colorless solid.
LCMS m/z: 608 [M+H] ⁺
HPLC retention time: 1.00 minutes (analysis condition A)

５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ａ６、１．０５ｇ、１．９７ｍｍｏｌ）をＴＨＦ（１６．８ｍＬ）及び水（８．４ｍＬ）に溶解させ、０℃で水酸化リチウム一水和物（４１５ｍｇ、９．８８ｍｍｏｌ）を加え、室温で２時間攪拌した。反応混合物にトリフルオロ酢酸（３０５ｍＬ）を加え、減圧濃縮した。得られた残渣を水で洗浄して、表題化合物（１．０６ｇ、８５％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５１８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６８分（分析条件Ｃ） Compound a22:
5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid trifluoroacetate

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate (compound a6, 1.05 g, 1. 97 mmol) was dissolved in THF (16.8 mL) and water (8.4 mL), lithium hydroxide monohydrate (415 mg, 9.88 mmol) was added at 0° C. and stirred at room temperature for 2 hours. Trifluoroacetic acid (305 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue obtained was washed with water to give the title compound (1.06 g, 85%) as a colorless solid.
LCMS m/z: 518 [M+H] ⁺
HPLC retention time: 0.68 minutes (analytical condition C)

化合物ａ１２の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸トリフルオロ酢酸塩（化合物ａ２２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５７７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．５８分（分析条件Ｃ） Compound a23:
5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid under the same conditions as in the production example of compound a12 The title compound was synthesized from the trifluoroacetate (compound a22) and the corresponding amine.
LCMS m/z: 577 [M+H] ⁺
HPLC retention time: 0.58 minutes (analytical condition C)

５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－Ｎ－（２－ヒドロキシエトキシ）ベンズアミド（化合物ａ２３、３２０ｍｇ、０．５５５ｍｍｏｌ）を無水ＤＭＦ（３ｍＬ）に溶解させ、０℃でトリエチルアミン（０．１１６ｍＬ、０．８３３ｍｍｏｌ）及びｔｅｒｔ－ブチルジメチルクロロシラン（０．１００ｍＬ、０．７１７ｍｍｏｌ）を加え、室温で１６時間攪拌した。その後、さらにトリエチルアミン（０．１１６ｍＬ、０．８３３ｍｍｏｌ）及びｔｅｒｔ－ブチルジメチルクロロシラン（０．１００ｍＬ、０．７１７ｍｍｏｌ）を加え、７時間攪拌した。反応混合物を逆相カラムクロマトグラフィー（１０ｍＭ酢酸アンモニウム水溶液／メタノール）で精製して、表題化合物（３０２ｍｇ、７９％）を黄色固体として得た。
ＬＣＭＳ ｍ／ｚ： ６９１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９８分（分析条件Ｃ） Compound a24:
5-[(2-amino-3-fluoropyridin-4-yl)methyl]-N-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-3,4-difluoro-2-(2-fluoro -4-iodoanilino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide (compound a23 , 320 mg, 0.555 mmol) was dissolved in anhydrous DMF (3 mL), triethylamine (0.116 mL, 0.833 mmol) and tert-butyldimethylchlorosilane (0.100 mL, 0.717 mmol) were added at 0 °C and Stirred for 16 hours. After that, additional triethylamine (0.116 mL, 0.833 mmol) and tert-butyldimethylchlorosilane (0.100 mL, 0.717 mmol) were added and stirred for 7 hours. The reaction mixture was purified by reverse-phase column chromatography (10 mM aqueous ammonium acetate/methanol) to give the title compound (302 mg, 79%) as a yellow solid.
LCMS m/z: 691 [M+H] ⁺
HPLC retention time: 0.98 minutes (analytical condition C)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－Ｎ－［２－［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシエトキシ］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ２４）及び対応するスルファモイルクロリドより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ７９８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１１分（分析条件Ｃ） Compound a25:
N-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro- 2-(2-fluoro-4-iodoanilino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-N-[2-[tert-butyl(dimethyl)silyl]oxyethoxy] under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from -3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a24) and the corresponding sulfamoyl chloride.
LCMS m/z: 798 [M+H] ⁺
HPLC retention time: 1.11 minutes (analytical condition C)

Ｎ－［２－［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシエトキシ］－５－［［２－（エチルスルファモイルアミノ）－３－フルオロピリジン－４－イル］メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ２５、１８ｍｇ、０．０２３ｍｍｏｌ）を無水ＴＨＦ（０．２ｍＬ）に溶解させ、０℃で１ＭテトラブチルアンモニウムフルオリドＴＨＦ溶液（２７μＬ、０．２７ｍｍｏｌ）を加え、２時間攪拌した。反応混合物を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（１４ｍｇ、９１％）を黄色固体として得た。
ＬＣＭＳ ｍ／ｚ： ６８４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７９分（分析条件Ｃ） Compound A-44:
5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxy ethoxy)benzamide

N-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro- 2-(2-Fluoro-4-iodoanilino)benzamide (compound a25, 18 mg, 0.023 mmol) was dissolved in anhydrous THF (0.2 mL) and treated at 0° C. with 1 M tetrabutylammonium fluoride THF solution (27 μL, 0.000 mL). 27 mmol) was added and stirred for 2 hours. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (14 mg, 91%) as a yellow solid.
LCMS m/z: 684 [M+H] ⁺
HPLC retention time: 0.79 minutes (analysis condition C)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－Ｎ－［２－［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシエトキシ］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ２４）及び対応するスルファモイルクロリドより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６９８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８３分（分析条件Ｃ） Compound A-45:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxy ethoxy)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-N-[2-[tert-butyl(dimethyl)silyl]oxyethoxy] under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from -3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (compound a24) and the corresponding sulfamoyl chloride.
LCMS m/z: 698 [M+H] ⁺
HPLC retention time: 0.83 minutes (analysis condition C)

化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（４－シクロプロピル－２－フルオロアニリノ）－３，４－ジフルオロベンズアミド（化合物ａ９）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５７８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８９分（分析条件Ｃ） Compound A-46:
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl] methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3, The title compound was synthesized from 4-difluorobenzamide (compound a9) and the corresponding 4-nitrophenyl sulfamate.
LCMS m/z: 578 [M+H] ⁺
HPLC retention time: 0.89 minutes (analysis condition C)

化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－Ｎ－シクロプロピル－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ａ１０）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ７０４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９７分（分析条件Ｃ） Compound A-47:
N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4- yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-N-cyclopropyl-3,4-difluoro-2-(2-fluoro The title compound was synthesized from 4-iodoanilino)benzamide (compound a10) and the corresponding 4-nitrophenyl sulfamate.
LCMS m/z: 704 [M+H] ⁺
HPLC retention time: 0.97 minutes (analysis condition C)

水（８１ｍＬ）を入れた反応容器を外温０℃に冷却し、濃硫酸（１６２ｍＬ）を加えた。続いて２，３，４－トリフルオロ安息香酸（２７．０ｇ、１５３ｍｍｏｌ）及び硫酸カリウム（４０１ｍｇ、２．３０ｍｍｏｌ）を加え、外温５５℃に加温した。臭素酸ナトリウム（２５．４ｇ、１６９ｍｍｏＬ）及び水（１０８ｍＬ）から調製した水溶液を２．５時間かけて滴下し、２．５時間攪拌した。反応混合物を０℃に冷却した後、亜硫酸ナトリウム（２４．３ｇ、１６１ｍｍｏｌ）及び水（３２４ｍＬ）から調製した水溶液を加えた。結晶をろ取し、水（１６２ｍＬ）で洗浄し、通風乾燥して、表題化合物（２７．９ｇ、７１％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ２５３［Ｍ－Ｈ］^－
ＨＰＬＣ保持時間： ０．６６分（分析条件Ｃ） Compound a26:
5-bromo-2,3,4-trifluorobenzoic acid

A reaction vessel containing water (81 mL) was cooled to an external temperature of 0° C., and concentrated sulfuric acid (162 mL) was added. Subsequently, 2,3,4-trifluorobenzoic acid (27.0 g, 153 mmol) and potassium sulfate (401 mg, 2.30 mmol) were added and heated to an external temperature of 55°C. An aqueous solution prepared from sodium bromate (25.4 g, 169 mmol) and water (108 mL) was added dropwise over 2.5 hours and stirred for 2.5 hours. After cooling the reaction mixture to 0° C., an aqueous solution prepared from sodium sulfite (24.3 g, 161 mmol) and water (324 mL) was added. The crystals were collected by filtration, washed with water (162 mL) and air dried to give the title compound (27.9 g, 71%) as a colorless solid.
LCMS m/z: 253 [MH] ^-
HPLC retention time: 0.66 minutes (analytical condition C)

１Ｍリチウムビス（トリメチルシリル）アミドＴＨＦ溶液（２０６ｍＬ、２０６ｍｍｏｌ）を入れた反応容器を外温－１５℃に冷却し、４－シクロプロピル－２－フルオロアニリン（１１．６ｇ、７６．５ｍｍｏｌ）のＴＨＦ（３０ｍＬ）溶液を滴下した。さらに、５－ブロモ－２，３，４－トリフルオロ安息香酸（化合物ａ２６、１５．０ｇ、５８．８ｍｍｏｌ）のＴＨＦ（１２０ｍＬ）溶液を３０分かけて滴下し、３０分間攪拌した。反応混合物に５Ｍ塩酸（１１８ｍＬ）を加え、室温に昇温し、酢酸イソプロピル（７５ｍＬ）で抽出した。有機層を水（７５ｍＬ）で２回、１５％塩化ナトリウム水溶液（７５ｍＬ）で１回順次洗浄し、減圧濃縮した。得られた濃縮残渣にアセトン（１２０ｍＬ）を加え、加熱溶解した後、水（４５ｍＬ）及び種晶（１５０ｍｇ）を加えて結晶を析出させた。得られたスラリーに水（４５ｍＬ）を加え、結晶をろ取した。アセトン／水（１／２）の混合液で洗浄し、減圧下外温４０℃で乾燥させて表題化合物（１９．４ｇ、８５％）を得た。
ＬＣＭＳ ｍ／ｚ： ３８６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６２分（分析条件Ｃ） Compound a27:
5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoic acid

A reaction vessel containing 1M lithium bis(trimethylsilyl)amide THF solution (206 mL, 206 mmol) was cooled to an external temperature of -15°C, and 4-cyclopropyl-2-fluoroaniline (11.6 g, 76.5 mmol) in THF ( 30 mL) solution was added dropwise. Furthermore, a THF (120 mL) solution of 5-bromo-2,3,4-trifluorobenzoic acid (compound a26, 15.0 g, 58.8 mmol) was added dropwise over 30 minutes, and the mixture was stirred for 30 minutes. 5M Hydrochloric acid (118 mL) was added to the reaction mixture, the temperature was raised to room temperature, and the mixture was extracted with isopropyl acetate (75 mL). The organic layer was washed twice with water (75 mL) and once with a 15% aqueous sodium chloride solution (75 mL), and concentrated under reduced pressure. Acetone (120 mL) was added to the obtained concentrated residue and dissolved by heating, and then water (45 mL) and seed crystals (150 mg) were added to precipitate crystals. Water (45 mL) was added to the resulting slurry, and crystals were collected by filtration. It was washed with a mixture of acetone/water (1/2) and dried under reduced pressure at an external temperature of 40° C. to give the title compound (19.4 g, 85%).
LCMS m/z: 386 [M+H] ⁺
HPLC retention time: 0.62 minutes (analytical condition C)

５－ブロモ－２－（４－シクロプロピル－２－フルオロアニリノ）－３，４－ジフルオロ安息香酸（化合物ａ２７、１３．０ｇ、３３．７ｍｍｏｌ）を入れた反応容器にアセトニトリル（１０４ｍＬ）、ＴＨＦ（２６ｍＬ）及び１，１’－カルボニルジイミダゾール（８．２ｇ、５０．５ｍｍｏｌ）を加え、室温で２時間攪拌した。反応混合物に２８％アンモニア水（１３ｍＬ）を加え、室温で３０分間攪拌した後、水（１１７ｍＬ）を１時間かけて加えた。結晶をろ取し、水で洗浄し、減圧下外温４０℃で乾燥させて表題化合物（１２．０ｇ、９３％）を得た。
ＬＣＭＳ ｍ／ｚ： ３８５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．５２分（分析条件Ｃ） Compound a28:
5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide

A reaction vessel containing 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoic acid (compound a27, 13.0 g, 33.7 mmol) was charged with acetonitrile (104 mL), THF (26 mL) and 1,1′-carbonyldiimidazole (8.2 g, 50.5 mmol) were added and stirred at room temperature for 2 hours. After adding 28% aqueous ammonia (13 mL) to the reaction mixture and stirring at room temperature for 30 minutes, water (117 mL) was added over 1 hour. The crystals were collected by filtration, washed with water and dried under reduced pressure at an external temperature of 40°C to obtain the title compound (12.0 g, 93%).
LCMS m/z: 385 [M+H] ⁺
HPLC retention time: 0.52 minutes (analytical condition C)

（１）Ｎ－［４－［［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシメチル］－３－フルオロピリジン－２－イル］アセトアミドの合成
反応容器にｔｅｒｔ－ブチル－［（２－クロロ－３－フルオロピリジン－４－イル）メトキシ］－ジメチルシラン（１８０ｇ、６５３ｍｍｏｌ）、Ｘａｎｔｐｈｏｓ（２２．７ｇ、３９．２ｍｍｏｌ）、炭酸カリウム（１３５ｇ、９７９ｍｍｏｌ）、アセトアミド（７７．１ｇ、１．３１ｍｏｌ）及び２－メチル－２－ブタノール（５４０ｍＬ）を加え、減圧脱気し、窒素で置換した。トリス（ジベンジリデンアセトン）ジパラジウム（０）（１４．９ｇ、１６．３ｍｍｏｌ）及びトルエン（５４０ｍＬ）を加え、さらに減圧脱気し、窒素で置換した。窒素雰囲気下、混合物を外温１２０℃に加温し、７時間攪拌した。外温を室温に冷却し、反応混合物をろ過し、トルエン（４５０ｍＬ）で洗浄した。ろ液に活性炭（９．００ｇ、７４９ｍｍｏｌ）を加え、室温で１時間攪拌した。反応混合物をろ過し、トルエン（１回目は２７０ｍＬ、２回目は１８０ｍＬ）で２回洗浄して、Ｎ－［４－［［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシメチル］－３－フルオロピリジン－２－イル］アセトアミドの粗生成物をトルエン溶液として得た。
ＬＣＭＳ ｍ／ｚ： ２９９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８１分（分析条件Ｃ） Compound a30:
N-[3-fluoro-4-(hydroxymethyl)pyridin-2-yl]acetamide methanesulfonate

(1) Synthesis of N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide tert-butyl-[(2-chloro-3-fluoro) in a reaction vessel Pyridin-4-yl)methoxy]-dimethylsilane (180 g, 653 mmol), Xantphos (22.7 g, 39.2 mmol), potassium carbonate (135 g, 979 mmol), acetamide (77.1 g, 1.31 mol) and 2-methyl -2-butanol (540 mL) was added, degassed under reduced pressure, and replaced with nitrogen. 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. Under a nitrogen atmosphere, the mixture was heated to an external temperature of 120° C. and stirred for 7 hours. After cooling the external temperature 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 stirred at room temperature for 1 hour. The reaction mixture was filtered and washed twice with toluene (270 mL first, 180 mL second) to give N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridine-2. -yl]acetamide was obtained as a toluene solution.
LCMS m/z: 299 [M+H] ⁺
HPLC retention time: 0.81 minutes (analytical condition C)

(2) Synthesis of compound a30 In a reaction vessel, a toluene solution of the obtained N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide, toluene (175 mL). ) and methanol (195 mL) were added, degassed under reduced pressure, and replaced with nitrogen. Methanesulfonic acid (188 g, 1.96 mol) was added dropwise at an external temperature of 10° C. and stirred at room temperature for 2 hours. The reaction mixture was cooled to an external temperature of 0° C. and stirred for 3 hours. The precipitate was collected by filtration and washed with a cooled mixture of toluene (312 mL) and methanol (78 mL). The solid collected by filtration and a mixture of toluene (1.1 L) and ethanol (492 mL) were added to the reactor and stirred at an external temperature of 0° C. for 1 hour. The solid was collected by filtration, washed with a mixture of toluene (281 mL) and ethanol (117 mL), and dried under reduced pressure at an external temperature of 40°C to obtain compound a30 (149 g, 81%).
LCMS m/z: 185 [M+H] ⁺
HPLC retention time: 0.30 minutes (analysis condition E)

Ｎ－［３－フルオロ－４－（ヒドロキシメチル）ピリジン－２－イル］アセトアミドメタンスルホン酸塩（化合物ａ３０、５０．０ｇ、１７８ｍｍｏｌ）及び２－メチルテトラヒドロフラン（７５０ｍＬ）を入れた反応容器に４－ジメチルアミノピリジン（５２．３ｇ、４２８ｍｍｏｌ）を室温で加えた。外温を０℃に冷却し、クロロギ酸メチル（２１．９ｇ、２３２ｍｍｏｌ）を加え、室温に昇温し、攪拌した。析出した固体をろ別し、ろ液を外温４０℃で減圧濃縮した。濃縮残渣に酢酸エチル（３００ｍＬ）を加え、室温で溶解させた後、ＤＩＰＥＡ（３１．２ｍＬ、１７８ｍｍｏｌ）、ヘプタン（１５０ｍＬ）及び種晶を加えた。結晶の析出を確認した後、ヘプタン（１Ｌ）を加えた。スラリーを外温０℃に冷却した後、結晶をろ取し、酢酸エチル／ヘプタン（２／７）の混合液で洗浄した。減圧下外温４０℃で乾燥させて、表題化合物（３１．３ｇ、７２％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ２４３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．３７分（分析条件Ｃ） Compound a31:
(2-acetamido-3-fluoropyridin-4-yl)methyl methyl carbonate

A reaction vessel containing N-[3-fluoro-4-(hydroxymethyl)pyridin-2-yl]acetamidomethanesulfonate (Compound a30, 50.0 g, 178 mmol) and 2-methyltetrahydrofuran (750 mL) was charged with 4- Dimethylaminopyridine (52.3 g, 428 mmol) was added at room temperature. The external temperature was cooled to 0° C., methyl chloroformate (21.9 g, 232 mmol) was added, the temperature was raised to room temperature, and the mixture was stirred. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure at an external temperature of 40°C. Ethyl acetate (300 mL) was added to the concentrated residue and dissolved at room temperature, then DIPEA (31.2 mL, 178 mmol), heptane (150 mL) and seed crystals were added. After confirming the precipitation of crystals, heptane (1 L) was added. After cooling the slurry to an external temperature of 0° C., the crystals were collected by filtration and washed with a mixed solution of ethyl acetate/heptane (2/7). Drying under reduced pressure at an external temperature of 40° C. gave the title compound (31.3 g, 72%) as a colorless solid.
LCMS m/z: 243 [M+H] ⁺
HPLC retention time: 0.37 minutes (analysis condition C)

反応容器に５－ブロモ－２－（４－シクロプロピル－２－フルオロアニリノ）－３，４－ジフルオロベンズアミド（化合物ａ２８、１０．０ｇ、２６．０ｍｍｏｌ）、ビス（ピナコラト）ジボロン（７．３ｇ、２８．６ｍｍｏｌ）、酢酸カリウム（７．６ｇ、７７．９ｍｍｏｌ）及び２－メチルテトラヒドロフラン（１５０ｍＬ）を加え、減圧脱気し、窒素で置換した。（２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピル－１，１’－ビフェニル）［２－（２’－アミノ－１，１’－ビフェニル）］パラジウム（ＩＩ）メタンスルホン酸塩（４４０ｍｇ、０．５２ｍｍｏｌ）を加え、さらに減圧脱気し、窒素で置換した。窒素雰囲気下、混合物を外温８０℃に加温し、６時間攪拌した。外温を室温に冷却し、炭酸カリウム（１０．８ｇ、７７．９ｍｍｏｌ）を加え、減圧脱気し、窒素置換した。（２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピル－１，１’－ビフェニル）［２－（２’－アミノ－１，１’－ビフェニル）］パラジウム（ＩＩ）メタンスルホン酸塩（１．１ｇ、１．３ｍｍｏｌ）を加え、さらに減圧脱気し、窒素置換した後、（２－アセトアミド－３－フルオロピリジン－４－イル）メチル メチル カルボネート（化合物ａ３１、１２．６ｇ、５１．９ｍｍｏｌ）の２－メチルテトラヒドロフラン（１５０ｍＬ）溶液を加えた。窒素雰囲気下、混合物を外温７０℃に加温し、水（９３５μＬ、５１．９ｍｍｏｌ）を２０分毎に３回加えた後、２０分間攪拌した。さらに、水（７．０ｍＬ）を滴下し、２時間攪拌し、Ｎ－アセチルシステイン（８４７ｍｇ、５．２ｍｍｏｌ）及び水（１５０ｍＬ）から調製した溶液を加え、１時間攪拌した。外温４０℃に冷却した後、水層を排出した。有機層を１５％塩化ナトリウム水溶液（１５０ｍＬ）で洗浄し、不溶物をろ過し、減圧濃縮した。得られた濃縮残渣にアセトニトリル（５００ｍＬ）を加え、外温１００℃に加熱し、溶解させた後、室温に冷却した。結晶をろ取し、アセトニトリル（２００ｍＬ）で洗浄し、減圧下外温４０℃で乾燥させて表題化合物（８．３４ｇ、６８％）を得た。
ＬＣＭＳ ｍ／ｚ： ４７１［Ｍ－Ｈ］^－
ＨＰＬＣ保持時間： ０．７４分（分析条件Ｃ） Compound a32:
5-[(2-acetamido-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide

5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (compound a28, 10.0 g, 26.0 mmol) and bis(pinacolato)diboron (7.3 g) were placed in a reaction vessel. , 28.6 mmol), potassium acetate (7.6 g, 77.9 mmol) and 2-methyltetrahydrofuran (150 mL) were added, degassed under reduced pressure, and replaced with nitrogen. (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonic acid Salt (440 mg, 0.52 mmol) was added and further degassed under reduced pressure and replaced with nitrogen. Under a nitrogen atmosphere, the mixture was heated to an external temperature of 80° C. and stirred for 6 hours. The external temperature was cooled to room temperature, potassium carbonate (10.8 g, 77.9 mmol) was added, degassed under reduced pressure, and replaced with nitrogen. (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonic acid A salt (1.1 g, 1.3 mmol) was added, and the gas was further degassed under reduced pressure. After purging with nitrogen, (2-acetamido-3-fluoropyridin-4-yl)methyl methyl carbonate (compound a31, 12.6 g, .9 mmol) in 2-methyltetrahydrofuran (150 mL) was added. Under a nitrogen atmosphere, the mixture was heated to an external temperature of 70° C., water (935 μL, 51.9 mmol) was added three times every 20 minutes, and then stirred for 20 minutes. Further, water (7.0 mL) was added dropwise and stirred for 2 hours, and a solution prepared from N-acetylcysteine (847 mg, 5.2 mmol) and water (150 mL) was added and stirred for 1 hour. After cooling to an external temperature of 40°C, the aqueous layer was discharged. The organic layer was washed with a 15% aqueous sodium chloride solution (150 mL), filtered to remove insoluble matter, and concentrated under reduced pressure. Acetonitrile (500 mL) was added to the resulting concentrated residue, heated to an external temperature of 100° C. for dissolution, and then cooled to room temperature. The crystals were collected by filtration, washed with acetonitrile (200 mL) and dried under reduced pressure at an external temperature of 40° C. to give the title compound (8.34 g, 68%).
LCMS m/z: 471 [MH] ^-
HPLC retention time: 0.74 minutes (analysis condition C)

製造例ａ９－２：
５－［（２－アセトアミド－３－フルオロピリジン－４－イル）メチル］－２－（４－シクロプロピル－２－フルオロアニリノ）－３，４－ジフルオロベンズアミド（化合物ａ３２、１００ｍｇ、０．２１ｍｍｏｌ）を入れた反応容器にメタノール（３ｍＬ）及び５Ｍ塩酸（０．４２ｍＬ、２．１ｍｍｏｌ）を加え、外温５０℃で６時間攪拌した。反応混合物を室温に冷却し、２Ｍ水酸化ナトリウム水溶液（１．１ｍＬ、２．１ｍｍｏｌ）を加えた。得られたスラリーに水（０．５ｍＬ）を加え、結晶をろ取した。メタノール／水（３／２）の混合液で洗浄し、減圧下外温４０℃で乾燥させて、化合物ａ９（７７．７ｍｇ、８５％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４３１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６１分（分析条件Ｃ） Compound a9:
5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide

Production Example a9-2:
5-[(2-acetamido-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (compound a32, 100 mg, 0.21 mmol ) was placed in a reaction vessel, methanol (3 mL) and 5 M hydrochloric acid (0.42 mL, 2.1 mmol) were added, and the mixture was stirred at an external temperature of 50° C. for 6 hours. The reaction mixture was cooled to room temperature and 2M aqueous sodium hydroxide solution (1.1 mL, 2.1 mmol) was added. Water (0.5 mL) was added to the resulting slurry, and crystals were collected by filtration. It was washed with a mixture of methanol/water (3/2) and dried under reduced pressure at an external temperature of 40° C. to give compound a9 (77.7 mg, 85%) as a colorless solid.
LCMS m/z: 431 [M+H] ⁺
HPLC retention time: 0.61 minutes (analysis condition C)

製造例Ａ－１－２：
５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（４－シクロプロピル－２－フルオロアニリノ）－３，４－ジフルオロベンズアミド（化合物ａ９、１００ｍｇ、０．２３２ｍｍｏｌ）を無水ＤＭＡ（１ｍＬ）に溶解させ、ピリジン（５６．４μＬ、０．６９７ｍｍｏｌ）を加えた。０℃に冷却した後、メチルスルファモイルクロリド（３０．２μＬ、０．３４９ｍｍｏｌ）を加え、１時間攪拌した。反応混合物にアセトニトリル（０．６ｍＬ）、水（０．３ｍＬ）及び種晶（１ｍｇ）を加え、室温に昇温し、水（０．７ｍＬ）及びアセトニトリル（０．４ｍＬ）を加え、２０時間攪拌した。析出物をろ取し、アセトニトリル／水（１／１）の混合液で洗浄して、化合物Ａ－１（９３．１ｍｇ、７７％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５２４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１３分（分析条件Ａ） Compound A-1:
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

Production Example A-1-2:
5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (compound a9, 100 mg, 0.232 mmol ) was dissolved in anhydrous DMA (1 mL) and pyridine (56.4 μL, 0.697 mmol) was added. After cooling to 0° C., methylsulfamoyl chloride (30.2 μL, 0.349 mmol) was added and stirred for 1 hour. Acetonitrile (0.6 mL), water (0.3 mL) and seed crystals (1 mg) were added to the reaction mixture, the temperature was raised to room temperature, water (0.7 mL) and acetonitrile (0.4 mL) were added, and the mixture was stirred for 20 hours. bottom. The precipitate was collected by filtration and washed with a mixture of acetonitrile/water (1/1) to give compound A-1 (93.1 mg, 77%) as a colorless solid.
LCMS m/z: 524 [M+H] ⁺
HPLC retention time: 1.13 minutes (analytical condition A)

（１）サンプルＡ－１ａ（ＦｏｒｍＩ）の調製
２－（４－シクロプロピル－２－フルオロアニリノ）－３，４－ジフルオロ－５－［［３－フルオロ－２－（メチルスルファモイルアミノ）ピリジン－４－イル］メチル］ベンズアミド（化合物Ａ－１、３．０３ｇ）にアセトン（１０．６ｍＬ）及びＤＭＳＯ（１．５１ｍＬ）を加え、室温で溶解させた。この溶液に２０％ナトリウムエトキシドエタノール溶液（３．０３ｍＬ）及び化合物Ａ－１のナトリウム塩の種晶（後述のサンプルＡ－１ｂ）を加え、室温で１時間攪拌し、次いでエタノール（１５．１ｍＬ）を加え、室温で４時間攪拌した。その後、さらにエタノール（１５．１ｍＬ）を加え、室温で４時間攪拌して、化合物Ａ－１のナトリウム塩（２．７４ｇ）を粉末状結晶として得た（サンプルＡ－１ａ（ＦｏｒｍＩ））。 Sodium salt of Compound A-1:
2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide sodium salt

(1) Preparation of sample A-1a (Form I) 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino) Acetone (10.6 mL) and DMSO (1.51 mL) were added to pyridin-4-yl]methyl]benzamide (Compound A-1, 3.03 g) and dissolved at room temperature. A 20% sodium ethoxide ethanol solution (3.03 mL) and seed crystals of the sodium salt of compound A-1 (Sample A-1b described later) were added to this solution, stirred at room temperature for 1 hour, and then ethanol (15.1 mL) was added. ) was added and stirred at room temperature for 4 hours. Thereafter, ethanol (15.1 mL) was further added, and the mixture was stirred at room temperature for 4 hours to obtain sodium salt (2.74 g) of compound A-1 as powdery crystals (sample A-1a (Form I)).

(2) Preparation of sample A-1b Compound A-1 (53.6 mg) was added with 20% sodium ethoxide ethanol solution (0.054 mL) and methyl isobutyl ketone (0.161 mL), stirred at room temperature for 30 minutes, Methyl isobutyl ketone (0.161 mL) was then added and stirred at 60° C. for 4 days. After that, DMSO (0.054 mL) was added and the mixture was stirred at 60° C. for 5 hours to obtain sodium salt of compound A-1 (25.6 mg) as powdery crystals (sample A-1b).

(3) Preparation of sample A-1c DMSO (4.26 mL) and 2M sodium hydroxide aqueous 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 sodium salt of compound A-1 (0.966 g) as powdery crystals (sample A-1c).

(4) Powder X-ray Diffraction Measurement Sample A-1a (Form I), 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)
Anticathode: Cu
Tube voltage: 45kV
Tube current: 200mA
Sampling width: 0.02°

The results of powder X-ray diffraction measurements are shown in FIGS. 1 to 3. FIG. FIG. 1 shows the powder X-ray diffraction pattern of sample A-1a (Form I). FIG. 2 shows the powder X-ray diffraction pattern of sample A-1b. FIG. 3 shows the powder X-ray diffraction pattern of sample A-1c. 1 to 3, the horizontal axis (X-axis) represents the diffraction angle 2θ (°), and the vertical axis (Y-axis) represents the diffraction intensity.

(5) Ion Chromatography When the ratio of sodium ions in the crystals of sample A-1a (Form I) was measured by ion chromatography, the molar ratio of sodium ions to compound A-1 was 0.99. This confirmed that sample A-1a was a monosodium salt. Ion chromatography was performed under the following conditions.
Measuring device: Dionex ICS-1600, AS-AP (manufactured by Thermo Fisher Scientific)
Column: Dionex IonPac CG16 (5×50 mm)/CS16 (5×250 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 μL
Detector: Conductivity detector Sample processing: Sample A-1a was suspended in a 20 mmol/L methanesulfonic acid solution at a concentration of 0.5 mg/mL, shaken and stirred for 17 hours to extract sodium ions, and the supernatant was removed. was measured.

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ａ６）より表題化合物を合成した。但し、無水ＤＭＡの代わりに無水ＮＭＰを用いた。
ＬＣＭＳ ｍ／ｚ： ４３６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．００分（分析条件Ｄ） Compound b1:
Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoate

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino) under the same conditions as in the Production Example of Compound A-25 The title compound was synthesized from methyl benzoate (compound a6). However, anhydrous NMP was used instead of anhydrous DMA.
LCMS m/z: 436 [M+H] ⁺
HPLC retention time: 1.00 minutes (analysis condition D)

３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［３－フルオロ－２－（メチルスルファモイルアミノ）ピリジン－４－イル］メチル］安息香酸メチル（化合物ｂ１、１５８ｍｇ、０．２５３ｍｍｏｌ）のＴＨＦ（４．８ｍＬ）及び水（２．４ｍＬ）混合溶液を０℃に冷却し、水酸化リチウム一水和物（６０．６ｍｇ、２．５３ｍｍｏｌ）を加え、室温で２時間攪拌した。反応混合物に２Ｍ塩酸を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤をろ去後、減圧濃縮して、表題化合物（１６１ｍｇ）を泡状物質として得た。
ＬＣＭＳ ｍ／ｚ： ６１１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６７分（分析条件Ｄ） Compound b2:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid

Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoate (compound b1, 158 mg, 0.253 mmol) in THF (4.8 mL) and water (2.4 mL) was cooled to 0° C., lithium hydroxide monohydrate (60.6 mg, 2.53 mmol) was added, and the mixture was stirred at room temperature. Stirred for 2 hours. 2M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the residue was concentrated under reduced pressure to give the title compound (161 mg) as a foamy substance.
LCMS m/z: 611 [M+H] ⁺
HPLC retention time: 0.67 minutes (analytical condition D)

化合物ａ８の製造例と同様の条件で、３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［３－フルオロ－２－（メチルスルファモイルアミノ）ピリジン－４－イル］メチル］安息香酸（化合物ｂ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６７０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０７分（分析条件Ａ） Compound B-1:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxy ethoxy)benzamide

Under the same conditions as in the production example of compound a8, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4- The title compound was synthesized from yl]methyl]benzoic acid (compound b2) and the corresponding amine.
LCMS m/z: 670 [M+H] ⁺
HPLC retention time: 1.07 minutes (Analysis condition A)

化合物ａ８の製造例と同様の条件で、３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［３－フルオロ－２－（メチルスルファモイルアミノ）ピリジン－４－イル］メチル］安息香酸（化合物ｂ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６８４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．５６分（分析条件Ｂ） Compound B-2:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-methoxy ethoxy)benzamide

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4- The title compound was synthesized from yl]methyl]benzoic acid (compound b2) and the corresponding amine.
LCMS m/z: 684 [M+H] ⁺
HPLC retention time: 1.56 minutes (analysis condition B)

化合物ａ８の製造例と同様の条件で、３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［３－フルオロ－２－（メチルスルファモイルアミノ）ピリジン－４－イル］メチル］安息香酸（化合物ｂ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６６４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７０分及び１．７２分（分析条件Ｂ） Compound B-3:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-methyl Cyclopropyl)benzamide (4-isomer mixture)

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4- The title compound was synthesized from yl]methyl]benzoic acid (compound b2) and the corresponding amine.
LCMS m/z: 664 [M+H] ⁺
HPLC retention time: 1.70 min and 1.72 min (analytical condition B)

化合物ａ１２の製造例と同様の条件で、３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［３－フルオロ－２－（メチルスルファモイルアミノ）ピリジン－４－イル］メチル］安息香酸（化合物ｂ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６８６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６９分（分析条件Ｂ） Compound B-6:
(+/-)-N-(2,2-difluorocyclopropyl)-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfur Moylamino)pyridin-4-yl]methyl]benzamide (racemate)

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4- The title compound was synthesized from yl]methyl]benzoic acid (compound b2) and the corresponding amine.
LCMS m/z: 686 [M+H] ⁺
HPLC retention time: 1.69 minutes (analysis condition B)

化合物Ｂ－５：
３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［３－フルオロ－２－（メチルスルファモイルアミノ）ピリジン－４－イル］メチル］－Ｎ－［（１Ｒ，２Ｒ）－（＋／－）－２－メチルシクロプロピル］ベンズアミド（ラセミ体）

３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［３－フルオロ－２－（メチルスルファモイルアミノ）ピリジン－４－イル］メチル］－Ｎ－（２－メチルシクロプロピル）ベンズアミド（４異性体混合物、化合物Ｂ－３、５７ｍｇ）を分取ＨＰＬＣ（ＹＭＣ Ｔｒｉａｒｔ Ｃ１８ ｐｌｕｓ ５μｍ、４．６×１５０ｍｍ ｃｏｌｕｍｎ、０．１％ＴＦＡ水溶液／０．１％ＴＦＡアセトニトリル溶液）で精製して、化合物Ｂ－４（１４．７ｍｇ）及び化合物Ｂ－５（４１ｍｇ）を各々固体として得た。
化合物Ｂ－４
ＬＣＭＳ ｍ／ｚ： ６６４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７０分（分析条件Ｂ）
化合物Ｂ－５
ＬＣＭＳ ｍ／ｚ： ６６４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７２分（分析条件Ｂ） Compound B-4:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(1S, 2R)-(+/-)-2-methylcyclopropyl]benzamide (racemate)

Compound B-5:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(1R, 2R)-(+/-)-2-methylcyclopropyl]benzamide (racemate)

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-methyl Cyclopropyl)benzamide (4-isomer mixture, compound B-3, 57 mg) was subjected to preparative HPLC (YMC Triart C18 plus 5 μm, 4.6×150 mm column, 0.1% TFA aqueous solution/0.1% TFA acetonitrile solution). to obtain compound B-4 (14.7 mg) and compound B-5 (41 mg) as solids.
Compound B-4
LCMS m/z: 664 [M+H] ⁺
HPLC retention time: 1.70 minutes (analysis condition B)
Compound B-5
LCMS m/z: 664 [M+H] ⁺
HPLC retention time: 1.72 minutes (analysis condition B)

化合物Ａ－２５、化合物ｂ２及び化合物ａ８の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ａ６）及び対応するスルホニルクロリドより表題化合物を合成した。但し、化合物Ａ－２５の製造例で用いたピリジン及び無水ＤＭＡの代わりにそれぞれトリエチルアミン及び無水ＤＣＭを用いた。
ＬＣＭＳ ｍ／ｚ： ６２３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６３分（分析条件Ｂ） 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- The title compound was synthesized from methyl fluoro-4-iodoanilino)benzoate (compound a6) and the corresponding sulfonyl chloride. However, triethylamine and anhydrous DCM were used in place of pyridine and anhydrous DMA used in the production example of compound A-25, respectively.
LCMS m/z: 623 [M+H] ⁺
HPLC retention time: 1.63 minutes (analysis condition B)

化合物Ａ－２５、化合物ｂ２及び化合物ａ８の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ａ６）及び対応するスルファモイルクロリドより表題化合物を合成した。但し、化合物Ａ－２５の製造例で用いたピリジン及び無水ＤＭＡの代わりにそれぞれトリエチルアミン及び無水ＤＣＭを用いた。
ＬＣＭＳ ｍ／ｚ： ６４０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０６分（分析条件Ａ） Compound B-9:
3,4-difluoro-5-[[3-fluoro-2-(2-hydroxyethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2- The title compound was synthesized from methyl fluoro-4-iodoanilino)benzoate (compound a6) and the corresponding sulfamoyl chloride. However, triethylamine and anhydrous DCM were used in place of pyridine and anhydrous DMA used in the production example of compound A-25, respectively.
LCMS m/z: 640 [M+H] ⁺
HPLC retention time: 1.06 minutes (Analysis condition A)

化合物Ａ－２５及び化合物ｂ２の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ａ６）及び対応するスルファモイルクロリドより表題化合物を合成した。但し、化合物Ａ－２５の製造例で用いた無水ＤＭＡの代わりに無水ＮＭＰを用いた。
ＬＣＭＳ ｍ／ｚ： ６９７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７１分（分析条件Ｄ） Compound b8:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(2-methylpropan-2-yl)oxycarbonylsulfamoylamino]pyridine-4- yl]methyl]benzoic acid

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4 -iodoanilino)methyl benzoate (compound a6) and the corresponding sulfamoyl chloride to synthesize the title compound. However, anhydrous NMP was used instead of anhydrous DMA used in the production example of compound A-25.
LCMS m/z: 697 [M+H] ⁺
HPLC retention time: 0.71 minutes (analysis condition D)

３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［３－フルオロ－２－［（２－メチルプロパン－２－イル）オキシカルボニルスルファモイルアミノ］ピリジン－４－イル］メチル］安息香酸（化合物ｂ８、１３１ｍｇ、０．１８８ｍｍｏｌ）の２，２，２－トリフルオロエタノール溶液（２．６ｍＬ）にクロロトリメチルシラン（７１．５μＬ、０．５６４ｍｍｏｌ）を加え、室温で１．５時間攪拌した。反応混合物を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（７５．０ｍｇ、６７％）を泡状物質として得た。
ＬＣＭＳ ｍ／ｚ： ５９７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６０分（分析条件Ｄ） Compound b9:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(sulfamoylamino)pyridin-4-yl]methyl]benzoic acid

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(2-methylpropan-2-yl)oxycarbonylsulfamoylamino]pyridine-4- Chlorotrimethylsilane (71.5 μL, 0.564 mmol) was added to a 2,2,2-trifluoroethanol solution (2.6 mL) of yl]methyl]benzoic acid (compound b8, 131 mg, 0.188 mmol), and the mixture was stirred at room temperature. Stirred for 1.5 hours. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid in water/0.1% formic acid in acetonitrile) to give the title compound (75.0 mg, 67%) as a foam.
LCMS m/z: 597 [M+H] ⁺
HPLC retention time: 0.60 minutes (analysis condition D)

化合物ａ１２の製造例と同様の条件で、３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［３－フルオロ－２－（スルファモイルアミノ）ピリジン－４－イル］メチル］安息香酸（化合物ｂ９）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５９６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１１分（分析条件Ａ） Compound B-10:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(sulfamoylamino)pyridin-4-yl]methyl]benzamide

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(sulfamoylamino)pyridin-4-yl ]methyl]benzoic acid (compound b9) and the corresponding amine to synthesize the title compound.
LCMS m/z: 596 [M+H] ⁺
HPLC retention time: 1.11 minutes (analytical condition A)

２Ｍ ＬＤＡ ＴＨＦ溶液（６．５３ｍＬ、１３．１ｍｍｏｌ）を－７８℃に冷却し、窒素雰囲気下、２，３，４－トリフルオロ安息香酸（１．００ｇ、５．６８ｍｍｏｌ）のＴＨＦ溶液（６ｍＬ）をゆっくり加えた。－７８℃で５０分間攪拌した後、ＤＭＦ（０．４８４ｍＬ、６．２５ｍｍｏｌ）をゆっくり加え、－１０℃で２時間攪拌した。別のフラスコ中で、２－クロロ－４－ヨードアニリン（１．４４ｇ、５．６８ｍｍｏｌ）のＴＨＦ溶液（１５ｍＬ）を－７８℃に冷却し、１Ｍリチウムビス（トリメチルシリル）アミドＴＨＦ溶液（１３．６ｍＬ、１３．６ｍｍｏｌ）を滴下し、３０分間攪拌した。攪拌後、先の反応混合物を加え、室温で２０時間攪拌した。反応混合物に水及び２Ｍ塩酸を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥させ、乾燥剤をろ去後、減圧濃縮して表題化合物の粗生成物（１．２ｇ）を得た。
ＬＣＭＳ ｍ／ｚ： ４３８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９１分（分析条件Ｇ） Compound b10:
2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-formylbenzoic acid

A 2M LDA THF solution (6.53 mL, 13.1 mmol) was cooled to −78° C. and a THF solution (6 mL) of 2,3,4-trifluorobenzoic acid (1.00 g, 5.68 mmol) was added under a nitrogen atmosphere. was added slowly. After stirring at -78°C for 50 minutes, DMF (0.484 mL, 6.25 mmol) was slowly added and stirred at -10°C for 2 hours. In a separate flask, a THF solution (15 mL) of 2-chloro-4-iodoaniline (1.44 g, 5.68 mmol) was cooled to −78° C. and a 1 M lithium bis(trimethylsilyl)amide THF solution (13.6 mL) was added. , 13.6 mmol) was added dropwise and stirred for 30 minutes. After stirring, the above reaction mixture was added and stirred at room temperature for 20 hours. Water and 2M hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to give the title compound as a crude product (1.2 g).
LCMS m/z: 438 [M+H] ⁺
HPLC retention time: 0.91 minutes (analysis condition G)

化合物ａ１及び化合物ａ２の製造例と同様の条件で、２－（２－クロロ－４－ヨードアニリノ）－３，４－ジフルオロ－５－ホルミル安息香酸（化合物ｂ１０）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６２０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０９分（分析条件Ｇ） Compound b12:
Methyl 2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate

The title compound was synthesized from 2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-formylbenzoic acid (compound b10) under the same conditions as in the production examples of compound a1 and compound a2.
LCMS m/z: 620 [M+H] ⁺
HPLC retention time: 1.09 minutes (analysis condition G)

化合物ａ５及び化合物ａ６の製造例と同様の条件で、２－（２－クロロ－４－ヨードアニリノ）－３，４－ジフルオロ－５－［（Ｅ）－［（４－メチルフェニル）スルホニルヒドラジニリデン］メチル］安息香酸メチル（化合物ｂ１２）より表題化合物を合成した。但し、化合物ａ５の製造例で用いた炭酸カリウムの代わりにＤＩＰＥＡを用いた。
ＬＣＭＳ ｍ／ｚ： ５４８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８９分（分析条件Ｃ） Compound b14:
Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate

2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene under the same conditions as in the production examples of compounds a5 and a6 ]methyl]methylbenzoate (compound b12) to synthesize the title compound. However, DIPEA was used instead of potassium carbonate used in the production example of compound a5.
LCMS m/z: 548 [M+H] ⁺
HPLC retention time: 0.89 minutes (analysis condition C)

化合物Ａ－１、化合物ｂ２及び化合物ａ８の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－クロロ－４－ヨードアニリノ）－３，４－ジフルオロ安息香酸メチル（化合物ｂ１４）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６５２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６７分（分析条件Ｂ） Compound B-11:
2-(2-chloro-4-iodoanilino)-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 The title compound was synthesized from methyl-3,4-difluorobenzoate (compound b14) and the corresponding 4-nitrophenyl sulfamate.
LCMS m/z: 652 [M+H] ⁺
HPLC retention time: 1.67 minutes (analysis condition B)

化合物Ａ－１、化合物ｂ２及び化合物ａ８の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－クロロ－４－ヨードアニリノ）－３，４－ジフルオロ安息香酸メチル（化合物ｂ１４）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。但し、化合物ａ８の製造例で用いた７ＭアンモニアＭｅＯＨ溶液の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６９２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７８分（分析条件Ｂ） 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 The title compound was synthesized from methyl-3,4-difluorobenzoate (compound b14) and the corresponding 4-nitrophenyl sulfamate. However, the corresponding amine was used instead of the 7M ammonia MeOH solution used in the production example of compound a8.
LCMS m/z: 692 [M+H] ⁺
HPLC retention time: 1.78 minutes (analysis condition B)

化合物Ａ－１、化合物ｂ２及び化合物ａ８の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－クロロ－４－ヨードアニリノ）－３，４－ジフルオロ安息香酸メチル（化合物ｂ１４）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。但し、化合物ａ８の製造例で用いた７ＭアンモニアＭｅＯＨ溶液の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ７２４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．８１分（分析条件Ｂ） Compound B-13:
2-(2-chloro-4-iodoanilino)-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-N-[(2 -methylpropan-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 The title compound was synthesized from methyl-3,4-difluorobenzoate (compound b14) and the corresponding 4-nitrophenyl sulfamate. However, the corresponding amine was used instead of the 7M ammonia MeOH solution used in the production example of compound a8.
LCMS m/z: 724 [M+H] ⁺
HPLC retention time: 1.81 minutes (analysis condition B)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ａ６）及び対応するスルホニルクロリドより表題化合物を合成した。但し、化合物Ａ－２５の製造例で用いたピリジン及び無水ＤＭＡの代わりにそれぞれトリエチルアミン及び無水ＤＣＭを、化合物ｂ２の製造例で用いた水酸化リチウム一水和物の代わりに１Ｍ水酸化ナトリウム水溶液を、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６３５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８７分（分析条件Ｃ） Compound B-14:
N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methanesulfonamido)pyridin-4-yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2- The title compound was synthesized from methyl fluoro-4-iodoanilino)benzoate (compound a6) and the corresponding sulfonyl chloride. However, instead of pyridine and anhydrous DMA used in the production example of compound A-25, triethylamine and anhydrous DCM, respectively, in place of lithium hydroxide monohydrate used in the production example of compound b2 1M aqueous sodium hydroxide solution , the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 635 [M+H] ⁺
HPLC retention time: 0.87 minutes (analytical condition C)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ａ６）及び対応するスルホニルクロリドより表題化合物を合成した。但し、化合物Ａ－２５の製造例で用いたピリジン及び無水ＤＭＡの代わりにそれぞれトリエチルアミン及び無水ＤＣＭを、化合物ｂ２の製造例で用いた水酸化リチウム一水和物の代わりに１Ｍ水酸化ナトリウム水溶液を、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６２５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８０分（分析条件Ｃ） Compound B-15:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methanesulfonamido)pyridin-4-yl]methyl]-N-methoxybenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2- The title compound was synthesized from methyl fluoro-4-iodoanilino)benzoate (compound a6) and the corresponding sulfonyl chloride. However, instead of pyridine and anhydrous DMA used in the production example of compound A-25, triethylamine and anhydrous DCM, respectively, in place of lithium hydroxide monohydrate used in the production example of compound b2 1M aqueous sodium hydroxide solution , the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 625 [M+H] ⁺
HPLC retention time: 0.80 minutes (analysis condition C)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ａ６）及び対応するスルホニルクロリドより表題化合物を合成した。但し、化合物Ａ－２５の製造例で用いたピリジン及び無水ＤＭＡの代わりにそれぞれトリエチルアミン及び無水ＤＣＭを、化合物ｂ２の製造例で用いた水酸化リチウム一水和物の代わりに１Ｍ水酸化ナトリウム水溶液を、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６３９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８３分（分析条件Ｃ） 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- The title compound was synthesized from methyl fluoro-4-iodoanilino)benzoate (compound a6) and the corresponding sulfonyl chloride. However, instead of pyridine and anhydrous DMA used in the production example of compound A-25, triethylamine and anhydrous DCM, respectively, in place of lithium hydroxide monohydrate used in the production example of compound b2 1M aqueous sodium hydroxide solution , the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 639 [M+H] ⁺
HPLC retention time: 0.83 minutes (analysis condition C)

３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）－５－ホルミル安息香酸（５．００ｇ、１１．９ｍｍｏｌ）の無水ＤＭＦ溶液（５９ｍＬ）に４－メチルベンゼンスルホニルヒドラジド（２．２１ｇ、１１．９ｍｍｏｌ）を加え、室温で３０分間攪拌した。次いで、ＨＯＯＢｔ（１．９４ｇ、１１．９ｍｍｏｌ）及びＥＤＣ・ＨＣｌ（２．２８ｇ、１１．９ｍｍｏｌ）を加え、室温で１．５時間攪拌した。反応混合物に７ＭアンモニアＭｅＯＨ溶液（３．３９ｍＬ、２３．８ｍｍｏｌ）を加え、室温で３０分間攪拌した後、固体をろ去し、ＤＭＦ（３０ｍＬ）で洗浄した。ろ液にアセトニトリル（９０ｍＬ）及び０．１Ｍ塩酸（９０ｍＬ）を加え、得られた固体をアセトニトリル／水の混合液で洗浄して、表題化合物（６．２７ｇ、９０％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５８９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９０分（分析条件Ｃ） Compound c1:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide

To a solution of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid (5.00 g, 11.9 mmol) in anhydrous DMF (59 mL) was added 4-methylbenzenesulfonyl hydrazide. (2.21 g, 11.9 mmol) was added and stirred at room temperature for 30 minutes. HOOBt (1.94 g, 11.9 mmol) and EDC.HCl (2.28 g, 11.9 mmol) were then added and stirred at room temperature for 1.5 hours. A 7M ammonia in MeOH solution (3.39 mL, 23.8 mmol) was added to the reaction mixture and stirred at room temperature for 30 minutes, after which the solid was filtered off and washed with DMF (30 mL). Acetonitrile (90 mL) and 0.1 M hydrochloric acid (90 mL) were added to the filtrate and the resulting solid was washed with a mixture of acetonitrile/water to give the title compound (6.27 g, 90%) as a colorless solid. .
LCMS m/z: 589 [M+H] ⁺
HPLC retention time: 0.90 minutes (analysis condition C)

化合物ａ３及び化合物ａ４の製造例と同様の条件で、４－ブロモ－２－フルオロピリジンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ２８９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．３８分（分析条件Ｃ） Compound c2:
[2-[(2,4-dimethoxyphenyl)methylamino]pyridin-4-yl]boronic acid

The title compound was synthesized from 4-bromo-2-fluoropyridine under the same conditions as in the production examples of compound a3 and compound a4.
LCMS m/z: 289 [M+H] ⁺
HPLC retention time: 0.38 minutes (analysis condition C)

化合物ａ５及び化合物ａ６の製造例と同様の条件で、３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［（Ｅ）－［（４－メチルフェニル）スルホニルヒドラジニリデン］メチル］ベンズアミド（化合物ｃ１）より表題化合物を合成した。但し、化合物ａ５の製造例で用いた［２－［（２，４－ジメトキシフェニル）メチルアミノ］－３－フルオロピリジン－４－イル］ボロン酸（化合物ａ４）の代わりに［２－［（２，４－ジメトキシフェニル）メチルアミノ］ピリジン－４－イル］ボロン酸（化合物ｃ２）を用いた。
ＬＣＭＳ ｍ／ｚ： ６４９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７１分（分析条件Ｃ） Compound c4:
5-[(2-aminopyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene under the same conditions as in the production examples of compounds a5 and a6 ]methyl]benzamide (compound c1) to synthesize the title compound. However, [2-[(2 ,4-dimethoxyphenyl)methylamino]pyridin-4-yl]boronic acid (compound c2) was used.
LCMS m/z: 649 [M+H] ⁺
HPLC retention time: 0.71 minutes (analysis condition C)

化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ｃ４）及び対応するスルファモイルクロリドより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５７８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．４２分（分析条件Ｂ） Compound C-1:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(sulfamoylamino)pyridin-4-yl]methyl]benzamide

5-[(2-aminopyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound c4 ) and the corresponding sulfamoyl chloride to synthesize the title compound.
LCMS m/z: 578 [M+H] ⁺
HPLC retention time: 1.42 minutes (analysis condition B)

化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ｃ４）及び対応するスルファモイルクロリドより表題化合物を合成した。但し、ピリジンの代わりにイミダゾールを用いた。
ＬＣＭＳ ｍ／ｚ： ６３６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１０分（分析条件Ａ） Compound C-2:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide

5-[(2-aminopyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound c4 ) and the corresponding sulfamoyl chloride to synthesize the title compound. However, imidazole was used instead of pyridine.
LCMS m/z: 636 [M+H] ⁺
HPLC retention time: 1.10 minutes (analytical condition A)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ｃ４）及び対応するスルファモイルクロリドより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５９２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０８分（分析条件Ａ） Compound C-3:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

5-[(2-aminopyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound c4 ) and the corresponding sulfamoyl chloride to synthesize the title compound.
LCMS m/z: 592 [M+H] ⁺
HPLC retention time: 1.08 minutes (analytical condition A)

化合物Ａ－４３の製造例と同様の条件で、５－［（２－アミノピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンズアミド（化合物ｃ４）及び対応するスルファモイルクロリドより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５９０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９２分（分析条件Ａ） Compound C-4:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-[[methyl-(methylamino)-oxo-λ6-sulfanylidene]amino]pyridin-4-yl]methyl]benzamide

5-[(2-aminopyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (Compound c4 ) and the corresponding sulfamoyl chloride to synthesize the title compound.
LCMS m/z: 590 [M+H] ⁺
HPLC retention time: 0.92 minutes (Analysis condition A)

４－ヨード－２－メチルアニリン（６３６ｍｇ、２．７３ｍｍｏｌ）の無水ＴＨＦ溶液（１．８ｍｌ）を－７８℃に冷却し、１．３Ｍリチウムビス（トリメチルシリル）アミドＴＨＦ溶液（５．０８ｍＬ、６．６０ｍｍｏｌ）を１時間かけて加え、１時間攪拌した。次いで、２，３，４－トリフルオロ－５－ビニル安息香酸（４６０ｍｇ、２．２８ｍｍｏｌ）の無水ＴＨＦ溶液（３．９ｍＬ）を加え、０℃で２時間攪拌した。反応混合物に水及び２Ｍ塩酸を加え、酢酸エチルで２回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、乾燥剤をろ去後、減圧濃縮した。得られた残渣をＤＣＭで懸濁洗浄して、表題化合物（６３１ｍｇ、６７％）を褐色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４１６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９９分（分析条件Ｅ） Compound c5:
5-ethenyl-3,4-difluoro-2-(4-iodo-2-methylanilino)benzoic acid

An anhydrous THF solution (1.8 ml) of 4-iodo-2-methylaniline (636 mg, 2.73 mmol) was cooled to −78° C. and treated with 1.3 M lithium bis(trimethylsilyl)amide THF solution (5.08 mL, 6.5 mL). 60 mmol) was added over 1 hour and stirred for 1 hour. An anhydrous THF solution (3.9 mL) of 2,3,4-trifluoro-5-vinylbenzoic acid (460 mg, 2.28 mmol) was then added and stirred at 0° C. for 2 hours. Water and 2M hydrochloric acid were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The resulting residue was suspended and washed with DCM to give the title compound (631 mg, 67%) as a brown solid.
LCMS m/z: 416 [M+H] ⁺
HPLC retention time: 0.99 minutes (analysis condition E)

５－エテニル－３，４－ジフルオロ－２－（４－ヨード－２－メチルアニリノ）安息香酸（化合物ｃ５、６２６ｍｇ、１．５１ｍｍｏｌ）の無水ＴＨＦ溶液（６．３ｍＬ）に１Ｍ炭酸水素ナトリウム水溶液（３．０２ｍＬ、３．０２ｍｍｏｌ）、過ヨウ素酸ナトリウム（１．２９ｇ、６．０３ｍｍｏｌ）及び酸化オスミウム（ＶＩＩＩ），マイクロカプセル化（３８．３ｍｇ、０．０１５ｍｍｏｌ）を加え、室温で６時間攪拌した。反応混合物に酢酸エチルを加え、１Ｍ塩酸及び０．２Ｍチオ硫酸ナトリウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥させ、乾燥剤をろ去後、減圧濃縮した。得られた残渣を酢酸エチル／ヘキサン（１／２５、４２ｍＬ）で懸濁洗浄し、固体をろ取した。得られた固体をヘキサンで洗浄して、表題化合物（５５８ｍｇ、８９％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４１８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８６分（分析条件Ｃ） Compound c6:
3,4-difluoro-5-formyl-2-(4-iodo-2-methylanilino)benzoic acid

5-Ethenyl-3,4-difluoro-2-(4-iodo-2-methylanilino)benzoic acid (Compound c5, 626 mg, 1.51 mmol) in anhydrous THF solution (6.3 mL) was added with 1M aqueous sodium bicarbonate solution (3 .02 mL, 3.02 mmol), sodium periodate (1.29 g, 6.03 mmol) and osmium(VIII) oxide, microencapsulated (38.3 mg, 0.015 mmol) were added and stirred at room temperature for 6 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1M hydrochloric acid and 0.2M aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The obtained residue was suspended and washed with ethyl acetate/hexane (1/25, 42 mL), and the solid was collected by filtration. The solid obtained was washed with hexane to give the title compound (558 mg, 89%) as a colorless solid.
LCMS m/z: 418 [M+H] ⁺
HPLC retention time: 0.86 minutes (analytical condition C)

化合物ｃ１、化合物ａ５、化合物ａ６及び化合物Ａ－１の製造例と同様の条件で、３，４－ジフルオロ－５－ホルミル－２－（４－ヨード－２－メチルアニリノ）安息香酸（化合物ｃ６）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６０６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２０分（分析条件Ａ） Compound C-5:
3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(4-iodo-2-methylanilino)benzamide

From 3,4-difluoro-5-formyl-2-(4-iodo-2-methylanilino)benzoic acid (compound c6) under the same conditions as in the production examples of compound c1, compound a5, compound a6 and compound A-1 The title compound was synthesized.
LCMS m/z: 606 [M+H] ⁺
HPLC retention time: 1.20 minutes (analytical condition A)

化合物ａ２、化合物ａ１０、化合物ａ５及び化合物Ａ－１の製造例と同様の条件で、３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）－５－ホルミル安息香酸より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６３１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７０分（分析条件Ｂ） Compound C-6:
N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-(methylsulfamoylamino)phenyl]methyl]benzamide

From 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid under the same conditions as in the production examples of compound a2, compound a10, compound a5 and compound A-1 The title compound was synthesized.
LCMS m/z: 631 [M+H] ⁺
HPLC retention time: 1.70 minutes (analysis condition B)

化合物ａ５の製造例と同様の条件で、３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［（Ｅ）－［（４－メチルフェニル）スルホニルヒドラジニリデン］メチル］安息香酸メチル（化合物ａ２）より表題化合物を合成した。但し、［２－［（２，４－ジメトキシフェニル）メチルアミノ］－３－フルオロピリジン－４－イル］ボロン酸（化合物ａ４）の代わりに（３－アミノ－２－フルオロフェニル）ボロン酸塩酸塩を用いた。
ＬＣＭＳ ｍ／ｚ： ５３１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９６分（分析条件Ｄ） Compound d1:
5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)methyl benzoate

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl] under the same conditions as in the production example of compound a5 The title compound was synthesized from methyl benzoate (compound a2). provided that (3-amino-2-fluorophenyl)boronic acid hydrochloride instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4) was used.
LCMS m/z: 531 [M+H] ⁺
HPLC retention time: 0.96 minutes (analysis condition D)

化合物ａ７の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５１７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９５分（分析条件Ｃ） Compound d2:
5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid

Methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound d1 ) to synthesize the title compound.
LCMS m/z: 517 [M+H] ⁺
HPLC retention time: 0.95 minutes (analytical condition C)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸（化合物ｄ２）より表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６５３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２４分（分析条件Ａ） Compound D-1:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(2-methoxyethylsulfamoylamino)phenyl]methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate under the same conditions as in the production examples of compound a8 and compound A-1 The title compound was synthesized from the acid (compound d2). However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 653 [M+H] ⁺
HPLC retention time: 1.24 minutes (analytical condition A)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸（化合物ｄ２）より表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６８１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．３５分（分析条件Ａ） Compound D-2:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methoxy-2-methylpropan-2-yl)sulfamoylamino]phenyl] methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate under the same conditions as in the production examples of compound a8 and compound A-1 The title compound was synthesized from the acid (compound d2). However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 681 [M+H] ⁺
HPLC retention time: 1.35 minutes (analytical condition A)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸（化合物ｄ２）より表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６７９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２７分（分析条件Ａ） Compound D-3:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[[(2R)-oxolan-2-yl]methylsulfamoylamino]phenyl]methyl] benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate under the same conditions as in the production examples of compound a8 and compound A-1 The title compound was synthesized from the acid (compound d2). However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 679 [M+H] ⁺
HPLC retention time: 1.27 minutes (analytical condition A)

化合物ａ８及び化合物Ａ－２５の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸（化合物ｄ２）より表題化合物を合成した。但し、化合物Ａ－２５の製造例で用いたメチルスルファモイルクロリドの代わりに対応するスルホニルクロリドを用いた。また、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６０８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２６分（分析条件Ａ） Compound D-4:
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate under the same conditions as in the production examples of compound a8 and compound A-25 The title compound was synthesized from the acid (compound d2). However, the corresponding sulfonyl chloride was used instead of the methylsulfamoyl chloride used in the production example of compound A-25. Pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 608 [M+H] ⁺
HPLC retention time: 1.26 minutes (analytical condition A)

化合物ａ８及び化合物Ａ－２５の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸（化合物ｄ２）より表題化合物を合成した。但し、化合物Ａ－２５の製造例で用いたメチルスルファモイルクロリドの代わりに対応するスルホニルクロリドを用いた。また、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６３８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６７分（分析条件Ｂ） Compound D-5:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(2-methoxyethylsulfonylamino)phenyl]methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate under the same conditions as in the production examples of compound a8 and compound A-25 The title compound was synthesized from the acid (compound d2). However, the corresponding sulfonyl chloride was used instead of the methylsulfamoyl chloride used in the production example of compound A-25. Pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 638 [M+H] ⁺
HPLC retention time: 1.67 minutes (analysis condition B)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸（化合物ｄ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６４９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７１分（分析条件Ｂ） Compound D-6:
N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate under the same conditions as in the production examples of compound a8 and compound A-1 The title compound was synthesized from the acid (compound d2) and the corresponding amine.
LCMS m/z: 649 [M+H] ⁺
HPLC retention time: 1.71 minutes (analysis condition B)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸（化合物ｄ２）及び対応するアミンより表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６３５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６５分（分析条件Ｂ） Compound D-7:
N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(sulfamoylamino)phenyl]methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate under the same conditions as in the production examples of compound a8 and compound A-1 The title compound was synthesized from the acid (compound d2) and the corresponding amine. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 635 [M+H] ⁺
HPLC retention time: 1.65 minutes (analysis condition B)

化合物ａ８及び化合物Ａ－２５の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸（化合物ｄ２）及び対応するアミンより表題化合物を合成した。但し、化合物Ａ－２５の製造例で用いたメチルスルファモイルクロリドの代わりに対応するスルホニルクロリドを用いた。また、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６４８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７７分（分析条件Ｂ） Compound D-8:
N-Cyclopropyl-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate under the same conditions as in the production examples of compound a8 and compound A-25 The title compound was synthesized from the acid (compound d2) and the corresponding amine. However, the corresponding sulfonyl chloride was used in place of the methylsulfamoyl chloride used in the production example of compound A-25. Pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 648 [M+H] ⁺
HPLC retention time: 1.77 minutes (analysis condition B)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸（化合物ｄ２）より表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６６３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９５分（分析条件Ｃ） Compound D-9:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclobutyl)sulfamoylamino]phenyl]methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate under the same conditions as in the production examples of compound a8 and compound A-1 The title compound was synthesized from the acid (compound d2). However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 663 [M+H] ⁺
HPLC retention time: 0.95 minutes (analytical condition C)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸（化合物ｄ２）及び対応するアミンより表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ７０３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０１分（分析条件Ｃ） Compound D-10:
N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclobutyl)sulfamoylamino]phenyl]methyl] benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate under the same conditions as in the production examples of compound a8 and compound A-1 The title compound was synthesized from the acid (compound d2) and the corresponding amine. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 703 [M+H] ⁺
HPLC retention time: 1.01 minutes (analysis condition C)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸（化合物ｄ２）及び対応するアミンより表題化合物を合成した。但し、化合物ａ８の製造例で用いたＤＩＰＥＡの代わりにトリエチルアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６３９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６２分（分析条件Ｂ） Compound D-11:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-N-methoxybenzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate under the same conditions as in the production examples of compound a8 and compound A-1 The title compound was synthesized from the acid (compound d2) and the corresponding amine. However, triethylamine was used instead of DIPEA used in the production example of compound a8.
LCMS m/z: 639 [M+H] ⁺
HPLC retention time: 1.62 minutes (analysis condition B)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸（化合物ｄ２）及び対応するアミンより表題化合物を合成した。但し、化合物ａ８の製造例で用いたＤＩＰＥＡの代わりにトリエチルアミンを、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６２５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８１分（分析条件Ｃ） Compound D-12:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(sulfamoylamino)phenyl]methyl]-N-methoxybenzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate under the same conditions as in the production examples of compound a8 and compound A-1 The title compound was synthesized from the acid (compound d2) and the corresponding amine. However, instead of DIPEA used in the production example of compound a8, triethylamine was used, and in place of 4-nitrophenyl methylsulfamate used in the production example of compound A-1, the corresponding 4-nitrophenyl sulfamate was used.
LCMS m/z: 625 [M+H] ⁺
HPLC retention time: 0.81 minutes (analytical condition C)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸（化合物ｄ２）及び対応するアミンより表題化合物を合成した。但し、化合物ａ８の製造例で用いたＤＩＰＥＡの代わりにトリエチルアミンを、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６９３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９５分（分析条件Ｃ） Compound D-13:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclobutyl)sulfamoylamino]phenyl]methyl]-N-methoxybenzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate under the same conditions as in the production examples of compound a8 and compound A-1 The title compound was synthesized from the acid (compound d2) and the corresponding amine. However, triethylamine was used in place of DIPEA used in the production example of compound a8, and the corresponding 4-nitrophenyl sulfamate was used in place of 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 693 [M+H] ⁺
HPLC retention time: 0.95 minutes (analytical condition C)

化合物ａ９、化合物ａ７、化合物ａ８及び化合物Ａ－２５の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）より表題化合物を合成した。但し、化合物ａ７の製造例で用いた水酸化リチウム一水和物の代わりに１Ｍ水酸化ナトリウム水溶液を用いた。
ＬＣＭＳ ｍ／ｚ： ５２３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．５８分（分析条件Ｂ） Compound D-14:
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro The title compound was synthesized from methyl-4-iodoanilino)benzoate (compound d1). However, instead of the lithium hydroxide monohydrate used in the production example of compound a7, a 1M sodium hydroxide aqueous solution was used.
LCMS m/z: 523 [M+H] ⁺
HPLC retention time: 1.58 minutes (analysis condition B)

化合物ａ９、化合物ａ７、化合物ａ８及び化合物Ａ－２５の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）より表題化合物を合成した。但し、化合物ａ７の製造例で用いた水酸化リチウム一水和物の代わりに１Ｍ水酸化ナトリウム水溶液を、化合物ａ８の製造例で用いた７ＭアンモニアＭｅＯＨ溶液の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ５６３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６８分（分析条件Ｂ） Compound D-15:
N-cyclopropyl-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro The title compound was synthesized from methyl-4-iodoanilino)benzoate (compound d1). However, a 1M sodium hydroxide aqueous solution was used instead of the lithium hydroxide monohydrate used in the production example of compound a7, and the corresponding amine was used instead of the 7M ammonia MeOH solution used in the production example of compound a8.
LCMS m/z: 563 [M+H] ⁺
HPLC retention time: 1.68 minutes (Analysis condition B)

化合物ａ９、化合物ａ７、化合物ａ８及び化合物Ａ－２５の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）より表題化合物を合成した。但し、化合物ａ７の製造例で用いた水酸化リチウム一水和物の代わりに１Ｍ水酸化ナトリウム水溶液を、化合物ａ８の製造例で用いた７ＭアンモニアＭｅＯＨ溶液の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ５５１［Ｍ－Ｈ］^－
ＨＰＬＣ保持時間： ０．８５分（分析条件Ｃ） Compound D-16:
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-N-methoxybenzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro The title compound was synthesized from methyl-4-iodoanilino)benzoate (compound d1). However, a 1M sodium hydroxide aqueous solution was used in place of the lithium hydroxide monohydrate used in the production example of compound a7, and the corresponding amine was used in place of the 7M ammonia MeOH solution used in the production example of compound a8.
LCMS m/z: 551 [MH] ^-
HPLC retention time: 0.85 minutes (analytical condition C)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。また、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６３８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６８分（分析条件Ｂ） Compound E-1:
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4- The title compound was synthesized from methyl iodoanilino)benzoate (compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step. Further, the corresponding amine was used in place of the tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 638 [M+H] ⁺
HPLC retention time: 1.68 minutes (Analysis condition B)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６８０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．８０分（分析条件Ｂ） Compound E-2:
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-[(2-methylpropan-2-yl ) oxy]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4- The title compound was synthesized from methyl iodoanilino)benzoate (compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 680 [M+H] ⁺
HPLC retention time: 1.80 minutes (analysis condition B)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。また、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６９４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７４分（分析条件Ｂ） Compound E-3:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[[1-(methoxymethyl)cyclopropyl]sulfonylamino]phenyl]methyl]-N-methoxy benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4- The title compound was synthesized from methyl iodoanilino)benzoate (compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step. Further, the corresponding amine was used in place of the tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 694 [M+H] ⁺
HPLC retention time: 1.74 minutes (analysis condition B)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ７３６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．８７分（分析条件Ｂ） Compound E-4:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[[1-(methoxymethyl)cyclopropyl]sulfonylamino]phenyl]methyl]-N-[ (2-methylpropan-2-yl)oxy]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4- The title compound was synthesized from methyl iodoanilino)benzoate (compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 736 [M+H] ⁺
HPLC retention time: 1.87 minutes (analysis condition B)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。また、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６６４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７３分（分析条件Ｂ） Compound E-5:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-N-methoxybenzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4- The title compound was synthesized from methyl iodoanilino)benzoate (compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step. Further, the corresponding amine was used in place of the tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 664 [M+H] ⁺
HPLC retention time: 1.73 minutes (analysis condition B)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ７０６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．８６分（分析条件Ｂ） Compound E-6:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-N-[(2- Methylpropan-2-yl)oxy]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4- The title compound was synthesized from methyl iodoanilino)benzoate (compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 706 [M+H] ⁺
HPLC retention time: 1.86 minutes (analysis condition B)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）より表題化合物を合成した。但し、スルファミド化工程では溶媒としてピリジンを用いた。また、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６０９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２３分（分析条件Ａ） Compound E-7:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4- The title compound was synthesized from methyl iodoanilino)benzoate (compound d1). However, pyridine was used as a solvent in the sulfamidation step. Further, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 609 [M+H] ⁺
HPLC retention time: 1.23 minutes (analytical condition A)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルファモイルクロリドより表題化合物を合成した。但し、スルファミド化工程では溶媒としてピリジンを用いた。また、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６９５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７４分（分析条件Ｄ） Compound e11:
tert-butyl N-[[3-[[5-carbamoyl-2,3-difluoro-4-(2-fluoro-4-iodoanilino)phenyl]methyl]-2-fluorophenyl]sulfamoyl]carbamate

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4- The title compound was synthesized from iodoanilino)methyl benzoate (compound d1) and the corresponding sulfamoyl chloride. However, pyridine was used as a solvent in the sulfamidation step. Further, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 695 [M+H] ⁺
HPLC retention time: 0.74 minutes (analytical condition D)

化合物ｂ９の製造例と同様の条件で、ｔｅｒｔ－ブチル Ｎ－［［３－［［５－カルバモイル－２，３－ジフルオロ－４－（２－フルオロ－４－ヨードアニリノ）フェニル］メチル］－２－フルオロフェニル］スルファモイル］カルバメート（化合物ｅ１１）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５９５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１７分（分析条件Ａ） Compound E-8:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(sulfamoylamino)phenyl]methyl]benzamide

Under the same conditions as in the production example of compound b9, tert-butyl N-[[3-[[5-carbamoyl-2,3-difluoro-4-(2-fluoro-4-iodoanilino)phenyl]methyl]-2- The title compound was synthesized from fluorophenyl]sulfamoyl]carbamate (compound e11).
LCMS m/z: 595 [M+H] ⁺
HPLC retention time: 1.17 minutes (analytical condition A)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－クロロ－４－ヨードアニリノ）－３，４－ジフルオロ安息香酸メチル（化合物ｂ１４）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。また、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６５４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７５分（分析条件Ｂ） Compound E-9:
2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide

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-25, compound b2 and compound a12 The title compound was synthesized from methyl-3,4-difluorobenzoate (compound b14) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step. Further, the corresponding amine was used in place of the tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 654 [M+H] ⁺
HPLC retention time: 1.75 minutes (analysis condition B)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－クロロ－４－ヨードアニリノ）－３，４－ジフルオロ安息香酸メチル（化合物ｂ１４）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。また、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６９６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．８７分（分析条件Ｂ） Compound E-10:
2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-[(2-methylpropan-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-25, compound b2 and compound a12 The title compound was synthesized from methyl-3,4-difluorobenzoate (compound b14) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step. Further, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 696 [M+H] ⁺
HPLC retention time: 1.87 minutes (analysis condition B)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－クロロ－４－ヨードアニリノ）－３，４－ジフルオロ安息香酸メチル（化合物ｂ１４）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。また、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６２４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７３分（分析条件Ｂ） Compound E-11:
2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]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-25, compound b2 and compound a12 The title compound was synthesized from methyl-3,4-difluorobenzoate (compound b14) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step. Further, the corresponding amine was used in place of tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 624 [M+H] ⁺
HPLC retention time: 1.73 minutes (analysis condition B)

化合物ａ５の製造例と同様の条件で、２－（２－クロロ－４－ヨードアニリノ）－３，４－ジフルオロ－５－［（Ｅ）－［（４－メチルフェニル）スルホニルヒドラジニリデン］メチル］安息香酸メチル（化合物ｂ１２）より表題化合物を合成した。但し、［２－［（２，４－ジメトキシフェニル）メチルアミノ］－３－フルオロピリジン－４－イル］ボロン酸（化合物ａ４）の代わりに（３－アミノ－２－フルオロフェニル）ボロン酸塩酸塩を、炭酸カリウムの代わりにＤＩＰＥＡを用いた。
ＬＣＭＳ ｍ／ｚ： ５４７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１３分（分析条件Ｃ） Compound e17:
Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-chloro-4-iodoanilino)-3,4-difluorobenzoate

2-(2-chloro-4-iodoanilino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl] under the same conditions as in the production example of compound a5 The title compound was synthesized from methyl benzoate (compound b12). provided that (3-amino-2-fluorophenyl)boronic acid hydrochloride instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4) with DIPEA instead of potassium carbonate.
LCMS m/z: 547 [M+H] ⁺
HPLC retention time: 1.13 minutes (analytical condition C)

化合物Ａ－１、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－２－（２－クロロ－４－ヨードアニリノ）－３，４－ジフルオロ安息香酸メチル（化合物ｅ１７）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ７２３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．８７分（分析条件Ｂ） Compound E-12:
2-(2-chloro-4-iodoanilino)-5-[[3-(cyclopropylsulfamoylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-[(2-methylpropane- 2-yl)oxy]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-2-(2-chloro-4-iodoanilino)-3,4 under the same conditions as in the production examples of compound A-1, compound b2 and compound a12 The title compound was synthesized from methyl-difluorobenzoate (compound e17) and the corresponding 4-nitrophenyl sulfamate.
LCMS m/z: 723 [M+H] ⁺
HPLC retention time: 1.87 minutes (analysis condition B)

化合物Ａ－２５の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６０９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０１分（分析条件Ｃ） Compound e20:
Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzoate

Methyl 5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate ( The title compound was synthesized from compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent.
LCMS m/z: 609 [M+H] ⁺
HPLC retention time: 1.01 minutes (analysis condition C)

３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［２－フルオロ－３－（メタンスルホンアミド）フェニル］メチル］安息香酸メチル（化合物ｅ２０、２３．０ｍｇ、０．０３８ｍｍｏｌ）のＴＨＦ（０．７ｍＬ）及び水（０．３ｍＬ）混合溶液に水酸化リチウム一水和物（７．９ｍｇ、０．１９ｍｍｏｌ）を加え、室温で２時間攪拌した。反応混合物を減圧濃縮し、１Ｍ塩酸（０．７６ｍＬ）を加え、さらに減圧濃縮した。得られた混合物の無水ＤＭＦ溶液（０．３ｍＬ）にＨＯＯＢｔ（９．３ｍｇ、０．０５７ｍｍｏｌ）及びＥＤＣ・ＨＣｌ（１０．９ｍｇ、０．０５７ｍｍｏｌ）を加え、室温で３時間攪拌した。次いで、０℃で７ＭアンモニアＭｅＯＨ溶液（２２μＬ、０．１５ｍｍｏｌ）を加え、３０分間攪拌した。反応混合物に１０％トリフルオロ酢酸水溶液（１ｍＬ）を加え、逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（１９．７ｍｇ、９７％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５９４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６１分（分析条件Ｂ） Compound E-13:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide

Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzoate (compound e20, 23.0 mg, 0. 038 mmol) in THF (0.7 mL) and water (0.3 mL), lithium hydroxide monohydrate (7.9 mg, 0.19 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, 1M 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 resulting mixture, and the mixture was stirred at room temperature for 3 hours. Then 7M ammonia in MeOH solution (22 μL, 0.15 mmol) was added at 0° C. and stirred for 30 minutes. A 10% trifluoroacetic acid aqueous solution (1 mL) was added to the reaction mixture, and the title compound (19.7 mg, 97% ) as a colorless solid.
LCMS m/z: 594 [M+H] ⁺
HPLC retention time: 1.61 minutes (analysis condition B)

化合物Ａ－２５及び化合物Ｅ－１３の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６３４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７２分（分析条件Ｂ） Compound E-14:
5-[[3-(Cyclopropylmethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino ) The title compound was synthesized from methyl benzoate (compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 634 [M+H] ⁺
HPLC retention time: 1.72 minutes (analysis condition B)

化合物Ａ－２５及び化合物Ｅ－１３の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、化合物Ａ－２５の製造例で用いた無水ＤＭＡの代わりに無水ＤＣＭを用いた。
ＬＣＭＳ ｍ／ｚ： ６４０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６７分（分析条件Ｂ） Compound E-15:
3,4-difluoro-5-[[2-fluoro-3-(3-fluoropropylsulfonylamino)phenyl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino ) The title compound was synthesized from methyl benzoate (compound d1) and the corresponding sulfonyl chloride. However, anhydrous DCM was used instead of anhydrous DMA used in the preparation of compound A-25.
LCMS m/z: 640 [M+H] ⁺
HPLC retention time: 1.67 minutes (analysis condition B)

化合物Ａ－２５及び化合物Ｅ－１３の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６３４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７２分（分析条件Ｂ） Compound E-16:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino ) The title compound was synthesized from methyl benzoate (compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 634 [M+H] ⁺
HPLC retention time: 1.72 minutes (analysis condition B)

化合物Ａ－２５及び化合物Ｅ－１３の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６３６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７７分（分析条件Ｂ） Compound E-17:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(2-methylpropylsulfonylamino)phenyl]methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino ) The title compound was synthesized from methyl benzoate (compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 636 [M+H] ⁺
HPLC retention time: 1.77 minutes (analysis condition B)

化合物Ａ－２５及び化合物Ｅ－１３の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６２２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７２分（分析条件Ｂ） Compound E-18:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(propylsulfonylamino)phenyl]methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino ) The title compound was synthesized from methyl benzoate (compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 622 [M+H] ⁺
HPLC retention time: 1.72 minutes (analysis condition B)

化合物Ａ－２５及び化合物Ｅ－１３の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６６４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７３分（分析条件Ｂ） Compound E-19:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[[1-(methoxymethyl)cyclopropyl]sulfonylamino]phenyl]methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino ) The title compound was synthesized from methyl benzoate (compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 664 [M+H] ⁺
HPLC retention time: 1.73 minutes (analysis condition B)

化合物Ａ－２５及び化合物Ｅ－１３の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６３４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７３分（分析条件Ｂ） Compound E-20:
5-[[3-(cyclobutylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino ) The title compound was synthesized from methyl benzoate (compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 634 [M+H] ⁺
HPLC retention time: 1.73 minutes (analysis condition B)

化合物Ａ－２５及び化合物Ｅ－１３の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６３６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６１分（分析条件Ｂ） Compound E-21:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxetan-3-ylsulfonylamino)phenyl]methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino ) The title compound was synthesized from methyl benzoate (compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 636 [M+H] ⁺
HPLC retention time: 1.61 minutes (analysis condition B)

化合物Ａ－２５及び化合物Ｅ－１３の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６２０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６８分（分析条件Ｂ） Compound E-22:
5-[[3-(Cyclopropylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino ) The title compound was synthesized from methyl benzoate (compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 620 [M+H] ⁺
HPLC retention time: 1.68 minutes (analysis condition B)

化合物Ａ－２５及び化合物Ｅ－１３の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、化合物Ａ－２５の製造例で用いたピリジン及び無水ＤＭＡの代わりにそれぞれトリエチルアミン及び無水ＤＣＭを用いた。
ＬＣＭＳ ｍ／ｚ： ６６４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６５分（分析条件Ｂ） Compound E-23:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino ) The title compound was synthesized from methyl benzoate (compound d1) and the corresponding sulfonyl chloride. However, triethylamine and anhydrous DCM were used in place of pyridine and anhydrous DMA used in the production example of compound A-25, respectively.
LCMS m/z: 664 [M+H] ⁺
HPLC retention time: 1.65 minutes (analysis condition B)

化合物Ａ－２５及び化合物Ｅ－１３の製造例と同様の条件で、５－［（３－アミノ－２－フルオロフェニル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｄ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６２２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．７１分（分析条件Ｂ） Compound E-24:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(propan-2-ylsulfonylamino)phenyl]methyl]benzamide

5-[(3-amino-2-fluorophenyl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino ) The title compound was synthesized from methyl benzoate (compound d1) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 622 [M+H] ⁺
HPLC retention time: 1.71 minutes (analysis condition B)

化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［２－フルオロ－３－（メタンスルホンアミド）フェニル］メチル］安息香酸メチル（化合物ｅ２０）より表題化合物を合成した。但し、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６３４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９２分（分析条件Ｃ） Compound E-25:
N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl under the same conditions as in the production examples of compound b2 and compound a12 ] The title compound was synthesized from methyl benzoate (compound e20). However, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 634 [M+H] ⁺
HPLC retention time: 0.92 minutes (analysis condition C)

化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［２－フルオロ－３－（メタンスルホンアミド）フェニル］メチル］安息香酸メチル（化合物ｅ２０）より表題化合物を合成した。但し、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６２４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８６分（分析条件Ｃ） Compound E-26:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]-N-methoxybenzamide

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl under the same conditions as in the production examples of compound b2 and compound a12 ] The title compound was synthesized from methyl benzoate (compound e20). However, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 624 [M+H] ⁺
HPLC retention time: 0.86 minutes (analytical condition C)

化合物ａ５及び化合物Ａ－２５の製造例と同様の条件で、３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［（Ｅ）－［（４－メチルフェニル）スルホニルヒドラジニリデン］メチル］ベンズアミド（化合物ｃ１）より表題化合物を合成した。但し、化合物ａ５の製造例で用いた［２－［（２，４－ジメトキシフェニル）メチルアミノ］－３－フルオロピリジン－４－イル］ボロン酸（化合物ａ４）の代わりに３－アミノフェニルボロン酸を用いた。
ＬＣＭＳ ｍ／ｚ： ５９１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８４分（分析条件Ｃ） Compound F-1:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-(methylsulfamoylamino)phenyl]methyl]benzamide

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonyl hydra The title compound was synthesized from dinylidene]methyl]benzamide (compound c1). However, instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4) used in the production example of compound a5, 3-aminophenylboronic acid was used.
LCMS m/z: 591 [M+H] ⁺
HPLC retention time: 0.84 minutes (analysis condition C)

化合物ａ５及び化合物Ａ－２５の製造例と同様の条件で、３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［（Ｅ）－［（４－メチルフェニル）スルホニルヒドラジニリデン］メチル］ベンズアミド（化合物ｃ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、化合物ａ５の製造例で用いた［２－［（２，４－ジメトキシフェニル）メチルアミノ］－３－フルオロピリジン－４－イル］ボロン酸（化合物ａ４）の代わりに３－アミノフェニルボロン酸を用いた。また、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ５９０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２６分（分析条件Ａ） Compound F-2:
5-[[3-(ethylsulfonylamino)phenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonyl hydra The title compound was synthesized from dinylidene]methyl]benzamide (compound c1) and the corresponding sulfonyl chloride. However, instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4) used in the production example of compound a5, 3-aminophenylboronic acid was used. Pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 590 [M+H] ⁺
HPLC retention time: 1.26 minutes (analytical condition A)

化合物ａ５及び化合物Ａ－２５の製造例と同様の条件で、３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［（Ｅ）－［（４－メチルフェニル）スルホニルヒドラジニリデン］メチル］ベンズアミド（化合物ｃ１）及び対応するスルホニルクロリドより表題化合物を合成した。但し、化合物ａ５の製造例で用いた［２－［（２，４－ジメトキシフェニル）メチルアミノ］－３－フルオロピリジン－４－イル］ボロン酸（化合物ａ４）の代わりに３－アミノフェニルボロン酸を用いた。また、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６２０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６５分（分析条件Ｂ） Compound F-3:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-(2-methoxyethylsulfonylamino)phenyl]methyl]benzamide

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonyl hydra The title compound was synthesized from dinylidene]methyl]benzamide (compound c1) and the corresponding sulfonyl chloride. However, instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4) used in the production example of compound a5, 3-aminophenylboronic acid was used. Pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 620 [M+H] ⁺
HPLC retention time: 1.65 minutes (Analysis condition B)

化合物ａ９及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸塩酸塩（化合物ａ７）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５２５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８３分（分析条件Ｃ） Compound g2:
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4 -Iodoanilino)benzoic acid hydrochloride (compound a7) to synthesize the title compound.
LCMS m/z: 525 [M+H] ⁺
HPLC retention time: 0.83 minutes (analysis condition C)

化合物ａ１０の製造例と同様の条件で、２－（４－シクロプロピル－２－フルオロアニリノ）－３，４－ジフルオロ－５－［［３－フルオロ－２－（メチルスルファモイルアミノ）ピリジン－４－イル］メチル］安息香酸（化合物ｇ２）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５６４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６１分（分析条件Ｂ） Compound G-1:
N-cyclopropyl-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl ] benzamide

2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine The title compound was synthesized from -4-yl]methyl]benzoic acid (compound g2).
LCMS m/z: 564 [M+H] ⁺
HPLC retention time: 1.61 minutes (analysis condition B)

２－（４－シクロプロピル－２－フルオロアニリノ）－３，４－ジフルオロ－５－［［３－フルオロ－２－（メチルスルファモイルアミノ）ピリジン－４－イル］メチル］安息香酸（化合物ｇ２、２０ｍｇ、０．０３８ｍｍｏｌ）の無水ＤＭＦ溶液（０．２ｍＬ）にＯ－メチルヒドロキシアミン塩酸塩（６．４ｍｇ、０．０７６ｍｍｏｌ）、プロピルホスホン酸無水物（環状トリマー）（５６μＬ、０．０９５ｍｍｏｌ）及びトリエチルアミン（２７μＬ、０．１９ｍｍｏｌ）を加え、室温で１６時間攪拌した。反応混合物を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（１４ｍｇ、６６％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５５４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．５３分（分析条件Ｂ） Compound G-2:
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy benzamide

2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid (compound g2, 20 mg, 0.038 mmol) in anhydrous DMF (0.2 mL) O-methylhydroxyamine hydrochloride (6.4 mg, 0.076 mmol), propylphosphonic anhydride (cyclic trimer) (56 μL, 0.095 mmol) ) and triethylamine (27 μL, 0.19 mmol) were added and stirred at room temperature for 16 hours. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (14 mg, 66%) as a colorless solid.
LCMS m/z: 554 [M+H] ⁺
HPLC retention time: 1.53 minutes (analysis condition B)

化合物ａ２１、化合物Ａ－１及び化合物Ｇ－２の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸塩酸塩（化合物ａ７）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５９２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．５２分（分析条件Ｂ） Compound G-3:
2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-( The title compound was synthesized from 2-fluoro-4-iodoanilino)benzoic acid hydrochloride (compound a7).
LCMS m/z: 592 [M+H] ⁺
HPLC retention time: 1.52 minutes (analysis condition B)

化合物ａ２１、化合物Ａ－１及び化合物Ｇ－２の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸塩酸塩（化合物ａ７）より表題化合物を合成した。但し、化合物ａ２１の製造例で用いた臭化銅（Ｉ）の代わりに塩化銅（Ｉ）を用いた。
ＬＣＭＳ ｍ／ｚ： ５４８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．５０分（分析条件Ｂ） Compound G-4:
2-(4-chloro-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-( The title compound was synthesized from 2-fluoro-4-iodoanilino)benzoic acid hydrochloride (compound a7). However, copper (I) chloride was used instead of copper (I) bromide used in the production example of compound a21.
LCMS m/z: 548 [M+H] ⁺
HPLC retention time: 1.50 minutes (analysis condition B)

化合物ａ９、化合物ａ７、化合物ａ１２及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ａ６）より表題化合物を合成した。但し、化合物ａ７の製造例で用いた水酸化リチウム一水和物の代わりに１Ｍ水酸化ナトリウム水溶液を、化合物ａ１２の製造例で用いたＤＩＰＥＡの代わりにトリエチルアミンを用いた。また、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６１８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９５分（分析条件Ｃ） Compound G-5:
N-cyclopropyl-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine -4-yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2- The title compound was synthesized from methyl (2-fluoro-4-iodoanilino)benzoate (compound a6). However, 1M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate used in the production example of compound a7, and triethylamine was used instead of DIPEA used in the production example of compound a12. Further, the corresponding amine was used in place of the tert-butoxyamine hydrochloride used in the production example of compound a12, and the corresponding 4-nitrophenyl methylsulfamate used in the production example of compound A-1 was replaced with the corresponding sulfamate 4- Nitrophenyl was used.
LCMS m/z: 618 [M+H] ⁺
HPLC retention time: 0.95 minutes (analytical condition C)

化合物ａ９、化合物ａ７、化合物ａ１２及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ａ６）より表題化合物を合成した。但し、化合物ａ７の製造例で用いた水酸化リチウム一水和物の代わりに１Ｍ水酸化ナトリウム水溶液を、化合物ａ１２の製造例で用いたＤＩＰＥＡの代わりにトリエチルアミンを用いた。また、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６０８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９０分（分析条件Ｃ） Compound G-6:
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl] Methyl]-N-methoxybenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2- The title compound was synthesized from methyl (2-fluoro-4-iodoanilino)benzoate (compound a6). However, 1M aqueous sodium hydroxide solution was used instead of lithium hydroxide monohydrate used in the production example of compound a7, and triethylamine was used instead of DIPEA used in the production example of compound a12. Further, the corresponding amine was used in place of the tert-butoxyamine hydrochloride used in the production example of compound a12, and the corresponding 4-nitrophenyl methylsulfamate used in the production example of compound A-1 was replaced with the corresponding sulfamate 4- Nitrophenyl was used.
LCMS m/z: 608 [M+H] ⁺
HPLC retention time: 0.90 minutes (analysis condition C)

化合物Ａ－２５、化合物ａ９、化合物ａ７及び化合物ａ１２の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ａ６）及び対応するスルホニルクロリドより表題化合物を合成した。但し、化合物Ａ－２５の製造例で用いたピリジン及び無水ＤＭＡの代わりにそれぞれトリエチルアミン及び無水ＤＣＭを、化合物ａ７の製造例で用いた水酸化リチウム一水和物の代わりに１Ｍ水酸化ナトリウム水溶液を用いた。また、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ５６３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８８分（分析条件Ｃ） Compound G-7:
N-cyclopropyl-2-(4-cyclopropyl-2-fluoroanilino)-5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluorobenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2- The title compound was synthesized from methyl (2-fluoro-4-iodoanilino)benzoate (compound a6) and the corresponding sulfonyl chloride. However, instead of pyridine and anhydrous DMA used in the production example of compound A-25, triethylamine and anhydrous DCM, respectively, in place of lithium hydroxide monohydrate used in the production example of compound a7 1M aqueous sodium hydroxide solution Using. Further, the corresponding amine was used in place of the tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 563 [M+H] ⁺
HPLC retention time: 0.88 minutes (analytical condition C)

化合物Ａ－２５、化合物ａ９、化合物ａ７及び化合物ａ１２の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ａ６）及び対応するスルホニルクロリドより表題化合物を合成した。但し、化合物Ａ－２５の製造例で用いたピリジン及び無水ＤＭＡの代わりにそれぞれトリエチルアミン及び無水ＤＣＭを、化合物ａ７の製造例で用いた水酸化リチウム一水和物の代わりに１Ｍ水酸化ナトリウム水溶液を用いた。また、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ５５３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８２分（分析条件Ｃ） Compound G-8:
2-(4-cyclopropyl-2-fluoroanilino)-5-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-N-methoxybenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2- The title compound was synthesized from methyl (2-fluoro-4-iodoanilino)benzoate (compound a6) and the corresponding sulfonyl chloride. However, instead of pyridine and anhydrous DMA used in the production example of compound A-25, triethylamine and anhydrous DCM, respectively, in place of lithium hydroxide monohydrate used in the production example of compound a7 1M aqueous sodium hydroxide solution Using. Further, the corresponding amine was used in place of the tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 553 [M+H] ⁺
HPLC retention time: 0.82 minutes (analysis condition C)

化合物Ａ－２５、化合物ａ９、化合物ａ７及び化合物ａ１２の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ａ６）及び対応するスルホニルクロリドより表題化合物を合成した。但し、化合物Ａ－２５の製造例で用いたピリジン及び無水ＤＭＡの代わりにそれぞれトリエチルアミン及び無水ＤＣＭを、化合物ａ７の製造例で用いた水酸化リチウム一水和物の代わりに１Ｍ水酸化ナトリウム水溶液を用いた。また、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ５３９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７９分（分析条件Ｃ） Compound G-9:
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methanesulfonamido)pyridin-4-yl]methyl]-N-methoxybenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2- The title compound was synthesized from methyl (2-fluoro-4-iodoanilino)benzoate (compound a6) and the corresponding sulfonyl chloride. However, instead of pyridine and anhydrous DMA used in the production example of compound A-25, triethylamine and anhydrous DCM, respectively, in place of lithium hydroxide monohydrate used in the production example of compound a7 1M aqueous sodium hydroxide solution Using. Further, the corresponding amine was used in place of the tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 539 [M+H] ⁺
HPLC retention time: 0.79 minutes (analysis condition C)

５－（（２－アミノ－３－フルオロピリジン－４－イル）メチル）－３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）安息香酸メチル（化合物ａ６、５００ｍｇ、０．９４１ｍｍｏｌ）、３－メルカプトプロピオン酸２－エチルヘキシル（２２６ｍｇ、１．０４ｍｍｏｌ）、Ｘａｎｔｐｈｏｓ（１０９ｍｇ、０．１８８ｍｍｏｌ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（８６ｍｇ、０．０９４ｍｍｏｌ）及びＤＩＰＥＡ（０．４９２ｍＬ、２．８２ｍｍｏｌ）の１，４－ジオキサン懸濁液（１７ｍＬ）を１１０℃で１時間攪拌した。反応混合物にアセトニトリルを加え、セライトろ過し、ろ液を減圧濃縮した。得られた残渣を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（５８４ｍｇ、ｑｕａｎｔ．）を黄色粘性油状物質として得た。
ＬＣＭＳ ｍ／ｚ： ６２２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１４分（分析条件Ｇ） Compound h1:
5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-[3-(2-ethylhexaoxy)-3-oxopropyl]sulfanyl-2-fluoroanilino]- Methyl 3,4-difluorobenzoate

5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)methyl benzoate (compound a6, 500 mg, 0.941 mmol), 2-ethylhexyl 3-mercaptopropionate (226 mg, 1.04 mmol), Xantphos (109 mg, 0.188 mmol), tris(dibenzylideneacetone)dipalladium(0) (86 mg, 0.094 mmol) and DIPEA (0.492 mL, 2.82 mmol) in 1,4-dioxane suspension (17 mL) was stirred at 110° C. for 1 hour. Acetonitrile was added to the reaction mixture, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (584 mg, quant.) as a yellow viscous oil.
LCMS m/z: 622 [M+H] ⁺
HPLC retention time: 1.14 minutes (analytical condition G)

５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－［４－［３－（２－エチルヘキサオキシ）－３－オキソプロピル］スルファニル－２－フルオロアニリノ］－３，４－ジフルオロ安息香酸メチル（化合物ｈ１、５８４ｍｇ、０．９３９ｍｍｏｌ）のメタノール溶液（９ｍＬ）を０℃に冷却し、２５％ナトリウムメトキシドメタノール溶液（１．２９ｍＬ、５．６４ｍｍｏｌ）を加え、室温で３時間攪拌した。次いで、０℃で（ブロモジフルオロメチル）ホスホン酸ジエチル（１．００ｇ、３．７６ｍｍｏｌ）を加え、室温で１０分間攪拌した。反応混合物を０℃に冷却し、２５％ナトリウムメトキシドメタノール溶液（１．２９ｍＬ、５．６４ｍｍｏｌ）及び（ブロモジフルオロメチル）ホスホン酸ジエチル（１．５１ｇ、５．６４ｍｍｏｌ）を加え、室温で２０分間攪拌した。反応混合物を０℃に冷却し、ギ酸（０．２１３ｍＬ、５．６４ｍｍｏｌ）を加え、減圧濃縮した。得られた残渣を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（１９５ｍｇ、４３％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４８８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８１分（分析条件Ｇ） Compound h2:
Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzoate

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-[3-(2-ethylhexaoxy)-3-oxopropyl]sulfanyl-2-fluoroanilino]- A methanol solution (9 mL) of methyl 3,4-difluorobenzoate (compound h1, 584 mg, 0.939 mmol) was cooled to 0° C., 25% sodium methoxide methanol solution (1.29 mL, 5.64 mmol) was added, Stir at room temperature for 3 hours. Diethyl (bromodifluoromethyl)phosphonate (1.00 g, 3.76 mmol) was then added at 0° C. and stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0° C. and 25% sodium methoxide methanol solution (1.29 mL, 5.64 mmol) and diethyl (bromodifluoromethyl)phosphonate (1.51 g, 5.64 mmol) were added and stirred at room temperature for 20 minutes. Stirred. The reaction mixture was cooled to 0° C., formic acid (0.213 mL, 5.64 mmol) was added and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (195 mg, 43%) as a colorless solid.
LCMS m/z: 488 [M+H] ⁺
HPLC retention time: 0.81 minutes (analytical condition G)

５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－［４－（ジフルオロメチルスルファニル）－２－フルオロアニリノ］－３，４－ジフルオロ安息香酸メチル（化合物ｈ２、６０．０ｍｇ、０．１２３ｍｍｏｌ）及び７ＭアンモニアＭｅＯＨ溶液（１．８０ｍＬ、１２．６ｍｍｏｌ）の混合物を、マイクロウェーブ反応装置を用いて封管中８５℃で６時間攪拌した。反応混合物を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィー（０．０５％トリフルオロ酢酸水溶液／０．０５％トリフルオロ酢酸アセトニトリル溶液）で精製して、表題化合物（５３．２ｇ、９１％）を黄色油状物質として得た。
ＬＣＭＳ ｍ／ｚ： ４７３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６３分（分析条件Ｃ） Compound h3:
5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluorobenzoate (compound h2, 60.0 mg, 0.123 mmol) and 7M ammonia in MeOH solution (1.80 mL, 12.6 mmol) was stirred in a sealed tube at 85° C. for 6 hours using a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.05% trifluoroacetic acid aqueous solution/0.05% trifluoroacetic acid acetonitrile solution) to give the title compound (53.2 g, 91 %) was obtained as a yellow oil.
LCMS m/z: 473 [M+H] ⁺
HPLC retention time: 0.63 minutes (analysis condition C)

化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－［４－（ジフルオロメチルスルファニル）－２－フルオロアニリノ］－３，４－ジフルオロベンズアミド（化合物ｈ３）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５６６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．４９分（分析条件Ｂ） Compound H-1:
2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-[4-(difluoromethylsulfanyl)-2-fluoroanilino] under the same conditions as in Production Example of Compound A-1 The title compound was synthesized from -3,4-difluorobenzamide (compound h3).
LCMS m/z: 566 [M+H] ⁺
HPLC retention time: 1.49 minutes (analysis condition B)

２，２，６，６－テトラメチルピペリジン（２．５３ｇ、１７．９ｍｍｏｌ）の無水ＴＨＦ溶液（３０ｍＬ）を－７８℃に冷却し、窒素雰囲気下、１．６Ｍ ｎ－ブチルリチウムヘキサン溶液（１１．２ｍＬ、１７．９ｍｍｏｌ）を加え、５分間攪拌した。反応混合物を２，３，４－トリフルオロ安息香酸（１．５０ｇ、８．５２ｍｍｏｌ）のＴＨＦ溶液（９．０ｍＬ）に－７８℃で加え、１０分間攪拌し、次いで無水ＤＭＦ（０．７５９ｍＬ、９．８０ｍｍｏｌ）を加え、０℃で２時間攪拌した。別のフラスコ中で、ベンゾ［ｂ］チオフェノン－５－アミン（１．６５ｇ、１１．１ｍｍｏｌ）のＴＨＦ溶液（３０ｍＬ）を－７８℃に冷却し、１．３Ｍリチウムビス（トリメチルシリル）アミドＴＨＦ溶液（１５．１ｍＬ、１９．６ｍｍｏｌ）及び先の反応混合物を加え、室温で２４時間攪拌した。反応混合物に２Ｍ塩酸を加え、２４時間攪拌した後、水及び２Ｍ塩酸を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、乾燥剤をろ去後、減圧濃縮した。得られた残渣を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（６０９ｍｇ、２１％）を灰色固体として得た。
ＬＣＭＳ ｍ／ｚ： ３３４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８０分（分析条件Ｃ） Compound h4:
2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-formylbenzoic acid

A solution of 2,2,6,6-tetramethylpiperidine (2.53 g, 17.9 mmol) in anhydrous THF (30 mL) was cooled to −78° C. and treated with a 1.6 M n-butyllithium hexane solution (11 .2 mL, 17.9 mmol) was added and stirred for 5 minutes. The reaction mixture was added to a solution of 2,3,4-trifluorobenzoic acid (1.50 g, 8.52 mmol) in THF (9.0 mL) at −78° C., stirred for 10 minutes, then anhydrous DMF (0.759 mL, 9.80 mmol) was added and stirred at 0° C. for 2 hours. In a separate flask, a THF solution (30 mL) of benzo[b]thiophenon-5-amine (1.65 g, 11.1 mmol) was cooled to −78° C. and a 1.3 M lithium bis(trimethylsilyl)amide THF solution ( 15.1 mL, 19.6 mmol) and the previous reaction mixture were added and stirred at room temperature for 24 hours. After adding 2M hydrochloric acid to the reaction mixture and stirring for 24 hours, water and 2M hydrochloric acid were added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (609 mg, 21%) as a gray solid.
LCMS m/z: 334 [M+H] ⁺
HPLC retention time: 0.80 minutes (analysis condition C)

２－（１－ベンゾチオフェン－５－イルアミノ）－３，４－ジフルオロ－５－ホルミル安息香酸（化合物ｈ４、６０８ｍｇ、１．８２ｍｍｏｌ）の無水ＤＭＦ懸濁液（９．１ｍＬ）にＨＯＯＢｔ（５９５ｍｇ、３．６５ｍｍｏｌ）及びＥＤＣ・ＨＣｌ（６９９ｍｇ、３．６５ｍｍｏｌ）を加え、室温で１．５時間攪拌した。次いで、０℃で７ＭアンモニアＭｅＯＨ溶液（０．９１２ｍＬ、６．３８ｍｍｏｌ）を加え、３０分間攪拌し、さらに、０℃で４－メチルベンゼンスルホニルヒドラジド（３４０ｍｇ、１．８２ｍｍｏｌ）を加え、室温で１６時間攪拌した。反応混合物をろ過した後、ろ液にアセトニトリル（１４ｍＬ）及び０．１Ｍ塩酸（１００ｍＬ）を加えた。固体をろ過後、水で洗浄して、表題化合物（４１２ｍｇ、４５％）を淡褐色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５０１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８３分（分析条件Ｃ） Compound h5:
2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzamide

HOOBt (595 mg, 3.65 mmol) and EDC.HCl (699 mg, 3.65 mmol) were added and stirred at room temperature for 1.5 hours. Then add 7M ammonia in MeOH solution (0.912 mL, 6.38 mmol) at 0° C., stir for 30 minutes, then add 4-methylbenzenesulfonyl hydrazide (340 mg, 1.82 mmol) at 0° C., and add 16 at room temperature. Stirred for hours. After filtering the reaction mixture, acetonitrile (14 mL) and 0.1 M hydrochloric acid (100 mL) were added to the filtrate. After filtering the solid, it was washed with water to give the title compound (412 mg, 45%) as a pale brown solid.
LCMS m/z: 501 [M+H] ⁺
HPLC retention time: 0.83 minutes (analysis condition C)

化合物ａ５及び化合物ａ６の製造例と同様の条件で、２－（１－ベンゾチオフェン－５－イルアミノ）－３，４－ジフルオロ－５－［（Ｅ）－［（４－メチルフェニル）スルホニルヒドラジニリデン］メチル］ベンズアミド（化合物ｈ５）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ４２９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．５７分（分析条件Ｃ） Compound h7:
5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(1-benzothiophen-5-ylamino)-3,4-difluorobenzamide

2-(1-Benzothiophen-5-ylamino)-3,4-difluoro-5-[(E)-[(4-methylphenyl)sulfonyl hydrazide was prepared under the same conditions as in the Production Examples of Compound a5 and Compound a6. The title compound was synthesized from lidene]methyl]benzamide (compound h5).
LCMS m/z: 429 [M+H] ⁺
HPLC retention time: 0.57 minutes (analysis condition C)

化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（１－ベンゾチオフェン－５－イルアミノ）－３，４－ジフルオロベンズアミド（化合物ｈ７）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５２２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０６分（分析条件Ａ） Compound H-2:
2-(1-benzothiophen-5-ylamino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(1-benzothiophen-5-ylamino)-3,4- The title compound was synthesized from difluorobenzamide (compound h7).
LCMS m/z: 522 [M+H] ⁺
HPLC retention time: 1.06 minutes (Analysis condition A)

５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（１－ベンゾチオフェン－５－イルアミノ）－３，４－ジフルオロベンズアミド（化合物ｈ７、２２ｍｇ、０．０５１ｍｍｏｌ）の無水アセトニトリル溶液（０．３ｍＬ）を０℃に冷却し、Ｎ－フルオロ－Ｎ’－（クロロメチル）トリエチレンジアミンビス（テトラフルオロボラート）（９．５ｍｇ、０．０２７ｍｍｏｌ）を加え、２．５時間攪拌した。次いで、さらにＮ－フルオロ－Ｎ’－（クロロメチル）トリエチレンジアミンビス（テトラフルオロボラート）（８．０ｍｇ、０．０２３ｍｍｏｌ）を加え、１時間攪拌した。反応混合物を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィー（０．０５％トリフルオロ酢酸水溶液／０．０５％トリフルオロ酢酸アセトニトリル溶液）で精製して、表題化合物（８．０ｍｇ、３５％）を褐色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４４７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６１分（分析条件Ｃ） Compound h8:
5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]benzamide

of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(1-benzothiophen-5-ylamino)-3,4-difluorobenzamide (compound h7, 22 mg, 0.051 mmol) An anhydrous acetonitrile solution (0.3 mL) was cooled to 0° C., N-fluoro-N′-(chloromethyl)triethylenediaminebis(tetrafluoroborate) (9.5 mg, 0.027 mmol) was added, and 2.5 Stirred for hours. Then, more N-fluoro-N'-(chloromethyl)triethylenediaminebis(tetrafluoroborate) (8.0 mg, 0.023 mmol) was added and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.05% trifluoroacetic acid aqueous solution/0.05% trifluoroacetic acid acetonitrile solution) to give the title compound (8.0 mg, 35 %) was obtained as a brown solid.
LCMS m/z: 447 [M+H] ⁺
HPLC retention time: 0.61 minutes (analysis condition C)

化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－３，４－ジフルオロ－２－［（４－フルオロ－１－ベンゾチオフェン－５－イル）アミノ］ベンズアミド（化合物ｈ８）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５４０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１０分（分析条件Ａ） Compound H-3:
3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl ] benzamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-[(4-fluoro-1-benzo The title compound was synthesized from thiophen-5-yl)amino]benzamide (compound h8).
LCMS m/z: 540 [M+H] ⁺
HPLC retention time: 1.10 minutes (analytical condition A)

２，３，４－トリフルオロフェノール（５．０５ｇ、３４．１ｍｍｏｌ）の無水アセトン溶液（１０１ｍＬ）に炭酸カリウム（９．９０ｇ、７１．６ｍｍｏｌ）及び４－メトキシベンジルクロリド（５．５５ｍＬ、４０．９ｍｍｏｌ）を加え、７０℃で８時間攪拌した。反応混合物に水（１５０ｍＬ）を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥させ、乾燥剤をろ去後、減圧濃縮した。得られた残渣にＤＭＳＯ（１５ｍＬ）及び水（１００ｍＬ）を加え、得られた固体を洗浄して、表題化合物（８．７２ｇ、９５％）を灰色固体として得た。
ＬＣＭＳ ｍ／ｚ： ２６７［Ｍ－Ｈ］^－
ＨＰＬＣ保持時間： ０．９２分（分析条件Ｃ） Compound h9:
1,2,3-trifluoro-4-[(4-methoxyphenyl)methoxy]benzene

Potassium carbonate (9.90 g, 71.6 mmol) and 4-methoxybenzyl chloride (5.55 mL, 40.5 mL) were added to a solution of 2,3,4-trifluorophenol (5.05 g, 34.1 mmol) in anhydrous acetone (101 mL). 9 mmol) was added and stirred at 70° C. for 8 hours. Water (150 mL) was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. DMSO (15 mL) and water (100 mL) were added to the residue obtained and the solid obtained was washed to give the title compound (8.72 g, 95%) as a gray solid.
LCMS m/z: 267 [MH] ^-
HPLC retention time: 0.92 minutes (analysis condition C)

２，２，６，６－テトラメチルピペリジン（４．１５ｍＬ、２４．６ｍｍｏｌ）の無水ＴＨＦ溶液（１５ｍＬ）を－７８℃に冷却し、窒素雰囲気下、１．６Ｍリチウムビス（トリメチルシリル）アミドヘキサン溶液（１５．４ｍＬ、２４．６ｍｍｏｌ）を加え、１０分間攪拌した。反応混合物を１，２，３－トリフルオロ－４－［（４－メトキシフェニル）メトキシ］ベンゼン（化合物ｈ９、３．００ｇ、１１．２ｍｍｏｌ）の無水ＴＨＦ溶液（１５ｍＬ）に－７８℃で加え、３時間攪拌し、次いで二酸化炭素ガスを注入しながら３０分間攪拌した。反応混合物に１Ｍ塩酸（６０ｍＬ）を加え、酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥させ、乾燥剤をろ去後、減圧濃縮した。得られた残渣を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（１．３２ｇ、３４％）を灰色固体として得た。
ＬＣＭＳ ｍ／ｚ： ３１１［Ｍ－Ｈ］^－
ＨＰＬＣ保持時間： ０．８０分（分析条件Ｃ） Compound h10:
2,3,4-trifluoro-5-[(4-methoxyphenyl)methoxy]benzoic acid

A solution of 2,2,6,6-tetramethylpiperidine (4.15 mL, 24.6 mmol) in anhydrous THF (15 mL) was cooled to −78° C. and treated under a nitrogen atmosphere with a 1.6 M lithium bis(trimethylsilyl)amidohexane solution. (15.4 mL, 24.6 mmol) was added and stirred for 10 minutes. The reaction mixture was added to a solution of 1,2,3-trifluoro-4-[(4-methoxyphenyl)methoxy]benzene (compound h9, 3.00 g, 11.2 mmol) in anhydrous THF (15 mL) at −78° C. The mixture was stirred for 3 hours and then stirred for 30 minutes while carbon dioxide gas was introduced. 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, filtered to remove the desiccant, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (1.32 g, 34%) as a gray solid.
LCMS m/z: 311 [MH] ^-
HPLC retention time: 0.80 minutes (analysis condition C)

化合物ｃ５、化合物ａ１及び化合物ａ６の製造例と同様の条件で、２，３，４－トリフルオロ－５－［（４－メトキシフェニル）メトキシ］安息香酸（化合物ｈ１０）より表題化合物を合成した。但し、化合物ｃ５の製造例で用いた４－ヨード－２－メチルアニリンの代わりに２－フルオロ－４－ヨードアニリンを、化合物ａ１の製造例で用いたトルエンの代わりに無水ＴＨＦを用いた。
ＬＣＭＳ ｍ／ｚ： ４２４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９１分（分析条件Ｃ） Compound h13:
Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-hydroxybenzoate

The title compound was synthesized from 2,3,4-trifluoro-5-[(4-methoxyphenyl)methoxy]benzoic acid (compound h10) under the same conditions as in the production examples of compound c5, compound a1 and compound a6. However, 2-fluoro-4-iodoaniline was used in place of 4-iodo-2-methylaniline used in the production example of compound c5, and anhydrous THF was used in place of toluene used in the production example of compound a1.
LCMS m/z: 424 [M+H] ⁺
HPLC retention time: 0.91 minutes (analysis condition C)

３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－ヒドロキシ安息香酸メチル（化合物ｈ１３、３７５ｍｇ、０．８８６ｍｍｏｌ）のＤＣＭ溶液（１５ｍＬ）に［２－［（２，４－ジメトキシフェニル）メチルアミノ］－３－フルオロピリジン－４－イル］ボロン酸（化合物ａ４、８１４ｍｇ、２．６６ｍｍｏｌ）、モレキュラーシーブス４Ａ（３７５ｍｇ）、テトラキス（アセトニトリル）銅（Ｉ）ヘキサフルオロホスファート（４９５ｍｇ、１．３３ｍｍｏｌ）及びピリジン（０．２８７ｍＬ、３．５５ｍｍｏｌ）を加え、室温で２．５時間攪拌した。次いで、さらに［２－［（２，４－ジメトキシフェニル）メチルアミノ］－３－フルオロピリジン－４－イル］ボロン酸（化合物ａ４、２３１ｍｇ、０．７５３ｍｍｏｌ）を加え、４時間攪拌した。反応混合物にＮ－アセチルシステイン（４３４ｍｇ、２．６６ｍｍｏｌ）を加え、３時間攪拌した。固形物をろ過し、ＤＣＭ（１０ｍＬ）で洗浄し、ろ液を減圧濃縮した。得られた残渣を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（１６８ｍｇ、２８％）を泡状物質として得た。
ＬＣＭＳ ｍ／ｚ： ６８４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０７分（分析条件Ｃ） Compound h14:
Methyl 5-[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]oxy-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate

[2-[(2,4- Dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4, 814 mg, 2.66 mmol), molecular sieves 4A (375 mg), tetrakis(acetonitrile) copper(I) hexafluorophosphate (495 mg) , 1.33 mmol) and pyridine (0.287 mL, 3.55 mmol) were added and stirred at room temperature for 2.5 hours. Then, further [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4, 231 mg, 0.753 mmol) was added and stirred for 4 hours. N-Acetylcysteine (434 mg, 2.66 mmol) was added to the reaction mixture and stirred for 3 hours. The solids were filtered, washed with DCM (10 mL) and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (168 mg, 28%) as a foam.
LCMS m/z: 684 [M+H] ⁺
HPLC retention time: 1.07 minutes (analysis condition C)

化合物ａ６、化合物Ｅ－１３及び化合物Ａ－１の製造例と同様の条件で、５－［２－［（２，４－ジメトキシフェニル）メチルアミノ］－３－フルオロピリジン－４－イル］オキシ－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸メチル（化合物ｈ１４）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６１２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．５５分（分析条件Ｂ） Compound H-4:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]oxybenzamide

5-[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]oxy- The title compound was synthesized from methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound h14).
LCMS m/z: 612 [M+H] ⁺
HPLC retention time: 1.55 minutes (analysis condition B)

６－ブロモ－Ｎ，Ｎ－ビス（４－メトキシベンジル）ピリジン－２－アミン（１．２２ｇ、２．９５ｍｍｏｌ）の無水ＴＨＦ溶液（１２ｍＬ）を－４０℃に冷却し、窒素雰囲気下、１．６Ｍリチウムビス（トリメチルシリル）アミドＴＨＦ溶液（１．８５ｍＬ、２．９５ｍｍｏｌ）を加え、３０分間攪拌した。反応混合物を３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）－５－ホルミル安息香酸（４１４ｍｇ、０．９８４ｍｍｏｌ）の無水ＴＨＦ溶液（２．４ｍＬ）に－７８℃で加え、２０分間攪拌した。反応混合物に１Ｍ塩酸（２ｍＬ）を加え、減圧濃縮した。得られた残渣を逆相カラムクロマトグラフィー（１０ｍＭ酢酸アンモニウム水溶液／メタノール）で精製して、表題化合物（１９２ｍｇ、２６％）を黄色固体として得た。
ＬＣＭＳ ｍ／ｚ： ７５６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０６分（分析条件Ｅ） Compound h17:
5-[[6-[bis[(4-methoxyphenyl)methyl]amino]pyridin-2-yl]-hydroxymethyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid

A solution of 6-bromo-N,N-bis(4-methoxybenzyl)pyridin-2-amine (1.22 g, 2.95 mmol) in anhydrous THF (12 mL) was cooled to −40° C. and treated under nitrogen atmosphere. 6M Lithium bis(trimethylsilyl)amide in THF (1.85 mL, 2.95 mmol) was added and stirred for 30 minutes. The reaction mixture was added to anhydrous THF solution (2.4 mL) of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid (414 mg, 0.984 mmol) at -78°C. and stirred for 20 minutes. 1M Hydrochloric acid (2 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (10 mM aqueous ammonium acetate/methanol) to give the title compound (192 mg, 26%) as a yellow solid.
LCMS m/z: 756 [M+H] ⁺
HPLC retention time: 1.06 minutes (analysis condition E)

５－［［６－［ビス［（４－メトキシフェニル）メチル］アミノ］ピリジン－２－イル］－ヒドロキシメチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸（化合物ｈ１７、１３０ｍｇ、０．１６２ｍｍｏｌ）のＤＣＭ溶液（０．８ｍＬ）にトリエチルシラン（０．１２９ｍＬ、０．８１０ｍｍｏｌ）、トリフルオロ酢酸（０．５２０ｍＬ、６．７５ｍｍｏｌ）及びトリフルオロメタンスルホン酸（１４μＬ、０．１６２ｍｍｏｌ）を加え、室温で１時間攪拌した。次いで、さらにトリエチルシラン（０．１２９ｍＬ、０．８１０ｍｍｏｌ）及びトリフルオロメタンスルホン酸（１４μＬ、０．１６２ｍｍｏｌ）を加え、室温で５時間攪拌した。反応混合物を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（７２．７ｍｇ、９０％）を桃色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５００［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６１分（分析条件Ｃ） Compound h18:
5-[(6-aminopyridin-2-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid

5-[[6-[bis[(4-methoxyphenyl)methyl]amino]pyridin-2-yl]-hydroxymethyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoic acid ( To a DCM solution (0.8 mL) of compound h17, 130 mg, 0.162 mmol) was added triethylsilane (0.129 mL, 0.810 mmol), trifluoroacetic acid (0.520 mL, 6.75 mmol) and trifluoromethanesulfonic acid (14 μL, 0.162 mmol) was added and stirred at room temperature for 1 hour. Then, additional triethylsilane (0.129 mL, 0.810 mmol) and trifluoromethanesulfonic acid (14 μL, 0.162 mmol) were added and stirred at room temperature for 5 hours. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (72.7 mg, 90%) as a pink solid.
LCMS m/z: 500 [M+H] ⁺
HPLC retention time: 0.61 minutes (analysis condition C)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（６－アミノピリジン－２－イル）メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）安息香酸（化合物ｈ１８）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５９２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１９分（分析条件Ａ） Compound H-5:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[6-(methylsulfamoylamino)pyridin-2-yl]methyl]benzamide

5-[(6-aminopyridin-2-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoin under the same conditions as in the production examples of compound a8 and compound A-1 The title compound was synthesized from the acid (compound h18).
LCMS m/z: 592 [M+H] ⁺
HPLC retention time: 1.19 minutes (analytical condition A)

化合物ｃ５、化合物ｃ６、化合物ｃ１、化合物ａ５、化合物ａ６及び化合物Ａ－１の製造例と同様の条件で、２，４－ジフルオロ－５－ビニル安息香酸より表題化合物を合成した。但し、化合物ｃ５の製造例で用いた４－ヨード－２－メチルアニリンの代わりに２－フルオロ－４－ヨードアニリンを用いた。
ＬＣＭＳ ｍ／ｚ： ５９２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１７分（分析条件Ａ） Compound I-1:
4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide

The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under the same conditions as in the production examples of compound c5, compound c6, compound c1, compound a5, compound a6 and compound A-1. However, 2-fluoro-4-iodoaniline was used in place of 4-iodo-2-methylaniline used in the production example of compound c5.
LCMS m/z: 592 [M+H] ⁺
HPLC retention time: 1.17 minutes (analytical condition A)

化合物ｃ５、化合物ｃ６、化合物ｃ１、化合物ａ５、化合物ａ６及び化合物Ａ－１の製造例と同様の条件で、２，４－ジフルオロ－５－ビニル安息香酸より表題化合物を合成した。但し、化合物ｃ５の製造例で用いた４－ヨード－２－メチルアニリンの代わりに２－フルオロ－４－ヨードアニリンを、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６０６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６２分（分析条件Ｂ） Compound I-2:
5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-4-fluoro-2-(2-fluoro-4-iodoanilino)benzamide

The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under the same conditions as in the production examples of compound c5, compound c6, compound c1, compound a5, compound a6 and compound A-1. However, instead of 4-iodo-2-methylaniline used in the production example of compound c5, 2-fluoro-4-iodoaniline was used in place of 4-nitrophenyl methylsulfamate used in the production example of compound A-1. 4-nitrophenyl sulfamate corresponding to was used.
LCMS m/z: 606 [M+H] ⁺
HPLC retention time: 1.62 minutes (analysis condition B)

化合物ｃ５、化合物ｃ６、化合物ｃ１、化合物ａ５、化合物ａ６及び化合物Ａ－１の製造例と同様の条件で、２，４－ジフルオロ－５－ビニル安息香酸より表題化合物を合成した。但し、化合物ｃ５の製造例で用いた４－ヨード－２－メチルアニリンの代わりに２－フルオロ－４－ヨードアニリンを、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６１８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６４分（分析条件Ｂ） Compound I-3:
5-[[2-(Cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-4-fluoro-2-(2-fluoro-4-iodoanilino)benzamide

The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under the same conditions as in the production examples of compound c5, compound c6, compound c1, compound a5, compound a6 and compound A-1. However, instead of 4-iodo-2-methylaniline used in the production example of compound c5, 2-fluoro-4-iodoaniline was used in place of 4-nitrophenyl methylsulfamate used in the production example of compound A-1. 4-nitrophenyl sulfamate corresponding to was used.
LCMS m/z: 618 [M+H] ⁺
HPLC retention time: 1.64 minutes (analytical condition B)

化合物ｃ５、化合物ｃ６、化合物ｃ１、化合物ａ５、化合物ａ６及び化合物Ａ－１の製造例と同様の条件で、２，４－ジフルオロ－５－ビニル安息香酸より表題化合物を合成した。但し、化合物ｃ５の製造例で用いた４－ヨード－２－メチルアニリンの代わりに２－フルオロ－４－ヨードアニリンを、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６３６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１９分（分析条件Ａ） Compound I-4:
4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide

The title compound was synthesized from 2,4-difluoro-5-vinylbenzoic acid under the same conditions as in the production examples of compound c5, compound c6, compound c1, compound a5, compound a6 and compound A-1. However, instead of 4-iodo-2-methylaniline used in the production example of compound c5, 2-fluoro-4-iodoaniline was used in place of 4-nitrophenyl methylsulfamate used in the production example of compound A-1. 4-nitrophenyl sulfamate corresponding to was used.
LCMS m/z: 636 [M+H] ⁺
HPLC retention time: 1.19 minutes (analytical condition A)

（２－アミノ－３－フルオロピリジン－４－イル）メタノール（１０．３ｇ、７２．７ｍｍｏｌ）のＤＣＭ懸濁液（９１ｍＬ）に塩化チオニル（１０．６ｍＬ、１４５ｍｍｏｌ）を１０分かけて加え、室温で６５分間攪拌した。反応混合物をろ過した後、得られた固体を酢酸エチルに溶解させ、炭酸水素ナトリウム水溶液で洗浄した。有機層を無水硫酸マグネシウムで乾燥させ、乾燥剤をろ去後、減圧濃縮して２－アミノ－４－（クロロメチル）－３－フルオロピリジンの粗生成物（１０．３ｇ）を得た。 Compound j1:
Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate

To a suspension of (2-amino-3-fluoropyridin-4-yl)methanol (10.3 g, 72.7 mmol) in DCM (91 mL) was added thionyl chloride (10.6 mL, 145 mmol) over 10 minutes and the mixture was allowed to cool to room temperature. for 65 minutes. After filtering the reaction mixture, the resulting solid was dissolved in ethyl acetate and washed with an aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to obtain a crude product of 2-amino-4-(chloromethyl)-3-fluoropyridine (10.3 g).

Methyl 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (7.90 g, 19.7 mmol) and tetrabutylammonium iodide (0.726 g, 1.97 mmol) of crude 2-amino-4-(chloromethyl)-3-fluoropyridine (3.47 g) in 1,3-dimethyl-2-imidazolidinone solution (39 mL). and tripotassium phosphate (5.00 g, 23.6 mmol) were added and stirred at 50° C. for 4 hours. Water was added to the reaction mixture and the resulting solid was collected by filtration and washed with a mixture of acetonitrile/water to give the title compound (10.3 g, 60%).
LCMS m/z: 527 [M+H] ⁺
HPLC retention time: 0.63 minutes (analysis condition C)

化合物ａ７の製造例と同様の条件で、メチル ５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｊ１）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５１３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７６分（分析条件Ｅ） Compound j2:
5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid hydrochloride

Methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6- The title compound was synthesized from oxopyridine-3-carboxylate (compound j1).
LCMS m/z: 513 [M+H] ⁺
HPLC retention time: 0.76 minutes (analytical condition E)

化合物ａ８の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸塩酸塩（化合物ｊ２）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５１２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８４分（分析条件Ｅ） Compound j3:
5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide

5-[(2-Amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo The title compound was synthesized from pyridine-3-carboxylic acid hydrochloride (compound j2).
LCMS m/z: 512 [M+H] ⁺
HPLC retention time: 0.84 minutes (analysis condition E)

化合物Ａ－２５の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボキサミド（化合物ｊ３）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６０５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９５分（分析条件Ａ） Compound J-1:
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide

Under the same conditions as in the Production Example of Compound A-25, 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6 -oxopyridine-3-carboxamide (compound j3) to synthesize the title compound.
LCMS m/z: 605 [M+H] ⁺
HPLC retention time: 0.95 minutes (analytical condition A)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸塩酸塩（化合物ｊ２）より表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６４９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９７分（分析条件Ａ） Compound J-2:
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine- 3-carboxamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylic acid hydrochloride (compound j2). However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 649 [M+H] ⁺
HPLC retention time: 0.97 minutes (analytical condition A)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸塩酸塩（化合物ｊ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６４５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．４０分（分析条件Ｂ） Compound J-5:
N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxo pyridine-3-carboxamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylic acid hydrochloride (compound j2) and the corresponding amine.
LCMS m/z: 645 [M+H] ⁺
HPLC retention time: 1.40 minutes (analysis condition B)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸塩酸塩（化合物ｊ２）及び対応するアミンより表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６７１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．４７分（分析条件Ｂ） Compound J-6:
N-cyclopropyl-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6- Oxopyridine-3-carboxamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylic acid hydrochloride (compound j2) and the corresponding amine. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 671 [M+H] ⁺
HPLC retention time: 1.47 minutes (analysis condition B)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸塩酸塩（化合物ｊ２）及び対応するアミンより表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６８９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．４３分（分析条件Ｂ） Compound J-7:
N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl- 6-oxopyridine-3-carboxamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylic acid hydrochloride (compound j2) and the corresponding amine. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 689 [M+H] ⁺
HPLC retention time: 1.43 minutes (analysis condition B)

化合物ａ１２及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸塩酸塩（化合物ｊ２）及び対応するアミンより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６３５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２９分（分析条件Ｂ） Compound J-8:
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine -3-carboxamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylic acid hydrochloride (compound j2) and the corresponding amine.
LCMS m/z: 635 [M+H] ⁺
HPLC retention time: 1.29 minutes (analysis condition B)

化合物ａ１２及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸塩酸塩（化合物ｊ２）及び対応するアミンより表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６７９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．３１分（分析条件Ｂ） Compound J-9:
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6 - oxopyridine-3-carboxamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylic acid hydrochloride (compound j2) and the corresponding amine. However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 679 [M+H] ⁺
HPLC retention time: 1.31 minutes (analysis condition B)

化合物ａ１２及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸塩酸塩（化合物ｊ２）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６７７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．４６分（分析条件Ｂ） Compound J-10:
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropane -2-yl)oxy]-6-oxopyridine-3-carboxamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylic acid hydrochloride (compound j2).
LCMS m/z: 677 [M+H] ⁺
HPLC retention time: 1.46 minutes (analysis condition B)

化合物ａ１２及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸塩酸塩（化合物ｊ２）より表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ７０３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．５２分（分析条件Ｂ） Compound J-11:
5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-N-[(2-methyl Propan-2-yl)oxy]-6-oxopyridine-3-carboxamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylic acid hydrochloride (compound j2). However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 703 [M+H] ⁺
HPLC retention time: 1.52 minutes (analysis condition B)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸塩酸塩（化合物ｊ２）より表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６３１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．３７分（分析条件Ｂ） Compound J-13:
5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3- Carboxamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylic acid hydrochloride (compound j2). However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 631 [M+H] ⁺
HPLC retention time: 1.37 minutes (analysis condition B)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸塩酸塩（化合物ｊ２）より表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６１９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．３５分（分析条件Ｂ） Compound J-14:
5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylic acid hydrochloride (compound j2). However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 619 [M+H] ⁺
HPLC retention time: 1.35 minutes (analysis condition B)

化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸塩酸塩（化合物ｊ２）より表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６５９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７７分（分析条件Ｃ） Compound J-15:
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]-1-methyl-6- Oxopyridine-3-carboxamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylic acid hydrochloride (compound j2). However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 659 [M+H] ⁺
HPLC retention time: 0.77 minutes (analytical condition C)

化合物ａ９及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボキサミド（化合物ｊ３）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５１９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．３１分（分析条件Ｂ） Compound J-3:
2-(4-cyclopropyl-2-fluoroanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine- 3-carboxamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxamide (compound j3).
LCMS m/z: 519 [M+H] ⁺
HPLC retention time: 1.31 minutes (analysis condition B)

化合物ａ９及び化合物Ａ－１の製造例と同様の条件で、５－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボキサミド（化合物ｊ３）より表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ５４５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．３７分（分析条件Ｂ） Compound J-4:
2-(4-cyclopropyl-2-fluoroanilino)-5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-1-methyl-6-oxopyridine -3-carboxamide

5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxamide (compound j3). However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 545 [M+H] ⁺
HPLC retention time: 1.37 minutes (analysis condition B)

化合物ｊ１、化合物Ａ－２５及び化合物ａ７の製造例と同様の条件で、２－アミノ－４－（ヒドロキシメチル）ピリジンより表題化合物を合成した。但し、化合物Ａ－２５の製造例で用いたメチルスルファモイルクロリドの代わりに対応するスルホニルクロリドを用いた。また、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ５８７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６４分（分析条件Ｃ） Compound j12:
5-[[2-(ethylsulfonylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid

The title compound was synthesized from 2-amino-4-(hydroxymethyl)pyridine under the same conditions as in the production examples of compound j1, compound A-25 and compound a7. However, the corresponding sulfonyl chloride was used instead of the methylsulfamoyl chloride used in the production example of compound A-25. Pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 587 [M+H] ⁺
HPLC retention time: 0.64 minutes (analytical condition C)

５－［［２－（エチルスルホニルアミノ）ピリジン－４－イル］メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸（化合物ｊ１２、１０ｍｇ、０．０１７ｍｍｏｌ）及び塩化アンモニウム（２．７４ｍｇ、０．０５１ｍｍｏｌ）のＤＭＦ溶液（８５μＬ）を０℃に冷却し、ＨＡＴＵ（１３．０ｍｇ、０．０３４ｍｍｏｌ）及びＤＩＰＥＡ（１７．９μＬ、０．１０２ｍｍｏｌ）を加え、室温で終夜攪拌した。反応混合物を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（７．２ｍｇ、２９％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５８６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．２４分（分析条件Ｂ） Compound J-12:
5-[[2-(ethylsulfonylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide

5-[[2-(ethylsulfonylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid (compound j12, 10 mg A DMF solution (85 μL) of ammonium chloride (2.74 mg, 0.051 mmol) and ammonium chloride (2.74 mg, 0.051 mmol) was cooled to 0° C. and HATU (13.0 mg, 0.034 mmol) and DIPEA (17.9 μL, 0.102 mmol) were added. ) was added and stirred overnight at room temperature. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (7.2 mg, 29%) as a colorless solid.
LCMS m/z: 586 [M+H] ⁺
HPLC retention time: 1.24 minutes (analysis condition B)

２－（（２－フルオロ－４－ヨードフェニル）アミノ）－１－メチル－６－オキソ－１，６－ジヒドロピリジン－３－カルボン酸メチル（１３２ｍｇ、０．３２８ｍｍｏｌ）のアセトニトリル溶液（２．７ｍＬ）に（クロロメチレン）ジメチルイミニウムクロリド（１６８ｍｇ、１．３１ｍｍｏｌ）を加え、室温で１．５時間攪拌した。反応混合物に水を加え、３０分間攪拌した後、固体をろ取して表題化合物（１０８ｍｇ、７６％）を得た。
ＬＣＭＳ ｍ／ｚ： ４３１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８０分（分析条件Ｃ） Compound k1:
Methyl 2-(2-fluoro-4-iodoanilino)-5-formyl-1-methyl-6-oxopyridine-3-carboxylate

Acetonitrile solution (2.7 mL) of methyl 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (132 mg, 0.328 mmol) (Chloromethylene)dimethyliminium chloride (168 mg, 1.31 mmol) was added to and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and after stirring for 30 minutes, the solid was collected by filtration to obtain the title compound (108 mg, 76%).
LCMS m/z: 431 [M+H] ⁺
HPLC retention time: 0.80 minutes (analysis condition C)

化合物ａ２、化合物ａ５及び化合物ａ６の製造例と同様の条件で、メチル ２－（２－フルオロ－４－ヨードアニリノ）－５－ホルミル－１－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｋ１）より表題化合物を合成した。但し、化合物ａ２の製造例で用いた４－メチルベンゼンスルホニルヒドラジドの代わりに２－ニトロベンゼン－１－スルホノヒドラジドを用いた。また、化合物ａ５の製造例で用いた［２－［（２，４－ジメトキシフェニル）メチルアミノ］－３－フルオロピリジン－４－イル］ボロン酸（化合物ａ４）及び炭酸カリウムの代わりにそれぞれ［２－フルオロ－３－［（２－メチルプロパン－２－イル）オキシカルボニルアミノ］フェニル］ボロン酸及びＤＩＰＥＡを用いた。
ＬＣＭＳ ｍ／ｚ： ５２６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９０分（分析条件Ｃ） Compound k4:
Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylate

Methyl 2-(2-fluoro-4-iodoanilino)-5-formyl-1-methyl-6-oxopyridine-3-carboxylate (compound k1 ) to synthesize the title compound. However, 2-nitrobenzene-1-sulfonohydrazide was used in place of 4-methylbenzenesulfonylhydrazide used in the production example of compound a2. Further, instead of [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4) and potassium carbonate used in the production example of compound a5, [2 -Fluoro-3-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]boronic acid and DIPEA were used.
LCMS m/z: 526 [M+H] ⁺
HPLC retention time: 0.90 minutes (analysis condition C)

化合物ｂ２、化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、メチル ５－［（３－アミノ－２－フルオロフェニル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｋ４）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６０４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．３７分（分析条件Ｂ） Compound K-1:
2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-1-methyl-6-oxopyridine-3-carboxamide

Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylate (compound k4).
LCMS m/z: 604 [M+H] ⁺
HPLC retention time: 1.37 minutes (analysis condition B)

化合物ｂ２、化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、メチル ５－［（３－アミノ－２－フルオロフェニル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｋ４）より表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６１８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．４１分（分析条件Ｂ） Compound K-2:
5-[[3-(ethylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide

Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylate (compound k4). However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 618 [M+H] ⁺
HPLC retention time: 1.41 minutes (analysis condition B)

化合物ｂ２、化合物ａ８及び化合物Ａ－１の製造例と同様の条件で、メチル ５－［（３－アミノ－２－フルオロフェニル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｋ４）より表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６３０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．４３分（分析条件Ｂ） Compound K-3:
5-[[3-(Cyclopropylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide

Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylate (compound k4). However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 630 [M+H] ⁺
HPLC retention time: 1.43 minutes (analysis condition B)

化合物ｂ２、化合物ａ１０及び化合物Ａ－１の製造例と同様の条件で、メチル ５－［（３－アミノ－２－フルオロフェニル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｋ４）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６４４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．４８分（分析条件Ｂ） Compound K-4:
N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-1-methyl-6-oxopyridine-3- Carboxamide

Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylate (compound k4).
LCMS m/z: 644 [M+H] ⁺
HPLC retention time: 1.48 minutes (analysis condition B)

化合物ｂ２、化合物ａ１０及び化合物Ａ－１の製造例と同様の条件で、メチル ５－［（３－アミノ－２－フルオロフェニル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｋ４）より表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６７０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．５３分（分析条件Ｂ） Compound K-5:
N-cyclopropyl-5-[[3-(cyclopropylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3 - carboxamide

Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylate (compound k4). However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 670 [M+H] ⁺
HPLC retention time: 1.53 minutes (analysis condition B)

化合物ｂ２、化合物ａ１０及び化合物Ａ－１の製造例と同様の条件で、メチル ５－［（３－アミノ－２－フルオロフェニル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｋ４）より表題化合物を合成した。但し、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６５８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．５２分（分析条件Ｂ） Compound K-13:
N-cyclopropyl-5-[[3-(ethylsulfamoylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3- Carboxamide

Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylate (compound k4). However, the corresponding 4-nitrophenyl sulfamate was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1.
LCMS m/z: 658 [M+H] ⁺
HPLC retention time: 1.52 minutes (analysis condition B)

化合物Ａ－２５、化合物ｂ２及び化合物ａ８の製造例と同様の条件で、メチル ５－［（３－アミノ－２－フルオロフェニル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｋ４）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６２９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．４８分（分析条件Ｂ） Compound K-6:
2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-1-methyl-6-oxopyridine-3-carboxamide

Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylate (compound k4) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 629 [M+H] ⁺
HPLC retention time: 1.48 minutes (analysis condition B)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、メチル ５－［（３－アミノ－２－フルオロフェニル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｋ４）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。また、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６５９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．４７分（分析条件Ｂ） Compound K-7:
2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-N-methoxy-1-methyl-6-oxopyridine -3-carboxamide

Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylate (compound k4) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step. Further, the corresponding amine was used in place of the tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 659 [M+H] ⁺
HPLC retention time: 1.47 minutes (Analysis condition B)

化合物Ａ－２５、化合物ｂ２及び化合物ａ８の製造例と同様の条件で、メチル ５－［（３－アミノ－２－フルオロフェニル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｋ４）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。また、化合物ａ８の製造例で用いた７ＭアンモニアＭｅＯＨ溶液の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６６９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．５９分（分析条件Ｂ） Compound K-11:
N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-1-methyl-6-oxo pyridine-3-carboxamide

Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylate (compound k4) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step. Further, the corresponding amine was used instead of the 7M ammonia MeOH solution used in the production example of compound a8.
LCMS m/z: 669 [M+H] ⁺
HPLC retention time: 1.59 minutes (analysis condition B)

化合物Ａ－２５、化合物ｂ２及び化合物ａ１２の製造例と同様の条件で、メチル ５－［（３－アミノ－２－フルオロフェニル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｋ４）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ７０１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．６２分（分析条件Ｂ） Compound K-12:
2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-[(1-methylcyclopropyl)sulfonylamino]phenyl]methyl]-1-methyl-N-[(2-methylpropane -2-yl)oxy]-6-oxopyridine-3-carboxamide

Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1- The title compound was synthesized from methyl-6-oxopyridine-3-carboxylate (compound k4) and the corresponding sulfonyl chloride. However, pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 701 [M+H] ⁺
HPLC retention time: 1.62 minutes (analysis condition B)

化合物Ａ－２５及び化合物ｂ２の製造例と同様の条件で、メチル ５－［（３－アミノ－２－フルオロフェニル）メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｋ４）及び対応するスルホニルクロリドより表題化合物を合成した。但し、スルホンアミド化工程では溶媒としてピリジンを用いた。
ＬＣＭＳ ｍ／ｚ： ６０４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７７分（分析条件Ｃ） Compound k11:
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid

Methyl 5-[(3-amino-2-fluorophenyl)methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6 under the same conditions as in the production examples of compound A-25 and compound b2 -oxopyridine-3-carboxylate (compound k4) and the corresponding sulfonyl chloride to synthesize the title compound. However, pyridine was used as a solvent in the sulfonamidation step.
LCMS m/z: 604 [M+H] ⁺
HPLC retention time: 0.77 minutes (analytical condition C)

化合物ａ１０の製造例と同様の条件で、５－［［３－（エチルスルホニルアミノ）－２－フルオロフェニル］メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸（化合物ｋ１１）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６４３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．５３分（分析条件Ｂ） Compound K-8:
N-cyclopropyl-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide

5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo The title compound was synthesized from pyridine-3-carboxylic acid (compound k11).
LCMS m/z: 643 [M+H] ⁺
HPLC retention time: 1.53 minutes (analysis condition B)

化合物ａ１２の製造例と同様の条件で、５－［［３－（エチルスルホニルアミノ）－２－フルオロフェニル］メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸（化合物ｋ１１）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６７５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．５７分（分析条件Ｂ） Compound K-9:
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-N-[(2-methylpropan-2-yl)oxy ]-6-oxopyridine-3-carboxamide

5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo The title compound was synthesized from pyridine-3-carboxylic acid (compound k11).
LCMS m/z: 675 [M+H] ⁺
HPLC retention time: 1.57 minutes (Analysis condition B)

５－［［３－（エチルスルホニルアミノ）－２－フルオロフェニル］メチル］－２－（２－フルオロ－４－ヨードアニリノ）－１－メチル－６－オキソピリジン－３－カルボン酸（化合物ｋ１１、２２．０ｍｇ、０．０３６ｍｍｏｌ）の無水ＤＭＦ溶液（０．２６４ｍＬ）にＨＯＯＢｔ（８．９２ｍｇ、０．０５５ｍｍｏｌ）及びＥＤＣ・ＨＣｌ（１０．５ｍｇ、０．０５５ｍｍｏｌ）を加え、室温で３時間攪拌した。次いで、０℃で７ＭアンモニアＭｅＯＨ溶液（２０．８μＬ、０．１４６ｍｍｏｌ）を加え、１時間攪拌した。反応混合物を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（１５．８ｍｇ、７２％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ６０３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．４２分（分析条件Ｂ） Compound K-10:
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide

5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxylic acid (compounds k11, 22 .0 mg, 0.036 mmol) in anhydrous DMF (0.264 mL) was added with HOOBt (8.92 mg, 0.055 mmol) and EDC.HCl (10.5 mg, 0.055 mmol) and stirred at room temperature for 3 hours. Then, 7M ammonia MeOH solution (20.8 μL, 0.146 mmol) was added at 0° C. and stirred for 1 hour. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (15.8 mg, 72%) as a colorless solid.
LCMS m/z: 603 [M+H] ⁺
HPLC retention time: 1.42 minutes (analysis condition B)

化合物ｃ５及び化合物ａ１の製造例と同様の条件で、２－ブロモ－５－フルオロピリジン－４－カルボン酸より表題化合物を得た。但し、化合物ｃ５の製造例で用いた４－ヨード－２－メチルアニリンの代わりに２－フルオロ－４－トリメチルシリルアニリンを用いた。
ＬＣＭＳ ｍ／ｚ： ３９７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１７分（分析条件Ｇ） Compound l2:
Methyl 2-bromo-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate

The title compound was obtained from 2-bromo-5-fluoropyridine-4-carboxylic acid under the same conditions as in the production examples of compound c5 and compound a1. However, 2-fluoro-4-trimethylsilylaniline was used in place of 4-iodo-2-methylaniline used in the production example of compound c5.
LCMS m/z: 397 [M+H] ⁺
HPLC retention time: 1.17 minutes (analytical condition G)

化合物ｌ３ｂ：
５－（２－フルオロ－４－トリメチルシリルアニリノ）－４－メトキシカルボニルピリジン－２－カルボン酸

メチル ２－ブロモ－５－（２－フルオロ－４－トリメチルシリルアニリノ）ピリジン－４－カルボキシラート（化合物ｌ２、２．５ｇ、６．２９ｍｍｏｌ）、１，１，３－トリオキソ－１，２－ベンゾチアゾール－２－カルバルデヒド（２．６６ｇ、６１２．６ｍｍｏｌ）、Ｘａｎｔｐｈｏｓ（７２８ｍｇ、１．２６ｍｍｏｌ）、酢酸パラジウム（１４１ｍｇ、０．６２９ｍｍｏｌ）及び炭酸ナトリウム（１．６７ｇ、１５．７ｍｍｏｌ）の無水ＤＭＦ懸濁液（６３ｍＬ）にトリエチルシラン（２．０１ｍＬ、１２．６ｍｍｏｌ）の無水ＤＭＦ溶液（６３ｍＬ）を加え、室温で１０分間、次いで７５℃で２．５時間攪拌した。反応混合物を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、化合物ｌ３ａ（０．４ｇ、１８％）及び化合物ｌ３ｂ（１．４ｇ、６１％）を各々黄色固体として得た。
化合物ｌ３ａ
ＬＣＭＳ ｍ／ｚ： ３４７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０６分（分析条件Ｇ）
化合物ｌ３ｂ
ＬＣＭＳ ｍ／ｚ： ３６３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９２分（分析条件Ｇ） Compound l3a:
Methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-formylpyridine-4-carboxylate

Compound l3b:
5-(2-fluoro-4-trimethylsilylanilino)-4-methoxycarbonylpyridine-2-carboxylic acid

Methyl 2-bromo-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate (compound l2, 2.5 g, 6.29 mmol), 1,1,3-trioxo-1,2-benzo Thiazole-2-carbaldehyde (2.66 g, 612.6 mmol), Xantphos (728 mg, 1.26 mmol), palladium acetate (141 mg, 0.629 mmol) and sodium carbonate (1.67 g, 15.7 mmol) in anhydrous DMF. An anhydrous DMF solution (63 mL) of triethylsilane (2.01 mL, 12.6 mmol) was added to the turbid solution (63 mL), and the mixture was stirred at room temperature for 10 minutes and then at 75° C. for 2.5 hours. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid in water/0.1% formic acid in acetonitrile) to yield compound 13a (0.4 g, 18%) and compound 13b (1.4 g, 61%). were each obtained as a yellow solid.
compound l3a
LCMS m/z: 347 [M+H] ⁺
HPLC retention time: 1.06 minutes (analysis condition G)
compound l3b
LCMS m/z: 363 [M+H] ⁺
HPLC retention time: 0.92 minutes (analysis condition G)

メチル ５－（２－フルオロ－４－トリメチルシリルアニリノ）－２－ホルミルピリジン－４－カルボキシラート（化合物ｌ３ａ、５００ｍｇ、１．４４ｍｍｏｌ）の無水ＴＨＦ溶液（１４ｍＬ）に１ＭボランテトラヒドロフランコンプレックスＴＨＦ溶液（４．３３ｍＬ、４．３３ｍｍｏｌ）を加え、室温で１時間攪拌した。反応混合物に酢酸（０．４９６ｍＬ、８．６６ｍｍｏｌ）を加え、減圧濃縮した。得られた残渣を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（３６０ｍｇ、７２％）を淡黄色固体として得た。
ＬＣＭＳ ｍ／ｚ： ３４９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９１分（分析条件Ｇ） Compound l4:
Methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-(hydroxymethyl)pyridine-4-carboxylate

A 1 M borane tetrahydrofuran complex THF solution (4 .33 mL, 4.33 mmol) was added and stirred at room temperature for 1 hour. Acetic acid (0.496 mL, 8.66 mmol) was added to the reaction mixture and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (360 mg, 72%) as a pale yellow solid.
LCMS m/z: 349 [M+H] ⁺
HPLC retention time: 0.91 minutes (analysis condition G)

５－（２－フルオロ－４－トリメチルシリルアニリノ）－４－メトキシカルボニルピリジン－２－カルボン酸（化合物ｌ３ｂ、５７０ｍｇ、１．５７ｍｍｏｌ）の無水ＴＨＦ溶液（１６ｍＬ）にボランジメチルスルフィドコンプレックス（０．７４７ｍＬ、７．８６ｍｍｏｌ）を加え、室温で２時間攪拌した。反応混合物に酢酸（１．５８ｍＬ、２７．６ｍｍｏｌ）を加え、減圧濃縮した。得られた残渣を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（３５０ｍｇ、６４％）を淡黄色固体として得た。
ＬＣＭＳ ｍ／ｚ： ３４９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９１分（分析条件Ｇ） Compound l4:
Methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-(hydroxymethyl)pyridine-4-carboxylate

5-(2-fluoro-4-trimethylsilylanilino)-4-methoxycarbonylpyridine-2-carboxylic acid (compound l3b, 570 mg, 1.57 mmol) in anhydrous THF (16 mL) was added with borane dimethylsulfide complex (0.747 mL). , 7.86 mmol) was added and stirred at room temperature for 2 hours. Acetic acid (1.58 mL, 27.6 mmol) was added to the reaction mixture and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (350 mg, 64%) as a pale yellow solid.
LCMS m/z: 349 [M+H] ⁺
HPLC retention time: 0.91 minutes (analysis condition G)

メチル ５－（２－フルオロ－４－トリメチルシリルアニリノ）－２－（ヒドロキシメチル）ピリジン－４－カルボキシラート（化合物ｌ４、４００ｍｇ、１．１５ｍｍｏｌ）のＤＣＭ溶液（１２ｍＬ）に塩化チオニル（０．１６８ｍＬ、２．３０ｍｍｏｌ）を加え、室温で５０分間攪拌した。反応混合物を減圧濃縮して表題化合物の粗生成物（４００ｍｇ）を得た。
ＬＣＭＳ ｍ／ｚ： ３６７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１１分（分析条件Ｇ） Compound l5:
Methyl 2-(chloromethyl)-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate

To a solution of methyl 5-(2-fluoro-4-trimethylsilylanilino)-2-(hydroxymethyl)pyridine-4-carboxylate (Compound 14, 400 mg, 1.15 mmol) in DCM (12 mL) was added thionyl chloride (0.168 mL). , 2.30 mmol) was added and stirred at room temperature for 50 minutes. The reaction mixture was concentrated under reduced pressure to obtain the crude title compound (400 mg).
LCMS m/z: 367 [M+H] ⁺
HPLC retention time: 1.11 minutes (analytical condition G)

メチル ２－（クロロメチル）－５－（２－フルオロ－４－トリメチルシリルアニリノ）ピリジン－４－カルボキシラート（化合物ｌ５、５８４ｍｇ、１．５９ｍｍｏｌ）、［２－［（２，４－ジメトキシフェニル）メチルアミノ］－３－フルオロピリジン－４－イル］ボロン酸（化合物ａ４、７３１ｍｇ、２．３９ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（１８４ｍｇ、０．１５９ｍｍｏｌ）及び炭酸カリウム（６６０ｍｇ、４．７８ｍｍｏｌ）の１，４－ジオキサン懸濁液（１７ｍＬ）を１１０℃で２時間攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、乾燥剤をろ去後、減圧濃縮した。得られた残渣をカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製して、表題化合物（５８３ｍｇ、６２％）を黄色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５９３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１３分（分析条件Ｇ） Compound l6:
methyl 2-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxy rat

Methyl 2-(chloromethyl)-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate (compound 15, 584 mg, 1.59 mmol), [2-[(2,4-dimethoxyphenyl) methylamino]-3-fluoropyridin-4-yl]boronic acid (compound a4, 731 mg, 2.39 mmol), tetrakistriphenylphosphine palladium (184 mg, 0.159 mmol) and potassium carbonate (660 mg, 4.78 mmol) in 1 ,4-dioxane suspension (17 mL) was stirred at 110° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate) to give the title compound (583 mg, 62%) as a yellow solid.
LCMS m/z: 593 [M+H] ⁺
HPLC retention time: 1.13 minutes (analytical condition G)

化合物ａ６の製造例と同様の条件で、メチル ２－［［２－［（２，４－ジメトキシフェニル）メチルアミノ］－３－フルオロピリジン－４－イル］メチル］－５－（２－フルオロ－４－トリメチルシリルアニリノ）ピリジン－４－カルボキシラート（化合物ｌ６）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ４４３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８３分（分析条件Ｇ） Compound l7:
Methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate

Methyl 2-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-5-(2-fluoro- The title compound was synthesized from 4-trimethylsilylanilino)pyridine-4-carboxylate (Compound 16).
LCMS m/z: 443 [M+H] ⁺
HPLC retention time: 0.83 minutes (analysis condition G)

メチル ２－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－５－（２－フルオロ－４－トリメチルシリルアニリノ）ピリジン－４－カルボキシラート（化合物ｌ７、３００ｍｇ、０．６７８ｍｍｏｌ）の無水ＤＣＭ溶液（１４ｍＬ）を０℃に冷却し、一塩化ヨウ素（２２０ｍｇ、１．３６ｍｍｏｌ）を加え、０℃で３０分間、次いで室温で３時間攪拌した。反応混合物を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィーで精製して、表題化合物（３２０ｍｇ、９５％）を黄色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４９７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６９分（分析条件Ｇ） Compound l8:
Methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)pyridine-4-carboxylate

Methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-trimethylsilylanilino)pyridine-4-carboxylate (Compound l7, 300mg, 0.678mmol) A solution of in anhydrous DCM (14 mL) was cooled to 0° C., iodine monochloride (220 mg, 1.36 mmol) was added and stirred at 0° C. for 30 minutes, then at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by reverse phase column chromatography to give the title compound (320 mg, 95%) as a yellow solid.
LCMS m/z: 497 [M+H] ⁺
HPLC retention time: 0.69 minutes (analysis condition G)

化合物ａ７、化合物Ｋ－１０及び化合物Ａ－１の製造例と同様の条件で、メチル ２－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－５－（２－フルオロ－４－ヨードアニリノ）ピリジン－４－カルボキシラート（化合物ｌ８）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５７５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．３６分（分析条件Ｂ） Compound L-1:
5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide

Methyl 2-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4 -Iodoanilino)pyridine-4-carboxylate (Compound 18) to synthesize the title compound.
LCMS m/z: 575 [M+H] ⁺
HPLC retention time: 1.36 minutes (analysis condition B)

メチル ２－アミノ－６－シアノピリジン－３－カルボキシラート（９．１４ｇ、５１．６ｍｍｏｌ）の酢酸（１００ｍＬ）及びメタノール（１００ｍＬ）混合溶液にパラジウム担持活性炭粉末触媒（１０％パラジウム）（９３３ｍｇ、０．８７７ｍｍｏｌ）を加え、水素雰囲気下、室温で４時間攪拌した。反応混合物をセライトろ過し、ろ液を減圧濃縮して表題化合物の粗生成物（１５．３ｇ）を得た。
ＬＣＭＳ ｍ／ｚ： １８２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．２６分（分析条件Ｇ） Compound m1:
Methyl 2-amino-6-(aminomethyl)pyridine-3-carboxylate diacetate

Palladium-supported activated carbon powder catalyst (10% palladium) (933 mg, 0 .877 mmol) was added and stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (15.3 g) of the title compound.
LCMS m/z: 182 [M+H] ⁺
HPLC retention time: 0.26 minutes (analysis condition G)

メチル ２－アミノ－６－（アミノメチル）ピリジン－３－カルボキシラート二酢酸塩（化合物ｍ１、１４．７ｇ、４８．８ｍｍｏｌ）のギ酸溶液（２３０ｍＬ）に無水酢酸（１１５ｍＬ、１．２２ｍｏｌ）を３０分かけて加え、７０℃で終夜攪拌した。反応混合物を減圧濃縮し、得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、乾燥剤をろ去後、減圧濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィーで精製して、表題化合物（８．１６ｇ、８０％）を黄色固体として得た。
ＬＣＭＳ ｍ／ｚ： ２１０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．２９分（分析条件Ｇ） Compound m2:
Methyl 2-amino-6-(formamidomethyl)pyridine-3-carboxylate

To a solution of methyl 2-amino-6-(aminomethyl)pyridine-3-carboxylate diacetate (compound m1, 14.7 g, 48.8 mmol) in formic acid (230 mL) was added acetic anhydride (115 mL, 1.22 mol) in 30 It was added in minutes and stirred at 70° C. overnight. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography to give the title compound (8.16 g, 80%) as a yellow solid.
LCMS m/z: 210 [M+H] ⁺
HPLC retention time: 0.29 minutes (analysis condition G)

メチル ２－アミノ－６－（ホルムアミドメチル）ピリジン－３－カルボキシラート（化合物ｍ２、９．２５ｇ、４４．２ｍｍｏｌ）の無水アセトニトリル溶液（４００ｍＬ）にＮ－ブロモスクシンイミド（７．８７ｇ、４４．２ｍｍｏｌ）を数回に分けて加え、室温で１時間攪拌した。反応混合物を減圧濃縮し、得られた残渣に水を加えた。得られた固体を水で洗浄して、表題化合物（１２．０ｇ、９４％）を黄色固体として得た。
ＬＣＭＳ ｍ／ｚ： ２８８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．５２分（分析条件Ｇ） Compound m3:
Methyl 2-amino-5-bromo-6-(formamidomethyl)pyridine-3-carboxylate

To a solution of methyl 2-amino-6-(formamidomethyl)pyridine-3-carboxylate (compound m2, 9.25 g, 44.2 mmol) in anhydrous acetonitrile (400 mL) was added N-bromosuccinimide (7.87 g, 44.2 mmol). was added in several portions and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and water was added to the resulting residue. The solid obtained was washed with water to give the title compound (12.0 g, 94%) as a yellow solid.
LCMS m/z: 288 [M+H] ⁺
HPLC retention time: 0.52 minutes (analytical condition G)

メチル ２－アミノ－５－ブロモ－６－（ホルムアミドメチル）ピリジン－３－カルボキシラート（化合物ｍ３、１２．０ｇ、４１．７ｍｍｏｌ）の無水トルエン懸濁液（２００ｍＬ）に塩化ホスホリル（１７．５ｍＬ、１８７ｍｍｏｌ）を加え、９５℃で１時間攪拌した。反応混合物を減圧濃縮し、得られた残渣に飽和炭酸水素ナトリウム水溶液及び水を加えた。得られた固体を水で洗浄し、ＤＣＭに溶解させ、無水硫酸マグネシウムで乾燥させた。乾燥剤をろ去後、減圧濃縮して、表題化合物（１０．５ｇ、９３％）を淡褐色固体として得た。
ＬＣＭＳ ｍ／ｚ： ２７０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６５分（分析条件Ｇ） Compound m4:
Methyl 5-amino-8-bromoimidazo[1,5-a]pyridine-6-carboxylate

Phosphoryl chloride (17.5 mL, 187 mmol) was added and stirred at 95° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution and water were added to the resulting residue. The solid obtained was washed with water, dissolved in DCM and dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the residue was concentrated under reduced pressure to give the title compound (10.5 g, 93%) as a pale brown solid.
LCMS m/z: 270 [M+H] ⁺
HPLC retention time: 0.65 minutes (analytical condition G)

メチル ５－アミノ－８－ブロモイミダゾ［１，５－ａ］ピリジン－６－カルボキシラート（化合物ｍ４、１．５８ｇ、５．８５ｍｍｏｌ）及び二炭酸ジ－ｔｅｒｔ－ブチル（３．１９ｇ、１４．６ｍｍｏｌ）の無水ＤＣＭ溶液（５０ｍＬ）に４－ジメチルアミノピリジン（１４３ｍｇ、１．１７ｍｍｏｌ）を加え、室温で２時間攪拌した。反応混合物を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーで精製して、表題化合物（２．５ｇ、９１％）を黄色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４７０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９５分（分析条件Ｇ） Compound m5:
Methyl 5-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-8-bromoimidazo[1,5-a]pyridine-6-carboxylate

Methyl 5-amino-8-bromoimidazo[1,5-a]pyridine-6-carboxylate (compound m4, 1.58 g, 5.85 mmol) and di-tert-butyl dicarbonate (3.19 g, 14.6 mmol ) in anhydrous DCM (50 mL) was added 4-dimethylaminopyridine (143 mg, 1.17 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (2.5 g, 91%) as a yellow solid.
LCMS m/z: 470 [M+H] ⁺
HPLC retention time: 0.95 minutes (analysis condition G)

メチル ５－［ビス［（２－メチルプロパン－２－イル）オキシカルボニル］アミノ］－８－ブロモイミダゾ［１，５－ａ］ピリジン－６－カルボキシラート（化合物ｍ５、２．５ｇ、５．３２ｍｍｏｌ）、カリウムビニルトリフルオロボラート（１．０７ｇ、７．９７ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（６１４ｍｇ、０．５３２ｍｍｏｌ）及び炭酸セシウム（５．２０ｇ、１６．０ｍｍｏｌ）の１，４－ジオキサン（４０ｍＬ）及び水（１０ｍＬ）混合懸濁液を１００℃で２時間攪拌した。反応混合物を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。乾燥剤をろ去後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーで精製して、表題化合物（１．６８ｇ、７６％）を黄色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４１８［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８９分（分析条件Ｇ） Compound m6:
Methyl 5-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-8-ethenylimidazo[1,5-a]pyridine-6-carboxylate

Methyl 5-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-8-bromoimidazo[1,5-a]pyridine-6-carboxylate (compound m5, 2.5 g, 5.32 mmol ), potassium vinyltrifluoroborate (1.07 g, 7.97 mmol), tetrakistriphenylphosphine palladium (614 mg, 0.532 mmol) and cesium carbonate (5.20 g, 16.0 mmol) in 1,4-dioxane (40 mL). and water (10 mL) was stirred at 100° C. for 2 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the residue was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to give the title compound (1.68 g, 76%) as a yellow solid.
LCMS m/z: 418 [M+H] ⁺
HPLC retention time: 0.89 minutes (analysis condition G)

化合物ｃ６及び化合物ａ６の製造例と同様の条件で、メチル ５－［ビス［（２－メチルプロパン－２－イル）オキシカルボニル］アミノ］－８－エテニルイミダゾ［１，５－ａ］ピリジン－６－カルボキシラート（化合物ｍ６）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ２２０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．４８分（分析条件Ｇ） Compound m8:
Methyl 5-amino-8-formylimidazo[1,5-a]pyridine-6-carboxylate trifluoroacetate

Methyl 5-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-8-ethenylimidazo[1,5-a]pyridine-6- The title compound was synthesized from the carboxylate (compound m6).
LCMS m/z: 220 [M+H] ⁺
HPLC retention time: 0.48 minutes (analytical condition G)

メチル ５－アミノ－８－ホルミルイミダゾ［１，５－ａ］ピリジン－６－カルボキシラートトリフルオロ酢酸塩（化合物ｍ８、４７５ｍｇ、１．４３ｍｍｏｌ）、ｐ－トルエンスルホン酸一水和物（５４．２ｍｇ、０．２８５ｍｍｏｌ）及び２，２－ジメチル－１，３－プロパンジオール（７４２ｍｇ、７．１３ｍｍｏｌ）のトルエン懸濁液（３０ｍＬ）を１１０℃で終夜攪拌した。反応混合物にＤＩＰＥＡ（１ｍＬ）を加え、減圧濃縮した。得られた残渣を逆相カラムクロマトグラフィーで精製して、表題化合物（３４０ｍｇ、７８％）を赤色固体として得た。
ＬＣＭＳ ｍ／ｚ： ３０６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６６分（分析条件Ｇ） Compound m9:
Methyl 5-amino-8-(5,5-dimethyl-1,3-dioxan-2-yl)imidazo[1,5-a]pyridine-6-carboxylate

Methyl 5-amino-8-formylimidazo[1,5-a]pyridine-6-carboxylate trifluoroacetate (compound m8, 475 mg, 1.43 mmol), p-toluenesulfonic acid monohydrate (54.2 mg , 0.285 mmol) and 2,2-dimethyl-1,3-propanediol (742 mg, 7.13 mmol) in toluene (30 mL) was stirred at 110° C. overnight. DIPEA (1 mL) was added to the reaction mixture and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to give the title compound (340 mg, 78%) as a red solid.
LCMS m/z: 306 [M+H] ⁺
HPLC retention time: 0.66 minutes (analytical condition G)

メチル ５－アミノ－８－（５，５－ジメチル－１，３－ジオキサン－２－イル）イミダゾ［１，５－ａ］ピリジン－６－カルボキシラート（化合物ｍ９、３４０ｍｇ、１．１１ｍｍｏｌ）のアセトニトリル懸濁液（１５ｍＬ）を０℃に冷却し、塩化銅（Ｉ）（１６５ｍｇ、１．６７ｍｍｏｌ）及び塩化銅（ＩＩ）（２２５ｍｇ、１．６７ｍｍｏｌ）を加えた。次いで、亜硝酸ｔｅｒｔ－ブチル（１７２ｍｇ、１．６７ｍｍｏｌ）を加え、室温で３０分間攪拌した。反応混合物を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィーで精製して、表題化合物（２３７ｍｇ、６６％）を赤色固体として得た。
ＬＣＭＳ ｍ／ｚ： ３２５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７７分（分析条件Ｇ） Compound m10:
Methyl 5-chloro-8-(5,5-dimethyl-1,3-dioxan-2-yl)imidazo[1,5-a]pyridine-6-carboxylate

Acetonitrile of methyl 5-amino-8-(5,5-dimethyl-1,3-dioxan-2-yl)imidazo[1,5-a]pyridine-6-carboxylate (compound m9, 340 mg, 1.11 mmol) The suspension (15 mL) was cooled to 0° C. and copper(I) chloride (165 mg, 1.67 mmol) and copper(II) chloride (225 mg, 1.67 mmol) were added. Then tert-butyl nitrite (172 mg, 1.67 mmol) was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by reverse phase column chromatography to give the title compound (237 mg, 66%) as a red solid.
LCMS m/z: 325 [M+H] ⁺
HPLC retention time: 0.77 minutes (analysis condition G)

メチル ５－クロロ－８－（５，５－ジメチル－１，３－ジオキサン－２－イル）イミダゾ［１，５－ａ］ピリジン－６－カルボキシラート（化合物ｍ１０、２３７ｍｇ、０．７３０ｍｍｏｌ）、炭酸セシウム（７１３ｍｇ、２．１９ｍｍｏｌ）及び２－フルオロ－４－ヨードアニリン（３４６ｍｇ、１．４６ｍｍｏｌ）のＤＭＡ懸濁液（４ｍＬ）を５０℃で終夜攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させ、乾燥剤をろ去後、減圧濃縮した。得られた残渣を逆相カラムクロマトグラフィーで精製して、表題化合物（２１０ｍｇ、５５％）を黄色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５２６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０２分（分析条件Ｇ） Compound m11:
Methyl 8-(5,5-dimethyl-1,3-dioxan-2-yl)-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylate

Methyl 5-chloro-8-(5,5-dimethyl-1,3-dioxan-2-yl)imidazo[1,5-a]pyridine-6-carboxylate (compound m10, 237mg, 0.730mmol), carbonate A DMA suspension (4 mL) of cesium (713 mg, 2.19 mmol) and 2-fluoro-4-iodoaniline (346 mg, 1.46 mmol) was stirred at 50° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to give the title compound (210 mg, 55%) as a yellow solid.
LCMS m/z: 526 [M+H] ⁺
HPLC retention time: 1.02 minutes (analysis condition G)

メチル ８－（５，５－ジメチル－１，３－ジオキサン－２－イル）－５－（２－フルオロ－４－ヨードアニリノ）イミダゾ［１，５－ａ］ピリジン－６－カルボキシラート（化合物ｍ１１、２１０ｍｇ、０．４００ｍｍｏｌ）の水（２ｍＬ）及びＴＦＡ（２ｍＬ）混合懸濁液を室温で１時間攪拌した。反応混合物を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（１６８ｍｇ、９６％）を黄色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４４０［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８４分（分析条件Ｇ） Compound m12:
Methyl 5-(2-fluoro-4-iodoanilino)-8-formylimidazo[1,5-a]pyridine-6-carboxylate

methyl 8-(5,5-dimethyl-1,3-dioxan-2-yl)-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylate (compound m11, 210 mg, 0.400 mmol) in water (2 mL) and TFA (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (168 mg, 96%) as a yellow solid. Obtained.
LCMS m/z: 440 [M+H] ⁺
HPLC retention time: 0.84 minutes (analytical condition G)

化合物ａ２、化合物ａ５及び化合物ａ６の製造例と同様の条件で、メチル ５－（２－フルオロ－４－ヨードアニリノ）－８－ホルミルイミダゾ［１，５－ａ］ピリジン－６－カルボキシラート（化合物ｍ１２）より表題化合物を合成した。但し、化合物ａ２の製造例で用いたＥｔＯＨの代わりにＭｅＯＨを用いた。
ＬＣＭＳ ｍ／ｚ： ５３６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．５４分（分析条件Ｆ） Compound m15:
Methyl 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylate trifluoroacetate

Methyl 5-(2-fluoro-4-iodoanilino)-8-formylimidazo[1,5-a]pyridine-6-carboxylate (compound m12 ) to synthesize the title compound. However, MeOH was used instead of EtOH used in the production example of compound a2.
LCMS m/z: 536 [M+H] ⁺
HPLC retention time: 0.54 minutes (analytical condition F)

メチル ８－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－５－（２－フルオロ－４－ヨードアニリノ）イミダゾ［１，５－ａ］ピリジン－６－カルボキシラートトリフルオロ酢酸塩（化合物ｍ１５、６０ｍｇ、０．０９２ｍｍｏｌ）及び水酸化リチウム一水和物（７８ｍｇ、１．８５ｍｍｏｌ）のＴＨＦ（３ｍＬ）及び水（２ｍＬ）混合懸濁液を５０℃で終夜攪拌した。反応混合物を、ギ酸を加えて酸性にした後、減圧濃縮した。得られた残渣を逆相カラムクロマトグラフィー（０．１％ＴＦＡ水溶液／０．１％ＴＦＡアセトニトリル溶液）で精製して、表題化合物（４２ｍｇ、７２％）を黄色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５２２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．４５分（分析条件Ｆ） Compound m16:
8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylic acid trifluoroacetate

Methyl 8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylate trifluoroacetate A mixed suspension of (compound m15, 60 mg, 0.092 mmol) and lithium hydroxide monohydrate (78 mg, 1.85 mmol) in THF (3 mL) and water (2 mL) was stirred at 50° C. overnight. The reaction mixture was acidified by adding formic acid and then concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% TFA aqueous solution/0.1% TFA acetonitrile solution) to give the title compound (42 mg, 72%) as a yellow solid.
LCMS m/z: 522 [M+H] ⁺
HPLC retention time: 0.45 minutes (analytical condition F)

８－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－５－（２－フルオロ－４－ヨードアニリノ）イミダゾ［１，５－ａ］ピリジン－６－カルボン酸トリフルオロ酢酸塩（化合物ｍ１６、４２ｍｇ、０．０６６ｍｍｏｌ）のＤＭＦ溶液（１．６ｍＬ）を０℃に冷却し、ＨＡＴＵ（３９０ｍｇ、１．０３ｍｍｏｌ）、塩化アンモニウム（６７．２ｍｇ、１．２６ｍｍｏｌ）及びＤＩＰＥＡ（０．２５３ｍＬ、１．４５ｍｍｏｌ）を加え、室温で５時間攪拌した。反応混合物を減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィー（０．１％ＴＦＡ水溶液／０．１％ＴＦＡアセトニトリル溶液）で精製して、表題化合物（２５ｍｇ、６０％）を黄色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５２１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．４１分（分析条件Ｆ） Compound m17:
8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxamide trifluoroacetate

8-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5-a]pyridine-6-carboxylic acid trifluoroacetate ( A DMF solution (1.6 mL) of compound m16, 42 mg, 0.066 mmol) was cooled to 0° C. and treated with HATU (390 mg, 1.03 mmol), ammonium chloride (67.2 mg, 1.26 mmol) and DIPEA (0.253 mL). , 1.45 mmol) was added and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% TFA aqueous solution/0.1% TFA acetonitrile solution) to give the title compound (25 mg, 60%) as a yellow solid. Obtained.
LCMS m/z: 521 [M+H] ⁺
HPLC retention time: 0.41 minutes (analytical condition F)

化合物Ａ－１の製造例と同様の条件で、８－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－５－（２－フルオロ－４－ヨードアニリノ）イミダゾ［１，５－ａ］ピリジン－６－カルボキサミドトリフルオロ酢酸塩（化合物ｍ１７）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６１４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．１８分（分析条件Ｂ） Compound M-1:
5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide

8-[(2-Amino-3-fluoropyridin-4-yl)methyl]-5-(2-fluoro-4-iodoanilino)imidazo[1,5- The title compound was synthesized from a]pyridine-6-carboxamide trifluoroacetate (compound m17).
LCMS m/z: 614 [M+H] ⁺
HPLC retention time: 1.18 minutes (analysis condition B)

２－フルオロ－４－ヨードアニリン（２．２６ｇ、９．５２ｍｍｏｌ）の無水ＴＨＦ溶液（８ｍｌ）を－７８℃に冷却し、２Ｍ ＬＤＡ ＴＨＦ／ヘプタン／エチルベンゼン溶液（７．１４ｍＬ、１４．３ｍｍｏｌ）を加え、３０分間攪拌した。次いで、４，６－ジクロロ－５－フルオロピリジン－３－カルボン酸（１．００ｇ、４．７６ｍｍｏｌ）の無水ＴＨＦ溶液（８ｍＬ）を加え、－７８℃で３０分間攪拌した。その後、反応混合物に水及び６Ｍ塩酸を加えてｐＨを１から２とし、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥させ、乾燥剤をろ去後、減圧濃縮した。得られた残渣から再結晶（ＤＣＭ）を行って、表題化合物（８５０ｍｇ、４４％）を淡褐色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４１１［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８５分（分析条件Ｇ） Compound n1:
6-chloro-5-fluoro-4-(2-fluoro-4-iodoanilino)pyridine-3-carboxylic acid

A solution of 2-fluoro-4-iodoaniline (2.26 g, 9.52 mmol) in anhydrous THF (8 ml) was cooled to −78° C. and a 2 M LDA THF/heptane/ethylbenzene solution (7.14 mL, 14.3 mmol) was added. added and stirred for 30 minutes. An anhydrous THF solution (8 mL) of 4,6-dichloro-5-fluoropyridine-3-carboxylic acid (1.00 g, 4.76 mmol) was then added and stirred at -78°C for 30 minutes. After that, water and 6M hydrochloric acid were added to the reaction mixture to adjust the pH to 1 to 2, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. Recrystallization (DCM) from the resulting residue afforded the title compound (850 mg, 44%) as a pale brown solid.
LCMS m/z: 411 [M+H] ⁺
HPLC retention time: 0.85 minutes (analytical condition G)

化合物ａ１の製造例と同様の条件で、６－クロロ－５－フルオロ－４－（２－フルオロ－４－ヨードアニリノ）ピリジン－３－カルボン酸（化合物ｎ１）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ４２５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０４分（分析条件Ｇ） Compound n2:
Methyl 6-chloro-5-fluoro-4-(2-fluoro-4-iodoanilino)pyridine-3-carboxylate

The title compound was synthesized from 6-chloro-5-fluoro-4-(2-fluoro-4-iodoanilino)pyridine-3-carboxylic acid (compound n1) under the same conditions as in the production example of compound a1.
LCMS m/z: 425 [M+H] ⁺
HPLC retention time: 1.04 minutes (analysis condition G)

メチル ６－クロロ－５－フルオロ－４－（２－フルオロ－４－ヨードアニリノ）ピリジン－３－カルボキシラート（化合物ｎ２、３５０ｍｇ、０．８２４ｍｍｏｌ）のＤＭＳＯ溶液（２．７５ｍＬ）に炭酸カリウム（５７０ｍｇ、４．１２ｍｍｏｌ）及びＮ－ヒドロキシアセトアミド（１８６ｍｇ、２．４７ｍｍｏｌ）を加え、１００℃で１時間攪拌した。反応混合物に水を加え、得られた固体を水及びＤＣＭで洗浄して、表題化合物（２８１ｍｇ、８４％）を淡褐色固体として得た。
ＬＣＭＳ ｍ／ｚ： ４０７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７２分（分析条件Ｇ） Compound n3:
Methyl 5-fluoro-4-(2-fluoro-4-iodoanilino)-6-hydroxypyridine-3-carboxylate

Potassium carbonate (570 mg, 4.12 mmol) and N-hydroxyacetamide (186 mg, 2.47 mmol) were added and stirred at 100° C. for 1 hour. Water was added to the reaction mixture and the solid obtained was washed with water and DCM to give the title compound (281 mg, 84%) as a light brown solid.
LCMS m/z: 407 [M+H] ⁺
HPLC retention time: 0.72 minutes (analytical condition G)

［２－（ベンズヒドリリデンアミノ）－３－フルオロピリジン－４－イル］メタノール（２．３０ｇ、７．５１ｍｍｏｌ）の無水ＤＣＭ溶液（３７．５ｍＬ）にＤＩＰＥＡ（３．９３ｍＬ、２２．５ｍｍｏｌ）及びメタンスルホン酸無水物（２．０７ｇ、１１．３ｍｍｏｌ）を加え、室温で３０分間攪拌した。次いで、臭化リチウム（３．２６ｇ、３７．５ｍｍｏｌ）の無水ＴＨＦ溶液（０．５ｍＬ）を加え、室温で２時間攪拌した。反応混合物に水を加え、ＤＣＭで抽出した。有機層を無水硫酸ナトリウムで乾燥させ、乾燥剤をろ去後、減圧濃縮した。得られた残渣を逆相カラムクロマトグラフィーで精製して、表題化合物（９９０ｍｇ、３４％）を黄色半固体として得た。
ＬＣＭＳ ｍ／ｚ： ３６９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９４分（分析条件Ｇ） Compound n4:
N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-1,1-diphenylmethanimine

DIPEA (3.93 mL, 22.5 mmol) and Methanesulfonic anhydride (2.07 g, 11.3 mmol) was added and stirred at room temperature for 30 minutes. A solution of lithium bromide (3.26 g, 37.5 mmol) in anhydrous THF (0.5 mL) was then added and stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to give the title compound (990 mg, 34%) as a yellow semi-solid.
LCMS m/z: 369 [M+H] ⁺
HPLC retention time: 0.94 minutes (analysis condition G)

メチル ５－フルオロ－４－（２－フルオロ－４－ヨードアニリノ）－６－ヒドロキシピリジン－３－カルボキシラート（化合物ｎ３、３０ｍｇ、０．０７４ｍｍｏｌ）の無水ＤＭＦ溶液（０．７３９ｍＬ）に水素化リチウム（１．８５ｍｇ、０．２２２ｍｍｏｌ）を加え、室温で３０分間攪拌した。次いで、Ｎ－［４－（ブロモメチル）－３－フルオロピリジン－２－イル］－１，１－ジフェニルメタンイミン（化合物ｎ４、８２ｍｇ、０．２２２ｍｍｏｌ）の無水ＴＨＦ溶液（０．５ｍＬ）を加え、室温で１時間攪拌した。その後、水素化リチウム（１ｍｇ、０．１２６ｍｍｏｌ）と化合物ｎ４（２５ｍｇ、０．０６８ｍｍｏｌ）の無水ＴＨＦ溶液（０．５ｍＬ）とをさらに加え、室温で１時間攪拌した。反応混合物を０℃に冷却し、酢酸（２１．１μＬ）及び水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥させ、乾燥剤をろ去後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製して、表題化合物（１９ｍｇ、３７％）を無色固体として得た。
ＬＣＭＳ ｍ／ｚ： ６９５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０５分（分析条件Ｇ） Compound n5:
Methyl 1-[[2-(benzhydrylideneamino)-3-fluoropyridin-4-yl]methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxy rat

To a solution of methyl 5-fluoro-4-(2-fluoro-4-iodoanilino)-6-hydroxypyridine-3-carboxylate (compound n3, 30 mg, 0.074 mmol) in anhydrous DMF (0.739 mL) was added lithium hydride ( 1.85 mg, 0.222 mmol) was added and stirred at room temperature for 30 minutes. Then, an anhydrous THF solution (0.5 mL) of N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-1,1-diphenylmethanimine (Compound n4, 82 mg, 0.222 mmol) was added and and stirred for 1 hour. After that, additional lithium hydride (1 mg, 0.126 mmol) and compound n4 (25 mg, 0.068 mmol) in anhydrous THF (0.5 mL) were added and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C., acetic acid (21.1 μL) and water were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (19 mg, 37%) as a colorless solid.
LCMS m/z: 695 [M+H] ⁺
HPLC retention time: 1.05 minutes (analysis condition G)

化合物ａ６、化合物ａ７及び化合物Ｋ－１０の製造例と同様の条件で、メチル １－［［２－（ベンズヒドリリデンアミノ）－３－フルオロピリジン－４－イル］メチル］－５－フルオロ－４－（２－フルオロ－４－ヨードアニリノ）－６－オキソピリジン－３－カルボキシラート（化合物ｎ５）より表題化合物を合成した。但し、化合物ａ６の製造例と同様の条件で反応を行う最初の工程では４Ｍ塩酸を添加した。
ＬＣＭＳ ｍ／ｚ： ５１６［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．５２分（分析条件Ｃ） Compound n8:
1-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxamide

Methyl 1-[[2-(benzhydrylideneamino)-3-fluoropyridin-4-yl]methyl]-5-fluoro-4 was prepared under the same conditions as in the production examples of compound a6, compound a7 and compound K-10. The title compound was synthesized from -(2-fluoro-4-iodoanilino)-6-oxopyridine-3-carboxylate (compound n5). However, 4M hydrochloric acid was added in the first step where the reaction was carried out under the same conditions as in the production example of compound a6.
LCMS m/z: 516 [M+H] ⁺
HPLC retention time: 0.52 minutes (analytical condition C)

化合物Ａ－１の製造例と同様の条件で、１－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－５－フルオロ－４－（２－フルオロ－４－ヨードアニリノ）－６－オキソピリジン－３－カルボキサミド（化合物ｎ８）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６０９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．９４分（分析条件Ａ） Compound N-1:
5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide

1-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6 under the same conditions as in the production example of compound A-1 -oxopyridine-3-carboxamide (compound n8) to synthesize the title compound.
LCMS m/z: 609 [M+H] ⁺
HPLC retention time: 0.94 minutes (Analysis condition A)

化合物Ａ－１の製造例と同様の条件で、１－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－５－フルオロ－４－（２－フルオロ－４－ヨードアニリノ）－６－オキソピリジン－３－カルボキサミド（化合物ｎ８）及び対応するスルファミン酸 ４－ニトロフェニルより表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ６３７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０４分（分析条件Ａ） Compound N-2:
5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide

1-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino)-6 under the same conditions as in the production example of compound A-1 -oxopyridine-3-carboxamide (compound n8) and the corresponding 4-nitrophenyl sulfamate to synthesize the title compound.
LCMS m/z: 637 [M+H] ⁺
HPLC retention time: 1.04 minutes (analysis condition A)

化合物ａ１６及び化合物Ａ－１の製造例と同様の条件で、１－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－５－フルオロ－４－（２－フルオロ－４－ヨードアニリノ）－６－オキソピリジン－３－カルボキサミド（化合物ｎ８）より表題化合物を合成した。
ＬＣＭＳ ｍ／ｚ： ５２９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８８分（分析条件Ａ） Compound N-3:
5-fluoro-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-4-(2-fluoro-4-methylsulfanylanilino)-6-oxopyridine- 3-carboxamide

1-[(2-amino-3-fluoropyridin-4-yl)methyl]-5-fluoro-4-(2-fluoro-4-iodoanilino )-6-oxopyridine-3-carboxamide (compound n8) to synthesize the title compound.
LCMS m/z: 529 [M+H] ⁺
HPLC retention time: 0.88 minutes (analytical condition A)

化合物ｃ５、化合物ａ１及び化合物ｎ３の製造例と同様の条件で、４，６－ジクロロ－５－メチルピリジン－３－カルボン酸より表題化合物を合成した。但し、化合物ｃ５の製造例で用いた４－ヨード－２－メチルアニリンの代わりに２－フルオロ－４－ヨードアニリンを用いた。
ＬＣＭＳ ｍ／ｚ： ４０３［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７６分（分析条件Ｇ） Compound p3:
Methyl 4-(2-fluoro-4-iodoanilino)-6-hydroxy-5-methylpyridine-3-carboxylate

The title compound was synthesized from 4,6-dichloro-5-methylpyridine-3-carboxylic acid under the same conditions as in the production examples of compound c5, compound a1 and compound n3. However, 2-fluoro-4-iodoaniline was used in place of 4-iodo-2-methylaniline used in the production example of compound c5.
LCMS m/z: 403 [M+H] ⁺
HPLC retention time: 0.76 minutes (analytical condition G)

化合物ｎ４、化合物ｂ２、化合物ｍ１７、化合物ａ６及び化合物Ａ－１の製造例と同様の条件で、メチル ４－（２－フルオロ－４－ヨードアニリノ）－６－ヒドロキシ－５－メチルピリジン－３－カルボキシラート（化合物ｐ３）より表題化合物を合成した。但し、化合物ｂ２の製造例で用いた水酸化リチウム一水和物の代わりに２Ｍ水酸化ナトリウム水溶液を、化合物ａ６の製造例で用いたトリフルオロ酢酸の代わりに４Ｍ塩化水素１，４－ジオキサン溶液を用いた。
ＬＣＭＳ ｍ／ｚ： ６０５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６６分（分析条件Ｃ） Compound P-1:
4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide

Methyl 4-(2-fluoro-4-iodoanilino)-6-hydroxy-5-methylpyridine-3-carboxy was prepared under the same conditions as in the production examples of compound n4, compound b2, compound m17, compound a6 and compound A-1. The title compound was synthesized from lato (compound p3). However, instead of lithium hydroxide monohydrate used in the production example of compound b2, 2M aqueous sodium hydroxide solution was used, and instead of trifluoroacetic acid used in the production example of compound a6, 4M hydrogen chloride 1,4-dioxane solution. was used.
LCMS m/z: 605 [M+H] ⁺
HPLC retention time: 0.66 minutes (analytical condition C)

化合物ｎ４、化合物ｂ２、化合物ｍ１７、化合物ａ６及び化合物Ａ－１の製造例と同様の条件で、メチル ４－（２－フルオロ－４－ヨードアニリノ）－６－ヒドロキシ－５－メチルピリジン－３－カルボキシラート（化合物ｐ３）より表題化合物を合成した。但し、化合物ｂ２の製造例で用いた水酸化リチウム一水和物の代わりに２Ｍ水酸化ナトリウム水溶液を、化合物ａ６の製造例で用いたトリフルオロ酢酸の代わりに４Ｍ塩化水素１，４－ジオキサン溶液を、化合物Ａ－１の製造例で用いたメチルスルファミン酸 ４－ニトロフェニルの代わりに対応するスルファミン酸 ４－ニトロフェニルを用いた。
ＬＣＭＳ ｍ／ｚ： ６５９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７６分（分析条件Ｃ） Compound P-3:
4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]-5-methyl-6- Oxopyridine-3-carboxamide

Methyl 4-(2-fluoro-4-iodoanilino)-6-hydroxy-5-methylpyridine-3-carboxy was prepared under the same conditions as in the production examples of compound n4, compound b2, compound m17, compound a6 and compound A-1. The title compound was synthesized from lato (compound p3). However, instead of lithium hydroxide monohydrate used in the production example of compound b2, 2M aqueous sodium hydroxide solution was used, and instead of trifluoroacetic acid used in the production example of compound a6, 4M hydrogen chloride 1,4-dioxane solution. was used in place of the 4-nitrophenyl methylsulfamate used in the production example of compound A-1 with the corresponding 4-nitrophenyl sulfamate.
LCMS m/z: 659 [M+H] ⁺
HPLC retention time: 0.76 minutes (analytical condition C)

化合物ｎ４及び化合物ａ６の製造例と同様の条件で、メチル ４－（２－フルオロ－４－ヨードアニリノ）－６－ヒドロキシ－５－メチルピリジン－３－カルボキシラート（化合物ｐ３）より表題化合物を合成した。但し、化合物ｎ４の製造例で用いたＮ－［４－（ブロモメチル）－３－フルオロピリジン－２－イル］－１，１－ジフェニルメタンイミンの代わりにジｔｅｒｔ－ブチル ２－［４－（ブロモメチル）－３－フルオロピリジン－２－イル］イミノプロパンジオエートを、化合物ａ６の製造例で用いたトリフルオロ酢酸の代わりに４Ｍ塩化水素１，４－ジオキサン溶液を用いた。
ＬＣＭＳ ｍ／ｚ： ５２７［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７２分（分析条件Ｇ） Compound p9:
Methyl 4-(2-fluoro-4-iodoanilino)-6-hydroxy-5-methylpyridine-3-carboxylate

The title compound was synthesized from methyl 4-(2-fluoro-4-iodoanilino)-6-hydroxy-5-methylpyridine-3-carboxylate (compound p3) under the same conditions as in the production examples of compound n4 and compound a6. . However, instead of N-[4-(bromomethyl)-3-fluoropyridin-2-yl]-1,1-diphenylmethanimine used in the production example of compound n4, di-tert-butyl 2-[4-(bromomethyl) -3-fluoropyridin-2-yl]iminopropanedioate was used, and 4M hydrogen chloride in 1,4-dioxane was used instead of trifluoroacetic acid used in the production example of compound a6.
LCMS m/z: 527 [M+H] ⁺
HPLC retention time: 0.72 minutes (analytical condition G)

化合物Ａ－２５の製造例と同様の条件で、メチル ４－（２－フルオロ－４－ヨードアニリノ）－６－ヒドロキシ－５－メチルピリジン－３－カルボキシラート（化合物ｐ９）及びエチルスルホニルクロリドより表題化合物を合成した。但し、ピリジンの代わりにＤＩＰＥＡを、無水ＤＭＡの代わりに無水ＤＣＭを用いた。
ＬＣＭＳ ｍ／ｚ： ６１９［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８７分（分析条件Ｇ） Compound p10:
Methyl 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxylate

The title compound was obtained from methyl 4-(2-fluoro-4-iodoanilino)-6-hydroxy-5-methylpyridine-3-carboxylate (compound p9) and ethylsulfonyl chloride under the same conditions as in the production example of compound A-25. was synthesized. However, DIPEA was used instead of pyridine and anhydrous DCM was used instead of anhydrous DMA.
LCMS m/z: 619 [M+H] ⁺
HPLC retention time: 0.87 minutes (analytical condition G)

化合物ｂ２及び化合物Ｋ－１０の製造例と同様の条件で、メチル １－［［２－（エチルスルホニルアミノ）－３－フルオロピリジン－４－イル］メチル］－４－（２－フルオロ－４－ヨードアニリノ）－５－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｐ１０）より表題化合物を合成した。但し、化合物ｂ２の製造例で用いた水酸化リチウム一水和物の代わりに１Ｍ水酸化ナトリウム水溶液を用いた。
ＬＣＭＳ ｍ／ｚ： ６０４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６７分（分析条件Ｃ） Compound P-2:
1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide

Methyl 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4- The title compound was synthesized from iodoanilino)-5-methyl-6-oxopyridine-3-carboxylate (compound p10). However, a 1M sodium hydroxide aqueous solution was used instead of the lithium hydroxide monohydrate used in the production example of compound b2.
LCMS m/z: 604 [M+H] ⁺
HPLC retention time: 0.67 minutes (analytical condition C)

化合物ｂ２及び化合物Ｋ－１０の製造例と同様の条件で、メチル １－［［２－（エチルスルホニルアミノ）－３－フルオロピリジン－４－イル］メチル］－４－（２－フルオロ－４－ヨードアニリノ）－５－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｐ１０）より表題化合物を合成した。但し、化合物ｂ２の製造例で用いた水酸化リチウム一水和物の代わりに１Ｍ水酸化ナトリウム水溶液を、化合物Ｋ－１０の製造例で用いた７ＭアンモニアＭｅＯＨ溶液の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６４４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７４分（分析条件Ｃ） Compound P-4:
N-cyclopropyl-1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine- 3-carboxamide

Methyl 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4- The title compound was synthesized from iodoanilino)-5-methyl-6-oxopyridine-3-carboxylate (compound p10). However, 1M aqueous sodium hydroxide solution was used instead of 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: 644 [M+H] ⁺
HPLC retention time: 0.74 minutes (analysis condition C)

化合物ｂ２及び化合物Ｋ－１０の製造例と同様の条件で、メチル １－［［２－（エチルスルホニルアミノ）－３－フルオロピリジン－４－イル］メチル］－４－（２－フルオロ－４－ヨードアニリノ）－５－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｐ１０）より表題化合物を合成した。但し、化合物ｂ２の製造例で用いた水酸化リチウム一水和物の代わりに１Ｍ水酸化ナトリウム水溶液を、化合物Ｋ－１０の製造例で用いた７ＭアンモニアＭｅＯＨ溶液の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６３４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６７分（分析条件Ｃ） Compound P-5:
1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-N-methoxy-5-methyl-6-oxopyridine-3 - carboxamide

Methyl 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4- The title compound was synthesized from iodoanilino)-5-methyl-6-oxopyridine-3-carboxylate (compound p10). However, 1M aqueous sodium hydroxide solution was used instead of 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 (analytical condition C)

化合物ｂ２、化合物ａ１２及び化合物Ａ－２５の製造例と同様の条件で、メチル １－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－４－（２－フルオロ－４－ヨードアニリノ）－５－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｐ９）より表題化合物を合成した。但し、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６４５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．７３分（分析条件Ｃ） Compound P-6:
N-cyclopropyl-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxo pyridine-3-carboxamide

Methyl 1-[(2-amino-3-fluoropyridin-4-yl)methyl]-4-(2-fluoro-4-iodoanilino )-5-methyl-6-oxopyridine-3-carboxylate (compound p9) to synthesize the title compound. However, the corresponding amine was used instead of the tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 645 [M+H] ⁺
HPLC retention time: 0.73 minutes (analysis condition C)

化合物ｂ２、化合物ａ１２及び化合物Ａ－２５の製造例と同様の条件で、メチル １－［（２－アミノ－３－フルオロピリジン－４－イル）メチル］－４－（２－フルオロ－４－ヨードアニリノ）－５－メチル－６－オキソピリジン－３－カルボキシラート（化合物ｐ９）より表題化合物を合成した。但し、化合物ａ１２の製造例で用いたｔｅｒｔ－ブトキシアミン塩酸塩の代わりに対応するアミンを用いた。
ＬＣＭＳ ｍ／ｚ： ６３５［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．６５分（分析条件Ｃ） Compound P-7:
4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-5-methyl-6-oxopyridine -3-carboxamide

Methyl 1-[(2-amino-3-fluoropyridin-4-yl)methyl]-4-(2-fluoro-4-iodoanilino )-5-methyl-6-oxopyridine-3-carboxylate (compound p9) to synthesize the title compound. However, the corresponding amine was used instead of tert-butoxyamine hydrochloride used in the production example of compound a12.
LCMS m/z: 635 [M+H] ⁺
HPLC retention time: 0.65 minutes (analytical condition C)

３，４－ジフルオロ－２－（（２－フルオロ－４－ヨードフェニル）アミノ）－５－ホルミル安息香酸（２０．０ｇ、４７．５ｍｍｏｌ）をトルエン（２００ｍＬ）に懸濁させ、メチルヒドキシルアミン塩酸塩（４．７３ｇ、５６．６ｍｍｏｌ）及びトリエチルアミン（５．７５ｇ、５６．８ｍｍｏｌ）を加え、１００℃で４時間攪拌した。反応混合物に水（２００ｍＬ）を加え、１Ｍ塩酸でｐＨ５に調整し、酢酸エチルで２回抽出した。有機層を食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤をろ去後、減圧濃縮して、表題化合物（２０ｇ、９４％）を緑色固体として得た。 Compound aa01:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-methoxyiminomethyl]benzoic acid

3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid (20.0 g, 47.5 mmol) was suspended in toluene (200 mL) and treated with methylhydroxylamine. Hydrochloride (4.73 g, 56.6 mmol) and triethylamine (5.75 g, 56.8 mmol) were added and stirred at 100° C. for 4 hours. Water (200 mL) was added to the reaction mixture, adjusted to pH 5 with 1M hydrochloric acid, and extracted twice with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the residue was concentrated under reduced pressure to give the title compound (20 g, 94%) as a green solid.

３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［（Ｅ）－メトキシイミノメチル］安息香酸（化合物ａａ０１、６．００ｇ、１３．３ｍｍｏｌ）のＴＨＦ（１００ｍＬ）及びＭｅＯＨ（５０ｍＬ）混合懸濁液を０℃に冷却し、２Ｍジアゾメチルトリメチルシランヘキサン溶液（１０ｍＬ、２０ｍｍｏｌ）を加え、室温で２時間攪拌した。反応混合物に水を加え、酢酸エチルで２回抽出した。有機層を飽和食塩水で２回洗浄し、有機層を無水硫酸ナトリウムで乾燥させた。乾燥剤をろ去後、減圧濃縮して、表題化合物（５．１０ｇ、８２％）を灰白色固体として得た。 Compound aa02:
Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-methoxyiminomethyl]benzoate

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-methoxyiminomethyl]benzoic acid (compound aa01, 6.00 g, 13.3 mmol) in THF (100 mL) and MeOH (50 mL) The mixed suspension was cooled to 0° C., 2M diazomethyltrimethylsilane hexane solution (10 mL, 20 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the residue was concentrated under reduced pressure to give the title compound (5.10 g, 82%) as an off-white solid.

メチル ３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［（Ｅ）－メトキシイミノメチル］ベンゾエート（化合物ａａ０２、５．００ｇ、１０．８ｍｍｏｌ）のジクロロメタン（２００ｍＬ）溶液を０℃に冷却し、ジクロロ酢酸（１１．０ｇ、８６．２ｍｍｏｌ）及びボラン－ピリジン錯体（７．９３ｇ、８６．２ｍｍｏｌ）を加え、室温で１６時間攪拌した。反応混合物に炭酸水素ナトリウム水溶液を加え、ジクロロメタンで２回抽出した。有機層を飽和食塩水で２回洗浄し、有機層を無水硫酸ナトリウムで乾燥させた。乾燥剤をろ去後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／石油エーテル）で精製して、表題化合物（３．００ｇ、６０％）を白色固体として得た。 Compound aa03:
Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(methoxyamino)methyl]benzoate

A solution of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-methoxyiminomethyl]benzoate (compound aa02, 5.00 g, 10.8 mmol) in dichloromethane (200 mL) was After cooling to 0° C., dichloroacetic acid (11.0 g, 86.2 mmol) and borane-pyridine complex (7.93 g, 86.2 mmol) were added and stirred at room temperature for 16 hours. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the residue was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.00 g, 60%) as a white solid.

メチル ３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［（メトキシアミノ）メチル］ベンゾエート（化合物ａａ０３、３．００ｇ、６．４４ｍｍｏｌ）をジクロロメタン（１００ｍＬ）に溶解させ、トリエチルアミン（９７５ｍｇ、９．６５ｍｍｏｌ）を加えた。さらに－１０℃で２－クロロ－２－（ヒドロキシミノ）酢酸エチル（９２３ｍｇ、６．７６ｍｍｏｌ）を滴下し、同温度で２０分間攪拌した。反応混合物に水を加え、ジクロロメタンで２回抽出した。有機層を飽和食塩水で２回洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤をろ去後、ろ液を減圧濃縮して、表題化合物（１．１ｇ、７０％）を白色固体として得た。 Compound aa04:
Methyl 5-[[(2-acetyloxyacetyl)-methoxyamino]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate

Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(methoxyamino)methyl]benzoate (compound aa03, 3.00 g, 6.44 mmol) was dissolved in dichloromethane (100 mL), Triethylamine (975 mg, 9.65 mmol) was added. Furthermore, ethyl 2-chloro-2-(hydroxymino)acetate (923 mg, 6.76 mmol) was added dropwise at -10°C, and the mixture was stirred at the same temperature for 20 minutes. Water was added to the reaction mixture and extracted twice with dichloromethane. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the filtrate was concentrated under reduced pressure to give the title compound (1.1 g, 70%) as a white solid.

メチル ５－［［（２－アセチルオキシアセチル）－メトキシアミノ］メチル］－３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）ベンゾエート（化合物ａａ０４、２．２０ｇ、３．８９ｍｍｏｌ）をメタノール（１００ｍＬ）に溶解させ、炭酸カリウム（５３６ｍｇ、３．８８ｍｍｏｌ）を０℃で加え、同温度で２０分間攪拌した。反応混合物に塩化アンモニウム水溶液を加え、ジクロロメタンで２回抽出した。有機層を飽和食塩水で２回洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤をろ去後、減圧濃縮して、表題化合物（１．８０ｇ、８８％）を白色固体として得た。 Compound aa05:
Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[(2-hydroxyacetyl)-methoxyamino]methyl]benzoate

methyl 5-[[(2-acetyloxyacetyl)-methoxyamino]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (compound aa04, 2.20 g, 3.89 mmol) It was dissolved in methanol (100 mL), potassium carbonate (536 mg, 3.88 mmol) was added at 0° C., and the mixture was stirred at the same temperature for 20 minutes. An aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the residue was concentrated under reduced pressure to give the title compound (1.80 g, 88%) as a white solid.

２－メチル－プロパン－２－オール（４．３ｇ、５８．１ｍｍｏｌ）をジクロロメタン（１００ｍＬ）に溶解させ、－５℃でイソシアン酸クロロスルホニル（８．１５ｇ、５８．５ｍｍｏｌ）を加え、同温度で３０分間攪拌した。さらに、トリエチルアミン（１７．４ｇ、１７２ｍｍｏｌ）及び２Ｍメチルアミン ジクロロメタン溶液（３０ｍＬ）を加え、室温で３時間攪拌した。反応混合物を１Ｍ塩酸及び飽和食塩水で洗浄し、有機層を無水硫酸ナトリウムで乾燥させた。乾燥剤をろ去後、ろ液を減圧濃縮して、表題化合物（４．０ｇ、３３％）を白色固体として得た。 Compound aa06:
tert-butyl N-(methylsulfamoyl) carbamate

2-Methyl-propan-2-ol (4.3 g, 58.1 mmol) was dissolved in dichloromethane (100 mL), chlorosulfonyl isocyanate (8.15 g, 58.5 mmol) was added at -5°C, and the mixture was stirred at the same temperature. Stirred for 30 minutes. Furthermore, triethylamine (17.4 g, 172 mmol) and 2M methylamine dichloromethane solution (30 mL) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with 1M hydrochloric acid and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the filtrate was concentrated under reduced pressure to give the title compound (4.0 g, 33%) as a white solid.

メチル ３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［（２－ヒドロキシアセチル）－メトキシアミノ］メチル］ベンゾエート（化合物ａａ０５、１．８０ｇ、３．４３ｍｍｏｌ）を無水ＴＨＦ（５０ｍＬ）に溶解させ、トリフェニルホスフィン（１．３５ｇ、５．１５ｍｍｏｌ）及びｔｅｒｔ－ブチル Ｎ－（メチルスルファモイル）カルバメート（化合物ａａ０６、８６５ｍｇ、４．１１ｍｍｏｌ）を加えた。さらに０℃でアゾジカルボン酸ジイソプロピル（１．０４ｇ、５．１５ｍｍｏｌ）を加え、室温で２時間攪拌した。反応混合物に水を加え、酢酸エチルで３回抽出した。有機層を飽和食塩水で３回洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤をろ去後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（石油エーテル／酢酸エチル）で精製して、表題化合物（１．５０ｇ、６１％）を白色固体として得た。 Compound aa07:
Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[methoxy-[2-[(2-methylpropan-2-yl)oxycarbonyl-(methylsulfamoyl)amino] Acetyl] amino] methyl] benzoate

Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[(2-hydroxyacetyl)-methoxyamino]methyl]benzoate (compound aa05, 1.80 g, 3.43 mmol) was added anhydrous Dissolve in THF (50 mL) and add triphenylphosphine (1.35 g, 5.15 mmol) and tert-butyl N-(methylsulfamoyl)carbamate (compound aa06, 865 mg, 4.11 mmol). Furthermore, diisopropyl azodicarboxylate (1.04 g, 5.15 mmol) was added at 0° C. and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layer was washed with saturated brine three times and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the residue was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (1.50 g, 61%) as a white solid.

メチル ３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［メトキシ－［２－［（２－メチルプロパン－２－イル）オキシカルボニル－（メチルスルファモイル）アミノ］アセチル］アミノ］メチル］ベンゾエート（化合物ａａ０７、１．５０ｇ、２．０９ｍｍｏｌ）のＴＨＦ（５０ｍＬ）溶液を０℃に冷却し、１Ｍ水酸化リチウム水溶液（２０．９ｍＬ、２０．９ｍｍｏｌ）を加え、室温で１６時間攪拌した。反応混合物に１Ｍ塩酸を加えてｐＨ４に調整し、酢酸エチルで２回抽出した。有機層を飽和食塩水で２回洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤をろ去後、減圧濃縮し、得られた残渣を逆相カラムクロマトグラフィー（０．５％トリフルオロ酢酸水溶液／０．５％トリフルオロ酢酸アセトニトリル溶液）で精製して、表題化合物（０．８０ｇ、５４％）を白色固体として得た。 Compound aa08:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[methoxy-[2-[(2-methylpropan-2-yl)oxycarbonyl-(methylsulfamoyl)amino]acetyl ]amino]methyl]benzoic acid

Methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[methoxy-[2-[(2-methylpropan-2-yl)oxycarbonyl-(methylsulfamoyl)amino] A solution of acetyl]amino]methyl]benzoate (compound aa07, 1.50 g, 2.09 mmol) in THF (50 mL) was cooled to 0° C. and 1M aqueous lithium hydroxide (20.9 mL, 20.9 mmol) was added, and the mixture was brought to room temperature. and stirred for 16 hours. The reaction mixture was adjusted to pH 4 by adding 1M hydrochloric acid and extracted twice with ethyl acetate. The organic layer was washed twice with saturated brine and dried over anhydrous sodium sulfate. After removing the drying agent by filtration and concentrating under reduced pressure, the resulting residue was purified by reverse phase column chromatography (0.5% trifluoroacetic acid aqueous solution/0.5% trifluoroacetic acid acetonitrile solution) to give the title compound (0 .80 g, 54%) as a white solid.

３，４－ジフルオロ－２－（２－フルオロ－４－ヨードアニリノ）－５－［［メトキシ－［２－［（２－メチルプロパン－２－イル）オキシカルボニル－（メチルスルファモイル）アミノ］アセチル］アミノ］メチル］安息香酸（化合物ａａ０８、８０ｍｇ、０．１１４ｍｍｏｌ）の無水ＤＭＦ溶液（０．６ｍＬ）にＥＤＣ・ＨＣｌ（３３ｍｇ）、３，４－ジヒドロ－３－ヒドロキシ－４－オキソ－１，２，３－ベンゾトリアジン（２８ｍｇ）、２－アミノオキシエタノール（２５μＬ）及びＤＩＰＥＡ（０．１０ｍＬ）を加え、室温で３時間攪拌した。反応混合物を逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（４９ｍｇ、５６％）を無色液体として得た。
ＬＣＭＳ ｍ／ｚ： ７６２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： ０．８９分（分析条件Ｃ） Compound aa09:
tert-butyl N-[2-[[2,3-difluoro-4-(2-fluoro-4-iodoanilino)-5-(2-hydroxyethoxycarbamoyl)phenyl]methyl-methoxyamino]-2-oxoethyl]- N-(methylsulfamoyl) carbamate

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[methoxy-[2-[(2-methylpropan-2-yl)oxycarbonyl-(methylsulfamoyl)amino]acetyl ]amino]methyl]benzoic acid (Compound aa08, 80 mg, 0.114 mmol) in anhydrous DMF solution (0.6 mL) was added EDC.HCl (33 mg), 3,4-dihydro-3-hydroxy-4-oxo-1, 2,3-Benzotriazine (28 mg), 2-aminooxyethanol (25 μL) and DIPEA (0.10 mL) were added and stirred at room temperature for 3 hours. The reaction mixture was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (49 mg, 56%) as a colorless liquid.
LCMS m/z: 762 [M+H] ⁺
HPLC retention time: 0.89 minutes (analysis condition C)

ｔｅｒｔ－ブチル Ｎ－［２－［［２，３－ジフルオロ－４－（２－フルオロ－４－ヨードアニリノ）－５－（２－ヒドロキシエトキシカルバモイル）フェニル］メチル－メトキシアミノ］－２－オキソエチル］－Ｎ－（メチルスルファモイル）カルバメート（化合物ａａ０９、８４．９ｍｇ、１．１１ｍｍｏｌ）を４Ｍ塩化水素１，４－ジオキサン溶液（１．７ｍＬ）に溶解させ、室温で攪拌した。反応混合物を濃縮した後、逆相カラムクロマトグラフィー（０．１％ギ酸水溶液／０．１％ギ酸アセトニトリル溶液）で精製して、表題化合物（４９ｍｇ、６６％）を白色固体として得た。
ＬＣＭＳ ｍ／ｚ： ６６２［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．００分（分析条件Ａ） Compound AA-1:
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[[methoxy-[2-(methylsulfamoylamino)acetyl]amino]methyl]benzamide

tert-butyl N-[2-[[2,3-difluoro-4-(2-fluoro-4-iodoanilino)-5-(2-hydroxyethoxycarbamoyl)phenyl]methyl-methoxyamino]-2-oxoethyl]- N-(Methylsulfamoyl)carbamate (compound aa09, 84.9 mg, 1.11 mmol) was dissolved in 4 M hydrogen chloride solution in 1,4-dioxane (1.7 mL) and stirred at room temperature. The reaction mixture was concentrated and then purified by reverse-phase column chromatography (0.1% formic acid aqueous solution/0.1% formic acid acetonitrile solution) to give the title compound (49 mg, 66%) as a white solid.
LCMS m/z: 662 [M+H] ⁺
HPLC retention time: 1.00 minutes (analysis condition A)

３－［（２－フルオロ－３－ニトロフェニル）メチル］－４－メチル－７－ピリミジン－２－イルオキシクロメン－２－オン（２．５０ｇ、５．８４ｍｍｏｌ）の無水ＴＨＦ（８０ｍＬ）溶液に窒素雰囲気下、－７８℃で１Ｍリチウムビス（トリメチルシリル）アミドのＴＨＦ溶液（６１．４ｍＬ）を加え、０℃で３時間攪拌した。二酸化炭素を反応容器内に加え、反応混合物を二酸化炭素雰囲気下、－２０℃～０℃でさらに６０分間攪拌した。反応混合物に水を加え、酢酸エチルで３回抽出し、有機層を無水硫酸ナトリウムで乾燥させた。乾燥剤をろ去後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール）で精製して、表題化合物（２．０ｇ、７４％）を黄色固体として得た。 Compound aa19:
2-[3-[(2-fluoro-3-nitrophenyl)methyl]-2-oxo-7-pyrimidin-2-yloxychromen-4-yl]acetic acid

To a solution of 3-[(2-fluoro-3-nitrophenyl)methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one (2.50 g, 5.84 mmol) in anhydrous THF (80 mL) Under nitrogen atmosphere, 1M lithium bis(trimethylsilyl)amide in THF (61.4 mL) was added at -78°C, and the mixture was stirred at 0°C for 3 hours. Carbon dioxide was added into the reaction vessel and the reaction mixture was stirred at −20° C. to 0° C. for an additional 60 minutes under a carbon dioxide atmosphere. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate three times, and the organic layer was dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the residue was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (2.0 g, 74%) as a yellow solid.

２－［３－［（２－フルオロ－３－ニトロフェニル）メチル］－２－オキソ－７－ピリミジン－２－イルオキシクロメン－４－イル］酢酸（化合物ａａ１９、１００ｍｇ、０．２１ｍｍｏｌ）をジクロロメタン（１０ｍＬ）及び無水ＤＭＦ（１ｍＬ）に溶解させ、ＨＡＴＵ（９１．２ｍｇ、０．２４ｍｍｏｌ）及びＤＩＰＥＡ（５６．８ｍｇ、０．４４ｍｍｏｌ）を加え、室温で１０分間攪拌した。反応混合物に２－アミノオキシエタノールのジクロロメタン溶液を加え、さらに２時間攪拌した。反応混合物に水を加え、ジクロロメタンで３回抽出し、有機層を無水硫酸ナトリウムで乾燥させた。乾燥剤をろ去後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール）で精製して、表題化合物（７０ｍｇ、５９％）を黄色固体として得た。 Compound aa20:
2-[3-[(2-fluoro-3-nitrophenyl)methyl]-2-oxo-7-pyrimidin-2-yloxychromen-4-yl]-N-(2-hydroxyethoxy)acetamide

2-[3-[(2-Fluoro-3-nitrophenyl)methyl]-2-oxo-7-pyrimidin-2-yloxychromen-4-yl]acetic acid (compound aa19, 100 mg, 0.21 mmol) in dichloromethane (10 mL) and anhydrous DMF (1 mL), HATU (91.2 mg, 0.24 mmol) and DIPEA (56.8 mg, 0.44 mmol) were added and stirred at room temperature for 10 minutes. A dichloromethane solution of 2-aminooxyethanol was added to the reaction mixture, and the mixture was further stirred for 2 hours. Water was added to the reaction mixture, extracted three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the residue was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (70 mg, 59%) as a yellow solid.

２－［３－［（２－フルオロ－３－ニトロフェニル）メチル］－２－オキソ－７－ピリミジン－２－イルオキシクロメン－４－イル］－Ｎ－（２－ヒドロキシエトキシ）アセトアミド（化合物ａａ２０、２０ｍｇ、０．０４ｍｍｏｌ）を２，２，２－トリフルオロエタノール（５ｍＬ）に溶解させ、パラジウム／炭素（５ｍｇ）を加え、水素雰囲気下、１６時間攪拌した。反応混合物をろ過し、ろ液を濃縮して、表題化合物を固体として得た。 Compound aa21:
2-[3-[(3-amino-2-fluorophenyl)methyl]-2-oxo-7-pyrimidin-2-yloxychromen-4-yl]-N-(2-hydroxyethoxy)acetamide

2-[3-[(2-fluoro-3-nitrophenyl)methyl]-2-oxo-7-pyrimidin-2-yloxychromen-4-yl]-N-(2-hydroxyethoxy)acetamide (compound aa20 , 20 mg, 0.04 mmol) was dissolved in 2,2,2-trifluoroethanol (5 mL), palladium/carbon (5 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to give the title compound as a solid.

２－［３－［（３－アミノ－２－フルオロフェニル）メチル］－２－オキソ－７－ピリミジン－２－イルオキシクロメン－４－イル］－Ｎ－（２－ヒドロキシエトキシ）アセトアミド（化合物ａａ１２、９５ｍｇ、０．２０ｍｍｏｌ）を無水ＤＭＦ（１０ｍＬ）に溶解させ、ピリジン（３２ｍｇ、０．４０ｍｍｏｌ）及び４－ジメチルアミノピリジン（２．４ｍｇ、０．０２ｍｍｏｌ）を加えた。さらにメチルスルファモイルクロリド（５２ｍｇ、０．３２ｍｍｏｌ）の無水ＤＭＦ（５ｍＬ）溶液を－４０℃で１０分かけて加え、０℃で４時間攪拌した。反応混合物に１Ｍ塩酸を加え、酢酸エチルで抽出した。有機層を炭酸水素ナトリウム水溶液及び食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。乾燥剤をろ去後、減圧濃縮し、得られた残渣を薄層クロマトグラフィーで精製して、表題化合物（１０ｍｇ、９％）を白色固体として得た。
ＬＣＭＳ ｍ／ｚ： ５７４［Ｍ＋Ｈ］^＋
ＨＰＬＣ保持時間： １．０６分（分析条件Ａ） Compound AA-2:
2-[3-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-2-oxo-7-pyrimidin-2-yloxychromen-4-yl]-N-(2-hydroxy ethoxy)acetamide

2-[3-[(3-amino-2-fluorophenyl)methyl]-2-oxo-7-pyrimidin-2-yloxychromen-4-yl]-N-(2-hydroxyethoxy)acetamide (compound aa12 , 95 mg, 0.20 mmol) was dissolved in anhydrous DMF (10 mL) and pyridine (32 mg, 0.40 mmol) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol) were added. Further, a solution of methylsulfamoyl chloride (52 mg, 0.32 mmol) in anhydrous DMF (5 mL) was added at −40° C. over 10 minutes and stirred at 0° C. for 4 hours. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the residue was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography to give the title compound (10 mg, 9%) as a white solid.
LCMS m/z: 574 [M+H] ⁺
HPLC retention time: 1.06 minutes (Analysis condition A)

[Test example]
In the following test examples, the compounds described in the above production examples are represented by the compound numbers used in the above production examples. In addition, ref-1 is available from Bioorg. Med. Chem. Lett. 2008, vol. 18, no. 24, p. 6501-6504 compound 34, that is, the compound represented by the following formula (A). In addition, ref-2 is available from Bioorg. Med. Chem. Lett. 2013, vol. 23, no. 8, p. 2384-2390, that is, the compound represented by the following formula (B). In addition, ref-3 and ref-4 were obtained from ChemMedChem. 2015, vol. 10, no. 12, p. 2004-2013 Compound 9 and Compound 10, ie compounds represented by the following formulas (C) and (D). In addition, ref-5 is available from ACS Medchem. Lett. 2014, vol. 5, no. 4, p. 309-314, ie, the compound represented by the following formula (E).

ref-1:
N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide (PD0325901)

ref-2:
4-fluoro-2-(2-fluoro-4-iodoanilino)-6-[3-(methylsulfamoylamino)phenoxy]benzamide

ref-3:
3-(2-fluoro-4-iodoanilino)-5-[3-(propan-2-ylsulfonylamino)phenoxy]pyridine-4-carboxamide

ref-4:
3-[3-(Cyclopropylsulfonylamino)phenoxy]-5-(2-fluoro-4-iodoanilino)pyridine-4-carboxamide

ref-5:
3-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one (CH5126766)

(Test example 1)
Effects on the interaction of RAF1 and MEK1
Effects of the compounds shown in FIGS. 4 to 11 on the interaction between RAF1 and MEK1 were investigated using Biacore 8K (GE Healthcare) as follows.

RAF1 (Carna Biosciences) fused with a GST tag was immobilized on the surface of Sensor Chip CM5 (GE Healthcare) using Anti-GST Antibody (GE Healthcare). Thereafter, a running buffer (blank), a 40 nM MEK1 solution, or a mixed solution of 40 nM MEK1 and 3 μM test compound was flowed over the surface of the sensor chip for 120 seconds, and then the running buffer was flowed. As MEK1, MEK1 Recombinant Human protein, Inactive (Thermo Fisher Scientific) was used. As a running buffer, PBS ₍ Sigma -Aldrich), and a running buffer was also used for the preparation of the sample solution. Measurements were made at 15°C. Both RAF1 and MEK1 were dephosphorylated with Lambda Protein Phosphatase (New England Biolabs) before use, and MEK1 was purified by size exclusion chromatography.

The resulting sensorgram (a graph showing the temporal change in the amount of MEK1 bound to immobilized RAF1) was subjected to double-referencing with Biacore Insight Evaluation Software, and further, RAF1 was analyzed using TIBCO Spotfire. Sensorgrams were normalized by immobilized amount. The normalized sensorgrams are shown in Figures 4-11. Above each sensorgram, an experiment ID, a Biacore channel number, and a compound number are written in order (where "no compound" indicates that there is no test compound). In each sensorgram, the horizontal axis (X-axis) represents the time (seconds) after the start of addition of the sample solution, and the vertical axis (Y-axis) represents the normalized MEK1 binding amount.

(Test example 2)
Effect on phosphorylation of MEK and ERK
Western blotting was performed as follows to determine how the compounds (ref-5 and compound A-1) shown in FIG. 12 affect intracellular phosphorylation of MEK and ERK.

A549 cells were seeded in a 12-well plate at 400,000 cells per well, and placed in a 5% carbon dioxide gas incubator at 37°C using Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (manufactured by Sigma). cultured. The next day, the test compound (0.3 μM ref-5 or 0.05 μM 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. Extracted proteins were separated by SDS-PAGE and transferred to PVDF membranes. After blocking, the PVDF membrane was treated with Phospho-MEK1/2 (Ser217/221) antibody, MEK1/2 antibody, Phospho-ERK1/2 (Thr202/Tyr204) antibody, or ERK1/2 antibody (both manufactured by Cell Signaling Technology). processed. After washing the primary antibody, it was treated with an HRP-labeled secondary antibody (manufactured by Cell Signaling Technology). After washing, signals were detected by a chemiluminescence method using Chemi-Lumi One Super (manufactured by Nacalai). FIG. 12 is an electropherogram showing the results of Western blotting. In FIG. 12, “p-MEK” and “p-ERK” represent phosphorylated MEK and phosphorylated ERK, respectively.

(Test example 3)
MEK1 inhibitory activity
The MEK1 inhibitory activity of the compounds listed in Table 3 below was evaluated by fluorescence polarization as follows.

A test compound, CRAF (manufactured by Thermo Fisher), MEK1 (manufactured by Thermo Fisher) and ERK2 (manufactured by Carna Biosciences) were mixed in a buffer containing ATP and allowed to react at 30° C. for 60 minutes. Then, FAM-labeled Erktide (manufactured by Molecular Devices) was added and reacted at 30° C. for 45 minutes. Furthermore, IMAP (registered trademark) Progressive Binding Reagent (manufactured by Molecular Devices) was added and reacted at room temperature for 15 minutes. After the reaction, fluorescence polarization was measured with a fluorescence plate reader, and the 50% inhibitory concentration ( _IC50 ) was calculated based on the inhibition rate against the control group containing no test compound. Table 3 shows the results.

(Test example 4)
BRAF inhibitory activity
The BRAF inhibitory activity of the compounds listed in Table 3 below was evaluated by the time-resolved fluorescence-fluorescence resonance energy transfer method as follows.

A test compound, BRAF (manufactured by Eurofins) and MEK1 (manufactured by Thermo Fisher) were mixed in a buffer containing ATP and allowed to react at 30° C. for 90 minutes. Then, LANCE (registered trademark) Eu-Phospho-MEK1/2 (Ser217/221) antibody (manufactured by PerkinElmer) was added and allowed to react at room temperature for 60 minutes. After the reaction, fluorescence resonance energy transfer was measured with a fluorescence plate reader, and the 50% inhibitory concentration ( _IC50 ) was calculated based on the inhibition rate against the control group containing no test compound. Table 3 shows the results.

(Test Example 5)
Cell growth inhibitory activity
The cell growth inhibitory activity of the compounds listed in Table 3 below was evaluated by measuring the ATP level in viable cells as follows.

After serially diluting the test compound with DMSO, it was diluted 25-fold with Ca ²⁺ and Mg ²⁺ -free phosphate-buffered saline, and this was dispensed into a 96-well plate at 5 μL per well. A cell suspension of human lung cancer cell lines A549, Calu-6 or NCI-H2122 (all obtained from ATCC) was added with 10% fetal bovine serum (manufactured by Sigma) in the following medium to obtain the following cell numbers. was prepared as follows. 95 μL of this cell suspension was dispensed per well to the plate to which the test compound was added, and cultured in a 37° C. 5% carbon dioxide gas incubator. After 4 days, 80 μL of CellTiter-Glo® (Promega) was added to each well and bioluminescence was measured with a fluorescence plate reader. A 50% inhibitory concentration (IC ₅₀ ) was calculated based on the inhibition rate against a control group containing no test compound. Table 3 shows the results.
A549: Dulbecco's Modified Eagle Medium (manufactured by Sigma); 2000 cells/95 μL
Calu-6: Eagle minimal essential medium (manufactured by Sigma); 4000 cells/95 μL
NCI-H2122: RPMI-1640 medium (manufactured by Sigma); 2000 cells/95 μL

(Test example 6)
Human liver microsome metabolic stability
The compounds shown in Table 3 below were tested for metabolic stability in human liver microsomes using Biomek 3000 (Beckman Coulter) as follows.

400 μL of 1 mg/mL human liver microsomes (XENOTECH)/0.1 M potassium phosphate buffer (pH 7.4) was dispensed into a 96-well plate per well. A DMSO solution (4 μL) of 200 μM test compound was then added and incubated until 37° C. was reached. A solution (200 μL) of 2 mM NADPH (ORIENTAL YEAST)/0.1 M potassium phosphate buffer (pH 7.4) incubated at 37° C. was added to this reaction solution (200 μL). After 0, 5, 15 or 30 minutes of addition, the reaction solution (50 μL) was added to acetonitrile (100 μL) to stop the metabolic reaction. A 1 μM warfarin aqueous solution (50 μL) was added as an internal standard to each reaction solution in which the metabolic reaction had been terminated. The reaction solution was filtered, followed by LC/MS/MS (LC: NEXERA manufactured by SHIMADZU; MS: 4000Qtrap manufactured by ABSciex; Column: Ascentis Express C18 HPLC column (5 cm × 2.1 mm, 2.7 µm); ionization method: electrospray ionization method. ) was analyzed. From the resulting test compound/internal standard peak area ratio, the residual rate relative to the amount of the test compound at 0 minutes was calculated. Elimination rate constant (ke) was calculated from the incubation time and residual rate using the kinetic equation of the primary elimination process, and liver-specific clearance (CLint) was calculated using the following formula. Table 3 shows the results.
CLint (µL/min/mg) = ke (min ^-1 )/human liver microsome concentration (mg protein/µL)

(Test Example 7)
In vivo antitumor effect
The effect of compound A-1 on cancer cells with KRAS mutation was evaluated using tumor-bearing mice as follows.

Human lung cancer cell line Calu-6 with KRAS mutation was injected subcutaneously into the ventral region of nude mice (CAnN.Cg-Foxn1nu/CrlCrlj, female, 5 weeks old, Charles River Laboratories) with a 26G injection needle. Implanted into mice by injection. 17 days after transplantation when the tumor volume reached approximately 200 mm ³ , the mice were divided into 5 groups (8 mice per group) according to the dosage of the test compound, and administration of the test compound was started. Mice in group 4 (A-1 administration group) were given 0.0625 mg/kg and 0.25 mg each time using 10% DMSO/10% Cremophor EL/15% PEG400/15% HPCD as a vehicle. /kg, 1 mg/kg or 4 mg/kg of Compound A-1 was administered orally. The remaining one group (vehicle control group) of mice was orally administered with the solvent alone. The test compound or vehicle was administered once a day for 10 days.

Tumor volumes were measured at 20, 24 and 27 days post-implantation. The tumor volume was calculated according to the following formula after measuring the major axis and minor axis of the tumor using vernier calipers. The results are shown in FIG. FIG. 13 is a graph showing changes in tumor volume (mean±standard deviation) over time. The horizontal axis (X-axis) represents days post-implantation and the vertical axis (Y-axis) represents 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, RAF/MEK complex stabilizers, MEK inhibitors, pharmaceutical compositions, and pharmaceutical compositions for treating or preventing cell proliferative diseases of the present disclosure are useful for treating or preventing cell proliferative diseases, particularly It can be used for the treatment or prevention of cancer.

Claims (10)

A pharmaceutical composition for treating or preventing a cell proliferative disease, comprising a compound represented by the following general formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt: A pharmaceutical composition containing it as an active ingredient.

[In the formula,
Ring A is represented by the following general formula (2), (3), (4) or (5) (wherein the bonds marked with *, ** and *** are -NH-, -CONH- and -CH ₂ -.) is a group represented by

X ₁ , X ₂ , X ₃ , X ₄ , X ₅ and X ₆ are each independently -CR ₂ = or -N=;
R ₂ is a hydrogen atom, a halogen atom or a C1-6 alkyl group,
R ₁ is -S(=O) ₂ -NH-R ₈ or -S(=O) ₂ -R ₈ ;
R ₈ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group is substituted with a halogen atom, a hydroxy group, a C1-6 alkoxy group, a C3-6 cycloalkyl group or a C3-6 heterocycloalkyl group; ), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group,
R ₃ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3 ~6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group) or a C1-6 alkoxy group (the C1-6 alkoxy group is substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group ) and
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 hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group or a C1-6 alkylthio group, or R ₆ and R ₄ together with the carbon atom to which they are attached form an unsaturated hetero 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 general formula (2) or (4),
R ₈ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group),
R ₃ is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group);
R ₆ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, R ₄ is a halogen atom or a cyclopropyl group,
_R7 is a hydrogen atom or a methyl group,
A pharmaceutical composition according to claim 1 . The pharmaceutical composition according to claim 1, wherein the compound represented by general formula (1) is a compound represented by general formula (6) below.

[In the formula,
X ₁ , X ₂ , X ₃ and X ₄ are each independently -CR ₂ = or -N=;
R ₂ is a hydrogen atom, a halogen atom or a C1-6 alkyl group,
R ₁ is -S(=O) ₂ -NH-R ₈ or -S(=O) ₂ -R ₈ ;
R ₈ is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group),
R ₃ is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 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, and R ₄ is a halogen atom or a cyclopropyl group. ] R ₂ is a hydrogen atom or a halogen atom,
R ₈ is a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 The cycloalkyl group may be substituted with a C1-6 alkyl group.)
R ₃ is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group);
_R5 is a halogen atom,
R ₆ is a hydrogen atom and R ₄ is a halogen atom or a cyclopropyl group,
The pharmaceutical composition according to any one of claims 1-3. A pharmaceutical composition for treating or preventing a cell proliferative disease,
N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide ,
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide,
N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino ) benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2- methylpropan-2-yl)oxy]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide ,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxy ethoxy)benzamide,
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide,
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide,
4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
N-cyclopropyl-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxo pyridine-3-carboxamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]- N-methoxybenzamide,
3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide,
2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide,
2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide ,
3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl ] benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]oxybenzamide,
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine -3-carboxamide,
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-N-[(2-methylpropane -2-yl)oxy]-6-oxopyridine-3-carboxamide,
5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide ,
5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide,
5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide ,
5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide ,
5-fluoro-4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]-6-oxopyridine-3-carboxamide ,
4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide , and 1-[[2-(ethylsulfonylamino)-3-fluoropyridin-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide A pharmaceutical composition containing, as an active ingredient, a compound selected from or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt. A pharmaceutical composition for treating or preventing a cell proliferative disease,
N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide ,
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide,
N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino ) benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2- methylpropan-2-yl)oxy]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide ,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxy ethoxy)benzamide,
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide,
5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamido)phenyl]methyl]benzamide,
4-fluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, and N-cyclopropyl-2 from -(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide A pharmaceutical composition containing a selected compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt as an active ingredient. A pharmaceutical composition for treating or preventing a cell proliferative disease,
N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide , and 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide A pharmaceutical composition containing a selected compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt as an active ingredient. A pharmaceutical composition for treating or preventing a cell proliferative disease,
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide or its pharmaceutical A pharmaceutical composition containing, as an active ingredient, an above-acceptable salt or a pharmaceutically acceptable solvate of said compound or salt. A pharmaceutical composition for treating or preventing a cell proliferative disease,
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide or sodium thereof A pharmaceutical composition containing a salt or potassium salt or a pharmaceutically acceptable solvate of said compound or salt as an active ingredient. The pharmaceutical composition according to any one of claims 1 to 9, wherein said cell proliferative disease is cancer.

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