JP2020023441A - Novel compound useful for egfr inhibition and tumor treatment - Google Patents

Novel compound useful for egfr inhibition and tumor treatment Download PDF

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JP2020023441A
JP2020023441A JP2016215520A JP2016215520A JP2020023441A JP 2020023441 A JP2020023441 A JP 2020023441A JP 2016215520 A JP2016215520 A JP 2016215520A JP 2016215520 A JP2016215520 A JP 2016215520A JP 2020023441 A JP2020023441 A JP 2020023441A
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cancer
tumor
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彰夫 王子田
Akio Ojida
彰夫 王子田
眞弓 小野
Mayumi Ono
眞弓 小野
公佑 渡
Kosuke Watari
公佑 渡
直哉 進藤
Naoya Shindo
直哉 進藤
大和 渕田
Yamato Fuchida
大和 渕田
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Kyushu University NUC
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

To develop a covalent drug which is less in concern of side effect and safe by searching a reaction group having milder reactivity and changing to a Michael acceptor, and designing an agent molecule by using the same.SOLUTION: The invention relates to for example a compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, or the like.SELECTED DRAWING: None

Description

本発明は、EGFR阻害及び腫瘍治療に有用な新規化合物に関する。詳しくは、EGFRに対するコバレント阻害剤として標的特異性が向上した新規化合物に関する。   The present invention relates to novel compounds useful for EGFR inhibition and tumor treatment. More specifically, the present invention relates to a novel compound having improved target specificity as a covalent inhibitor for EGFR.

タンパク質機能を共有結合形成により不可逆的に阻害するコバレントドラッグは、長い創薬研究の中でこれまでに数多く開発されている。コバレントドラッグの最も代表的なものとしては、アスピリンやβ?ラクタム系抗生物質などが知られているが、その他にも様々な受容体や酵素を標的とした化合物が薬として開発されており、幅広い疾患領域で用いられている。コバレントドラッグは、通常の分子間相互作用に基づいた可逆的阻害剤とは異なり、共有結合の形成により持続的かつ強力な阻害能の発現が可能となるなどの優れた利点を有する。これまでコバレントドラッグの開発は、非特異的反応（オフターゲットラベリング）に基づく副作用の懸念から、製薬企業では一般に避けられる傾向にあった。しかしながら、近年では、上記の利点に着目したコバレントドラッグ開発が、主にがん（腫瘍）に対する創薬研究において積極的に進められている。   Many covalent drugs that irreversibly inhibit protein function by forming covalent bonds have been developed in many drug discovery studies. Aspirin and β-lactam antibiotics are known as the most representative of covalent drugs, but other compounds targeting various receptors and enzymes have been developed as drugs, and Used in disease areas. Covalent drugs, unlike ordinary reversible inhibitors based on molecular interactions, have excellent advantages such as formation of a covalent bond, which enables sustained and potent inhibitory expression. Until now, the development of covalent drugs has generally tended to be avoided by pharmaceutical companies due to concerns about side effects based on non-specific reactions (off-target labeling). However, in recent years, development of covalent drugs focusing on the above advantages has been actively promoted mainly in drug discovery research for cancer (tumor).

コバレントドラッグに用いる反応性基として最も重要な特性は、非特異的な反応を起こさない制御された穏やかな反応性である。現在、この制御された穏やかな反応性を有するTCI (targeted covalent inhibitor)の開発が盛んであるが、アファチニブも含めて、これらのTCIのほとんどは、タンパク質中のシステインに対する反応基としてマイケルアクセプター（α,β-不飽和ケトン）を有している。しかしながら、このマイケルアクセプターは、反応性が高く、他のタンパク質と非特異的な反応を起こしやすい（すなわち副作用の危険性が高い）事が報告されている（非特許文献１）。   The most important property as a reactive group used for a covalent drug is a controlled mild reactivity that does not cause nonspecific reaction. At present, development of TCI (targeted covalent inhibitor) having this controlled mild reactivity is active. Most of these TCIs, including afatinib, have a Michael acceptor (reactive group) as a reactive group for cysteine in a protein. α, β-unsaturated ketone). However, it has been reported that this Michael acceptor has high reactivity and is likely to cause non-specific reactions with other proteins (that is, high risk of side effects) (Non-Patent Document 1).

Cravatt, B. F. et al., Nature Chem. Biol., vol. 10, p. 760-767, 2014Cravatt, B.F.et al., Nature Chem. Biol., Vol. 10, p. 760-767, 2014

このような状況下において、マイケルアクセプターに変わる、より穏やかな反応性を有する反応基を探索し、これを用いて薬剤分子をデザインすることで、副作用の懸念の少ない安全なコバレントドラッグの開発が望まれていた。   Under such circumstances, by searching for a reactive group having milder reactivity instead of Michael acceptor and designing a drug molecule using this, the development of a safe covalent drug with less concern for side effects will be possible. Was wanted.

本発明は、上記状況を考慮してなされたもので、以下に示す、等を提供するものである。
（１）下記式(I)： The present invention has been made in view of the above situation, and provides the following.
(1) The following formula (I):

〔式(I)中、
L1はリンカー部を表し、
R1は、水素原子、又は任意に置換されていてもよい炭化水素基を表し、場合によりL1の一部と環構造を形成していてもよく、
R2及びR3は、それぞれ独立して、任意に置換されていてもよい任意の構造の有機基を表し、
m及びnは、それぞれ独立して、０〜２の整数を表す。〕
で示される化合物、又はその薬理学的に許容し得る塩。
（２）前記リンカー部は、単結合、又は、-RL1-NH-若しくは-RL1-CO-NH-（ここで、RL1は任意に置換されていてもよい任意の構造の有機基を表す。）を表す、前記（１）記載の化合物、又はその薬理学的に許容し得る塩。 (In the formula (I),
L 1 represents a linker moiety,
R 1 represents a hydrogen atom or a hydrocarbon group which may be optionally substituted, and may optionally form a ring structure with a part of L 1 ;
R 2 and R 3 each independently represent an organic group having any structure that may be optionally substituted,
m and n each independently represent an integer of 0 to 2. ]
Or a pharmacologically acceptable salt thereof.
(2) The linker moiety is a single bond or -RL 1 -NH- or -RL 1 -CO-NH- (where R L1 is an organic group having any structure that may be optionally substituted. Or a pharmacologically acceptable salt thereof.

（３）下記式(II)： (3) Formula (II) below:

〔式(II)中、L2はリンカー部を表し、
R4は、水素原子、又は任意に置換されていてもよい炭化水素基を表し、場合によりL2の一部と環構造を形成していてもよく、
R5は、それぞれ独立して、任意に置換されていてもよい任意の構造の有機基を表し、
pは、０〜２の整数を表す。〕
で示される化合物、又はその薬理学的に許容し得る塩。
（４）前記リンカー部は、単結合、又は、-RL2-NH-（ここで、RL2は任意に置換されていてもよい任意の構造の有機基を表す。）を表す、前記（３）記載の化合物、又はその薬理学的に許容し得る塩。 (In the formula (II), L 2 represents a linker moiety,
R 4 represents a hydrogen atom or a hydrocarbon group which may be optionally substituted, and optionally may form a ring structure with a part of L 2 ;
R 5 each independently represents an organic group having any structure that may be optionally substituted,
p represents an integer of 0 to 2. ]
Or a pharmacologically acceptable salt thereof.
(4) the linker portion is a single bond, or, -R L2 -NH- (wherein, R L2 represents. The organic group of any of the structures which may be optionally substituted) representative of the (3 )) Or a pharmacologically acceptable salt thereof.

（５）式(I)で示される化合物が、下記構造式で示される化合物からなる群から選ばれる少なくとも１つである、前記（１）又は（２）記載の化合物、又はその薬理学的に許容し得る塩。 (5) The compound according to the above (1) or (2), wherein the compound represented by the formula (I) is at least one selected from the group consisting of compounds represented by the following structural formulas, or pharmacologically: Acceptable salts.

（６）式(II)で示される化合物が、下記構造式で示される化合物からなる群から選ばれる少なくとも１つである、前記（３）又は（４）記載の化合物、又はその薬理学的に許容し得る塩。 (6) The compound according to the above (3) or (4), wherein the compound represented by the formula (II) is at least one selected from the group consisting of compounds represented by the following structural formulas, or pharmacologically thereof. Acceptable salts.

（７）前記（１）〜（６）のいずれか１つに記載の化合物、又はその薬理学的に許容し得る塩、あるいはそれらの水和物若しくは溶媒和物を有効成分として含む、医薬組成物又は試薬。
（８）腫瘍の治療用のものである、前記（７）記載の医薬組成物又は試薬。
（９）腫瘍が、肺がん、乳がん、前立腺がん、頭部がん、頸部がん、皮膚がん、卵巣がん、子宮内膜がん、甲状腺がん、結腸がん、直腸がん、食道がん、胃がん、腎臓がん、肝臓がん、膀胱がん、膵臓がん、脳腫瘍、脊髄腫瘍、血液がん、及び骨がんからなる群より選ばれる少なくとも１種である、前記（８）記載の医薬組成物又は試薬。 (7) A pharmaceutical composition comprising the compound according to any one of the above (1) to (6), or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. Object or reagent.
(8) The pharmaceutical composition or the reagent according to the above (7), which is used for treating a tumor.
(9) The tumor is lung cancer, breast cancer, prostate cancer, head cancer, neck cancer, skin cancer, ovarian cancer, endometrial cancer, thyroid cancer, colon cancer, rectal cancer, (8) being at least one selected from the group consisting of esophageal cancer, stomach cancer, kidney cancer, liver cancer, bladder cancer, pancreatic cancer, brain tumor, spinal cord tumor, blood cancer, and bone cancer. )) A pharmaceutical composition or reagent according to the above.

（１０）腫瘍が、非小細胞肺がんである、前記（８）又は（９）記載の医薬組成物又は試薬。
（１１）前記（１）〜（６）のいずれか１つに記載の化合物、又はその薬理学的に許容し得る塩、あるいはそれらの水和物若しくは溶媒和物を有効成分として含む、EGFR阻害剤。
（１２）コバレント阻害剤である、前記（１１）記載の阻害剤。
（１３）腫瘍の治療用の薬剤を製造するための前記（１）〜（６）のいずれか１つに記載の化合物、又はその薬理学的に許容し得る塩、あるいはそれらの水和物若しくは溶媒和物の使用。
（１４）腫瘍が、肺がん、乳がん、前立腺がん、頭部がん、頸部がん、皮膚がん、卵巣がん、子宮内膜がん、甲状腺がん、結腸がん、直腸がん、食道がん、胃がん、腎臓がん、肝臓がん、膀胱がん、膵臓がん、脳腫瘍、脊髄腫瘍、血液がん、及び骨がんからなる群より選ばれる少なくとも１種である、前記（１３）記載の使用。 (10) The pharmaceutical composition or the reagent according to (8) or (9), wherein the tumor is a non-small cell lung cancer.
(11) EGFR inhibition comprising the compound according to any one of the above (1) to (6), or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. Agent.
(12) The inhibitor according to (11), which is a covalent inhibitor.
(13) The compound according to any one of the above (1) to (6), or a pharmaceutically acceptable salt thereof, or a hydrate or a hydrate thereof, for producing a medicament for treating a tumor. Use of solvates.
(14) The tumor is lung cancer, breast cancer, prostate cancer, head cancer, neck cancer, skin cancer, ovarian cancer, endometrial cancer, thyroid cancer, colon cancer, rectal cancer, Said (13) which is at least one selected from the group consisting of esophageal cancer, stomach cancer, kidney cancer, liver cancer, bladder cancer, pancreatic cancer, brain tumor, spinal cord tumor, blood cancer, and bone cancer ) Described use.

（１５）腫瘍が、非小細胞肺がんである、前記（１３）又は（１４）記載の使用。
（１６）前記（１）〜（６）のいずれか１つに記載の化合物、又はその薬理学的に許容し得る塩、あるいはそれらの水和物若しくは溶媒和物を含む、腫瘍の治療用キット。
（１７）腫瘍が、肺がん、乳がん、前立腺がん、頭部がん、頸部がん、皮膚がん、卵巣がん、子宮内膜がん、甲状腺がん、結腸がん、直腸がん、食道がん、胃がん、腎臓がん、肝臓がん、膀胱がん、膵臓がん、脳腫瘍、脊髄腫瘍、血液がん、及び骨がんからなる群より選ばれる少なくとも１種である、前記（１６）記載のキット。
（１８）腫瘍が、非小細胞肺がんである、前記（１６）又は（１７）記載のキット。 (15) The use according to (13) or (14), wherein the tumor is a non-small cell lung cancer.
(16) A kit for treating a tumor, comprising the compound according to any one of the above (1) to (6), or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof. .
(17) If the tumor is lung cancer, breast cancer, prostate cancer, head cancer, neck cancer, skin cancer, ovarian cancer, endometrial cancer, thyroid cancer, colon cancer, rectal cancer, (16) which is at least one selected from the group consisting of esophageal cancer, gastric cancer, kidney cancer, liver cancer, bladder cancer, pancreatic cancer, brain tumor, spinal cord tumor, blood cancer, and bone cancer. ).
(18) The kit according to (16) or (17), wherein the tumor is a non-small cell lung cancer.

（１９）前記（１）〜（６）のいずれか１つに記載の化合物、又はその薬理学的に許容し得る塩、あるいはそれらの水和物若しくは溶媒和物を被験対象に投与することを特徴とする、腫瘍の治療方法。
（２０）腫瘍が、肺がん、乳がん、前立腺がん、頭部がん、頸部がん、皮膚がん、卵巣がん、子宮内膜がん、甲状腺がん、結腸がん、直腸がん、食道がん、胃がん、腎臓がん、肝臓がん、膀胱がん、膵臓がん、脳腫瘍、脊髄腫瘍、血液がん、及び骨がんからなる群より選ばれる少なくとも１種である、前記（１９）記載の方法。
（２１）腫瘍が、非小細胞肺がんである、前記（１９）又は（２０）記載の方法。 (19) administering the compound according to any one of the above (1) to (6), a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof to a subject. A method for treating a tumor, characterized by:
(20) The tumor is lung cancer, breast cancer, prostate cancer, head cancer, neck cancer, skin cancer, ovarian cancer, endometrial cancer, thyroid cancer, colon cancer, rectal cancer, (19) which is at least one selected from the group consisting of esophageal cancer, stomach cancer, kidney cancer, liver cancer, bladder cancer, pancreatic cancer, brain tumor, spinal cord tumor, blood cancer, and bone cancer. ) Described method.
(21) The method according to (19) or (20) above, wherein the tumor is a non-small cell lung cancer.

本発明によれば、副作用の懸念の少ない安全なコバレントドラッグとして有用な新規化合物を提供することができる。
本発明の化合物は、EGFR阻害剤として、また腫瘍治療剤の有効成分として優れた有用性及び実用性を有するものである。 ADVANTAGE OF THE INVENTION According to this invention, the novel compound useful as a safe covalent drug with little concern about side effects can be provided.
The compound of the present invention has excellent utility and practicality as an EGFR inhibitor and as an active ingredient of a therapeutic agent for tumors.

ゲル蛍光アッセイによるタンパク質ラベル化特異性の評価結果(A431細胞)を示す図である。FIG. 9 shows the results of evaluating protein labeling specificity by gel fluorescence assay (A431 cells). 細胞増殖阻害活性の評価結果(S431, H1975, PC9細胞) を示す図である。FIG. 9 shows the evaluation results of cell growth inhibitory activity (S431, H1975, PC9 cells). NS-062化合物のEGFRに対するリン酸化阻害活性の評価結果(H1975細胞)を示す図である。左図は、NS-062処理後にすぐに解析した結果であり、右図は、NS-062処理後、洗浄8時間後に解析した結果である。FIG. 9 shows the evaluation results (H1975 cells) of the phosphorylation inhibitory activity of NS-062 compounds on EGFR. The left figure shows the results of analysis immediately after NS-062 treatment, and the right figure shows the results of analysis 8 hours after washing with NS-062. in vivo抗腫瘍試験 (H1975 cell, 5 x 106 cell /mouse, 20 mg / kg, bid, po)の結果を示す図である。It is a figure which shows the result of an in vivo antitumor test (H1975 cell, 5 * 10 < 6 > cell / mouse, 20 mg / kg, bid, po). 投与期間終了後におけるマウスの体重変化を示す図である。It is a figure which shows the weight change of a mouse | mouth after the administration period ends.

以下、本発明を詳細に説明する。本発明の範囲はこれらの説明に拘束されることはなく、以下の例示以外についても、本発明の趣旨を損なわない範囲で適宜変更し実施することができる。
なお、本明細書において引用された全ての刊行物、例えば先行技術文献、及び公開公報、特許公報その他の特許文献は、参照として本明細書に組み込まれる。 Hereinafter, the present invention will be described in detail. The scope of the present invention is not limited by these descriptions, and can be appropriately modified and implemented in a range that does not impair the gist of the present invention, other than the following examples.
All publications cited in this specification, for example, prior art documents, and publications, patent publications, and other patent documents are incorporated herein by reference.


１．本発明の化合物
本発明は、前述したとおり、下記式(I)、及び下記式(II)で示される化合物に係るものである。以下、下記式(I)、及び下記式(II)で示される化合物を合わせて「本発明の化合物」という。
1. Compounds of the Present Invention As described above, the present invention relates to compounds represented by the following formulas (I) and (II). Hereinafter, the compounds represented by the following formulas (I) and (II) are collectively referred to as “compounds of the present invention”.

上記式(I)においては、
L1はリンカー部を表す。リンカー部の構造としては、任意の構造を採り得るが、好ましくは、単結合、又は、-RL1-NH-若しくは-RL1-CO-NH-が挙げられる。ここで、RL1としては、限定はされないが、例えば、任意に置換されていてもよい任意の構造の有機基が好ましい。特に好ましくは、後述する実施例１中の表Ａでリストアップされている各種化合物の構造中の、L1に相当する部分、又は任意に置換されていてもよい当該部分などが挙げられる。 In the above formula (I),
L 1 represents a linker moiety. The structure of the linker portion, but may take any structure, preferably a single bond, or include -R L1 -NH- or -R L1 -CO-NH-. Here, R L1 is not limited, but is preferably, for example, an organic group having an arbitrary structure that may be optionally substituted. Particularly preferably, in the structure of various compounds listed in Table A in Example 1 described below, a portion corresponding to L 1, or the like may this portion be substituted and the like as desired.

R1は、水素原子、又は任意に置換されていてもよい炭化水素基を表し、場合によりL1の一部と環構造を形成していてもよい。特に好ましくは、後述する実施例１中の表Ａでリストアップされている各種化合物の構造中の、R1に相当する部分、又は任意に置換されていてもよい当該部分などが挙げられる。
R2は、それぞれ独立して、任意に置換されていてもよい任意の構造の有機基を表し、好ましくは、-NH-R21が挙げられる。ここで、R21としては、限定はされず、例えば、任意に置換されていてもよい任意の構造の有機基が好ましく、より好ましくは、任意に置換されていてもよいアリール基（例えば、フェニル基等）及び複素環基などである。特に好ましくは、後述する実施例１中の表Ａでリストアップされている各種化合物の構造中の、R2又はR21に相当する部分、又は任意に置換されていてもよい当該部分などが挙げられる。 R 1 represents a hydrogen atom or an optionally substituted hydrocarbon group, and optionally may form a ring structure with a part of L 1 . Particularly preferably, in the structure of various compounds listed in Table A in Example 1 described below, a portion corresponding to R 1, or the like may this portion be substituted and the like as desired.
R 2 each independently represents an organic group having an arbitrary structure which may be optionally substituted, and is preferably —NH—R 21 . Here, R 21 is not limited, and is preferably, for example, an organic group having an arbitrary structure which may be optionally substituted, and more preferably an aryl group which may be optionally substituted (for example, phenyl Group) and a heterocyclic group. Particularly preferably, a portion corresponding to R 2 or R 21 in the structures of various compounds listed in Table A in Example 1 described later, or a portion which may be optionally substituted, and the like are mentioned. Can be

R3は、それぞれ独立して、任意に置換されていてもよい任意の構造の有機基を表し、好ましくは、-O-R31が挙げられる。ここで、R31としては、限定はされず、例えば、任意に置換されていてもよい任意の構造の有機基が好ましく、より好ましくは、任意に置換されていてもよい炭化水素基、ヘテロ炭化水素基、又はこれらの一部が環構造を形成しているものが挙げられる。特に好ましくは、後述する実施例１中の表Ａでリストアップされている各種化合物の構造中の、R3又はR31に相当する部分、又は任意に置換されていてもよい当該部分などが挙げられる。
m及びnは、それぞれ独立して、０〜２の整数を表し、好ましくは１又は２である。 R 3 each independently represents an organic group having an arbitrary structure that may be optionally substituted, and is preferably —OR 31 . Here, R 31 is not limited, and is preferably, for example, an organic group having an arbitrary structure which may be optionally substituted, and more preferably, an optionally substituted hydrocarbon group or heterocarbon group. Examples thereof include a hydrogen group or a group in which a part of these forms a ring structure. Particularly preferably, a portion corresponding to R 3 or R 31 in the structure of each compound listed in Table A in Example 1 described later, or a portion which may be optionally substituted, and the like are mentioned. Can be
m and n each independently represent an integer of 0 to 2, and preferably 1 or 2.

上記式(II)においては、
L2はリンカー部を表す。リンカー部の構造としては、任意の構造を採り得るが、好ましくは、単結合、又は、-RL2-NH-が挙げられる。ここで、RL2としては、限定はされないが、例えば、任意に置換されていてもよい任意の構造の有機基が好ましい。特に好ましくは、後述する実施例２中の表Ｂでリストアップされている各種化合物の構造中の、L2に相当する部分、又は任意に置換されていてもよい当該部分などが挙げられる。
R4は、水素原子、又は任意に置換されていてもよい炭化水素基を表し、場合によりL2の一部と環構造を形成していてもよい。特に好ましくは、後述する実施例２中の表Ｂでリストアップされている各種化合物の構造中の、R4に相当する部分、又は任意に置換されていてもよい当該部分などが挙げられる。 In the above formula (II),
L 2 represents a linker unit. The structure of the linker portion, but may take any structure, preferably a single bond, or, -R L2 -NH- and the like. Here, RL2 is not limited, but is preferably, for example, an organic group having an arbitrary structure that may be optionally substituted. Particularly preferably, in the structure of various compounds listed in Table B in Example 2 to be described later, a portion corresponding to L 2, or the like may this portion be substituted and the like as desired.
R 4 represents a hydrogen atom or an optionally substituted hydrocarbon group, and may optionally form a ring structure with a part of L 2 . Particularly preferably, in the structure of various compounds listed in Table B in Example 2 to be described later, a portion corresponding to R 4, or the like may this portion be substituted and the like as desired.

R5は、それぞれ独立して、任意に置換されていてもよい任意の構造の有機基を表し、好ましくは、ハロゲン基、任意に置換されていてもよい炭化水素基、任意に置換されていてもよい複素環基（例えば、インドール基等）及びアリール基などである。特に好ましくは、後述する実施例２中の表Ｂでリストアップされている各種化合物の構造中の、R5に相当する部分、又は任意に置換されていてもよい当該部分などが挙げられる。
pは、０〜２の整数を表し、好ましくは１又は２である。 R 5 each independently represents an organic group having an arbitrary structure which may be optionally substituted, and is preferably a halogen group, an optionally substituted hydrocarbon group, or an optionally substituted And a heterocyclic group (eg, an indole group) and an aryl group. Particularly preferably, in the structure of various compounds listed in Table B in Example 2 to be described later, a portion corresponding to R 5, or the like may this portion be substituted and the like as desired.
p represents an integer of 0 to 2, and is preferably 1 or 2.

本発明においては、上記式(I)で示される化合物の具体例としては、限定はされないが、下記構造式で示される化合物などが好ましく挙げられる。なお、これら化合物については、後述する実施例１中の表Ａでリストアップされている化合物も参照することができる。   In the present invention, specific examples of the compound represented by the above formula (I) include, but are not limited to, compounds represented by the following structural formulas. As for these compounds, the compounds listed in Table A in Example 1 described later can also be referred to.

なかでも、上記式(I)で示される化合物の具体例としては、下記構造式の化合物（本実施例でいうNS-062化合物）が好ましい。   Among them, as a specific example of the compound represented by the above formula (I), a compound having the following structural formula (NS-062 compound in the present example) is preferable.

また、本発明においては、上記式(II)で示される化合物の具体例としては、限定はされないが、下記構造式で示される化合物などが好ましく挙げられる。なお、これら化合物については、後述する実施例２中の表Ｂでリストアップされている化合物も参照することができる。   In the present invention, specific examples of the compound represented by the above formula (II) are not limited, but preferably include a compound represented by the following structural formula. As for these compounds, the compounds listed in Table B in Example 2 described later can also be referred to.

なかでも、上記式(II)で示される化合物の具体例としては、下記構造式の化合物（本実施例でいうNSP-037化合物）が好ましい。   Among them, as a specific example of the compound represented by the above formula (II), a compound having the following structural formula (NSP-037 compound in this example) is preferable.

本発明の化合物は、上述した各化合物の薬理学的に許容し得る塩の形態であってもよい。
本発明の化合物の薬理学的に許容し得る塩としては、限定はされないが、例えば、ハロゲン化水素酸塩（例えば、塩酸塩、臭化水素酸塩、及びヨウ化水素酸塩など）、無機酸塩（例えば、硫酸塩、硝酸塩、過塩素酸塩、リン酸塩、炭酸塩、及び重炭酸塩など）、有機カルボン酸塩（例えば、酢酸塩、トリフルオロ酢酸塩、マレイン酸塩、酒石酸塩、フマル酸塩、及びクエン酸塩など）、有機スルホン酸塩（例えば、メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、及びカンファースルホン酸塩など）、アミノ酸塩（例えば、アスパラギン酸塩、及びグルタミン酸塩など）、四級アミン塩、アルカリ金属塩（例えば、ナトリウム塩、及びカリウム塩など）、アルカリ土類金属塩（例えば、マグネシウム塩、及びカルシウム塩など）などが好ましく挙げられる。 The compound of the present invention may be in the form of a pharmacologically acceptable salt of each compound described above.
Pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, for example, hydrohalides (eg, hydrochloride, hydrobromide, and hydroiodide), inorganic Acid salts (eg, sulfates, nitrates, perchlorates, phosphates, carbonates, and bicarbonates), organic carboxylate salts (eg, acetate, trifluoroacetate, maleate, tartrate) , Fumarate, and citrate), organic sulfonates (eg, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, and camphorsulfonate) ), Amino acid salts (eg, aspartate and glutamate), quaternary amine salts, alkali metal salts (eg, sodium and potassium salts), Earth metal salts (such as magnesium and calcium salts,) are preferably used.

また、本発明の化合物としては、その誘導体も含まれる。誘導体としては、本発明の化合物由来の化学構造を有する等、当業者の技術常識に基づいて本発明の化合物の誘導体と考えられるものであればよく、限定はされないが、例えば、EGFR阻害活性や腫瘍の治療効果が本発明の化合物と同程度ものが好ましい。   The compounds of the present invention also include derivatives thereof. Derivatives having a chemical structure derived from the compound of the present invention, such as those having a chemical structure derived from the compound of the present invention based on the common general knowledge of those skilled in the art, are not limited, and include, for example, EGFR inhibitory activity and Preferably, the therapeutic effect on the tumor is comparable to that of the compound of the present invention.

本発明の化合物やその誘導体としては、例えば、生体内で酸化、還元、加水分解、又は抱合などの代謝を受けるものも包含するほか、生体内で酸化、還元、又は加水分解などの代謝を受けて本発明の化合物やその誘導体を生成する化合物（いわゆるプロドラッグ）も含まれる。本発明において、プロドラッグとは、薬理学的に許容し得る、通常プロドラッグにおいて使用される基で親化合物を修飾した化合物をいい、例えば、安定性や持続性の改善等の特性が付与され、腸管内等で親化合物に変換されて効果を発現することが期待できる化合物をいう。例えば、本発明の化合物のプロドラッグは、対応するハロゲン化物等のプロドラッグ化試薬を用いて、常法により、当該化合物中のプロドラッグ化の可能な基（例えば、水酸基、アミノ基、その他の基）から選択される１以上の任意の基に、常法に従い適宜プロドラッグを構成する基を導入した後、必要に応じ、単離精製することにより製造することができる。ここで、上記プロドラッグを構成する基としては、限定はされないが、例えば、低級アルキル−ＣＯ−、低級アルキル−Ｏ−低級アルキレン−ＣＯ−、低級アルキル−ＯＣＯ−低級アルキレン−ＣＯ−、低級アルキル−ＯＣＯ−、及び低級アルキル−Ｏ−低級アルキレン−ＯＣＯ−等が好ましく挙げられる。   The compounds of the present invention and derivatives thereof include, for example, those that undergo metabolism such as oxidation, reduction, hydrolysis, or conjugation in vivo, and those that undergo metabolism such as oxidation, reduction, or hydrolysis in vivo. (A so-called prodrug) which produces the compound of the present invention or a derivative thereof. In the present invention, a prodrug refers to a pharmacologically acceptable compound obtained by modifying a parent compound with a group usually used in a prodrug, and for example, is imparted with properties such as improved stability and durability. And a compound that can be expected to exhibit its effect by being converted to the parent compound in the intestinal tract and the like. For example, a prodrug of a compound of the present invention can be a prodrug-forming group (for example, a hydroxyl group, an amino group, other The group can be produced by introducing a group constituting a prodrug into one or more arbitrary groups selected from the group) according to a conventional method, and then, if necessary, isolating and purifying the group. Here, the group constituting the prodrug is not limited, and examples thereof include lower alkyl-CO-, lower alkyl-O-lower alkylene-CO-, lower alkyl-OCO-lower alkylene-CO-, and lower alkyl. -OCO- and lower alkyl-O-lower alkylene-OCO- are preferred.

さらに、本発明の化合物は、化合物の構造上生じ得るすべての異性体（例えば、幾何異性体、不斉炭素に基づく光学異性体、回転異性体、立体異性体、及び互変異性体等）及びこれら異性体の２種以上の混合物をも包含し、便宜上の構造式の記載等に限定されるものではない。また、本発明の化合物は、S-体、R-体又はRS-体のいずれであってもよく、限定はされない。さらに、本発明の化合物は、その種類により水和物や溶媒和物の形で存在する場合もあり、本発明においては当該水和物及び溶媒和物も本発明の化合物に含まれるものとし、後述する本発明の医薬組成物及び試薬や、EGFR阻害剤の有効成分として用いることができる。当該溶媒和物としては、限定はされないが、例えば、エタノールとの溶媒和物等が挙げられる。   Further, the compounds of the present invention include all isomers that can occur in the structure of the compound (for example, geometric isomers, optical isomers based on asymmetric carbon, rotamers, stereoisomers, tautomers, and the like) and It also includes a mixture of two or more of these isomers, and is not limited to the description of the structural formula for convenience. The compound of the present invention may be in any of the S-form, R-form and RS-form, and is not limited. Further, the compound of the present invention may exist in the form of a hydrate or a solvate depending on the kind thereof, and in the present invention, the hydrate and the solvate are also included in the compound of the present invention. It can be used as an active ingredient of the pharmaceutical composition and reagent of the present invention described below, and an EGFR inhibitor. Examples of the solvate include, but are not limited to, a solvate with ethanol and the like.


２．医薬組成物、EGFR阻害剤等
本発明の医薬組成物又は試薬、及び、本発明のEGFR阻害剤は、前述したとおり、本発明の化合物、又はその薬理学的に許容し得る塩、あるいはそれらの水和物若しくは溶媒和物（以下、「本発明の化合物等」ということがある。）を有効成分として含むことを特徴とするものである。上記試薬としては、例えば研究用試薬なども含まれる。本明細書においては、「本発明の医薬組成物」には当該試薬も包含され得るものとする。
本発明の医薬組成物としては、限定はされないが、腫瘍の治療用の医薬組成物が好ましい。
なお、本発明は、(i) 本発明の化合物等を用いること、具体的には例えば本発明の化合物等の有効量を被験対象に投与することを含む、腫瘍の治療方法、又はEGFR阻害方法、(ii) 当該腫瘍の治療用の薬剤、又はEGFR阻害剤を製造するための本発明の化合物等の使用、(iii) 当該腫瘍の治療用、又はEGFR阻害用の本発明の化合物等の使用、並びに、(iv) 当該腫瘍の治療用、又はEGFR阻害用の本発明の化合物等も含むものである。
2. Pharmaceutical composition, EGFR inhibitor, etc.The pharmaceutical composition or reagent of the present invention, and the EGFR inhibitor of the present invention, as described above, the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. It is characterized by containing a hydrate or a solvate (hereinafter, sometimes referred to as “the compound of the present invention”) as an active ingredient. The reagent includes, for example, a research reagent. In the present specification, the “pharmaceutical composition of the present invention” may include the reagent.
The pharmaceutical composition of the present invention is not limited, but is preferably a pharmaceutical composition for treating a tumor.
Note that the present invention provides a method for treating a tumor, or a method for inhibiting EGFR, comprising (i) using a compound or the like of the present invention, specifically, for example, administering an effective amount of the compound or the like to a subject. (Ii) use of the compound of the present invention or the like for producing an agent for treating the tumor or an EGFR inhibitor, (iii) use of the compound or the like of the present invention for treating the tumor or inhibiting EGFR And (iv) the compound of the present invention for treating the tumor or for inhibiting EGFR.

本発明において、当該腫瘍の治療としては、具体的には、例えば、当該腫瘍の治療の進行抑制、予後改善、及び／又は再発防止等も含まれる。
本発明において、治療対象となる腫瘍は、限定はされないが、肺がん、乳がん、前立腺がん、頭部がん、頸部がん、皮膚がん、卵巣がん、子宮内膜がん、甲状腺がん、結腸がん、直腸がん、食道がん、胃がん、腎臓がん、肝臓がん、膀胱がん、膵臓がん、脳腫瘍、脊髄腫瘍、血液がん、及び骨がんからなる群より選ばれる少なくとも１種が好ましく挙げられる。なかでも、肺がんとしては、非小細胞肺がん、及び小細胞肺がんが挙げられるが、非小細胞肺がんがより好ましい。 In the present invention, the treatment of the tumor specifically includes, for example, suppression of progress of treatment of the tumor, improvement of prognosis, and / or prevention of recurrence.
In the present invention, tumors to be treated are not limited, but include lung cancer, breast cancer, prostate cancer, head cancer, cervical cancer, skin cancer, ovarian cancer, endometrial cancer, and thyroid gland. Selected from the group consisting of cancer, colon, rectum, esophagus, stomach, kidney, liver, bladder, pancreas, brain, spinal cord, blood, and bone At least one of them is preferably mentioned. Among them, examples of lung cancer include non-small cell lung cancer and small cell lung cancer, but non-small cell lung cancer is more preferable.

本発明の医薬組成物、及びEGFR阻害剤において、有効成分としての本発明の化合物等の含有割合は、限定はされず、適宜設定することができるが、例えば、医薬組成物やEGFR阻害剤の全体に対して、0.01〜99重量％の範囲内とすることができ、好ましくは、0.01〜30重量％、より好ましくは0.05〜20重量％、さらに好ましくは0.1〜10重量％の範囲内としてもよい。有効成分の含有割合が上記範囲内であることにより、本発明の医薬組成物、及びEGFR阻害剤は、腫瘍の治療効果、EGFR阻害能を十分に発揮することができる。   In the pharmaceutical composition of the present invention, and the EGFR inhibitor, the content ratio of the compound of the present invention as an active ingredient is not limited and can be appropriately set, for example, a pharmaceutical composition or an EGFR inhibitor. The total amount can be in the range of 0.01 to 99% by weight, preferably 0.01 to 30% by weight, more preferably 0.05 to 20% by weight, and even more preferably 0.1 to 10% by weight. Good. When the content ratio of the active ingredient is within the above range, the pharmaceutical composition of the present invention and the EGFR inhibitor can sufficiently exhibit a therapeutic effect on tumor and EGFR inhibitory ability.

本発明の医薬組成物、及びEGFR阻害剤は、被験対象としてのヒト又は非ヒト哺乳動物（例えば、ラット、ウサギ、ヒツジ、ブタ、ウシ、ネコ、イヌ、サルなど）に対して、種々の投与経路、具体的には、経口、又は非経口（例えば静脈内注射（静注）、筋肉内注射、腹腔内注射、皮下注射、直腸投与、経皮投与）で投与することができる。従って、本発明に使用する本発明の化合物等は、単独で用いることも可能であるが、投与経路に応じて慣用される方法により薬学的に許容し得る担体を用いて適当な剤形に製剤化して用いることができる。   The pharmaceutical composition of the present invention and the EGFR inhibitor are administered to human or non-human mammals (eg, rats, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.) by various methods. It can be administered by a route, specifically, orally or parenterally (eg, intravenous injection (intravenous injection), intramuscular injection, intraperitoneal injection, subcutaneous injection, rectal administration, transdermal administration). Therefore, although the compound of the present invention used in the present invention can be used alone, it can be formulated into an appropriate dosage form using a pharmaceutically acceptable carrier by a method commonly used depending on the administration route. Can be used.

剤形としては、経口剤では、例えば、錠剤、散剤、細粒剤、顆粒剤、被覆錠剤、カプセル剤、内用水剤、懸濁剤、乳剤、シロップ剤、及びトローチ剤等が挙げられ、非経口剤では、例えば、注射剤（点滴剤を含む）、吸入剤、軟膏剤、点鼻剤、及びリポソーム剤等が挙げられる。なお、上述した各種経口剤とする場合、本発明の医薬組成物、及びEGFR阻害剤は、場合によりサプリメント剤（例えば機能性食品に該当する）として利用することもできる。
これら製剤の製剤化に用い得る担体としては、例えば、通常用いられる賦形剤、結合剤、崩壊剤、滑沢剤、着色剤、及び矯味矯臭剤のほか、必要に応じ、安定化剤、乳化剤、吸収促進剤、界面活性剤、pH調整剤、防腐剤、抗酸化剤、増量剤、湿潤化剤、表面活性化剤、分散剤、緩衝剤、保存剤、溶解補助剤、及び無痛化剤等が挙げられ、医薬品製剤の原料として用いることができる公知の成分を配合して常法により製剤化することが可能である。 Examples of the dosage form include oral preparations such as tablets, powders, fine granules, granules, coated tablets, capsules, solutions for internal use, suspensions, emulsions, syrups, troches and the like. Examples of oral preparations include injections (including drops), inhalants, ointments, nasal drops, and liposomes. When the above-mentioned various oral preparations are used, the pharmaceutical composition of the present invention and the EGFR inhibitor can be optionally used as a supplement (for example, a functional food).
Carriers that can be used in the preparation of these preparations include, for example, commonly used excipients, binders, disintegrants, lubricants, coloring agents, and flavoring agents, if necessary, stabilizers, emulsifiers , Absorption promoters, surfactants, pH adjusters, preservatives, antioxidants, bulking agents, wetting agents, surface activators, dispersants, buffers, preservatives, solubilizing agents, and soothing agents, etc. A known component that can be used as a raw material of a pharmaceutical preparation can be formulated into a preparation by a conventional method.

当該成分として使用可能な無毒性のものとしては、例えば、大豆油、牛脂、及び合成グリセライド等の動植物油；流動パラフィン、スクワラン、及び固形パラフィン等の炭化水素；ミリスチン酸オクチルドデシル、及びミリスチン酸イソプロピル等のエステル油；セトステアリルアルコール、及びベヘニルアルコール等の高級アルコール；シリコン樹脂；シリコン油；ポリオキシエチレン脂肪酸エステル、ソルビタン脂肪酸エステル、グリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン硬化ひまし油、及びポリオキシエチレン−ポリオキシプロピレンブロックコポリマー等の界面活性剤；ヒドロキシエチルセルロース、ポリアクリル酸、カルボキシビニルポリマー、ポリエチレングリコール、ポリビニルピロリドン、及びメチルセルロース等の水溶性高分子；エタノール、及びイソプロパノール等の低級アルコール；グリセリン、プロピレングリコール、ジプロピレングリコール、ソルビトール、及びポリエチレングリコール等の多価アルコール（ポリオール）；グルコース、及びショ糖等の糖；無水ケイ酸、ケイ酸アルミニウムマグネシウム、及びケイ酸アルミニウム等の無機粉体；塩化ナトリウム、リン酸ナトリウム等の無機塩；精製水等が挙げられ、いずれもその塩またはその水和物であってもよい。   Non-toxic substances usable as the component include, for example, animal and vegetable oils such as soybean oil, tallow, and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane, and solid paraffin; octyldodecyl myristate, and isopropyl myristate Higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, and Surfactants such as polyoxyethylene-polyoxypropylene block copolymers; hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, Water-soluble polymers such as vinylpyrrolidone and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols (polyols) such as glycerin, propylene glycol, dipropylene glycol, sorbitol, and polyethylene glycol; glucose and sucrose; Sugars; inorganic powders such as silicic anhydride, aluminum magnesium silicate, and aluminum silicate; inorganic salts such as sodium chloride and sodium phosphate; purified water and the like. There may be.

賦形剤としては、例えば、乳糖、果糖、コーンスターチ、白糖、ブドウ糖、マンニトール、ソルビット、結晶セルロース、及び二酸化ケイ素等が、結合剤としては、例えば、ポリビニルアルコール、ポリビニルエーテル、メチルセルロース、エチルセルロース、アラビアゴム、トラガント、ゼラチン、シェラック、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルピロリドン、ポリプロピレングリコール・ポリオキシエチレン・ブロックポリマー、及びメグルミン等が、崩壊剤としては、例えば、澱粉、寒天、ゼラチン末、結晶セルロース、炭酸カルシウム、炭酸水素ナトリウム、クエン酸カルシウム、デキストリン、ペクチン、及びカルボキシメチルセルロース・カルシウム等が、滑沢剤としては、例えば、ステアリン酸マグネシウム、タルク、ポリエチレングリコール、シリカ、及び硬化植物油等が、着色剤としては医薬品に添加することが許可されているものが、矯味矯臭剤としては、例えば、ココア末、ハッカ脳、芳香散、ハッカ油、竜脳、及び桂皮末等が、それぞれ好ましく挙げられ、いずれもその塩又はそれらの水和物であってもよい。   As an excipient, for example, lactose, fructose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide, and the like, as a binder, for example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic , Tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol polyoxyethylene block polymer, and meglumine, as disintegrants, for example, starch, agar, gelatin powder, crystalline cellulose, Calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, and carboxymethylcellulose calcium are examples of lubricants. , Magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oils and the like are permitted to be added to pharmaceuticals as coloring agents, but as flavoring agents, for example, cocoa powder, peppermint brain, aroma Powder, peppermint oil, dragon brain, cinnamon powder and the like are each preferably mentioned, and all of them may be salts or hydrates thereof.

本発明の医薬組成物、及びEGFR阻害剤の投与量は、一般には、製剤中の有効成分（本発明の化合物等）の配合割合を考慮した上で、投与対象（患者）の年齢、体重、病気の種類・進行状況や、投与経路、投与回数（／1日）、投与期間等を勘案し、適宜、広範囲に設定することができる。
本発明の医薬組成物、及びEGFR阻害剤を、非経口剤又は経口剤として用いる場合について、以下に具体的に説明する。
非経口剤として用いる場合、一般にその形態は限定されないが、各種注射剤の場合は、例えば、単位投与量アンプル又は多投与量容器の状態や、使用時に溶解液に再溶解させる凍結乾燥粉末の状態で提供され得る。当該非経口剤には、有効成分となる本発明の化合物等のほかに、各種形態に応じ、公知の各種賦形材や添加剤を上記有効成分の効果が損なわれない範囲で含有することができる。例えば、各種注射剤の場合は、水、グリセロール、プロピレングリコールや、ポリエチレングリコール等の脂肪族ポリアルコール等が挙げられる。 The dose of the pharmaceutical composition of the present invention and the dose of the EGFR inhibitor are generally determined in consideration of the mixing ratio of the active ingredient (the compound of the present invention) in the preparation, and the age, body weight, It can be appropriately set in a wide range in consideration of the type and progress of the disease, the administration route, the number of administrations (one day), the administration period, and the like.
The case where the pharmaceutical composition of the present invention and the EGFR inhibitor are used as a parenteral agent or an oral agent will be specifically described below.
When used as a parenteral preparation, its form is not particularly limited, but in the case of various injections, for example, the state of a unit dose ampule or a multi-dose container, or the state of a lyophilized powder to be redissolved in a dissolution solution at the time of use Can be provided by The parenteral preparation may contain, in addition to the compound of the present invention, which is an active ingredient, various known excipients and additives according to various forms as long as the effects of the active ingredient are not impaired. it can. For example, in the case of various injections, examples thereof include water, glycerol, propylene glycol, and aliphatic polyalcohols such as polyethylene glycol.

非経口剤の投与量（１日あたり）は、限定はされないが、例えば各種注射剤であれば、一般には、有効成分となる本発明の化合物等を、適用対象（被験者、患者等）の体重1kgあたり、0.01〜1000mg、0.05〜500mg、又は0.1〜50 mg服用できる量とすることができ、あるいは0.5〜20 mg服用できる量や1〜10 mg服用できる量とすることもできる。
経口剤として用いる場合、一般にその形態は限定されず、前述した剤形のいずれであってもよいし、使用する際に再溶解させる乾燥生成物にしてもよい。当該経口剤には、有効成分となる本発明の化合物等のほかに、各種形態に応じ、公知の各種賦形材や添加剤を上記有効成分の効果が損なわれない範囲で含有することができる。例えば、結合剤（シロップ、アラビアゴム、ゼラチン、ソルビトール、トラガカント、ポリビニルピロリドン等）、充填材（乳糖、糖、コーンスターチ、馬鈴薯でんぷん、リン酸カルシウム、ソルビトール、グリシン等）、潤滑剤（ステアリン酸マグネシウム、タルク、ポリエチレングリコール、シリカ等）、崩壊剤（各種でんぷん等）、および湿潤剤（ラウリル硫酸ナトリウム等）等が挙げられる。 The dosage (per day) of the parenteral preparation is not limited. For example, in the case of various injections, the compound of the present invention or the like as an active ingredient is generally used as a body weight of a subject (subject, patient, etc.). The amount can be 0.01 to 1000 mg, 0.05 to 500 mg, or 0.1 to 50 mg per kg, or can be 0.5 to 20 mg or 1 to 10 mg per kg.
When used as an oral preparation, the form is not particularly limited, and may be any of the above-mentioned dosage forms, or may be a dry product that is redissolved when used. The oral preparation may contain, in addition to the compound of the present invention, which is an active ingredient, various known excipients and additives according to various forms as long as the effects of the active ingredient are not impaired. . For example, binders (syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, etc.), fillers (lactose, sugar, corn starch, potato starch, calcium phosphate, sorbitol, glycine, etc.), lubricants (magnesium stearate, talc, Polyethylene glycol, silica and the like), disintegrants (various starches and the like), wetting agents (sodium lauryl sulfate and the like) and the like.

経口剤の投与量（１日あたり）は、一般には、有効成分となる本発明の化合物等を、適用対象（被験者、患者等）の体重1 kgあたり、0.05〜5000mg、0.1■1000mg、又は0.1〜100 mg服用できる量とすることができ、あるいは0.5〜50 mg服用できる量や1〜10 mg服用できる量とすることもできる。また、経口剤中の有効成分の配合割合は、限定はされず、１日あたりの投与回数等を考慮して、適宜設定することができる。   In general, the dose (per day) of an oral preparation is such that the compound of the present invention, which is an active ingredient, is administered in an amount of 0.05 to 5000 mg, 0.1 to 1000 mg, or 0.1 mg / kg body weight of a subject (subject, patient, etc.). It can be an amount that can be taken up to 100 mg, or an amount that can be taken 0.5 to 50 mg or 1 to 10 mg. The proportion of the active ingredient in the oral preparation is not limited, and can be appropriately set in consideration of the number of times of administration per day.

３．キット
腫瘍の治療を行うに当たっては、又はEGFRの阻害を行うに当たっては、本発明の化合物等を含むキット（具体例として、前述した本発明の医薬組成物、及びEGFR阻害剤を含むキット）を用いることができる。
当該キットにおける本発明の化合物等の形態は、限定はされないが、安定性（保存性）及び使用容易性等を考慮し、例えば溶解した状態で備えられていてもよい。
当該キットは、本発明の化合物等以外にも、適宜、他の構成要素を含むことができる。
当該キットは、構成要素として少なくとも前述した本発明の化合物等を備えているものであればよい。従って、前記腫瘍の治療などに必須となる構成要素の全てを、当該本発明の化合物等と共に備えているものであってもよいし、別々に備えているものであってもよく、限定はされない。 3. Kit In treating a tumor or in inhibiting EGFR, a kit containing the compound of the present invention or the like (specifically, a kit containing the above-described pharmaceutical composition of the present invention and a EGFR inhibitor) is used. be able to.
The form of the compound of the present invention and the like in the kit is not limited, but may be provided in a dissolved state, for example, in consideration of stability (preservability) and ease of use.
The kit can appropriately contain other components in addition to the compound of the present invention and the like.
The kit only needs to include at least the compound of the present invention described above as a component. Therefore, all of the components essential for the treatment of the tumor or the like may be provided together with the compound of the present invention or the like, or may be provided separately, and are not limited. .


以下に、実施例を挙げて本発明をより具体的に説明するが、本発明はこれらに限定されるものではない。
Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto.

化合物の反応性を簡便にスクリーニングできるペプチドを用いた独自の蛍光アッセイ系を構築し、コバレントドラッグに適した反応性基の探索から研究を開始した。α-ハロアセチル基を中心とした様々な反応性基について検討した結果 (Table 1)、システイン残基と反応する穏やかな反応性基として「α-クロロフルオロアセタミド基」を新たに見出した。α-クロロフルオロアセタミド基は、穏やかな反応性と同時に、阻害剤の機能を阻害しにくい小さな分子サイズ、水溶液中での高い化学的安定性など、コバレントドラッグ開発に適した特徴を有する。   A unique fluorescent assay system using a peptide that can easily screen the reactivity of a compound was constructed, and research began by searching for a reactive group suitable for a covalent drug. As a result of examining various reactive groups centering on α-haloacetyl group (Table 1), “α-chlorofluoroacetamide group” was newly found as a mild reactive group that reacts with cysteine residue. The α-chlorofluoroacetamide group has characteristics suitable for covalent drug development, such as mild reactivity, a small molecular size that does not easily inhibit the function of the inhibitor, and high chemical stability in an aqueous solution.

次に、EGFR受容体阻害剤であるキナゾリン型の抗がん剤に、α-クロロフルオロアセタミド基の有用性を組み込んだコバレントドラッグ開発を進めた。   Next, we proceeded with the development of a covalent drug that incorporates the usefulness of α-chlorofluoroacetamide group into a quinazoline-type anticancer drug that is an EGFR receptor inhibitor.

α-クロロフルオロアセタミド基とキナゾリン誘導体の間のリンカーに様々な構造を持つアミノ酸を用いて構造活性相関を行った。アッセイは、がん細胞(PC9, H1975, A431など)に対する細胞増殖阻害活性で評価を行った（Table 2）。なお、本実施例におけるアッセイ・評価に用いるために合成した化合物を、実施例１の末尾の表Ａにリストアップした。また、これら化合物の合成方法については、後述する実施例３に示したNS-062（二塩酸塩）化合物の合成方法が、適宜、参照される。   Structure-activity relationships were performed using amino acids with various structures as linkers between α-chlorofluoroacetamide group and quinazoline derivatives. The assay was evaluated for its cell growth inhibitory activity against cancer cells (PC9, H1975, A431, etc.) (Table 2). The compounds synthesized for use in the assays and evaluations in this example are listed in Table A at the end of Example 1. As for the method for synthesizing these compounds, the method for synthesizing the NS-062 (dihydrochloride) compound shown in Example 3 described below is appropriately referred to.

その結果、リンカーとしてD?プロリンを有する化合物NS-058がT790M・L858R二重変異を持つEGFRを発現するH1975細胞に対して強い細胞増殖阻害活を示した。興味あることにL-プロリンを持つリンカーとして持つNS-067の活性は極めて弱かった。
次に強い活性を示したNS-058のアルキン誘導体とアファチニブのアルキン誘導体を用いてタンパク質ラベル化の選択性について評価を行った (図１)。その結果、α-クロロフルオロアセタミド基を持つNS-058誘導体は、極めて特異的にEGFRと反応することがわかった。一方で、マイケルアクセプターを持つアファチニブ誘導体は、他のタンパク質に対する非特異的なラベル化が認められた。 As a result, the compound NS-058 having D-proline as a linker showed strong cell growth inhibitory activity against H1975 cells expressing EGFR having a T790M / L858R double mutation. Interestingly, the activity of NS-067 as a linker with L-proline was extremely weak.
Next, the selectivity of protein labeling was evaluated using an alkyne derivative of NS-058 and an alkyne derivative of afatinib which showed strong activity (FIG. 1). As a result, it was found that the NS-058 derivative having an α-chlorofluoroacetamide group reacted specifically with EGFR. On the other hand, afatinib derivatives having a Michael acceptor showed non-specific labeling for other proteins.

NS-058の水溶性を改善したNS-061, NS-062と、アファチニブとの活性の結果を、図２及びTable 3にまとめた。NS-061, NS-062 はともにT790M・L858R二重変異を持つEGFRを発現するH1975細胞に対して強い増殖阻害活性を持ち、そのIC50値はアファチニブとほぼ同様であった。一方で、NS-061およびNS-062の野生型のEGFRを発現するA431細胞に対する増殖阻害活性は、アファチニブよりも弱かった。アファチニブは野生型のEGFRに対する阻害活性を持つため下痢や皮膚障害などの副作用を持つことが知られている。したがって、A431/ H1975の活性比の高いNS-061およびNS-062は、アファチニブよりも副作用が軽減できる可能がある。   The results of the activities of NS-061 and NS-062 with improved water solubility of NS-058 and afatinib are summarized in FIG. 2 and Table 3. Both NS-061 and NS-062 had strong growth inhibitory activity against H1975 cells expressing EGFR having the T790M / L858R double mutation, and their IC50 values were almost the same as those of afatinib. On the other hand, the growth inhibitory activity of NS-061 and NS-062 on A431 cells expressing wild-type EGFR was weaker than that of afatinib. Afatinib is known to have side effects such as diarrhea and skin disorders due to its inhibitory activity against wild-type EGFR. Therefore, NS-061 and NS-062, which have a high A431 / H1975 activity ratio, may have fewer side effects than afatinib.

NS-062を用いてH1975細胞におけるリン酸化阻害活性をウェスタンブロッティングを用いて評価したところ、EGFRに対する濃度依存的なリン酸化阻害活性が認められた（図３ 左）。また、このリン酸化阻害活性は、H1975細胞をNS-062で処理して洗浄した８時間後にも持続していた（図３ 右）。この結果は、NS-062がEGFRと共有結合を形成して不可逆的な阻害をしていることを意味する。 When phosphorylation inhibitory activity in H1975 cells was evaluated using NS-062 by Western blotting, a concentration-dependent phosphorylation inhibitory activity on EGFR was observed (FIG. 3, left). This phosphorylation inhibitory activity was maintained 8 hours after H1975 cells were treated with NS-062 and washed (FIG. 3, right). This result indicates that NS-062 forms a covalent bond with EGFR and is irreversibly inhibited.

ヌードマウスにH1975細胞を移植して、NS-062およびアファチニブの経口投与試験（20 mg/kg 、1日２回）を行ったところ (図４)、NS-062は、コントロール群との比較で有意に腫瘍増殖抑制効果を示した。その効果はアファチニブと同定度であった。また、投与期間２５日後のマウスの体重減少率は、アファチニブと比較してNS-062の方が軽度であった (図５)。   When H1975 cells were implanted into nude mice and NS-062 and afatinib were administered orally (20 mg / kg, twice a day) (FIG. 4), NS-062 was compared with the control group. Significantly showed tumor growth inhibitory effect. The effect was afatinib and identity. In addition, the weight loss rate of the mice 25 days after the administration period was lower in NS-062 than in afatinib (FIG. 5).

以下、本実施例におけるアッセイ・評価に用いるために合成した化合物のリスト（一部の化合物について評価結果あり）を示す。   Hereinafter, a list of compounds synthesized for use in the assay / evaluation in this example (some compounds have evaluation results) is shown.

NS-062などのキナゾリン骨格を有する第二世代型のEGFR阻害剤と並行して、オシメルチニブに代表される第三世代型のピリジミン骨格をもつコバレントドラッグの開発も合わせて行っている。これまでにオシメルチニブの構造を鋳型として、クロロフルオロアセタミド基とピリミジン環の間に様々なアミノ酸をリンカーとして導入した誘導体およびピリミジン環の５位に様々な置換基を導入した誘導体を合成して構造活性相関を行った。各化合物に活性は、T790M・L858R二重変異EGFR を発現するH1975細胞および野生型のEGFRを発現するA431ならびにH292細胞に対する増殖阻害活性により評価を行った。なお、本実施例におけるアッセイ・評価に用いるために合成した化合物を、実施例２の末尾の表Ｂにリストアップした。また、これら化合物の合成方法については、後述する実施例４に示したNSP-037化合物の合成方法が、適宜、参照される。   In parallel with the second-generation EGFR inhibitor having a quinazoline skeleton such as NS-062, the development of a covalent drug having a third-generation pyridimine skeleton typified by osimertinib is also underway. So far, using the structure of osimertinib as a template, a derivative with various amino acids introduced as a linker between the chlorofluoroacetamide group and the pyrimidine ring and a derivative with various substituents introduced at the 5-position of the pyrimidine ring have been synthesized. Structure-activity relationships were performed. The activity of each compound was evaluated by its growth inhibitory activity on H1975 cells expressing T790M / L858R double mutant EGFR and A431 and H292 cells expressing wild-type EGFR. The compounds synthesized for use in the assays and evaluations in this example are listed in Table B at the end of Example 2. As for the method for synthesizing these compounds, the method for synthesizing the NSP-037 compound shown in Example 4 described later is appropriately referred to.

その結果、リンカー部位にL-アラニンをもつ化合物が高い活性を示すこと(Table 4)、ピリミジン環５位にはトリフルオアセチル基をもつ化合物の活性が強い活性を示すことが明らかとなった(Table 5)。最終的に開発候補化合物として得られた化合物NSP-037は、T790M・L858R二重変異EGFRを発現するH1975細胞に対する増殖阻害活性はオシメルチニブと同等である一方で、野生型EGFRを発現するH292細胞に対する阻害活性は、オシメルチニブに比べて弱かった。したがって、A431/ H292の活性比の高いNSP-037は、オシメルチニブよりも副作用が軽減できる可能を有する。   As a result, it was clarified that the compound having L-alanine at the linker moiety exhibited high activity (Table 4), and the compound having a trifluoroacetyl group at the 5-position of the pyrimidine ring exhibited strong activity (Table 4). Five). Compound NSP-037 finally obtained as a development candidate compound, the growth inhibitory activity against H1975 cells expressing T790M / L858R double mutant EGFR is equivalent to osimertinib, while against H292 cells expressing wild-type EGFR The inhibitory activity was weaker than that of osimertinib. Therefore, NSP-037, which has a high A431 / H292 activity ratio, has the potential to reduce side effects as compared to osimertinib.

以下、本実施例におけるアッセイ・評価に用いるために合成した化合物のリスト（一部の化合物について評価結果あり）を示す。   Hereinafter, a list of compounds synthesized for use in the assay / evaluation in this example (some compounds have evaluation results) is shown.

NS-062二塩酸塩の合成
下記スキームにより、NS-062化合物（前記表Ａも参照）の二塩酸塩を合成した。
各中間体の合成手順も含めて、以下に詳しく説明する。 Synthesis of NS-062 Dihydrochloride The dihydrochloride of the NS-062 compound (see also Table A above) was synthesized according to the following scheme.
This is described in detail below, including the procedure for synthesizing each intermediate.

[中間体2] (Denny, W. A. et al. J. Med. Chem. 1996, 39, 918-928.参照)
4-フルオロアントラニル酸 (12.5 g, 80.4 mmol) を100 mLのホルムアミドに溶解し、150度で6時間加熱撹拌した。室温に放冷したのち、200 mLの氷水で希釈した。析出した固体を吸引濾取し、冷水とエーテルで洗浄したのち真空下60度にて加熱乾燥させ、中間体2を淡褐色の固体として10.6 g、81%収率で得た。 [Intermediate 2] (see Denny, WA et al. J. Med. Chem. 1996, 39, 918-928.)
4-Fluoroanthranilic acid (12.5 g, 80.4 mmol) was dissolved in 100 mL of formamide, and heated and stirred at 150 degrees for 6 hours. After allowing to cool to room temperature, the mixture was diluted with 200 mL of ice water. The precipitated solid was collected by suction filtration, washed with cold water and ether, and dried by heating at 60 ° C. under vacuum to obtain 10.6 g of Intermediate 2 as a pale brown solid in an 81% yield.

[中間体3]1
氷冷下、発煙硝酸40 mLに対し濃硫酸40 mLを滴下した。引き続き氷冷下、この混合物に対し中間体2 (10.6 g, 64.6 mmol) を徐々に加えたのち、110度で3時間加熱撹拌した。室温に放冷したのち、反応混合物を1リットルの氷水に滴下した。析出した固体を吸引濾取し、冷水とエーテルで洗浄したのち真空下乾燥させ、中間体3を淡黄色の固体として11.4 g、85%収率で得た。 [Intermediate 3] 1
Under ice-cooling, 40 mL of concentrated sulfuric acid was added dropwise to 40 mL of fuming nitric acid. Subsequently, under ice-cooling, Intermediate 2 (10.6 g, 64.6 mmol) was gradually added to the mixture, and the mixture was heated and stirred at 110 ° C. for 3 hours. After allowing to cool to room temperature, the reaction mixture was added dropwise to 1 liter of ice water. The precipitated solid was collected by suction filtration, washed with cold water and ether, and dried under vacuum to obtain 11.4 g of Intermediate 3 as a pale yellow solid in a 85% yield.

[中間体4]
中間体3 (11.4 g, 54.6 mmol) と五塩化リン (17.1 g, 82.1 mmol) を300 mLのナスフラスコに加えて還流冷却器と塩化カルシウム管を装着し、予め160度に加熱した油浴中で4時間加熱撹拌した。油浴を外し、反応混合物が固化するまで撹拌しながら約30分放冷した。200 mLのヘキサンを加えて固体をガラス棒で粉砕し、懸濁液を室温で1時間撹拌した。固体を吸引濾取し、200 mLのヘキサンに再懸濁させた。再び固体を吸引濾取し、ヘキサンで入念に洗浄したのちに真空下50度で加熱乾燥させ、中間体4を淡黄色固体として8.80 g、71%収率で得た。 [Intermediate 4]
Intermediate 3 (11.4 g, 54.6 mmol) and phosphorus pentachloride (17.1 g, 82.1 mmol) were added to a 300 mL eggplant flask, fitted with a reflux condenser and a calcium chloride tube, and placed in an oil bath heated to 160 ° C in advance. For 4 hours. The oil bath was removed and allowed to cool for about 30 minutes with stirring until the reaction mixture solidified. 200 mL of hexane was added and the solid was triturated with a glass rod and the suspension was stirred at room temperature for 1 hour. The solid was filtered off with suction and resuspended in 200 mL of hexane. The solid was again collected by suction filtration, washed thoroughly with hexane, and then dried by heating at 50 ° C. under vacuum to obtain 8.80 g of Intermediate 4 as a pale yellow solid in a 71% yield.

1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 8.0 Hz, 1H), 8.31 (s, 1H), 7.80 (d, J = 12.4 Hz, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.75 (d, J = 8.0 Hz, 1H), 8.31 (s, 1H), 7.80 (d, J = 12.4 Hz, 1H).

[中間体5]
中間体5 (8.80 g, 38.7 mmol) と3-クロロ-4-フルオロアニリン (5.86 g, 40.3 mmol) を2-イソプロパノール200 mLとジクロロメタン100 mLの混合溶媒に懸濁し、室温で3時間撹拌した。溶媒を減圧留去したのち、酢酸エチルと飽和重曹水を加えた。水層を酢酸エチルで3回抽出したのち、集めた有機層を飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥させ、濾過したのちに溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー (3:1ヘキサン-酢酸エチル) によって精製し、中間体5を橙色固体として8.00 g、62%収率で得た。 [Intermediate 5]
Intermediate 5 (8.80 g, 38.7 mmol) and 3-chloro-4-fluoroaniline (5.86 g, 40.3 mmol) were suspended in a mixed solvent of 200 mL of 2-isopropanol and 100 mL of dichloromethane, and stirred at room temperature for 3 hours. After evaporating the solvent under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added. After the aqueous layer was extracted three times with ethyl acetate, the collected organic layers were washed with saturated saline. The organic layer was dried over sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (3: 1 hexane-ethyl acetate) to obtain Intermediate 5 as an orange solid (8.00 g, yield 62%).

1H NMR (500 MHz, DMSO-d6) δ 10.49 (s, 1H), 9.57 (d, J = 8.0 Hz, 1H), 8.73 (s, 1H), 8.14-8.11 (m, 1H), 7.84 (d, J= 12.5 Hz, 1H), 7.82-7.78 (m, 1H), 7.48 (t, J= 9.0 Hz, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.49 (s, 1H), 9.57 (d, J = 8.0 Hz, 1H), 8.73 (s, 1H), 8.14-8.11 (m, 1H), 7.84 ( d, J = 12.5 Hz, 1H), 7.82-7.78 (m, 1H), 7.48 (t, J = 9.0 Hz, 1H).

[中間体6]
窒素雰囲気下中間体5 (3.37 g, 10.0 mmol) とトリメチルシラノールカリウム塩 (3.21 g, 25.0 mmol) を40 mLのジメチルホルムアミドに溶解し、室温で10分間撹拌した。これに4-(3-ヒドロキシプロピル)モルホリン(3.46 mL, 25.0 mmol) を加え、60度で5時間加熱撹拌した。反応溶液を酢酸エチルで希釈し、飽和重曹水を加えた。水層を酢酸エチルで3回抽出したのち、集めた有機層を飽和重曹水および飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥させ、濾過したのちに溶媒を減圧留去した。粗生成物をシリカゲルカラムクロマトグラフィー (5:1酢酸エチル-メタノール) によって精製し、黄色固体を得た。この固体を200 mLのエタノールに溶解し、塩化スズ(II) 5.67 g (29.9 mmol) を加えて終夜加熱還流した。室温まで放冷したのち、200 mLの飽和重曹水を加えて室温で20分間撹拌した。クロロホルム-イソプロパノール混合溶媒 (5:1) で希釈し、固形物をセライトで濾別した。有機層を分離し、水層をクロロホルム-イソプロパノール混合溶媒 (5:1) でさらに2回抽出した。集めた有機層を飽和食塩水で洗浄したのち硫酸ナトリウムで乾燥させ、濾過したのちに溶媒を減圧留去した。生じた固体を真空下乾燥させ、中間体6を1.41 g、33%収率で得た。 [Intermediate 6]
Under a nitrogen atmosphere, Intermediate 5 (3.37 g, 10.0 mmol) and potassium trimethylsilanol (3.21 g, 25.0 mmol) were dissolved in 40 mL of dimethylformamide, and the mixture was stirred at room temperature for 10 minutes. To this was added 4- (3-hydroxypropyl) morpholine (3.46 mL, 25.0 mmol), and the mixture was heated with stirring at 60 ° C for 5 hours. The reaction solution was diluted with ethyl acetate, and a saturated aqueous sodium hydrogen carbonate solution was added. After the aqueous layer was extracted three times with ethyl acetate, the collected organic layers were washed with saturated aqueous sodium hydrogen carbonate and saturated saline. The organic layer was dried over sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (5: 1 ethyl acetate-methanol) to obtain a yellow solid. This solid was dissolved in 200 mL of ethanol, 5.67 g (29.9 mmol) of tin (II) chloride was added, and the mixture was heated under reflux overnight. After allowing to cool to room temperature, 200 mL of saturated aqueous sodium hydrogen carbonate was added, and the mixture was stirred at room temperature for 20 minutes. The mixture was diluted with a mixed solvent of chloroform-isopropanol (5: 1), and the solid was filtered off through celite. The organic layer was separated, and the aqueous layer was further extracted twice with a mixed solvent of chloroform-isopropanol (5: 1). The collected organic layer was washed with saturated saline, dried over sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure. The resulting solid was dried under vacuum to give Intermediate 6 in 1.41 g, 33% yield.

1H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.34 (s, 1H), 8.17 (dd, J = 6.5, 2.5 Hz, 1H), 7.81-7.75 (m, 1H), 7.36 (t, J = 9.5 Hz, 1H), 7.35 (s, 1H), 7.06 (s, 1H), 5.32 (s, 2H), 4.17 (t, J = 6.5 Hz, 2H), 3.56 (t, J = 4.5 Hz, 4H), 2.51-2.46 (m, 2H), 2.37 (bs, 4H), 1.96 (quint, J = 6.5 Hz, 2H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.35 (s, 1H), 8.34 (s, 1H), 8.17 (dd, J = 6.5, 2.5 Hz, 1H), 7.81-7.75 (m, 1H), 7.36 (t, J = 9.5 Hz, 1H), 7.35 (s, 1H), 7.06 (s, 1H), 5.32 (s, 2H), 4.17 (t, J = 6.5 Hz, 2H), 3.56 (t, J = 4.5 Hz, 4H), 2.51-2.46 (m, 2H), 2.37 (bs, 4H), 1.96 (quint, J = 6.5 Hz, 2H).

[中間体7]
窒素雰囲気下、中間体6 (1.22 g, 2.83 mmol) とBoc-D-プロリン (936 mg, 4.35 mmol) を30 mLのジクロロメタンに溶解した。これにプロピルホスホン酸無水物 (T3P、50%酢酸エチル溶液, 2.30 mL, 5.63 mmol)、ジイソプロピルエチルアミン (2.0 mL, 11.5 mmol)、および4-ジメチルアミノピリジン(78.0 mg, 0.638 mmol) を順次加え、室温で5時間撹拌した。Boc-D-プロリン (306 mg, 1.42 mmol)、T3P (50%酢酸エチル溶液, 1.15 mL, 2.82 mmol)、ジイソプロピルエチルアミン (1.0 mL, 5.75 mmol) を追加し、さらに3時間室温で撹拌した。この反応溶液に対し20 mLの4規定塩酸-酢酸エチル溶液を加え、室温で1時間撹拌した。飽和重曹水で中和したのち水層を酢酸エチルで3回抽出し、集めた有機層を飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥させ、濾過したのちに溶媒を減圧留去した。粗生成物をシリカゲルカラムクロマトグラフィー (10:1クロロホルム-メタノール) によって精製し、中間体7を淡褐色固体として1.27 g、85%収率で得た。 [Intermediate 7]
Under a nitrogen atmosphere, Intermediate 6 (1.22 g, 2.83 mmol) and Boc-D-proline (936 mg, 4.35 mmol) were dissolved in 30 mL of dichloromethane. To this, propylphosphonic anhydride (T3P, 50% ethyl acetate solution, 2.30 mL, 5.63 mmol), diisopropylethylamine (2.0 mL, 11.5 mmol), and 4-dimethylaminopyridine (78.0 mg, 0.638 mmol) were sequentially added, Stirred at room temperature for 5 hours. Boc-D-proline (306 mg, 1.42 mmol), T3P (50% ethyl acetate solution, 1.15 mL, 2.82 mmol), and diisopropylethylamine (1.0 mL, 5.75 mmol) were added, and the mixture was further stirred at room temperature for 3 hours. To this reaction solution, 20 mL of 4N hydrochloric acid-ethyl acetate solution was added, and the mixture was stirred at room temperature for 1 hour. After neutralization with saturated aqueous sodium hydrogen carbonate, the aqueous layer was extracted three times with ethyl acetate, and the collected organic layers were washed with saturated saline. The organic layer was dried over sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (10: 1 chloroform-methanol) to obtain 1.27 g of Intermediate 7 as a pale brown solid in 85% yield.

1H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H), 9.82 (s, 1H), 9.07 (s, 1H), 8.48 (s, 1H), 8.08-8.04 (m, 1H), 7.77-7.73 (m, 1H), 7.39 (t, J = 9.0 Hz, 1H), 7.26 (s, 1H), 4.27 (t, J = 6.0 Hz, 2H), 3.85-3.76 (m, 1H), 3.57 (t, J = 4.5 Hz, 4H), 3.43 (bs, 1H), 3.05-2.97 (m, 1H), 2.86-2.79 (m, 1H), 2.55 (t, J = 7.5 Hz, 2H), 2.40 (bs, 4H), 2.13-2.05 (m, 1H), 2.02-1.95 (m, 2H), 1.90-1.82 (m, 1H), 1.71-1.60 (m, 2H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.62 (s, 1H), 9.82 (s, 1H), 9.07 (s, 1H), 8.48 (s, 1H), 8.08-8.04 (m, 1H), 7.77-7.73 (m, 1H), 7.39 (t, J = 9.0 Hz, 1H), 7.26 (s, 1H), 4.27 (t, J = 6.0 Hz, 2H), 3.85-3.76 (m, 1H), 3.57 (t, J = 4.5 Hz, 4H), 3.43 (bs, 1H), 3.05-2.97 (m, 1H), 2.86-2.79 (m, 1H), 2.55 (t, J = 7.5 Hz, 2H), 2.40 ( bs, 4H), 2.13-2.05 (m, 1H), 2.02-1.95 (m, 2H), 1.90-1.82 (m, 1H), 1.71-1.60 (m, 2H).

[NS-062二塩酸塩]
窒素雰囲気下、中間体7 (1.23 g, 2.32 mmol) およびクロロフルオロ酢酸ナトリウム (692 mg, 5.14 mmol) を10 mLのジメチルホルムアミドに溶解した。これにT3P (50%酢酸エチル溶液, 1.89 mL, 4.63 mmol)、ジイソプロピルエチルアミン (1.62 mL, 9.30 mmol) を順次加え、室温で4時間撹拌した。クロロフルオロ酢酸ナトリウム塩 (312 mg, 2.32 mmol)、T3P (50%酢酸エチル溶液, 0.95 mL, 2.32 mmol)、ジイソプロピルエチルアミン (0.81 mL, 4.64 mmol) を追加し、室温で終夜撹拌した。反応溶液を酢酸エチルで希釈し、飽和重曹水を加え水層を酢酸エチルで3回抽出したのち集めた有機層を飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥させ、濾過したのちに溶媒を減圧留去した。粗生成物をシリカゲルカラムクロマトグラフィー (3:1酢酸エチル-メタノール) によって精製し、NS-062を淡褐色非晶質として1.01 g、70%収率で得た。 [NS-062 dihydrochloride]
Under a nitrogen atmosphere, Intermediate 7 (1.23 g, 2.32 mmol) and sodium chlorofluoroacetate (692 mg, 5.14 mmol) were dissolved in 10 mL of dimethylformamide. T3P (50% ethyl acetate solution, 1.89 mL, 4.63 mmol) and diisopropylethylamine (1.62 mL, 9.30 mmol) were sequentially added thereto, and the mixture was stirred at room temperature for 4 hours. Chlorofluoroacetic acid sodium salt (312 mg, 2.32 mmol), T3P (50% ethyl acetate solution, 0.95 mL, 2.32 mmol) and diisopropylethylamine (0.81 mL, 4.64 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate was added, the aqueous layer was extracted three times with ethyl acetate, and the collected organic layers were washed with saturated saline. The organic layer was dried over sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (3: 1 ethyl acetate-methanol) to obtain 1.01 g of NS-062 as a light brown amorphous in 70% yield.

1H NMR (500 MHz, DMSO-d6, a pair of two diastereomers) δ 9.88 and 9.87 (s, 1H), 9.76 and 9.50 (s, 1H), 8.80 and 8.71 (s, 1H), 8.14 and 8.13 (s, 1H), 8.15-8.06 (m, 1H), 7.83-7.75 (m, 1H), 7.46-7.39 (m, 1H), 7.30 and 7.28 (s, 1H), 7.20 and 7.15 (d, J = 48.5 Hz, 1H), 4.86-4.71 (m, 1H), 4.32-4.20 (m, 2H), 3.82-3.70 (m, 1H), 3.65-3.50 (m, 6H), 2.40 (bs, 4H), 2.29-2.17 (m, 1H), 2.15-1.90 (m, 6H). 1 H NMR (500 MHz, DMSO-d 6 , a pair of two diastereomers) δ 9.88 and 9.87 (s, 1H), 9.76 and 9.50 (s, 1H), 8.80 and 8.71 (s, 1H), 8.14 and 8.13 ( s, 1H), 8.15-8.06 (m, 1H), 7.83-7.75 (m, 1H), 7.46-7.39 (m, 1H), 7.30 and 7.28 (s, 1H), 7.20 and 7.15 (d, J = 48.5 Hz, 1H), 4.86-4.71 (m, 1H), 4.32-4.20 (m, 2H), 3.82-3.70 (m, 1H), 3.65-3.50 (m, 6H), 2.40 (bs, 4H), 2.29- 2.17 (m, 1H), 2.15-1.90 (m, 6H).

NS-062 (1.01 g, 1.62 mmol) を50 mLの酢酸エチルと5 mLのメタノールに溶解し、4規定塩酸-酢酸エチル溶液 (1.6 mL, 6.4 mmol) を加え室温で15分間撹拌した。溶媒を減圧留去したのち、ジエチルエーテルを加えた。析出した固体を吸引を濾取したのち真空下60度で加熱乾燥させ、NS-062二塩酸塩を淡黄色固体として1.06 g、94%収率で得た。   NS-062 (1.01 g, 1.62 mmol) was dissolved in 50 mL of ethyl acetate and 5 mL of methanol, 4N hydrochloric acid-ethyl acetate solution (1.6 mL, 6.4 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. After the solvent was distilled off under reduced pressure, diethyl ether was added. The precipitated solid was collected by filtration under suction, and then dried by heating at 60 ° C. under vacuum to obtain 1.06 g of NS-062 dihydrochloride as a pale yellow solid in a yield of 94%.

1H NMR (500 MHz, DMSO-d6, a pair of two diastereomers) δ 11.51 (bs, 1H), 11.40 (bs, 1H), 9.96 and 9.94 (s, 1H), 9.12 and 9.07 (s, 1H), 8.89 (s, 1H), 8.00-7.94 (m, 1H), 7.70-7.63 (m, 1H), 7.57-7.49 (m, 2H), 7.27 and 7.19 (d, J = 48.5 Hz, 1H), 5.10-4.92 (m, 1H), 4.4-54.35 (m, 2H), 4.01-3.40 (m, 13H), 2.48-2.40 (m, 2H), 2.39-2.20 (m, 1H), 2.12-1.95 (m, 2H),
 1 H NMR (500 MHz, DMSO-d 6 , a pair of two diastereomers) δ 11.51 (bs, 1H), 11.40 (bs, 1H), 9.96 and 9.94 (s, 1H), 9.12 and 9.07 (s, 1H) , 8.89 (s, 1H), 8.00-7.94 (m, 1H), 7.70-7.63 (m, 1H), 7.57-7.49 (m, 2H), 7.27 and 7.19 (d, J = 48.5 Hz, 1H), 5.10 -4.92 (m, 1H), 4.4-54.35 (m, 2H), 4.01-3.40 (m, 13H), 2.48-2.40 (m, 2H), 2.39-2.20 (m, 1H), 2.12-1.95 (m, 2H),

NSP-037の合成
下記スキームにより、NSP-037化合物（前記表Ｂも参照）を合成した。
各中間体の合成手順も含めて、以下に詳しく説明する。 Synthesis of NSP-037 An NSP-037 compound (see also Table B above) was synthesized according to the following scheme.
This is described in detail below, including the procedure for synthesizing each intermediate.

[中間体9]
5-フルオロ-2-ニトロアニソール (8) (5.03 g, 29.4 mmol) を32 mLのアセトンと4 mLの蒸留水に溶解し、亜鉛粉末(8.10 g, 124 mmol) を加えた。氷冷下、塩化アンモニウム17.0 gを徐々に注意深く加え、室温で終夜撹拌した。セライトで固形物を吸引濾過したのち溶媒を減圧留去し、残渣を水と酢酸エチルで希釈した。有機層を水と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥させた。溶媒を減圧留去したのちシリカゲルカラムクロマトグラフィー (5:1〜3:1 ヘキサン-酢酸エチル) で精製し、中間体9を淡褐色油状物質として2.03 g、50%収率で得た。 [Intermediate 9]
5-Fluoro-2-nitroanisole (8) (5.03 g, 29.4 mmol) was dissolved in 32 mL of acetone and 4 mL of distilled water, and zinc powder (8.10 g, 124 mmol) was added. Under ice cooling, 17.0 g of ammonium chloride was gradually and carefully added, and the mixture was stirred at room temperature overnight. After suction filtration of a solid substance with celite, the solvent was distilled off under reduced pressure, and the residue was diluted with water and ethyl acetate. The organic layer was washed with water and saturated saline, and dried with magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (5: 1 to 3: 1 hexane-ethyl acetate) to obtain 2.03 g of Intermediate 9 as a pale brown oily substance in a 50% yield.

1H NMR (500 MHz, DMSO-d6) δ 7.69-7.63 (m, 1H), 6.78 (dd, J = 11.0, 2.0 Hz, 1H), 6.70 (td, J = 8.4, 1.5 Hz, 1H), 4.00 (s, 3H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.69-7.63 (m, 1H), 6.78 (dd, J = 11.0, 2.0 Hz, 1H), 6.70 (td, J = 8.4, 1.5 Hz, 1H), 4.00 (s, 3H).

[中間体10]
中間体9 (2.0 g, 14.2 mmol) に15 mLの濃硫酸を滴下したのち、氷冷下硝酸カリウム(1.52 g, 15.0 mmol) を徐々に加えた。終夜室温で撹拌したのちに反応混合液を氷水に加え、水酸化ナトリウム水溶液で塩基性とした。析出した固体を濾取し、濾液をジクロロメタンで2回抽出した。濾取した固体も有機層に溶解させ、飽和食塩水で洗浄したのち硫酸ナトリウムで乾燥させた。これを濾過し、濾液にシリカゲルを加えて溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー (3:1~2:1 ヘキサン-酢酸エチル) で精製し、中間体10を黄色固体として1.90 g、72％収率で得た。 [Intermediate 10]
After 15 mL of concentrated sulfuric acid was added dropwise to Intermediate 9 (2.0 g, 14.2 mmol), potassium nitrate (1.52 g, 15.0 mmol) was gradually added under ice-cooling. After stirring at room temperature overnight, the reaction mixture was added to ice water and made basic with aqueous sodium hydroxide. The precipitated solid was collected by filtration, and the filtrate was extracted twice with dichloromethane. The solid collected by filtration was also dissolved in the organic layer, washed with saturated saline, and dried over sodium sulfate. This was filtered, silica gel was added to the filtrate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (3: 1 to 2: 1 hexane-ethyl acetate) to obtain 1.90 g of Intermediate 10 as a yellow solid in a 72% yield.

1H NMR (500 MHz, DMSO-d6) δ 7.34 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 13.0 Hz, 1H), 5.24 (s, 2H), 3.91 (s, 3H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.34 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 13.0 Hz, 1H), 5.24 (s, 2H), 3.91 (s, 3H) .

[中間体12]
窒素雰囲気下、インドール (132 mg, 1.13 mmol) を脱水1,2-ジクロロエタンに溶解し、氷冷下メチルマグネシウムブロミド (3 Mジエチルエーテル溶液, 5.85 mL, 17.6 mmol) を滴下した。氷冷下30分間撹拌したのち、3 mLのジクロロメタンに溶解した2,4-ジクロロ-5-トリフルオロメチルピリミジン (11) (122 mg, 0.56 mmol) を滴下した。室温で2時間、次いで60度で4時間撹拌し、反応溶液を水と酢酸エチルで希釈した。有機層を分離し、水層を酢酸エチルで抽出して集めた有機層を硫酸ナトリウムで乾燥させた。溶媒を減圧留去したのち残渣をシリカゲルカラムクロマトグラフィー (4:1~3:1 ヘキサン-酢酸エチル) で精製し、中間体12を黄色固体として79.2 mg、47%収率で得た。 [Intermediate 12]
Under a nitrogen atmosphere, indole (132 mg, 1.13 mmol) was dissolved in dehydrated 1,2-dichloroethane, and methylmagnesium bromide (3 M diethyl ether solution, 5.85 mL, 17.6 mmol) was added dropwise under ice cooling. After stirring for 30 minutes under ice cooling, 2,4-dichloro-5-trifluoromethylpyrimidine (11) (122 mg, 0.56 mmol) dissolved in 3 mL of dichloromethane was added dropwise. The mixture was stirred at room temperature for 2 hours and then at 60 degrees for 4 hours, and the reaction solution was diluted with water and ethyl acetate. The organic layer was separated, the aqueous layer was extracted with ethyl acetate, and the collected organic layer was dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (4: 1 to 3: 1 hexane-ethyl acetate) to obtain 79.2 mg of Intermediate 12 as a yellow solid in a 47% yield.

1H NMR (400 MHz, DMSO-d6) δ 12.22 (bs, 1H), 9.01 (s, 1H), 8.26 (d, J = 3.2 Hz, 1H), 8.08 (s, 1H), 7.55 (d, J = 3.2 Hz, 1H), 7.25-7.29 (m, 2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.22 (bs, 1H), 9.01 (s, 1H), 8.26 (d, J = 3.2 Hz, 1H), 8.08 (s, 1H), 7.55 (d, J = 3.2 Hz, 1H), 7.25-7.29 (m, 2H).

[中間体13]
中間体12 (78.0 mg, 0.26 mmol)、中間体10 (51.0 mg, 0.28 mmol)、およびパラトルエンスルホン酸一水和物 (55.0 mg, 0.29 mmol) を15 mLの2-ペンタノールに溶解し、終夜加熱還流させた。室温に放冷後、ヘキサンを加えて析出した固体を吸引濾取し、真空下乾燥させて中間体13を黄色固体として84.0 mg、72%収率で得た。 [Intermediate 13]
Intermediate 12 (78.0 mg, 0.26 mmol), Intermediate 10 (51.0 mg, 0.28 mmol), and paratoluenesulfonic acid monohydrate (55.0 mg, 0.29 mmol) were dissolved in 15 mL of 2-pentanol, Heated to reflux overnight. After allowing to cool to room temperature, hexane was added, and the precipitated solid was collected by suction filtration and dried under vacuum to obtain 84.0 mg of Intermediate 13 as a yellow solid in a 72% yield.

1H NMR (400 MHz, DMSO-d6) δ 11.84 (bs, 1H), 9.26 (s, 1H), 8.73 (s, 1H), 8.55 (d, J = 4.2 Hz, 1H), 7.67 (bs, 1H), 7.46-7.48 (m, 2H), 7.17(t, J = 7.8 Hz, 1H), 7.10 (d, J = 4.0 Hz, 1H), 6.98 (bs, 1H), 3.95 (s, 3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.84 (bs, 1H), 9.26 (s, 1H), 8.73 (s, 1H), 8.55 (d, J = 4.2 Hz, 1H), 7.67 (bs, 1H), 7.46-7.48 (m, 2H), 7.17 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 4.0 Hz, 1H), 6.98 (bs, 1H), 3.95 (s, 3H).

[中間体14]
中間体13 (81.0 mg, 0.18 mmol) とN,N,N’-トリメチルエチレンジアミン (0.10 mL, 0.770 mmol) を5 mLのN,N-ジメチルアセトアミドに溶解し、1.5時間120度で加熱撹拌した。室温に放冷したのち飽和重曹水を加え、酢酸エチルで2回抽出した。集めた有機層を飽和食塩水で洗浄したのち硫酸ナトリウムで乾燥し、濾過ののち溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー (150:10:1 クロロホルム-メタノール-24% アンモニア水) で精製し、中間体14を赤色非晶質として56.3 mg, 59%収率で得た。 [Intermediate 14]
Intermediate 13 (81.0 mg, 0.18 mmol) and N, N, N'-trimethylethylenediamine (0.10 mL, 0.770 mmol) were dissolved in 5 mL of N, N-dimethylacetamide, and heated and stirred at 120 degrees for 1.5 hours. After allowing to cool to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted twice with ethyl acetate. The collected organic layer was washed with saturated saline, dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (150: 10: 1 chloroform-methanol-24% aqueous ammonia) to obtain 56.3 mg of Intermediate 14 as a red amorphous in a 59% yield.

1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 9.04 (s, 1H), 8.65 (s, 1H), 8.08-7.99 (m, 2H), 7.85 (s, 1H), 7.44 (d, J = 4.0 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.02-6.94 (m, 1H), 6.81 (s, 1H), 3.87 (s, 3H), 3.35-3.20 (m, 2H), 2.85 (s, 3H), 2.49-2.45 (m, 2H), 2.14 (s, 6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.79 (s, 1H), 9.04 (s, 1H), 8.65 (s, 1H), 8.08-7.99 (m, 2H), 7.85 (s, 1H), 7.44 (d, J = 4.0 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.02-6.94 (m, 1H), 6.81 (s, 1H), 3.87 (s, 3H), 3.35-3.20 (m, 2H), 2.85 (s, 3H), 2.49-2.45 (m, 2H), 2.14 (s, 6H).

[中間体15]
中間体14 (55.0 mg, 0.104 mmol) を9 mLのエタノールと3 mLの水に溶解し、鉄粉末 (29.0 mg, 0.519 mmol) および塩化アンモニウム (5.6 mg, 0.104 mmol) を加え2.5時間加熱還流した。溶媒を減圧留去したのち、30 mLのクロロホルムと3 mLのメタノールを加え室温で30分間撹拌した。溶液を濾過し、濾液を硫酸マグネシウムで乾燥させた。濾過ののち溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー (100:10:1 クロロホルム-メタノール-24% アンモニア水) で精製した。得られた非晶質をジエチルエーテルに溶解し、PTFEメンブレンフィルターで濾過したのち溶媒を減圧留去することで中間体15を黄色固体として30.0 mg、59%収率で得た。 [Intermediate 15]
Intermediate 14 (55.0 mg, 0.104 mmol) was dissolved in 9 mL of ethanol and 3 mL of water, and iron powder (29.0 mg, 0.519 mmol) and ammonium chloride (5.6 mg, 0.104 mmol) were added, and the mixture was heated under reflux for 2.5 hours. . After evaporating the solvent under reduced pressure, 30 mL of chloroform and 3 mL of methanol were added, and the mixture was stirred at room temperature for 30 minutes. The solution was filtered and the filtrate was dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (100: 10: 1 chloroform-methanol-24% aqueous ammonia). The obtained amorphous was dissolved in diethyl ether, filtered through a PTFE membrane filter, and the solvent was distilled off under reduced pressure to obtain 30.0 mg of Intermediate 15 as a yellow solid in a 59% yield.

1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.79 (s, 1H), 8.59 (s, 1H), 8.12 (bs, 1H), 7.84 (s, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 7.01 (bs, 1H), 6.94 (s, 1H), 6.76 (s, 1H), 3.66 (s, 3H), 2.92 (t, J= 6.6 Hz, 2H), 2.63 (s, 3H), 2.48 (t, J= 6.6 Hz, 2H), 2,22 (s, 6H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.76 (s, 1H), 8.79 (s, 1H), 8.59 (s, 1H), 8.12 (bs, 1H), 7.84 (s, 1H), 7.43 ( d, J = 7.2 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 7.01 (bs, 1H), 6.94 (s, 1H), 6.76 (s, 1H), 3.66 (s, 3H), 2.92 (t, J = 6.6 Hz, 2H), 2.63 (s, 3H), 2.48 (t, J = 6.6 Hz, 2H), 2,22 (s, 6H).

[中間体16]
窒素雰囲気下、中間体15 (29.0 mg, 0.0581 mmol) とBoc-L-アラニン (22.0 mg, 0.116 mmol) を3 mLのジクロロメタンに溶解した。これにプロピルホスホン酸無水物 (T3P、50%酢酸エチル溶液, 68.4μL, 0.116 mmol) およびジイソプロピルエチルアミン (30.0μL, 0.174 mmol) を加え、室温で1時間撹拌した。反応溶液に飽和重曹水を加え、ジクロロメタン-イソプロパノール混合溶媒(4:1) で2回抽出し、集めた有機層を飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥させ、濾過したのちに溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー (150:10:1 クロロホルム-メタノール-24% アンモニア水) によって精製し、黄色油状物質を得た。
これを1 mLの酢酸エチルに溶解し、4規定塩酸-酢酸エチル溶液 (1.5 mL) を加え室温で30分間撹拌した。飽和重曹水で溶液を塩基性にしたのち、ジクロロメタン-イソプロパノール混合溶媒(4:1) で2回抽出し、集めた有機層を飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥させ、濾過したのちに溶媒を減圧留去し、中間体16を黄色非晶質として30.0 mg, 91%収率で得た。 [Intermediate 16]
Under a nitrogen atmosphere, intermediate 15 (29.0 mg, 0.0581 mmol) and Boc-L-alanine (22.0 mg, 0.116 mmol) were dissolved in 3 mL of dichloromethane. To this were added propylphosphonic anhydride (T3P, 50% ethyl acetate solution, 68.4 μL, 0.116 mmol) and diisopropylethylamine (30.0 μL, 0.174 mmol), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted twice with a mixed solvent of dichloromethane and isopropanol (4: 1). The collected organic layer was washed with saturated saline. The organic layer was dried over sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (150: 10: 1 chloroform-methanol-24% aqueous ammonia) to obtain a yellow oily substance.
This was dissolved in 1 mL of ethyl acetate, 4N hydrochloric acid-ethyl acetate solution (1.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. After making the solution basic with saturated aqueous sodium bicarbonate, the mixture was extracted twice with a mixed solvent of dichloromethane and isopropanol (4: 1), and the collected organic layers were washed with saturated saline. The organic layer was dried over sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure to obtain 30.0 mg of Intermediate 16 as a yellow amorphous in a 91% yield.

1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 10.17 (bs, 1H), 9.07 (s, 1H), 8.59 (s, 1H), 8.39 (s, 1H), 8.03 (bs, 1H), 7.84 (s, 1H), 7.41 (d, J = 3.8 Hz, 1H), 7.11 (t, J = 8.4 Hz, 1H), 7.00 (s, 1H), 6.93 (bs, 1H), 3.74 (s, 3H), 3.40-3.35 (m, 1H), 2.97 (t, J = 7.0 Hz, 2H), 2.69 (s, 3H), 2.39 (t, J = 7.0 Hz, 2H), 2.14 (s, 6H), 1.21 (d, J = 3.4 Hz, 3H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.74 (s, 1H), 10.17 (bs, 1H), 9.07 (s, 1H), 8.59 (s, 1H), 8.39 (s, 1H), 8.03 ( bs, 1H), 7.84 (s, 1H), 7.41 (d, J = 3.8 Hz, 1H), 7.11 (t, J = 8.4 Hz, 1H), 7.00 (s, 1H), 6.93 (bs, 1H), 3.74 (s, 3H), 3.40-3.35 (m, 1H), 2.97 (t, J = 7.0 Hz, 2H), 2.69 (s, 3H), 2.39 (t, J = 7.0 Hz, 2H), 2.14 (s , 6H), 1.21 (d, J = 3.4 Hz, 3H).

[NSP-037]
窒素雰囲気下、中間体16 (29.0 mg, 0.0508 mmol) とクロロフルオロ酢酸ナトリウム (21.0 mg，0.153 mmol) を3 mLのジクロロメタンに溶解した。これにプロピルホスホン酸無水物 (T3P、50%酢酸エチル溶液, 90.0μL, 0.153 mmol)、ジイソプロピルエチルアミン (27.0μL, 0.153 mmol)、および4-ジメチルアミノピリジン(3.1 mg, 0.0254 mmol) を順次加え、室温で4.5時間撹拌した。反応溶液に飽和重曹水を加え、酢酸エチルで2回抽出し、集めた有機層を飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥させ、濾過したのちに溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー (150:10:1 クロロホルム-メタノール-24% アンモニア水) によって精製したのち、得られた油状物質をPTFEメンブレンフィルターで濾過した。これを少量の酢酸エチルに溶解し、ヘキサンを加えて析出した固体を濾取し、真空下乾燥させることでNSP-037を白色固体として20.0 mg、58%収率で得た。 [NSP-037]
Under a nitrogen atmosphere, Intermediate 16 (29.0 mg, 0.0508 mmol) and sodium chlorofluoroacetate (21.0 mg, 0.153 mmol) were dissolved in 3 mL of dichloromethane. To this, propylphosphonic anhydride (T3P, 50% ethyl acetate solution, 90.0 μL, 0.153 mmol), diisopropylethylamine (27.0 μL, 0.153 mmol), and 4-dimethylaminopyridine (3.1 mg, 0.0254 mmol) were sequentially added, Stirred at room temperature for 4.5 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The collected organic layers were washed with saturated saline. The organic layer was dried over sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (150: 10: 1 chloroform-methanol-24% aqueous ammonia), and the obtained oil was filtered through a PTFE membrane filter. This was dissolved in a small amount of ethyl acetate, hexane was added, and the precipitated solid was collected by filtration and dried under vacuum to obtain 20.0 mg of NSP-037 as a white solid in a 58% yield.

1H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 9.78 (s, 1H), 9.09 (s, 1H), 9.00 (t, J = 8.5 Hz, 1H), 8.61 (s, 1H), 8.21 (s, 1H), 8.05 (bs, 1H), 7.85 (s, 1H), 7.43 (d, J = 4.0 Hz, 1H), 7.12 (t, J = 7.3 Hz, 1H), 7.03 (s, 1H), 6.96 (bs, 1H), 6.78 (d, J = 47.0 Hz, 1H), 4.53-4.48 (m, 1H), 3.76 (s, 3H), 3.00-2.91 (m, 2H), 2.69 (s, 3H), 2.37-2.35 (m, 2H), 2.20 (s, 6H), 1.34 (d, J = 6.5 Hz, 3H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.77 (s, 1H), 9.78 (s, 1H), 9.09 (s, 1H), 9.00 (t, J = 8.5 Hz, 1H), 8.61 (s, 1H), 8.21 (s, 1H), 8.05 (bs, 1H), 7.85 (s, 1H), 7.43 (d, J = 4.0 Hz, 1H), 7.12 (t, J = 7.3 Hz, 1H), 7.03 ( s, 1H), 6.96 (bs, 1H), 6.78 (d, J = 47.0 Hz, 1H), 4.53-4.48 (m, 1H), 3.76 (s, 3H), 3.00-2.91 (m, 2H), 2.69 (s, 3H), 2.37-2.35 (m, 2H), 2.20 (s, 6H), 1.34 (d, J = 6.5 Hz, 3H).

NSP-037は立体異性体の混合物であり、いくつかのピークは二重に重なって観測された。 NSP-037 was a mixture of stereoisomers, and some peaks were observed as double overlap.

Claims (21)

下記式(I)：
〔式(I)中、
L1はリンカー部を表し、
R1は、水素原子、又は任意に置換されていてもよい炭化水素基を表し、場合によりL1の一部と環構造を形成していてもよく、
R2及びR3は、それぞれ独立して、任意に置換されていてもよい任意の構造の有機基を表し、
m及びnは、それぞれ独立して、０〜２の整数を表す。〕
で示される化合物、又はその薬理学的に許容し得る塩。 The following formula (I):
(In the formula (I),
L 1 represents a linker moiety,
R 1 represents a hydrogen atom or a hydrocarbon group which may be optionally substituted, and may optionally form a ring structure with a part of L 1 ;
R 2 and R 3 each independently represent an organic group having any structure that may be optionally substituted,
m and n each independently represent an integer of 0 to 2. ]
Or a pharmacologically acceptable salt thereof. 前記リンカー部は、単結合、又は、-RL1-NH-若しくは-RL1-CO-NH-（ここで、RL1は任意に置換されていてもよい任意の構造の有機基を表す。）を表す、請求項１記載の化合物、又はその薬理学的に許容し得る塩。 The linker moiety is a single bond or —RL 1 —NH— or —RL 1 —CO—NH— (where R L1 represents an organic group having any structure that may be optionally substituted.) The compound according to claim 1, which represents: or a pharmacologically acceptable salt thereof. 下記式(II)：
〔式(II)中、L2はリンカー部を表し、
R4は、水素原子、又は任意に置換されていてもよい炭化水素基を表し、場合によりL2の一部と環構造を形成していてもよく、
R5は、それぞれ独立して、任意に置換されていてもよい任意の構造の有機基を表し、
pは、０〜２の整数を表す。〕
で示される化合物、又はその薬理学的に許容し得る塩。 Formula (II) below:
(In the formula (II), L 2 represents a linker moiety,
R 4 represents a hydrogen atom or a hydrocarbon group which may be optionally substituted, and optionally may form a ring structure with a part of L 2 ;
R 5 each independently represents an organic group having any structure that may be optionally substituted,
p represents an integer of 0 to 2. ]
Or a pharmacologically acceptable salt thereof. 前記リンカー部は、単結合、又は、-RL2-NH-（ここで、RL2は任意に置換されていてもよい任意の構造の有機基を表す。）を表す、請求項３記載の化合物、又はその薬理学的に許容し得る塩。 The compound according to claim 3, wherein the linker moiety represents a single bond or —R L2 —NH— (where R L2 represents an organic group having an arbitrary structure that may be optionally substituted). Or a pharmacologically acceptable salt thereof. 式(I)で示される化合物が、下記構造式で示される化合物からなる群から選ばれる少なくとも１つである、請求項１又は２記載の化合物、又はその薬理学的に許容し得る塩。
3. The compound according to claim 1 or 2, wherein the compound represented by the formula (I) is at least one selected from the group consisting of compounds represented by the following structural formulas, or a pharmaceutically acceptable salt thereof.
式(II)で示される化合物が、下記構造式で示される化合物からなる群から選ばれる少なくとも１つである、請求項３又は４記載の化合物、又はその薬理学的に許容し得る塩。
The compound according to claim 3 or 4, wherein the compound represented by the formula (II) is at least one selected from the group consisting of compounds represented by the following structural formulas, or a pharmacologically acceptable salt thereof.
請求項１〜６のいずれか１項に記載の化合物、又はその薬理学的に許容し得る塩、あるいはそれらの水和物若しくは溶媒和物を有効成分として含む、医薬組成物又は試薬。   A pharmaceutical composition or a reagent comprising, as an active ingredient, the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. 腫瘍の治療用のものである、請求項７記載の医薬組成物又は試薬。   The pharmaceutical composition or reagent according to claim 7, which is used for treating a tumor. 腫瘍が、肺がん、乳がん、前立腺がん、頭部がん、頸部がん、皮膚がん、卵巣がん、子宮内膜がん、甲状腺がん、結腸がん、直腸がん、食道がん、胃がん、腎臓がん、肝臓がん、膀胱がん、膵臓がん、脳腫瘍、脊髄腫瘍、血液がん、及び骨がんからなる群より選ばれる少なくとも１種である、請求項８記載の医薬組成物又は試薬。   Tumors are lung, breast, prostate, head, neck, skin, ovary, endometrial, thyroid, colon, rectum, esophagus The medicament according to claim 8, which is at least one selected from the group consisting of stomach cancer, kidney cancer, liver cancer, bladder cancer, pancreatic cancer, brain tumor, spinal cord tumor, blood cancer, and bone cancer. Composition or reagent. 腫瘍が、非小細胞肺がんである、請求項８又は９記載の医薬組成物又は試薬。   The pharmaceutical composition or reagent according to claim 8 or 9, wherein the tumor is a non-small cell lung cancer. 請求項１〜６のいずれか１項に記載の化合物、又はその薬理学的に許容し得る塩、あるいはそれらの水和物若しくは溶媒和物を有効成分として含む、EGFR阻害剤。   An EGFR inhibitor comprising the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. コバレント阻害剤である、請求項１１記載の阻害剤。   The inhibitor according to claim 11, which is a covalent inhibitor. 腫瘍の治療用の薬剤を製造するための請求項１〜６のいずれか１項に記載の化合物、又はその薬理学的に許容し得る塩、あるいはそれらの水和物若しくは溶媒和物の使用。   Use of the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, for the manufacture of a medicament for treating a tumor. 腫瘍が、肺がん、乳がん、前立腺がん、頭部がん、頸部がん、皮膚がん、卵巣がん、子宮内膜がん、甲状腺がん、結腸がん、直腸がん、食道がん、胃がん、腎臓がん、肝臓がん、膀胱がん、膵臓がん、脳腫瘍、脊髄腫瘍、血液がん、及び骨がんからなる群より選ばれる少なくとも１種である、請求項１３記載の使用。   Tumors are lung, breast, prostate, head, neck, skin, ovary, endometrial, thyroid, colon, rectum, esophagus The use according to claim 13, which is at least one selected from the group consisting of, stomach cancer, kidney cancer, liver cancer, bladder cancer, pancreatic cancer, brain tumor, spinal cord tumor, blood cancer, and bone cancer. . 腫瘍が、非小細胞肺がんである、請求項１３又は１４記載の使用。   15. Use according to claim 13 or 14, wherein the tumor is a non-small cell lung cancer. 請求項１〜６のいずれか１項に記載の化合物、又はその薬理学的に許容し得る塩、あるいはそれらの水和物若しくは溶媒和物を含む、腫瘍の治療用キット。   A kit for treating a tumor, comprising the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. 腫瘍が、肺がん、乳がん、前立腺がん、頭部がん、頸部がん、皮膚がん、卵巣がん、子宮内膜がん、甲状腺がん、結腸がん、直腸がん、食道がん、胃がん、腎臓がん、肝臓がん、膀胱がん、膵臓がん、脳腫瘍、脊髄腫瘍、血液がん、及び骨がんからなる群より選ばれる少なくとも１種である、請求項１６記載のキット。   Tumors are lung, breast, prostate, head, neck, skin, ovary, endometrial, thyroid, colon, rectum, esophagus 17. The kit according to claim 16, wherein the kit is at least one selected from the group consisting of stomach cancer, kidney cancer, liver cancer, bladder cancer, pancreatic cancer, brain tumor, spinal cord tumor, blood cancer, and bone cancer. . 腫瘍が、非小細胞肺がんである、請求項１６又は１７記載のキット。   The kit according to claim 16 or 17, wherein the tumor is a non-small cell lung cancer. 請求項１〜６のいずれか１項に記載の化合物、又はその薬理学的に許容し得る塩、あるいはそれらの水和物若しくは溶媒和物を被験対象に投与することを特徴とする、腫瘍の治療方法。   A compound according to any one of claims 1 to 6, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, which is administered to a subject. Method of treatment. 腫瘍が、肺がん、乳がん、前立腺がん、頭部がん、頸部がん、皮膚がん、卵巣がん、子宮内膜がん、甲状腺がん、結腸がん、直腸がん、食道がん、胃がん、腎臓がん、肝臓がん、膀胱がん、膵臓がん、脳腫瘍、脊髄腫瘍、血液がん、及び骨がんからなる群より選ばれる少なくとも１種である、請求項１９記載の方法。   Tumors are lung, breast, prostate, head, neck, skin, ovary, endometrial, thyroid, colon, rectum, esophagus 20. The method according to claim 19, wherein the method is at least one selected from the group consisting of stomach cancer, kidney cancer, liver cancer, bladder cancer, pancreatic cancer, brain tumor, spinal cord tumor, blood cancer, and bone cancer. . 腫瘍が、非小細胞肺がんである、請求項１９又は２０記載の方法。   21. The method according to claim 19 or 20, wherein the tumor is a non-small cell lung cancer.
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