JPWO2021155262A5 - - Google Patents

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JPWO2021155262A5
JPWO2021155262A5 JP2022546069A JP2022546069A JPWO2021155262A5 JP WO2021155262 A5 JPWO2021155262 A5 JP WO2021155262A5 JP 2022546069 A JP2022546069 A JP 2022546069A JP 2022546069 A JP2022546069 A JP 2022546069A JP WO2021155262 A5 JPWO2021155262 A5 JP WO2021155262A5
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cancer
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cell
treatment
brg1
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JP2023512039A (en
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Priority claimed from PCT/US2021/015876 external-priority patent/WO2021155262A1/en
Publication of JP2023512039A publication Critical patent/JP2023512039A/en
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他の実施形態は、特許請求の範囲に見出される。
以下に、上記実施形態から把握できる技術思想を付記として記載する。
［付記１］
以下の構造を有する化合物：

またはその薬学的に許容される塩。
［付記２］
前記化合物が、以下の構造：

を有するか、またはその薬学的に許容される塩である、付記１に記載の化合物。
［付記３］
前記化合物が、以下の構造：

を有するか、またはその薬学的に許容される塩である、付記２に記載の化合物。
［付記４］
前記化合物が、以下の構造：

を有するか、またはその薬学的に許容される塩である、付記１に記載の化合物。
［付記５］
以下の構造を有する化合物：

またはその薬学的に許容される塩。
［付記６］
前記化合物が、以下の構造：

を有するか、またはその薬学的に許容される塩である、付記５に記載の化合物。
［付記７］
前記化合物が、以下の構造：

を有するか、またはその薬学的に許容される塩である、付記６に記載の化合物。
［付記８］
前記化合物が、以下の構造：

を有するか、またはその薬学的に許容される塩である、付記５に記載の化合物。
［付記９］
付記１～８のいずれか１項に記載の化合物及び薬学的に許容される賦形剤を含む、医薬組成物。
［付記１０］
細胞または対象におけるＢＡＦ複合体の活性を低下させる方法であって、前記細胞を有効量の付記１～８のいずれか１項に記載の化合物または付記９に記載の医薬組成物と接触させるか、または前記対象にそれを投与することを含む、前記方法。
［付記１１］
細胞または対象におけるＢＲＭを阻害する方法であって、前記細胞を有効量の付記１～８のいずれか１項に記載の化合物または付記９に記載の医薬組成物と接触させるか、または前記対象にそれを投与することを含む、前記方法。
［付記１２］
細胞または対象におけるＢＲＧ１を阻害する方法であって、前記細胞を有効量の付記１～８のいずれか１項に記載の化合物または付記９に記載の医薬組成物と接触させるか、または前記対象にそれを投与することを含む、前記方法。
［付記１３］
細胞または対象におけるＢＲＭ及びＢＲＧ１を阻害する方法であって、前記細胞を有効量の付記１～８のいずれか１項に記載の化合物または付記９に記載の医薬組成物と接触させるか、または前記対象にそれを投与することを含む、前記方法。
［付記１４］
細胞または対象におけるアポトーシスを誘導する方法であって、前記細胞を有効量の付記１～８のいずれか１項に記載の化合物または付記９に記載の医薬組成物と接触させるか、または前記対象にそれを投与することを含む、前記方法。
［付記１５］
前記細胞ががん細胞である、及び／または前記対象ががんを有する、付記１０～１４のいずれか１項に記載の方法。
［付記１６］
ＢＡＦ複合体関連障害の治療を、それを必要とする対象において行う方法であって、前記対象に、有効量の付記１～８のいずれか１項に記載の化合物または付記９に記載の医薬組成物を投与することを含む、前記方法。
［付記１７］
ＢＲＧ１機能喪失変異に関連する障害の治療を、それを必要とする対象において行う方法であって、前記対象に、有効量の付記１～８のいずれか１項に記載の化合物または付記９に記載の医薬組成物を投与することを含む、前記方法。
［付記１８］
前記対象が、ＢＲＧ１機能喪失障害を有すると決定される、付記１６または１７に記載の方法。
［付記１９］
前記ＢＡＦ複合体関連障害またはＢＲＧ１機能喪失変異に関連する障害が、がん、ウイルス感染、コフィン・シリス、神経線維腫症（例えば、ＮＦ－１、ＮＦ－２、または多発性神経鞘腫症）または多発性髄膜腫である、付記１６～１８のいずれか１項に記載の方法。
［付記２０］
がんの治療を、それを必要とする対象において行う方法であって、前記対象に、有効量の付記１～８のいずれか１項に記載の化合物または付記９に記載の医薬組成物を投与することを含む、前記方法。
［付記２１］
がんの腫瘍成長を減少させることを、それを必要とする対象において行う方法であって、前記対象に、有効量の付記１～８のいずれか１項に記載の化合物または付記９に記載の医薬組成物を投与することを含む、前記方法。
［付記２２］
がんの転移性進行を抑制することを、それを必要とする対象において行う方法であって、前記対象に、有効量の付記１～８のいずれか１項に記載の化合物または付記９に記載の医薬組成物を投与することを含む、前記方法。
［付記２３］
がんの転移性コロニー形成を抑制することを、それを必要とする対象において行う方法であって、前記対象に、有効量の付記１～８のいずれか１項に記載の化合物または付記９に記載の医薬組成物を投与することを含む、前記方法。
［付記２４］
がん中でのＢＲＧ１及び／またはＢＲＭのレベル及び／または活性を低下させることを、それを必要とする対象において行う方法であって、前記対象に、有効量の付記１～８のいずれか１項に記載の化合物または付記９に記載の医薬組成物を投与することを含む、前記方法。
［付記２５］
前記がんが、非小細胞肺癌、大腸癌、膀胱癌、原発不明癌、神経膠腫、乳癌、黒色腫、非黒色腫皮膚癌、子宮内膜癌、食道胃癌、食道癌、膵癌、肝胆道癌、軟組織肉腫、卵巣癌、頭頸部癌、腎細胞癌、骨癌、非ホジキンリンパ腫、小細胞肺癌、前立腺癌、胎児性腫瘍、胚細胞腫瘍、子宮頸癌、甲状腺癌、唾液腺癌、消化管神経内分泌腫瘍、子宮肉腫、胃腸間質腫瘍、ＣＮＳ癌、胸腺腫瘍、副腎皮質癌、虫垂癌、小腸癌、陰茎癌、骨癌、または血液癌である、付記２０～２４のいずれか１項に記載の方法。
［付記２６］
前記がんが、食道癌である、付記２５に記載の方法。
［付記２７］
前記がんが、非小細胞肺癌、大腸癌、膀胱癌、原発不明癌、神経膠腫、乳癌、黒色腫、非黒色腫皮膚癌、子宮内膜癌、陰茎癌、骨癌、腎細胞癌、前立腺癌、または血液癌である、付記２５に記載の方法。
［付記２８］
前記がんが、非小細胞肺癌である、付記２５に記載の方法。
［付記２９］
前記がんが、黒色腫、前立腺癌、乳癌、骨癌、腎細胞癌、または血液癌である、付記２７に記載の方法。
［付記３０］
前記がんが、黒色腫である、付記２９に記載の方法。
［付記３１］
前記黒色腫が、ブドウ膜黒色腫、粘膜黒色腫、または皮膚黒色腫である、付記３０に記載の方法。
［付記３２］
前記黒色腫が、ブドウ膜黒色腫である、付記３１に記載の方法。
［付記３３］
前記がんが、前立腺癌である、付記２９に記載の方法。
［付記３４］
前記がんが、血液癌である、付記２９に記載の方法。
［付記３５］
前記血液癌が、多発性骨髄腫、大細胞リンパ腫、急性Ｔ細胞白血病、急性骨髄性白血病、骨髄異形成症候群、免疫グロブリンＡラムダ骨髄腫、びまん性混合型組織球性リンパ腫及びリンパ球性リンパ腫、Ｂ細胞リンパ腫、急性リンパ芽球性白血病、びまん性大細胞リンパ腫、または非ホジキンリンパ腫である、付記３４に記載の方法。
［付記３６］
前記がんが、乳癌である、付記２９に記載の方法。
［付記３７］
前記乳癌が、ＥＲ陽性乳癌、ＥＲ陰性乳癌、トリプルポジティブ乳癌、またはトリプルネガティブ乳癌である、付記３６に記載の方法。
［付記３８］
前記がんが、骨癌である、付記２７に記載の方法。
［付記３９］
前記骨癌が、ユーイング肉腫である、付記３８に記載の方法。
［付記４０］
前記がんが、腎細胞癌腫である、付記２７に記載の方法。
［付記４１］
前記腎細胞癌が、小眼球症転写因子ファミリー転座腎細胞癌である、付記４０に記載の方法。
［付記４２］
前記がんが、ＢＲＧ１及び／またはＢＲＭタンパク質を発現する、付記２０～４１のいずれか１項に記載の方法。
［付記４３］
前記対象またはがんが、ＢＲＧ１機能喪失変異を有する、付記２０～４２のいずれか１項に記載の方法。
［付記４４］
前記ＢＲＧ１機能喪失変異が、前記タンパク質のＡＴＰアーゼ触媒ドメインにある、付記４３に記載の方法。
［付記４５］
前記ＢＲＧ１機能喪失変異が、ＢＲＧ１のＣ末端での欠失である、付記４３に記載の方法。
［付記４６］
前記がんが、上皮成長因子受容体変異及び／または未分化リンパ腫キナーゼ駆動因子変異を有さない、または有さないと決定されている、付記２０～４５のいずれか１項に記載の方法。
［付記４７］
前記がんが、ＫＲＡＳ変異、ＧＮＡＱ中の変異、ＧＮＡ１１中の変異、ＰＬＣＢ４中の変異、ＣＹＳＬＴＲ２中の変異、ＢＡＰ１中の変異、ＳＦ３Ｂ１中の変異、ＥＩＦ１ＡＸ中の変異、ＴＦＥ３転座、ＴＦＥＢ転座、ＭＩＴＦ転座、ＥＺＨ２変異、ＳＵＺ１２変異、及び／またはＥＥＤ変異を有する、または有すると決定されている、付記２０～４６のいずれか１項に記載の方法。
［付記４８］
前記がんが、転移性である、付記２０～４７のいずれか１項に記載の方法。
［付記４９］
前記がんが、抗がん療法に耐性があるか、または抗がん療法による以前の治療に応答していない、付記２０～４８のいずれか１項に記載の方法。
［付記５０］
前記抗がん療法が、化学療法剤または細胞傷害性剤、免疫療法、外科手術、放射線療法、温熱療法、または光凝固、またはそれらの組み合わせである、付記４９に記載の方法。
［付記５１］
前記抗がん療法が、化学療法剤または細胞傷害性剤である、付記５０に記載の方法。
［付記５２］
前記化学療法剤または細胞傷害性剤が、マイトジェン活性化プロテインキナーゼ（ＭＥＫ）阻害剤及び／またはプロテインキナーゼＣ（ＰＫＣ）阻害剤である、付記５１に記載の方法。
［付記５３］
前記がんが、ＰＫＣ阻害剤に耐性があるか、またはＰＫＣ阻害剤による以前の治療に応答していない、付記２０～５２のいずれか１項に記載の方法。
［付記５４］
前記方法が、抗がん療法を前記対象に施すことをさらに含む、付記２０～５３のいずれか１項に記載の方法。
［付記５５］
前記抗がん療法が、化学療法剤または細胞傷害性剤、免疫療法、外科手術、放射線療法、温熱療法、または光凝固、またはそれらの組み合わせである、付記５４に記載の方法。
［付記５６］
前記抗がん療法が、外科手術、ＭＥＫ阻害剤、及び／またはＰＫＣ阻害剤、またはそれらの組み合わせである、付記５４または５５に記載の方法。
［付記５７］
前記ＭＥＫ阻害剤が、セルメチニブ、ビニメチニブ、またはタメチニブである、付記５６に記載の方法。
［付記５８］
前記ＰＫＣ阻害剤が、ソトラスタウリンまたはＩＤＥ１９６である、付記５６に記載の方法。
［付記５９］
ウイルス感染症の治療を、それを必要とする対象において行う方法であって、前記対象に、有効量の付記１～８のいずれか１項に記載の化合物または付記９に記載の医薬組成物を投与することを含む、前記方法。
［付記６０］
前記ウイルス感染症が、Ｒｅｔｒｏｖｉｒｉｄａｅ科のウイルス、Ｈｅｐａｄｎａｖｉｒｉｄａｅ科のウイルス、Ｆｌａｖｉｖｉｒｉｄａｅ科のウイルス、Ａｄｅｎｏｖｉｒｉｄａｅ科のウイルス、Ｈｅｒｐｅｓｖｉｒｉｄａｅ科のウイルス、Ｐａｐｉｌｌｏｍａｖｉｒｉｄａｅ科のウイルス、Ｐａｒｖｏｖｉｒｉｄａｅ科のウイルス、Ｐｏｌｙｏｍａｖｉｒｉｄａｅ科のウイルス、Ｐａｒａｍｙｘｏｖｉｒｉｄａｅ科のウイルス、またはＴｏｇａｖｉｒｉｄａｅ科のウイルスによる感染症である、付記５９に記載の方法。
［付記６１］
前記有効量の前記化合物が、参照と比較して、ＢＲＧ１のレベル及び／または活性を少なくとも５％低下させる、付記１０～６０のいずれか１項に記載の方法。
［付記６２］
前記有効量の前記化合物が、参照と比較して、少なくとも１２時間、ＢＲＧ１のレベル及び／または活性を少なくとも５％低下させる、付記６１に記載の方法。
［付記６３］
前記有効量の前記化合物が、参照と比較して、ＢＲＭのレベル及び／または活性を少なくとも５％低下させる、付記１０～６２のいずれか１項に記載の方法。
［付記６４］
前記有効量の前記化合物が、参照と比較して、少なくとも１２時間、ＢＲＭのレベル及び／または活性を少なくとも５％低下させる、付記６３に記載の方法。 Other embodiments are found in the claims.
Below, technical ideas that can be understood from the above embodiments will be described as additional notes.
[Additional note 1]
Compounds with the following structure:

or a pharmaceutically acceptable salt thereof.
[Additional note 2]
The compound has the following structure:

or a pharmaceutically acceptable salt thereof.
[Additional note 3]
The compound has the following structure:

or a pharmaceutically acceptable salt thereof.
[Additional note 4]
The compound has the following structure:

or a pharmaceutically acceptable salt thereof.
[Additional note 5]
Compounds with the following structure:

or a pharmaceutically acceptable salt thereof.
[Additional note 6]
The compound has the following structure:

or a pharmaceutically acceptable salt thereof.
[Additional note 7]
The compound has the following structure:

or a pharmaceutically acceptable salt thereof.
[Additional note 8]
The compound has the following structure:

or a pharmaceutically acceptable salt thereof.
[Additional note 9]
A pharmaceutical composition comprising a compound according to any one of Supplementary Notes 1 to 8 and a pharmaceutically acceptable excipient.
[Additional note 10]
A method of reducing the activity of a BAF complex in a cell or a subject, the method comprising: contacting said cell with an effective amount of a compound according to any one of appendices 1 to 8 or a pharmaceutical composition according to appendix 9; or said method comprising administering said same to said subject.
[Additional note 11]
A method of inhibiting BRM in a cell or a subject, the method comprising: contacting said cell with an effective amount of a compound according to any one of appendices 1 to 8 or a pharmaceutical composition according to appendix 9; said method comprising administering the same.
[Additional note 12]
A method of inhibiting BRG1 in a cell or a subject, the method comprising: contacting said cell with an effective amount of a compound according to any one of appendices 1 to 8 or a pharmaceutical composition according to appendix 9; said method comprising administering the same.
[Additional note 13]
A method of inhibiting BRM and BRG1 in a cell or a subject, the method comprising: contacting said cell with an effective amount of a compound according to any one of appendices 1 to 8 or a pharmaceutical composition according to appendix 9; The method comprises administering the same to a subject.
[Additional note 14]
A method of inducing apoptosis in a cell or a subject, the method comprising: contacting said cell with an effective amount of a compound according to any one of appendices 1 to 8 or a pharmaceutical composition according to appendix 9; said method comprising administering the same.
[Additional note 15]
15. The method according to any one of appendices 10 to 14, wherein the cells are cancer cells and/or the subject has cancer.
[Additional note 16]
A method for treating a BAF complex-related disorder in a subject in need thereof, comprising administering to said subject an effective amount of a compound according to any one of appendices 1 to 8 or a pharmaceutical composition according to appendix 9. said method comprising administering an agent.
[Additional note 17]
A method for treating a disorder associated with a BRG1 loss-of-function mutation in a subject in need thereof, comprising administering to said subject an effective amount of a compound according to any one of appendices 1 to 8 or according to appendix 9. said method comprising administering a pharmaceutical composition of the invention.
[Additional note 18]
18. The method of appendix 16 or 17, wherein the subject is determined to have a BRG1 loss of function disorder.
[Additional note 19]
The BAF complex-related disorder or BRG1 loss-of-function mutation-related disorder may be cancer, viral infection, coffin syris, neurofibromatosis (e.g., NF-1, NF-2, or multiple schwannomatosis). or multiple meningioma, the method according to any one of appendices 16 to 18.
[Additional note 20]
A method for treating cancer in a subject in need thereof, comprising administering to said subject an effective amount of the compound according to any one of appendices 1 to 8 or the pharmaceutical composition according to appendix 9. The method described above, comprising:
[Additional note 21]
A method of reducing cancer tumor growth in a subject in need thereof, the method comprising administering to said subject an effective amount of a compound according to any one of appendices 1 to 8 or a compound according to appendix 9. The method comprising administering a pharmaceutical composition.
[Additional note 22]
A method for suppressing the metastatic progression of cancer in a subject in need thereof, the method comprising: administering to said subject an effective amount of the compound according to any one of appendices 1 to 8 or the compound according to appendix 9; said method comprising administering a pharmaceutical composition of the invention.
[Additional note 23]
A method for inhibiting metastatic colonization of cancer in a subject in need thereof, the method comprising: administering to said subject an effective amount of a compound according to any one of appendices 1 to 8 or a compound according to appendix 9; Said method comprising administering a pharmaceutical composition as described.
[Additional note 24]
A method for reducing the level and/or activity of BRG1 and/or BRM in cancer in a subject in need thereof, the method comprising administering to said subject an effective amount of any one of appendices 1 to 8. 9. The method comprising administering a compound according to paragraph 9 or a pharmaceutical composition according to paragraph 9.
[Additional note 25]
The cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, esophageal cancer, pancreatic cancer, hepatobiliary tract cancer. Cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell cancer, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal tract cancer Neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical cancer, appendiceal cancer, small intestine cancer, penile cancer, bone cancer, or hematological cancer, according to any one of appendices 20 to 24. Method described.
[Additional note 26]
The method according to appendix 25, wherein the cancer is esophageal cancer.
[Additional note 27]
The cancer is non-small cell lung cancer, colon cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, penile cancer, bone cancer, renal cell cancer, The method according to appendix 25, which is prostate cancer or blood cancer.
[Additional note 28]
The method according to appendix 25, wherein the cancer is non-small cell lung cancer.
[Additional note 29]
28. The method according to appendix 27, wherein the cancer is melanoma, prostate cancer, breast cancer, bone cancer, renal cell cancer, or blood cancer.
[Additional note 30]
The method according to appendix 29, wherein the cancer is melanoma.
[Additional note 31]
31. The method according to appendix 30, wherein the melanoma is uveal melanoma, mucosal melanoma, or cutaneous melanoma.
[Additional note 32]
32. The method according to appendix 31, wherein the melanoma is uveal melanoma.
[Additional note 33]
The method according to appendix 29, wherein the cancer is prostate cancer.
[Additional note 34]
The method according to appendix 29, wherein the cancer is a blood cancer.
[Additional note 35]
The blood cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic lymphoma, and lymphocytic lymphoma, 35. The method according to appendix 34, wherein the patient has B cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-Hodgkin's lymphoma.
[Appendix 36]
The method according to appendix 29, wherein the cancer is breast cancer.
[Additional note 37]
37. The method according to appendix 36, wherein the breast cancer is ER-positive breast cancer, ER-negative breast cancer, triple-positive breast cancer, or triple-negative breast cancer.
[Appendix 38]
The method according to appendix 27, wherein the cancer is bone cancer.
[Additional note 39]
39. The method according to appendix 38, wherein the bone cancer is Ewing's sarcoma.
[Additional note 40]
The method according to appendix 27, wherein the cancer is renal cell carcinoma.
[Additional note 41]
41. The method according to appendix 40, wherein the renal cell carcinoma is microphthalmia transcription factor family translocation renal cell carcinoma.
[Additional note 42]
42. The method according to any one of appendices 20 to 41, wherein the cancer expresses BRG1 and/or BRM protein.
[Additional note 43]
43. The method according to any one of appendices 20 to 42, wherein the subject or cancer has a BRG1 loss-of-function mutation.
[Additional note 44]
44. The method of claim 43, wherein the BRG1 loss-of-function mutation is in the ATPase catalytic domain of the protein.
[Additional note 45]
44. The method according to appendix 43, wherein the BRG1 loss-of-function mutation is a deletion at the C-terminus of BRG1.
[Additional note 46]
46. The method of any one of appendices 20 to 45, wherein the cancer does not have, or has been determined to have, an epidermal growth factor receptor mutation and/or an anaplastic lymphoma kinase driver mutation.
[Additional note 47]
The cancer has a KRAS mutation, a mutation in GNAQ, a mutation in GNA11, a mutation in PLCB4, a mutation in CYSLTR2, a mutation in BAP1, a mutation in SF3B1, a mutation in EIF1AX, TFE3 translocation, TFEB translocation. , MITF translocation, EZH2 mutation, SUZ12 mutation, and/or EED mutation.
[Additional note 48]
48. The method according to any one of appendices 20 to 47, wherein the cancer is metastatic.
[Additional note 49]
49. The method of any one of Clauses 20-48, wherein the cancer is resistant to anti-cancer therapy or has not responded to previous treatment with anti-cancer therapy.
[Additional note 50]
50. The method of clause 49, wherein the anti-cancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, hyperthermia, or photocoagulation, or a combination thereof.
[Additional note 51]
51. The method according to appendix 50, wherein the anti-cancer therapy is a chemotherapeutic agent or a cytotoxic agent.
[Additional note 52]
52. The method according to appendix 51, wherein the chemotherapeutic agent or cytotoxic agent is a mitogen-activated protein kinase (MEK) inhibitor and/or a protein kinase C (PKC) inhibitor.
[Additional note 53]
53. The method of any one of Clauses 20 to 52, wherein the cancer is resistant to a PKC inhibitor or has not responded to previous treatment with a PKC inhibitor.
[Additional note 54]
54. The method of any one of appendices 20 to 53, wherein the method further comprises administering anti-cancer therapy to the subject.
[Additional note 55]
55. The method of clause 54, wherein the anti-cancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, hyperthermia, or photocoagulation, or a combination thereof.
[Additional note 56]
56. The method of clause 54 or 55, wherein the anti-cancer therapy is surgery, a MEK inhibitor, and/or a PKC inhibitor, or a combination thereof.
[Additional note 57]
57. The method of appendix 56, wherein the MEK inhibitor is selumetinib, binimetinib, or tametinib.
[Additional note 58]
57. The method according to appendix 56, wherein the PKC inhibitor is sotrastaurin or IDE196.
[Additional note 59]
A method for treating a viral infection in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to any one of appendices 1 to 8 or the pharmaceutical composition according to appendix 9. The method comprising administering.
[Additional note 60]
The viral infection may be caused by a virus of the Retroviridae family, a virus of the Hepadnaviridae family, a virus of the Flaviviridae family, a virus of the Adenoviridae family, a virus of the Herpesviridae family, a virus of the Papillomaviridae family, a virus of the Parvoviridae family. Virus, Polyomaviridae virus, Paramyxoviridae virus , or an infection caused by a Togaviridae family virus, the method according to appendix 59.
[Additional note 61]
61. The method of any one of clauses 10 to 60, wherein the effective amount of the compound reduces the level and/or activity of BRG1 by at least 5% compared to a reference.
[Additional note 62]
62. The method of clause 61, wherein said effective amount of said compound reduces the level and/or activity of BRG1 by at least 5% for at least 12 hours compared to a reference.
[Additional note 63]
63. The method of any one of clauses 10 to 62, wherein the effective amount of the compound reduces the level and/or activity of BRM by at least 5% compared to a reference.
[Additional note 64]
64. The method of clause 63, wherein said effective amount of said compound reduces the level and/or activity of BRM by at least 5% for at least 12 hours compared to a reference.

Claims (15)

式（Ａ）の構造を有する化合物：

またはその薬学的に許容される塩。 Compound having the structure of formula (A) :

or a pharmaceutically acceptable salt thereof. 前記式（Ａ）の化合物が、以下の構造：

を有するか、またはその薬学的に許容される塩である、請求項１に記載の化合物。 The compound of formula (A) has the following structure:

or a pharmaceutically acceptable salt thereof. 前記式（Ａ）の化合物が、以下の構造：

を有するか、またはその薬学的に許容される塩である、請求項２に記載の化合物。 The compound of formula (A) has the following structure:

or a pharmaceutically acceptable salt thereof. 前記式（Ａ）の化合物が、以下の構造：

を有するか、またはその薬学的に許容される塩である、請求項１に記載の化合物。 The compound of formula (A) has the following structure:

or a pharmaceutically acceptable salt thereof. 請求項１～４のいずれか１項に記載の化合物及び薬学的に許容される賦形剤を含む、医薬組成物。 A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient. 細胞または対象におけるＢＡＦ複合体の活性を低下させる治療、細胞または対象におけるＢＲＭを阻害する治療、細胞または対象におけるＢＲＧ１を阻害する治療、細胞または対象におけるＢＲＭ及びＢＲＧ１を阻害する治療、あるいは細胞または対象におけるアポトーシスを誘導する治療のための医薬の製造のための請求項１～４のいずれか１項に記載の化合物または請求項５に記載の医薬組成物の使用であって、任意に、前記細胞ががん細胞である及び／または前記対象ががんを有する、使用。 A treatment that reduces the activity of a BAF complex in a cell or a subject, a treatment that inhibits BRM in a cell or a subject, a treatment that inhibits BRG1 in a cell or a subject, a treatment that inhibits BRM and BRG1 in a cell or a subject, or a treatment that inhibits BRM and BRG1 in a cell or a subject. 6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 for the manufacture of a medicament for the treatment of inducing apoptosis in is a cancer cell and/or said subject has cancer . それを必要とする対象における、ＢＡＦ複合体関連障害の治療、あるいはＢＲＧ１機能喪失変異に関連する障害の治療のための医薬の製造のための請求項１～４のいずれか１項に記載の化合物または請求項５に記載の医薬組成物の使用であって、任意に前記対象がＢＲＧ１機能喪失障害を有すると決定される、任意に前記ＢＡＦ複合体関連障害またはＢＲＧ１機能喪失変異に関連する障害が、がん、ウイルス感染、コフィン・シリス、神経線維腫症（例えば、ＮＦ－１、ＮＦ－２、または多発性神経鞘腫症）または多発性髄膜腫である使用。 A compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of a BAF complex-related disorder or a BRG1 loss-of-function mutation-related disorder in a subject in need thereof. or the use of a pharmaceutical composition according to claim 5 , optionally wherein said subject is determined to have a BRG1 loss-of-function disorder, optionally said BAF complex-associated disorder or a BRG1 loss-of-function mutation associated disorder. , cancer, viral infection, coffin syris, neurofibromatosis (eg, NF-1, NF-2, or multiple schwannomatosis) or multiple meningioma . それを必要とする対象においてがんの治療のための医薬の製造のための請求項１～４のいずれか１項に記載の化合物または請求項５に記載の医薬組成物の使用。 Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 for the manufacture of a medicament for the treatment of cancer in a subject in need thereof . がんの腫瘍成長を減少させる治療、またはがんの転移性進行を抑制する治療、またはがんの転移性コロニー形成を抑制する治療、またはがん中でのＢＲＧ１及び／またはＢＲＭのレベル及び／または活性を低下させる治療のための医薬の製造のための請求項１～４のいずれか１項に記載の化合物または請求項５に記載の医薬組成物の使用。 A treatment that reduces tumor growth of a cancer, or a treatment that inhibits metastatic progression of a cancer, or a treatment that inhibits metastatic colonization of a cancer, or a treatment that reduces the level and level of BRG1 and/or BRM in a cancer . 6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 for the manufacture of a medicament for the treatment of decreasing activity . 前記がんが、非小細胞肺癌、大腸癌、膀胱癌、原発不明癌、神経膠腫、乳癌、黒色腫、非黒色腫皮膚癌、子宮内膜癌、食道胃癌、食道癌、膵癌、肝胆道癌、軟組織肉腫、卵巣癌、頭頸部癌、腎細胞癌、骨癌、非ホジキンリンパ腫、小細胞肺癌、前立腺癌、胎児性腫瘍、胚細胞腫瘍、子宮頸癌、甲状腺癌、唾液腺癌、消化管神経内分泌腫瘍、子宮肉腫、胃腸間質腫瘍、ＣＮＳ癌、胸腺腫瘍、副腎皮質癌、虫垂癌、小腸癌、陰茎癌、骨癌、または血液癌である、請求項８～９のいずれか１項に記載の使用。 The cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary origin, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, esophageal cancer, pancreatic cancer, hepatobiliary tract cancer. Cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell cancer, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal tract cancer Any one of claims 8 to 9 , which is a neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical cancer, appendiceal cancer, small intestine cancer, penile cancer, bone cancer, or hematological cancer. Uses as described in. 前記がんが、黒色腫である、請求項１０に記載の使用。 11. The use according to claim 10 , wherein the cancer is melanoma. 前記黒色腫が、ブドウ膜黒色腫である、請求項１１に記載の使用。 12. The use according to claim 11 , wherein the melanoma is uveal melanoma. 前記がんが、血液癌である、請求項１０に記載の使用。 11. The use according to claim 10 , wherein the cancer is a hematological cancer. 前記血液癌が、多発性骨髄腫、大細胞リンパ腫、急性Ｔ細胞白血病、急性骨髄性白血病、骨髄異形成症候群、免疫グロブリンＡラムダ骨髄腫、びまん性混合型組織球性リンパ腫及びリンパ球性リンパ腫、Ｂ細胞リンパ腫、急性リンパ芽球性白血病、びまん性大細胞リンパ腫、または非ホジキンリンパ腫である、請求項１３に記載の使用。 The blood cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic lymphoma, and lymphocytic lymphoma, 14. The use according to claim 13 , which is B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-Hodgkin's lymphoma. 前記がんが、ＢＲＧ１及び／またはＢＲＭタンパク質を発現する、または前記対象またはがんが、ＢＲＧ１機能喪失変異を有する、または前記ＢＲＧ１機能喪失変異が、タンパク質のＡＴＰアーゼ触媒ドメインにある、または前記がんが、上皮成長因子受容体変異及び／または未分化リンパ腫キナーゼ駆動因子変異を有さない、または有さないと決定されている、または前記がんが、ＫＲＡＳ変異、ＧＮＡＱ中の変異、ＧＮＡ１１中の変異、ＰＬＣＢ４中の変異、ＣＹＳＬＴＲ２中の変異、ＢＡＰ１中の変異、ＳＦ３Ｂ１中の変異、ＥＩＦ１ＡＸ中の変異、ＴＦＥ３転座、ＴＦＥＢ転座、ＭＩＴＦ転座、ＥＺＨ２変異、ＳＵＺ１２変異、及び／またはＥＥＤ変異を有する、または有すると決定されている、または前記がんが転移性である、請求項８～１４のいずれか１項に記載の使用。 the cancer expresses BRG1 and/or BRM proteins, or the subject or cancer has a BRG1 loss-of-function mutation, or the BRG1 loss-of-function mutation is in the ATPase catalytic domain of the protein, or the cancer does not have or has been determined to have no epidermal growth factor receptor mutations and/or anaplastic lymphoma kinase driver mutations, or the cancer has a KRAS mutation, a mutation in GNAQ, a mutation in mutations in PLCB4, mutations in CYSLTR2, mutations in BAP1, mutations in SF3B1, mutations in EIF1AX, TFE3 translocations, TFEB translocations, MITF translocations, EZH2 mutations, SUZ12 mutations, and/or EED The use according to any one of claims 8 to 14 , wherein the cancer has or is determined to have a mutation or is metastatic .
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