JP7387616B2 - Pd-l1アンタゴニストとしてのインダン-アミン - Google Patents
Pd-l1アンタゴニストとしてのインダン-アミン Download PDFInfo
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- JP7387616B2 JP7387616B2 JP2020544264A JP2020544264A JP7387616B2 JP 7387616 B2 JP7387616 B2 JP 7387616B2 JP 2020544264 A JP2020544264 A JP 2020544264A JP 2020544264 A JP2020544264 A JP 2020544264A JP 7387616 B2 JP7387616 B2 JP 7387616B2
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- cancer
- alkyl
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- acceptable salt
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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Description
これは、2018年2月22日に出願された、米国特許仮出願第62/633,973号の、米国特許法119条(e)項の下での優先的恩恵を主張する出願であり、この仮出願は全ての目的に関して、その全体が引用により本明細書中に組み込まれている。
該当なし
該当なし
プログラムされた細胞死タンパク質-1(PD-1)は、その2つのリガンドPD-L1又はPD-L2との相互作用時に、負のシグナルを送達する、CD28スーパーファミリーの一員である。PD-1及びそのリガンドは、広範に発現され、且つT細胞の活性化及び寛容において多種多様な免疫制御の役割を果たす。PD-1及びそのリガンドは、感染性免疫及び腫瘍免疫を弱め、且つ慢性の感染症及び腫瘍の進行を促進することに関与している。
一態様において、下記式(I)を有する化合物:
略語及び定義
本明細書において使用される用語「ある又はその(a、an又はthe)」は、1つのメンバーによる態様のみを含むのではなく、2以上のメンバーによる態様も含む。例えば、単数形(a、an及びthe)は、文脈が別に明確に指摘しない限りは、複数の言及も含む。従って例えば「ある細胞」の言及は、複数のそのような細胞を含み、且つ「その物質」の言及は、1又は複数の当業者に公知の物質の言及を含む、などである。
一態様において、本開示は、式(I)の化合物:
(式中、
R1は、式(IIa)又は式(IIb)から選択され:
Lは、以下からなる群から選択され:
Zは、アゼチジニル、ピロリジニル、ピペリジニル、モルホリニル、ピリジル、ピリミジニル、グアニジニル、キヌクリジン、及び8-アザビシクロ[3.2.1]オクタンからなる群から選択され、その各々は任意に、ハロゲン、ヒドロキシ、C1-3アルキル、-NH2、-NHC1-3アルキル、-N(C1-3アルキル)2、-O-C1-3アルキル、C1-3ヒドロキシアルキル、C1-3ハロアルキル及び-CO2Hから独立して選択された1~3個の基により置換されるか、又は
Zは、-CO2Rz1及び-NRz1Rz2からなる群から選択され;ここで、Rz1は、H、C1-8アルキル、C1-8ハロアルキル及びC1-8ヒドロキシアルキルからなる群から選択され;並びに、Rz2は、-C1-8アルキル、C1-8ハロアルキル、C1-8アルキル-COOH、C1-8アルキル-OH、C1-8アルキル-CONH2、C1-8アルキル-SO2NH2、C1-8アルキル-PO3H2、C1-8アルキル-C(O)NHOH、-C(O)-C1-8アルキル-OH、-C(O)-C1-8アルキル-COOH、C3-10シクロアルキル、-C3-10シクロアルキル-COOH、-C3-10シクロアルキル-OH、C4-8ヘテロシクリル、-C4-8ヘテロシクリル-COOH、-C4-8ヘテロシクリル-OH、-C1-8アルキル-C4-8ヘテロシクリル、-C1-8アルキル-C3-10シクロアルキル、C5-10ヘテロアリール及び-C1-8アルキル-C5-10ヘテロアリールから選択され;
各R2a、R2b及びR2cは、H、ハロゲン、-CN、-Rd、-CO2Re、-CONReRf、-OC(O)NReRf、-NRfC(O)Re、-NRfC(O)2Rd、-NRe-C(O)NReRf、-NReRf、-ORe、-X2-ORe、-X2-NReRf、-X2-CO2Re、-SF5、及び-S(O)2NReRfからなる群から独立して選択され、ここで各X2は、C1-4アルキレンであり;各Re及びRfは、水素、C1-8アルキル、及びC1-8ハロアルキルから独立して選択されるか、又は同じ窒素原子に結合された場合、その窒素原子と一緒に、環員としてN、O及びSから選択された0~2個の追加のヘテロ原子を有し、並びにオキソにより任意に置換された、5もしくは6-員環を形成することができ;各Rdは、C1-8アルキル、C2-8アルケニル、及びC1-8ハロアルキルからなる群から独立して選択され;
R3は、-NRgRh及びC4-12ヘテロシクリルからなる群から選択され、ここでC4-12ヘテロシクリルは、1~6個のR3aにより任意に置換され;
各R3aは、ハロゲン、-CN、-Ri、-CO2Rj、-CONRjRk、-CONHC1-6アルキル-OH、-C(O)Rj、-OC(O)NRjRk、-NRjC(O)Rk、-NRjC(O)2Rk、-CONHOH、-PO3H2、-NRj-X3-C(O)2Rk、-NRjC(O)NRjRk、-NRjRk、-ORj、-S(O)2NRjRk、-O-X3-ORj、-O-X3-NRjRk、-O-X3-CO2Rj、-O-X3-CONRjRk、-X3-ORj、-X3-NRjRk、-X3-CO2Rj、-X3-CONRjRk、-X3-CONHSO2Rj及びSF5からなる群から独立して選択され;ここで、X3は、C1-6アルキレンであり、及び任意にOH、SO2NH2、CONH2、C(O)NHOH、PO3H2、COO-C1-8アルキル又はCO2Hにより更に置換され、ここで各Rj及びRkは、水素、OH、SO2NH2、CONH2、C(O)NHOH、PO3H2、COO-C1-8アルキルもしくはCO2Hから選択される1~2個の置換基により任意に置換されたC1-8アルキル、並びにOH、SO2NH2、CONH2、C(O)NHOH、PO3H2、COO-C1-8アルキルもしくはCO2Hから選択される1~2個の置換基により任意に置換されたC1-8ハロアルキルから独立して選択されるか、又は同じ窒素原子に結合された場合、Rj及びRkは、窒素原子と一緒に、環員としてN、OもしくはSから選択された0~2個の追加のヘテロ原子を有し、並びにオキソにより任意に置換された、5もしくは6-員環を形成することができ;各Riは、その各々は、OH、SO2NH2、CONH2、C(O)NHOH、PO3H2、COO-C1-8アルキルもしくはCO2Hにより任意に置換されてよい、-OH、C1-8アルキル、C2-8アルケニル、及びC1-8ハロアルキルからなる群から独立して選択され;
Rgは、H、C1-8ハロアルキル及びC1-8アルキルからなる群から選択され;
Rhは、-C1-8アルキル、C1-8ハロアルキル、C1-8ヒドロキシアルキル、C1-8アルキル-CO2Rj、C1-8アルキル-CONRjRk、及びC1-8アルキル-CONHSO2Rj、C1-8アルキル-SO2NRjRk、C1-8アルキル-PO3H2、C1-8 アルキル-C(O)NHOH、C1-8アルキル-NRh1Rh2、-C(O)Rj、C3-10シクロアルキル、-C3-10シクロアルキル-COORj、-C3-10シクロアルキル-ORj、C4-8ヘテロシクリル、-C4-8ヘテロシクリル-COORj、-C4-8ヘテロシクリル-ORj、-C1-8アルキル-C4-8ヘテロシクリル、-C(=O)OC1-8アルキル-C4-8ヘテロシクリル、-C1-8アルキル-C3-10 シクロアルキル、C5-10ヘテロアリール、-C1-8アルキル-C5-10 ヘテロアリール、-C1-8アルキル-C6-10アリール、-C1-8アルキル-(C=O)-C6-10アリール、-CO2-C1-8アルキル-O2C-C1-8アルキル、-C1-8アルキル-NH(C=O)-C2-8アルケニル、-C1-8アルキル-NH(C=O)-C1-8アルキル、-C1-8アルキル-NH(C=O)-C2-8アルキニル、-C1-8アルキル-(C=O)-NH-C1-8アルキル-COORj、及び任意にCO2Hにより置換された-C1-8 アルキル-(C=O)-NH-C1-8 アルキル-ORjから選択されるか;又は
Rhは、それが結合したNと一緒に、1~3個の天然のアミノ酸及び0~2個の非天然のアミノ酸を含むモノ-、ジ-又はトリ-ペプチドであり、ここで
非天然のアミノ酸は、C2-4ヒドロキシアルキル、C1-3アルキル-グアニジニル、及びC1-4アルキル-ヘテロアリールからなる群から選択されるアルファ炭素置換基を有し、
各天然又は非天然のアミノ酸のアルファ炭素は、メチル基により、任意に更に置換され、並びに
モノ-、ジ-、もしくはトリ-ペプチドの末端部分は、C(O)OH、C(O)O-C1-6アルキル、及びPO3H2からなる群から選択され、ここで
Rh1及びRh2は、各々独立してH、C1-6アルキル、及びC1-4ヒドロキシアルキルからなる群から選択され;
RhのC1-8アルキル部分は、OH、COOH、SO2NH2、CONH2、C(O)NHOH、COO-C1-8アルキル、PO3H2及び1~2個のC1-3アルキル置換基により任意に置換されたC5-6ヘテロアリールから独立して選択された1~3個の置換基により任意に更に置換され、
RhのC5-10ヘテロアリール及びC6-10アリール部分は、OH、B(OH)2、COOH、SO2NH2、CONH2、C(O)NHOH、PO3H2、COO-C1-8アルキル、C1-4アルキル、C1-4アルキル-OH、C1-4アルキル-SO2NH2、C1-4アルキルCONH2、C1-4アルキル-C(O)NHOH、C1-4アルキル-PO3H2、C1-4アルキル-COOH及びフェニルから独立して選択された1~3個の置換基により任意に置換され、並びに
RhのC4-8ヘテロシクリル及びC3-10シクロアルキル部分は、1~4個のRw置換基により任意に置換され;
各Rw置換基は、C1-4アルキル、C1-4アルキル-OH、C1-4アルキル-COOH、C1-4アルキル-SO2NH2、C1-4アルキルCONH2、C1-4アルキル-C(O)NHOH、C1-4アルキル-PO3H、OH、COO-C1-8 アルキル、COOH、SO2NH2、CONH2、C(O)NHOH、PO3H2及びオキソから独立して選択され;
R4は、O-C1-8アルキル、O-C1-8ハロアルキル、C6-10アリール、C5-10ヘテロアリール、-O-C1-4アルキル-C4-7ヘテロシクロアルキル、-O-C1-4アルキル-C6-10アリール及び-O-C1-4アルキル-C5-10ヘテロアリールからなる群から選択され、その各々は1~5個のR4aにより任意に置換され;
各R4aは、ハロゲン、-CN、-Rm、-CO2Rn、-CONRnRp、-C(O)Rn、-OC(O)NRnRp、-NRnC(O)Rp、-NRnC(O)2Rm、-NRn-C(O)NRnRp、-NRnRp、-ORn、-O-X4-ORn、-O-X4-NRnRp、-O-X4-CO2Rn、-O-X4-CONRnRp、-X4-ORn、-X4-NRnRp、-X4-CO2Rn、-X4-CONRnRp、-SF5、-S(O)2RnRp、-S(O)2NRnRp、C3-7シクロアルキル及びC4-7ヘテロシクロアルキルからなる群から独立して選択され、ここでシクロアルキル環及びヘテロシクロアルキル環は、1~5個のRtにより任意に置換され、ここで各Rtは、C1-8アルキル、C1-8ハロアルキル、-CO2Rn、-CONRnRp、-C(O)Rn、-OC(O)NRnRp、-NRnC(O)Rp、-NRnC(O)2Rm、-NRn-C(O)NRnRp、-NRnRp、-ORn、-O-X4-ORn、-O-X4-NRnRp、-O-X4-CO2Rn、-O-X4-CONRnRp、-X4-ORn、-X4-NRnRp、-X4-CO2Rn、-X4-CONRnRp、-SF5、及び-S(O)2NRnRpからなる群から独立して選択され;
ここで、各X4は、C1-6アルキレンであり;各Rn及びRpは、水素、C1-8アルキル、及びC1-8ハロアルキルから独立して選択されるか、又は同じ窒素原子に結合された場合、その窒素原子と一緒に、環員としてN、OもしくはSから選択された0~2個の追加のヘテロ原子を有し、並びにオキソにより任意に置換された、5もしくは6-員環を形成することができ;各Rmは、C1-8アルキル、C2-8アルケニル、及びC1-8ハロアルキルからなる群から独立して選択され;並びに、任意に2個のR4a置換基が隣接原子上にある場合、これらは一緒に、オキソにより任意に置換された縮合した5又は6-員の炭素環又は複素環を形成し;
下付文字nは、0、1、2又は3であり;
各R5は、ハロゲン、-CN、-Rq、-CO2Rr、-CONRrRs、-C(O)Rr、-OC(O)NRrRs、-NRrC(O)Rs、-NRrC(O)2Rq、-NRr-C(O)NRrRs、-NRrRs、-ORr、-O-X5-ORr、-O-X5-NRrRs、-O-X5-CO2Rr、-O-X5-CONRrRs、-X5-ORr、-X5-NRrRs、-X5-CO2Rr、-X5-CONRrRs、-SF5、-S(O)2NRrRsからなる群から独立して選択され、ここで各X5は、C1-4アルキレンであり;各Rr及びRsは、水素、C1-8アルキル、及びC1-8ハロアルキルから独立して選択されるか、又は同じ窒素原子に結合された場合、その窒素原子と一緒に、環員としてN、OもしくはSから選択された0~2個の追加のヘテロ原子を有し、並びにオキソにより任意に置換された、5もしくは6-員環を形成することができ;各Rqは、C1-8アルキル、及びC1-8ハロアルキルからなる群から独立して選択され;
R6aは、H、C1-4アルキル及びC1-4ハロアルキルからなる群から選択され;
下付文字mは、0、1、2、3又は4であり;
各R6bは、F、C1-4アルキル、O-Ru、C1-4ハロアルキル、NRuRvからなる群から独立して選択され、ここで各Ru及びRvは、水素、C1-8アルキル、及びC1-8ハロアルキルから独立して選択されるか、又は同じ窒素原子に結合された場合、その窒素原子と一緒に、環員としてN、OもしくはSから選択された0~2個の追加のヘテロ原子を有し、並びにオキソにより任意に置換された、5もしくは6-員環を形成することができる)。
本明細書に提供される化合物に加え、それらの化合物の組成物は、典型的には医薬担体又は希釈剤を含むであろう。
本開示の化合物は、免疫調節物質として使用することができる。本開示の化合物は、インビトロ及びインビボの両方での、様々な状況における、PD-1及び/又はPD-L1のアゴニスト、アンタゴニスト、部分アゴニスト、逆アゴニスト、インヒビターとして使用することができる。一部の実施態様において、本開示の化合物は、PD-1/PD-L1タンパク質-タンパク質相互作用のインヒビターとして使用することができる。一部の実施態様において、本開示の化合物は、PD-L1のインヒビターとして使用することができる。一部の実施態様において、本開示の化合物は、CD80/PD-L1タンパク質-タンパク質相互作用のインヒビターとして使用することができる。一部の実施態様において、本開示の化合物は、インビトロ又はインビボにおいて、PD-1とPD-L1及び/又はPD-1とCD80及び/又はPD-1とPD-L2の間の相互作用を阻害するために使用することができる。一部の実施態様において、本開示の化合物は、VISTA及び/又はTIM-3を阻害するために使用することができる。一部の実施態様において、本開示の化合物は、PD-1/PD-L1タンパク質-タンパク質相互作用のインヒビター並びにVISTA及び/又はTIM-3のインヒビターであることができる。一部の実施態様において、本開示の化合物は、PD-1/PD-L1タンパク質-タンパク質相互作用のインヒビターであることに加え、CTLA-4及び/又はBTLA及び/又はLAG-3及び/又はKLRG-1及び/又は2B4及び/又はCD160及び/又はHVEM及び/又はCD48及び/又はE-カドヘリン及び/又はMHC-II及び/又はガレクチン-9及び/又はCD86及び/又はPD-L2及び/又はVISTA及び/又はTIM-3及び/又はCD80のインヒビターであることができる。
本開示の化合物及び他の薬物を含む併用薬は、その中に両方の構成要素が単独の製剤中に含まれるか、又は個別の製剤として投与される、組合せ調製品として投与されてよい。個別の製剤による投与は、同時投与及びしばらくの間隔を伴う投与を含む。しばらくの間隔を伴う投与の場合、本開示の化合物は、最初に投与され、引き続き別の薬物が投与されることができるか、又は別の薬物が最初に、引き続き本開示の化合物が投与されることができる。それぞれの薬物の投与方法は、同じ又は異なってよい。
約0.1mg~約140mg/kg体重/日の水準の用量レベルは、PD-1/PD-L1相互作用に関与する状態の治療又は予防において有用である(約0.5mg~約7g/ヒト患者/日)。単独の剤形を作製するために担体材料と組合せることができる活性成分の量は、治療される宿主及び特定の投与様式に応じて変動するであろう。単位剤形は、一般に活性成分約1mg~約500mgを含むであろう。経口、経皮、静脈内、又は皮下投与される化合物に関して、血清濃度5ng(ナノグラム)/mL~10μg(マイクログラム)/mL血清を達成するのに十分量の化合物が投与されることが好ましく、より好ましくは血清濃度20ng~1μg/ml血清を達成するのに十分な化合物が投与されるべきであり、最も好ましくは血清濃度50ng/ml~200ng/ml血清を達成するのに十分な化合物が投与されるべきである。滑膜への直接注射(関節炎の治療のため)に関して、十分な化合物は、およそ1マイクロモルの局所濃度を達成するように投与されるべきである。
以下の実施例は、式(I)、(Ia)又は(Ib)の化合物を含む、本開示の化合物を作製する様々な方法を例証している。以下の実施例は、例証のために提供され、請求された開示を限定するものではない。
+、20000nM≧IC50≧500nM;
++、500nM>IC50≧5nM;
+++、5nM>IC50。
表1において保持時間の決定に使用した逆相HPLC条件:
カラム:ZORBAX (SB-C18 2.1×50mm、5μm)
移動相A:95%H2O、5%MeCN(0.1%ギ酸含有)
移動相B:5%H2O、95%MeCN(0.1%ギ酸含有)
流量:1.0mL/分
勾配:3.5分間で20%から100%までのB
プレートは、PBS中のヒトPD-L1(R&Dから入手)の1μg/mLと共に、4℃で一晩コーティングした。次にウェルを、0.05%TWEEN-20を含む、PBS中の2%BSA(W/V)により、37℃で1時間ブロックした。プレートを、PBS/0.05%TWEEN-20により3回洗浄し、試料をELISAプレート中の希釈媒体中に1:5で希釈した。ヒトPD-1及びビオチン0.3μg/mL(ACRO Biosystems)を添加し、37℃で1時間インキュベーションし、次にPBS/0.05%TWEEN-20により3回洗浄した。二次ブロックを、PBS中の2%SA(W/V)/0.05%TWEEN-20により、37℃で10分間添加し、PBS/0.05%TWEEN-20により3回洗浄した。ストレプトアビジン-HRPを、37℃で1時間添加し、その後PBS/0.05%TWEEN-20により3回洗浄した。TMB基質を添加し、37℃で20分間反応させた。停止溶液(2N水性H2SO4)を添加した。吸光度を、マイクロプレート分光光度計を用い、450nmで測定した。結果を表1に示す。
Claims (21)
- 式(I):
R1は、式(IIb)から選択され:
Lは、以下からなる群から選択され:
Zは、ピペリジニルであり、任意に、ハロゲン、ヒドロキシ、C1-3アルキル、-NH2、-NHC1-3アルキル、-N(C1-3アルキル)2、-O-C1-3アルキル、C1-3ヒドロキシアルキル、C1-3ハロアルキル及び-CO2Hから独立して選択された1~3個の基により置換されるか、
各R2a、R2b及びR2cは、H、ハロゲン、-CN、-Rd、-CO2Re、-CONReRf、-OC(O)NReRf、-NRfC(O)Re、-NRfC(O)2Rd、-NRe-C(O)NReRf、-NReRf、-ORe、-X2-ORe、-X2-NReRf、-X2-CO2Re、-SF5、及び-S(O)2NReRfからなる群から独立して選択され、ここで各X2は、C1-4アルキレンであり;各Re及びRfは、水素、C1-8アルキル、及びC1-8ハロアルキルから独立して選択されるか、又は同じ窒素原子に結合された場合、その窒素原子と一緒に、環員としてN、O及びSから選択された0~2個の追加のヘテロ原子を有し、並びにオキソにより任意に置換された、5もしくは6-員環を形成することができ;各Rdは、C1-8アルキル、C2-8アルケニル、及びC1-8ハロアルキルからなる群から独立して選択され;
R 3 は、
R4は、O-C1-8アルキルであり;
各R5は、ハロゲン、-CN、-Rq、-CO2Rr、-CONRrRs、-C(O)Rr、-OC(O)NRrRs、-NRrC(O)Rs、-NRrC(O)2Rq、-NRr-C(O)NRrRs、-NRrRs、-ORr、-O-X5-ORr、-O-X5-NRrRs、-O-X5-CO2Rr、-O-X5-CONRrRs、-X5-ORr、-X5-NRrRs、-X5-CO2Rr、-X5-CONRrRs、-SF5、及び-S(O)2NRrRsからなる群から独立して選択され、ここで各X5は、C1-4アルキレンであり;各Rr及びRsは、水素、C1-8アルキル、及びC1-8ハロアルキルから独立して選択されるか、又は同じ窒素原子に結合された場合、その窒素原子と一緒に、環員としてN、O及びSから選択された0~2個の追加のヘテロ原子を有し、並びにオキソにより任意に置換された、5もしくは6-員環を形成することができ;各Rqは、C1-8アルキル、及びC1-8ハロアルキルからなる群から独立して選択され;
R6aは、H、C1-4アルキル及びC1-4ハロアルキルからなる群から選択され;
各R6bは、F、C1-4アルキル、O-Ru、C1-4ハロアルキル、及びNRuRvからなる群から独立して選択され、ここで各Ru及びRvは、水素、C1-8アルキル、及びC1-8ハロアルキルから独立して選択されるか、又は同じ窒素原子に結合された場合、その窒素原子と一緒に、環員としてN、O及びSから選択された0~2個の追加のヘテロ原子を有し、並びにオキソにより任意に置換された、5もしくは6-員環を形成することができ;
下付文字mは、0,1、2、3又は4であり;
下付文字nは、0,1、2又は3である)
の化合物又はその医薬として許容される塩。 - 下記式(Ia):
- 下記式(Ib):
- 前記基Z-L-が、
- 前記基Z-L-が、
- 前記基Z-L-が、
- 前記R2a、R2b及びR2cの各々が、水素、ハロゲン、CN、C1-4アルキル、及びC1-4ハロアルキルからなる群から独立して選択される、請求項1~6のいずれか1項に記載の化合物、又はその医薬として許容される塩。
- 前記R3が、
- 前記R3が、
- 前記R4が、
- 前記R4が、
- 前記nが、0である、請求項1~9のいずれか1項に記載の化合物、又はその医薬として許容される塩。
-
- 下記:
- 請求項1~14のいずれか1項に記載の化合物、又はその医薬として許容される塩、及び医薬として許容される賦形剤を含有する、医薬組成物。
- 治療的有効量の、請求項1~14のいずれか1項に記載の化合物、又はその医薬として許容される塩を含む、対象におけるPD-1シグナル伝達経路により媒介される免疫応答を調節するための医薬組成物。
- 治療的有効量の、請求項1~14のいずれか1項に記載の化合物、又はその医薬として許容される塩を含む、免疫応答を増強、刺激、調節及び/又は増大することを必要とする対象において、免疫応答を増強、刺激、調節及び/又は増大するための医薬組成物。
- 治療的有効量の、請求項1~14のいずれか1項に記載の化合物、又はその医薬として許容される塩を含む、癌細胞の成長、増殖、又は転移の阻害を必要とする対象において、癌細胞の成長、増殖、又は転移を阻害するための医薬組成物。
- 治療的有効量の、請求項1~14のいずれか1項に記載の化合物、又はその医薬として許容される塩を含む、PD-1シグナル伝達経路により媒介される疾患又は障害に罹患したもしくは易罹患性である対象を治療するための医薬組成物。
- 前記対象が、感染症、細菌感染症、ウイルス感染症、真菌感染症、固形癌、悪性血液疾患、免疫障害、炎症疾患、及び癌からなる群から選択される疾患又は障害に罹患している、請求項16~19のいずれか1項に記載の医薬組成物。
- 前記疾患又は障害が、メラノーマ、膠芽細胞腫、食道腫瘍、鼻咽喉癌、ブドウ膜メラノーマ、リンパ腫、リンパ球性リンパ腫、原発性CNSリンパ腫、T細胞リンパ腫、びまん性大細胞型B細胞リンパ腫、原発性縦隔大細胞型B細胞リンパ腫、前立腺癌、去勢抵抗性前立腺癌、慢性骨髄性白血病、カポジ肉腫、線維肉腫、脂肪肉腫、軟骨肉腫、骨原性肉腫、血管肉腫、リンパ管肉腫、滑液腫、髄膜腫、平滑筋肉腫、横紋筋肉腫、軟組織肉腫、肉腫、敗血症、胆管腫瘍、基底細胞癌、胸腺腫瘍、甲状腺癌、副甲状腺癌、子宮癌、副腎癌、肝臓感染症、メルケル細胞癌、神経腫瘍、濾胞中心リンパ腫、結腸癌、ホジキン病、非ホジキンリンパ腫、白血病、慢性又は急性白血病、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ芽球性白血病、慢性リンパ球性白血病、多発性骨髄腫、卵巣腫瘍、骨髄異形成症候群、皮膚又は眼球内悪性黒色腫、腎細胞癌、小細胞肺癌、肺癌、中皮腫、乳癌、扁平非小細胞肺癌(SCLC)、非扁平NSCLC、結腸直腸癌、卵巣癌、胃癌、肝細胞癌、膵臓癌腫、膵臓癌、膵管腺癌、頭頸部扁平上皮癌、頭頸部癌、消化管癌、胃の癌、HIV、A型肝炎、B型肝炎、C型肝炎、D型肝炎、ヘルペスウイルス、パピローマウイルス、インフルエンザ、骨癌、皮膚癌、直腸癌、肛門癌、精巣癌、卵管癌、子宮内膜癌、子宮頚癌、膣癌、陰門癌、食道癌、小腸癌、内分泌系癌、尿道癌、陰茎癌、膀胱癌、腎臓癌、尿管癌、腎盂癌、中枢神経系(CNS)腫瘍、血管新生腫瘍、脊髄腫瘍、脳幹神経膠腫、下垂体腺腫、類表皮癌、石綿肺、癌腫、腺癌、乳頭状癌、嚢胞腺癌、気管支癌、腎細胞癌腫、移行上皮癌、絨毛癌、精上皮腫、胎生期癌、ウィルムス腫瘍、多形腺腫、肝細胞乳頭腫、腎尿細管腺腫、嚢胞腺腫、乳頭腫、腺腫、平滑筋腫、横紋筋腫、血管腫、リンパ管腫、骨腫、軟骨腫、脂肪腫及び線維腫からなる群から選択される、請求項19記載の医薬組成物。
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