JP2021534158A - イミダゾ[4,5−c]キノリン誘導体のNLRP3モジュレーター - Google Patents
イミダゾ[4,5−c]キノリン誘導体のNLRP3モジュレーター Download PDFInfo
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- JP2021534158A JP2021534158A JP2021507737A JP2021507737A JP2021534158A JP 2021534158 A JP2021534158 A JP 2021534158A JP 2021507737 A JP2021507737 A JP 2021507737A JP 2021507737 A JP2021507737 A JP 2021507737A JP 2021534158 A JP2021534158 A JP 2021534158A
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- 239000000341 volatile oil Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000013389 whole blood assay Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229940055760 yervoy Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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Abstract
Description
本出願は、2018年8月16日出願の米国仮出願番号第62/764,900号に対する優先権を主張するものであって、その内容の全てを参照により本明細書に組み込むものである。
本開示は、NLRP3シグナル伝達の増加が、対象(例えばヒト)における病理および/または症状および/または難治性の病状、疾患または障害(例えば、T細胞浸潤の少ないがん)の進行および/または治療に関与する、自然免疫活性の不足を正常化し得る病状、疾患または障害などの治療に有用なNLRP3を調節する(例えば、刺激または一部刺激する)、化学物質群(例えば、化合物またはその化合物の医薬的に許容される塩、および/または水和物、および/または共結晶、および/または合剤)を特徴とする。本開示はまた、上記化合物の組成物ならびに他のその使用および製造方法を特徴とする。
第1態様において、本発明は、とりわけ式(I):
R1は、独立して、1〜3個のハロゲンで置換されている非分岐C2-6アルキレン、0〜3個のハロゲンで置換されている分岐C3-6アルキレン、および0〜3個のハロゲンで置換されているC3-6シクロアルキルから選択され;
R2、R3およびR5は、それぞれ独立して、H、ハロゲン、シアノ、C1-4アルキル、C1-4ハロアルキル、C1-4アルコキシ、およびC1-4ハロアルコキシから選択され;
R4は、独立して、N、N(Ra)、O、およびSからそれぞれ独立して選択される、1〜4個の環原子を含む5員ヘテロアリールであり、ここでヘテロアリールは0〜3個のRbで置換され;
R6は、独立して、5〜6個の環原子(このうち1〜3個の環原子は、N(Rc)、O、およびSからそれぞれ独立して選択される)を含むヘテロシクリルであり、ここでヘテロシクリルは、0〜3個のRdで置換されるか;または5〜6個の環原子(このうち1〜4個の環原子は、N、N(Rc)、O、およびSからそれぞれ独立して選択される)を含むヘテロアリールであり、ここでヘテロアリールは、0〜3個のRdで置換され;
R7は、独立して、HまたはC1-4アルキルであり;
Yは、独立して、C1-3アルキレンであり;
RaおよびRcは、それぞれ独立して、HおよびC1-4アルキルから選択され;および
RbおよびRdは、それぞれ独立して、ハロゲン、シアノ、C1-4アルキル、C1-4ハロアルキル、C1-4アルコキシ、およびC1-4ハロアルコキシから選択される]の化合物、またはその互変異性体または医薬的に許容される塩を提供する。
R1は、独立して、1〜3個のFで置換されている非分岐C2-4アルキレン、0〜2個のFで置換されている分岐C3-4アルキレンおよびC3-4シクロアルキルから選択され;
R2、R3およびR5は、それぞれ独立して、H、ハロゲンおよびC1-4アルキルから選択され;
R4は、独立して、ピラゾリル、チエニルまたはイソチアゾリルであり;
R6は、独立して、0〜2個のRdで置換されたチアゾリル、0〜2個のRdで置換されたピリジル、および
Yは、独立して、C1-2アルキレンであり;および
Rdは、それぞれ独立して、ハロゲン、C1-4アルキル、およびC1-4アルコキシから選択される]の化合物、またはその互変異性体または医薬的に許容される塩を提供する。
R1は、独立して、エチル、2,2-ジフルオロエチル、イソプロピル、シクロプロピル、およびシクロブチルから選択され;
R6は、独立して、0〜2個のRdで置換されたチアゾリル、0〜2個のRdで置換されたピリジル、および
Yは、独立して、-CH2-または-CH2CH2-であり;および
Rdは、それぞれ独立して、ハロゲン、C1-4アルキルまたはC1-4アルコキシである]の化合物、またはその互変異性体または医薬的に許容される塩を提供する。
R1は、独立して、2,2-ジフルオロエチル、イソプロピル、シクロプロピル、およびシクロブチルから選択され;
R6は、独立して、0〜1個のRdで置換されたチアゾリル、0〜1個のRdで置換されたピリジルおよび
Yは、独立して、-CH2-または-CH2CH2-であり;および
Rdは、独立して、F、ClまたはOCH3である]の化合物、またはその互変異性体または医薬的に許容される塩を提供する。
R1は、独立して、2,2-ジフルオロエチルまたはイソプロピルであり;
R6は、独立して、0〜1個のRdで置換されたチアゾリル、0〜1個のRdで置換されたピリジル、および
Yは、独立して、-CH2-または-CH2CH2-であり;および
Rdは、独立して、F、ClまたはOCH3である]の化合物、またはその互変異性体または医薬的に許容される塩を提供する。
R1は、独立して、シクロプロピルまたはシクロブチルであり;
R6は、独立して、0〜1個のRdで置換されたチアゾリル、0〜1個のRdで置換されたピリジル、および
Yは、独立して、-CH2-または-CH2CH2-であり;および
Rdは、独立して、F、ClまたはOCH3である]の化合物、またはその互変異性体または医薬的に許容される塩を提供する。
R1は、独立して、2,2-ジフルオロエチル、イソプロピル、シクロプロピル、およびシクロブチルから選択され;
R6は、独立して、0〜1個のRdで置換されたチアゾリルまたは0〜1個のRdで置換されたピリジルであり;
Yは、独立して、-CH2-または-CH2CH2-であり;および
Rdは、独立して、F、ClまたはOCH3である]の化合物、またはその互変異性体または医薬的に許容される塩を提供する。
R1は、独立して、2,2-ジフルオロエチル、イソプロピル、シクロプロピル、およびシクロブチルから選択され;
R6は、独立して、
Yは、独立して、-CH2-または-CH2CH2-であり;および
Rdは、独立して、F、ClまたはOCH3である]の化合物、またはその互変異性体または医薬的に許容される塩を提供する。
ある態様において、本明細書に記載の化学物質(例えば、本明細書で一般的または特異的に記載されている化合物またはその医薬的に許容される塩またはそれを含む組成物)をNLRP3に接触させることを含む、NLRP3活性の調節方法(例えば、刺激、一部刺激、拮抗)が特徴付けられている。好ましい実施態様において、NLRP3活性の調節方法は、刺激および一部刺激することである。ある実施態様において、NLRP3活性の調節方法は刺激することである。ある実施態様において、NLRP3活性の調節方法は、一部刺激することである。その方法には、インビトロの方法(例えば、1つ以上のNLRP3を含む細胞(例えば、THP-1細胞)を含むサンプルに、上記化学物質を接触させること)が含まれる。また、その方法には、インビボの方法(例えば、NLRP3シグナル伝達の増加が、病理および/または症状および/または疾患の進行(例えばがん;例えば難治性がん)に関与する自然免疫活性の不足を正常化し得る疾患を有する対象(例えばヒト)に、化学物質を投与すること)も含まれる。
本明細書に記載の本開示の理解を進めるために、様々な他の用語が下記で定義される。一般に、本明細書で用いられる命名法および本明細書に記載の有機化学、医薬品化学、および薬理学における実験手順は、当業者に周知であり、一般に用いられる。特に断りが無い限り、本明細書で用いるあらゆる専門用語および科学用語は、一般に、本開示に関連する当業者により一般に理解されるものと同じ意味を持つ。
一部の実施態様において、化学物質(例えば、NLRP3を調節する(例えば、刺激するまたは一部刺激する)化合物、またはその医薬的に許容される塩、および/または水和物、および/または共結晶、および/または合剤)は、化学物質および1つ以上の医薬的に許容される賦形剤、本明細書に記載の1つ以上の別の治療剤を適宜含んでもよい医薬組成物として投与される。
一部の実施態様において、本明細書に記載の化学物質群またはその医薬組成物は、許容されるあらゆる投与経路により、その必要のある対象に投与され得る。許容される投与経路は、以下に限らないが、口腔内、皮膚、子宮頚管内、鼻腔内、気管内、腸内、硬膜外、間質内、腹腔内、動脈内、気管支内、滑液包内、脳内、大槽内、冠動脈内、真皮内、管内、十二指腸内、硬膜内、表皮内、食道内、胃内、歯肉内、回腸内、リンパ管内、髄内、髄膜内、筋肉内、卵巣内、腹腔内、前立腺内、肺内、腔内(intrasinal)、髄腔内、滑膜内、精巣内、くも膜下内、管内、腫瘍内、子宮内、血管内、静脈内、経鼻、経鼻胃、経口、非経口、経皮、経硬膜、直腸、呼吸器(吸入)、皮下、舌下、粘膜下、局所、経皮、経粘膜、経気管、尿管、尿道および腟内投与が挙げられる。特定の実施態様において、好ましい投与経路は、非経口投与(例えば、腫瘍内投与)である。特定の実施態様において、好ましい投与経路は、全身投与である。
投薬量は、患者の要望、治療する症状の重症度および用いられる特定の化合物によって変更されてもよい。特定の状況に対する適切な投薬量の決定は、医薬分野における当業者により決定され得る。1日の総投薬量は、1日を通して、分割されても、少量ずつ投与されても、または連続送達を提供する手段により投与されてもよい。
前記投薬量は、1日あたりの基準量(例えば、単回用量として、または2回以上の分割用量として)または1日あたりではない基準量(例えば、隔日、2日毎、3日毎、週に1回、週に2回、2週に1回、1ヶ月に1回)で投与され得る。
一部の実施態様において、NLRP3シグナル伝達の増加により、病状、疾患または障害(例えばがん)の病変および/または症状および/または進行に関与する自然免疫活性の不足を補正し得る、病状、疾患または障害(例えば、不十分な免疫応答に関連する病状、疾患または障害)を有する対象を治療する方法が提供される。
本明細書に記載のいずれかの方法において、対象はがんを有し得る。本明細書に記載のいずれかの方法の、一部の例において、哺乳動物は、がんを有すると確認されているか、またはがんを有すると診断されている。
本開示は、単剤療法計画ならびに併用療法計画の両方を意図する。
一部の実施態様において、本明細書に記載の方法は、前記治療が必要な対象(例えば患者)を同定する工程(例えば、生検、内視鏡または当業者には既知の他の従来法による)をさらに含む。ある実施態様において、NLRP3タンパク質は、特定のがん種のバイオマーカーとして機能し得る。
当業者に理解され得るように、本明細書の式の化合物の合成方法は、当業者に明かである。例えば、本明細書に記載の化合物は、例えば、1つ以上の本明細書に記載の方法および/または例えば、その内容の全てを参照により本明細書に組み込む、US 2015/0056224に記載の方法を用いて合成され得る。本明細書に記載の化合物を合成する際に有用な、合成における化学変換および保護基の方法論(保護および脱保護)は当業者に既知であり、例えば、R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994);およびL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995)、およびその続編に記載されるものを含む。本発明の化合物の製造に用いられる出発物質は公知であり、既知の方法によって製造されるか、または市販品として入手可能である。当業者は、本明細書に記載の条件および試薬が、当分野において認められる代替物で置き換えられ得ることも認識している。例えば、多くの反応において、トリエチルアミンは、その他の塩基、例えば非求核性塩基(例えばジイソプロピルアミン、1,8-ジアザビシクロウンデカ-7-エン、2,6-ジ-tert-ブチルピリジン、またはテトラブチルホスファゼン)で置き換えられ得る。
スキーム1の第1ステップは、適切な官能基を有するキノリン(i)(Lはハロゲン(例えばブロマイド))から出発する。スキーム1の第1ステップでは、化合物(i)を適切なアミンおよび塩基(例えばトリエチルアミン)で、溶媒(例えばジクロロメタン)中、適切な温度(例えば室温)で処理し、化合物(ii)を得てもよい。
スキーム1の第2ステップでは、化合物(iv)を溶媒(例えばエタノール)中、適切な還元剤(例えば水素ガス存在下のPt/C)で処理し、化合物(iii)を得てもよい。
スキーム1の第3ステップでは、化合物(iii)を適切な官能基を有するカルボン酸(例えばN-Bocグリシンまたは3-(tert-ブトキシカルボニルアミノ)プロパン酸)、適切なカップリング剤(例えばHATU)、および適切なアミン(例えばトリエチルアミン)で、溶媒(例えばジクロロメタン)中、適当な温度(例えば室温)で処理し、化合物(iv)を得てもよい。
スキーム1の第4ステップでは、化合物(iv)を適切な塩基(例えば水酸化ナトリウム)で、溶媒(例えばメタノール)中、適当な温度(例えば75℃)で処理し、化合物(v)を得てもよい。
スキーム1の第5ステップでは、化合物(v)を溶媒(例えばジクロロメタン)中、適切な酸化剤(例えばm-CPBA)で処理し、化合物(vi)を得てもよい。
スキーム1の第6ステップでは、化合物(vi)を溶媒(例えばジクロロメタン)中、試薬(例えば、トシルクロリド)およびアミン(例えばアンモニア)で処理し、化合物(vii)を得てもよい。
スキーム1の第7ステップでは、化合物(vii)を、適切なボロン酸エステル(例えば、3-(テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール)の触媒(例えばPd(dppf)Cl2ジクロロメタン複合体)および塩基(例えば炭酸セシウム)存在下で、混合溶媒(例えばジオキサン/水)中、適切な温度(例えば100℃)で処理し、化合物(viii)を得てもよい。
スキーム1の第8ステップでは、化合物(viii)をHCl/ジオキサン、またはTFAで処理し、化合物(x)を得てもよい。
スキーム1の第9ステップでは、溶媒(例えばDMF)中、化合物(x)を適切な酸、カップリング剤(例えばHATU)、および塩基(例えばヒューニッヒ塩基)で処理し、式(I)の化合物を得てもよい。
PMA分化THP-1細胞におけるIL-1β生成の測定
THP-1細胞は、American Type Culture Collectionから購入し、サプライヤーの取扱説明書に従って継代培養を行った。実験前に、細胞をRPMI 1640(10%加熱不活性化FBS、ペニシリン(100ユニット/mL)およびストレプトマイシン(100μg/mL)含有)中で培養し、実験準備を行う前に対数期で保持した。実験前に、THP-1をPMA(ホルボール12-ミリステート13-アセテート、10μg/mL)で24時間処理した。実験日に培養液を除去し、接触させる細胞をトリプシンで2分間処理し、細胞を次いで回収し、PBS(リン酸緩衝食塩水)で洗浄し、遠沈し、RPMI(2%加熱不活性化FBS含有)に1x106細胞/mLの濃度で再懸濁し、100μLを96ウェルプレートに播種した。化合物をジメチルスルホキシド(DMSO)に溶解し、所望の濃度(例えば100、30、10、3、1、0.3または0.1μM)になるまで培地に加えた。細胞を、化合物と共に4時間インキュベートした。細胞を含まない上清を回収し、IL-1βの生成をELISAにより評価した。ビークルのみのコントロールを各実験に対して同時に行った。最終的なDMSO濃度は1%であった。化合物は、PMA分化THP-1細胞において、用量に応じてIL-1β生成の増加を示した。
THP-1細胞は、American Type Culture Collectionから購入し、サプライヤーの取扱説明書に従って継代培養を行った。実験前に、細胞をRPMI 1640(10%加熱不活性化FBS、ペニシリン(100ユニット/mL)、ストレプトマイシン(100μg/mL)、HEPES(10mM)およびピルビン酸ナトリウム(1mM)含有)中で培養し、実験準備を行う前に対数期で保持した。実験前に、THP-1細胞をPMA(ホルボール12-ミリステート13-アセテート、20μg/mL)で終夜処理した。実験日に培養液を除去し、接触する細胞をトリプシンで2分間処理し、細胞を次いで回収し、PBS(リン酸緩衝食塩水)で洗浄し、遠心分離によりペレット状にし、384ウェルプレート中、RPMI(2%加熱不活性化FBS含有)に50,000細胞/ウェルの濃度で再懸濁した。細胞を含まない上清を回収し、IL-1βの生成をELISAにより評価した。化合物をジメチルスルホキシド(DMSO)に溶解し、所望の濃度(例えば100、30、10、3、1、0.3または0.1μM)になるまで培地に加えた。細胞を化合物と共に2時間インキュベートした。ビークルのみのコントロールを各実験に対して同時に行った。最終的なDMSO濃度は1%であった。化合物は、PMA分化THP-1細胞において、用量に応じてIL-1β生成の増加を示した。
化合物のDMSO溶液の段階希釈液を低容量384ウェルプレートに、ECHO 550 acoustic dispenser(Labcyte)を用いて100nL/ウェルで加え、アッセイ中の最終的な出発濃度が10μMになるようにした。
T175フラスコ中の、10%FBS含有RPMI(Gibco,11875)培地中の1x106細胞/mLの密度のTHP-1細胞を、分化させるために、最終濃度が50ng/mLのホルボール12-ミリステート13-アセテート(PMA、Sigma,P1585)で終夜37℃、5%CO2で処理した。dPBSでウェルを濯いだ翌日後、0.5%トリプシンを用いて細胞を回収した。2%FBS含有RPMI培地中、50μL/ウェルで50,000細胞にあたる、1x106細胞/mLの細胞溶液を調製した。マルチチャンネルピペットを用いて、384ウェル黒色透明底組織培養処理プレート(Greiner,781090)中の化合物希釈液に、細胞を播種した。該プレートを37℃、5%CO2のインキュベーターで2時間インキュベートした。
2時間インキュベート後、該細胞プレートを、遠心機を用いて5分間1200rpmで回転させた。Felix(CyBio)を用いて、上清(8μL)を384ウェルの低容量白色ProxiPlate(Perkin Elmer,6008230)に移した。ヒトIL-1βのhTRFキット(CISBIO,62HIL1BPEG)を用いて上清を分析した。該キット説明書に従ってIL-1β検量線を作成し、次いでキットの抗体をキット説明書の1:20ではなく、1:40で希釈した。混合した時点で、プレートに5μL/ウェルで抗体を加えた。このプレートを密封し、4℃で終夜インキュベートした。このプレートを次いでhTRFレーザーを用いてPerkin Elmer EnVision(665/615nm)で測定した。化合物は用量に応じて、IL-1β生成の増加を示した。
化合物のDMSO段階希釈液を低容量384ウェルプレートに、ECHO 550 acoustic dispenser(Labcyte)を用いて100nL/ウェルで加え、アッセイ中の最終的な出発濃度が10uMになるようにした。
健常ドナーから得たヒト静脈全血を、1ng/mLのLPS(Invivogen,Cat#tlrl-eblps)で、95%空気/5%CO2の加湿インキュベーター中、37℃で4時間予め処理した。処理した血液を化合物のプレートに加え、さらに37℃で4時間インキュベートした。上清中のIL-1βを、AlphLISAキット(Cat#AL220)を用いてメーカーの説明書に従って測定した。化合物は、用量に応じてIL-1β生成の増加を示した。EC50は、前処理は行ったが化合物では処理していない血液をベースラインとして用いて決定した。
C57BL/6マウス由来の不死化マウスマクロファージを、Eicke Latz氏(University of Bonn/University of Massachusetts Worcester(MA))から得た。該細胞を、0.05%トリプシンを用いて回収し、PBSで洗浄した。細胞を2%FBS含有DMEM(Gibco,11965)の25uL中、30,000細胞/ウェルで播種し、37℃、5%CO2で10分間インキュベートした。LPS-EB(Invivogen、tlr-eblps)を、5uL/ウェルで最終濃度が200ng/mLになるまで加え、細胞を37℃、5%CO2で2時間インキュベートした。
化合物のDMSO段階希釈液を低容量384ウェルプレート中の細胞に、ECHO 550 acoustic dispenser(Labcyte)を用いて60nL/ウェルで、アッセイ中の最終的な出発濃度が50uMになるように加え、化合物と共に37℃、5%CO2でさらに2時間インキュベートした。
2時間インキュベート後、該細胞プレートを、遠心機を用いて5分間1200rpmで回転させた。Felix(CyBio)を用いて、上清(8μL)を384ウェルの低容量白色ProxiPlate(Perkin Elmer,6008230)に移した。ヒトIL-1βのhTRFキット(CISBIO,62MIL1BPEH)を用いて上清を分析した。該キット説明書に従ってIL-1β検量線を作成した(キットの抗体はキット説明書の1:20ではなく、1:40で希釈した)。混合した時点で、プレートに5μL/ウェルで抗体を加えた。このプレートを密封し、4℃で終夜インキュベートした。このプレートをhTRFレーザーを用いてPerkin Elmer EnVision(665/615nm)で測定した。次いでデータをIL-1βのpg/mL量に変換した。化合物は、用量に応じてIL-1β生成の増加を示した。
TLR7またはTLR8遺伝子およびNF-kB/AP1誘導性SEAP(分泌型胎盤アルカリホスファターゼ;Invivogen,San Diego(CA))レポーター遺伝子が共発現し、対数的に増殖するヒトHEK-Blue細胞を、384ウェルプレートの各ウェルに加え(15,000細胞/20μL/ウェル)、37℃、5%CO2で24時間静置した。翌日、試料化合物またはDMSOをacoustic liquid handling technologyを用いて各ウェルに分配(100nL/ウェル)し、細胞を続いて37℃、5%CO2で18時間インキュベートした。直前に調整したQUANTI-Blue試薬(メーカーの説明書に従って調製;Invivogen,San Diego(CA))をHEK-Blue TLR Nf-kB-SEAP細胞反応に加え、30分後にプレートリーダー機器(Envision)を用いて細胞のSEAP生成を測定した。あらゆるEC50値(半数効果濃度)は、独自のデータ分析ソフトウェアを用いて決定した。規格化EC50値とは、50μMの標準試料で処理した細胞から得た標準RLU(発光量)値を用いて、Yの最大値を100%と設定して定義される絶対値である。
7-ブロモ-4-クロロ-3-ニトロキノリン(2g、6.96mmol、1当量)およびTEA(1.06g、10.43mmol、1.5当量)/DCM(80mL)の撹拌混合物に、シクロブタンアミン(0.59g、8.35mmol、1.2当量)を室温で滴下して加えた。この混合物を終夜室温で撹拌した。得られた混合物を減圧濃縮した。これにより7-ブロモ-N-シクロブチル-3-ニトロキノリン-4-アミン(1.8g、80.32%)を粗製黄色固体として得た。LC-MS: (ES, m/z): [M+H]+ =322.0
7-ブロモ-N-シクロブチル-3-ニトロキノリン-4-アミン(4.8g、14.89mmol、1当量)/アセトニトリル(180mL)の撹拌溶液に、Pt/C(0.85g、4.35mmol、0.29当量)を少しずつ室温で加えた。この混合物を水素雰囲気下、室温で終夜撹拌した。固体を濾過した。得られた溶液を減圧濃縮した。これにより7-ブロモ-N4-シクロブチルキノリン-3,4-ジアミン(4.23g、97.2%)を黄色固体として得た。LC-MS: (ES, m/z): [M+H]+ =292.0
7-ブロモ-N4-シクロブチルキノリン-3,4-ジアミン(2.04g、6.98mmol、1当量)および3-(tert-ブトキシカルボニルアミノ)プロパン酸(1.45g、7.680mmol、1.1当量)/DCM(30mL)の撹拌混合物に、HATU(7.96g、20.94mmol、3当量)およびDIEA(1.80g、13.96mmol、2当量)を室温で加えた。この混合物を室温で6時間撹拌した。得られた混合物を減圧濃縮した。これによりtert-ブチル3-(7-ブロモ-4-(シクロブチルアミノ)キノリン-3-イルアミノ)-3-オキソプロピルカルバメート(3.0g、94.3%)を黄色固体として得た。得られた粗製生成物の混合物は、次のステップにおいてさらに精製せずに直接用いた。LC-MS (ES, m/z): [M+H]+=463.2
tert-ブチル3-(7-ブロモ-4-(シクロブチルアミノ)キノリン-3-イルアミノ)-3-オキソプロピルカルバメート(3.15g、6.813mmol、1当量)およびNaOH(2.72g、68.12mmol、10当量)/EtOH(60mL)の混合物を室温で撹拌した。この混合物を75℃で4時間撹拌した。得られた混合物を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒: CH2Cl2/MeOH(19:1))で精製し、tert-ブチル2-(7-ブロモ-1-シクロブチル-1H-イミダゾ[4,5-c]キノリン-2-イル)エチルカルバメート(1.97g、63.5%)を橙色固体として得た。LC-MS: (ES, m/z): [M+H]+=457.1
tert-ブチルN-(2-[7-ブロモ-1-シクロブチル-1H-イミダゾ[4,5-c]キノリン-2-イル]エチル)カルバメート(1.7g、3.81mmol、1当量)およびm-CPBA(1.32g、7.63mmol、2当量)/DCM(30mL)の溶液を、25℃で2時間撹拌した。得られた混合物を真空濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒: CH2Cl2/MeOH(20:1))で精製し、7-ブロモ-2-(2-[[(tert-ブトキシ)カルボニル]アミノ]エチル)-1-シクロブチル-1H-イミダゾ[4,5-c]キノリン-5-イウム-5-オレート(1.33g、75.52%)を黄色固体として得た。LC-MS: [M+H]+=461.1
7-ブロモ-2-(2-[[(tert-ブトキシ)カルボニル]アミノ]エチル)-1-シクロブチル-1H-イミダゾ[4,5-c]キノリン-5-イウム-5-オレート(1.4g、3.03mmol、1当量)およびNH4OH(10mL)/DCM(30mL)の撹拌溶液に、TsCl(1.16g、6.06mmol、2当量)を25℃で加えた。得られた混合物を25℃で2時間撹拌した後、真空濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒: CH2Cl2/MeOH(60:1))で精製し、tert-ブチルN-(2-[4-アミノ-7-ブロモ-1-シクロブチル-1H-イミダゾ[4,5-c]キノリン-2-イル]エチル)カルバメート(1.1g、78.7%)を黄色固体として得た。LC-MS: (ES, m/z): [M+H]+=460.1
tert-ブチルN-(2-[4-アミノ-7-ブロモ-1-シクロブチル-1H-イミダゾ[4,5-c]キノリン-2-イル]エチル)カルバメート(500mg、1.08mmol、1当量)、3-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール(421.48mg、2.17mmol、2当量)、Cs2CO3(1061.59mg、3.25mmol、3当量)およびH2O(0.1mL)/ジオキサン(10mL)の撹拌溶液に、Pd(dppf)Cl2(158.94mg、0.217mmol、0.2当量)を窒素雰囲気下で加えた。得られた混合物を窒素雰囲気下、90℃で3時間撹拌した。その後、真空濃縮した。得られた混合物を濾過し、濾過ケーキをMeOH(3x15mL)で洗浄した。この濾液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒: CH2Cl2/MeOH(8:1))で精製し、tert-ブチルN-[2-[4-アミノ-1-シクロブチル-7-(1H-ピラゾール-5-イル)-1H-イミダゾ[4,5-c]キノリン-2-イル]エチル]カルバメート(310mg、63.8%)を褐色固体として得た。LC-MS: (ES, m/z): [M+H]+=448.2
tert-ブチルN-[2-[4-アミノ-1-シクロブチル-7-(1H-ピラゾール-5-イル)-1H-イミダゾ[4,5-c]キノリン-2-イル]エチル]カルバメート(370mg、0.827mmol、1当量)およびHCl/ジオキサン(8mL)のDCM(3mL)溶液を、25℃で2時間撹拌した。得られた混合物を真空濃縮し、2-(2-アミノエチル)-1-シクロブチル-7-(1H-ピラゾール-5-イル)-1H-イミダゾ[4,5-c]キノリン-4-アミン・2HCl(370mg)を粗製黄色として得た。LC-MS: (ES, m/z): [M+H]+ = 348.2
2-(2-アミノエチル)-1-シクロブチル-7-(1H-ピラゾール-5-イル)-1H-イミダゾ[4,5-c]キノリン-4-アミン(80mg、0.230mmol、1当量)、5-フルオロピリジン-2-カルボン酸(35.74mg、0.253mmol、1.1当量)、HATU(131.33mg、0.34mmol、1.5当量)およびDIEA(89.28mg、0.69mmol、3当量)/DCM(5mL)の溶液を、25℃で16時間撹拌した。得られた混合物を真空濃縮した。粗製生成物を分取HPLC(条件:カラム: XBridge Prep OBD C18 カラム、30x150mm、5um; 移動相: 水(10mmol/L NH4HCO3)およびACN(移動相Bを10%〜40%で7分溶出);検出器:UV(254/210nm))で精製し、N-[2-[4-アミノ-1-シクロブチル-7-(1H-ピラゾール-5-イル)-1H-イミダゾ[4,5-c]キノリン-2-イル]エチル]-5-フルオロピリジン-2-カルボキサミド(24.4mg、22.52%)を灰白色固体として得た。
A: PoroShell HPH C18、3.0mmx50mm、粒子径 2.7μm; 移動相A: 水(5mM重炭酸アンモニウム含有); 移動相B: アセトニトリル; 温度: 40℃; グラジエント: 5%B〜60%Bで3分かけて溶出後、次いで95%Bまで0.2分かけて溶出し、次いで95%Bで1.0分間溶出; 流速: 1mL/分; 検出: MSおよびUV
B: Express C18、2.1mmx50mm、粒子径 2.7μm; 移動相A: 水(0.05%TFA含有); 移動相B: アセトニトリル(0.05%TFA含有); 温度: 40℃; グラジエント: 5%B〜40%Bで2分かけて溶出後、次いで100%Bで0.75分かけて溶出し、次いで95%Bで0.65分間溶出; 流速: 1mL/分; 検出: MSおよびUV
C: カラム: Kinetex XB-C18、3.0mmx50mm、粒子径 2.6μm; 移動相A: 水(0.1%TFA含有); 移動相B: アセトニトリル(0.1%TFA含有); 温度: 40℃; グラジエント: 5%B〜100%Bで2.0分かけて溶出後、次いで100%Bで0.6分間溶出; 流速: 1.2mL/分; 検出: MSおよびUV
D: カラム: Waters Acquity、2.1mmx50mm、粒子径 1.7μm; 移動相A: 水(0.05%TFA含有); 移動相B: アセトニトリル(0.05%TFA含有); 温度: 50℃; グラジエント: 2%B〜98%Bで1分かけて溶出後、次いで98%Bで0.5分間溶出; 流速: 0.8mL/分; 検出: MSおよびUV
E: カラム: Waters XBridge C18、2.1mmx50mm、粒子径 1.7μm; 移動相A: 5:95 アセトニトリル:水(0.1%トリフルオロ酢酸含有); 移動相B: 95:5 アセトニトリル:水(0.1%トリフルオロ酢酸含有); 温度: 50℃; グラジエント: 0%B〜100%Bで3分かけて溶出後、次いで100%Bで0.50分間溶出; 流速: 1mL/分; 検出: MSおよびUV
Claims (16)
- 式(I):
R1は、独立して、1〜3個のハロゲンで置換されている非分岐C2-6アルキレン、0〜3個のハロゲンで置換されている分岐C3-6アルキレン、および0〜3個のハロゲンで置換されているC3-6シクロアルキルから選択され;
R2、R3およびR5は、それぞれ独立して、H、ハロゲン、シアノ、C1-4アルキル、C1-4ハロアルキル、C1-4アルコキシ、およびC1-4ハロアルコキシから選択され;
R4は、独立して、N、N(Ra)、O、およびSからそれぞれ独立して選択される、1〜4個の環原子を含む5員ヘテロアリールであり、ここでヘテロアリールは0〜3個のRbで置換され;
R6は、独立して、5〜6個の環原子(このうち1〜3個の環原子は、N(Rc)、O、およびSからそれぞれ独立して選択される)を含むヘテロシクリルであり、ここでヘテロシクリルは、0〜3個のRdで置換されるか;または5〜6個の環原子(このうち1〜4個の環原子は、N、N(Rc)、O、およびSからそれぞれ独立して選択される)を含むヘテロアリールであり、ここでヘテロアリールは、0〜3個のRdで置換され;
R7は、独立して、HまたはC1-4アルキルであり;
Yは、独立して、C1-3アルキレンであり;
RaおよびRcは、それぞれ独立して、HおよびC1-4アルキルから選択され;および
RbおよびRdは、それぞれ独立して、ハロゲン、シアノ、C1-4アルキル、C1-4ハロアルキル、C1-4アルコキシ、およびC1-4ハロアルコキシから選択される]の化合物、またはその互変異性体または医薬的に許容される塩。 - R1が、独立して、1〜3個のFで置換されている非分岐C2-4アルキレン、0〜2個のFで置換されている分岐C3-4アルキレンおよびC3-4シクロアルキルから選択され;
R2、R3およびR5が、それぞれ独立して、H、ハロゲンおよびC1-4アルキルから選択され;
R4が、独立して、ピラゾリル、チエニルまたはイソチアゾリルから選択され;
R6が、独立して、0〜2個のRdで置換されたチアゾリル、0〜2個のRdで置換されたピリジル、および
Yは、独立して、C1-2アルキレンであり;および
Rdは、それぞれ独立して、ハロゲン、C1-4アルキル、およびC1-4アルコキシから選択される、請求項1に記載の化合物。 - 実施例1〜20から選択される化合物、またはその医薬的に許容される塩である、請求項1に記載の化合物。
- 請求項1〜5のいずれか一項で特許請求される化合物またはその医薬的に許容される塩、および1つ以上の医薬的に許容される賦形剤を含む、医薬組成物。
- 薬剤として用いるための、請求項1〜5のいずれか一項に記載の化合物またはその医薬的に許容される塩、または請求項6に記載の医薬組成物。
- がん治療に用いるための、請求項1〜5のいずれか一項で特許請求される化合物またはその医薬的に許容される塩、または請求項6で特許請求される医薬組成物。
- がんが、急性骨髄性白血病、副腎皮質がん、カポジ肉腫、リンパ腫、肛門がん、虫垂癌、奇形腫/ラブドイド腫瘍、基底細胞がん、胆管がん、膀胱がん、骨がん、脳がん、乳がん、気管支腫瘍、カルチノイド腫瘍、心臓腫瘍、子宮頸がん、脊索腫、慢性リンパ性白血病、慢性骨髄増殖性腫瘍、結腸がん、結腸直腸がん、頭蓋咽頭腫、胆管がん、子宮内膜がん、上衣腫、食道がん、鼻腔神経芽細胞腫、ユーイング肉腫、眼腫瘍、卵管がん、胆嚢がん、消化管カルチノイド腫瘍、消化管間質腫瘍、胚細胞腫瘍、有毛細胞白血病、頭頸部がん、心臓腫瘍、肝臓がん、下咽頭がん、膵臓がん、腎臓がん、喉頭がん、慢性骨髄性白血病、口唇および口腔がん、肺がん、黒色腫、メルケル細胞がん、中皮腫、口唇がん、口唇部がん、骨肉腫、卵巣がん、陰茎がん、咽頭がん、前立腺がん、直腸がん、唾液腺がん、皮膚がん、小腸がん、軟部組織肉腫、精巣がん、喉のがん、甲状腺がん、尿道がん、子宮がん、腟がん、および外陰がんから選択される、請求項8に記載の化合物、またはその医薬的に許容される塩または医薬組成物。
- がんが、難治性がんである、請求項8または請求項9に記載の化合物、またはその医薬的に許容される塩または医薬組成物。
- がんが、乳がん、結腸がん、直腸がん、結腸直腸がん、膵臓がん、および前立腺がんから選択される、請求項8に記載の化合物、またはその医薬的に許容される塩または医薬組成物。
- 請求項8に記載の用途のための、化合物またはその医薬的に許容される塩または医薬組成物であって、上記がんは、ホルモン受容体陽性乳がん、マイクロサテライト安定性結腸がんまたは直腸がん、膵臓がんおよび前立腺がんから選択される。
- 化合物が、1つ以上の別のがん治療と組み合わせて投与される、請求項8〜12のいずれか一項に記載の化合物、またはその医薬的に許容される塩または医薬組成物。
- 1つ以上の別のがん治療に、手術、放射線療法、化学療法、毒素治療、免疫療法、凍結療法または遺伝子治療、またはその組み合わせが含まれる、請求項13に記載の化合物、またはその医薬的に許容される塩または医薬組成物。
- 別のがん治療に、ニボルマブ、ペムブロリズマブ、PDR001、MEDI-0680、セミピリマブ、JS001、BGB-A317、INCSHR1210、TSR-042、GLS-010、AM-0001、STI-1110、AGEN2034、MGD013、IBI308、BMS-936559、アテゾリズマブ、デュルバルマブ、アベルマブ、STI-1014、CX-072、LY3300054、CK-301、ウレルマブ、PF-05082566、MEDI6469、TRX518、バルリルマブ、CP-870893、BMS-986016、MGA271、リリルマブ、IPH2201、エマクツズマブ、INCB024360、ガルニセルチブ、ウロクプルマブ、BKT140、バビツキシマブ、CC-90002、ベバシズマブ、MNRP1685A、イピリムマブ、MK-1308、AGEN-1884、およびトレメリムマブから選択される1つ以上の薬剤が含まれる、請求項13に記載の化合物、またはその医薬的に許容される塩または医薬組成物。
- 別のがん治療に、ニボルマブ、イピリムマブ、ペムブロリズマブ、アテゾリズマブ、デュルバルマブおよびアベルマブから選択される1つ以上の薬剤が含まれる、請求項13に記載の化合物、またはその医薬的に許容される塩または医薬組成物。
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