JP2017533244A - ミオカルディン関連転写因子および血清応答因子(mrtf/srf)媒介性遺伝子転写の阻害剤ならびにその使用方法 - Google Patents
ミオカルディン関連転写因子および血清応答因子(mrtf/srf)媒介性遺伝子転写の阻害剤ならびにその使用方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- 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
- C07D401/10—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 carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—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
- C07D405/02—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
- C07D405/06—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 carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—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
- C07D405/02—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
- C07D405/10—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 carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—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
- C07D405/14—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 three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
Description
本発明は、国立衛生研究所により授けられた付与番号R01 AR066049−01の下で政府支援を受けてなされた。政府は、本発明において特定の権利を有す。
関連出願の相互参照
背景
細胞成長、増殖、移動、および浸潤は、多くの成長因子、マイトジェン、および走化性物質に依存している。組織培養における細胞の成長用の培地は、一般に、血清(例えばウシ胎児血清)を含有し、血清も、癌細胞および線維芽細胞の移動および浸潤を刺激する。血清での細胞の処理は、血清応答因子(「SRF」)を介した遺伝子転写の強い活性化をもたらす(Norman et al., Cell 55:989-1003 (1988)を参照されたい)。SRFは、細胞形質転換および上皮間充織転換に関連している(Iwahara et al., Oncogene 22:5946-5957 (2003); Psichari et al., J Biol Chem 277:29490-29495 (2002)を参照されたい)。
従って、癌および繊維化を治療および管理できる標的療法のための新しい化合物および方法の必要性が存在する。
Xは、
Hetは、ヘテロアリールであり;
Yは、CH2、C=O、CHOH、CHF、CF2、NR5、NCONHR5、NCOR5、NCO2R5、NSO2R5、S(O)2、またはSであり;
Zは、
mは、0、1、または2であり;
nは、0、1、または2であり;
pは、0または1であり;
qは、0、1、または2であり;
R1は、ヘテロアリールであり;
各R2は、独立して、ハロ、C1〜6アルキル、OC1〜C6アルキル、OC0〜6アルキレン−アリール、OC0〜6アルキレン−ヘテロアリール、SO2NR5 2、CN、またはSO2C1〜3アルキルであり;
R3は、H、ハロ、OH、C1〜3アルキル、またはOC1〜3アルキルであり;
各R4は、独立して、H、F、C1〜3アルキル、OR5、NR5 2、NR5CONHR5、NR5COR5、NR5CO2R5、NR5SO2R5であるか、またはR4両方は、それらが結合している炭素と共に、C=O、C=CH2、もしくはC3〜7シクロアルキルを形成し;
各R5は、独立して、H、C1〜6アルキル、C3〜7シクロアルキル、C2〜6アルケニル、C3〜6アルキレン−エーテル、C0〜6アルキレン−アリール、C0〜6アルキレン−ヘテロアリールであるか、または2つのR5は、それらが結合している窒素と共に、3〜7の原子の複素環を形成し;
R6は、H、ハロ、C1〜3ハロアルキル、またはOC1〜3ハロアルキルであり;
R7は、HまたはC1〜3アルキルであり;
但し、
(a)Xが、
(b)R1が、非置換型フラニル、非置換型チオフェニル、非置換型チアゾリル、非置換型オキサゾリル、もしくは非置換型オキサジアゾリルである場合には、
(i)Xは、
(ii)YはCH2以外であるか;もしくは
(iii)Zは、
(iv)R2はCl以外であるか;もしくは
(v)R3はH以外であるか;もしくは
(vi)少なくとも1つのR4はH以外であるか;もしくは
(vi)pは1以外である、
前記化合物を与える。
mは、0、1、または2であり;
nは、0、1、または2であり;
AおよびBの一方は、CR6であり、もう一方は、CR6またはNであり;
Yは、CH2、C=O、CHOH、CHF、CF2、NR5、NCONHR5、NCOR5、NCO2R5、またはNSO2R5であり;
R1は、ヘテロアリールであり;
各R2は、独立して、ハロ、C1〜6アルキル、OC1〜C6アルキル、OC0〜6アルキレン−アリール、OC0〜6アルキレン−ヘテロアリール、またはSO2NR5 2であり;
R3は、H、ハロ、OH、C1〜3アルキル、またはOC1〜3アルキルであり;
各R4は、独立して、H、F、C1〜3アルキル、OR5、NR5 2、NR5CONHR5、NR5COR5、NR5CO2R5、NR5SO2R5であるか、またはR4両方は、それらが結合している炭素と共に、C=O、C=CH2、もしくはC3〜7シクロアルキルを形成し;
各R5は、独立して、H、C1〜6アルキル、C3〜7シクロアルキル、C2〜6アルケニル、C3〜6アルキレン−エーテル、C0〜6アルキレン−アリール、C0〜6アルキレン−ヘテロアリールであるか、または2つのR5は、それらが結合している窒素と共に、3〜7の原子の複素環を形成し;
各R6は、独立して、H、ハロ、C1〜3ハロアルキル、またはOC1〜3ハロアルキルであり;
R7は、HまたはC1〜3アルキルであり;
但し、nが0であり、mが1であり、AおよびBがそれぞれCHであり、R2がハロ(例えば、クロロ)であり、各R4がHであり、YがCH2である場合には、R1は、非置換型フラニル、非置換型チオフェニル、非置換型チアゾリル、非置換型オキサゾリル、または非置換型オキサジアゾリル以外である、前記化合物を与える。
AおよびBはそれぞれCHであるか、またはAおよびBのうちの一方はCHで、他方はNであり;
Yは、CH2、NMe、NCH2Ph、NCONHiPr、NCONHPh、NCONH−シクロペンチル、NCONHCH2CH=CH2、NCOMe、NCOEt、NCOiPr、NCO(パラ−メトキシフェニル)、NCO2Et、NCO2Pr、NCO2Ph、NCO2CH2Ph、またはNCO2CH2CH2OMeあり;
R1は、ピロリル、ピラゾリル、イミダゾリル、フラニル、チオフェニル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、またはチアゾリルであり;
R3は、H、F、またはメチルであり;
但し、AおよびBがそれぞれCHであり、YがCH2である場合には、R1は、非置換型フラニル、非置換型チオフェニル、非置換型チアゾリル、非置換型オキサゾリル、および非置換型オキサジアゾリル以外である。
ミオカルディン関連転写因子および/または血清応答因子によって媒介される遺伝子転写を阻害し得る化合物であって、他の小分子阻害剤を超える効力を示す(例えば、インビトロでSSc皮膚線維芽細胞において筋線維芽細胞マーカーを阻害するのに、ピルフェニドンよりも約100倍強力である)前記化合物が、本明細書で開示される。本明細書で開示される阻害剤は、癌または線維症などの疾患を治療または予防し、苦しんでいる個体のクオリティオブライフを改善するために使用され得る。
定義
用語「ハロアルキル」は、1個以上のハロゲンで置換されているアルキル基を表す。
MRTF/SRF媒介性遺伝子転写の小分子阻害剤
Xは、
Hetは、ヘテロアリールであり;
Yは、CH2、C=O、CHOH、CHF、CF2、NR5、NCONHR5、NCOR5、NCO2R5、NSO2R5、S(O)2、またはSであり;
Zは、
mは、0、1、または2であり;
nは、0、1、または2であり;
pは、0または1であり;
qは、0、1、または2であり;
R1は、ヘテロアリールであり;
各R2は、独立して、ハロ、C1〜6アルキル、OC1〜C6アルキル、OC0〜6アルキレン−アリール、OC0〜6アルキレン−ヘテロアリール、SO2NR5 2、CN、またはSO2C1〜3アルキルであり;
R3は、H、ハロ、OH、C1〜3アルキル、またはOC1〜3アルキルであり;
各R4は、独立して、H、F、C1〜3アルキル、OR5、NR5 2、NR5CONHR5、NR5COR5、NR5CO2R5、NR5SO2R5であるか、またはR4両方は、それらが結合している炭素と共に、C=O、C=CH2、もしくはC3〜7シクロアルキルを形成し;
各R5は、独立して、H、C1〜6アルキル、C3〜7シクロアルキル、C2〜6アルケニル、C3〜6アルキレン−エーテル、C0〜6アルキレン−アリール、C0〜6アルキレン−ヘテロアリールであるか、または2つのR5は、それらが結合している窒素と共に、3〜7の原子の複素環を形成し;
R6は、H、ハロ、C1〜3ハロアルキル、またはOC1〜3ハロアルキルであり;
R7は、HまたはC1〜3アルキルであり;
但し、
(a)Xが、
(b)R1が、非置換型フラニル、非置換型チオフェニル、非置換型チアゾリル、非置換型オキサゾリル、もしくは非置換型オキサジアゾリルである場合には、
(i)Xは、
(ii)YはCH2以外であるか;もしくは
(iii)Zは、
(iv)R2はCl以外であるか;もしくは
(v)R3はH以外であるか;もしくは
(vi)少なくとも1つのR4はH以外であるか;もしくは
(vi)pは1以外である、
前記化合物が本明細書で与えられる。
mは、0、1、または2であり;
nは、0、1、または2であり;
AおよびBの一方は、CR6であり、もう一方は、CR6またはNであり;
Yは、CH2、C=O、CHOH、CHF、CF2、NR5、NCONHR5、NCOR5、NCO2R5、またはNSO2R5であり;
R1は、ヘテロアリールであり;
各R2は、独立して、ハロ、C1〜6アルキル、OC1〜6アルキル、OC0〜6アルキレン−アリール、OC0〜6アルキレン−ヘテロアリール、またはSO2NR5 2であり;
R3は、H、ハロ、OH、C1〜3アルキル、またはOC1〜3アルキルであり;
各R4は、独立して、H、F、C1〜3アルキル、OR5、NR5 2、NR5CONHR5、NR5COR5、NR5CO2R5、NR5SO2R5であるか、またはR4両方は、それらが結合している炭素と共に、C=O、C=CH2、もしくはC3〜7シクロアルキルを形成し;
各R5は、独立して、H、C1〜6アルキル、C3〜7シクロアルキル、C2〜6アルケニル、C3〜6アルキレン−エーテル、C0〜6アルキレン−アリール、C0〜6アルキレン−ヘテロアリールであるか、または2つのR5は、それらが結合している窒素と共に、3〜7の原子の複素環を形成し;
各R6は、独立して、H、ハロ、C1〜3ハロアルキル、またはOC1〜3ハロアルキルであり;
R7は、HまたはC1〜3アルキルであり;
但し、nが0であり、mが1であり、AおよびBがそれぞれCHであり、R2がハロ(例えば、クロロ)であり、各R4がHであり、YがCH2である場合には、R1は、非置換型フラニル、非置換型チオフェニル、非置換型チアゾリル、非置換型オキサゾリル、および非置換型オキサジアゾリル以外である、
前記化合物も本明細書で与えられる。
フェニル環上の−N(R7)−(CH2)n−部分に関してオルトである。いくつかの実施形態において、R2は、フェニル環上の−N(R7)−(CH2)n−部分に関してメタである。様々な場合において、R2は、フェニル環上の−N(R7)−(CH2)n−部分に関してパラである。これらの実施形態のいずれかにおいて、R2は、ハロ(例えば、F、Cl、Br、またはI)であり得る。いくつかの実施形態において、R2は、C1〜6アルキル(例えば、メチル、エチル、プロピル、イソプロピル、n−ブチル、sec−ブチル、tert−ブチル、ペンチル、またはヘキシル)である。いくつかの場合において、R2は、OC1〜6アルキル(例えば、O−メチル、O−エチル、O−プロピル、O−イソプロピル、O−n−ブチル、O−sec−ブチル、O−tert−ブチル、ペンチル、またはヘキシル)である。様々な実施形態において、R2は、OC0〜6アルキレン−アリール(例えば、CH2−フェニルもしくはフェニル)またはOC0〜6アルキレン−ヘテロアリールである。いくつかの場合において、R2は、SO2NR5 2(例えば、SO2NH2、SO2NHCH3、またはSO2N(CH3)2)である。
AおよびBはそれぞれCHであるか、またはAおよびBのうちの一方はCHで、他方はNであり;
Yは、CH2、NMe、NCH2Ph、NCONHiPr、NCONHPh、NCONH−シクロペンチル、NCONHCH2CH=CH2、NCOMe、NCOEt、NCOiPr、NCO(パラ−メトキシフェニル)、NCO2Et、NCO2Pr、NCO2Ph、NCO2CH2Ph、またはNCO2CH2CH2OMeあり;
R1は、ピロリル、ピラゾリル、イミダゾリル、フラニル、チオフェニル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、またはチアゾリルであり;
R3は、H、F、またはメチルであり;
但し、AおよびBがそれぞれCHであり、YがCH2である場合には、R1は、非置換型フラニル、非置換型チオフェニル、非置換型チアゾリル、非置換型オキサゾリル、および非置換型オキサジアゾリル以外である。
Yは、CH2、NMe、NCH2Ph、NCONHiPr、NCONHPh、NCONH−シクロペンチル、NCONHCH2CH=CH2、NCOMe、NCOEt、NCOiPr、NCO(パラ−メトキシフェニル)、NCO2Et、NCO2Pr、NCO2Ph、NCO2CH2Ph、またはNCO2CH2CH2OMeあり;
R1は、ピロリル、ピラゾリル、イミダゾリル、フラニル、チオフェニル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、またはチアゾリルであり;
R3は、H、F、またはメチルである。
MRTF/SRF媒介性遺伝子転写の阻害剤の合成
スキーム1
方法
医薬製剤
キット
材料および方法
Dual Luciferaseアッセイ
WST1細胞生存率アッセイ
SRE.L−ルシフェラーゼレポーターアッセイ
健常なヒトドナーからの皮膚線維芽細胞を、72時間、10ng/mLのTGFβ1による刺激と共に、または前記刺激なしで、示された濃度の化合物E−02またはE−019(および0.1%DMSOコントロール)で処理した。次に、細胞を、α−SMAに対する一次抗体、次いでフルオロフォア結合二次抗体+DAPIで検出した。細胞を、蛍光顕微鏡を用いて40Xの倍率で撮像した。数量化のために、3つのランダムな非オーバーラップの視野からの細胞を、処理について知らない観察者によって、α−SMA陽性または非陽性としてスコアリングした。図1および2を参照されたい。
製造1:3−((4−クロロフェニル)カルバモイル)−3−フルオロピペリジン−1−カルボン酸)tert−ブチル
製造2:N−(4−クロロフェニル)−3−フルオロピペリジン−3−カルボキサミドトリフルオロ酢酸塩
実施例1:N−(4−クロロフェニル)−3−フルオロ−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
製造3:3−((4−クロロフェニル)カルバモイル)ピペリジン−1−カルボン酸tert−ブチル
製造4:N−(4−クロロフェニル)ピペリジン−3−カルボキサミドトリフルオロ酢酸塩
実施例2:N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例3:1−(3−(5−クロロフラン−2−イル)ベンゾイル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
製造5:2−((4−クロロフェニル)カルバモイル)ピペラジン−1,4−ジカルボン酸1−ベンジル 4−(tert−ブチル)
製造6:2−((4−クロロフェニル)カルバモイル)ピペラジン−1−カルボン酸ベンジル
実施例4:2−((4−クロロフェニル)カルバモイル)−4−(3−(フラン−2−イル)ベンゾイル)ピペラジン−1−カルボン酸ベンジル
製造7:N−(4−クロロフェニル)−4−(3−(フラン−2−イル)ベンゾイル)ピペラジン−2−カルボキサミド
実施例5:N−(4−クロロフェニル)−4−(3−(フラン−2−イル)ベンゾイル)−1−プロピオニルピペラジン−2−カルボキサミド
実施例6:N−(4−クロロフェニル)−4−(3−(フラン−2−イル)ベンゾイル)−1−イソブチリルピペラジン−2−カルボキサミド
実施例7:N−(4−クロロフェニル)−4−(3−(フラン−2−イル)ベンゾイル)−1−(4−メトキシベンゾイル)ピペラジン−2−カルボキサミド
実施例8:1−アセチル−N−(4−クロロフェニル)−4−(3−(フラン−2−イル)ベンゾイル)ピペラジン−2−カルボキサミド
尿素類に関する基本手順
実施例9:N2−(4−クロロフェニル)−4−(3−(フラン−2−イル)ベンゾイル)−N1−フェニルピペラジン−1,2−ジカルボキサミド
実施例10:N2−(4−クロロフェニル)−4−(3−(フラン−2−イル)ベンゾイル)−N1−イソプロピルピペラジン−1,2−ジカルボキサミド
実施例11:N2−(4−クロロフェニル)−N1−シクロペンチル−4−(3−(フラン−2−イル)ベンゾイル)ピペラジン−1,2−ジカルボキサミド
実施例12:N1−アリル−N2−(4−クロロフェニル)−4−(3−(フラン−2−イル)ベンゾイル)ピペラジン−1,2−ジカルボキサミド
実施例13:2−((4−クロロフェニル)カルバモイル)−4−(3−(フラン−2−イル)ベンゾイル)ピペラジン−1−カルボン酸プロピル
カルバメート類に関する基本手順
実施例14:2−((4−クロロフェニル)カルバモイル)−4−(3−(フラン−2−イル)ベンゾイル)ピペラジン−1−カルボン酸エチル
実施例15:2−((4−クロロフェニル)カルバモイル)−4−(3−(フラン−2−イル)ベンゾイル)ピペラジン−1−カルボン酸フェニル
実施例16:2−((4−クロロフェニル)カルバモイル)−4−(3−(フラン−2−イル)ベンゾイル)ピペラジン−1−カルボン酸2−メトキシエチル
実施例17:1−ベンジル−N−(4−クロロフェニル)−4−(3−(フラン−2−イル)ベンゾイル)ピペラジン−2−カルボキサミド
実施例18:N−(4−クロロフェニル)−4−(3−(フラン−2−イル)ベンゾイル)−1−メチルピペラジン−2−カルボキサミド
製造8:3−((4−クロロフェニル)カルバモイル)−5−ヒドロキシピペリジン−1−カルボン酸tert−ブチル
製造9:3−((4−クロロフェニル)カルバモイル)−5−オキソピペリジン−1−カルボン酸tert−ブチル
製造10:5−((4−クロロフェニル)カルバモイル)−3,3−ジフルオロピペリジン−1−カルボン酸tert−ブチル
製造11:N−(4−クロロフェニル)−5,5−ジフルオロピペリジン−3−カルボキサミド
実施例19:N−(4−クロロフェニル)−5,5−ジフルオロ−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
製造12:3−((4−クロロフェニル)カルバモイル)−5−メチレンピペリジン−1−カルボン酸tert−ブチル
製造13:N−(4−クロロフェニル)−5−メチレンピペリジン−3−カルボキサミドトリフルオロ酢酸塩
実施例20:N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)−5−メチレンピペリジン−3−カルボキサミド
製造14:5−((4−クロロフェニル)カルバモイル)−3,3−ジメトキシピペリジン−1−カルボン酸tert−ブチル
製造15:N−(4−クロロフェニル)−5,5−ジメトキシピペリジン−3−カルボキサミド
実施例21:N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)−5,5−ジメトキシピペリジン−3−カルボキサミド
実施例22:N−(4−クロロフェニル)−1−(3−(チオフェン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例23:N−(4−クロロフェニル)−1−{[5−(フラン−2−イル)ピリジン−3−イル]カルボニル}ピペリジン−3−カルボキサミド
実施例24:N−(4−クロロフェニル)−1−{[4−(フラン−2−イル)ピリジン−2−イル]カルボニル}ピペリジン−3−カルボキサミド
実施例25:N−(4−クロロフェニル)−5,5−ジフルオロ−1−{[4−(フラン−2−イル)ピリジン−2−イル]カルボニル}ピペリジン−3−カルボキサミド
実施例26:N−(4−クロロフェニル)−5,5−ジフルオロ−1−{[5−(フラン−2−イル)ピリジン−3−イル]カルボニル}ピペリジン−3−カルボキサミド
製造16:1−(tert−ブトキシカルボニル)−5−((tert−ブチルジメチルシリル)オキシ)ピペリジン−3−カルボン酸
製造17:3−((tert−ブチルジメチルシリル)オキシ)−5−((4−クロロフェニル)カルバモイル)ピペリジン−1−カルボン酸tert−ブチル
製造18:5−((tert−ブチルジメチルシリル)オキシ)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
製造19:5−((tert−ブチルジメチルシリル)オキシ)−N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例27:N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)−5−ヒドロキシピペリジン−3−カルボキサミド
製造20:3−((4−クロロフェニル)カルバモイル)−3−メチルピペリジン−1−カルボン酸t−ブチル
製造21:N−(4−クロロフェニル)−3−メチルピペリジン−3−カルボキサミド
実施例28:N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)−3−メチルピペリジン−3−カルボキサミド
実施例29:N−(4−クロロフェニル)−1−(3−(5−メチルフラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例30:1−(3−(1H−ピラゾール−1−イル)ベンゾイル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
実施例31:1−(3−(1H−ピラゾール−4−イル)ベンゾイル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
実施例32:1−(3−(1H−ピラゾール−3−イル)ベンゾイル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
ピペリジン類とのアミドカップリングに関する基本手順
実施例34:N−(4−クロロフェニル)−1−(6−(フラン−2−イル)ピリミジン−4−カルボニル)ピペリジン−3−カルボキサミド
製造22:1−メチル−1H−ベンゾ[d]イミダゾール−2−カルボン酸メチル
製造23:1−メチル−1H−ベンゾ[d]イミダゾール−2−カルボン酸
実施例35:N−(4−クロロフェニル)−1−(1−メチル−1H−ベンゾ[d]イミダゾール−2−カルボニル)ピペリジン−3−カルボキサミド
実施例36:1−(2−ブロモチアゾール−5−カルボニル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
実施例37:N−(4−クロロフェニル)−1−(2−(フラン−2−イル)チアゾール−5−カルボニル)ピペリジン−3−カルボキサミド
実施例38:N−(4−クロロフェニル)−1−(2−(フラン−2−イル)チアゾール−4−カルボニル)ピペリジン−3−カルボキサミド
実施例39:N−(4−クロロフェニル)−1−(5−(フラン−2−イル)イソオキサゾール−3−カルボニル)ピペリジン−3−カルボキサミド
実施例40:N−(4−クロロフェニル)−1−(5−(フラン−2−イル)−1H−ピラゾール−3−カルボニル)ピペリジン−3−カルボキサミド
製造25:3−フルオロ−5−(ピリジン−4−イル)安息香酸
実施例41:N−(4−クロロフェニル)−5,5−ジフルオロ−1−(3−フルオロ−5−(ピリジン−4−イル)ベンゾイル)ピペリジン−3−カルボキサミド
製造26:5−ブロモニコチン酸
製造27:1−(5−ブロモニコチノイル)−N−(4−クロロフェニル)−5,5−ジフルオロピペリジン−3−カルボキサミド
実施例42:1−([3,4´−ビピリジン]−5−カルボニル)−N−(4−クロロフェニル)−5,5−ジフルオロピペリジン−3−カルボキサミド
製造28:5−((メチルスルホニル)オキシ)ピペリジン−1,3−ジカルボン酸1−(tert−ブチル) 3−メチル
製造29:5−アジドピペリジン−1,3−ジカルボン酸1−(tert−ブチル) 3−メチル
製造30:5−アジド−1−(tert−ブトキシカルボニル)ピペリジン−3−カルボン酸
製造31:3−アジド−5−((4−クロロフェニル)カルバモイル)ピペリジン−1−カルボン酸tert−ブチル
製造32:5−アジド−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
製造33:5−アジド−N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例43:5−アミノ−N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例44:N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)−5−(メチルアミノ)ピペリジン−3−カルボキサミド
製造34:5−ヒドロキシピペリジン−1,3−ジカルボン酸1−(tert−ブチル) 3−メチル
製造35:1−(tert−ブトキシカルボニル)−5−メトキシピペリジン−3−カルボン酸
製造36:3−((4−クロロフェニル)カルバモイル)−5−メトキシピペリジン−1−カルボン酸tert−ブチル
製造37:N−(4−クロロフェニル)−5−メトキシピペリジン−3−カルボキサミド
実施例45:N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)−5−メトキシピペリジン−3−カルボキサミド−ジアステレオマーA
実施例46:N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)−5−メトキシピペリジン−3−カルボキサミド−ジアステレオマーB
実施例47:N−(4−クロロフェニル)−5,5−ジフルオロ−1−(3−(1−メチル−1H−イミダゾール−5−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例48:5−(ベンジルアミノ)−N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例49:N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)−5−プロピオンアミドピペリジン−3−カルボキサミド
実施例50:N−(4−クロロフェニル)−5,5−ジフルオロ−1−(3−(ピリミジン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
製造38:5−オキソピペリジン−1,3−ジカルボン酸1−(tert−ブチル) 3−メチル
製造39:5,5−ジフルオロピペリジン−1,3−ジカルボン酸1−(tert−ブチル) 3−メチル
製造40:3,3−ジフルオロ−5−(ヒドロキシメチル)ピペリジン−1−カルボン酸tert−ブチル
製造41:3,3−ジフルオロ−5−(((メチルスルホニル)オキシ)メチル)ピペリジン−1−カルボン酸tert−ブチル
製造42:5−((4−クロロフェノキシ)メチル)−3,3−ジフルオロピペリジン−1−カルボン酸tert−ブチル
製造43:5−((4−クロロフェノキシ)メチル)−3,3−ジフルオロピペリジン
実施例51:(3−(1H−ピラゾール−4−イル)フェニル)(5−((4−クロロフェノキシ)メチル)−3,3−ジフルオロピペリジン−1−イル)メタノン
製造44:2−((4−クロロフェニル)カルバモイル)チオモルホリン−4−カルボン酸tert−ブチル
製造45:N−(4−クロロフェニル)チオモルホリン−2−カルボキサミド
実施例52:N−(4−クロロフェニル)−4−(3−(フラン−2−イル)ベンゾイル)チオモルホリン−2−カルボキサミド
実施例53:N−(4−クロロフェニル)−4−(3−(フラン−2−イル)ベンゾイル)チオモルホリン−2−カルボキサミド 1,1−ジオキシド
実施例54:5−ベンズアミド−N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド ジアステレオマーA
実施例55:5−ベンズアミド−N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド ジアステレオマーB
実施例56:5−((4−クロロフェニル)カルバモイル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−イル)カルバミン酸フェニル
実施例57:5−((4−クロロフェニル)カルバモイル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−イル)カルバミン酸メチル
実施例58:5−((4−クロロフェニル)カルバモイル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−イル)カルバミン酸エチル
実施例59:(5−((4−クロロフェノキシ)メチル)−3,3−ジフルオロピペリジン−1−イル)(3−(フラン−2−イル)フェニル)メタノン
製造46:3−(ベンジル(メチル)アミノ)−5−((4−クロロフェニル)カルバモイル)ピペリジン−1−カルボン酸tert−ブチル
製造47:5−(ベンジル(メチル)アミノ)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
実施例60:5−(ベンジル(メチル)アミノ)−N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド−ジアステレオマーA
実施例61:5−(ベンジル(メチル)アミノ)−N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド−ジアステレオマーB
製造48:3−((4−クロロフェニル)スルホンアミド)ピペリジン−1−カルボン酸tert−ブチル
製造49:4−クロロ−N−(ピペリジン−3−イル)ベンゼンスルホンアミド
実施例62:4−クロロ−N−(1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−イル)ベンゼンスルホンアミド
製造50:N−(4−クロロフェニル)−5−オキシピペリジン−3−カルボキサミド
実施例63:N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)−5−オキソピペリジン−3−カルボキサミド
製造51:3−((4−クロロフェニル)カルバモイル)−5−(ジメチルアミノ)ピペリジン−1−カルボン酸tert−ブチル
製造52:N−(4−クロロフェニル)−5−(ジメチルアミノ)ピペリジン−3−カルボキサミド
実施例64:N−(4−クロロフェニル)−5−(ジメチルアミノ)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
製造53:3−(4−クロロベンズアミド)ピペリジン−1−カルボン酸tert−ブチル
製造54:4−クロロ−N−(ピペリジン−3−イル)ベンズアミド
実施例65:4−クロロ−N−(1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−イル)ベンズアミド
製造55:3−(((メチルスルホニル)オキシ)メチル)ピペリジン−1−カルボン酸tert−ブチル
製造56:3−((4−クロロフェノキシ)メチル)ピペリジン−1−カルボン酸tert−ブチル
製造57:3−((4−クロロフェノキシ)メチル)ピペリジン
実施例66:(3−((4−クロロフェノキシ)メチル)ピペリジン−1−イル)(3−(フラン−2−イル)フェニル)メタノン
実施例67:1−(3−(1H−ピラゾール−1−イル)ベンゾイル)−N−(4−クロロフェニル)−5,5−ジフルオロピペリジン−3−カルボキサミド
実施例68:N−(4−クロロフェニル)−5,5−ジフルオロ−1−(3−(ピリジン−4−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例69:N−(4−クロロフェニル)−1−(5−メチル−2−フェニルオキサゾール−4−カルボニル)ピペリジン−3−カルボキサミド
実施例70:1−(2−(1H−ベンゾ[d]イミダゾール−2−イル)アセチル)−N−(4−クロロフェニル)−5,5−ジフルオロピペリジン−3−カルボキサミド
実施例71:1−(2−(ベンゾフラン−2−イル)アセチル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
実施例72:N−(4−クロロフェニル)−1−(4−メチル−2−フェニルチアゾール−5−カルボニル)ピペリジン−3−カルボキサミド
実施例73:N−(4−クロロフェニル)−1−(2−フェニルチアゾール−4−カルボニル)ピペリジン−3−カルボキサミド
実施例74:1−(ベンゾ[d]チアゾール−5−カルボニル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
実施例75:1−(1H−ベンゾ[d]イミダゾール−2−カルボニル)−N−(4−クロロフェニル)−5,5−ジフルオロ−ピペリジン−3−カルボキサミド
実施例76:N−(4−クロロフェニル)−5,5−ジフルオロ−1−(1H−インドール−6−カルボニル)ピペリジン−3−カルボキサミド
実施例77:N−(4−クロロフェニル)−1−(2−(2−(4−フルオロフェニル)チアゾール−4−イル)−2−メチルプルパノイル)−ピペリジン−3−カルボキサミド
実施例78:N−(4−クロロフェニル)−1−(2−(2−(4−フルオロフェニル)チアゾール−4−イル)アセチル)ピペリジン−3−カルボキサミド
実施例79:N−(4−クロロフェニル)−1−(6−フルオロ−1H−インドール−2−カルボニル)ピペリジン−3−カルボキサミド
実施例80:N−(4−クロロフェニル)−1−(1H−インドール−2−カルボニル)ピペリジン−3−カルボキサミド
実施例81:N−(4−クロロフェニル)−1−(5−メトキシ−1H−インドール−2−カルボニル)ピペリジン−3−カルボキサミド
実施例82:N−(4−クロロフェニル)−1−(1H−インダゾール−5−カルボニル)ピペリジン−3−カルボキサミド
実施例83:1−(3−(1H−インドール−3−イル)プロパノイル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
実施例84:1−(2−(1H−インドール−3−イル)アセチル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
実施例85:N−(4−クロロフェニル)−1−(1H−インダゾール−4−カルボニル)ピペリジン−3−カルボキサミド
実施例86:N−(4−クロロフェニル)−1−(1H−インドール−6−カルボニル)ピペリジン−3−カルボキサミド
実施例87:N−(4−クロロフェニル)−1−(1H−インドール−5−カルボニル)ピペリジン−3−カルボキサミド
実施例88:N−(4−クロロフェニル)−1−(1H−インダゾール-3−カルボニル)ピペリジン−3−カルボキサミド
実施例89:1−(1H−ベンゾ[d]イミダゾール−2−カルボニル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
実施例90:1−(2−(1H−ピラゾール−1−イル)ベンゾイル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
実施例91:1−(2−(1H−イミダゾール−1−イル)ベンゾイル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
実施例92:N−(4−クロロフェニル)−1−(2−(フラン−2−イル)ベンゾイル)ピペリジン−3− カルボキサミド
実施例93:N−(4−クロロフェニル)−1−(1H−インダゾール−6−カルボニル)ピペリジン−3−カルボキサミド
実施例94:1−(ベンゾフラン−5−カルボニル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
製造2:1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボン酸
実施例95:1−(3−(フラン−2−イル)ベンゾイル)−N−(4−(メチルスルホニル)フェニル)ピペリジン−3−カルボキサミド
実施例96:N−(4−クロロフェニル)−5,5−ジフルオロ−1−(3−(ピリジン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例97:N−(2,6−ジフロオロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例98:1−(3−(1H−イミダゾール−2−イル)ベンゾイル)−N−(4−クロロフェニル)−5,5−ジフルオロピペリジン−3−カルボキサミド
実施例99:N−(4−クロロフェニル)−5,5−ジフルオロ−1−(3−(ピリミジン−5−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例100:N−(4−クロロフェニル)−5,5−ジフルオロ−1−(3−(ピリジン-3−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例101:N−(2−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
製造3:1−((4−(1H−ピラゾール−1−イル)フェニル)(ブトキシ)メチル)−N−(4−クロロフェニル)−ピペリジン−3−カルボキサミド
実施例102:1−(1−(4−(1H−ピラゾール−1−イル)フェニル)エチル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド(ジアステレオマーB)
実施例103:1−(1−(4−(1H−ピラゾール−1−イル)フェニル)エチル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド(ジアステレオマーA)
実施例104:N−(4−シアノフェニル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例105:N−(4−フルオロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例106:1−(3−(1H−ピラゾール−4−イル)ベンゾイル)−N−(4−クロロフェニル)−5,5−ジフルオロピペリジン−3−カルボキサミド
実施例107:N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)ピロリジン−3−カルボキサミド
実施例108:N−(4−クロロフェニル)−1−(3−(フラン−2−イル)ベンゾイル)−N−メチルピペリジン−3−カルボキサミド
実施例109:1−(4−(1H−ピロール−1−イル)ベンゾイル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
実施例110:1−(4−(1H−ピロール−1−イル)ベンジル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
実施例111:1−(3−(フラン−2−イル)ベンゾイル)−N−(p−トリル)ピペリジン−3−カルボキサミド
実施例112:N−(4−クロロベンジル)−1−(3−(フラン−2−イル)ベンゾイル)ピペリジン−3−カルボキサミド
実施例113:N−(4−クロロフェニル)−1−(4−(エチルアミノ)ベンジル)ピペリジン−3−カルボキサミド
実施例114:1−(4−(1H−ピラゾール−1−イル)ベンジル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
実施例115:1−(3−(1H−イミダゾール−1−イル)ベンゾイル)−N−(4−クロロフェニル)ピペリジン−3−カルボキサミド
開示の態様
mは、0、1、または2であり;
nは、0、1、または2であり;
AおよびBの一方は、CR6であり、もう一方は、CR6またはNであり;
Yは、CH2、C=O、CHOH、CHF、CF2、NR5、NCONHR5、NCOR5、NCO2R5、またはNSO2R5であり;
R1は、ヘテロアリールであり;
各R2は、独立して、ハロ、C1〜6アルキル、OC1〜C6アルキル、OC0〜6アルキレン−アリール、OC0〜6アルキレン−ヘテロアリール、またはSO2NR5 2であり;
R3は、H、ハロ、OH、C1〜3アルキル、またはOC1〜3アルキルであり;
各R4は、独立して、H、F、C1〜3アルキル、OR5、NR5 2、NR5CONHR5、NR5COR5、NR5CO2R5、NR5SO2R5であるか、またはR4両方は、それらが結合している炭素と共に、C=O、C=CH2、もしくはC3〜7シクロアルキルを形成し;
各R5は、独立して、H、C1〜6アルキル、C3〜7シクロアルキル、C2〜6アルケニル、C3〜6アルキレン−エーテル、C0〜6アルキレン−アリール、C0〜6アルキレン−ヘテロアリールであるか、または2つのR5は、それらが結合している窒素と共に、3〜7の原子の複素環を形成し;
各R6は、独立して、H、ハロ、C1〜3ハロアルキル、またはOC1〜3ハロアルキルであり;
R7は、HまたはC1〜3アルキルであり;
但し、nが0であり、mが1であり、AおよびBがそれぞれCHであり、R2がクロロであり、各R4がHであり、YがCH2である場合には、R1は、フラニル、チオフェニル、チアゾリル、オキサゾリル、またはオキサジアゾリル以外である、
前記化合物を本明細書で与える。
Claims (46)
- 式(II)の化合物またはその薬剤的に許容できる塩であって、
Xは、
Hetは、ヘテロアリールであり;
Yは、CH2、C=O、CHOH、CHF、CF2、NR5、NCONHR5、NCOR5、NCO2R5、NSO2R5、S(O)2、またはSであり;
Zは、
mは、0、1、または2であり;
nは、0、1、または2であり;
pは、0または1であり;
qは、0、1、または2であり;
R1は、ヘテロアリールであり;
各R2は、独立して、ハロ、C1〜6アルキル、OC1〜6アルキル、OC0〜6アルキレン−アリール、OC0〜6アルキレン−ヘテロアリール、SO2NR5 2、CN、またはSO2C1〜3アルキルであり;
R3は、H、ハロ、OH、C1〜3アルキル、またはOC1〜3アルキルであり;
各R4は、独立して、H、F、C1〜3アルキル、OR5、NR5 2、NR5CONHR5、NR5COR5、NR5CO2R5、NR5SO2R5であるか、またはR4両方は、それらが結合している炭素と共に、C=O、C=CH2、もしくはC3〜7シクロアルキルを形成し;
各R5は、独立して、H、C1〜6アルキル、C3〜7シクロアルキル、C2〜6アルケニル、C3〜6アルキレン−エーテル、C0〜6アルキレン−アリール、C0〜6アルキレン−ヘテロアリールであるか、または2つのR5は、それらが結合している窒素と共に、3〜7の原子の複素環を形成し;
R6は、H、ハロ、C1〜3ハロアルキル、またはOC1〜3ハロアルキルであり;
R7は、HまたはC1〜3アルキルであり;
但し、
(a)Xが、
(b)R1が、非置換型フラニル、非置換型チオフェニル、非置換型チアゾリル、非置換型オキサゾリル、もしくは非置換型オキサジアゾリルである場合には、
(i)Xは、
(ii)YはCH2以外であるか;もしくは
(iii)Zは、
(iv)R2はCl以外であるか;もしくは
(v)R3はH以外であるか;もしくは
(vi)少なくとも1つのR4はH以外であるか;もしくは
(vi)pは1以外である、
前記化合物。 - pが1である、請求項1に記載の化合物。
- Xが、
- HETが、ピリジル、ピラゾリル、オキサゾリル、イソオキサゾリル、チアゾリル、インドリル、インダゾリル、ベンゾフラニル、ベンゾチアゾリル、ベンゾイミダゾリル、ピラジニル、ピリミジニル、ピロリル、イミダゾリル、またはフラニルである、請求項3に記載の化合物。
- HETが、ピリジル、ピラゾリル、オキサゾリル、イソオキサゾリル、チアゾリル、インドリル、インダゾリル、ベンゾフラニル、ベンゾチアゾリル、ベンゾイミダゾリル、またはピリミジニルである、請求項4に記載の化合物。
- HETが、
- qが0である、請求項3〜6のいずれか一項に記載の化合物。
- R7が、独立して、HまたはCH3である、請求項3〜7のいずれか一項に記載の化合物。
- Xが、
- R1が、ピロリル、ピラゾリル、イミダゾリル、トリアゾリル、フラニル、チオフェニル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、チアゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、テトラゾリル、およびチアジアゾリルからなる群から選択される、請求項9に記載の化合物。
- R1が、ピロリル、ピラゾリル、イミダゾリル、フラニル、チオフェニル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、またはチアゾリルである、請求項10に記載の化合物。
- R1が、
- R6が、Hまたはハロである、請求項9〜12のいずれか一項に記載の化合物。
- Xが、
- Xが、
- Zが、
- 各R7がHまたはCH3であり、nが0である、請求項16に記載の化合物。
- Yが、CH2、NR5、NCONHR5、NCOR5、NCO2R5、S(O)2、またはSであり、R5が、C1〜6アルキル、C3〜7シクロアルキル、C2〜6アルケニル、C3〜6アルキレン−エーテル、またはC0〜6アルキレン−アリールである、請求項1〜17のいずれか一項に記載の化合物。
- Yが、CH2、NMe、NCH2Ph、NCONHiPr、NCONHPh、NCONH−シクロペンチル、NCONHCH2CH=CH2、NCOMe、NCOEt、NCOiPr、NCO(パラ−メトキシフェニル)、NCO2Et、NCO2Pr、NCO2Ph、NCO2CH2Ph、NCO2CH2CH2OMe、S(O)2、またはSである、請求項18に記載の化合物。
- YがCH2である、請求項19に記載の化合物。
- R3が、H、F、またはMeである、請求項1〜20のいずれか一項に記載の化合物。
- R3がHである、請求項21に記載の化合物。
- 各R4がHである、請求項1〜22のいずれか一項に記載の化合物。
- 各R4がFである、請求項1〜22のいずれか一項に記載の化合物。
- (a)一方のR4がHであり、もう一方のR4がOH、OMe、NR5 2、NR5COR5、もしくはNR5CO2R5であるか;または
(b)各R4が、FもしくはOMeであるか;または
(c)両方のR4が、それらが結合している炭素と共にC=OもしくはC=CH2を形成する、
請求項1〜22のいずれか一項に記載の化合物。 - 一方のR4が、NH2、NHMe、NMe2、NHCH2Ph、N(Me)CH2Ph、NHC(O)Et、NHC(O)Ph、NHCO2Me、NHCO2Et、およびNHCO2Phからなる群から選択される、請求項25に記載の化合物。
- mが1であり、R2がハロである、請求項1〜26のいずれか一項に記載の化合物。
- R2がClである、請求項27に記載の化合物。
- ClがZに対してパラである、請求項28に記載の化合物。
- 少なくとも1つのR2が、F、CN、SO2Me、またはMeである、請求項1〜26のいずれか一項に記載の化合物。
-
- E−019、E−023、E−024、E−029、E−031、E−042、E−050、E−068、E−072、E−086、E−087、E−089、E−090、およびE−100からなる群から選択される、請求項31に記載の化合物。
- 請求項1〜32のいずれか一項に記載の化合物および薬剤的に許容できる賦形剤を含んでなる医薬製剤。
- 請求項33に記載の医薬製剤および前記医薬製剤を患者に投与するための説明書を含んでなるキット。
- 細胞内でMRTF/SRF媒介性遺伝子転写を阻害する方法であって、前記遺伝子転写を阻害する量の請求項1〜32のいずれか一項に記載の化合物と前記細胞を接触させることを含んでなる、前記方法。
- 前記接触がインビボで起こる、請求項35に記載の方法。
- 前記接触が、それを必要とする患者への投与を含んでなる、請求項35または36に記載の方法。
- 前記患者が、MRTF/SRF媒介性遺伝子転写の機能障害に関連する疾患に罹患している、請求項37に記載の方法。
- 患者のMRTF/SRF媒介性遺伝子転写の機能障害に関連する疾患を治療する方法であって、治療有効量の請求項33に記載の医薬製剤を前記患者に投与することを含んでなる、前記方法。
- 前記疾患が、癌、線維症、糖尿病、インスリン感受性、機能亢進性血小板、代謝性疾患、炎症、炎症性疾患、肺動脈高血圧、神経損傷後の軸索再生、レイノー現象、脳血管疾患、循環器疾患、勃起不全、およびそれらの組み合わせからなる群から選択される、請求項38または39に記載の方法。
- 前記癌が、線維肉腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨肉腫、脊索腫、血管肉腫、内皮肉腫(endotheliosarcoma)、リンパ管肉腫、ユーイング腫瘍、リンパ管内皮肉腫(lymphangioendotheliosarcoma)、滑膜腫、中皮腫、平滑筋肉腫、横紋筋肉腫、結腸癌、膵臓癌、乳癌、卵巣癌、前立腺癌、有棘細胞癌、基底細胞癌、腺癌、汗腺癌、皮脂腺癌、乳頭状癌、乳頭状腺癌、嚢胞腺癌、髄様癌、気管支癌、腎細胞癌、肝癌、胆管癌、絨毛癌、セミノーマ、胎生期癌、ウィルムス腫瘍、子宮頸癌、精巣腫瘍、肺癌、小細胞肺癌、膀胱癌、上皮癌、グリオーマ、星状細胞腫、髄芽腫、頭蓋咽頭腫、上衣腫、松果体腫、血管芽細胞腫、聴神経腫、希突起グリオーマ、髄膜腫、メラノーマ、神経芽細胞腫、網膜芽細胞腫、神経膠芽細胞腫、白血病、巨核芽球性白血病、真性多血症、リンパ腫、多発性骨髄腫、ヴァルデンストレームマクログロブリン血症、重鎖病、およびこれらの組み合わせからなる群から選択される、請求項40に記載の方法。
- 前記癌が、巨核芽球性白血病、メラノーマ、乳癌、前立腺癌、神経膠芽細胞腫、またはこれらの組み合わせである、請求項41に記載の方法。
- 前記線維症が、全身性硬化症、肺線維症、心臓線維症、肝線維症、肝硬変、腎線維症、慢性腎不全、肺線維症、腎性全身性線維症、移植片対宿主病、デュピュイトラン拘縮、炎症性腸疾患、クローン病、眼線維症、緑内障、線維柱帯切除後線維症、角膜線維症、翼状片、グレーブス眼症(Grauves opthmalopathy)、糖尿病性網膜症、加齢性黄斑変性症、術後癒着、反応性線維症、慢性心不全、またはこれらの組み合わせである、請求項40に記載の方法。
- 前記線維症が、全身性硬化症または特発性肺線維症である、請求項43に記載の方法。
- 前記代謝性疾患が、肥満、糖尿病、インスリン抵抗性、またはこれらの組み合わせである、請求項40に記載の方法。
- 前記糖尿病がII型糖尿病である、請求項45に記載の方法。
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WO2016073847A3 (en) | 2016-09-09 |
EP3215150A2 (en) | 2017-09-13 |
JP6902466B2 (ja) | 2021-07-14 |
EP3215150A4 (en) | 2018-03-28 |
US20160145251A1 (en) | 2016-05-26 |
ES2928502T3 (es) | 2022-11-18 |
US10662183B2 (en) | 2020-05-26 |
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