JP6700284B2 - Cftr活性を増加するための化合物、組成物及び方法 - Google Patents
Cftr活性を増加するための化合物、組成物及び方法 Download PDFInfo
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- JP6700284B2 JP6700284B2 JP2017533772A JP2017533772A JP6700284B2 JP 6700284 B2 JP6700284 B2 JP 6700284B2 JP 2017533772 A JP2017533772 A JP 2017533772A JP 2017533772 A JP2017533772 A JP 2017533772A JP 6700284 B2 JP6700284 B2 JP 6700284B2
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- Prior art keywords
- cyclobutyl
- mmol
- alkyl
- carboxamide
- phenyl
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- 125000001424 substituent group Chemical group 0.000 claims description 80
- 125000000623 heterocyclic group Chemical group 0.000 claims description 72
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
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Classifications
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Description
本出願は、2015年7月31日に出願された米国仮出願第62/199,661号、2015年7月24日に出願された同第62/196,839号、2015年1月12日に出願された同第62/102,244号、及び2014年12月23日に出願された同第62/096,374号の利益及び優先権を主張し、これらの各々の内容は、ここに、その全体が参照により本明細書に組み込まれる。
ならびにその薬学的に許容される塩、立体異性体、及びプロドラッグであって、式中、
X1は、CR33またはNであり、
X3は、O、S、及びNRhhからなる群から選択され、
ppは、1、2、または3であり、
R11は、各出現に関して、水素、ハロゲン、C1-4アルキル(1、2、または3個のハロゲンで任意に置換されている)からなる群から独立して選択され、
R31は、水素、ハロゲン、及びC1-4アルキルからなる群から選択され、
R33は、H、ハロゲン、C1-4アルキル、及び−NR’R’’からなる群から選択され、
L1は、C1-6アルキレン、C3-6シクロアルキレン、C3-6シクロアルキレン−C1-4アルキレン、C1-3アルキレン−NRhh−S(O)w−、−C1-3アルキレン−S(O)w−NRhh−、C3-6シクロアルキレン−C0-2アルキレン−S(O)w−NRhh、及びC3-6シクロアルキレン−C0-2アルキレンNRhh−S(O)w−からなる群から選択され、L1は、ハロゲン、ヒドロキシル、及びC1−3アルキル(Rffから各々独立して選択される1、2、または3個の置換基によって任意に置換されている)からなる群から選択される1、2、または3個の置換基によって任意に置換されていてもよく、
R44は、H、ハロゲン、ヒドロキシル、C1-3アルコキシ、複素環、ならびにO、N、及びSから各々選択される1、2、または3個のヘテロ原子を有する、5〜6員単環式または8〜10員二環式ヘテロアリールから選択され、複素環及びヘテロアリールは、Rggから各々独立して選択される1または2個の置換基によって任意に置換されていてもよく、
Rffは、各出現に関して、ハロゲン、ヒドロキシル、C1-4アルキル、C1-4アルコキシ、C2-4アルケニル、C3-6シクロアルキル、−NR’R’’、−NR’−S(O)w−C1-3アルキル、S(O)w−NR’R’’、及び−S(O)w−C1-3アルキルからなる群から選択され(式中、wは、0、1、または2である)、C1-4アルキル、C1-4アルコキシ、C2-4アルケニル、及びC3-6シクロアルキルは、ハロゲン、ヒドロキシル、−NR’R’’、−NR’−S(O)w−C1-3アルキル、S(O)w−NR’R’’、及び−S(O)w−C1-3アルキルからなる群から各々独立して選択される1、2、または3個の置換基によって任意に置換されていてもよく、Rggは、各出現に関して、ハロゲン、ヒドロキシル、−NR’R’’、−NR’R’’、−NR’−S(O)w−C1-3アルキル、−S(O)w−NR’R’’、及び−S(O)w−C1-3アルキル(式中、wは、0、1、または2である);C1-6アルキル、C3-6シクロアルキル、及びC1-6アルケニル(C1-6アルキル、C3-6シクロアルキル、C1-6アルケニルは、Rjjから各々独立して選択される1、2、または3個の置換基によって任意に置換されている);ならびにRllから各々独立して選択される1、2、または3個の置換基によって任意に置換された複素環からなる群から選択され、
Rjjは、各出現に関して、ハロゲン、ヒドロキシル、C3-6シクロアルキル、C1-6アルコキシ(Rkkから各々独立して選択される1、2、または3個の置換基によって任意に置換されている)、複素環、C(O)OH、−C(O)OC1-6アルキル、−NR’R’’、−NR’−S(O)w−C1-3アルキル、−S(O)w−NR’R’’、及び−S(O)w−C1-3アルキル(式中、wは、0、1、または2である)からなる群から選択され、
Rkkは、各出現に関して、ハロゲン、ヒドロキシル、C1-6アルキル(ハロゲン、ヒドロキシル、C3-6シクロアルキル、及び複素環(C1-6アルキルによって任意に置換されている)から各々独立して選択される1、2、または3個の置換基によって任意に置換されている)、C3-6シクロアルキル(ハロゲン、ヒドロキシル、及びC1-6アルキルから各々独立して選択される1、2、または3個の置換基によって任意に置換されている)、フェニル、複素環(ハロゲン、ヒドロキシル、及びC1-6アルキルから独立して選択される1、2、または3個の置換基によって任意に置換されている)、ならびにヘテロアリールからなる群から選択され、
Rllは、各出現に関して、ハロゲン、ヒドロキシル、C1-6アルキル(ハロゲン、ヒドロキシル、及びC3-6シクロアルキルから各々独立して選択される1、2、または3個の置換基によって任意に置換されている)、ならびに複素環(ハロゲン、ヒドロキシル、及びC1-6アルキルから独立して選択される1、2、または3個の置換基によって任意に置換されている)からなる群から選択され、
R’及びR’’は、各出現に関して、H及びC1-4アルキルから各々独立して選択されるか、あるいはそれらが結合している窒素と共に複素環を形成し、
wは、0、1、または2であり、
Rhhは、各出現に関して、H、C1-6アルキル、及びC3-6シクロアルキルからなる群から選択される、化合物が、本明細書に開示される。
ならびにその薬学的に許容される塩、立体異性体、及びプロドラッグであって、式中、
X1は、CR33またはNであり、
X3は、O、S、及びNRhhからなる群から選択され、
ppは、1、2、または3であり、
R11は、各出現に関して、水素、ハロゲン、C1-4アルキル(1、2、または3個のハロゲンで任意に置換されている)からなる群から独立して選択され、
R31は、水素、ハロゲン、及びC1-4アルキルからなる群から選択され、
R33は、H、ハロゲン、C1-4アルキル、及び−NR’R’’からなる群から選択され、R’及びR’’は、各出現に関して、H及びC1-4アルキルから各々独立して選択されるか、あるいはそれらが結合している窒素と共に複素環を形成し、
L1は、C1-6アルキレン、C3-6シクロアルキレン、C3-6シクロアルキレン−C1-4アルキレン、C1-3アルキレン−NRhh−S(O)w−、−C1-3アルキレン−S(O)w−NRhh−、C3-6シクロアルキレン−C0-2アルキレン−S(O)w−NRhh、及びC3-6シクロアルキレン−C0-2アルキレンNRhh−S(O)w−からなる群から選択され、L1は、ハロゲン、ヒドロキシル、及びC1−3アルキル(Rffから各々独立して選択される1、2、または3個の置換基によって任意に置換されている)からなる群から選択される1、2、または3個の置換基によって任意に置換されていてもよく、
R44は、H、ハロゲン、ヒドロキシル、C1-3アルコキシ、フェニル、−O−フェニル、−NR’−フェニル、複素環、ならびにO、N、及びSから各々選択される1、2、または3個のヘテロ原子を有する、5〜6員単環式または8〜10員二環式ヘテロアリールから選択され、フェニル、−O−フェニル、−NR’−フェニル、複素環、及びヘテロアリールは、Rggから各々独立して選択される1または2個の置換基によって任意に置換されていてもよく、
Rffは、各出現に関して、ハロゲン、ヒドロキシル、C1-4アルキル、C1-4アルコキシ、C2-4アルケニル、C3-6シクロアルキル、−NR’R’’、−NR’−S(O)w−C1-3アルキル、S(O)w−NR’R’’、及び−S(O)w−C1-3アルキルからなる群から選択され(式中、wは、0、1、または2である)、C1-4アルキル、C1-4アルコキシ、C2-4アルケニル、及びC3-6シクロアルキルは、ハロゲン、ヒドロキシル、−NR’R’’、−NR’−S(O)w−C1-3アルキル、S(O)w−NR’R’’、及び−S(O)w−C1-3アルキルからなる群から各々独立して選択される1、2、または3個の置換基によって任意に置換されていてもよく、
Rggは、各出現に関して、
a)ハロゲン、ヒドロキシル、シアノ、−NR’R’’、−NR’−S(O)w−C1-3アルキル、−S(O)w−NR’R’’、及び−S(O)w−C1-3アルキル(式中、wは、0、1、または2である)、
b)C1-6アルキル、C3-6シクロアルキル、及びC1-6アルケニル(C1-6アルキル、C3-6シクロアルキル、及びC1-6アルケニルは、Rjjから各々独立して選択される1、2、または3個の置換基によって任意に置換されている)、ならびに
c)Rllから各々独立して選択される1、2、または3個の置換基によって任意に置換された複素環からなる群から選択され、
Rjjは、各出現に関して、ハロゲン、ヒドロキシル、C3-6シクロアルキル、C3-6シクロアルコキシ、C1-6アルコキシ(Rkkから各々独立して選択される1、2、または3個の置換基によって任意に置換されている)、複素環、C(O)OH、−C(O)OC1-6アルキル、−NR’R’’、−NR’−S(O)w−C1-3アルキル、−S(O)w−NR’R’’、及び−S(O)w−C1-3アルキル(式中、wは、0、1、または2である)からなる群から選択され、
Rkkは、各出現に関して、ハロゲン、ヒドロキシル、C1-6アルキル(ハロゲン、ヒドロキシル、C3-6シクロアルキル、及び複素環(C1-6アルキルによって任意に置換されている)から各々独立して選択される1、2、または3個の置換基によって任意に置換されている)、C3-6シクロアルキル(ハロゲン、ヒドロキシル、及びC1-6アルキルから各々独立して選択される1、2、または3個の置換基によって任意に置換されている)、フェニル、複素環(ハロゲン、ヒドロキシル、及びC1-6アルキルから独立して選択される1、2、または3個の置換基によって任意に置換されている)、ならびにヘテロアリールからなる群から選択され、
Rllは、各出現に関して、ハロゲン、ヒドロキシル、C1-6アルキル(ハロゲン、ヒドロキシル、及びC3-6シクロアルキルから各々独立して選択される1、2、または3個の置換基によって任意に置換されている)、ならびに複素環(ハロゲン、ヒドロキシル、及びC1-6アルキルから独立して選択される1、2、または3個の置換基によって任意に置換されている)からなる群から選択され、
R’及びR’’は、各出現に関して、H及びC1-4アルキルから各々独立して選択され、
wは、0、1、または2であり、
Rhhは、各出現に関して、H、C1-6アルキル、及びC3-6シクロアルキルからなる群から選択される、化合物が、本明細書に開示される。
からなる群から選択され、
式中、R29は、C1-6アルキル(ハロゲン、ヒドロキシル、C1-6アルコキシ、及びシクロアルキルからなる群から各々独立して選択される1、2、または3個の置換基によって任意に置換されている)、ならびに複素環(ハロゲン、ヒドロキシルC1-6アルキル、及びC1-6アルコキシからなる群から各々独立して選択される1、2、または3個の置換基によって任意に置換されている)から選択される。例えば、R29は、
からなる群から選択されてもよい。
式中、qqは、0または1である。例えば、開示化合物は、ある特定の実施形態において以下の式を有してもよい。
からなる群から選択され、
式中、Xは、各出現に関して、O、S、NRhh、C、C(R88)、及びC(R88)(R99)からなる群から独立して選択され、X2は、各出現に関して、O、S、及びNRhhからなる群から独立して選択され、R’’は、HまたはC1-4アルキルであり、各R66、R77、R88、及びR99は、各出現に関して、H及びRggから独立して選択され、nは、0、1、2、または3である。
式中、X2は、O、S、またはNRhh(上で定義された)からなる群から選択され、
R76は、C1-6アルキル(1個以上の酸素原子またはNR’’によって任意に分断されており、ハロゲン、ヒドロキシル、S(O)w−C1-3アルキル(wは、0、1、または2である)、C3-6シクロアルキル(複素環、C1-6アルキル、及びハロゲンから選択される1個以上の置換基によって任意に置換されている)、及び複素環(複素環、C1-6アルキル、及びハロゲンから選択される1個以上の置換基によって任意に置換されている)からなる群から選択される1個以上の置換基によって任意に置換されている);ならびに複素環(ハロゲン、ヒドロキシル、S(O)w−C1-3アルキル(wは、0、1、または2である)、C3-6シクロアルキル(複素環、C1-6アルキル、及びハロゲンから選択される1個以上の置換基によって任意に置換されている)及び複素環(複素環、C1-6アルキル、及びハロゲンから選択される1個以上の置換基によって任意に置換されている)からなる群から選択される。
(Ia)
(IIa)
またはその薬学的に許容される塩、プロドラッグ、もしくは溶媒和物であって、式中、
R1は、
からなる群から選択され、
R2は、任意に置換されたアリール及び任意に置換されたヘテロアリールからなる群から選択され、
R3a及びR3bは、水素、任意に置換されたC1−C10アルキル、任意に置換されたC2−C10アルケニル、任意に置換されたC2−C10アルキニル、任意に置換されたC3−C12シクロアルキル、任意に置換されたC3−C12シクロアルケニル、任意に置換されたアリール、ハロ、ORc、NRdRd、C(O)ORc、NO2、CN、C(O)Rc、C(O)C(O)Rc、C(O)NRdRd、NRdC(O)Rc、NRdS(O)nRc、N(Rd)(COORc)、NRdC(O)C(O)Rc、NRdC(O)NRdRd、NRdS(O)nNRdRd、NRdS(O)nRc、S(O)nRc、S(O)nNRdRd、OC(O)ORc、(C=NRd)Rc、任意に置換された複素環、及び任意に置換されたヘテロアリールからなる群から各々独立して選択され、
R4aは、水素、任意に置換されたC1−C10アルキル、任意に置換されたC2−C10アルケニル、任意に置換されたC2−C10アルキニル、任意に置換されたC3−C12シクロアルキル、任意に置換されたC3−C12シクロアルケニル、任意に置換されたアリール、ハロ、ORc、S(O)nRc、NRdRd、C(O)ORc、NO2、CN、C(O)Rc、C(O)C(O)Rc、C(O)NRdRd、NRdC(O)Rc、NRdS(O)Rc、N(Rd)(COORc)、NRdC(O)C(O)Rc、NRdC(O)NRdRd、NRdS(O)nRdRd、NRdS(O)nRc、S(O)NRdRd、OC(O)ORc、(C=NRd)Rc、任意に置換された複素環、及び任意に置換されたヘテロアリールからなる群から選択され、
R4bは、水素、任意に置換されたC1−C10アルキル、任意に置換されたC2−C10アルケニル、任意に置換されたC2−C10アルキニル、任意に置換されたC3−C12シクロアルキル、任意に置換されたC3−C12シクロアルケニル、任意に置換されたアリール、任意に置換された複素環、及び任意に置換されたヘテロアリールからなる群から選択され、
Raは、水素、任意に置換されたC1−C10アルキル、任意に置換されたC2−C10アルケニル、任意に置換されたC2−C10アルキニル、任意に置換されたC3−C12シクロアルキル、任意に置換されたC3−C12シクロアルケニル、任意に置換された複素環、任意に置換されたアリール、任意に置換されたヘテロアリール、C(O)ORc、C(O)Rc、C(O)C(O)Rc、及びS(O)nRcからなる群から選択されるか、
あるいは代替的に、Ra及びそれが結合している窒素原子が、隣接するC(Rb1)(Rb1)またはC(Rb2)(Rb2)と共に、1個以上の環窒素原子を含有する、任意に置換された4〜12員複素環を形成し、該複素環は、酸素及び硫黄から選択される1個以上の環ヘテロ原子を任意に含有し、
各Rb1及びRb2は、各出現に関して、水素、任意に置換されたC1−C10アルキル、任意に置換されたC2−C10アルケニル、任意に置換されたC2−C10アルキニル、任意に置換されたC3−C12シクロアルキル、任意に置換されたC3−C12シクロアルケニル、任意に置換された複素環、任意に置換されたアリール、任意に置換されたヘテロアリール、ハロ、ORc、NRdRd、C(O)ORc、NO2、CN、C(O)Rc、C(O)C(O)Rc、C(O)NRdRd、NRdC(O)Rc、NRdS(O)nRc、N(Rd)(COORc)、NRdC(O)C(O)Rc、NRdC(O)NRdRd、NRdS(O)nNRdRd、NRdS(O)nRc、S(O)nRc、S(O)nNRdRd、OC(O)ORc、及び(C=NRd)Rcからなる群から独立して選択されるか、あるいは代替的に、2個のジェミナルなRb1基または2個のジェミナルなRb2基、及びそれらが結合している炭素が、共にC(O)基を形成するか、あるいはなおも代替的に、2個のジェミナルなRb1基または2個のジェミナルなRb2基が、それらが結合している炭素原子と共に、各々が任意に置換されている、スピロC3−C12シクロアルキル、スピロC3−C12シクロアルケニル、スピロ複素環、スピロアリール、またはスピロヘテロアリールを形成し、
Yは、S(O)n、NRd、NRdS(O)n、NRdS(O)nNRd、NRdC(O)、NRdC(O)O、NRdC(O)C(O)、NRdC(O)NRd、S(O)nNRd、及びOからなる群から選択され、
各Rcは、各出現に関して、水素、任意に置換されたC1−C10アルキル、任意に置換されたC2−C10アルケニル、任意に置換されたC2−C10アルキニル、任意に置換されたC3−C12シクロアルキル、任意に置換されたC3−C12シクロアルケニル、任意に置換された複素環、任意に置換されたアリール、及び任意に置換されたヘテロアリールからなる群から独立して選択され、
各Rdは、各出現に関して、水素、任意に置換されたC1−C10アルキル、任意に置換されたC2−C10アルケニル、任意に置換されたC2−C10アルキニル、任意に置換されたC1−C10アルコキシ、任意に置換されたC3−C12シクロアルキル、任意に置換されたC3−C12シクロアルケニル、任意に置換された複素環、任意に置換されたアリール、及び任意に置換されたヘテロアリールからなる群から独立して選択されるか、あるいは2個のジェミナルなRd基が、それらが結合している窒素原子と共に、任意に置換された複素環または任意に置換されたヘテロアリールを形成し、
kは、0または1であり、
mは、0、1、2、3、4、または5であり、
各nは、独立して0、1、または2である、化合物も、本明細書に開示される。
からなる群から選択され、
式中、各Xは、独立してO、S、またはNRgであり、
各Rgは、ハロゲン、C1−C4アルキル、C3−C6シクロアルキルからなる群から独立して選択され、
各R6、R7、及びR8は、各出現に関して、水素、C1−C6アルキル、C2−C6アルケニル、C2−C16アルキニル、C3−C7シクロアルキル、C3−C7シクロアルケニル、フェニル、複素環、ヘテロアリール、ハロ、ヒドロキシル、カルボキシル、ORc、NRdRd、C(O)ORc、CN、C(O)Rcからなる群から独立して選択され、R6、R7、及びR8のC1-6アルキル、C2−C6アルケニル、C2−C16アルキニル、C3−C7シクロアルキル、C3−C7シクロアルケニル、フェニル、複素環、及びヘテロアリールは、ハロ、ヒドロキシル、C1-6アルキル、及びC1-6アルコキシから選択される1、2、または3個の置換基によって各々任意に置換されていてもよく、
Rcは、C1-4アルキルであり、
Rdは、各出現に関して、H及びC1-4アルキルからなる群から独立して選択されるか、あるいは2個のRdが、それらが結合しているNと共に複素環を形成する。
(Ib)
(IIb)
式中、R11は、水素、任意に置換されたC1−C10アルキル、任意に置換されたC2−C10アルケニル、任意に置換されたC2−C10アルキニル、及びハロからなる群から選択される。ある特定の実施形態において、R4aは、任意に置換されたC3−C7シクロアルキル(例えば、任意に置換されたシクロプロピルまたは任意に置換されたシクロブチル)である。
を有する置換基で置換されており、
各Rhは、各出現に関して、水素、ハロ、ヒドロキシル、C1−C6アルキル、及びC3−C6シクロアルキルからなる群から独立して選択されるか、あるいは2個のジェミナルなRh基が、それらが結合している炭素原子と共に独立して任意に置換された炭素環または複素環を形成し、
R9は、水素、ハロ、CN、ヒドロキシル、メチル(ハロゲン及びヒドロキシルから選択される1、2、または3個の置換基によって任意に置換されている)、C2−C4アルケニル、C2−C4アルキニル、C3−C6シクロアルキル、C1-6アルコキシ、NRdRd、C(O)ORc、NO2、CN、C(O)Rc、C(O)C(O)Rc、C(O)NRdRd、NRdC(O)Rc、NRdS(O)nRc、NRd(COORc)、NRdC(O)C(O)Rc、NRdC(O)NRdRd、NRdS(O)nNRdRd、NRdS(O)nRc、S(O)nRc、S(O)nNRdRd、OC(O)ORc、(C=NRd)Rcからなる群から選択され、
Rcは、各出現に関して、H、C1−C6アルキル、C3-6シクロアルキル、複素環、及びヘテロアリールからなる群から独立して選択され、
Rdは、各出現に関して、H及びC1-4アルキルから独立して選択されるか、あるいは2個のRdが、それらが結合しているNと共に複素環を形成し、pは、0、1、または2である。
からなる群から選択されてもよく、式中、
各R10は、水素、任意に置換されたC1−C6アルキル、任意に置換されたC2−C6アルケニル、任意に置換されたC2−C6アルキニル、任意に置換されたC3−C6シクロアルキル、任意に置換されたC3−C6シクロアルケニル、任意に置換されたアリール、ハロ、ORc、NRdRd、C(O)ORc、NO2、CN、C(O)Rc、C(O)C(O)Rc、C(O)NRdRd、NRdC(O)Rc、NRdS(O)nRc、NRd(COORc)、NRdC(O)C(O)Rc、NRdC(O)NRdRd、NRdS(O)nNRdRd、NRdS(O)nRc、S(O)nRc、S(O)nNRdRd、OC(O)ORc、(C=NRd)Rc、任意に置換された複素環、及び任意に置換されたヘテロアリールからなる群から独立して選択されるか、代替的に、2個のジェミナルなR10基が、それらが結合している炭素原子と共に、各々が任意に置換されている、スピロC3−C7シクロアルキル、スピロC3−C7シクロアルケニル、スピロ複素環、スピロアリール、またはスピロヘテロアリールを形成するか、あるいはなおも代替的に、2個のビシナルなR10基が、それらが結合している炭素原子と共に、各々が任意に置換されている、C4−C8シクロアルキル、C4−C8シクロアルケニル、4〜8員複素環、アリール、及びヘテロアリールからなる群から選択される、任意に置換された縮合環式基を形成するか、あるいは更に代替的に、非隣接炭素原子に結合している2個のR10基が、それらが結合している炭素原子と共に、各々が任意に置換されている、C3−C8シクロアルキル、C3−C8シクロアルケニル、及び4〜8員複素環からなる群から選択される架橋環式基を形成し、
各Rhは、水素、ハロ、任意に置換されたC1−C10アルキル、及び任意に置換されたC3−C6シクロアルキルからなる群から独立して選択されるか、あるいは2個のジェミナルなRb基が、それらが結合している炭素原子と共に独立して任意に置換された複素環または任意に置換されたヘテロアリールを形成し、
R9は、水素、任意に置換されたC1−C10アルキル、任意に置換されたC2−C10アルケニル、任意に置換されたC2−C10アルキニル、任意に置換されたC3−C12シクロアルキル、任意に置換されたC3−C12シクロアルケニル、任意に置換されたアリール、ハロ、ORc、NRdRd、C(O)ORc、NO2、CN、C(O)Rc、C(O)C(O)Rc、C(O)NRdRd、NRdC(O)Rc、NRdS(O)nRc、NRd(COORc)、NRdC(O)C(O)Rc、NRdC(O)NRdRd、NRdS(O)nNRdRd、NRdS(O)nRc、S(O)nRc、S(O)nNRdRd、OC(O)ORc、(C=NRd)Rc、任意に置換された複素環、及び任意に置換されたヘテロアリールからなる群から選択され、pは、0、1、または2である。
という記号は、本明細書に記載されるように、一重、二重、または三重結合であり得る結合を表す。炭素−炭素二重結合のまわりの置換基は、「Z」または「E」立体配置にあるものとして指定され、「Z」及び「E」という用語は、IUPAC標準に従って使用される。別途特定されない限り、二重結合を図示する構造は、「E」異性体及び「Z」異性体の両方を包括する。炭素−炭素二重結合のまわりの置換基は、代替的に「シス」または「トランス」と呼ばれてもよく、「シス」は二重結合の同一側の置換基を表し、「トランス」は二重結合の反対側の置換基を表す。
tert−ブチル(シス−3−アジドシクロブチル)カルバメートの調製
トランス−3−(3−フェニルイソオキサゾール−5−カルボキサミド)シクロブタン−1−カルボン酸の調製
(R)−2−メトキシプロパンヒドラジドの調製
実施例1:N−(2−メトキシエチル)−3−フェニルイソオキサゾール−5−カルボキサミド:
実施例2:3−フェニル−N−((テトラヒドロフラン−2−イル)メチル)イソオキサゾール−5−カルボキサミド:
実施例3:N−(2−モルフォリノエチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例4:N−(3−(1H−イミダゾール−1−イル)プロピル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例5:N−トランス−3−(5−(ヒドロキシメチル)−1H−1,2,3−トリアゾール−1−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例7:N−(3−(1−メチル−1H−ピラゾール−5−イル)プロピル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例8:N−(2−メトキシエチル)−4−フェニルフラン−2−カルボキサミド:
実施例9:4−フェニル−N−((テトラヒドロフラン−2−イル)メチル)フラン−2−カルボキサミド:
実施例10:N−(2−モルフォリノエチル)−4−フェニルフラン−2−カルボキサミド
実施例11:N−(3−(1H−イミダゾール−1−イル)プロピル)−4−フェニルフラン−2−カルボキサミド:
実施例12:N−シクロプロピル−4−フェニルフラン−2−カルボキサミド:
実施例13:N−(トランス−3−(5−(1−(メチルスルホニル)エチル)−1,3,4−オキサジアゾール−2−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例14:N−(トランス−3−(5−((R)−1−メトキシエチル)−1,3,4−オキサジアゾール−2−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例17:N−(トランス−3−(5−(1−シクロブトキシエチル)−1,3,4−オキサジアゾール−2−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例18:N−(トランス−3−(5−(1−(シクロブチルメトキシ)エチル)−1,3,4−オキサジアゾール−2−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例19:N−(トランス−3−(5−(1−(オキセタン−3−イルメトキシ)エチル)−1,3,4−オキサジアゾール−2−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例20:N−(トランス−3−(5−((R)−1−((1−メチルアゼチジン−3−イル)メトキシ)エチル)−1,3,4−オキサジアゾール−2−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例21:N−(トランス−3−(5−(1−メチルアゼチジン−3−イル)−1,3,4−オキサジアゾール−2−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミドトリフルオロ酢酸
実施例22:N−トランス−3−(5−(オキセタン−3−イル)−1,3,4−オキサジアゾール−2−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例23:N−(トランス−3−(5−(1,1−ジオキシドチエタン−3−イル)−1,3,4−オキサジアゾール−2−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例24及び25:N−シス−(3−(5−(1−(1−メチルピペリジン−4−イル)アゼチジン−3−イル)−1,3,4−オキサジアゾール−2−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド及びN−トランス−(3−(5−(1−(1−メチルピペリジン−4−イル)アゼチジン−3−イル)−1,3,4−オキサジアゾール−2−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例26:3−フェニル−N−(トランス−3−(5−(1−(2,2,2−トリフルオロエチル)アゼチジン−3−イル)−1,3,4−オキサジアゾール−2−イル)シクロブチル)イソオキサゾール−5−カルボキサミド
実施例27:N−(トランス−3−(5−(1−(シクロブチルメチル)アゼチジン−3−イル)−1,3,4−オキサジアゾール−2−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例28及び29:N−(シス−3−(5−(ヒドロキシメチル)−1H−1,2,3−トリアゾール−1−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド及びN−(シス−3−(4−(ヒドロキシメチル)−1H−1,2,3−トリアゾール−1−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例30及び31:N−(トランス−3−(5−(オキセタン−3−イル)−1H−1,2,3−トリアゾール−1−イル)シクロブチル)−5−フェニルイソオキサゾール−3−カルボキサミド及びN−(トランス−3−(4−(オキセタン−3−イル)−1H−1,2,3−トリアゾール−1−イル)シクロブチル)−5−フェニルイソオキサゾール−3−カルボキサミド
実施例32及び33:N−(トランス−3−(4−(1−メチルアゼチジン−3−イル)−1H−1,2,3−トリアゾール−1−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド及びN−(トランス−3−(5−(1−メチルアゼチジン−3−イル)−1H−1,2,3−トリアゾール−1−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例34:N−(トランス−3−(5−(1−(メチルスルホニル)エチル)−1H−1,2,3−トリアゾール−1−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
ステップ1:N−[トランス−3−[4/5−[(1R)−1−ヒドロキシエチル]−1H−1,2,3−トリアゾール−1−イル]シクロブチル]カルバメート:DMF(5mL)中tert−ブチルN−[トランス−3−アジドシクロブチル]カルバメート(2g、9.42mmol、1.00当量)と(2R)−ブタ−3−イン−2−オール(3.3g、47.08mmol、5.00当量)との溶液を、油浴中100℃で一晩撹拌した。結果として生じた混合物を真空下で濃縮した。残渣を、酢酸エチル/石油エーテル(3:1)を有するシリカゲルカラム上に適用して、2.1g(79%)のtert−ブチルN−[トランス−3−[4/5−[(1R)−1−ヒドロキシエチル]−1H−1,2,3−トリアゾール−1−イル]シクロブチル]カルバメートの混合物を淡黄色固体として得た。LC−MS(ES,m/z):[M+H]+=283.2.
N−(トランス−3−(5−(1−(メチルスルホニル)エチル)−1H−1,2,3−トリアゾール−1−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミドの調製:
実施例35:N−(トランス−3−(4−(1−(メチルスルホニル)エチル)−1H−1,2,3−トリアゾール−1−イル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例36:3−(4−フルオロフェニル)−N−(トランス−3−(5−((R)−1−ヒドロキシエチル)−1,3,4−オキサジアゾール−2−イル)シクロブチル)イソオキサゾール−5−カルボキサミド
実施例37及び38:N−((1S,3s)−3−((5−((R)−1−ヒドロキシエチル)−1,3,4−オキサジアゾール−2−イル)メチル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド及びN−((1R,3r)−3−((5−((R)−1−ヒドロキシエチル)−1,3,4−オキサジアゾール−2−イル)メチル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例39及び40:3−(4−フルオロフェニル)−N−[(1s,3s)−3−([5−[(1R)−1−ヒドロキシエチル]−1,3,4−オキサジアゾール−2−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド及び3−(4−フルオロフェニル)−N−[(1r,3r)−3−([5−[(1R)−1−ヒドロキシエチル]−1,3,4−オキサジアゾール−2−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド
実施例41及び42:3−フェニル−N−[(1s,3s)−3−([5−[(1R)−1−ヒドロキシエチル]−1,3,4−チアジアゾール−2−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド及び3−フェニル−N−[(1r,3r)−3−([5−[(1R)−1−ヒドロキシエチル]−1,3,4−チアジアゾール−2−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド
実施例43及び44:3−(4−フルオロフェニル)−N−[(1s,3s)−3−([5−[(1R)−1−ヒドロキシエチル]−1,3,4−チアジアゾール−2−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド及び3−(4−フルオロフェニル)−N−[(1r,3r)−3−([5−[(1R)−1−ヒドロキシエチル]−1,3,4−チアジアゾール−2−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド
実施例45及び46:N−[(1s,3s)−3−([5−[(1R)−1−ヒドロキシエチル]−1,3,4−オキサジアゾール−2−イル]メチル)シクロブチル]−3−(チオフェン−2−イル)−1,2−オキサゾール−5−カルボキサミド及びN−[(1r,3r)−3−([5−[(1R)−1−ヒドロキシエチル]−1,3,4−オキサジアゾール−2−イル]メチル)シクロブチル]−3−(チオフェン−2−イル)−1,2−オキサゾール−5−カルボキサミド
実施例47及び48:N−((1r,3r)−3−((5−(ヒドロキシメチル)−1H−1,2,3−トリアゾール−1−イル)メチル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド及びN−((1r,3r)−3−((4−(ヒドロキシメチル)−1H−1,2,3−トリアゾール−1−イル)メチル)シクロブチル)−3−フェニルイソオキサゾール−5−カルボキサミド
実施例49:3−フェニル−N−[(1r,3r)−3−[5−(オキセタン−2−イル)−1,3,4−オキサジアゾール−2−イル]シクロブチル]−1,2−オキサゾール−5−カルボキサミド
実施例50:4−フルオロ−3−フェニル−N−[(1r,3r)−3−[5−[(1R)−1−ヒドロキシエチル]−1,3,4−オキサジアゾール−2−イル]シクロブチル]−1,2−オキサゾール−5−カルボキサミド
実施例51及び52:3−フェニル−N−[(1s,3s)−3−[5−[(1R)−1−ヒドロキシエチル]−1H−1,2,3−トリアゾール−1−イル]シクロブチル]−1,2−オキサゾール−5−カルボキサミド及び3−フェニル−N−[(1s,3s)−3−[4−[(1R)−1−ヒドロキシエチル]−1H−1,2,3−トリアゾール−1−イル]シクロブチル]−1,2−オキサゾール−5−カルボキサミド
実施例53及び54:3−フェニル−N−[(1s,3s)−3−[5−[(1S)−1−ヒドロキシエチル]−1H−1,2,3−トリアゾール−1−イル]シクロブチル]−1,2−オキサゾール−5−カルボキサミド及び3−フェニル−N−[(1s,3s)−3−[4−[(1S)−1−ヒドロキシエチル]−1H−1,2,3−トリアゾール−1−イル]シクロブチル]−1,2−オキサゾール−5−カルボキサミド
実施例55及び56:3−フェニル−N−[(1s,3s)−3−([5−[(1R)−1−ヒドロキシエチル]−1H−1,2,3−トリアゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド及び3−フェニル−N−[(1s,3s)−3−([4−[(1R)−1−ヒドロキシエチル]−1H−1,2,3−トリアゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド
実施例57及び58:3−フェニル−N−[(1s,3s)−3−([5−[(1S)−1−ヒドロキシエチル]−1H−1,2,3−トリアゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド及び3−フェニル−N−[(1s,3s)−3−([4−[(1S)−1−ヒドロキシエチル]−1H−1,2,3−トリアゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド。
実施例59及び60:3−フェニル−N−[(1r,3r)−3−([5−[(1R)−1−ヒドロキシエチル]−1H−1,2,3−トリアゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド及び3−フェニル−N−[(1r,3r)−3−([4−[(1R)−1−ヒドロキシエチル]−1H−1,2,3−トリアゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド
実施例61及び62:3−フェニル−N−[(1r,3r)−3−([5−[(1S)−1−ヒドロキシエチル]−1H−1,2,3−トリアゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド及び3−フェニル−N−[(1r,3r)−3−([4−[(1S)−1−ヒドロキシエチル]−1H−1,2,3−トリアゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド
実施例63及び64:3−フェニル−N−[(1r,3r)−3−([3−[(1R)−1−ヒドロキシエチル]−1H−ピラゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド及び3−フェニル−N−[(1r,3r)−3−([3−[(1S)−1−ヒドロキシエチル]−1H−ピラゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド
実施例65及び66:3−フェニル−N−[(1s,3s)−3−([3−[(1S)−1−ヒドロキシエチル]−1H−ピラゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド(フロントピーク)及び3−フェニル−N−[(1s,3s)−3−([3−[(1R)−1−ヒドロキシエチル]−1H−ピラゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド(第2のピーク)
実施例67及び68:3−フェニル−N−[(1r,3r)−3−([4−[(1S)−1−ヒドロキシエチル]−1H−ピラゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド(フロントピーク)及び3−フェニル−N−[(1r,3r)−3−([4−[(1R)−1−ヒドロキシエチル]−1H−ピラゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド(第2のピーク)
実施例69及び70:3−フェニル−N−[(1s,3s)−3−([4−[(1R)−1−ヒドロキシエチル]−1H−ピラゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド(フロントピーク)及び3−フェニル−N−[(1s,3s)−3−([4−[(1S)−1−ヒドロキシエチル]−1H−ピラゾール−1−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド(第2のピーク)
実施例71:3−フェニル−N−[(1r,3r)−3−(4−フルオロフェノキシメチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド。
実施例72:3−フェニル−N−[(1s,3s)−3−(4−フルオロフェノキシメチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド
実施例73:3−フェニル−N−[(1r,3r)−3−(4−シアノフェノキシメチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド
実施例74:3−フェニル−N−[(1s,3s)−3−(4−シアノフェノキシメチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド
実施例75及び76:3−(5−フルオロチオフェン−2−イル)−N−[(1s,3s)−3−([5−[(1R)−1−ヒドロキシエチル]−1,3,4−オキサジアゾール−2−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド及び3−(5−フルオロチオフェン−2−イル)−N−[(1r,3r)−3−([5−[(1R)−1−ヒドロキシエチル]−1,3,4−オキサジアゾール−2−イル]メチル)シクロブチル]−1,2−オキサゾール−5−カルボキサミド
実施例77:CFTR活性アッセイ
i.ウッシング測定
1.ベンザミルを頂端チャンバーに適用して、ENaCナトリウムチャネルを阻害する。
2.ホルスコリンを両方のチャンバーに適用して、ΔF508−CFTRをリン酸化によって活性化する。
3.ゲニステインを両方のチャンバーに適用して、ΔF508−CFTRチャネル開放を増強する。
4.CFTRinh−172を頂端チャンバーに適用して、ΔF508−CFTR Cl−コンダクタンスを阻害する。
ii.hBE等価電流(Ieq)アッセイ
1.ベースラインVT値及びGT値を、約20分間測定した。
2.ベンザミルを添加して、ENaCを15分間遮断した。
3.ホルスコリンに加えてVX−770を添加して、ΔF508−CFTRを27分間最大限に活性化した。
4.ブメタニドを添加して、NaK2Cl共輸送体を阻害し、クロライドの選択を停止した。
実施例78
i.ウッシング測定
1.ベンザミルを頂端チャンバーに適用して、ENaCナトリウムチャネルを阻害する。
2.ホルスコリンを両方のチャンバーに適用して、ΔF508−CFTRをリン酸化によって活性化する。
3.アイバカフトールまたはゲニステインを頂端チャンバーに適用して、ΔF508−CFTRチャネル開放を増強する。
4.CFTRinh−172を頂端チャンバーに適用して、ΔF508−CFTR Cl−コンダクタンスを阻害する。
i.ウッシング測定
上で考察されたように、ウッシング測定を用いてCFTR活性を測定することが可能である。この方法において、嚢胞性線維症を引き起こすクラスIII変異を有する一次肺上皮細胞(hBE)を、ウッシング測定の前、SnapWell(商標)フィルタプレート上の気液界面中で、最低4週間分化させる。化合物で治療する前、細胞を30分間頂端で粘液洗浄を行う。基底外側培地を除去し、DMSOストックから、その最終濃度まで希釈した対象となる化合物を含有する培地で置換する。治療した細胞を37℃及び5%のCO2で24時間インキュベートする。治療期間の終了時、フィルタ上の細胞をウッシングチャンバーに移動させ、30分間平衡化する。短絡電流を電位クランプモード(V保持=0mV)で測定し、全アッセイを36℃〜36.5℃の温度で実行する。電位が安定化した後、チャンバーをクランプし、データを5秒毎のパルス読み取りによって記録する。ベースライン電流安定化後、以下の添加を適用し、電流の変化及び細胞の耐性を監視する。
1.ベンザミルを頂端チャンバーに適用して、ENaCナトリウムチャネルを阻害する。
2.ホルスコリンを両方のチャンバーに適用して、ΔF508−CFTRをリン酸化によって活性化する。
3.VX−770またはゲニステインを頂端チャンバーに適用して、ΔF508−CFTRチャネル開放を増強する。
4.CFTRinh−172を頂端チャンバーに適用して、ΔF508−CFTR Cl−コンダクタンスを阻害する。
実施例80
i.ウッシング測定
1.ベンザミルを頂端チャンバーに適用して、ENaCナトリウムチャネルを阻害する。
2.ホルスコリンを両方のチャンバーに適用して、ΔF508−CFTRをリン酸化によって活性化する。
3.VX−770またはゲニステインを頂端チャンバーに適用して、ΔF508−CFTRチャネル開放を増強する。
4.CFTRinh−172を頂端チャンバーに適用して、ΔF508−CFTR Cl−コンダクタンスを阻害する。
ii.hBE等価電流(Ieq)アッセイ
1.ベースラインVT値及びGT値を約20分間測定する。
2.ベンザミルを添加して、ENaCを15分間遮断する。
3.ホルスコリンに加えてVX−770(アイバカフトール)を添加して、ΔF508−CFTRを27分間最大限に活性化する。
4.ブメタニドを添加して、NaK2Cl共輸送体を阻害し、クロライドの選択を停止した。
参照による組み込み
均等物
Claims (12)
- 式IIIで表される化合物、ならびにその薬学的に許容される塩、立体異性体。
(式中、
X1は、Nであり、
ppは、1、2、または3であり、
R11は、各出現に関して、水素、ハロゲン、及びC1−4アルキル(1、2、または3個のハロゲンで任意に置換されている)からなる群から独立して選択され、
R31は、水素、フッ素及びC1−4アルキルからなる群から選択され、
L1は、C3−5シクロアルキレン、C3−6シクロアルキレン−C1−4アルキレン、C1−3アルキレン−NRhh−S(O)w−、−C1−3アルキレン−S(O)w−NRhh−、C3−6シクロアルキレン−C0−2アルキレン−S(O)w−NRhh、及びC3−6シクロアルキレン−C0−2アルキレンNRhh−S(O)w−からなる群から選択され、L1は、ハロゲン、ヒドロキシル、及びC1−3アルキル(Rffから各々独立して選択される1、2、または3個の置換基によって任意に置換されている)からなる群から選択される1、2、または3個の置換基によって任意に置換されていてもよく、
R44は、ハロゲン、ヒドロキシル、C1−3アルコキシ、フェニル、−O−フェニル、−NR’−フェニルならびにO、N、及びSから各々選択される1、2、または3個のヘテロ原子を有する、5〜6員単環式または8〜10員二環式ヘテロアリールから選択され、フェニル、−O−フェニル、−NR’−フェニル及びヘテロアリールは、Rggから各々独立して選択される1または2個の置換基によって任意に置換されていてもよく、
Rffは、各出現に関して、ハロゲン、ヒドロキシル、C1−4アルキル、C1−4アルコキシ、C2−4アルケニル、C3−6シクロアルキル、−NR’R’’、−NR’−S(O)w−C1−3アルキル、S(O)w−NR’R’’、及び−S(O)w−C1−3アルキルからなる群から選択され(式中、wは、0、1、または2である)、C1−4アルキル、C1−4アルコキシ、C2−4アルケニル、及びC3−6シクロアルキルは、ハロゲン、ヒドロキシル、−NR’R’’、−NR’−S(O)w−C1−3アルキル、S(O)w−NR’R’’、及び−S(O)w−C1−3アルキルからなる群から各々独立して選択される1、2、または3個の置換基によって任意に置換されていてもよく、
Rggは、各出現に関して、ハロゲン、ヒドロキシル、シアノ、−NR’R’’、−NR’−S(O)w−C1−3アルキル、−S(O)w−NR’R’’、及び−S(O)w−C1−3アルキル(式中、wは、0、1、または2である)、複素環、C1−6アルキル、C3−6シクロアルキル、ならびにC1−6アルケニルからなる群から選択され、C1−6アルキル、C3−6シクロアルキル、及びC1−6アルケニルは、Rjjから各々独立して選択される1、2、または3個の置換基によって任意に置換されており、複素環は、Rllから各々独立して選択される1、2、または3個の置換基によって任意に置換されており、
Rjjは、各出現に関して、ハロゲン、ヒドロキシル、C1−6アルコキシ(Rkkから各々独立して選択される1、2、または3個の置換基によって任意に置換されている)、C3−6シクロアルキル、C3−6シクロアルコキシ、複素環、C(O)OH、−C(O)OC1−6アルキル、−NR’R’’、−NR’−S(O)w−C1−3アルキル、−S(O)w−NR’R’’、及び−S(O)w−C1−3アルキル(式中、wは、0、1、または2である)からなる群から選択され、
Rkkは、各出現に関して、ハロゲン、ヒドロキシル、C1−6アルキル(ハロゲン、ヒドロキシル、C3−6シクロアルキル、及び複素環(C1−6アルキルによって任意に置換されている)から各々独立して選択される1、2、または3個の置換基によって任意に置換されている)、C3−6シクロアルキル(ハロゲン、ヒドロキシル、及びC1−6アルキルから各々独立して選択される1、2、または3個の置換基によって任意に置換されている)、フェニル、複素環(ハロゲン、ヒドロキシル、及びC1−6アルキルから独立して選択される1、2、または3個の置換基によって任意に置換されている)、ならびにヘテロアリールからなる群から選択され、
Rllは、各出現に関して、ハロゲン、ヒドロキシル、C1−6アルキル(ハロゲン、ヒドロキシル、及びC3−6シクロアルキルから各々独立して選択される1、2、または3個の置換基によって任意に置換されている)、ならびに複素環(ハロゲン、ヒドロキシル、及びC1−6アルキルから独立して選択される1、2、または3個の置換基によって任意に置換されている)からなる群から選択され、
R’及びR’’は、各出現に関して、H、C1−4アルキル、フェニル、及び複素環から各々独立して選択され、
wは、0、1、または2であり、
Rhhは、各出現に関して、H、C1−6アルキル、及びC3−6シクロアルキルからなる群から選択される、化合物。 - L1は、C3−5シクロアルキレン、またはC3−6シクロアルキレン−C1−4アルキレンである請求項1に記載の化合物。
- R31は、HまたはFである請求項1または2に記載の化合物。
- Rggは、
からなる群から選択され、
式中、R29は、C1−6アルキル(ハロゲン、ヒドロキシル、C1−6アルコキシ、及びシクロアルキルからなる群から各々独立して選択される1、2、または3個の置換基によって任意に置換されている)、ならびに複素環(ハロゲン、ヒドロキシルC1−6アルキル、及びC1−6アルコキシからなる群から各々独立して選択される1、2、または3個の置換基によって任意に置換されている)から選択される請求項1〜3のいずれか一項に記載の化合物。 - R29は、
からなる群から選択される請求項4に記載の化合物。 - 以下によって表され、
式中、qqは、0または1である請求項1〜5のいずれか一項に記載の化合物。 - 以下によって表される請求項1〜6のいずれか一項に記載の化合物。
- R44は、
からなる群から選択され、
式中、X 2 は、O、S、及びNRhhからなる群から独立して選択され、R’’は、HまたはC1−4アルキルであり、各R66、R77、R88、及びR99は、各出現に関して、H及びRggから独立して選択され、nは、0、1、2、または3である請求項1〜7のいずれか一項に記載の化合物。 - 各R66、R77、R88、及びR99は、各出現に関して、水素、ハロゲン、ヒドロキシル、C1−6アルキル、C3−6シクロアルキル、及び複素環からなる群から独立して選択され、C1−6アルキル、C3−6シクロアルキル、及び複素環は、ヒドロキシル、C1−6アルキル、C1−6アルコキシ(C3−6シクロアルキル、複素環、−C1−2アルキル−複素環、及びC1−2アルキル−C3−6シクロアルキルによって任意に置換されている)、−S(O)w−C1−3アルキル(wは、0、1、または2である)、ならびに−NR’S(O)2C1−6アルキルからなる群から各々独立して選択される1、2、または3個の置換基によって任意に置換されており、
R’は、各出現に関して、H及びC1−4アルキルから独立して選択される請求項8に記載の化合物。 - ppは、1または2であり、R11は、H、Fまたはメチルから選択される請求項1〜9のいずれか一項に記載の化合物。
- 以下からなる群から選択される化合物及びその薬学的に許容される塩。
- 請求項1〜11のいずれか一項に記載の化合物と、薬学的に許容される担体または賦形剤とを含む医薬組成物。
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RU2017126232A3 (ja) | 2019-06-17 |
CN107207487A (zh) | 2017-09-26 |
AU2022228100A1 (en) | 2022-09-29 |
RU2017126232A (ru) | 2019-01-29 |
EP3237411A2 (en) | 2017-11-01 |
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SA517381828B1 (ar) | 2022-09-07 |
JP2018500343A (ja) | 2018-01-11 |
IL276426A (en) | 2020-09-30 |
MA41253A (fr) | 2017-10-31 |
AU2020256305A1 (en) | 2020-11-12 |
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