JP2021534148A - 新規スルフォンアミドウレア化合物 - Google Patents
新規スルフォンアミドウレア化合物 Download PDFInfo
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- JP2021534148A JP2021534148A JP2021507616A JP2021507616A JP2021534148A JP 2021534148 A JP2021534148 A JP 2021534148A JP 2021507616 A JP2021507616 A JP 2021507616A JP 2021507616 A JP2021507616 A JP 2021507616A JP 2021534148 A JP2021534148 A JP 2021534148A
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Classifications
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- 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
- C07D401/12—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 chain containing hetero atoms as chain links
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- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
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Abstract
Description
Qは、OまたはSから選択され、
R1およびR3は、それぞれ独立に、水素または飽和もしくは不飽和ヒドロカルビル基であり、ヒドロカルビル基は、直鎖もしくは分枝鎖であっても、または環式基であっても、もしくは環式基を含んでもよく、ヒドロカルビル基は、任意に置換されてもよく、ヒドロカルビル基は、炭素骨格内に1個または複数のヘテロ原子N、OまたはSを任意に含んでもよく、
R1およびR3は、それらが結合される窒素原子と一緒に、3〜12員環式基を任意に形成してもよく、環式基は、任意に置換されてもよく、および
R2は、α位で置換された環式基であり、R2は、さらに任意に置換されてもよい。
(i)各水素原子は、ハロ;−CN;−NO2;−N3;−Rβ;−OH;−ORβ;−Rα−ハロ;−Rα−CN;−Rα−NO2;−Rα−N3;−Rα−Rβ;−Rα−OH;−Rα−ORβ;−SH;−SRβ;−SORβ;−SO2H;−SO2Rβ;−SO2NH2;−SO2NHRβ;−SO2N(Rβ)2;−Rα−SH;−Rα−SRβ;−Rα−SORβ;−Rα−SO2H;−Rα−SO2Rβ;−Rα−SO2NH2;−Rα−SO2NHRβ;−Rα−SO2N(Rβ)2;−Si(Rβ)3;−O−Si(Rβ)3;−Rα−Si(Rβ)3;−Rα−O−Si(Rβ)3;−NH2;−NHRβ;−N(Rβ)2;−N(O)(Rβ)2;−N+(Rβ)3;−Rα−NH2;−Rα−NHRβ;−Rα−N(Rβ)2;−Rα−N(O)(Rβ)2;−Rα−N+(Rβ)3;−CHO;−CORβ;−COOH;−COORβ;−OCORβ;−Rα−CHO;−Rα−CORβ;−Rα−COOH;−Rα−COORβ;−Rα−OCORβ;−C(=NH)Rβ;−C(=NH)NH2;−C(=NH)NHRβ;−C(=NH)N(Rβ)2;−C(=NRβ)Rβ;−C(=NRβ)NHRβ;−C(=NRβ)N(Rβ)2;−C(=NOH)Rβ;−C(N2)Rβ;−Rα−C(=NH)Rβ;−Rα−C(=NH)NH2;−Rα−C(=NH)NHRβ;−Rα−C(=NH)N(Rβ)2;−Rα−C(=NRβ)Rβ;−Rα−C(=NRβ)NHRβ;−Rα−C(=NRβ)N(Rβ)2;−Rα−C(=NOH)Rβ;−Rα−C(N2)Rβ;−NH−CHO;−NRβ−CHO;−NH−CORβ;−NRβ−CORβ;−CONH2;−CONHRβ;−CON(Rβ)2;−Rα−NH−CHO;−Rα−NRβ−CHO;−Rα−NH−CORβ;−Rα−NRβ−CORβ;−Rα−CONH2;−Rα−CONHRβ;−Rα−CON(Rβ)2;−O−Rα−OH;−O−Rα−ORβ;−O−Rα−NH2;−O−Rα−NHRβ;−O−Rα−N(Rβ)2;−O−Rα−N(O)(Rβ)2;−O−Rα−N+(Rβ)3;−NH−Rα−OH;−NH−Rα−ORβ;−NH−Rα−NH2;−NH−Rα−NHRβ;−NH−Rα−N(Rβ)2;−NH−Rα−N(O)(Rβ)2;−NH−Rα−N+(Rβ)3;−NRβ−Rα−OH;−NRβ−Rα−ORβ;−NRβ−Rα−NH2;−NRβ−Rα−NHRβ;−NRβ−Rα−N(Rβ)2;−NRβ−Rα−N(O)(Rβ)2;−NRβ−Rα−N+(Rβ)3;−N(O)Rβ−Rα−OH;−N(O)Rβ−Rα−ORβ;−N(O)Rβ−Rα−NH2;−N(O)Rβ−Rα−NHRβ;−N(O)Rβ−Rα−N(Rβ)2;−N(O)Rβ−Rα−N(O)(Rβ)2;−N(O)Rβ−Rα−N+(Rβ)3;−N+(Rβ)2−Rα−OH;−N+(Rβ)2−Rα−ORβ;−N+(Rβ)2−Rα−NH2;−N+(Rβ)2−Rα−NHRβ;−N+(Rβ)2−Rα−N(Rβ)2;または−N+(Rβ)2−Rα−N(O)(Rβ)2;から独立に選択される基で任意に置換されてもよく、および/または
(ii)同じ炭素原子または窒素原子に結合した任意の2個の水素原子は、オキソ(=O)、=S、=NHまたは=NRβから独立に選択されるπ結合した置換基で任意に置換されてもよく、および/または
(iii)任意のイオウ原子は、オキソ(=O)、=NHまたは=NRβから独立に選択される1個または2個のπ結合置換基で任意に置換されてもよく、および/または
(iv)同じ任意に置換されてもよい基もしくは部分内の、同じまたは異なる原子に結合した任意の2個の水素原子は、−O−、−S−、−NH−、−N=N−、−N(Rβ)−、N(O)(Rβ)−、−N+(Rβ)2−または−Rα−から独立に選択される架橋置換基で任意に置換されてもよく;
各−Rα−は、アルキレン、アルケニレンまたはアルキニレン基から独立に選択され、アルキレン、アルケニレンまたはアルキニレン基は、骨格に1〜6個の原子を含有し、アルキレン、アルケニレンまたはアルキニレン基の骨格の中の1個または複数の炭素原子は、1個または複数のヘテロ原子N、OまたはSで任意に置換されてもよく、アルキレン、アルケニレンまたはアルキニレン基の骨格の中の1個または複数の−CH2−基は、1個または複数の−N(O)(Rβ)−または−N+(Rβ)2−基で任意に置換されてもよく、アルキレン、アルケニレンまたはアルキニレン基は、1個または複数のハロおよび/または−Rβ基で任意に置換されてもよく;
各−Rβは、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニルもしくはC2−C6環式基から独立に選択されるか、または同じ窒素原子に結合した任意の2個もしくは3個の−Rβは、それらが結合される窒素原子と一緒に、C2−C7環式基を形成しており、任意の−Rβは、1個または複数のC1−C4アルキル、C1−C4ハロアルキル、C3−C7シクロアルキル、C3−C7ハロシクロアルキル、−O(C1−C4アルキル)、−O(C1−C4ハロアルキル)、−O(C3−C7シクロアルキル)、−O(C3−C7ハロシクロアルキル)、−CO(C1−C4アルキル)、−CO(C1−C4ハロアルキル)、−COO(C1−C4アルキル)、−COO(C1−C4ハロアルキル)、ハロ、−OH、−NH2、−CN、−C≡CH、オキソ(=O)、または4〜6員複素環式基で任意に置換されてもよい。
(i)各水素原子は、ハロ;−CN;−NO2;−N3;−Rβ;−OH;−ORβ;−Rα−ハロ;−Rα−CN;−Rα−NO2;−Rα−N3;−Rα−Rβ;−Rα−OH;−Rα−ORβ;−SH;−SRβ;−SORβ;−SO2H;−SO2Rβ;−SO2NH2;−SO2NHRβ;−SO2N(Rβ)2;−Rα−SH;−Rα−SRβ;−Rα−SORβ;−Rα−SO2H;−Rα−SO2Rβ;−Rα−SO2NH2;−Rα−SO2NHRβ;−Rα−SO2N(Rβ)2;−NH2;−NHRβ;−N(Rβ)2;−N+(Rβ)3;−Rα−NH2;−Rα−NHRβ;−Rα−N(Rβ)2;−Rα−N+(Rβ)3;−CHO;−CORβ;−COOH;−COORβ;−OCORβ;−Rα−CHO;−Rα−CORβ;−Rα−COOH;−Rα−COORβもしくは−Rα−OCORβから独立に選択される基で任意に置換されてもよく、および/または
(ii)同じ炭素原子に結合した任意の2個の水素原子は、オキソ(=O)、=S、=NHまたは=NRβから独立に選択されるπ結合した置換基で任意に置換されてもよく、および/または
(iii)同じ任意に置換されてもよい基または部分内の、同じまたは異なる原子に結合した任意の2個の水素原子は、−O−、−S−、−NH−、−N(Rβ)−、−N+(Rβ)2−または−Rα−から独立に選択される架橋した置換基で任意に置換されてもよく;
各−Rα−は、アルキレン、アルケニレンまたはアルキニレン基から独立に選択され、アルキレン、アルケニレンまたはアルキニレン基は、骨格に1〜6個の原子を含有し、アルキレン、アルケニレンまたはアルキニレン基の骨格の中の1個または複数の炭素原子は、1個または複数のヘテロ原子N、OまたはSで任意に置換されてもよく、アルキレン、アルケニレンまたはアルキニレン基の骨格の中の単一の−CH2−基は、−N+(Rβ)2−基で任意に置換されてもよく、アルキレン、アルケニレンまたはアルキニレン基は、1個または複数のハロおよび/または−Rβ基で任意に置換されてもよく;
各−Rβは、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニルもしくはC2−C6環式基から独立に選択されるか、または同じ窒素原子に結合した任意の2個もしくは3個の−Rβは、それらが結合される窒素原子と一緒に、C2−C7環式基を形成しており、任意の−Rβは、1個または複数のC1−C4アルキル、C1−C4ハロアルキル、C3−C7シクロアルキル、−O(C1−C4アルキル)、−O(C1−C4ハロアルキル)、−O(C3−C7シクロアルキル)、ハロ、−OH、−NH2、−CN、−C≡CH、オキソ(=O)、または4〜6員複素環式基で任意に置換されてもよい。
(i)各水素原子は、ハロ;−CN;−NO2;−N3;−Rβ;−OH;−ORβ;−Rα−ハロ;−Rα−CN;−Rα−NO2;−Rα−N3;−Rα−Rβ;−Rα−OH;−Rα−ORβ;−SH;−SRβ;−SORβ;−SO2H;−SO2Rβ;−SO2NH2;−SO2NHRβ;−SO2N(Rβ)2;−Rα−SH;−Rα−SRβ;−Rα−SORβ;−Rα−SO2H;−Rα−SO2Rβ;−Rα−SO2NH2;−Rα−SO2NHRβ;−Rα−SO2N(Rβ)2;−NH2;−NHRβ;−N(Rβ)2;−Rα−NH2;−Rα−NHRβ;−Rα−N(Rβ)2;−CHO;−CORβ;−COOH;−COORβ;−OCORβ;−Rα−CHO;−Rα−CORβ;−Rα−COOH;−Rα−COORβまたは−Rα−OCORβから独立に選択される基で任意に置換されてもよく、および/または
(ii)同じ炭素原子に結合した任意の2個の水素原子は、オキソ(=O)、=S、=NHまたは=NRβから独立に選択されるπ結合した置換基で任意に置換されてもよく、および/または
(iii)同じ任意に置換されてもよい基もしくは部分内の、同じもしくは異なる原子に結合した任意の2個の水素原子は、−O−、−S−、−NH−、−N(Rβ)−、もしくは−Rα−から独立に選択される架橋した置換基で任意に置換されてもよく;
各−Rα−は、アルキレン、アルケニレンまたはアルキニレン基から独立に選択され、アルキレン、アルケニレンまたはアルキニレン基は、骨格に1〜6個の原子を含有し、アルキレン、アルケニレンまたはアルキニレン基の骨格の中の1個または複数の炭素原子は、1個または複数のヘテロ原子N、OまたはSで任意に置換されてもよく、アルキレン、アルケニレンまたはアルキニレン基は、1個または複数のハロおよび/または−Rβ基で任意に置換されていてもよく;
各−Rβは、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニルもしくはC2−C6環式基から独立に選択されるか、または同じ窒素原子に結合した任意の2個の−Rβは、それらが結合される窒素原子と一緒に、C2−C6環式基を形成しており、任意の−Rβは、1個または複数のC1−C4アルキル、ハロ、−OH、または4〜6員複素環式基で任意に置換されてもよい。
典型的には、置換された基は、1、2、3または4個の置換基、より典型的には1、2または3個の置換基、より典型的には1個または2個の置換基、より典型的には1個の置換基を含む。
特に断りのない限り、任意に置換されてもよい基または部分(例えば、R1)の任意の二価架橋置換基(例えば、−O−、−S−、−NH−、−N(Rβ)−、−N(O)(Rβ)−、−N+(Rβ)2−または−Rα−)は、指定された基または部分だけに結合されていなければならず、第二の基または部分(例えば、R2)そのものが任意に置換され得るとしても、第二の基または部分に結合されていなくてもよい。
特に断りのない限り、基に、ハロアルキルまたはハロメチル基などの、用語「ハロ」が前に付く場合、該当する基は、フルオロ、クロロ、ブロモおよびヨードから独立に選択される1個または複数のハロ基で置換されていることが理解されなければならない。典型的にはハロ置換基の最大数は、ハロの接頭辞を含まない対応する基での置換に利用可能な水素原子の数によってのみ限定される。例えばハロメチル基は、1、2または3個のハロ置換基を含んでもよい。ハロエチルまたはハロフェニル基は、1、2、3、4または5個のハロ置換基を含んでもよい。同様に、特に断りのない限り、基に特定のハロ基が前に付く場合、該当する基は特定のハロ基の1個または複数で置換されていることが理解されなければならない。例えば用語「フルオロメチル」は、1、2、または3個のフルオロ基で置換されたメチル基を指す。
同様に、特に断りのない限り、基が「ハロ置換」と言われる場合、該当する基はフルオロ、クロロ、ブロモおよびヨードから独立に選択される1個または複数のハロ基で置換されていることが理解されなければならない。典型的には、ハロ置換基の最大数は、ハロ置換されたと言われる基での置換に利用可能な水素原子の数によってのみ限定される。例えばハロ置換メチル基は、1、2または3個のハロ置換基を含んでもよい。ハロ置換エチルまたはハロ置換フェニル基は、1、2、3、4または5個のハロ置換基を含んでもよい。
特に断りのない限り、元素への任意の参照は、その元素の全ての同位体への参照を考慮しなければならない。従って、例えば、特に断りのない限り、水素への任意の参照は、ジュウテリウムおよびトリチウムを含む全ての水素同位体を包含すると見なされる。
炭素骨格中に1個もしくは複数のヘテロ原子N、OもしくはSを含むヒドロカルビルもしくは他の基を参照する場合、またはN、OもしくはS原子により置き換えられているヒドロカルビルもしくは他の基の炭素原子を参照する場合、意図されるのは、
−CH2−が、−NH−、−O−もしくは−S−により置換されること、
−CH3が、−NH2、−OHもしくは−SHにより置換されること、
−CH=が、−N=により置換されること、
CH2=が、NH=、O=もしくはS=により置換されること、または
CH≡が、N≡により置換されること、
であるが、但し、得られる基が少なくとも1個の炭素原子を含むことを条件とする。例えばメトキシ、ジメチルアミノおよびアミノエチル基は、それらの炭素骨格中に1個または複数のヘテロ原子N、OまたはSを含むヒドロカルビルであると見なされる。
−CH2−が、
−CH2−が、
一実施形態では、R1およびR3は、両方が水素でない。
各−Rα−は、アルキレン、アルケニレンまたはアルキニレン基から独立に選択され、アルキレン、アルケニレンまたはアルキニレン基は、骨格に1〜6個の原子を含有し、アルキレン、アルケニレンまたはアルキニレン基の骨格の中の1個または複数の炭素原子は、1個または複数のヘテロ原子N、OまたはSで任意に置換されてもよく、アルキレン、アルケニレンまたはアルキニレン基の骨格の中の1個または複数の−CH2−基は、1個または複数の−N(O)(Rβ)−または−N+(Rβ)2−基で任意に置換されてもよく、アルキレン、アルケニレンまたはアルキニレン基は、1個または複数のハロおよび/または−Rβ基で任意に置換されてもよく;
各−Rβは、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニルもしくはC2−C6環式基から独立に選択されるか、または同じ窒素原子に結合した任意の2個もしくは3個の−Rβは、それらが結合される窒素原子と一緒に、C2−C7環式基を形成しており、任意の−Rβは、1個または複数のC1−C4アルキル、C1−C4ハロアルキル、C3−C7シクロアルキル、C3−C7ハロシクロアルキル、−O(C1−C4アルキル)、−O(C1−C4ハロアルキル)、−O(C3−C7シクロアルキル)、−O(C3−C7ハロシクロアルキル)、−CO(C1−C4アルキル)、−CO(C1−C4ハロアルキル)、−COO(C1−C4アルキル)、−COO(C1−C4ハロアルキル)、ハロ、−OH、−NH2、−CN、−C≡CH、オキソ(=O)、または4〜6員複素環式基で任意に置換されてもよい。
各−Rα−は、アルキレン、アルケニレンまたはアルキニレン基から独立に選択され、アルキレン、アルケニレンまたはアルキニレン基は、骨格に1〜6個の原子を含有し、アルキレン、アルケニレンまたはアルキニレン基の骨格の中の1個または複数の炭素原子は、1個または複数のヘテロ原子N、OまたはSで任意に置換されてもよく、アルキレン、アルケニレンまたはアルキニレン基の骨格の中の単一の−CH2−基は、−N+(Rβ)2−基で任意に置換されてもよく、アルキレン、アルケニレンまたはアルキニレン基は、1個または複数のハロおよび/または−Rβ基で任意に置換されてもよく;
各−Rβは、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニルもしくはC2−C6環式基から独立に選択されるか、または同じ窒素原子に結合した任意の2個もしくは3個の−Rβは、それらが結合される窒素原子と一緒に、C2−C7環式基を形成しており、任意の−Rβは、1個または複数のC1−C4アルキル、C1−C4ハロアルキル、C3−C7シクロアルキル、−O(C1−C4アルキル)、−O(C1−C4ハロアルキル)、−O(C3−C7シクロアルキル)、ハロ、−OH、−NH2、−CN、−C≡CH、オキソ(=O)、または4〜6員複素環式基で任意に置換されてもよい。
各−Rα−は、アルキレン、アルケニレンまたはアルキニレン基から独立に選択され、アルキレン、アルケニレンまたはアルキニレン基は、骨格に1〜6個の原子を含有し、アルキレン、アルケニレンまたはアルキニレン基の骨格の中の1個または複数の炭素原子は、1個または複数のヘテロ原子N、OまたはSで任意に置換されてもよく、アルキレン、アルケニレンまたはアルキニレン基は、1個または複数のハロおよび/または−Rβ基で任意に置換されていてもよく;
各−Rβは、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニルもしくはC2−C6環式基から独立に選択されるか、または同じ窒素原子に結合した任意の2個の−Rβは、それらが結合される窒素原子と一緒に、C2−C6環式基を形成しており、任意の−Rβは、1個または複数のC1−C4アルキル、ハロ、−OH、または4〜6員複素環式基で任意に置換されてもよい。
mは、1、2、または3であり、
nは、1、2または3であり、
各R10は、−(CH2)p−NH2、−(CH2)p−NHR11、−(CH2)p−N(R11)2、または1個もしくは2個の環窒素原子を含む4〜6員飽和複素環式基から独立に選択され、複素環式基は、1個または2個のC1−C3アルキル基で任意に置換されてもよく、または
2個のR10は、それらが結合される原子と一緒に、1個または2個の環窒素原子を含む3〜6員飽和複素環式基を形成し、複素環式基は、1個または2個のC1−C3アルキル基で任意に置換されてもよく、
各R11は、C1−C3アルキルまたはシクロプロピルから独立に選択されるか、または同じ窒素原子に結合される2個のR11は、一緒にC2−C5アルキレンを形成してもよく、
pは、0、1、または2であり;および
R2は、αおよびα’位で置換された環式基であり、R2は、さらに任意に置換されてもよい。
誤解を避けるために記すと、R10は、R10が結合されるアゼチジニル、ピロリジニルまたはピペリジニル基の環炭素原子のいずれかに直接結合し得ることに留意されたい。
一実施形態では、mは、1または2である。一実施形態では、mは、1である。別の実施形態では、mは2である。
Vは、CR44R46、NR44またはNR48であり、
R40およびR42、またはR40およびR43、またはR41およびR42、またはR41およびR44の1個は一緒に、−CH2−、−CH2CH2−、−O−CH2−、またはNR45−CH2−を形成し、残りのR40、R41、R42、R43、および存在する場合には、R44、は水素であり、
R45は、水素、メチルまたはエチルから選択され、
R46は、−(CH2)q−NH2、−(CH2)q−NHR47、−(CH2)q−N(R47)2、または1個もしくは2個の環窒素原子を含む4〜6員飽和複素環式基から選択され、複素環式基は、1個または2個のC1−C3アルキル基で任意に置換されてもよく、
各R47は、C1−C3アルキルまたはシクロプロピルから独立に選択されるか、または2個のR47は、一緒にC2−C5アルキレンを形成してもよく、
qは0、1、または2であり、
R48は、C1−C4アルキルまたはC3−C4シクロアルキルから選択され、および
R2は、αおよびα’位で置換された環式基であり、R2は、さらに任意に置換されてもよい。
誤解を避けるために記すと、VがNR44であり、R41およびR44が一緒に、−O−CH2−またはNR45−CH2−を形成する場合、NR44の窒素原子は、−O−CH2−の酸素原子またはNR45−CH2−の窒素原子に直接結合しないことに留意されたい。
一実施形態では、Vは、CHR46またはNR48である。
一実施形態では、Vは、NR48である。一実施形態では、R48は、C1−C3アルキルまたはシクロプロピルから選択される。一実施形態では、R48は、メチル、エチル、n−プロピル、イソプロピルまたはシクロプロピルから選択される。
一実施形態では、Vは、CHR46であり、R46は、NMe2、NEt2またはピロリジニルから選択される。
R49は、−CH2−または−CH2CH2−であり、
V1は、CHR46、NHまたはNR48であり、
V2はCR46またはNであり、および
R46、R48およびR2は、式(IB)に基づき定義される。
W、X、YおよびZは、2個の環窒素原子が相互に直接結合していないという条件下で、それぞれ独立に、−CH2−、−CH(R18)−、−C(R18)2−、−NH−または−N(R18)−から選択され、
各R18は、C1−C3アルキルまたはシクロプロピルから独立に選択されるか、または2個のR18は、一緒にC2−C6アルキレンを形成してもよく、および
R2は、αおよびα’位で置換された環式基であり、R2は、さらに任意に置換されてもよい。
一実施形態では、W、X、YおよびZの3個は−CH2−であり、W、X、YおよびZの内の1個は−N(R18)−である。
R20は、結合またはC1−C5アルキレンから選択され、
R21は、N(R22)2または1個または2個の環窒素原子を含む4〜6員飽和複素環式基であり、複素環式基は、1個または2個のC1−C4アルキル基で任意に置換されてもよく、
各R22は、水素、C1−C5アルキルまたはC3−C5シクロアルキルから独立に選択されるか、または2個のR22は、一緒にC2−C5アルキレンを形成してもよく、
R23は、水素およびC1−C5アルキル、C3−C5シクロアルキルまたは−(CH2)t−Phから選択され;
tは、0、1、2、3または4であり、および
R2は、αおよびα’位で置換された環式基であり、R2は、さらに任意に置換されてもよく、
ただし、R21がN(R22)2である場合、R20がC1−C5アルキレンから選択される場合である。
一実施形態では、R21は、4〜6員飽和複素環式基であり、R20は、−CH2−または−CH2CH2−から選択される。
R30は、結合またはC1−C3アルキレンから選択され、
R31は、C1−C3アルキルまたはシクロプロピルから選択され、
R32およびR34、またはR32およびR35、またはR33およびR35、またはR33およびR36、またはR33およびR37、またはR34およびR36の1個は一緒に、−CH2−、−CH2CH2−、−O−CH2−、または−NR38−CH2−を形成し、残りのR33、R34、R35、R36、およびR37は水素であり、R32は、残っている場合には、水素、C1−C4アルキルまたはC3−C4シクロアルキルから選択され、
R38は、水素、メチルまたはエチルから選択され、および
R2は、αおよびα’位で置換された環式基であり、R2は、さらに任意に置換されてもよい。
誤解を避けるために記すと、R32およびR34、またはR32およびR35が一緒に、−O−CH2−またはNR38−CH2−を形成する場合、−NR32の窒素原子は、−O−CH2−の酸素原子または−NR38−CH2−の窒素原子に直接結合されないことに留意されたい。
R27は、1、2または3個の環窒素原子を含む5員複素芳香環式基であり、複素芳香環は、1個または2個のC1−C4アルキルまたはC3−C4シクロアルキル基で任意に置換されてもよく、
R28は、水素、C1−C3アルキルまたはシクロプロピルから選択され、および
R2は、αおよびα’位で置換された環式基であり、R2は、さらに任意に置換されてもよい。
誤解を避けるために記すと、それは、化合物の残部の窒素原子に直接結合されるR27の5員飽和複素芳香環式基の環炭素原子であることに留意されたい。
別の実施形態では、R2は、αおよびα’位で置換された環式基であり、R2は、さらに任意に置換されてもよい。例えば、R2は、αおよびα’位で置換されたシクロアルキル、シクロアルケニルまたは非芳香族複素環式基であってもよい。
R2の親環式基のαおよび/またはα’位の他の典型的な置換基としては、それぞれ、α,βおよび/またはα’,β’位にまたがって親環式基に縮合されているシクロアルキル、シクロアルケニル、非芳香族複素環式、アリール、またはヘテロアリール環を挙げることができる。このような縮合環式基は、以下でさらに詳細に記載される。
から選択される式を有し、式中、
A1およびA2は、任意に置換されてもよいアルキレンまたはアルケニレン基からそれぞれ独立に選択され、アルキレンまたはアルケニレン基の骨格中の1個または複数の炭素原子は、1個または複数のヘテロ原子N、OまたはSで任意に置換されてもよく、
各Raは、−Raa、−ORaaまたは−CORaaから独立に選択され、
各Rbは、水素、ハロ、−NO2、−CN、−Raa、−ORaaまたは−CORaaから独立に選択されるが、
但し、環窒素原子に直接結合される任意のRaまたはRbがハロ、−NO2、−CNまたは−ORaaでないことを条件とし、
各Rcは、水素、ハロ、−OH、−NO2、−CN、−Rcc、−ORcc、−CORcc、−COORcc、−CONH2、−CONHRccまたは−CON(Rcc)2から独立に選択され;
各Raaは、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニルまたは3〜7員環式基から独立に選択され、各Raaは、任意に置換されており;および
各Rccは、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニルもしくは3〜7員環式基から独立に選択されるか、または同じ窒素原子に結合した任意の2個のRccは、それらが結合される窒素原子と一緒に、3〜7員複素環式基を形成していてもよく、各Rccは、任意に置換されている。
各B1は、C1−C4アルキル、C2−C4アルケニル、C2−C4アルキニル、C3−C6シクロアルキルもしくはフェニル基、または1個もしくは2個の環ヘテロ原子Nおよび/またはOを含有する4〜6員複素環式基から独立に選択されるか、あるいは2個のB1が、それらが結合される窒素原子と一緒に、1個または2個の環ヘテロ原子Nおよび/またはOを含有する4〜6員複素環式基を形成していてもよく、任意のB1は、任意にハロ置換されてもよく、および/または−OH、−NH2、−OB12、−NHB12もしくは−N(B12)2から独立に選択される1個もしくは2個の置換基で任意に置換されてもよく;
各B11は、C1−C8アルキレンまたはC2−C8アルケニレン基から独立に選択され、アルキレンまたはアルケニレン基の骨格中の1個または2個の炭素原子は、1個または2個のヘテロ原子Nおよび/またはOで任意に置換されてもよく、アルキレンまたはアルケニレン基は、任意にハロ置換されてもよく、および/または−OH、−NH2、−OB12、−NHB12もしくは−N(B12)2から独立に選択される1個もしくは2個の置換基で置換されてもよく;
各B12は、C1−C3アルキルまたはC1−C3ハロアルキル基から独立に選択される。典型的には、任意の二価基−B11−は、4〜6員縮合環を形成する。
式中、R5およびR6は、C1−C4アルキル、C1−C4ハロアルキル、C3−C4シクロアルキニルおよびC3−C4ハロシクロアルキルから独立に選択され、Rdは、水素、ハロ、−OH、−NO2、−CN、−Rdd、−ORdd、−CORdd、−COORdd、−CONH2、−CONHRddまたは−CON(Rdd)2であり、各−Rddは、C1−C4アルキル、C1−C4ハロアルキル、C3−C4シクロアルキニルおよびC3−C4ハロシクロアルキルから独立に選択される。典型的には、R5およびR6は、C1−C4アルキルから独立に選択され、Rdは、水素、ハロ、−CN、C1−C3アルキル、C1−C3ハロアルキル、シクロプロピルまたはハロシクロプロピルである。より典型的には、R5およびR6は、C1−C4アルキルから独立に選択され、Rdは、水素またはハロである。
典型的には、A1およびA2は、任意に置換されてもよい直鎖アルキレン基または任意に置換されてもよい直鎖アルケニレン基からそれぞれ独立に選択され、アルキレンまたはアルケニレン基の骨格中の1個または2個の炭素原子は、窒素および酸素から独立に選択される1個または2個のヘテロ原子で任意に置換されてもよい。より典型的には、A1およびA2は、任意に置換されてもよい直鎖アルキレン基からそれぞれ独立に選択され、アルキレン基の骨格中の1個の炭素原子は、酸素原子で任意に置換されてもよい。典型的には、A1またはA2中のヘテロ原子は、別の環ヘテロ原子に直接結合されない。典型的には、A1およびA2は、非置換であるか、または1個または複数のハロ、ヒドロキシル、−CN、−NO2、−B3もしくは−OB3基で置換されており、B3は、任意にハロ置換されてもよいC1−C4アルキル基である。より典型的には、A1およびA2は、非置換であるか、または1個もしくは複数のフルオロおよび/またはクロロ基で置換されている。R2が、A1およびA2基の両方を含有する場合、A1およびA2は、同じであるまたは異なっていてもよい。典型的には、A1およびA2は、同じである。
から選択され、式中、R6は、C1−C4アルキル、C1−C4ハロアルキル、C3−C4シクロアルキルまたはC3−C4ハロシクロアルキルであり、Rfは、水素、ハロ、−OH、−NO2、−CN、−Rff、−ORff、−CORff、−COORff、−CONH2、−CONHRffまたは−CON(Rff)2であり、各−Rffは、C1−C4アルキル、C1−C4ハロアルキル、C3−C4シクロアルキニルおよびC3−C4ハロシクロアルキルから独立に選択される。典型的には、R6は、C1−C4アルキルであり、Rfは、水素、ハロ、−CN、C1−C3アルキル、C1−C3ハロアルキル、シクロプロピルまたはハロシクロプロピルである。典型的には、R6は、C1−C4アルキルであり、Rfは、水素またはハロである。
各B4は、C1−C4アルキル、C2−C4アルケニル、C2−C4アルキニル、C3−C6シクロアルキルもしくはフェニル基、または1個もしくは2個の環ヘテロ原子Nおよび/またはOを含有する4〜6員複素環式基から独立に選択されるか、あるいは2個のB4が、それらが結合される窒素原子と一緒に、1個または2個の環ヘテロ原子Nおよび/またはOを含有する4〜6員複素環式基を形成していてもよく、任意のB4は、任意にハロ置換されてもよく、および/または−OH、−NH2、−OB45、−NHB45もしくは−N(B45)2から独立に選択される1個もしくは2個の置換基で任意に置換されてもよく、
各B44は、C1−C8アルキレンまたはC2−C8アルケニレン基から独立に選択され、アルキレンまたはアルケニレン基の骨格中の1個または2個の炭素原子は、1個または2個のヘテロ原子Nおよび/またはOで任意に置換されてもよく、アルキレンまたはアルケニレン基は、任意にハロ置換されてもよく、および/または−OH、−NH2、−OB45、−NHB45もしくは−N(B45)2から独立に選択される1個もしくは2個の置換基で任意に置換されてもよく、
各B45は、C1−C3アルキルまたはC1−C3ハロアルキル基から独立に選択される。
典型的には、任意の二価基−B44−は、4〜6員縮合環を形成する。
R7は、C1−C4アルキル、C1−C4ハロアルキル、C3−C6シクロアルキニルまたはC3−C6ハロシクロアルキルであり、R8は、5または6員の任意に置換されてもよい複素環または芳香族基であり、Rgは、水素、ハロ、−OH、−NO2、−CN、−Rgg、−ORgg、−CORgg、−COORgg、−CONH2、−CONHRggまたは−CON(Rgg)2であり、各−Rggは、C1−C4アルキル、C1−C4ハロアルキル、C3−C4シクロアルキニルおよびC3−C4ハロシクロアルキルから独立に選択される。一実施形態では、複素環または芳香族基の任意の置換基は、ハロ、−OH、−NH2、−CN、−NO2、−B5、−OB5、−NHB5、−N(B5)2、−CONH2、−CONHB5、−CON(B5)2、−NHCOB5、−NB5COB5、または−B55−から独立に選択され、
各B5は、C1−C4アルキル、C2−C4アルケニル、C2−C4アルキニル、C3−C6シクロアルキルもしくはフェニル基、または1個もしくは2個の環ヘテロ原子Nおよび/またはOを含有する4〜6員複素環式基から独立に選択されるか、あるいは2個のB5が、それらが結合される窒素原子と一緒に、1個または2個の環ヘテロ原子Nおよび/またはOを含有する4〜6員複素環式基を形成していてもよく、任意のB5は、任意にハロ置換されてもよく、および/または−OH、−NH2、−OB56、−NHB56もしくは−N(B56)2から独立に選択される1個もしくは2個の置換基で任意に置換されてもよく、
各B55は、C1−C8アルキレンまたはC2−C8アルケニレン基から独立に選択され、アルキレンまたはアルケニレン基の骨格中の1個または2個の炭素原子は、1個または2個のヘテロ原子Nおよび/またはOで任意に置換されてもよく、アルキレンまたはアルケニレン基は、任意にハロ置換されてもよく、および/または−OH、−NH2、−OB56、−NHB56もしくは−N(B56)2から独立に選択される1個もしくは2個の置換基で任意に置換されてもよく、
各B56は、C1−C3アルキルまたはC1−C3ハロアルキル基から独立に選択される。
R8は、5または6員の任意に置換されてもよい複素環または芳香族基である。一実施形態では、複素環または芳香族基の任意の置換基は、ハロ、−OH、−NH2、−CN、−NO2、−B6、−OB6、−NHB6、−N(B6)2、−CONH2、−CONHB6、−CON(B6)2、−NHCOB6、−NB6COB6、または−B66−から独立に選択され、
各B6は、C1−C4アルキル、C2−C4アルケニル、C2−C4アルキニル、C3−C6シクロアルキルもしくはフェニル基、または1個もしくは2個の環ヘテロ原子Nおよび/またはOを含有する4〜6員複素環式基から独立に選択されるか、あるいは2個のB6が、それらが結合される窒素原子と一緒に、1個または2個の環ヘテロ原子Nおよび/またはOを含有する4〜6員複素環式基を形成していてもよく、任意のB6は、任意にハロ置換されてもよく、および/または−OH、−NH2、−OB67、−NHB67もしくは−N(B67)2から独立に選択される1個もしくは2個の置換基で任意に置換されてもよく、
各B66は、C1−C8アルキレンまたはC2−C8アルケニレン基から独立に選択され、アルキレンまたはアルケニレン基の骨格中の1個または2個の炭素原子は、1個または2個のヘテロ原子Nおよび/またはOで任意に置換されてもよく、アルキレンまたはアルケニレン基は、任意にハロ置換されてもよく、および/または−OH、−NH2、−OB67、−NHB67もしくは−N(B67)2から独立に選択される1個もしくは2個の置換基で任意に置換されてもよく、
各B67は、C1−C3アルキルまたはC1−C3ハロアルキル基から独立に選択される。
各B7は、C1−C4アルキル、C2−C4アルケニル、C2−C4アルキニル、C3−C6シクロアルキルもしくはフェニル基、または1個もしくは2個の環ヘテロ原子Nおよび/またはOを含有する4〜6員複素環式基から独立に選択されるか、あるいは2個のB7が、それらが結合される窒素原子と一緒に、1個または2個の環ヘテロ原子Nおよび/またはOを含有する4〜6員複素環式基を形成していてもよく、任意のB7は、任意にハロ置換されてもよく、および/または−OH、−NH2、−OB78、−NHB78もしくは−N(B78)2から独立に選択される1個もしくは2個の置換基で任意に置換されてもよく、
各B77は、C1−C8アルキレンまたはC2−C8アルケニレン基から独立に選択され、アルキレンまたはアルケニレン基の骨格中の1個または2個の炭素原子は、1個または2個のヘテロ原子Nおよび/またはOで任意に置換されてもよく、アルキレンまたはアルケニレン基は、任意にハロ置換されてもよく、および/または−OH、−NH2、−OB78、−NHB78もしくは−N(B78)2から独立に選択される1個もしくは2個の置換基で任意に置換されてもよく、
各B78は、C1−C3アルキルまたはC1−C3ハロアルキル基から独立に選択される。
各B8は、C1−C4アルキル、C2−C4アルケニル、C2−C4アルキニル、C3−C6シクロアルキルもしくはフェニル基、または1個もしくは2個の環ヘテロ原子Nおよび/またはOを含有する4〜6員複素環式基から独立に選択されるか、あるいは2個のB8が、それらが結合される窒素原子と一緒に、1個または2個の環ヘテロ原子Nおよび/またはOを含有する4〜6員複素環式基を形成していてもよく、任意のB8は、任意にハロ置換されてもよく、および/または−OH、−NH2、−OB89、−NHB89もしくは−N(B89)2から独立に選択される1個もしくは2個の置換基で任意に置換されてもよく、
各B88は、C1−C8アルキレンまたはC2−C8アルケニレン基から独立に選択され、アルキレンまたはアルケニレン基の骨格中の1個または2個の炭素原子は、1個または2個のヘテロ原子Nおよび/またはOで任意に置換されてもよく、アルキレンまたはアルケニレン基は、任意にハロ置換されてもよく、および/または−OH、−NH2、−OB89、−NHB89もしくは−N(B89)2から独立に選択される1個もしくは2個の置換基で任意に置換されてもよく、
各B89は、C1−C3アルキルまたはC1−C3ハロアルキル基から独立に選択される。
各B9は、C1−C4アルキル、C2−C4アルケニル、C2−C4アルキニル、C3−C6シクロアルキルもしくはフェニル基、または1個もしくは2個の環ヘテロ原子Nおよび/またはOを含有する4〜6員複素環式基から独立に選択されるか、あるいは2個のB9が、それらが結合される窒素原子と一緒に、1個または2個の環ヘテロ原子Nおよび/またはOを含有する4〜6員複素環式基を形成していてもよく、任意のB9は、任意にハロ置換されてもよく、および/または−OH、−NH2、−OB98、−NHB98もしくは−N(B98)2から独立に選択される1個もしくは2個の置換基で任意に置換されてもよく、
各B99は、C1−C8アルキレンまたはC2−C8アルケニレン基から独立に選択され、アルキレンまたはアルケニレン基の骨格中の1個または2個の炭素原子は、1個または2個のヘテロ原子Nおよび/またはOで任意に置換されてもよく、アルキレンまたはアルケニレン基は、任意にハロ置換されてもよく、および/または−OH、−NH2、−OB98、−NHB98もしくは−N(B98)2から独立に選択される1個もしくは2個の置換基で任意に置換されてもよく、
各B98は、C1−C3アルキルまたはC1−C3ハロアルキル基から独立に選択される。
(i)フェニル、または5もしくは6員ヘテロアリール基は、α位で、−R4、−OR4および−COR4から選択される置換基で置換されており、R4は、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニルまたはC2−C6環式基から選択され、R4は、1個または複数のハロ基で任意に置換されており、および
任意選択により、フェニル、または5もしくは6員ヘテロアリール基は、α’位で、−R14、−OR14および−COR14から選択される置換基で置換されており、R14は、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニルまたはC2−C6環式基から選択され、R14は、1個または複数のハロ基で任意に置換されており、および
任意選択により、フェニル、または5もしくは6員ヘテロアリール基は、さらに置換されており(典型的には、ハロ、−NO2、−CN、−COOR15、−CONH2、−CONHR15または−CON(R15)2から独立に選択される1、2または3個の置換基により置換され、各−R15は、C1−C4アルキルまたはC1−C4ハロアルキル基から独立に選択される)、または
(ii)フェニル、または5もしくは6員ヘテロアリール基は、α,β位にまたがって親フェニル、または5もしくは6員ヘテロアリール基に縮合され、1個または複数のハロ基で任意に置換されてもよい、シクロアルキル、シクロアルケニル、非芳香族複素環式、アリール、またはヘテロアリール環で置換されており、および
任意選択により、フェニル、または5もしくは6員ヘテロアリール基は、α’位で、−R4、−OR4および−COR4から選択される置換基でさらに置換されており、R4は、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニルまたはC2−C6環式基から選択され、R4は、1個または複数のハロ基で任意に置換されており、および
任意選択により、フェニル、または5もしくは6員ヘテロアリール基は、さらに置換されており(典型的には、ハロ、−NO2、−CN、−COOR15、−CONH2、−CONHR15または−CON(R15)2から独立に選択される1個または2個の置換基により置換され、各−R15は、C1−C4アルキルまたはC1−C4ハロアルキル基から独立に選択される)、または
(iii)フェニル、または5もしくは6員ヘテロアリール基は、α,β位にまたがって親フェニル、または5もしくは6員ヘテロアリール基に縮合され、1個または複数のハロ基で任意に置換されてもよい第一のシクロアルキル、シクロアルケニル、非芳香族複素環式、アリール、またはヘテロアリール環で置換されており、および
フェニル、または5もしくは6員ヘテロアリール基は、α’,β’位にまたがって親フェニル、または5もしくは6員ヘテロアリール基に縮合され、1個または複数のハロ基で任意に置換されてもよい第二のシクロアルキル、シクロアルケニル、非芳香族複素環式、アリール、またはヘテロアリール環で置換されており、および
任意選択により、フェニル基は、さらに置換されており(典型的には、ハロ、−NO2、−CN、−COOR15、−CONH2、−CONHR15または−CON(R15)2から選択される置換基により置換され、各−R15は、C1−C4アルキルまたはC1−C4ハロアルキル基から独立に選択される)、または
(iv)フェニル、または5もしくは6員ヘテロアリール基は、α位で、フェニル、ピリジニル、ピリミジニル、ピラゾリル、イミダゾリル、トリアゾリルまたはテトラヒドロピラニルから選択される一価複素環式基または一価芳香族基で置換されており、一価複素環または芳香族基は、ハロ、C1−C3アルキル、C1−C3ハロアルキル、−R12−OR13、−R12−N(R13)2、−R12−CNまたは−R12−C≡CR13から独立に選択される1個または2個の置換基で任意に置換されてもよく、一価複素環または芳香族基の環原子は、親フェニルまたは5もしくは6員ヘテロアリール基のα環原子に直接結合され;R12は、結合またはC1−C3アルキレン基から独立に選択され、R13は、水素またはC1−C3アルキルまたはC1−C3ハロアルキル基から独立に選択され、および
任意選択により、フェニル、または5もしくは6員ヘテロアリール基は、α’位で、−R4、−OR4および−COR4から選択される置換基でさらに置換されており、R4は、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニルまたはC2−C6環式基から選択され、R4は、1個または複数のハロ基で任意に置換されており、および
任意選択により、フェニル、または5もしくは6員ヘテロアリール基は、さらに置換されており(典型的には、ハロ、−NO2、−CN、−COOR15、−CONH2、−CONHR15または−CON(R15)2から独立に選択される1、2または3個の置換基により置換され、各−R15は、C1−C4アルキルまたはC1−C4ハロアルキル基から独立に選択される)、または
(v)フェニル、または5もしくは6員ヘテロアリール基は、α位で、フェニル、ピリジニル、ピリミジニル、ピラゾリル、イミダゾリル、トリアゾリルまたはテトラヒドロピラニルから選択される一価複素環式基または一価芳香族基で置換されており、一価複素環または芳香族基は、ハロ、C1−C3アルキル、C1−C3ハロアルキル、−R12−OR13、−R12−N(R13)2、−R12−CNまたは−R12−C≡CR13から独立に選択される1個または2個の置換基で任意に置換されてもよく、一価複素環または芳香族基の環原子は、親フェニルまたは5もしくは6員ヘテロアリール基のα環原子に直接結合され;R12は、結合またはC1−C3アルキレン基から独立に選択され、R13は、水素またはC1−C3アルキルまたはC1−C3ハロアルキル基から独立に選択され、および
任意選択により、フェニル、または5もしくは6員ヘテロアリール基は、α’,β’位にまたがって親フェニル、または5もしくは6員ヘテロアリール基に縮合され、1個または複数のハロ基で任意に置換されてもよいシクロアルキル、シクロアルケニル、非芳香族複素環式、アリール、またはヘテロアリール環でさらに置換されており;
任意選択により、フェニル、または5もしくは6員ヘテロアリール基は、さらに置換される(典型的には、ハロ、−NO2、−CN、−COOR15、−CONH2、−CONHR15または−CON(R15)2から独立に選択される1個または2個の置換基により置換され、各−R15は、C1−C4アルキルまたはC1−C4ハロアルキル基から独立に選択される)。
・湿潤型および乾燥型加齢黄斑変性(Doyle et al.,Nature Medicine,18:791−798,2012;およびTarallo et al.,Cell,149(4):847−59,2012)、糖尿病性網膜症(Loukovaara et al.Acta Ophthalmol.2017;95(8):803−808)、および視神経損傷(Puyang et al.Sci Rep.6:20998,2016 Feb 19)などの眼科疾患、
・非アルコール性脂肪性肝炎(NASH)(Henao−Meija et al.,Nature,482:179−185,2012)、肝臓の虚血再灌流障害(Yu et al.,Transplantation,103(2):353−362,2019)、劇症肝炎(Pourcet et al.,Gastroenterology,154(5):1449−1464,e20,2018)、肝線維症(Zhang et al.,Parasit Vectors,12(1):29,2019)、肝不全(Wang et al.,Hepatol Res,48(3):E194−E202,2018)を含む肝臓疾患;
・腎石灰化症(Anders et al.,Kidney Int,93(3):656−669,2018)、慢性結晶腎症を含む腎線維症(Ludwig−Portugall et al.,Kidney Int,90(3):525−39,2016)、および腎性高血圧(Krishnan et al.,Br J Pharmacol,173(4):752−65,2016)を含む腎疾患、
・糖尿病性脳症(Zhai et al.,Molecules,23(3):522,2018)、糖尿病性網膜症(Zhang et al.,Cell Death Dis,8(7):e2941,2017)、および糖尿病性低アディポネクチン血症(Zhang et al.,Biochimica et Biophysica Acta(BBA)− Molecular Basis of Disease,1863(6):1556−1567,2017)を含む糖尿病関連状態、
・肺虚血再灌流障害(Xu et al.,Biochemical and Biophysical Research Communications,503(4):3031−3037,2018)、上皮間葉転換(EMT)(Li et al.,Experimental Cell Research,362(2):489−497,2018)、接触過敏症(水疱性類天疱瘡など(Fang et al.J Dermatol Sci,83(2):116−23,2016))、アトピー性皮膚炎(Niebuhr et al.Allergy,69(8):1058−67,2014)、化膿性汗腺炎(Alikhan et al.,J Am Acad Dermatol,60(4):539−61,2009)、尋常性ざ瘡(Qin et al.,J Invest Dermatol,134(2):381−88,2014)、およびサルコイドーシス(Jager et al.Am J Respir Crit Care Med、191:A5816、2015)を含む肺および皮膚における炎症反応(Primiano et al.J Immunol.197(6):2421−33)、
・関節内の炎症反応(Braddock et al.,Nat.Rev.Drug Disc.,3:1−10,2004)および変形性関節症(Jin et al.,PNAS,108(36):14867−14872,2011)、
・筋萎縮性側索硬化症(Gugliandolo et al.,Inflammation,41(1):93−103,2018)、
・嚢胞性線維症(Iannitti et al.Nat.Commun,7:10791,2016)、
・脳卒中(Walsh et al.,Nature Reviews,15:84−97,2014)、
・慢性腎臓疾患(Granata et al.,PLoS One,10(3):e0122272,2015)、
・シェーグレン症候群(Vakrakou et al.,Journal of Autoimmunity,91:23−33,2018)、
・鎌状赤血球症(Vogel et al.,Blood,130(Suppl 1):2234,2017)、および
・潰瘍性大腸炎およびクローン病(Braddock et al.,Nat Rev Drug Disc,3:1−10,2004;Neudecker et al.,J Exp Med,214(6):1737−52,2017;Wu et al.,Mediators Inflamm,2018:3048532,2018;およびLazaridis et al.,Dig Dis Sci,62(9):2348−56,2017)、ならびに敗血症(腸上皮破壊)(Zhang et al.,Dig Dis Sci,63(1):81−91,2018)を含む大腸炎および炎症性腸疾患。
(i)炎症性障害の結果として生じる炎症、例えば、自己炎症性疾患、非炎症性障害の症状として生じる炎症、感染の結果として生じる炎症、または外傷、傷害もしくは自己免疫に続発する炎症を含む炎症、
(ii)急性散在性脳脊髄炎、アジソン病、強直性脊椎炎、抗リン脂質抗体症候群(APS)、抗合成酵素抗体症候群、再生不良性貧血、自己免疫性副腎炎、自己免疫性肝炎、自己免疫性卵巣炎、自己免疫性多内分泌腺不全、自己免疫性甲状腺炎、セリアック病、クローン病、1型糖尿病(T1D)、グッドパスチャー症候群、グレーブス病、ギラン・バレー症候群(GBS)、橋本病、特発性血小板減少性紫斑病、川崎病、全身性エリテマトーデス(SLE)を含むエリテマトーデス、原発性進行性多発性硬化症(PPMS)、続発性進行性多発性硬化症(SPMS)および一次性進行型多発性硬化症(RRMS)を含む多発性硬化症(MS)、重症筋無力症、オプソクローヌス・ミオクローヌス症候群(OMS)、視神経炎、オード甲状腺炎、天疱瘡、悪性貧血、多発性関節炎、原発性胆汁性胆管炎、関節リウマチ(RA)、乾癬性関節炎、若年性特発性関節炎またはスチル病、難治性難治性痛風関節炎、ライター症候群、シェーグレン症候群、全身性硬化症、全身性結合組織障害、高安動脈炎、側頭動脈炎、温式自己免疫性溶血性貧血、ウェゲナー肉芽腫症、全身性脱毛、ベーチェット病、シャーガス病、自律神経障害、子宮内膜症、化膿性汗腺炎(HS)、間質性膀胱炎、神経筋緊張症、乾癬、サルコイドーシス、強皮症、潰瘍性大腸炎、シュニッツラー症候群、マクロファージ活性化症候群、ブラウ症候群、白斑、または外陰部痛などの自己免疫性疾患、
(iii)肺癌、膵臓癌、胃癌(gastric cancer)、骨髄異形成症候群、急性リンパ球性白血病(ALL)および急性骨髄性白血病(AML)を含む白血病、副腎癌、肛門癌、基底細胞および扁平上皮癌、胆管癌、膀胱癌、骨癌、脳および脊髄腫瘍、乳癌、子宮頸癌、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、慢性骨髄単球性白血病(CMML)、大腸癌、子宮内膜癌、食道癌、ユーイング肉腫ファミリー腫瘍、目の癌、胆嚢癌、消化管悪性腫瘍、消化管間質腫瘍(GIST)、妊娠性絨毛疾患、神経膠腫、ホジキンリンパ腫、カポジ肉腫、腎臓癌、喉頭および下咽頭癌、肝臓癌、肺悪性腫瘍、皮膚T細胞リンパ腫を含むリンパ腫、悪性中皮腫、黒色腫皮膚癌、メルケル細胞皮膚癌、多発性骨髄腫、鼻腔および副鼻腔癌、鼻咽頭癌、神経芽腫、非ホジキンリンパ腫、非小細胞肺癌、口腔および口咽頭癌、骨肉腫、卵巣癌、精巣癌、脳下垂体腫瘍、前立腺癌、網膜芽細胞種、横紋筋肉腫、唾液腺癌、皮膚癌、小細胞肺癌、小腸癌、軟組織肉腫、胃癌(stomach cancer)、精巣癌、胸腺癌、未分化甲状腺癌を含む甲状腺癌、子宮肉腫、膣癌、外陰部癌、ワルデンストレームマクログロブリン血症、およびウィルムス腫瘍を含む癌;
(iv)ウィルス感染症(例えば、インフルエンザウィルス、ヒト免疫不全ウィルス(HIV)、アルファウィルス(チクングニアおよびロスリバーウィルスなど)、フラビウィルス(デングウィルスおよびジカウィルスなど)、ヘルペスウィルス(エプスタイン・バー・ウィルス、サイトメガロウィルス、膵島帯状疱疹ウィルス、およびKSHVなど)、ポックスウィルス(ワクシニアウィルス(改変ワクシニアウィルスアンカラ)およびミクソーマウィルスなど)、アデノウィルス(アデノウィルス5など)、またはパピローマウィルス由来)、細菌感染症(例えば、スタフィロコッカス・アウレウス、ヘリコバクター・ピロリ、バシラス・アントラシス、ボルダテラ・ペルツシス、ブルクホルデリア・シュードマレイ、コリネバクテリウム・ジフテリア(Corynebacterium diptheriae)、クロストリジウム・テタニ、クロストリジウム・ボツリヌム、ストレプトコッカス・ニューモニエ、ストレプトコッカス・ピオゲネス、リステリア・モノサイトゲネス、ヘモフィリス・インフルエンザ、パステウレラ・ムルトシダ、シゲラ・ディセンテリエ、マイコバクテリウム・チュベルクローシス、マイコバクテリウム・レプラエ、マイコプラズマ・ニューモニエ、マイコプラズマ・ホミニス、ナイセリア・メニンギティディス、ナイセリア・ゴノレア、リケッチア・リケッチイ、レジオネラ・ニューモフィラ、クレブシエラ・ニューモニエ、シュードモナス・アエルギノサ、プロピオニバクテリウム・アクネス、トレポネーマ・パリダム、クラミジア・トラコマティス、ビブリオ・コレラ、サルモネラ・タイフィムリウム、サルモネラ・タイフィ、ボレリア・ブルグドルフェリまたはエルシニア・ペスティス由来)、真菌感染症(例えば、カンジダまたはアスペルギルス種由来)、原生動物感染症(例えば、プラスモジウム、バベシア、ギアルジア、エンタモエバ、リーシュマニア症またはトリパノソーム由来)、蠕虫感染症(例えば、住血吸虫、回虫、条虫または吸虫)およびプリオン感染症を含む感染症;
(v)パーキンソン病、アルツハイマー病、認知症、運動ニューロン疾患、ハンチントン病、脳マラリア、肺炎球菌性髄膜炎による脳傷害、頭蓋内動脈瘤、脳内出血、敗血症関連脳症、術後認知機能障害、早期脳損傷、外傷性脳傷害、および筋萎縮性側索硬化症などの中枢神経系疾患、
(vi)2型糖尿病(T2D)、アテローム性硬化症、肥満、痛風および偽痛風などの代謝疾患、
(vii)高血圧、虚血、MI後虚血性再灌流傷害を含む再灌流傷害、虚血発作を含む発作、一過性虚血発作、再発性心筋梗塞を含む心筋梗塞、充血性心不全および駆出率が保持される心不全を含む心不全、心肥大および線維症、塞栓症、腹部大動脈瘤を含む動脈瘤、およびドレスラー症候群を含む心膜炎などの心血管疾患、
(viii)慢性閉塞性肺疾患(COPD)、アレルギー性、好酸球性喘息、およびステロイド耐性喘息などの喘息、石綿肺、珪肺症、ナノ粒子誘導炎症、嚢胞性線維症および特発性肺線維症を含む呼吸器疾患、
(ix)進行性線維症ステージF3およびF4を含む非アルコール性脂肪肝臓疾患(NAFLD)および非アルコール性脂肪性肝炎(NASH)、アルコール性脂肪肝臓疾患(AFLD)、アルコール性脂肪性肝炎(ASH)、肝臓の虚血再灌流障害、劇症肝炎、肝線維症、ならびに肝不全を含む肝臓疾患、
(x)慢性腎臓疾患、シュウ酸塩腎症、腎石灰化症、糸球体腎炎、糖尿病性腎症、慢性結晶腎症を含む腎線維症、および腎性高血圧を含む腎臓疾患、
(xi)目の上皮の疾患、加齢黄斑変性(AMD)(乾燥型および湿潤型)、ブドウ膜炎、角膜感染、糖尿病性腎症、視神経損傷、ドライアイ、および緑内障を含む眼科疾患、
(xii)接触皮膚炎およびアトピー性皮膚炎などの皮膚炎、接触過敏症、日焼け、皮膚病変、化膿性汗腺炎(HS)、他の嚢胞誘発性皮膚疾患、および集簇性ざ瘡を含む皮膚疾患、
(xiii)リンパ管炎およびキャッスルマン病などのリンパ病、
(xiv)うつ病および精神的ストレスなどの精神障害、
(xv)移植片対宿主病、
(xvi)機械的アロディニアを含むアロディニア、
(xvii)糖尿病性脳症、糖尿病性網膜症、および糖尿病性低アディポネクチン血症、および
(xviii)個体がNLRP3の生殖系または体細胞系非サイレント変異を有すると決定された任意の疾患。
(i)癌、
(ii)感染症、
(iii)中枢神経系疾患、
(iv)心血管疾患、
(v)肝臓疾患、
(vi)眼疾患、または
(vii)皮膚疾患。
(i)癌、
(ii)感染症、
(iii)中枢神経系疾患、または
(iv)心血管疾患。
(i)集簇性ざ瘡、
(ii)アトピー性皮膚炎、
(iii)アルツハイマー病、
(iv)筋萎縮性側索硬化症、
(v)加齢黄斑変性(AMD)、
(vi)組織非形成性甲状腺癌、
(vii)クリオピリン関連周期性症候群(CAPS)、
(viii)接触皮膚炎、
(ix)嚢胞性線維症、
(x)うっ血性心不全、
(xi)慢性腎臓疾患、
(xii)クローン病、
(xiii)家族性寒冷自己炎症性症候群(FCAS)、
(xiv)ハンチントン病、
(xv)心不全、
(xvi)駆出率が保持される心不全、
(xvii)虚血性再灌流傷害、
(xviii)若年性特発性関節炎、
(xix)心筋梗塞、
(xx)マクロファージ活性化症候群、
(xxi)骨髄異形成症候群、
(xxii)多発性骨髄腫、
(xxiii)運動ニューロン病、
(xxiv)多発性硬化症、
(xxv)マックル・ウェルズ症候群、
(xxvi)非アルコール性脂肪性肝炎(NASH)、
(xxvii)新生児期発症多臓器系炎症性疾患(NOMID)、
(xxviii)パーキンソン病、
(xxix)鎌状赤血球症、
(xxx)全身型若年性特発性関節炎、
(xxxi)全身性エリテマトーデス、
(xxxii)外傷性脳損傷、
(xxxiii)一過性虚血発作、
(xxxiv)潰瘍性大腸炎、または
(xxxv)バロシン含有タンパク質疾患。
(i)接触過敏症、水疱性類天疱瘡、日焼け、乾癬、アトピー性皮膚炎、接触皮膚炎、アレルギー性接触皮膚炎、脂漏性皮膚炎、扁平苔癬、強皮症、天疱瘡、表皮水疱症、じんましん、紅斑、または脱毛などの皮膚病、
(ii)骨関節炎、全身若年性特発性関節炎、成人発症スチル病、再発性多発性軟骨炎、関節リウマチ、若年性慢性関節炎、痛風、または血清陰性脊椎関節症(例えば、強直性脊椎炎、乾癬性関節炎またはライター病)などの関節病、
(iii)多発性菌炎または重症筋無力症などの筋肉病、
(iv)炎症性腸疾患(クローン病および潰瘍性大腸炎を含む)、大腸炎、胃潰瘍、セリアック病、直腸炎、膵臓炎、好酸球性胃腸炎、マストサイトーシス、抗リン脂質症候群、または腸から離れた作用を有し得る食物関連アレルギー(例えば、偏頭痛、鼻炎または湿疹)などの消化管病;
(v)慢性閉塞性肺疾患(COPD)、喘息(好酸球性、気管支、アレルギー性、内因性、外因性または塵埃喘息、特に慢性または常習的な喘息、例えば遅発型喘息および気道過敏症)、気管支炎、鼻炎(急性鼻炎、アレルギー性鼻炎、アトピー性鼻炎、慢性鼻炎、乾酪性鼻炎、肥厚性鼻炎、化膿性鼻炎(rhinitis pumlenta)、乾燥性鼻炎、薬物性鼻炎、膜性鼻炎、季節性鼻炎、例えば、枯れ草熱、および血管運動性鼻炎を含む)、副鼻腔炎、特発性肺線維症(IPF)、サルコイドーシス、農夫肺、珪肺、石綿症、成人呼吸窮迫症候群、過敏性肺炎、または特発性間質性肺炎などの呼吸器系病、
(vi)アテローム性硬化症、ベーチェット病、脈管炎、またはウェゲナー肉芽腫症などの血管病、
(vii)全身性エリテマトーデス、シェーグレン症候群、全身性硬化症、橋本甲状腺炎、I型糖尿病、特発性血小板減少性紫斑病、またはグレーブス病などの自己免疫病、
(viii)ブドウ膜炎、アレルギー性結膜炎、または春季カタルなどの眼疾患、
(ix)多発性硬化症または脳脊髄炎などの神経病、
(x)後天性免疫不全症(AIDS)、急性もしくは慢性細菌感染、急性もしくは慢性寄生虫感染、急性もしくは慢性ウィルス感染、急性もしくは慢性真菌感染、髄膜炎、肝炎(A、BもしくはC型、または他のウィルス性肝炎)、腹膜炎、肺炎、喉頭蓋炎、マラリア、デング出血熱、リーシュマニア症、連鎖球菌筋炎、マイコバクテリウム・チュベルクローシス、マイコバクテリウム・アビウム・イントラセルラーレ、ニューモシスチス・カリニ肺炎、精巣炎/精巣上体炎、レジオネラ、ライム病、インフルエンザA型、エプスタイン・バー・ウィルス感染症、ウィルス性脳炎/無菌性髄膜炎、または骨盤内炎症性疾患などの感染または感染関連病、
(xi)メサンギウム増殖性糸球体腎炎、ネフローゼ症候群、腎炎、糸球体腎炎、急性腎不全、尿毒症、腎炎症候群、慢性結晶腎症を含む腎線維症、または腎性高血圧などの腎臓病、
(xii)キャッスルマン病などのリンパ病、
(xiii)高IgE症候群、ライ腫性ハンセン病、家族性血球貪食性リンパ組織球症、または移植片対宿主病などの免疫系の状態または免疫系に関与する状態、
(xiv)慢性活動性肝炎、非アルコール性脂肪性肝炎(NASH)、アルコール誘導性肝炎、非アルコール性脂肪性肝臓疾患(NAFLD)、アルコール性脂肪性肝臓疾患(AFLD)、アルコール性脂肪性肝炎(ASH)、原発性胆汁性肝硬変、劇症肝炎、肝線維症、または肝不全などの肝臓病、
(xv)上記癌を含む癌、
(xvi)熱傷、創傷、外傷、出血または脳卒中、
(xvii)放射線曝露、
(xviii)肥満症、および/または
(xix)炎症性痛覚過敏などの疼痛。
(i)化学療法剤、
(ii)抗体、
(iii)アルキル化剤、
(iv)代謝拮抗薬、
(v)抗血管新生薬、
(vi)植物アルカロイドおよび/もしくはテルペノイド、
(vii)トポイソメラーゼ阻害剤、
(viii)mTOR阻害剤、
(ix)スチルベノイド、
(x)STINGアゴニスト、
(xi)癌ワクチン、
(xii)免疫調節剤、
(xiii)抗生物質、
(xiv)抗真菌剤、
(xv)抗寄生虫剤、および/または
(xvi)その他の活性薬剤。
特に断りのない限り、全ての溶媒、試薬および化合物は購入したものであり、さらに精製せずに使用した。
略語
2−MeTHF:2−メチルテトラヒドロフラン
Ac2O:無水酢酸
AcOH:酢酸
aq:水性
B2Pin2:ビス(ピナコラト)ジボロン
Boc:tert−ブチルオキシカルボニル
br:幅広線
Cbz:カルボキシベンジル
CDI:1,1−カルボニル−ジイミダゾール
conc:濃縮された
d:二重線
DABCO:1,4−ジアザビシクロ[2.2.2]オクタン
DCE:1,2−ジクロロエタン(二塩化エチレンとも呼ばれる)
DCM:ジクロロメタン
DIPEA:N,N−ジイソプロピルエチルアミン(ヒューニッヒ塩基とも呼ばれる)
DMA:ジメチルアセトアミド
DMAP:4−ジメチルアミノピリジン(N,N−ジメチルピリジン−4−アミンとも呼ばれる)
DME:ジメトキシエタン
DMF:N,N−ジメチルホルムアミド
DMSO:ジメチルスルホキシド
EDC:1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド
eqまたはequiv:当量
(ES+):エレクトロスプレーイオン化、ポジティブモード
Et:エチル
EtOAc:酢酸エチル
EtOH:エタノール
h:時間
HATU:1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム 3−オキシドヘキサフルオロホスフェート
HPLC:高速液体クロマトグラフィー
LC:液体クロマトグラフィー
m:多重線
m−CPBA:3−クロロペルオキシ安息香酸
Me:メチル
MeCN:アセトニトリル
MeOH:メタノール
(M+H)+:プロトン化分子イオン
MHz:メガヘルツ
min:分(複数可)
MS:質量分析
Ms:メシル(メタンスルホニルとも呼ばれる)
MsCl:メシルクロリド(メタン塩化スルホニルとも呼ばれる)
MTBE:メチルtert−ブチルエーテル(tert−ブチルメチルエーテルとも呼ばれる)
m/z:質量電荷比
NaOtBu:ナトリウムtert−ブトキシド
NBS:1−ブロモピロリジン−2,5−ジオン(N−ブロモスクシンイミドとも呼ばれる)
NCS:1−クロロピロリジン−2,5−ジオン(N−クロロスクシンイミドとも呼ばれる)
NMP:N−メチルピロリジン
NMR:核磁気共鳴(分光法)
Pd2(dba)3:トリス(ジベンジリデンアセトン)ジパラジウム(0)
Pd(dppf)Cl2:[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)
PE:石油エーテル
Ph:フェニル
PMB:p−メトキシベンジル(4−メトキシベンジルとも呼ばれる)
prep−HPLC:分取高速液体クロマトグラフィー
prep−TLC:分取薄層クロマトグラフィー
PTSA:p−トルエンスルホン酸
q:四重線
RP:逆相
RT:室温
s:一重線
sat:飽和
SCX:固体支持型陽イオン交換(樹脂)
Sept:七重線
t:三重線
T3P:プロピルホスホン酸無水物
TBME:tert−ブチルメチルエーテル(メチルtert−ブチルエーテルとも呼ばれる)
TEA:トリエチルアミン
TFA:2,2,2−トリフルオロ酢酸
THF:テトラヒドロフラン
TLC:薄層クロマトグラフィー
wt%:重量パーセントまたは重量%
XPhos:2−ジシクロヘキシルホスフィノ−2’,4’,6’−トリイソプロピルビフェニル
核磁気共鳴
NMRスペクトルは、300、400または500MHzで記録した。スペクトルは、特に断りのない限り、298Kで測定し、溶媒共鳴に対して比較した。化学シフトは、パート・パー・ミリオンで報告される。スペクトルは、以下の装置の1種を用いて記録した:
・5mmBBO液体プローブを備えた400MHzでのBruker Avance III分光計、
・TopSpinプログラム制御下でICON−NMRを用いるBruker 400MHz分光計、
・Bruker 5mm SmartProb(商標)を備えた500MHzでのBruker Avance III HD分光計、
・Oxford instrumentsの7.05テスラ磁石、間接検出プローブおよびPFGモジュールを含む直結駆動コンソールを備えたAgilent VNMRS 300測定器、または
・Oxford instrumentsの7.05テスラ磁石、4核種自動切り替え可能プローブおよびMercury plusコンソールを備えたAgilent VNMRS 300測定器。
LC−MS法:SHIMADZU LCMS−2020、Agilent 1200 LC/G1956A MSDおよびAgilent 1200 G6110A、Agilent 1200 LC&Agilent 6110 MSDを使用。移動相:A:水中の0.025%NH3・H2O(v/v);B:アセトニトリル。カラム:Kinetex EVO C18 2.1x30mm、5μm。
方法1aおよび1b:40℃でのWaters Xselect CSH C18 XPカラム(4.6x30mm、2.5μm);流速2.5〜4.5mL/分、254nmでのUV検出を用い4分間にわたり0.1%v/vギ酸(方法1a)または水中の10mM NH4HCO3(方法1b)のいずれかを含有するH2O−MeCN勾配で溶出する。勾配の情報:0−3.00分、95%水−5%アセトニトリルから5%水−95%アセトニトリルまでの勾配形成;3.00−3.01分、5%水−95%アセトニトリルで保持、流速を4.5mL/分に上昇させ;3.01−3.50分、5%水−95%アセトニトリルで保持;3.50−3.60分、95%水−5%アセトニトリルに戻し、流速を3.50mL/分に低減し;3.60−3.90分、95%水−5%アセトニトリルで保持;3.90−4.00分、95%水−5%アセトニトリルで保持、流速を2.5mL/分に低減する。
方法1c:35℃でWaters XBidge BEH C18 XPカラム(2.1x50mm、2.5μm)を用いるUV検出器およびHP6130 MSD質量検出器を備えたAgilent 1290シリーズ;流速0.6mL/分;移動相A:酢酸アンモニウム(10mM);水/MeOH/アセトニトリル(900:60:40);移動相B:酢酸アンモニウム(10mM);水/MeOH/アセトニトリル(100:540:360);215および238nmでUV検出を用い4分間にわたる。勾配の情報:0−0.5分、80%A−20%Bで保持;0.5−2.0分、80%A−20%Bから100%Bまでの勾配を形成。
方法2aおよび2b:40℃でのWaters BEH C18(2.1x30mm、1.7μm);流速0.77mL/分、254nmでのUV検出を用い3分間にわたり0.1%v/vギ酸(方法2a)または水中の10mM NH4HCO3(方法2b)のいずれかを含有するH2O−MeCN勾配で溶出する。勾配の情報:0−0.11分、95%水−5%アセトニトリルで保持、流速0.77mL/分;0.11−2.15分、95%−5%アセトニトリルから5%水−95%アセトニトリルまでの勾配形成;2.15−2.49分、5%水−95%アセトニトリルで保持、流速0.77mL/分;2.49−2.56分、95%水−5%アセトニトリルに戻す;2.56−3.00分、95%水−5%アセトニトリルで保持、流速を0.77mL/分に低減。
方法1(酸性調製):Waters X−Select CSHカラムC18、5μm(19x50mm)、流速28mL/分、254nmのUV検出を用い0.1%v/vギ酸含有H2O−MeCN勾配で6.5分間にわたり溶出する。勾配の情報:0.0−0.2分、20%MeCN;0.2−5.5分、20%MeCNから40%MeCNまでの勾配形成;5.5−5.6分、40%MeCNから95%MeCNまでの勾配を形成;5.6−6.5分、95%MeCNで保持。
方法2(塩基性調製):Waters X−Bridge PrepカラムC18、5μm(19x50mm)、流速28mL/分、254nmのUV検出を用い10mMのNH4HCO3−MeCN勾配で6.5分間にわたり溶出する。勾配の情報:0.0−0.2分、10%MeCN;0.2−5.5分、10%MeCNから40%MeCNまでの勾配形成;5.5−5.6分、40%MeCNから95%MeCNまでの勾配を形成;5.6−6.5分、95%MeCNで保持。
方法3:Phenomenex Geminiカラム、10μm(150x25mm)、流速25mL/分、220および254nmのUV検出を使用し9分間にわたりpH10で0.04%NH3を含有する水−アセトニトリル勾配で溶出する。勾配の情報:0−9分、8%アセトニトリルから35%アセトニトリルまでの勾配形成;9−9.2分、35%アセトニトリルから100%アセトニトリルまでの勾配形成;9.2−15.2分、100%アセトニトリルで保持。
方法4:Revelis C18逆相12gカートリッジ[炭素含有量18%;表面積568m2/g;孔径65オングストローム;pH(5%スラリー)5.1;平均粒度40μm]、流速=30mL/分、215、235、254および280nmでのUV検出を使用し35分間にわたり水−メタノール勾配で溶出する。勾配の情報:0−5分、0%メタノールで保持;5−30分、0%メタノールから70%メタノールまで勾配形成;30−30.1分、70%から100%メタノールまで勾配形成;30.1−35分、100%メタノールで保持。
中間体A1:7−フルオロ−5−(2−メトキシピリジン−4−イル)−2,3−ジヒドロ−1H−インデン−4−アミン
ステップA:N−(7−フルオロ−2,3−ジヒドロ−1H−インデン−4−イル)ピバルアミド
1H NMR(CDCl3)δ7.68(dd,J=8.8,4.5Hz,1H),7.14(s,1H),6.87(t,J=8.6Hz,1H),3.01(t,J=7.5Hz,2H),2.85(t,J=7.5Hz,2H),2.18(p,J=7.5Hz,2H),1.34(s,9H).
LCMS m/z 236.3(M+H)+(ES+);234.2(M−H)−(ES−).
1H NMR(CDCl3)δ6.71(dd,J=9.0,8.2Hz,1H),6.46(dd,J=8.5,3.9Hz,1H),3.45(s,2H),2.96(t,J=7.6Hz,2H),2.77(t,J=7.5Hz,2H),2.16(p,J=7.6Hz,2H).
LCMS m/z 152.3(M+H)+(ES+).
1H NMR(CDCl3)δ7.08(d,J=7.8Hz,1H),3.06(t,J=7.5Hz,2H),2.95(t,J=7.5Hz,2H),2.20(p,J=7.6Hz,2H)、NH2は観察されなかった。
1H NMR(CDCl3)δ8.27(d,J=5.4Hz,1H),7.06(d,J=5.3Hz,1H),6.95(s,1H),6.73(d,J=9.0Hz,1H),4.03(s,3H),3.00(t,J=7.5Hz,2H),2.85(t,J=7.4Hz,2H),2.23(p,J=7.5Hz,2H)、NH2は観察されなかった。
LCMS m/z 259.3(M+H)+(ES+).
ステップA:N−(5−ブロモ−2,3−ジヒドロ−1H−インデン−4−イル)ピバルアミド
LCMS m/z 296.3(M+H)+(ES+).
1H NMR(CDCl3)δ7.23(d,J=7.9Hz,1H),6.57(d,J=8.0Hz,1H),3.92(s,2H),2.89(t,J=7.6Hz,2H),2.77(t,J=7.4Hz,2H),2.15(p,J=7.5Hz,2H).
1H NMR(CDCl3)δ8.26(d,J=5.4 Hz,1H),7.11(d,J=5.0 Hz,1H),7.01(d,J=7.7 Hz,1H),6.97(s,1H),6.80(d,J=7.6 Hz,1H),4.06(s,3H),2.98(t,J=7.6 Hz,2H),2.80(t,J=7.4 Hz,2H),2.19(p,J=7.5 Hz,2H)、NH2は観察されなかった。
LCMS m/z 241.3(M+H)+(ES+).
1H NMR(CDCl3)δ6.8(s,1H),2.89(m,8H)および2.09(m,4H).
1H NMR(CDCl3)δ7.95(s,1H),7.10(s,1H),2.93(t,J=7.5Hz,4H),2.86(t,4H),2.1 1(m,4H).
ステップA:4−ニトロ−1,2,3,5−テトラヒドロ−s−インダセン
1H NMR(CDCl3)δ7.50(s,1H),6.85(m,1H),6.66(m,1H),3.83(s,2H),3.38(t,2H),3.02(t,2H),2.18(m,2H).
1H NMR(CDCl3)δ6.94(s,1H),6.82(m,1H),6.50(m,1H),3.32(d,2H),2.92(dd,4H),2.17(q,2H).
ステップA:N−(6−ブロモ−4−ニトロ−2,3−ジヒドロ−1H−インデン−5−イル)アセトアミド
1H NMR(DMSO−d6)δ9.99(s,1H),7.85(s,1H),3.01−2.88(m,4H),2.07(p,J=7.5Hz,2H),2.00(s,3H).
LCMS m/z 299.0/301.0(M+H)+(ES+).
1H NMR(DMSO−d6)δ9.65(s,1H),7.41(s,1H),2.98−2.87(m,4H),2.20(s,3H),2.07−2.03(m,2H),1.99(s,3H).
LCMS m/z 235.2(M+H)+(ES+).
1H NMR(DMSO−d6)δ7.21(s,1H),6.61(s,2H),3.16(t,J=7.5 Hz,2H),2.76(t,J=7.6 Hz,2H),2.16(s,3H),2.00−1.94(m,2H).
LCMS m/z 193.4(M+H)+(ES+).
1H NMR(DMSO−d6)δ7.50(s,1H),2.94−2.86(m,4H),2.41(s,3H),2.09(p,J=7.6Hz,2H).
LCMS m/z 279.2(M+Na)+(ES+).
1H NMR(DMSO−d6)δ8.05(d,J=5.5Hz,1H),7.19(dd,J=5.5,1.7Hz,1H),7.08(d,J=1.6Hz,1H),5.12−4.86(m,1H),2.71−2.56(m,2H),2.21−2.08(m,5H),1.99−1.86(m,2H),1.76−1.59(m,2H).
LCMS m/z 271.0/273.0(M+H)+(ES+).
1H NMR(DMSO−d6)δ8.20(d,J=5.2Hz,1H),7.49(s,1H),6.81(dd,J=5.2,1.5Hz,1H),6.60(s,1H),5.07−4.85(m,1H),3.03−2.89(m,4H),2.74−2.57(m,2H),2.25−2.03(m,9H),2.04−1.95(m,3H),1.75−1.59(m,2H).
LCMS m/z 368.3(M+H)+(ES+).
1H NMR(DMSO−d6)δ8.21(d,J=5.1Hz,1H),6.73(dd,J=5.2,1.4Hz,1H),6.55−6.47(m,1H),6.45(s,1H),5.01(tt,J=8.8,4.2Hz,1H),4.14(s,2H),2.78(t,J=7.5Hz,2H),2.74−2.58(m,4H),2.27−2.09(m,5H),2.06−1.93(m,4H),1.88(s,3H),1.76−1.63(m,2H).
LCMS m/z 338.2(M+H)+(ES+).
ステップA:2−メトキシ−4−(6−メチル−4−ニトロ−2,3−ジヒドロ−1H−インデン−5−イル)ピリジン
1H NMR(DMSO−d6)δ8.24(d,J=5.2Hz,1H),7.51(s,1H),6.86(dd,J=5.3,1.4Hz,1H),6.68−6.66(m,1H),3.89(s,3H),3.04−2.90(m,4H),2.17−2.04(m,5H).
LCMS m/z 285.0(M+H)+(ES+).
1H NMR(DMSO−d6)δ8.24(d,J=5.2Hz,1H),6.77(dd,J=5.2,1.5Hz,1H),6.58(s,1H),6.45(s,1H),4.16(s,2H),3.89(s,3H),2.78(t,J=7.5Hz,2H),2.64(t,J=7.4Hz,2H),1.99(p,J=7.4Hz,2H),1.88(s,3H).
LCMS m/z 255.1(M+H)+(ES+).
ステップA:2−メチル−1−((2−(トリメチルシリル)エトキシ)メチル)−1H−イミダゾール
1H NMR(400MHz,CDCl3)δ6.90(s,2H),5.18(s,2H),3.47(t,2H),2.43(s,3H),0.89(t,2H)および0.01(s,9H).
LCMS:m/z 213.0(M+H)+(ES+).
1H NMR(400MHz,CDCl3)δ6.88(s,1H),5.25(s,2H),3.55(t,2H),2.42(s,3H),0.91(t,2H)および0.02(s,9H).
LCMS:m/z 292.9(M+H)+(ES+).
1H NMR(400MHz,CDCl3)δ6.88(s,1H),5.23(s,2H),5.20(s,1H),5.14(s,1H),3.52(t,2H),2.48(s,3H),2.08(s,3H),0.93(t,2H)および0.01(s,9H).
LCMS:m/z 253.0(M+H)+(ES+).
1H NMR(400MHz,CDCl3)δ6.66(s,1H),5.15(s,2H),3.49(t,2H),2.95−2.84(m,1H),2.43(s,3H),1.26(d,6H),0.91(t,2H)および0.02(s,9H).
LCMS:m/z 255.2(M+H)+(ES+).
1H NMR(400MHz,CDCl3)δ6.71(s,1H),2.99−2.93(m,1H),2.53(s,3H)および1.27(d,6H).
LCMS:m/z 125.3(M+H)+(ES+).
1H NMR(400MHz,CDCl3)δ8.73(dd,2H),7.27(dd,2H),6.77(s,1H),2.93−2.86(m,1H),2.48(s,3H)および1.29(d,6H).
LCMS:m/z 202.0(M+H)+(ES+).
1H NMR(400MHz,CDCl3)δ8.83(d,2H),7.22(d,2H),3.75−3.69(m,1H),2.25(s,3H)および1.36(d,6H).
LCMS:m/z 247.1(M+H)+(ES+).
1H NMR(400MHz,DMSO−d6)δ15.02(s,1H),8.99(d,2H),7.90(d,2H),3.25−3.15(m,1H),2.45(s,3H)および1.27(d,6H).
LCMS:m/z 217.1(M+H)+(ES+).
1H NMR(CDCl3)δ2.59(m,1H),2.39(s,3H),2.05(m,1H),2.19(s,6H),2.01(m,1H),1.40(s,1H),0.95(d,3H).
LCMS:m/z 117(M+H)+(ES+).
ステップA:tert−ブチル((1−イソプロピルアゼチジン−2−イル)メチル)カルバメート
1H NMR(CDCl3)δ5.75(bs,1H),3.60(bs,2H),3.48−3.34(m,1H),3.18(d,1H),2.98(q,1H),2.71−2.54(m,1H),2.06−1.92(m,2H),1.44(s,9H),1.02(dd,6H).
1H NMR(CD3OD)δ4.83−4.68(m,1H),4.20−3.99(m,2H),3.64−3.45(m,3H),2.73−2.38(m,2H),1.33(dd,6H).
ステップA:tert−ブチル 3−メチル−3,8−ジアザビシクロ[3.2.1]オクタン−8−カルボキシレート
1H NMR(CDCl3)δ4.14(bs,2H),2.67(d,2H),2.35−2.13(m,5H),1.91−1.78(m,4H),1.46(s,9H).
1H NMR(CD3OD)δ4.34(s,2H),3.73(d,2H),3.55(d,2H),2.94(s,3H),2.37−2.29(m,4H).
ステップA:tert−ブチル 3−エチル−3,8−ジアザビシクロ[3.2.1]オクタン−8−カルボキシレート
1H NMR(CDCl3)δ3.70(dd,2H),3.35(d,2H),3.20(dd,2H),2.55(q,2H),1.98−1.84(m,2H),1.76−1.56(m,2H),1.44(s,9H),1.15(t,3H).
1H NMR(CD3OD)δ4.36(d,2H),3.89−3.74(m,2H),3.73−3.63(m,2H),3.62−3.51(m,2H),2.53(d,1H),2.47−2.38(m,1H),2.36−2.19(m,2H),1.40(t,3H).
ステップA:tert−ブチル 3−イソプロピル−3,8−ジアザビシクロ[3.2.1]オクタン−8−カルボキシレート
1H NMR(CDCl3)δ4.14(d,2H),2.60(dd,3H),2.42(s,2H),1.90−1.70(m,4H),1.45(d,9H),0.98(d,6H).
1H NMR(CD3OD)δ4.35(d,2H),3.73(d,2H),3.61−3.51(m,3H),2.47−2.20(m,4H),1.44(d,J=6.6Hz,6H).
1H NMR(CD3OD)δ4.33(s,2H),3.86(d,2H),3.59(d,2H),3.21(q,2H),2.56−2.44(m,2H),2.35−2.22(m,2H),1.43(t,3H).
ステップA:tert−ブチル 8−イソプロピル−3,8−ジアザビシクロ[3.2.1]オクタン−3−カルボキシレート
1H NMR(CDCl3)δ3.81−3.55(m,4H),3.34(dd,2H),2.80(q,1H),1.98(m,2H),1.81−1.66(m,2H),1.45(s,9H),1.25(d,6H).
1H NMR(CD3OD)δ4.51(bs,2H),3.89(d,2H),3.57(d,2H),3.43−3.32(m,1H),2.55−2.38(m,2H),2.27(d,2H),1.48(d,6H).
ステップA:tert−ブチル 8−イソプロピル−3,8−ジアザビシクロ[3.2.1]オクタン−3−カルボキシレート
テトラヒドロフラン(5mL)およびメタノール(5mL)中のtert−ブチル(1R’、5S’)−3,8−ジアザビシクロ[3.2.1]オクタン−3−カルボキシレート(100mg、471μmol)および(1−エトキシシクロプロポキシ)トリメチルシラン(189μL、942μmol)の溶液に、酢酸(62.2mg,59.3μL、1.04mmol)、続いて、シアノ水素化ホウ素ナトリウム(44.4mg、707μmol)を加えた。反応混合物を50℃で撹拌した。一晩撹拌後、さらに、(1−エトキシシクロプロポキシ)トリメチルシラン(189μL、942μmol)、酢酸(62.2mg,59.3μL、1.04mmol)、およびシアノ水素化ホウ素ナトリウム(44.4mg、707μmol)を加えた。50℃で3日間撹拌後、反応混合物を減圧下で濃縮した。粗生成物をAgilent hydromatrix(高純度、不活性珪藻土吸着剤)上にコートし、ジクロロメタンおよびメタノール中のアンモニア(3.5M)の混合物を溶出液として使用する順相フラッシュクロマトグラフィーに供して、標記化合物(118mg、定量的収率)を得た。
1H NMR(CDCl3)δ3.87(td,1H),3.82−3.70(m,2H),3.68−3.56(m,1H),3.21(dd,2H),2.02−1.90(m,1H),1.83−1.63(m,2H),1.44(s,9H),1.33−1.16(m,2H),0.78(s,2H),0.54(d,2H).
1H NMR(CD3OD)δ4.38(d,2H),3.94(d,2H),3.55(d,2H),2.99(s,1H),2.64(d,2H),2.40−2.24(m,2H),1.35(d,2H),1.01(d,2H).
ステップA:tert−ブチル((1R,3s,5S)−8−メチル−8−アザビシクロ[3.2.1]オクタン−3−イル)カルバメート
1H NMR(CDCl3)δ4.46(s,1H),3.76(s,1H),3.20(s,2H),2.30(s,3H),2.17−1.90(m,2H),1.88−1.50(m,6H),1.38(s,9H).
1H NMR(CD3OD)δ4.06−3.98(m,2H),3.80−3.56(m,1H),2.81(s,3H),2.48−2.33(m,2H),2.31−2.17(m,5H),2.16−1.96(m,3H).
ステップA:tert−ブチル((1R,3r,5S)−8−イソプロピル−8−アザビシクロ[3.2.1]オクタン−3−イル)カルバメート
1H NMR(CDCl3)δ4.12−3.93(m,2H),3.90−3.70(m,1H),3.23−3.03(m,1H),2.60−2.38(m,2H),2.35−2.20(m,2H),2.14−2.02(m,3H),1.92−1.76(m,2H),1.49−1.34(m,15H).
1H NMR(CD3OD)δ4.31(s,1H),4.16(s,1H),3.83−3.60(m,2H),2.80−2.56(m,3H),2.48−2.33(m,2H),2.27−2.07(m,4H),2.03−1.90(m,1H),1.43−1.40(m,6H).
ステップA:tert−ブチル((1R,3s,5S)−3−(ジエチルアミノ)−8−アザビシクロ[3.2.1]オクタン−8−カルボキシレート
1H NMR(CDCl3)δ4.39−3.98(m,2H),3.19−2.98(m,1H),2.62−2.32(m,4H),1.95−1.80(m,2H),1.69−1.48(m,6H),1.41(s,9H),1.07−0.91(m,6H).
1H NMR(CD3OD)δ4.03−3.81(m,2H),3.62−3.39(m,1H),3.15−2.78(m,5H),2.02−1.90(m,4H),1.89−1.72(m,4H),1.09−0.98(m,6H).
1H NMR(CDCl3)δ4.38−4.02(m,2H),2.63−2.45(m,1H),2.16(s,6H),1.93−1.79(m,2H),1.73−1.45(m,6H),1.40(s,9H).
1H NMR(CDCl3)δ3.47(s,2H),3.13−3.01(m,2H),2.68−2.55(m,2H),2.43−2.29(m,1H),1.18−1.03(m,6H).
ステップA:tert−ブチル((1R,3r,5S)−3−(ピロリジン−1−イル)−8−アザビシクロ[3.2.1]オクタン−8−カルボキシレート
tert−ブチル((1R,3r,5S)−3−アミノ−8−アザビシクロ[3.2.1]オクタン−8−カルボキシレート(0.20g、0.88mmol)を無水アセトニトリル(12mL)に溶解した。その後、ヨウ化カリウム(33mg、0.20mmol)、炭酸カリウム(0.14g、1.0mmol)および1,4−ジブロモブタン(0.19g、0.10mL、0.86mmol)を連続的に加えた。反応混合物を6時間加熱環流した。反応混合物を室温に冷却し、溶媒を減圧下で留去した。シリカベースカラムクロマトグラフィー(DCM:メタノール中7NのNH3;9:1)で精製して、標記化合物(0.145g、58%)を無色油として得た。
1H NMR(CDCl3)δ4.23−3.95(m,2H),2.60−2.39(m,4H),2.33−2.15(m,1H),2.15−1.79(m,6H),1.78−1.61(m,6H),1.41(s,9H).
1H NMR(CD3OD)δ4.22−4.05(m,2H),3.85−3.69(m,3H),3.25−3.07(m,2H),2.93−2.66(m,2H),2.37−1.92(m,11H).
ステップA:tert−ブチル((1R,3r,5S)−3−(ジエチルアミノ)−8−アザビシクロ[3.2.1]オクタン−8−カルボキシレート
1H NMR(CDCl3)δ4.24−4.00(m,2H),2.68−2.42(m,5H),2.31−2.08(m,2H),1.97−1.83(m,2H),1.71−1.57(m,2H),1.40(s,9H),1.40−1.19(m,2H),1.04−0.85(m,6H).
1H NMR(CD3OD)δ4.25−4.11(m,2H),3.40−3.17(m,6H),2.88−2.73(m,2H),2.30−2.15(m,2H),2.12−2.01(m,2H),1.99−1.86(m,2H),1.43−1.31(m,6H).
ステップA:tert−ブチル((1R,3r,5S)−3−(ジメチルアミノ)−8−アザビシクロ[3.2.1]オクタン−8−カルボキシレート
1H NMR(CDCl3)δ4.28−4.01(m,2H),2.21(s,6H),2.17−1.99(m,3H),1.94−1.75(m,4H),1.72−1.51(m,2H),1.44(s,9H).
1H NMR(CD3OD)δ4.24−4.07(m,2H),3.64−3.50(m,1H),2.94(s,6H),2.83−2.66(m,2H),2.33−2.14(m,3H),2.13−1.97(m,4H).
ステップA:tert−ブチル((1R,3s,5S)−8−イソプロピル−8−アザビシクロ[3.2.1]オクタン−3−イル)カルバメート
1H NMR(CDCl3)δ5.21−4.89(m,1H),4.24−3.79(m,3H),3.21−2.82(m,1H),2.34−2.03(m,4H),2.01−1.78(m,4H),1.50−1.30(m,15H).
1H NMR(CD3OD)δ4.51−4.32(m,1H),4.29−4.18(m,1H),4.14−3.99(m,1H),3.83−3.65(m,1H),2.48−1.91(m,10H),1.59−1.37(m,6H).
ステップA:tert−ブチル((1R,3s,5S)−8−エチル−8−アザビシクロ[3.2.1]オクタン−3−イル)カルバメート
tert−ブチル((1R,3s,5S)−8−アザビシクロ[3.2.1]オクタン−3−イル)カルバメート(0.20g、0.88mmol)を無水アセトニトリル(12mL)に溶解し、アセトアルデヒド(0.12g、0.15mL、2.65mmol)を室温で加えた。20分後、トリアセトキシ水素化ホウ素ナトリウム(0.56g、2.65mmol)を加え、反応混合物を室温で一晩撹拌した。溶媒を留去し、粗製混合物をシリカベースカラムクロマトグラフィー(DCM:MeOH中7NのNH3;9:1)で精製して、標記化合物(0.18g、82%)を黄色油として得た。
1H NMR(CDCl3)δ3.37(s,2H),3.32−3.21(m,2H),2.56−2.45(m,2H),1.99−1.88(m,4H),1.84−1.76(m,4H),1.74−1.61(m,9H),1.19−1.10(m,3H).
1H NMR(CD3OD)δ4.23−4.08(m,2H),3.80−3.68(m,2H),3.19−3.04(m,2H),2.40−2.21(m,6H),2.13−2.05(m,2H),1.48−1.34(m,3H).
ステップA:tert−ブチル 6−メチル−3,6−ジアザビシクロ[3.2.0]ヘプタン−3−カルボキシレート
1H NMR(CDCl3)δ3.79(dd,1H),3.69(s,2H),3.39(t,1H),3.24(dd,2H),3.08(dd,1H),2.97(dt,1H),2.34(s,3H),1.47(s,9H).
1H NMR(CD3OD)δ5.01(s,1H),4.41−4.21(m,1H),4.14(s,1H),3.89−3.66(m,2H),3.62(t,2H),3.49−3.35(m,1H),3.05(s,3H).
ステップA:tert−ブチル 6−エチル−3,6−ジアザビシクロ[3.2.0]ヘプタン−3−カルボキシレート
1H NMR(CDCl3)δ3.78−3.53(m,3H),3.52−3.40(m,1H),3.23−3.07(m,3H),3.00−2.89(m,1H),2.58−2.46(m,2H),1.46(s,9H),0.96(t,3H).
1H NMR(CD3OD)δ5.07(s,1H),4.30−4.13(m,2H),3.85(d,1H),3.75−3.57(m,3H),3.53−3.35(m,3H),1.27(t,3H).
ステップA:tert−ブチル 6−イソプロピル−3,6−ジアザビシクロ[3.2.0]ヘプタン−3−カルボキシレート
1H NMR(CDCl3)δ3.94(bs,1H),3.67(bs,2H),3.45−3.29(m,2H),3.27−3.13(m,2H),2.97(bs,1H),2.60(bs,1H),1.47(s,9H),0.97(dd,6H).
1H NMR(CD3OD)δ5.22(t,1H),4.42−4.01(m,3H),3.88(d,1H),3.71−3.42(m,4H),1.32(dd,J=18.5,6.5Hz,6H).
ステップA:tert−ブチル 6−メチル−3,6−ジアザビシクロ[3.1.1]ヘプタン−3−カルボキシレート
1H NMR(CDCl3)δ3.66−3.48(m,4H),3.37(dd,2H),2.71−2.49(m,1H),2.19(d,3H),1.89(s,1H),1.55−1.43(m,9H).
1H NMR(DMSO−d6)δ4.41−4.10(m,2H),3.96(m,1H),3.82(m,1H),3.74−3.58(m,2H),3.30(s,3H),3.04−2.79(m,2H).
ステップA:メチル メチル−D−プロリネート
1H NMR(CDCl3)δ3.72(s,3H),3.13(dt,1H),2.93(dd,1H),2.38(s,3H),2.25(q,1H),2.12(m,1H),1.91(m,2H),1.79(m,1H).
LCMS:m/z 144(M+H)+(ES+).
1H NMR(CDCl3)δ7.22(bs,1H),3.03(m,1H),2.83(dd,1H),2.79(d,3H),2.34(s,3H),2.33(m,1H),2.18(m,2H),1.71(m,2H).
LCMS:m/z 143(M+H)+(ES+).
1H NMR(CDCl3)δ3.03(dt,1H),2.70(dd,1H),2.50(dd,1H),2.41(s,3H),2.35(s,3H),2.22(m,1H),2.18(m,2H),1.92(m,1H),1.63(m,2H),1.20(bs,1H).
LCMS:m/z 129(M+H)+(ES+).
1H NMR(400MHz,CDCl3)δ3.05−3.01(m,1H),2.72−2.68(m,1H),2.53−2.48(m,1H),2.44(s,3H),2.32(s,3H),2.28−2.23(m,1H),2.19−2.14(m,1H),1.95−1.88(m,1H)および1.76−1.60(m,3H).1xNHが欠落している。
1H NMR(400MHz,DMSO−d6)δ6.65(s,2H),4.31−4.23(m,1H),2.62(s,3H),2.61−2.56(m,2H),2.41−2.36(m,1H),2.20(s,3H),2.18−2.12(m,1H),2.05−1.98(m,1H)および1.78−1.71(m,1H).
LCMS:m/z 194.0(M+H)+(ES+).
実施例1:3−(N−メチル−N−(1−メチルピロリジン−3−イル)スルファモイル)−1−(5−(2−メトキシピリジン−4−イル)−2,3−ジヒドロ−1H−インデン−4−イル)ウレア
1H NMR(CD3OD)δ8.12(d,1H),7.19(d ,1H),7.13(d,1H),6.99(d,1H),6.83(s,1H),4.48(m,1H),3.92(s,3H),2.92(m,6H),2.82(m,2H),2.71(s,3H),2.50(s,3H),2.10(m,3H)および1.92(m,1H).
LCMS m/z 460(M+H)+(ES+);458(M−H)−(ES−).
1H NMR(CD3OD)δ8.12(d,1H),7.19(m,2H),7.09(d,1H),6.93(s,1H),3.92(s,3H),3.88(m,1H),3.65(m,1H),3.09(m,1H),2.98(m,6H),2.79(s,3H),2.69(s,3H),2.10(m,3H),1.97(m,2H)および1.60(m,1H).
LCMS:m/z 474(M+H)+(ES+).
1H NMR(CD3OD)δ8.14(d,1H),7.08(d,1H),6.98(m,2H),4.48(m,1H),3.92(s,3H),2.98(m,8H),2.71(s,3H),2.60(s,3H),2.10(m,3H)および1.92(m,1H).
LCMS:m/z 479(M+H)+(ES+).
1H NMR(CD3OD)δ8.12(d,1H),7.00(d,1H),6.90(d,1H),6.83(s,1H),3.92(s,3H),3.78(m,1H),3.55(m,1H),3.00(m,7H),2.79(s,3H),2.67(s,3H),2.19(m,3H),2.01(m,2H)および1.62(m,1H).
LCMS m/z 492(M+H)+(ES+);490(M−H)−(ES−).
一方、DCM(5mL)中クロロスルホニルイソシアネート(35mg、0.25mmol)の冷却(0℃)溶液に、7−フルオロ−5−(2−メトキシピリジン−4−イル)−2,3−ジヒドロ−1H−インデン−4−アミン(中間体A1;66mg、0.26mmol)を加えた。混合物を0℃で10分間攪拌した。
両方のDCM混合物を合わせ、1時間後に室温に到達させた。混合物を減圧下で蒸発乾固させ、逆相クロマトグラフィーにより精製して、標記化合物(4mg;5%)を白色固体として得た。
1H NMR(CD3OD)δ8.12(d,1H),7.02(d,1H),6.90(m,2H),4.54(m,1H),4.24(m,1H),3.92(s,3H),3.39(m,2H),2.98(m,4H),2.75(s,3H),2.20(m,2H),および1.64(m,2H).
LCMS m/z 476(M+H)+(ES+);474(M−H)−(ES−).
1H NMR(CD3OD)δ6.89(s,1H),3.44(t,2H),3.04(t,2H),2.95−2.74(m,11H),2.67(s,6H),2.03(m,4H).
LCMS m/z 381(M+H)+(ES+);379(M−H)−(ES−).
1H NMR(CD3OD)δ6.88(s,1H),3.56(t,2H),3.33(m,5H),2.82(m,11H),2.03(m,4H).
LCMS m/z 368(M+H)+(ES+);366(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.23(m,2H),3.07(m,2H),2.82(m,8H),2.70(s,6H),2.03(m,4H).
LCMS m/z 367(M+H)+(ES+);365(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.80(dd,1H),3.62(t,1H),3.43(q,1H),3.25(m,1H),3.03(p,1H),2.82(m,8H),2.38(s,6H),2.20(m,1H),2.03(m,4H),1.95(m,1H).
LCMS m/z 393(M+H)+(ES+);391(M−H)−(ES−).
((1,2,3,5,6,7−ヘキサヒドロ−s−インダセン−4−イル)カルバモイル)スルファモイルクロリド(中間体A4)(100mg、0.32mmol)およびN1−ベンジル−N2,N2−ジメチルエタン−1,2−ジアミン(178mg、1.00mmol)を使って、3−(N−(2−(ジメチルアミノ)−2−メチルプロピル)スルファモイル)−1−(1,2,3,5,6,7−ヘキサヒドロ−s−インダセン−4−イル)ウレア、カリウム塩(実施例57)に対する記載のように調製して、標記化合物(10mg、7%)を白色固体として得た。
1H NMR(CD3OD)δ7.48(d,2H),7.38(m,3H),6.91(s,1H),4.31(s,2H),3.46(t,2H),2.82(m,8H),2.71(t,2H),2.59(s,6H),2.03(m,4H).
LCMS m/z 457(M+H)+(ES+);455(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.60(m,1H),2.82(m,11H),2.74(m,2H),2.61(m,1H),2.50(m,1H),2.38(s,3H),2.03(m,6H).
LCMS m/z 393(M+H)+(ES+);391(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.51(t,2H),3.10(t,2H),2.95(d,2H),2.82(m,14H),2.03(m,4H),1.90(m,1H),0.99(m,6H).
LCMS m/z 423(M+H)+(ES+);421(M−H)−(ES−).
1H NMR(CD3OD)δ7.21(m,5H),6.91(s,1H),3.60(m,2H),3.41(m,2H),3.10(t,2H),3.01(t,2H)2.82(m,8H),2.76(s,6H),2.03(m,4H).
LCMS m/z 405(M+H)+(ES+);403(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.50(m,2H),3.05(m,4H),2.82(m,8H),2.38(s,3H)2.03(m,4H),1.97(m,4H).
LCMS m/z 405(M+H)+(ES+);403(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.79(m,1H),3.52(m,1H),2.98(m,2H),2.82(m,8H),2.58(m,1H),2.40(s,6H)2.03(m,4H),1.92(m,1H),1.80(m,1H),1.60(m,1H),1.42(m,1H).
LCMS m/z 407(M+H)+(ES+);405(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.79(m,1H),2.98(m,2H),2.82(m,8H),2.75(s,6H)2.03(m,4H),1.24(d,3H).
LCMS m/z 381(M+H)+(ES+);379(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.79(m,4H),3.06(m,1H),2.82(m,8H),2.18(s,6H)2.03(m,4H).
LCMS m/z 379(M+H)+(ES+);377(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.54(t,2H),3.24(t,2H),3.04(m,6H),2.82(m,8H),2.03(m,4H),1.21(t,9H).
LCMS:m/z 423(M+H)+(ES+);421(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.41(m,1H),3.20(m,1H),2.82(m,8H),2.43(m,4H),2.03(m,7H),1.95(s,1H),1.79(m,1H),1.60(m,1H),1.22(m,1H),1.10(t,3H).
LCMS:m/z 407(M+H)+(ES+);405(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.51(m,1H),3.18(m,1H),2.82(m,14H),2.03(m,4H),1.95(s,1H),1.70(m,6H).
LCMS:m/z 407(M+H)+(ES+);405(M−H)−(ES−).
無水DCM(6mL)中1−エチルピペラジン(36mg、0.32mmol)の溶液に、((1,2,3,5,6,7−ヘキサヒドロ−s−インダセン−4−イル)カルバモイル)スルファモイルクロリド(中間体A4)(100mg、0.32mmol)を窒素雰囲気下、0℃で加えた。混合物を0℃で1時間攪拌し、完全に変換した。溶媒を減圧下で留去した。逆相カラムクロマトグラフィーによる精製により(「実験方法」を参照)、標記化合物(40mg、33%)を白色固体として得た。
1H NMR(CD3OD)δ6.89(s,1H),3.56(s,1H),3.21(s,1H),3.02−2.92(m,2H),2.91−2.75(m,6H),2.74−2.62(m,1H),2.64−2.37(m,9H),2.18−1.91(m,4H),1.19−1.00(m,3H).
LCMS:m/z 393(M+H)+(ES+);391(M−H)−(ES−).
LCMS:m/z 421(M+H)+(ES+);419(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.02(m,4H),3.48(m,1H),2.82(m,8H),2.78(m,4H),2.03(m,4H),1.95(s,1H),1.83(m,4H).
LCMS m/z 405(M+H)+(ES+);403(M−H)−(ES−).
1H NMR(CD3OD)δ7.21(s,1H),7.13(d,1H),6.91(s,1H),6.80(d,1H),4.82(s,2H),2.82(t,4H),2.62(t,4H),2.03(m,4H).
LCMS:m/z 427(M+H)+(ES+);425(M−H)−(ES−).
LCMS m/z 393(M+H)+(ES+);391(M−H)−(ES−).
1H NMR(CD3OD)δ6.89(s,1H),4.82(s,2H),4.60(s,2H),3.17−3.02(m,3H),2.92−2.71(m,8H),2.14−1.94(m,4H),1.91(s,1H),1.28(d,J=6.5Hz,6H).
LCMS m/z:381(M+H)+(ES+);379(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.42(m,1H),3.02(m,2H),2.82(m,17H),2.03(m,4H),1.93(s,1H),1.29(d,3H).
LCMS:m/z 395(M+H)+(ES+);393(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.62(m,2H),3.38(m,2H),3.18(m,2H),2.82(m,8H),2.17(s,1H),2.03(m,4H),1.90(s,1H),1.35(d,12H).
LCMS:m/z 423(M+H)+(ES+);421(M−H)−(ES−).
1H NMR(CD3OD)δ6.93(s,1H),3.99(bs,2H),3.48(d,2H),3.39−3.32(m,2H),3.20−3.06(m,1H),2.83(dt,8H),2.11−1.98(m,8H),1.27(d,6H).
LCMS:m/z 433(M+H)+(ES+);431(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.13(m,1H),2.98(m,1H),2.82(m,9H),2.37(s,6H),2.17(s,1H),2.03(m,4H),1.05(d,3H).
LCMS:m/z 381(M+H)+(ES+);379(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.93(m,1H),3.72(m,1H),3.40(m,1H),3.06(m,1H),2.82(m,9H),2.64(s,3H),2.12(m,2H),2.03(m,4H),1.90(s,1H).
LCMS:m/z 379(M+H)+(ES+);377(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.63(t,2H),3.18(t,1H),3.00(t,1H),2.96(s,3H),2.82(m,8H),2.64(s,3H),2.16(s,1H),2.03(m,4H).
LCMS:m/z 367(M+H)+(ES+);365(M−H)−(ES−).
1H NMR(CD3OD)δ6.89(s,1H),4.57(s,1H),4.10(s,2H),3.65−3.50(m,1H),3.18−2.98(m,1H),2.93−2.71(m,8H),2.69−2.45(m,2H),2.44−1.93(m,10H),1.90(s,2H),1.36−1.30(m,6H).
LCMS:m/z 447(M+H)+(ES+);445(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.00(m,1H),3.78(t,2H),3.00(t,2H),2.82(m,8H),2.32(s,3H),2.03(m,4H).
LCMS:m/z 365(M+H)+(ES+);363(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.59(t,4H),3.02(t,2H),2.82(m,9H),2.60(m,1H),2.20(m,2H),2.03(m,4H).
LCMS:m/z 379(M+H)+(ES+);377(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.55(m,1H),3.24(m,1H),3.03(t,2H),2.82(m,8H),2.70(m,2H),2.60(m,1H),2.40(s,3H),2.10(m,1H),2.03(m,4H),1.18(d,6H).
LCMS:m/z 421(M+H)+(ES+);419(M−H)−(ES−).
1H NMR(CD3OD)δ6.92(s,1H),4.15(bs,2H),2.92−2.62(m,10H),2.40(d,2H),2.26(s,3H),2.16−1.98(m,6H),1.92−1.74(m,2H).
LCMS:m/z 405(M+H)+(ES+);403(M−H)−(ES−).
1H NMR(CD3OD)δ6.96(s,1H),4.20(s,2H),2.91−2.56(m,13H),2.05(p,6H),1.94−1.81(m,2H),1.04(d,6H).
LCMS:m/z 433(M+H)+(ES+);431(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.52(t,2H),3.25(t,2H),3.10(m,2H),2.82(m,8H),2.70(s,6H),2.03(m,4H),1.21(t,3H).
LCMS:m/z 395(M+H)+(ES+);393(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.27(m,2H),3.20(s,1H),3.00(m,5H),2.82(m,8H),2.03(m,4H),1.19(t,6H).
LCMS:m/z 395(M+H)+(ES+);393(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.55(m,2H),3.39(m,2H),3.10(s,3H),2.90(s,3H),2.82(m,8H),2.03(m,7H).
LCMS:m/z 409(M+H)+(ES+);407(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.42(m,1H),3.95(m,1H),3.70(d,1H),3.45(t,1H),3.05(t,1H),2.82(m,8H),2.66(s,6H),2.21(s,1H),2.03(m,4H),1.80(m,1H),1.60(m,4H).
LCMS:m/z 421(M+H)+(ES+);419(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.29(s,1H),3.62(s,1H),3.42(dd,2H),3.05(m,2H),2.82(m,11H),2.03(m,4H),1.56(s,2H).
LCMS:m/z 391(M+H)+(ES+);389(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.95(m,1H),3.01(dd,1H),2.82(m,8H),2.56(m,3H),2.38(s,3H),2.22(m,1H),2.03(m,6H),1.80(m,1H).
LCMS:m/z 379(M+H)+(ES+);377(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),2.82(m,8H),2.62(t,2H),2.24(dt,1H),2.03(m,6H),1.62(m,4H).
LCMS:m/z 416(M+H)+(ES+);414(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.80(m,1H),2.82(m,16H),2.03(m,6H).
LCMS:m/z 391(M+H)+(ES+);389(M−H)−(ES−).
1H NMR(CD3OD)δ6.89(s,1H),4.24−4.10(m,1H),3.95−3.77(m,1H),3.63−3.46(m,3H),3.26−3.06(m,2H),2.83(q,8H),2.42−2.28(m,1H),2.21(d,1H),2.02(p,4H),1.13(t,3H).
LCMS:m/z 393(M+H)+(ES+);391(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.07(t,2H),2.82(m,8H),2.62(m,2H),2.42(s,6H),2.03(m,4H),1.60(m,4H).
LCMS:m/z 395(M+H)+(ES+);393(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.66(m,1H),3.40(m,3H),3.17(m,1H),2.82(m,8H),2.67(q,4H),2.13(m,1H),2.03(m,4H),1.80(m,1H),1.80(t,6H).
LCMS:m/z 421(M+H)+(ES+);419(M−H)−(ES−).
1H NMR(CD3OD)δ6.89(s,1H),4.32−4.15(m,1H),3.82(m,1H),3.57(q,1H),3.47(dd,1H),3.24−3.15(m,2H),2.83(q,8H),2.43−2.16(m,2H),2.02(p,4H),1.22(d,3H),1.12(d,3H).
LCMS:m/z 407(M+H)+(ES+);405(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.55(t,4H),3.10(t,4H),2.82(m,8H),2.71(s,12H),2.03(m,4H).
LCMS:m/z 438(M+H)+(ES+);436(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.50(t,2H),3.40(m,1H),3.05(d,1H),2.82(m,8H),2.63(d,1H),2.23(s,3H),2.03(m,5H),1.75(m,1H),1.60(m,1H),1.20(m,1H).
LCMS:m/z 391(M+H)+(ES+);393(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.50(t,2H),3.20(q,2H),3.19(q,4H),2.82(m,11H),2.03(m,4H),1.23(t,6H).
LCMS:m/z 409(M+H)+(ES+);407(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.58(m,2H),3.0(t,1H),2.82(m,10H),2.03(m,4H),1.60(m,4H).
LCMS m/z 368(M+H)+(ES+);366(M−H)−(ES−).
1H NMR(CD3OD)δ7.38(s,1H),6.91(s,1H),6.17(s,1H),3.75(s,3H),2.82(m,8H),2.03(m,4H).
LCMS:m/z 376(M+H)+(ES+);374(M−H)−(ES−).
1H NMR(CD3OD)δ6.99(s,1H),4.26−4.02(m,1H),3.79−3.59(m,3H),2.91−2.73(m,9H),2.68(s,3H),2.31−2.16(m,2H),2.13−1.88(m,11H).
LCMS:m/z 419(M+H)+(ES+).
1H NMR(CD3OD)δ6.91(s,1H),3.75(t,1H),2.82(m,8H),2.55(s,6H),2.20(s,2H),2.03(m,4H),1.55(m,1H),1.20(s,6H).
LCMS:m/z 395(M+H)+(ES+);393(M−H)−(ES−).
1H NMR(CD3OD)δ7.20(m,5H),6.91(s,1H),3.59(t,2H),3.23(m,2H),3.18(t,2H),2.82(m,14H),2.63(t,2H),2.03(m,6H).
LCMS:m/z 485(M+H)+(ES+);483(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),2.98(s,6H),2.82(m,8H),2.40(m,2H),2.03(m,4H),1.47(s,6H).
LCMS:m/z 395(M+H)+(ES+);393(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.34(m,1H),3.40(m,1H),3.22(m,1H),3.04(m,4H),2.82(m,8H),2.73(m,1H),2.60(m,1H),2.31(m,1H),2.03(m,4H),1.95(m,1H).
LCMS:m/z 391(M+H)+(ES+);389(M−H)−(ES−).
LCMS:m/z 419(M+H)+(ES+);417(M−H)−(ES−).
LCMS:m/z 419(M+H)+(ES+);417(M−H)−(ES−).
1H NMR(CD3OD)δ6.92(s,1H),4.60(s,2H),4.14(s,2H),2.93−2.72(m,8H),2.30−2.09(m,4H),2.09−1.81(m,11H),1.49−1.21(m,6H).
LCMS:m/z 447(M+H)+(ES+);446(M−H)−(ES−).
1H NMR(CD3OD)δ6.90(s,1H),4.42−4.26(m,2H),3.60−3.41(m,1H),3.14−2.92(m,5H),2.92−2.77(m,9H),2.73−2.56(m,2H),2.37−2.19(m,2H),2.14−1.94(m,4H),1.75−1.54(m,2H),1.50−1.29(m,2H),1.28−1.15(m,6H).
LCMS:m/z 461(M+H)+(ES+).
1H NMR(CD3OD)δ7.42(s,1H),6.91(s,1H),6.19(s,1H),4.18(m,1H),2.82(m,8H),1.41(d,6H).
LCMS:m/z 404(M+H)+(ES+);402(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.60(m,1H),2.82(m,11H),2.74(m,2H),2.61(m,1H),2.50(m,1H),2.38(s,3H),2.03(m,6H).
LCMS:m/z 393(M+H)+(ES+);391(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.29(s,1H),3.62(s,1H),3.42(dd,2H),3.05(m,2H),2.82(m,11H),2.03(m,4H),1.55(m,2H).
LCMS:m/z 391(M+H)+(ES+);389(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.58(m,1H),3.42(m,1H),3.37(m,1H),3.03(m,1H),2.82(m,10H),2.42(m,1H),2.23(s,6H),2.03(m,5H),1.61(m,1H).
LCMS:m/z 407(M+H)+(ES+);405(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.58(t,2H),3.20(t,2H),3.12(d,2H),2.82(m,8H),2.72(m,1H),2.40(s,3H),2.03(m,4H).
LCMS:m/z 379(M+H)+(ES+);377(M−H)−(ES−).
1H NMR(CD3OD)δ6.92(s,1H),4.36−4.11(m,2H),3.02−2.91(m,5H),2.90−2.75(m,9H),2.60−2.41(m,2H),2.30−2.13(m,2H),2.11−1.98(m,5H),1.96−1.85(m,4H),1.84−1.69(m,2H),1.67−1.47(m,2H).
LCMS:m/z 459(M+H)+(ES+);457(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.27(t,2H),3.05(t,2H),2.82(m,8H),2.03(m,4H),1.25(s,9H).
LCMS:m/z 395(M+H)+(ES+).
1H NMR(CD3OD)δ6.91(s,1H),3.62(dd,1H),3.42(m,1H),3.39(m,1H),3.19(m,1H),2.99(m,1H),2.82(m,8H),2.62(m,4H),2.17(m,1H),2.03(m,4H),1.87(m,1H),1.80(m,4H).
LCMS:m/z 419(M+H)+(ES+).
1H NMR(CD3OD)δ6.91(s,1H),3.58(t,2H),3.50(m,2H),3.40(m,3H),3.12(m,2H),2.82(m,8H),2.20(m,2H),2.03(m,6H).
LCMS:m/z 405(M+H)+(ES+).
1H NMR(CD3OD)δ6.92(s,1H),3.94(s,2H),3.12−2.96(m,3H),2.93−2.74(m,9H),2.34−2.15(m,5H),2.13−1.99(m,7H),1.98−1.77(m,2H),1.39−1.24(m,3H).
LCMS:m/z 433(M+H)+(ES+).
1H NMR(CD3OD)δ6.95(s,1H),3.42−3.34(m,4H),3.26−3.17(m,2H),2.82(dt,8H),2.14−1.95(m,7H),1.83(d,2H),0.55−0.37(m,4H).
LCMS:m/z 431(M+H)+(ES+).
1H NMR(CD3OD)δ6.91(s,1H),4.60(m,1H),2.82(m,11H),2.74(m,2H),2.61(m,1H),2.50(m,1H),2.38(s,3H),2.03(m,6H).
LCMS:m/z 393(M+H)+(ES+);391(M−H)−(ES−).
1H NMR(CD3OD)δ6.95(s,1H),4.06(s,2H),2.96−2.80(m,7H),2.71(s,6H),2.36(s,1H),2.15−1.99(m,6H),1.96−1.70(m,7H),1.66−1.56(m,2H).
LCMS:m/z 433(M+H)+(ES+).
1H NMR(CD3OD)δ6.90(s,1H),4.40−4.19(m,2H),3.61−3.42(m,1H),3.18−2.91(m,4H),2.93−2.67(m,8H),2.35−2.10(m,2H),2.10−1.84(m,8H),1.75−1.61(m,2H),1.32−1.12(m,6H).
LCMS:m/z 461(M+H)+(ES+);459(M−H)−(ES−).
1H NMR(CD3OD)δ6.92(s,1H),4.41−4.19(m,2H),2.94−2.76(m,11H),2.56−2.43(m,7H),2.27−2.16(m,2H),2.14−1.96(m,5H),1.81−1.62(m,2H),1.57−1.39(m,2H).
LCMS:m/z 433(M+H)+(ES+);431(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.58(m,2H),3.22(m,2H),2.82(m,15H),2.03(m,8H).
LCMS:m/z 407(M+H)+(ES+);405(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.16(t,2H),2.82(m,10H),2.60(s,6H),2.03(m,4H),1.81(t,2H).
LCMS:m/z 381(M+H)+(ES+);379(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.36(m,1H),3.51(m,1H),3.21(m,1H),3.05(m,2H),2.82(m,14H),2.60(s,6H),2.03(m,9H),1.54(m,1H).
LCMS:m/z 407(M+H)+(ES+);405(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.12(m,1H),3.43(t,2H),3.19(t,2H),2.82(m,14H),2.03(m,4H),1.21(s,6H).
LCMS:m/z 409(M+H)+(ES+);407(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.07(m,4H),3.43(m,2H),2.97(m,1H),2.87(s,3H),2.82(m,8H),2.80(s,3H),2.03(m,4H).
LCMS:m/z 393(M+H)+(ES+);391(M−H)−(ES−).
1H NMR(CD3OD)δ6.90(s,1H),3.81(m,1H),3.57−3.50(m,2H),3.28−3.12(m,4H),3.10−3.04(m,1H),2.89−2.77(m,10H),2.09−1.98(m,4H),1.14(t,3H).
LCMS:m/z 405(M+H)+(ES+);403(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.71−4.59(m,1H),4.05−3.93(m,1H),3.89−3.71(m,2H),3.52(d,2H),3.25−3.00(m,2H),2.92−2.70(m,11H),2.08−1.95(m,4H).
LCMS:m/z 391(M+H)+(ES+);389(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.34(m,1H),3.61(m,2H),3.41(m,2H),3.12(m,3H),3.04(m,1H),2.82(m,8H),2.03(m,4H),1.01(d,3H),0.98(d,2H).
LCMS:m/z 419(M+H)+(ES+);417(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.95(m,1H),3.01(dd,1H),2.82(m,8H),2.56(m,3H),2.38(s,3H),2.22(m,1H),2.03(m,6H),1.80(m,1H).
LCMS:m/z 379(M+H)+(ES+);377(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.95(m,1H),3.01(dd,1H),2.82(m,8H),2.56(m,3H),2.38(s,3H),2.22(m,1H),2.03(m,6H),1.80(m,1H).
LCMS:m/z 379(M+H)+(ES+);377(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.55(m,2H),3.48(t,2H),2.99(m,2H),2.82(m,8H),2.67(m,2H),2.40(s,3H),2.03(m,4H),1.95(m,2H).
LCMS:m/z 393(M+H)+(ES+);391(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.50(d,2H),4.05(d,2H),3.73(t,2H),2.82(m,8H),2.78(s,3H),2.42(t,2H),2.03(m,4H).
LCMS:m/z 391(M+H)+(ES+);389(M−H)−(ES−).
1H NMR(CD3OD)δ6.89(s,1H),4.08(m,1H),3.67(d,1H),3.50(t,1H),3.15(m,1H0,2.99(m,1H),2.82(m,12H),2.40(s,3H),2.03(m,4H).
LCMS:m/z 391(M+H)+(ES+);389(M−H)−(ES−).
1H NMR(CD3OD)δ6.85(s,1H),3.98(m,1H),3.60(d,1H),3.40(t,1H),3.20(m,1H),3.05(m,2H),2.95(m,1H),2.82(m,9H),2.30(s,3H),2.03(m,4H).
LCMS:m/z 391(M+H)+(ES+);389(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),4.17(t,1H),3.59(d,2H),3.42(m,1H),3.18(m,1H),2.82(m,14H),2.70(m,1H),2.03(m,4H).
LCMS:m/z 391(M+H)+(ES+).
1H NMR(CD3OD)δ6.91(s,1H),3.78(d,2H),3.42(m,1H),3.08(m,2H),2.82(m,14H),2.20(m,2H),2.03(m,6H).
LCMS:m/z 408(M+H)+(ES+).
1H NMR(CD3OD)δ6.91(s,1H),3.41(d,1H),3.22(d,1H),3.17(m,3H),3.05(m,1H),2.99(m,1H),2.82(m,10H),2.42(s,3H),2.12(m,1H),2.03(m,4H).
LCMS:m/z 405(M+H)+(ES+);403(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.78(d,1H),3.50(m,2H),3.38(t,1H),3.07(m,1H),2.82(m,10H),2.48(m,1H),2.41(s,3H),2.03(m,4H),1.60(m,4H).
LCMS:m/z 419(M+H)+(ES+).
1H NMR(CD3OD)δ6.91(s,1H),4.09(d,1H),3.58(m,1H),3.43(m,1H),2.99(m,2H),2.82(m,10H),2.79(s,3H),2.42(m,1H),2.12(m,1H),2.03(m,4H),1.63(m,3H).
LCMS:m/z 419(M+H)+(ES+);417(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.38(m,2H),3.23(m,4H),3.12(m,4H),2.82(m,8H),2.65(s,3H),2.03(m,4H).
LCMS:m/z 405(M+H)+(ES+);403(M−H)−(ES−).
1H NMR(CD3OD)δ6.91(s,1H),3.85(m,2H),3.62(m,2H),2.82(m,15H),2.03(m,4H).
LCMS:m/z 391(M+H)+(ES+).
ステップA:(4−(ジメチルアミノ)ピリジン−1−イウム−1−カルボニル)(N−メチル−N−(1−メチルピロリジン−3−イル)スルファモイル)アミド
1H NMR(400MHz,CD3OD)δ8.70(d,J=6.0Hz,2H),7.50−7.48(m,2H),4.48−4.44(m,1H),3.30−2.92(m,5H),2.74(s,3H),2.63(s,3H),2.29(s,3H),2.15−1.98(m,2H),1.27(d,J=6.8Hz,6H).2xNHが欠落している。
LCMS:m/z 436.1(M+H)+(ES+).
1H NMR(CD3OD)δ8.11(dd,1H),7.19(d,1H),7.12(d,1H),7.02(dd,1H),6.85(d,1H),4.49(p,1H),3.93(s,3H),2.95(dt,5H),2.87−2.77(m,3H),2.71(s,3H),2.50(s,3H),2.18−2.02(m,3H),1.89(dq,1H).
LCMS:m/z 460(M+H)+(ES+).
1H NMR(CD3OD)δ8.11(d,1H),7.20(d,1H),7.12(d,1H),7.01(dd,1H),6.85(d,1H),4.49(p,1H),3.93(s,3H),3.07−2.79(m,8H),2.72(s,3H),2.52(s,3H),2.08(dp,3H),1.91(dq,1H).
LCMS:m/z 460(M+H)+(ES+).
1H NMR(CD3OD)δ7.21−7.02(m,1H),6.88−6.72(m,1H),6.54−6.37(m,1H),3.88−3.71(m,1H),3.71−3.56(m,1H),3.52−3.40(m,1H),3.32−3.28(m,2H),3.29−3.22(m,1H),3.12−2.97(m,1H),2.98−2.81(m,10H),2.27−2.14(m,1H),2.14−1.96(m,5H).
LCMS:m/z 405(M+H)+(ES+);403(M−H)−(ES−).
1H NMR(DMSO−d6)δ8.19(d,J=5.2Hz,1H),7.46(br s,1H),7.10(s,1H),6.72(dd,J=5.2,1.4Hz,1H),6.52(s,1H),5.04−4.95(m,1H),2.90(t,J=7.4Hz,2H),2.77−2.69(m,4H),2.64(s,6H),2.28−2.16(m,5H),2.09−1.94(m,7H),1.73−1.64(m,2H).1個の交換可能なプロトンが観察されなかった。
LCMS m/z 488.4(M+H)+(ES+);486.3(M−H)−(ES−).
1H NMR(DMSO−d6)δ9.66(br s,1H),8.22(d,J=5.2Hz,1H),7.46(s,1H),7.11(s,1H),6.75(dd,J=5.3,1.4Hz,1H),6.59(s,1H),3.89(s,3H),2.90(t,J=7.4Hz,2H),2.76−2.70(m,2H),2.66(s,6H),2.05−1.96(m,5H).
LCMS m/z 405.2(M+H)+(ES+).
ステップA:3−((S)−N−メチル−N−((−1−メチルピロリジン−2−イル)メチル)スルファモイル)−1−(1,2,3,5,6,7−ヘキサヒドロ−s−インダセン−4−イル)ウレア
1H NMR(400MHz,CD3OD)δ6.92(s,1H),3.80−3.70(m,2H),3.51−3.45(m,1H),3.30−3.24(m,1H),3.10−3.03(m,1H),2.91(s,3H),2.89−2.77(m,11H),2.24−2.18(m,1H)and 2.13−1.94(m,7H).2xNHが欠落している。
LCMS:m/z 407.2(M+H)+(ES+).
THF(10mL)中3−((S)−N−メチル−N−((−1−メチルピロリジン−2−イル)メチル)スルファモイル)−1−(1,2,3,5,6,7−ヘキサヒドロ−s−インダセン−4−イル)ウレア(30mg、73.79μmol、1当量)の溶液に、t−BuONa(7mg、73.79μmol、1当量)を0℃で加えた。反応混合物を5℃で30分間攪拌した。その後、反応混合物を減圧下で濃縮し、凍結乾燥して、標記化合物(20.92mg、65%収率、HPLCで98.1%純度)を白色固体として得た。
1H NMR(400MHz,CD3OD)δ6.87(s,1H),3.32−3.31(m,1H),3.12−3.03(m,2H),2.86−2.80(m,11H),2.58−2.55(m,1H),2.42(s,3H),2.31−2.26(m,1H),2.07−1.99(m,5H)and 1.77−1.67(m,3H).1xNHが欠落している。
LCMS:m/z 407.4(M−Na+2H)+(ES+).
NLRP3およびパイロトーシス
NLRP3の活性化が細胞のパイロトーシスをもたらし、この特徴が臨床疾患の顕在化において重要な部分を担うことは、十分に確立されている(Yan−gang Liu et al.,Cell Death & Disease,2017,8(2),e2579;Alexander Wree et al.,Hepatology,2014,59(3),898−910;Alex Baldwin et al.,Journal of Medicinal Chemistry,2016,59(5),1691−1710;Ema Ozaki et al.,Journal of Inflammation Research,2015,8,15−27;Zhen Xie & Gang Zhao,Neuroimmunology Neuroinflammation,2014,1(2),60−65;Mattia Cocco et al.,Journal of Medicinal Chemistry,2014,57(24),10366−10382;T.Satoh et al.,Cell Death & Disease,2013,4,e644)。そのため、NLRP3の阻害剤が、パイロトーシス、ならびに細胞からの炎症促進性サイトカイン(例えば、IL−1β)放出を阻止することが予測される。
THP−1細胞(ATCC #TIB−202)を、10%ウシ胎児血清(FBS)(Sigma #F0804)中の1mMピルビン酸ナトリウム(Sigma #S8636)およびペニシリン(100単位/ml)/ストレプトマイシン(0.1mg/ml)(Sigma #P4333)を補充したL−グルタミン含有RPMI(Gibco #11835)で生育させた。細胞を規定通りに継代し、培養飽和密度(約106細胞/ml)まで生育させた。実験当日に、THP−1細胞を回収し、RPMI培地(FBS不含)に再懸濁した。その後、細胞を計数し、生存率(>90%)をトリパンブルー(Sigma #T8154)によりチェックした。適切な希釈を行なって、625,000細胞/mlの濃度を得た。この希釈細胞溶液にLPS(Sigma #L4524)を添加して、1μg/mlの最終アッセイ濃度(FAC)を得た。40μlの最終調製物を、96ウェルプレートの各ウェルに分注した。このように調製したプレートを、化合物スクリーニングに用いた。
化合物スクリーニングのために、以下の段階的アッセイ法に従った。
1.RPMI培地(FBS不含)40μl中に1.0μg/mlのLPSを含有するTHP−1細胞を、poly−D−リシンをコーティングした96ウェルの黒色壁・透明底の細胞培養プレート(VWR #734−0317)に播種する(25,000細胞/ウェル)
2.5μlの化合物(10μMを最高用量とする8点ハーフログ希釈)またはビークル(DMSO 0.1%FAC)を適切なウェルに添加する
3.37℃、5%CO2で3時間インキュベートする
4.5μlのナイジェリシン(Sigma #N7143)(FAC 5μM)を全てのウェルに添加する
5.37℃、5%CO2で1時間インキュベートする
6.インキュベーション期間の終了時に、プレートを300xgで3分間遠心分離し、上清を除去する
7.その後、50μlのレサズリン(Sigma #R7017)(FBS不含のRPMI培地中のFAC 100μMレサズリン)を添加し、プレートを37℃、5%CO2でさらに1〜2時間インキュベートする
8.プレートをEx560nmおよびEm590nmのEnvisionリーダーで読み取る
9.IC50データを非線形回帰式にあてはめる(log阻害剤vs反応−可変傾斜4パラメーター)
全身送達では、化合物が血流内に存在する際にNLRP3を阻害する能力が非常に重要である。この理由のため、ヒト全血中のいくつかの化合物のNLRP3阻害活性を、以下のプロトコルに従って調査した。
Li−ヘパリンチューブ中のヒト全血を、志願者ドナーパネルの健康なドナーから取得した。
1.1μg/mlのLPSを含有する全血80μlを96ウェルの透明底細胞培養プレート(Corning #3585)に播種する
2.10μlの化合物(10μMを最高用量とする8点ハーフログ希釈)またはビークル(DMSO 0.1%FAC)を適切なウェルに添加する
3.37℃、5%CO2で3時間インキュベートする
4.10μlのナイジェリシン(Sigma #N7143)(10μM FAC)を全てのウェルに添加する
5.37℃、5%CO2で1時間インキュベートする
6.インキュベーション期間の終了時に、プレートを300xgで5分間遠心分離して細胞をペレット化し、上清20μlを取り出し、IL−1β分析用の96ウェルv底プレートに添加する(注:上清を含有するこれらのプレートは、−80℃で貯蔵して後日、分析できる)
7.IL−1βを、製造業者のプロトコル(Perkin Elmer−AlphaLisa IL−1 Kit AL220F−5000)に従って測定した
8.IC50データを非線形回帰式にあてはめる(log阻害剤vs反応−可変傾斜4パラメーター)
ヒト全血アッセイの結果を、HWB IC50として下表2にまとめる。
薬物動態パラメーターを、雄Sprague Dawleyラット(Charles River,UK、250〜350g;またはVital River Laboratory Animal Technology Co Ltd,Beijing,China,7〜9週齢)で測定した。動物を、試験中は個別に収容し、12時間の明暗周期の下で維持した。
静脈内投与では、化合物を2mL/kg投与量での水またはDMSO:PBS[10:90]中の溶液として処方し、尾静脈または頸静脈を介して投与した。経口投与では、化合物を5mL/kg投与量での水中の0.5%w/vメチルセルロース中溶液として処方し、経口投与した。
一連の血液試料(約120〜300μL)を、各動物から投与後の8つの時点(0.083、0.25、0.5、1、2、4、8および24時間)のそれぞれ、または投与後の12の時点(0.03、0.1、0.17、0.25、0.5、1、2、4、6、8、12および24時間)のそれぞれ、または投与前および投与後の9つの時点(0.25、0.5、1、2、4、6、8、12および24時間)のそれぞれで採取した。試料を、血漿生成のために最長30分間氷上に保持した後、遠心分離(10,000rpm(8,385g)で3分間;または5,696rpm(3,000g)で15分間)した。血漿を、生体分析の前にドライアイス上で凍結させた。PKパラメーターを、DotmaticsまたはPhoenix WinNonlin 6.3ソフトウエアを用いてLC−MS/MSデータから作成した。
表3および4に示された結果から明らかなように、本発明の化合物は、先行技術の化合物と比較して、有利な薬物動態性、例えば半減期T1/2、曲線下面積AUC、クリアランスClおよび/または生物学的利用度を示す。
本発明が例示の目的のみで上に記されているに過ぎないことは、理解されよう。実施例は、本発明の範囲を限定するものではない。以下の特許請求の範囲のみにより定められる本発明の範囲および主旨を逸脱することなく、様々な修正および実施形態を実施することが可能である。
Claims (15)
- 式(I):
Qは、OまたはSから選択され、
R1およびR3はそれぞれ独立に、水素または飽和もしくは不飽和ヒドロカルビル基であり、前記ヒドロカルビル基は、直鎖もしくは分枝鎖であってよく、または環式基であるもしくは環式基を含んでよく、前記ヒドロカルビル基は任意に、置換されてよく、かつ前記ヒドロカルビル基は、その炭素骨格中に1個または複数のヘテロ原子N、OまたはSを任意に含んでよく、
任意にR1およびR3は、それらが結合される窒素原子と一緒に3〜12員環式基を形成してよく、前記環式基は任意に、置換されてよく、および
R2は、α位で置換された環式基であり、R2は任意に、さらに置換されてよい、
化合物。 - R2は、アリールまたはヘテロアリール基であり、前記アリールまたはヘテロアリール基は、α’位で置換され、かつR2は任意に、さらに置換されてよい、請求項1に記載の化合物。
- R2は、アリールまたはヘテロアリール基であり、前記アリールまたはヘテロアリール基は、αおよびα’位で置換され、かつR2は任意に、さらに置換されてよい、請求項2に記載の化合物。
- R2は、縮合アリールまたは縮合ヘテロアリール基であり、第一のシクロアルキル、シクロアルケニル、非芳香族複素環式、アリールまたはヘテロアリール環は、α,β位にまたがって前記アリールまたはヘテロアリール基に縮合され、第二のシクロアルキル、シクロアルケニル、非芳香族複素環式、アリールまたはヘテロアリール環は、α’,β’位にまたがりアリールまたはヘテロアリール基に縮合され、R2は、さらに任意に置換されてもよい、請求項3に記載の化合物。
- R2は、α位で一価複素環式基または一価芳香族基で置換された環式基であり、前記複素環式基または芳香族基の環原子は、前記環式基のα−環原子に直接結合され、前記複素環式基または芳香族基は任意に、置換されてよく、かつ前記環式基は任意に、さらに置換されてよい、請求項1に記載の化合物。
- R2は、αおよびα’位で置換された環式基であり、R2は任意に、さらに置換されてよい、請求項1に記載の化合物。
- Qは、Oである、請求項1〜6のいずれか1項に記載の化合物。
- 請求項1〜8のいずれか1項に記載の化合物の薬学的に許容可能な塩、溶媒和物またはプロドラッグ。
- 請求項1〜8のいずれか1項に記載の化合物、または請求項9に記載の薬学的に許容可能な塩、溶媒和物またはプロドラッグ、および薬学的に許容可能な賦形剤を含む医薬組成物。
- 薬物での使用のための、請求項1〜8のいずれか1項に記載の化合物、または請求項9に記載の薬学的に許容可能な塩、溶媒和物またはプロドラッグ、または請求項10に記載の医薬組成物。
- 疾患、障害または状態の治療または予防での使用のための、請求項11に記載の化合物、薬学的に許容可能な塩、溶媒和物、プロドラッグまたは医薬組成物であって、前記疾患、障害または状態は、NLRP3の阻害に応答する、化合物、薬学的に許容可能な塩、溶媒和物、プロドラッグまたは医薬組成物。
- 疾患、障害または状態の治療または予防での使用のための、請求項11または12に記載の化合物、薬学的に許容可能な塩、溶媒和物、プロドラッグまたは医薬組成物であって、前記疾患、障害または状態は、下記から選択される、化合物、薬学的に許容可能な塩、溶媒和物、プロドラッグまたは医薬組成物:
(i)炎症;
(ii)自己免疫疾患;
(iii)癌;
(iv)感染症;
(v)中枢神経系疾患;
(vi)代謝疾患;
(vii)心血管疾患;
(viii)呼吸器疾患;
(ix)肝臓疾患;
(x)腎臓疾患;
(xi)眼科疾患;
(xii)皮膚疾患;
(xiii)リンパ状態;
(xiv)精神障害;
(xv)移植片対宿主病;
(xvi)異痛症;および
(xvii)個体がNLRP3において生殖系または体細胞系非サイレント変異を有すると決定されている任意の疾患。 - 疾患、障害または状態の治療または予防での使用のための、請求項11または12に記載の化合物、薬学的に許容可能な塩、溶媒和物、プロドラッグまたは医薬組成物であって、前記疾患、障害または状態は、下記から選択される、化合物、薬学的に許容可能な塩、溶媒和物、プロドラッグまたは医薬組成物:
(i)クリオピリン関連周期熱症候群(CAPS);
(ii)マックル・ウェルズ症候群(MWS);
(iii)家族性寒冷自己炎症性症候群(FCAS);
(iv)新生児期発症多臓器系炎症性疾患(NOMID);
(v)家族性地中海熱(FMF);
(vi)化膿性関節炎、壊疽性膿皮症およびアクネ症候群(PAPA);
(vii)高免疫グロブリンDおよび周期性発熱症候群(HIDS);
(viii)腫瘍壊死因子(TNF)受容体関連周期性症候群(TRAPS);
(ix)全身型若年性特発性関節炎;
(x)成人発症スチル病(AOSD);
(xi)再発性多発性軟骨炎;
(xii)シュニッツラー症候群;
(xiii)スウィート症候群;
(xiv)ベーチェット病;
(xv)抗合成酵素症候群;
(xvi)インターロイキン1受容体アンタゴニスト欠損症(DIRA);および
(xvii)A20ハプロ不全症(HA20)。 - NLRP3を阻害する方法であって、NLRP3を阻害するために、請求項1〜8のいずれか1項に記載の化合物、または請求項9に記載の薬学的に許容可能な塩、溶媒和物またはプロドラッグ、または請求項10に記載の医薬組成物の使用を含む、方法。
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