JP6537532B2 - 補体媒介障害の治療のための化合物 - Google Patents
補体媒介障害の治療のための化合物 Download PDFInfo
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- JP6537532B2 JP6537532B2 JP2016570944A JP2016570944A JP6537532B2 JP 6537532 B2 JP6537532 B2 JP 6537532B2 JP 2016570944 A JP2016570944 A JP 2016570944A JP 2016570944 A JP2016570944 A JP 2016570944A JP 6537532 B2 JP6537532 B2 JP 6537532B2
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- alkyl
- independently selected
- cycloalkyl
- compound
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Description
本出願は、2014年2月25日付けで出願された米国仮特許出願第61/944,189号、2014年7月10日付けで出願された米国仮特許出願第62/022,916号及び2014年9月5日付けで出願された米国仮特許出願第62/046,783号の利益を主張するものである。これらの各出願の全体が全ての目的で引用することにより本明細書の一部をなす。
Q2はC(R2R2’)、C(R2R2’)−C(R2R2’)、S、O、N(R2)又はC(R2R2’)Oであり、
Q3はN(R3)、S又はC(R3R3’)であり、
(a)X1及びX2は独立してN、CH若しくはCZであるか、又は(b)X1及びX2はともにC=Cであり、
Q1、Q2、Q3、X1及びX2は安定した化合物が得られるように選択される。
(c)水素、ハロゲン、ヒドロキシル、ニトロ、シアノ、アミノ、C1〜C6アルキル、C2〜C6アルケニル、C1〜C6アルコキシ、C2〜C6アルキニル、C2〜C6アルカノイル、C1〜C6チオアルキル、ヒドロキシC1〜C6アルキル、アミノC1〜C6アルキル、−C0〜C4アルキルNR9R10、−C(O)OR9、−OC(O)R9、−NR9C(O)R10、−C(O)NR9R10、−OC(O)NR9R10、−O(ヘテロアリール)、−NR9C(O)OR10、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシ(ここでR9及びR10はいずれの場合にも独立して水素、C1〜C6アルキル、及び(C3〜C7シクロアルキル)C0〜C4アルキルから選ばれる)、
(d)−C0〜C4アルキル(C3〜C7シクロアルキル)及び−O−C0〜C4アルキル(C3〜C7シクロアルキル)。
(e)R1及びR1’又はR3及びR3’はともに3員〜6員の炭素環式スピロ環、又はN、O若しくはSから独立して選ばれる1個若しくは2個のヘテロ原子を含有する3員〜6員の複素環式スピロ環を形成していてもよく、
(f)R2及びR2’はともに3員〜6員の炭素環式スピロ環を形成していてもよく、
(g)R2及びR2’がともに3員〜6員の複素環式スピロ環を形成していてもよく、いずれの場合もスピロ環(e)、(f)及び(g)は非置換であるか、又はハロゲン(特にF)、ヒドロキシル、シアノ、−COOH、C1〜C4アルキル(特にメチルを含む)、C2〜C4アルケニル、C2〜C4アルキニル、C1〜C4アルコキシ、C2〜C4アルカノイル、ヒドロキシC1〜C4アルキル、(モノ−及びジ−C1〜C4アルキルアミノ)C0〜C4アルキル、−C0〜C4アルキル(C3〜C7シクロアルキル)、−O−C0〜C4アルキル(C3〜C7シクロアルキル)、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換され、
(h)R1及びR2はともに3員の炭素環を形成していてもよく、
(i)R1及びR2はともに4員〜6員の炭素環、又はN、O及びSから独立して選ばれる1個若しくは2個のヘテロ原子を含有する4員〜6員の複素環を形成していてもよく、
(j)R2及びR3は隣接炭素原子に結合する場合に、ともに3員〜6員の炭素環又は3員〜6員の複素環を形成していてもよく、いずれの場合も環(h)、(i)及び(j)は非置換であるか、又はハロゲン(特にF)、ヒドロキシル、シアノ、−COOH、C1〜C4アルキル(特にメチルを含む)、C2〜C4アルケニル、C2〜C4アルキニル、C1〜C4アルコキシ、C2〜C4アルカノイル、ヒドロキシC1〜C4アルキル、(モノ−及びジ−C1〜C4アルキルアミノ)C0〜C4アルキル、−C0〜C4アルキル(C3〜C7シクロアルキル)、−O−C0〜C4アルキル(C3〜C7シクロアルキル)、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換されていてもよい。
(m)−CHO、−CONH2、又はC(O)C3〜C7シクロアルキルを含むC2〜C6アルカノイル、
(n)水素、−SO2NH2、−C(CH2)2F、−CH(CF3)NH2、C1〜C6アルキル、−C0〜C4アルキル(C3〜C7シクロアルキル)、−C(O)C0〜C2アルキル(C3〜C7シクロアルキル)、
(o)−CHO、−C(O)NH2、−C(O)NH(CH3)又はC2〜C6アルカノイル、
(p)水素、ヒドロキシル、ハロゲン、シアノ、ニトロ、−COOH、−SO2NH2、−C(NH2)C1〜C3アルキル、−C(NH2)C1〜C3ハロアルキル、−CF(C=CH2)、−C(=NCN)C1〜C6アルキル、C1〜C6アルキル、C2〜C6アルケニル、C1〜C6アルコキシ、−C0〜C4アルキル(C3〜C7シクロアルキル)、−C(O)C0〜C4アルキル(C3〜C7シクロアルキル)、−P(O)(OR9)2、−OC(O)R9、−C(O)OR9、−C(O)N(CH2CH2R9)(R10)、−NR9C(O)R10、フェニル、又は5員若しくは6員のヘテロアリール。
(q)水素、ハロゲン、ヒドロキシル、ニトロ、シアノ、アミノ、−COOH、C1〜C2ハロアルキル、C1〜C2ハロアルコキシ、
(r)C1〜C6アルキル、−C0〜C4アルキル(C3〜C7シクロアルキル)、C2〜C6アルケニル、C2〜C6アルカノイル、C1〜C6アルコキシ、C2〜C6アルケニルオキシ、−C(O)OR9、C1〜C6チオアルキル、−C0〜C4アルキルNR9R10、−C(O)NR9R10、−SO2R9、−SO2NR9R10、−OC(O)R9及び−C(NR9)NR9R10(いずれの場合も(r)は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、アミノ、−COOH、−CONH2、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選択される1つ若しくは複数の置換基で置換され、いずれの場合も(r)はフェニル、並びにN、O及びSから独立して選ばれる1個、2個又は3個のヘテロ原子を含有する4員〜7員の複素環から選ばれる1つの置換基でも任意に置換され、そのフェニル又は4員〜7員の複素環は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルカノイル、C1〜C6アルコキシ、(モノ−及びジ−C1〜C6アルキルアミノ)C0〜C4アルキル、C1〜C6アルキルエステル、−(C0〜C4アルキル)(C3〜C7シクロアルキル)、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換される)、
(s)−C(CH2)2R30。
(t)は式:
(u)は結合であり、
(v)は限定されるものではないが、
(w)ハロゲン、ヒドロキシル、−COOH、シアノ、C1〜C6アルキル、C2〜C6アルカノイル、C1〜C6アルコキシ、−C0〜C4アルキルNR9R10、−SO2R9、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシ、
(x)ニトロ、C2〜C6アルケニル、C2〜C6アルキニル、C1〜C6チオアルキル、−JC3〜C7シクロアルキル、−B(OH)2、−JC(O)NR9R23、−JOSO2OR21、−C(O)(CH2)1〜4S(O)R21、SR9、−O(CH2)1〜4S(O)NR21R22、−JOP(O)(OR21)(OR22)、−JP(O)(OR21)(OR22)、−JOP(O)(OR21)R22、−JP(O)(OR21)R22、−JOP(O)R21R22、−JP(O)R21R22、−JSP(O)(OR21)(OR22)、−JSP(O)(OR21)(R22)、−JSP(O)(R21)(R22)、−JNR9P(O)(NHR21)(NHR22)、−JNR9P(O)(OR21)(NHR22)、−JNR9P(O)(OR21)(OR22)、−JC(S)R21、−JNR21SO2R22、−JNR9S(O)NR10R22、−JNR9SO2NR10R22、−JSO2NR9COR22、−JSO2NR9CONR21R22、−JNR21SO2R22、−JC(O)NR21SO2R22、−JC(NH2)NR22、−JC(NH2)NR9S(O)2R22、−JOC(O)NR21R22、−JNR21C(O)OR22、−JNR21OC(O)R22、−(CH2)1〜4C(O)NR21R22、−JC(O)R24R25、−JNR9C(O)R21、−JC(O)R21、−JNR9C(O)NR10R22、−CCR21、−(CH2)1〜4OC(O)R21及び−JC(O)OR23(いずれの場合も(x)は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、アミノ、オキソ、−B(OH)2、−Si(CH3)3、−COOH、−CONH2、−P(O)(OH)2、C1〜C6アルキル、C1〜C6アルコキシ、−C0〜C2アルキル(モノ−及びジ−C1〜C4アルキルアミノ)、C1〜C6アルキルエステル、C1〜C4アルキルアミノ、C1〜C4ヒドロキシルアルキル、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換されていてもよい)、
(y)ナフチル、ナフチルオキシ、インダニル、N、O及びSから選ばれる1個又は2個のヘテロ原子を含有する(4員〜7員のヘテロシクロアルキル)C0〜C4アルキル、並びにN、O及びSから独立して選ばれる1個、2個又は3個のヘテロ原子を含有し、各環中に4個〜7個の環原子を含有する二環式複素環(いずれの場合も(y)は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルカノイル、C1〜C6アルコキシ、(モノ−及びジ−C1〜C6アルキルアミノ)C0〜C4アルキル、C1〜C6アルキルエステル、−C0〜C4アルキル(C3〜C7シクロアルキル)、−SO2R9、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換される)、並びに、
(z)テトラゾリル、(フェニル)C0〜C2アルキル、(フェニル)C1〜C2アルコキシ、フェノキシ、並びにN、O、B及びSから独立して選ばれる1個、2個又は3個のヘテロ原子を含有する5員又は6員のヘテロアリール(いずれの場合も(z)は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルカノイル、C1〜C6アルコキシ、(モノ−及びジ−C1〜C6アルキルアミノ)C0〜C4アルキル、C1〜C6アルキルエステル、−C0〜C4アルキル(C3〜C7シクロアルキル)、−SO2R9、−OSi(CH3)2C(CH3)3、−Si(CH3)2C(CH3)3、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換される)。
(a)本明細書に記載の式Iの化合物、並びにその薬学的に許容可能な塩及びプロドラッグ(その各々並びにその下位群(subgenuses)及び種の全てが個別に考慮され、具体的に記載される)、
(b)加齢黄斑変性(AMD)、網膜変性、発作性夜間血色素尿症(PNH)、多発性硬化症(MS)及び関節リウマチ(RA)、並びに本明細書に更に記載される他の障害を含む補体経路、例えばカスケードD因子によって媒介される障害の治療又は予防に使用される本明細書に記載の式Iの化合物、並びにその薬学的に許容可能な塩及びプロドラッグ、
(c)加齢黄斑変性(AMD)、網膜変性、発作性夜間血色素尿症(PNH)、多発性硬化症(MS)及び関節リウマチ(RA)、並びに本明細書に更に記載される他の障害を含む補体カスケードD因子によって媒介される障害の治療又は予防に使用される薬剤の製造における式Iの化合物、並びにその薬学的に許容可能な塩及びプロドラッグの使用、
(d)本明細書に記載の式Iの化合物を製造に使用することを特徴とする、加齢黄斑変性(AMD)、網膜変性、発作性夜間血色素尿症(PNH)、多発性硬化症(MS)及び関節リウマチ(RA)、並びに本明細書に更に記載される他の障害を含む補体カスケードD因子によって媒介される障害を治療又は予防する治療的使用を対象とする薬剤を製造するプロセス、
(e)宿主の治療に効果的な量の式Iの化合物、又はその薬学的に許容可能な塩若しくはプロドラッグを薬学的に許容可能な担体又は希釈剤とともに含む医薬配合物、
(f)他の化学物質から実質的に単離されたものを含む実質的に純粋な形態の本明細書に記載の式Iの化合物(例えば、少なくとも90%又は95%)、
(g)式Iの化合物及びその塩、組成物、投薬形態を製造するプロセス、並びに、
(h)有効量の本明細書に記載の式Iの化合物を含有する治療用生成物を調製するプロセス。
化合物は正式名称を用いて記載される。他に規定のない限り、本明細書で使用される全ての技術用語及び科学用語は、本発明が属する技術分野の当業者により一般に理解されるものと同じ意味を有する。
本発明によると、式I:
一態様では、本開示は、式Iの範囲内である式II、III、IV、V、VI、VII、VIII、IX、X、XI、XII、XIII、XIV、XV、XVI、XVII、XVIII、XIX、XX、XXI、XXII、XXIII、XXIV、XXV、XXVI、XXVII、XXVIII、XXIX及びXXXの化合物及び塩を含む。式II〜XXXに示される可変部分は、式Iについて発明の概要の欄に記載の定義又は本開示に記載の定義のいずれかを有する。
式Iの化合物、その薬学的に許容可能な塩又は組成物が補体D因子の優れた阻害剤であることが発見された。
(q)水素、ハロゲン、ヒドロキシル、ニトロ、シアノ、アミノ、−COOH、C1〜C2ハロアルキル、C1〜C2ハロアルコキシ、
(r)C1〜C6アルキル、−C0〜C4アルキル(C3〜C7シクロアルキル)、C2〜C6アルケニル、C2〜C6アルカノイル、C1〜C6アルコキシ、C2〜C6アルケニルオキシ、−C(O)OR9、C1〜C6チオアルキル、−C0〜C4アルキルNR9R10、−C(O)NR9R10、−SO2R9、−SO2NR9R10、−OC(O)R9及び−C(NR9)NR9R10(いずれの場合も(r)は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、アミノ、−COOH、−CONH2、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選択される1つ若しくは複数の置換基で置換され、いずれの場合も(r)はフェニル、並びにN、O及びSから独立して選ばれる1個、2個又は3個のヘテロ原子を含有する4員〜7員の複素環から選ばれる1つの置換基でも任意に置換され、そのフェニル又は4員〜7員の複素環は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルカノイル、C1〜C6アルコキシ、(モノ−及びジ−C1〜C6アルキルアミノ)C0〜C4アルキル、C1〜C6アルキルエステル、−(C0〜C4アルキル)(C3〜C7シクロアルキル)、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換される)、
(s)−C(CH2)2〜4R30。
一実施形態において、本開示は、
R12及びR13の一方はHであり、R12及びR13の他方は(s)−C(CH2)2R30から選ばれ、
ここで、R30は上記の発明の概要の欄に規定されるとおりである、
式Iの化合物を提供する。
R1、R1’、R2及びR3’は全て水素であり、
R2はフルオロであり、R3は、水素、−C0〜C4アルキル(C3〜C7シクロアルキル)又は−O−C0〜C4アルキル(C3〜C7シクロアルキル)であり、
R5は、水素、ハロゲン又はC1〜C2アルキルであり、
R11、R13、R14及びR15は、存在する場合、いずれの場合も独立して水素、ハロゲン、ヒドロキシル、アミノ、C1〜C4アルキル、C1〜C4アルコキシ、−C0〜C2アルキル(モノ−及びジ−C1〜C2アルキルアミノ)、トリフルオロメチル及びトリフルオロメトキシから選ばれ、
X12はCR12であり、
R12は(s):(s)−C(CH2)2R30から選ばれ、
ここで、R30は上記の発明の概要の欄に規定されるとおりである、
式Iの化合物を提供する。
mは0又は1であり、
R2はハロゲンであり、R2’は水素又はハロゲンであり、R3は、水素、ハロゲン、−C0〜C4アルキル(C3〜C7シクロアルキル)又は−O−C0〜C4アルキル(C3〜C7シクロアルキル)であり、
R6は、−C(O)C1〜C4アルキル、−C(O)NH2、−C(O)CF3、−C(O)(C3〜C7シクロアルキル)又は−エチル(シアノイミノ)であり、
R12及びR13の一方は、水素、ハロゲン、C1〜C4アルキル、C1〜C4アルコキシ、トリフルオロメチル及びトリフルオロメトキシから選択され;R12及びR13の他方は(s):(s)−C(CH2)2R30から選ばれ、
ここで、R30は上記の発明の概要の欄に規定されるとおりである、
式Iの化合物を提供する。
R12及びR13の一方は、水素、ヒドロキシル、ハロゲン、メチル又はメトキシであり;R12及びR13の他方は(s):(s)−C(CH2)2R30から選ばれ、
ここで、R30は上記の発明の概要の欄に規定されるとおりである、
式Iの化合物を提供する。
式I中の中心コア部分を下記に例示する:
Q2はC(R2R2’)、C(R2R2’)−C(R2R2’)、S、O、N(R2)又はC(R2R2’)Oであり、
Q3はN(R3)、S又はC(R3R3’)であり、
(a)X1及びX2は独立してN若しくはCHであるか、又は(b)X1及びX2はともにC=Cであり、
ここでQ1、Q2、Q3、X1及びX2は安定した化合物が得られるように選択される)。
(c)水素、ハロゲン、ヒドロキシル、ニトロ、シアノ、アミノ、C1〜C6アルキル、C2〜C6アルケニル、C1〜C6アルコキシ、C2〜C6アルキニル、C2〜C6アルカノイル、C1〜C6チオアルキル、ヒドロキシC1〜C6アルキル、アミノC1〜C6アルキル、−C0〜C4アルキルNR9R10、−C(O)OR9、−OC(O)R9、−NR9C(O)R10、−C(O)NR9R10、−OC(O)NR9R10、−O(ヘテロアリール)、−NR9C(O)OR10、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシ(ここでR9及びR10はいずれの場合にも独立して水素、C1〜C6アルキル、(C3〜C7シクロアルキル)C0〜C4アルキルから選ばれる)、
(d)−C0〜C4アルキル(C3〜C7シクロアルキル)及び−O−C0〜C4アルキル(C3〜C7シクロアルキル)。
代替的な実施の形態では、以下の環(e)、(f)、(g)、(h)、(i)又は(j)のいずれか1つが存在し得る:
(e)R1及びR1’又はR3及びR3’はともに3員〜6員の炭素環式スピロ環、又はN、O若しくはSから独立して選ばれる1個若しくは2個のヘテロ原子を含有する3員〜6員の複素環式スピロ環を形成していてもよく、
(f)R2及びR2’はともに3員〜6員の炭素環式スピロ環を形成していてもよく、
(g)R2及びR2’がともに3員〜6員の複素環式スピロ環を形成していてもよく、いずれの場合もスピロ環(e)、(f)及び(g)は非置換であるか、又はハロゲン(特にF)、ヒドロキシル、シアノ、−COOH、C1〜C4アルキル(特にメチルを含む)、C2〜C4アルケニル、C2〜C4アルキニル、C1〜C4アルコキシ、C2〜C4アルカノイル、ヒドロキシC1〜C4アルキル、(モノ−及びジ−C1〜C4アルキルアミノ)C0〜C4アルキル、−C0〜C4アルキル(C3〜C7シクロアルキル)、−O−C0〜C4アルキル(C3〜C7シクロアルキル)、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換され、
(h)R1及びR2はともに3員の炭素環を形成していてもよく、
(i)R1及びR2はともに4員〜6員の炭素環、又はN、O及びSから独立して選ばれる1個若しくは2個のヘテロ原子を含有する4員〜6員の複素環を形成していてもよく、
(j)R2及びR3は隣接炭素原子に結合する場合に、ともに3員〜6員の炭素環又は3員〜6員の複素環を形成していてもよく、いずれの場合も環(h)、(i)及び(j)は非置換であるか、又はハロゲン(特にF)、ヒドロキシル、シアノ、−COOH、C1〜C4アルキル(特にメチルを含む)、C2〜C4アルケニル、C2〜C4アルキニル、C1〜C4アルコキシ、C2〜C4アルカノイル、ヒドロキシC1〜C4アルキル、(モノ−及びジ−C1〜C4アルキルアミノ)C0〜C4アルキル、−C0〜C4アルキル(C3〜C7シクロアルキル)、−O−C0〜C4アルキル(C3〜C7シクロアルキル)、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換されていてもよい。
(t)は式:
(u)は結合であり、
(v)は限定されるものではないが、
(w)ハロゲン、ヒドロキシル、−COOH、シアノ、C1〜C6アルキル、C2〜C6アルカノイル、C1〜C6アルコキシ、−C0〜C4アルキルNR9R10、−SO2R9、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシ、
(x)ニトロ、C2〜C6アルケニル、C2〜C6アルキニル、C1〜C6チオアルキル、−JC3〜C7シクロアルキル、−B(OH)2、−JC(O)NR9R23、−JOSO2OR21、−C(O)(CH2)1〜4S(O)R21、SR9、−O(CH2)1〜4S(O)NR21R22、−JOP(O)(OR21)(OR22)、−JP(O)(OR21)(OR22)、−JOP(O)(OR21)R22、−JP(O)(OR21)R22、−JOP(O)R21R22、−JP(O)R21R22、−JSP(O)(OR21)(OR22)、−JSP(O)(OR21)(R22)、−JSP(O)(R21)(R22)、−JNR9P(O)(NHR21)(NHR22)、−JNR9P(O)(OR21)(NHR22)、−JNR9P(O)(OR21)(OR22)、−JC(S)R21、−JNR21SO2R22、−JNR9S(O)NR10R22、−JNR9SO2NR10R22、−JSO2NR9COR22、−JSO2NR9CONR21R22、−JNR21SO2R22、−JC(O)NR21SO2R22、−JC(NH2)NR22、−JC(NH2)NR9S(O)2R22、−JOC(O)NR21R22、−JNR21C(O)OR22、−JNR21OC(O)R22、−(CH2)1〜4C(O)NR21R22、−JC(O)R24R25、−JNR9C(O)R21、−JC(O)R21、−JNR9C(O)NR10R22、−CCR21、−(CH2)1〜4OC(O)R21及び−JC(O)OR23(いずれの場合も(x)は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、アミノ、オキソ、−B(OH)2、−Si(CH3)3、−COOH、−CONH2、−P(O)(OH)2、C1〜C6アルキル、C1〜C6アルコキシ、−C0〜C2アルキル(モノ−及びジ−C1〜C4アルキルアミノ)、C1〜C6アルキルエステル、C1〜C4アルキルアミノ、C1〜C4ヒドロキシルアルキル、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換されていてもよい)、
(y)ナフチル、ナフチルオキシ、インダニル、N、O及びSから選ばれる1個又は2個のヘテロ原子を含有する(4員〜7員のヘテロシクロアルキル)C0〜C4アルキル、並びにN、O及びSから独立して選ばれる1個、2個又は3個のヘテロ原子を含有し、各環中に4個〜7個の環原子を含有する二環式複素環(いずれの場合も(y)は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルカノイル、C1〜C6アルコキシ、(モノ−及びジ−C1〜C6アルキルアミノ)C0〜C4アルキル、C1〜C6アルキルエステル、−C0〜C4アルキル(C3〜C7シクロアルキル)、−SO2R9、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換される)、並びに、
(z)テトラゾリル、(フェニル)C0〜C2アルキル、(フェニル)C1〜C2アルコキシ、フェノキシ、並びにN、O、B及びSから独立して選ばれる1個、2個又は3個のヘテロ原子を含有する5員又は6員のヘテロアリール(いずれの場合も(z)は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルカノイル、C1〜C6アルコキシ、(モノ−及びジ−C1〜C6アルキルアミノ)C0〜C4アルキル、C1〜C6アルキルエステル、−C0〜C4アルキル(C3〜C7シクロアルキル)、−SO2R9、−OSi(CH3)2C(CH3)3、−Si(CH3)2C(CH3)3、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換される)。
別の実施形態では、−L−B−は、
R26、R27及びR28は独立して水素、ハロゲン、ヒドロキシル、ニトロ、シアノ、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルカノイル、C1〜C6アルコキシ、C1〜C6チオアルキル、(モノ−及びジ−C1〜C6アルキルアミノ)C0〜C4アルキル、(C3〜C7シクロアルキル)C0〜C4アルキル、(アリール)C0〜C4アルキル−、(ヘテロアリール)C0〜C4アルキル−及び−C0〜C4アルコキシ(C3〜C7シクロアルキル)から選ばれ、いずれの場合も水素、ハロゲン、ヒドロキシル、ニトロ、シアノ以外のR26、R27及びR28は非置換であるか、又はハロゲン、ヒドロキシル、アミノ、C1〜C2アルコキシ、C1〜C2ハロアルキル、(C3〜C7シクロアルキル)C0〜C4アルキル−及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換され、
R29は水素、C1〜C2アルキル、C1〜C2ハロアルキル又は−Si(CH3)2C(CH3)3である)である。
(m)−CHO、−CONH2、又はC(O)C3〜C7シクロアルキルを含むC2〜C6アルカノイル、
(n)水素、−SO2NH2、−C(CH2)2F、−CH(CF3)NH2、C1〜C6アルキル、−C0〜C4アルキル(C3〜C7シクロアルキル)、−C(O)C0〜C2アルキル(C3〜C7シクロアルキル)、
(o)−CHO、−C(O)NH2、−C(O)NH(CH3)又はC2〜C6アルカノイル、
(p)水素、ヒドロキシル、ハロゲン、シアノ、ニトロ、−COOH、−SO2NH2、−C(NH2)C1〜C3アルキル、−C(NH2)C1〜C3ハロアルキル、−CF(C=CH2)、−C(=NCN)C1〜C6アルキル、C1〜C6アルキル、C2〜C6アルケニル、C1〜C6アルコキシ、−C0〜C4アルキル(C3〜C7シクロアルキル)、−C(O)C0〜C4アルキル(C3〜C7シクロアルキル)、−P(O)(OR9)2、−OC(O)R9、−C(O)OR9、−C(O)N(CH2CH2R9)(R10)、−NR9C(O)R10、フェニル、又は5員若しくは6員のヘテロアリール。
本発明を更に示すために、式IA、IB、IC及びIDの様々な実施形態を提示する。これらは、本発明に提示の化合物における変化の一部を示すために例として提示され、式I〜XXXのいずれにも適用することができる。
本発明を更に示すために、式VIIの様々な実施形態を提示する。一態様では、本開示は式VII:
R8及びR8’は独立して水素、ハロゲン及びメチルから選ばれ、
R5は水素、ヒドロキシル、シアノ、−COOH、C1〜C6アルキル、C1〜C6アルコキシ、C2〜C6アルカノイル、−C0〜C4アルキル(C3〜C7シクロアルキル)、−C(O)C0〜C4アルキル(C3〜C7シクロアルキル)、C1〜C2ハロアルキル又はC1〜C2ハロアルコキシであり、
R6は−C(O)CH3、−C(O)NH2、−C(O)CF3、−C(O)(シクロプロピル)又は−エチル(シアノイミノ)であり、
R11及びR14は独立して水素、ハロゲン、ヒドロキシル、アミノ、ニトロ、シアノ、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルカノイル、C1〜C6アルコキシ、C1〜C6チオアルキル、−C0〜C4アルキル(モノ−及びジ−C1〜C6アルキルアミノ)、−C0〜C4アルキル(C3〜C7シクロアルキル)、−OC0〜C4アルキル(C3〜C7シクロアルキル)、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから選ばれる)の化合物及び塩を含む。
本明細書に開示の化合物は純粋な(neat)化学物質として投与することができるが、治療を必要とする宿主に対して有効量の選択される本明細書に記載の式Iの化合物を含む医薬組成物としても投与することができる。したがって、本開示は、有効量の式Iの化合物又は薬学的に許容可能な塩を少なくとも1つの薬学的に許容可能な担体とともに含む医薬組成物を提供する。医薬組成物は、活性薬剤として式Iの化合物又は塩のみ、又は代替的な実施形態では、式Iの化合物及び少なくとも1つの更なる活性薬剤を含有し得る。幾つかの実施形態では、医薬組成物は単位投薬形態中に約0.1mg〜約2000mg、約10mg〜約1000mg、約100mg〜約800mg又は約200mg〜約600mgの式Iの化合物、及び任意に約0.1mg〜約2000mg、約10mg〜約1000mg、約100mg〜約800mg又は約200mg〜約600mgの更なる活性薬剤を含有する投薬形態である。例は少なくとも25mg、50mg、100mg、200mg、250mg、300mg、400mg、500mg、600mg、700mg又は750mgの活性化合物又はその塩を含む投薬形態である。医薬組成物はモル比の式Iの化合物及び更なる活性薬剤も含み得る。例えば、医薬組成物は約0.5:1、約1:1、約2:1、約3:1又は約1.5:1〜約4:1のモル比の別の抗炎症剤を含有し得る。
本明細書に開示の化合物及び医薬組成物は補体経路、特に補体D因子によって変調される経路によって媒介される障害の治療又は予防に有用である。幾つかの実施形態では、障害は宿主における炎症性障害、免疫障害、自己免疫障害又は補体D因子関連障害である。一実施形態では、障害は眼障害である。本開示の化合物及び組成物によって治療又は予防され得る補体媒介障害としては、敗血症の炎症作用、全身性炎症反応症候群(SIRS)、虚血/再灌流傷害(I/R傷害)、乾癬、重症筋無力症、全身性エリテマトーデス(SLE)、発作性夜間血色素尿症(PNH)、遺伝性血管浮腫、多発性硬化症、外傷、熱傷、毛細血管漏出症候群、肥満、糖尿病、アルツハイマー型認知症、脳卒中、統合失調症、癲癇、加齢黄斑変性、緑内障、糖尿病性網膜症、喘息、アレルギー、急性呼吸窮迫症候群(ARDS)、非典型溶血性尿毒症症候群(aHUS)、溶血性尿毒症症候群(HUS)、嚢胞性線維症、心筋梗塞、ループス腎炎、クローン病、関節リウマチ、アテローム性動脈硬化症、移植片拒絶反応、胎児消失の予防、生体材料反応(例えば血液透析、インプラントにおける)、C3糸球体腎炎、腹部大動脈瘤、視神経脊髄炎(NMO)、血管炎、神経障害、ギランバレー症候群、外傷性脳損傷、パーキンソン病、不適切な又は望ましくない補体活性化の障害、血液透析合併症、超急性同種移植片拒絶、異種移植片拒絶、IL−2療法時のインターロイキン−2誘導毒性、炎症性障害、自己免疫疾患の炎症、成人呼吸窮迫症候群、火傷又は凍傷を含む熱傷害(thermal injury)、心筋炎、虚血後再灌流病態、バルーン血管形成術、心肺バイパス又は腎臓バイパスにおけるポストポンプ(post-pump)症候群、血液透析、腎臓虚血、大動脈再建術後の腸間膜動脈再灌流、免疫複合体障害及び自己免疫疾患、SLE腎炎、増殖性腎炎、肝線維症、溶血性貧血、組織再生及び神経再生が挙げられるが、これらに限定されない。加えて、他の既知の補体関連疾患は肺疾患及び障害、例えば呼吸困難、喀血、慢性閉塞性肺疾患(COPD)、気腫、肺塞栓症及び梗塞、肺炎、線維形成粉塵疾患(fibrogenic dust diseases)、不活性粉塵及び鉱物(例えばケイ素、炭塵、ベリリウム及びアスベスト)、肺線維症、有機粉塵疾患、化学傷害(刺激性ガス及び化学物質、例えば塩素、ホスゲン、二酸化硫黄、硫化水素、二酸化窒素、アンモニア及び塩酸に起因する)、煙傷害(smoke injury)、熱傷害(例えば火傷、凍傷)、気管支収縮、過敏性肺炎、寄生虫性疾患、グッドパスチャー症候群、肺血管炎、微量免疫型血管炎、免疫複合体関連炎症、ブドウ膜炎(ベーチェット病及びブドウ膜炎の他の亜型を含む)、抗リン脂質抗体症候群、関節炎、自己免疫心臓病、炎症性腸疾患、虚血再灌流傷害、バラクワ−サイモン(Barraquer-Simons)症候群、血液透析、全身性エリテマトーデス(systemic lupus)、エリテマトーデス(lupus erythematosus)、移植、中枢神経系の疾患及び他の神経変性病態、糸球体腎炎(膜増殖性糸球体腎炎を含む)、水疱形成性皮膚疾患(水疱性類天疱瘡、天痘瘡及び表皮水疱症を含む)、眼部瘢痕性類天疱瘡、MPGN II、ブドウ膜炎、成人黄斑変性、糖尿病性網膜症、網膜色素変性症、黄斑浮腫、ベーチェットブドウ膜炎、多病巣性脈絡膜炎、フォークト小柳原田症候群、中間部ブドウ膜炎、散弾脈絡網膜炎、交感性眼炎、眼部瘢痕性類天疱瘡、眼天痘瘡、非動脈炎性虚血性視神経症、術後炎症及び網膜静脈閉塞である。
一実施形態では、式Iの化合物又は塩は、少なくとも1つの更なる補体系の阻害剤又は異なる生物学的作用機序を有する第2の活性化合物と組み合わせて又は交互に与えることができる。一実施形態では、式Iの化合物又は塩は補体C5阻害剤又はC5転換酵素阻害剤と組み合わせて与えることができる。別の実施形態では、式Iの化合物又は塩はエクリズマブと組み合わせて与えることができる。一実施形態では、式Iの化合物又は塩はD因子の更なる阻害剤と組み合わせて与えることができる。
プロテアーゼ阻害剤:血漿由来C1−INH濃縮物、例えばCetor(商標)(Sanquin)、Berinert−P(商標)(CSL Behring、Lev Pharma)及びCinryze(商標)、並びに組み換えヒトC1阻害剤、例えばRhucin(商標)、
可溶性補体調節因子:可溶性補体受容体1(TP10)(Avant Immunotherapeutics)、sCR1−sLex/TP−20(Avant Immunotherapeutics)、MLN−2222/CAB−2(Millenium Pharmaceuticals)、Mirococept(Inflazyme Pharmaceuticals)、
治療用抗体:エクリズマブ/Soliris(Alexion Pharmaceuticals)、パキセリズマブ(Alexion Pharmaceuticals)、オファツムマブ(Genmab A/S)、TNX−234(Tanox)、TNX−558(Tanox)、TA106(Taligen Therapeutics)、ニュートラツマブ(G2 Therapies)、抗プロパージン(Novelmed Therapeutics)、HuMax−CD38(Genmab A/S)、
補体成分阻害剤:Compstatin/POT−4(Potentia Pharmaceuticals)、ARC1905(Archemix)、
受容体アゴニスト:PMX−53(Peptech Ltd.)、JPE−137(Jerini)、JSM−7717(Jerini)、
その他:組み換えヒトMBL(rhMBL;Enzon Pharmaceuticals)。
略語
(Boc)2O 二炭酸ジ−tert−ブチル
ACN アセトニトリル
AcOEt、EtOAc 酢酸エチル
CH3OH、MeOH メタノール
CsF フッ化セシウム
CuI ヨウ化第一銅
DCM、CH2Cl2 ジクロロメタン
DIEA、DIPEA N,N−ジイソプロピルエチルアミン
DMA N,N−ジメチルアセトアミド
DMF N,N−ジメチルホルムアミド
DMSO ジメチルスルホキシド
DPPA ジフェニルホスホリルアジド
Et3N、TEA トリエチルアミン
EtOAc 酢酸エチル
EtOH エタノール
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
HCl 塩酸
iPr2NEt N,N−ジイソプロピルエチルアミン
K2CO3 炭酸カリウム
LiOH 水酸化リチウム
MTBE メチルtブチルエーテル
Na2SO4 硫酸ナトリウム
NaCl 塩化ナトリウム
NaH 水素化ナトリウム
NaHCO3 重炭酸ナトリウム
NEt3、TEA トリエチルアミン
Pd(OAc)2 酢酸パラジウム
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)
Pd(PPh3)2Cl2 ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド
Pd(PPh3)4 テトラキス(トリフェニルホスフィン)パラジウム(0)
Pd2(dba)3 トリス(ジベンジリデンアセトン)ジパラジウム(0)
PPh3 トリフェニルホスフィン
RT 室温
TBTU O−ベンゾトリアゾリルテトラメチルイソウロニウムテトラフルオロボレート
tBuOK カリウムtert−ブトキシド
Tf2O トリフルオロメタンスルホン酸無水物
TFA トリフルオロ酢酸
THF テトラヒドロフラン
TMSBr ブロモトリメチルシラン
tR 保持時間
Zn(CN)2 シアン化亜鉛
全ての非水性反応は乾燥アルゴン又は窒素ガスの雰囲気下で無水溶媒を使用して行った。反応の進行及び標的化合物の純度は、下に挙げる2つの液体クロマトグラフィー(LC)法の一方を用いて決定した。出発物質、中間体及び最終生成物の構造は、NMR分光法及び質量分析を含む標準分析法を用いて確認した。
機器:WatersのAcquity Ultra Performance LC
カラム:ACQUITY UPLC BEH C18 2.1×50mm、1.7μm
カラム温度:40℃
移動相:溶媒A:H2O+0.05%FA;溶媒B:CH3CN+0.05%FA
流量:0.8mL/分
勾配:15%のBで0.24分間、勾配(15%→85%のB)で3.26分間、次いで85%のBで0.5分間
検出:UV(PDA)、ELS及びMS(EIモードでのSQ)
機器:株式会社島津製作所のLC−2010A HT
カラム:Athena、C18−WP、50×4.6mm、5μm
カラム温度:40℃
移動相:溶媒A:H2O/CH3OH/FA=90/10/0.1;溶媒B:H2O/CH3OH/FA=10/90/0.1
流量:3mL/分
勾配:30%のBで0.4分間、勾配(30%→100%のB)で3.4分間、次いで100%のBで0.8分間
検出:UV(220/254nm)
本発明の化合物は、例えば中心コアから調製することができる。一実施形態では、例えば中心コア構造1は、X1が窒素であり、PG=保護基であるN−保護アミノ酸である。一実施形態では、中心コアをアミンとカップリングして、構造2のアミドを生成する(ここでL−BはC(O)N部分を含む)。次いで、構造2を脱保護して構造3を生成することができる。構造3を構造4(A−COOH)とカップリングして、第2のアミド結合を生成し、式I内の化合物を形成する。その化学反応を経路1に示す。
A−C(O)−部分の調製の例は実施例1及び下記に見ることができる。
A−C(O)−部分への中心−L−B−シントンのカップリングの例は実施例1及び下記に見ることができる。
スキーム1. (2S,4R)−N−(2’−クロロ−2−フルオロ−[1,1’−ビフェニル]−3−イル)−4−フルオロピロリジン−2−カルボキサミドヒドロクロリド(Int−1)の合成
溶媒(ジオキサン 400mL、H2O 100mL)中のSM1(30g)、SM2(60g)、K2CO3(91g)及びPd(dppf)2Cl2(19.25g)の混合物を、圧力容器内で5分間アルゴンによりパージし、100℃で15時間撹拌した。溶媒を減圧下で除去し、残りの残渣をカラムクロマトグラフィーによって精製した。次いで、精製した物質をMeOHに溶解し、HCl/MeOHで処理した。溶媒を減圧下で除去し、残りの固体をIPA−ヘプタン(1/1)で洗浄して、SM3を得た。
SM4(530mg)のDCM(20mL)氷冷溶液に、1−クロロ−N,N,2−トリメチル−1−プロペニルアミン(0.333mL、1.1当量)を撹拌しながら滴加した。撹拌をこの温度で3時間続けた後、固体SM3(640mg、1.1当量)、続いてDIEA(1.12mL、3当量)を添加した。冷却浴を取り外し、反応混合物を室温で一晩撹拌した。次いで、反応混合物を水(20mL)に添加し、DCM(2×25mL)で抽出した。有機層をNaHCO3水溶液(20mL)、水(20mL)及びブライン(20mL)で続けて洗浄した後、Na2SO4で乾燥させ、減圧下で濃縮した。残りの残渣をカラムクロマトグラフィー(ヘキサン/EtOAcで溶出)によって精製し、SM5を得た。
(2S,4R)−tert−ブチル2−((2’−クロロ−2−フルオロ−[1,1’−ビフェニル]−3−イル)カルバモイル)−4−フルオロピロリジン−1−カルボキシレートSM5(700mg)をジオキサン(25mL)中の4N HClに取り、得られた反応混合物を室温で3時間撹拌した。次いで、溶媒を減圧下で除去し、残りの残渣Int−1を更に精製することなく直接使用した。
SM6(30g)のDCM(600mL)氷冷溶液に、1−クロロ−N,N,2−トリメチル−1−プロペニルアミン(18.7mL、1.1当量)を撹拌しながら滴加した。撹拌をこの温度で3時間続けた。次いで、固体SM7(24.48g、1.1当量)、続いてDIEA(67.2mL、3当量)を添加した。冷却浴を取り外し、反応混合物を室温で一晩撹拌した。溶媒をMeOH(30mL)とともに同時蒸発させた。次いで、残渣をクロロホルム(300mL)に溶解し、冷1N HCl水溶液(3×200mL)、水(300mL)及び飽和NaHCO3水溶液(300mL)で続けて洗浄した。有機層を乾燥させ(Na2SO4)、減圧下で濃縮した。残りの残渣をDCM及びヘプタンの1:1溶液(150mL)中で撹拌した。白色の固体を濾過によって単離し、高真空下で乾燥させて、SM8(37.3g)を得た。
SM8をDCMに溶解し、同量のTFAを添加した。混合物を室温で30分間撹拌した。揮発性物質を減圧下で除去し、残渣Int−2を更に精製することなく使用した。
表題化合物99b(310mg)を、3−ブロモチオフェン−2−カルバルデヒド99aから文献(Airey, J. et al. Synthesis 2014, 96-100)に従って調製した。1H NMR(400MHz,CDCl3,300K):δ 7.11(s,1H)、7.60(s,1H)、7.76+8.03(1H)、13.33+13.0(1H)。
DMF(10mL)中の1H−チエノ[3,2−c]ピラゾール99b(310mg、2.5mmol)をヨウ素(954mg、3.76mmol)、続いて粉末KOH(421mg、7.5mmol)で処理した。混合物を室温で一晩撹拌した。混合物を水(50mL)で希釈し、続いて10%Na2S2O3溶液(5mL)を添加した。混合物を酢酸エチル(3×50mL)で抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸マグネシウムで乾燥させた。溶液を濾過し、濃縮し、残渣99cを精製することなく次の工程に使用した。
工程2による残渣99cをCH3CN(50mL)に溶解した。この溶液にtert−ブチル2−ブロモアセテート(634mg、0.48mL、3.25mmol)及び固体炭酸カリウム(1.03g、7.5mmol)を添加した。混合物をアルゴン雰囲気下で一晩還流させた。反応混合物を室温まで冷却し、Celite(商標)のパッドを通して濾過した。固体ケーキをCH3CN(20mL)で洗浄し、合わせた溶液を減圧下で濃縮した。残りの残渣をカラムクロマトグラフィーによって精製して、純粋化合物99d(610mg)及び不純異性体tert−ブチル2−(3−ヨード−2H−チエノ[3,2−c]ピラゾール−2−イル)アセテート(130mg)を得た。1H NMR(400MHz,CDCl3):δ 1.45(s,9H)、4.93(s,2H)、6.93(d,J=5.2Hz,1H)、7.42(d,J=5.2Hz,1H)。LC/MS(EI) m/z:[M+H]+ 365。
共溶媒DMF(14mL)及び水(2mL)中のt−ブチル2−(3−ヨード−1H−チエノ[3,2−c]ピラゾール−1−イル)アセテート99d(610mg、1.67mmol)の脱気溶液に、ZN(CN)2(235mg、2.0mmol)、Pd(dppf)2(125mg、0.17mmol)及びPd2(dba)3(156mg、0.17mmol)をアルゴン雰囲気下で添加した。混合物を110℃で6時間加熱した。反応混合物を室温まで冷却し、揮発性物質を減圧下で除去した。残りの残渣を酢酸エチル(50mL)で希釈し、Celite(商標)のパッドを通して濾過した。固体を酢酸エチル(30mL)で洗浄した。合わせた有機溶液を減圧下で濃縮し、残りの残渣をカラムクロマトグラフィーによって精製して、表題化合物99e(290mg)を得た。1H NMR(400MHz,CDCl3,300K):δ 1.47(s,9H)、5.0(s,2H)、6.93(d,J=5.2Hz,1H)、7.52(d,J=5.2Hz,1H)。LC/MS(EI) m/z:[M+H]+ 264。
tert−ブチル2−(3−シアノ−1H−チエノ[3,2−c]ピラゾール−1−イル)アセテート(59mg、0.22mmol)のTFA(2mL)溶液をマイクロ波照射に140℃で30分間供した。混合物を減圧下で濃縮し、残渣をトルエン(10mL)とともに2回同時蒸発させた。乾燥させた残渣99fを次の工程に直接使用した。LC/MS(EI)m/z:226。
工程5による残渣99f(0.22mmol)の溶液に、DMF(2mL)中の(2S,4R)−N−(2’−クロロ−2−フルオロ−[1,1’−ビフェニル]−3−イル)−4−フルオロピロリジン−2−カルボキサミドヒドロクロリドInt−1(90mg、0.24mmol)、続いてHATU(109mg、0.29mmol)を添加し、DIEA(0.3mL)を室温で滴加した。反応混合物を室温で1時間撹拌し、揮発性物質を減圧下で除去した。残渣を20mLの10%炭酸ナトリウムで希釈し、酢酸エチル(3×20mL)で抽出した。合わせた有機溶液を水及びブラインで洗浄した後、MgSO4で乾燥させた。溶液を濾過し、溶媒を減圧下で除去した。残りの残渣をカラムクロマトグラフィーによって精製して、99(50.7mg)を得た。1H NMR(400MHz,DMSO−d6,300K):(主回転異性体) δ 2.00−2.19(m,1H)、2.47−2.53(m,1H)、3.75−3.88(m,1H)、4.02−4.11(m,1H)、4.70(t,J=8.8Hz,1H)、5.26(d,J=17.2Hz,1H)、5.38−5.49(m,2H)、6.97−7.01(m,1H)、7.05(d,J=5.2Hz,1H)、7.15(t,J=7.6Hz,1H)、7.30−7.41(m,4H)、7.51−7.54(m,2H)、7.60−7.62(m,1H)、7.89−7.93(m,1H)、9.92(s,1H);19F NMR(376MHz,DMSO−d6,300K):(主回転異性体) δ −126.8、−175.8。LC(方法A):tR=1.94分。LC/MS(EI) m/z:[M+H]+ 544。
4−ブロモ−2−メチルチオフェン113a(11g、62mmol)の−78℃に冷却した無水THF(100mL)溶液に、2M LDA−THF溶液(34mL、68mmol)をアルゴン雰囲気下で滴加した。混合物を−78℃で2時間撹拌した後、無水DMF(9.6mL、124mmol)を添加した。反応混合物を−78℃に1時間維持し、10%クエン酸水溶液(10mL)でクエンチした。揮発性物質を減圧下で除去し、残りの残渣を酢酸エチル(150mL)で希釈した。有機層を5%クエン酸水溶液(80mL)、水(100mL)及びブライン(50mL)で続けて洗浄した後、MgSO4で乾燥させた。溶液を濾過し、減圧下で濃縮して、淡黄色の油として113b(12.3g)を得て、これを更に精製することなく次の工程に使用した。
表題化合物113c(3.0g)を、3−ブロモ−5−メチルチオフェン−2−カルバルデヒド113b(12.2g)から文献(Airey, J. et al. Synthesis 2014, 96-100)に報告されるものと同様の方法で調製した。1H NMR(400MHz,CDCl3,300K):δ 2.49(s,3H)、6.86(s,1H)、7.65+7.89(1H)、12.83+13.10(1H)。LC/MS(EI) m/z:[M+H]+ 139。
表題化合物113dを、5−メチル−1H−チエノ[3,2−c]ピラゾール(1.0g)からスキーム3の工程2において記載されるものと同様の方法で調製した。
表題化合物113eを、スキーム3の工程3において記載されるものと同様の方法で3−ヨード−5−メチル−1H−チエノ[3,2−c]ピラゾールから調製した。1H NMR(400MHz,CDCl3):1.46(s,9H)、2.53(s,3H)、4.87(s,2H)、6.64(s,1H) ppm。MH+ 379.09。微量生成物はtert−ブチル2−(3−ヨード−5−メチル−2H−チエノ[3,2−c]ピラゾール−2−イル)アセテートである。1H NMR(400MHz,CDCl3,300K):δ 1.47(s,9H)、2.51(s,3H)、4.98(s,2H)、6.80(s,1H)。LC/MS(EI) m/z:[M+H]+ 379。
表題化合物113fを、tert−ブチル2−(3−ヨード−5−メチル−1H−チエノ[3,2−c]ピラゾール−1−イル)アセテート(823mg、2.15mmol)からスキーム3の工程4において記載されるものと同様の方法で調製した。1H NMR(400MHz,CDCl3,300K):δ 1.47(s,9H)、2.56(s,3H)、4.93(s,2H)、6.65(s,1H)。LC/MS(EI) m/z:[M+H]+ 278。
表題化合物113gを、tert−ブチル2−(3−シアノ−5−メチル−1H−チエノ[3,2−c]ピラゾール−1−イル)アセテート(143mg)からスキーム3の工程5において記載されるものと同様の方法で調製した。LC/MS(EI) m/z:[M+H]+ 240。
表題化合物113(86.9mg)を、2−(3−カルバモイル−5−メチル−1H−チエノ[3,2−c]ピラゾール−1−イル)酢酸(105mg、0.3mmol)からスキーム3の工程6において記載されるものと同様の方法で調製した。1H NMR(400MHz,DMSO−d6,300K):(主回転異性体) δ 2.06−2.19(m,1H)、2.39(s,3H)、2.40−2.55(m,1H)、3.74−3.87(m,1H)、4.02−4.10(m,1H)、4.69(t,J=8.8Hz,1H)、5.18(d,J=17.2Hz,1H)、5.31−5.51(m,2H)、6.79(s,1H)、7.0(t,J=7.2Hz,1H)、7.15(t,J=8.0Hz,1H)、7.24−7.46(m,4H)、7.50−7.53(m,2H)、7.87−7.92(m,1H)、9.92(s,1H);19F NMR(376MHz,DMSO−d6,300K):(主回転異性体) δ −126.71、−175.87。LC(方法A):tR=2.10分。LC/MS(EI) m/z:[M+H]+ 558。
エチル4,5,6,7−テトラヒドロ−1H−インダゾール−3−カルボキシレート104a(1.03g、5.35mmol)のCH3CN(50mL)溶液に、tert−ブチル2−ブロモアセテート(1.17g、0.89mL、6.0mmol)及び炭酸カリウム(1.5g、10.6mmol)を添加した。混合物をアルゴン雰囲気下で一晩還流させた。LC−MS分析により、2つの異性体が4:1の比率で形成されたことが示された。反応混合物を室温まで冷却し、Celite(商標)のパッドを通して濾過した。固体ケーキをCH3CN(20mL)で洗浄し、合わせた溶液を減圧下で濃縮した。残りの残渣をカラムクロマトグラフィーによって精製して、主要異性体エチル1−(2−(tert−ブトキシ)−2−オキソエチル)−4,5,6,7−テトラヒドロ−1H−インダゾール−3−カルボキシレート104b(1.37g)及び微量異性体エチル2−(2−(tert−ブトキシ)−2−オキソエチル)−4,5,6,7−テトラヒドロ−2H−インダゾール−3−カルボキシレート104c(0.28g)を得た。1H NMR(400MHz,CDCl3,300K):(主要異性体) δ 1.38(t,J=7.2Hz,3H)、1.45(s,9H)、1.75(m,2H)、1.82(m,2H)、2.52(t,J=5.2Hz,2H)、2.75(t,J=5.2Hz,2H)、4.37(q,J=7.2Hz,2H)、4.77(s,2H)。LC/MS(EI) m/z:309。1H NMR(400MHz,CDCl3,300K):(微量異性体) δ 1.35(t,J=7.2Hz,3H)、1.47(s,9H)、1.74−1.80(m,4H)、2.67(t,J=5.2Hz,2H)、2.75(t,J=5.2Hz,2H)、4.30(q,J=7.2Hz,2H)、5.11(s,2H)。LC/MS(EI) m/z:[M+H]+ 309。
エチル1−(2−(tert−ブトキシ)−2−オキソエチル)−4,5,6,7−テトラヒドロ−1H−インダゾール−3−カルボキシレート104b(1.35g、4.38mmol)をTFA(5mL)及びDCM(5mL)で処理し、室温で一晩撹拌した。揮発性物質を減圧下で除去し、残りの残渣をトルエン(10mL)で2回同時蒸発させた。乾燥させた残渣104dを直接次の工程に使用した。
工程2による残渣104dの溶液(375mg、1.5mmol)に、DMF(2mL)中の(2S,4R)−N−(2’−クロロ−2−フルオロ−[1,1’−ビフェニル]−3−イル)−4−フルオロピロリジン−2−カルボキサミドヒドロクロリド(560mg、1.5mmol)、続いてHATU(741mg、1.95mmol)を添加し、DIEA(4.5mmol、0.78mL)を滴加した。混合物を室温で1時間撹拌し、揮発性物質を減圧下で除去した。残りの残渣を10%炭酸ナトリウム水溶液(20mL)及び水(50mL)で希釈した後、酢酸エチル(3×50mL)で抽出した。合わせた有機抽出物を水及びブラインで洗浄した後、MgSO4で乾燥させた。溶液を濾過し、溶媒を減圧下で除去した。残りの残渣をカラムクロマトグラフィーによって精製し、表題化合物104e(608mg)を得た。LC/MS(EI)m/z:[M+H]+571。
工程3による化合物104e(608mg、1.06mmol)を、MeOH−THF−H2Oの混合物(3mL−3mL−3mL)に溶解し、LiOH(100mg、4.25mmol)で処理した。反応混合物を室温で一晩撹拌した。揮発性物質を減圧下で除去し、残りの残渣を10%クエン酸水溶液(10mL)で酸性化した。固体104fを濾過によって回収し、水で洗浄し、次の工程に使用するために真空乾燥した。LC/MS(EI) m/z:[M+H]+ 543。
工程4による酸104f(252mg、0.46mmol)をDMF(3mL)中のNH4Cl(125mg、2.32mmol)と混合した。この溶液にHATU(262mg、0.69mmol)を添加し、続いてDIEA(1.38mmol、0.24mL)を滴加した。混合物を室温で3時間撹拌し、揮発性物質を減圧下で除去した。残りの残渣を10%炭酸ナトリウム水溶液(15mL)及び水(15mL)で希釈した後、酢酸エチル(3×25mL)で抽出した。合わせた有機溶液を水及びブラインで洗浄した後、MgSO4で乾燥させた。混合物を濾過し、濾液を減圧下で濃縮した。残りの残渣をカラムクロマトグラフィーによって精製して、表題化合物104(160mg)を得た。1H NMR(400MHz,DMSO−d6,300K):(主回転異性体) δ 1.53−1.61(m,4H)、1.99−2.16(m,1H)、2.38−2.41(m,3H)、2.54−2.56(m,2H)、3.40−3.53(m,1H)、3.93−4.07(m,1H)、4.68(t,J=8.8Hz,1H)、4.90−5.14(m,2H)、5.36−5.49(1H)、6.93−7.19(m,4H)、7.32−7.43(m,3H)、7.52−7.54(m,1H)、7.92(t,J=6.8Hz,1H)、9.90(s,1H);19F NMR(376MHz,DMSO−d6,300K):(主回転異性体) δ −126.8、−176.06。LC(方法A):tR=2.02分。LC/MS(EI) m/z:[M+H]+ 542。
1−(1−アジドビニル)−3−クロロベンゼン105a(0.05g)(Donthiri et al. J. Org. Chem 2014, 79, 11277-11284によって報告されたように調製した)、メチル2−(3−アセチル−1H−ピラゾロ[3,4−c]ピリジン−1−イル)アセテート105b(0.195g)、CuI(1mg)及び4Å分子篩の混合物をバイアルに入れ、乾燥アセトニトリル(3mL)を添加した。密閉したバイアルを65℃で24時間加熱した。反応混合物を室温まで冷却し、溶媒を減圧下で除去した。残りの残渣をカラムクロマトグラフィー(溶離液:DCM)によって精製して、105c(20mg)を薄橙色の固体として得た。
工程1による固体105c(20mg、0.052mmol)をTHF(3mL)、水(0.3mL)及びMeOH(1mL)に取った後、1N NaOH水溶液(1mL)を添加した。得られた混合物を室温で一晩撹拌し、減圧下で濃縮した。残りの残渣をEtOAc及び水で希釈した。有機層を分離し、水層をEtOAcで繰り返し抽出した。合わせた有機層を乾燥させ、濃縮し、105dを薄黄色の固体として得て、これを次の工程にそのまま使用した。
2−(3−アセチル−8−(3−クロロフェニル)−1H−ピラゾロ[4,3−g]インドリジン−1−イル)酢酸105d(0.052mmol)及び(2S,4R)−N−(6−ブロモピリジン−2−イル)−4−フルオロピロリジン−2−カルボキサミドTFA塩(0.05mmol)の0℃〜5℃に冷却したDMF(1mL)溶液にDIEA(47μL)を添加した。次いで、HATU(24mg)をこの冷却溶液に添加し、冷却浴を取り外した。反応混合物を室温で30分間撹拌し、撹拌しながら水(10mL)中に注ぎ入れた。固体を濾過によって単離し、カラムクロマトグラフィー(溶離液:DCM中0→1.5%のMeOH)によって精製して、105(10mg)を薄黄色の固体として得た。1H NMR(400MHz,CDCl3,300K):(主回転異性体) δ 2.48−2.52(m,1H)、2.73(s,3H)、2.78−2.94(m,1H)、4.04−4.27(m,2H)、4.95(t,J=7.6Hz,1H)、5.51(d,J=52.4Hz,1H)、5.77(d,J=16Hz,1H)、5.88(d,J=16Hz,1H)、6.99(d,J=8.4Hz,1H)、7.19−7.23(m,2H)、7.54−7.56(m,1H)、7.69−7.71(m,2H)、7.75(d,J=8Hz,1H)、7.85(s,1H)、7.87(d,J=7.2Hz,1H)、8.97(br s,1H);31F NMR(376MHz,CDCl3,300K):(主回転異性体) δ −176.04;LC(方法A):tR=2.60分。LC/MS(EI) m/z:[M+H]+ 640。
ブロモインダゾール111a(3g)のDMF(30mL)溶液に、塩化アンモニウム(1.8g)及びDIEA(10.38mL)を添加した。反応混合物を氷浴内で冷却した後、HATU(5.7g)を添加した。反応混合物を室温まで温め、一晩撹拌した。反応混合物を、LiOH(630mg)を含有する水(300mL)中に注ぎ入れた。生成物を濾過によって単離し、水で洗浄した。黄褐色の固体を高真空下で乾燥させて、111b(2.15g)を得た。
無水アセトニトリル(40mL)中の7−ブロモ−1H−インダゾール−3−カルボキサミド111b(2.15g)、tert−ブチルブロモアセテート(1.45mL)及び炭酸カリウム(1.36g)の混合物を2時間還流させた。次いで、反応混合物を室温まで冷却し、溶媒を減圧下で除去した。残りの残渣を水(40mL)で超音波処理し、濾過した。得られた固体を水で十分に洗浄し、更にtert−ブチルメチルエーテル及びヘプタンの2:1混合物(30mL)で洗浄し、高真空下で乾燥させて、111c(2.5g)を得た。
DMF(5mL)及び水(1mL)中のtert−ブチル2−(7−ブロモ−3−カルバモイル−1H−インダゾール−1−イル)アセテート111c(0.5g)、シアン化亜鉛(0.198g)、Pd(dppf)Cl2(0.115g)及びPd2(dba)3(0.129g)の混合物を、アルゴンで5分間バブリングした。次いで、バイアルを密閉し、80℃で3時間加熱した。反応混合物を室温まで冷却した後、EtOAcで希釈した。次いで、混合物を水及び飽和水溶液NaHCO3溶液で洗浄した。分離した有機層を乾燥させ(Na2SO4)、濃縮した。残りの残渣をカラムクロマトグラフィー(DCM中0→2%のMeOH)によって精製し、僅かに黄色の固体(0.3g)を得た。次いで、固体をエーテル(3mL)で洗浄して、111d(0.23g)を無色の固体として得た。
表題化合物111eをtert−ブチル2−(3−カルバモイル−7−シアノ−1H−インダゾール−1−イル)アセテート(50mg)から、スキーム7の工程2において記載されるものと同様の方法で調製し、更に精製することなく次の工程に使用した。
上記工程4による2−(3−カルバモイル−7−シアノ−1H−インダゾール−1−イル)酢酸111eを、スキーム3の工程6において記載される手順を用いて(2S,4R)−N−(2’−クロロ−2−フルオロ−[1,1’−ビフェニル]−3−イル)−4−フルオロピロリジン−2−カルボキサミドヒドロクロリドとカップリングした。粗生成物をカラムクロマトグラフィー(DCM中0→2%のMeOH)によって精製して、表題化合物111(50mg)を得た。1H NMR(400MHz,CD3OD,300K):(主回転異性体) δ 2.65−2.75(m,1H)、4.1−4.14(m,1H)、4.16−4.24(m,1H)、4.89(t,J=8.4Hz,1H)、5.52(d,J=52.8Hz,1H)、5.73(d,J=17.6Hz,1H)、5.89(d,J=17.6Hz,1H)、7.07(t,J=7.2Hz,1H)、7.19(t,J=8Hz,1H)、7.28−7.44(m,5H)、7.49−7.59(m,1H)、7.87(d,J=7.2Hz,1H)、7.91(s,1H)、7.97(t,J=7.2Hz,1H)、8.59(d,J=8Hz,1H)。)。31F NMR(376MHz,CD3OD,300K):(主回転異性体) δ −178.5,−128.8。LC(方法A):tR=2.09分。LC/MS(EI) m/z:[M+H]+ 563。
アルゴン雰囲気下の3−ブロモ−2−フルオロアニリン117a(1.0g)、(5−アセチル−2−クロロフェニル)ボロン酸117b(3.132g)、Pd(dppf)Cl2(0.860g)及びK2CO3(3.64g)の混合物に、ジオキサン(40mL)及び水(10mL)を添加した。混合物をアルゴンで5分間バブリングし、撹拌しながら100℃で一晩加熱した。次いで、反応混合物をCelite(商標)のパッドを通して濾過し、濾液を減圧下で濃縮した。残りの残渣をカラムクロマトグラフィー(DCM中の0→0.5%のMeOH)によって精製して、117c(0.9g)を橙黄色の油として得た。
(2S,4R)−1−(tert−ブトキシカルボニル)−4−フルオロピロリジン−2−カルボン酸(0.25g、1.07mmol)のDCM(15mL)氷冷溶液に、1−クロロ−N,N,2−トリメチルプロパ−1−エン−1−アミン(1.2mmol、0.16mL、1.1当量)を撹拌しながら滴加した。撹拌をこの温度で3時間続けた。次いで、固体1−(3’−アミノ−6−クロロ−2’−フルオロ−[1,1’−ビフェニル]−3−イル)エタノン117c(256mg、0.97mmol)、続いてDIEA(0.56mL、3.6mmol、3当量)を添加した。冷却浴を取り外し、反応混合物を室温で一晩撹拌した。溶媒をMeOH(3mL)とともに同時蒸発させた。次いで、残りの残渣をクロロホルム(30mL)に溶解し、冷1N HCl水溶液(3×20mL)、水(30mL)及び飽和NaHCO3水溶液(30mL)で続けて洗浄した。有機層を乾燥させ(Na2SO4)、減圧下で濃縮した。最後に、残渣をDCM及びヘプタンの1:1溶液(15mL)とともに撹拌した。生成物を濾過によって単離し、高真空下で乾燥させて、117d(0.2g)を白色の固体として得た。
(2S,4R)−tert−ブチル2−((5’−アセチル−2’−クロロ−2−フルオロ−[1,1’−ビフェニル]−3−イル)カルバモイル)−4−フルオロピロリジン−1−カルボキシレート117d(110mg)をDCM(2mL)及びTFA(2mL)中で30分間撹拌した。揮発性物質を減圧下で除去し、得られた残渣117eを次の工程にそのまま使用した。
表題化合物117をスキーム8の工程3において記載されるものと同様の方法で調製した。これにより、(2S,4R)−N−(5’−アセチル−2’−クロロ−2−フルオロ−[1,1’−ビフェニル]−3−イル)−4−フルオロピロリジン−2−カルボキサミドTFA塩117e(工程3により得られる)を、DMF(1.5mL)中のHATU(0.104g)及びDIEA(0.2mL)を用いて2−(3−カルバモイル−1H−インダゾール−1−イル)酢酸(0.05g)とカップリングした。粗生成物をカラムクロマトグラフィー(DCM中0→2%のMeOH)によって精製して、117(60mg)を得た。1H NMR(400MHz,CD3OD,300K):(主回転異性体) δ 2.65−2.75(m,1H)、3.91−4.04(m,1H)、4.20−4.29(m,1H)、4.84(t,J=8Hz,1H)、5.48(d,J=52Hz,1H)、5.42(d,J=17.2Hz,1H)、5.57(d,J=17.2Hz,1H)、7.12(t,J=6.8Hz,1H)、7.21−7.32(m,2H)、7.43(t,J=7.2Hz,1H)、7.59(d,J=8.4Hz,1H)、7.65(d,J=8.4Hz,1H)、7.89(s,1H)、7.93(s,1H)、7.96−8.02(m,2H)、8.22(d,J=8Hz,1H)。31F NMR(376MHz,CD3OD,300K):(主回転異性体) δ −128.5、−178.6 ppm。LC(方法A):tR=1.92分。LC/MS(EI) m/z:[M+H]+ 580。
無水アセトニトリル(20mL)中の4−ブロモ−1H−ピラゾール−3−カルボキサミド110a(1.0g、5.26mmol)、tert−ブチルブロモアセテート(1.13g、0.84mL、5.78mmol)及び炭酸カリウム(798mg、5.78mmol)の混合物を5時間で還流させた。次いで、反応混合物を室温まで冷却し、溶媒を減圧下で除去した。残渣をDCM及び水の1:1混合物(100mL:100mL)に取った。2つの層を分離し、有機層を水(2×100mL)で洗浄した。最後に、有機層を乾燥させ(Na2SO4)、濃縮した。得られた残渣をカラムクロマトグラフィーによって精製して、tert−ブチル2−(4−ブロモ−3−カルバモイル−1H−ピラゾール−1−イル)アセテート110bを得た。
tert−ブチル2−(4−ブロモ−3−カルバモイル−1H−ピラゾール−1−イル)アセテート110b(150mg、0.49mmol)、(2−メトキシピリミジン−5−イル)ボロン酸(154mg、1mmol)、炭酸セシウム(380mg、1.17mmol)及びDMF(2mL)の混合物を圧力容器内で5分間アルゴンによりパージした。次いで、テトラキス(トリフェニルホスフィン)パラジウム(0)(30mg、0.025mmol)をアルゴン下で添加し、圧力容器を密閉し、マイクロ波を90℃で30分間照射した。反応混合物を室温まで冷却し、溶媒を減圧下で除去した。残りの残渣をカラムクロマトグラフィーによって精製して、110cを得た。
DCM(5mL)中のtert−ブチル2−(3−カルバモイル−4−(2−メトキシピリミジン−5−イル)−1H−ピラゾール−1−イル)アセテート110c(120mg、0.36mmol)を、TFA(5mL)で処理した。反応の完了後(LC−MS分析によって判断される)、溶媒を減圧下で除去した。残りの物質110dを直接次の工程に使用した。
工程3による2−(3−カルバモイル−4−(2−メトキシピリミジン−5−イル)−1H−ピラゾール−1−イル)酢酸110d(0.36mmol)をDMF(4mL)に溶解し、DIEA(1.8mmol)を添加し、これに続いて(2S,4R)−N−(2’−クロロ−2−フルオロ−[1,1’−ビフェニル]−3−イル)−4−フルオロピロリジン−2−カルボキサミドヒドロクロリド(120mg、0.32mmol)を5℃で添加した。次いで、HATU(287mg、0.76mmol)をこの温度でゆっくりと添加し、反応混合物を室温で3時間撹拌した。次いで、反応混合物を水(50mL+10gの固体NaCl)に添加し、DCM(2×25mL)で抽出した。有機層をNaHCO3水溶液(20mL)、水(20mL)及びブライン(20mL)で続けて洗浄した後、Na2SO4で乾燥させ、減圧下で濃縮した。残りの残渣をカラムクロマトグラフィー(DCM/CH3OHで溶出)によって精製して、表題化合物110を得た。1H NMR(400MHz,DMSO−d6,300K):(主回転異性体) δ 2.20−2.26(m,1H)、2.51−2.62(m,1H)、3.79−3.91(m,1H)、3.94(s,3H)、4.09−4.17(m,1H)、4.80(t,J=8.0Hz,1H)、5.17−5.41(m,2H)、5.50(d,J=7Hz,1H)、7.08(t,J=7.2Hz,1H)、7.24(t,J=8.0Hz,1H)、7.30(s,1H)、7.39−7.47(m,4H)、7.58−7.61(m,1H)、7.96−8.13(m,2H)、8.74(s,2H)、10.05(s,1H);19F NMR(376MHz,DMSO−d6,300K):(主回転異性体) δ −126.84、−175.97 ppm。LC(方法A):tR=1.85分。LC/MS(EI) m/z:[M+H]+ 596。
DCM(5mL)中のtert−ブチル2−(4−ブロモ−3−カルバモイル−1H−ピラゾール−1−イル)アセテート110b(120mg、0.40mmol)を、TFA(5mL)を用いてスキーム7の工程2に記載のものと同様の方法で処理した。揮発性物質を減圧下で除去し、残りの物質を次の合成工程に直接使用した。
表題化合物77(50mg)を、2−(4−ブロモ−3−カルバモイル−1H−ピラゾール−1−イル)酢酸77a及び(1R,3S,5R)−N−(2’−クロロ−2−フルオロ−[1,1’−ビフェニル]−3−イル)−2−アザビシクロ[3.1.0]ヘキサン−3−カルボキサミドヒドロクロリド(131mg)からスキーム5において記載されるものと同様の方法で調製した。1H NMR(400MHz,DMSO−d6,300K):(主回転異性体) δ 0.65(d,J=1.6Hz,1H)、0.97−1.02(m,1H)、1.86−1.88(m,1H)、2.24−2.29(m,2H)、3.66(t,J=5.2Hz,1H)、4.52−4.56(m,1H)、5.19−5.47(m,2H)、7.09(t,J=7.2Hz,1H)、7.24(t,J=8.0Hz,1H)、7.28(s,1H)、7.39−7.47(m,4H)、7.59−7.61(m,1H)、7.94(t,J=7.2Hz,1H)、7.99(s,1H)、9.79(s,1H);19F NMR(376MHz,DMSO−d6,300K):(主回転異性体) δ −126.64。LC(方法A):tR=1.97分。LC/MS(EI) m/z:[M+H]+ 560。
3−ブロモ−2−フルオロアニリン(0.5g、2.63mmol)、4,4,4’,4’,5,5,5’,5’−オクタメチル−2,2’−ビ(1,3,2−ジオキサボロラン)(1.67g、6.6mmol)及びKOAc(0.77g)のジオキサン(10mL)溶液を脱気し、アルゴンを2回再充填した。この溶液にPd(dppf)2Cl2(289mg)をアルゴン雰囲気下で添加した。溶液を90℃で15時間加熱した。反応混合物を室温まで冷却し、揮発性物質を減圧下で除去した。残りの残渣をカラムクロマトグラフィーによって精製して、80b(803mg)を得た。
2−フルオロ−3−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)アニリン80b(26.0g、110mmol)、1−ブロモ−2,4,5−トリフルオロベンゼン(12.5g、60mmol)及びK2CO3(38g、275mmol)のジオキサン(250mL)及び水(63mL)の共溶媒溶液を脱気し、アルゴンで2回再充填した。この溶液にPd(dppf)2Cl2(8.04g)をアルゴン雰囲気下で添加した。溶液を15時間還流させた。反応混合物を室温まで冷却し、揮発性物質を減圧下で除去した。残りの残渣をカラムクロマトグラフィーによって精製した。所望の生成物画分を回収し、濃縮した後、HCl/MeOHでの処理によってHCl塩80cを作製した。13.1gの80cが得られた。
(2S,4R)−1−(tert−ブトキシカルボニル)−4−フルオロピロリジン−2−カルボン酸(9.5g、40.7mmol)のDCM(200mL)氷冷溶液に、1−クロロ−N,N,2−トリメチル−1−プロペニルアミン(5.92mL、1.1当量)を撹拌しながら滴加した。撹拌をこの温度で3時間続けた後、固体2’−クロロ−2,4’,5’−トリフルオロ−[1,1’−ビフェニル]−3−アミンヒドロクロリド80c(13.1g、44.5mmol)、続いてDIEA(21.3mL)を添加した。冷却浴を取り外し、反応混合物を室温で一晩撹拌した。次いで、反応混合物を水(120mL)に添加し、DCM(2×120mL)で抽出した。有機層をNaHCO3水溶液(20mL)、水(20mL)及びブライン(20mL)で続けて洗浄した後、Na2SO4で乾燥させ、減圧下で濃縮した。残りの残渣をカラムクロマトグラフィー(ヘキサン/EtOAcで溶出)によって精製して、14.1gの所望の表題化合物80dを得た。
(2S,4R)−tert−ブチル2−((2’−クロロ−2,4’,5’−トリフルオロ−[1,1’−ビフェニル]−3−イル)カルバモイル)−4−フルオロピロリジン−1−カルボキシレート80d(1.0g)をジオキサン(10mL)中の4N HClに取り、得られた反応混合物を室温で2時間撹拌した。次いで、溶媒を減圧下で除去し、残りの残渣80eを更に精製することなく直接使用した。
1H−インダゾール−3−カルボキサミド80f(56g、347mmol)をCH3CN(500mL)に溶解した。この溶液にtert−ブチル2−ブロモアセテート(82g、61.5mL)及び炭酸カリウム(77.4g、560mmol)を添加した。混合物を90℃で3時間、アルゴン雰囲気下で加熱した。反応混合物を室温まで冷却し、Celite(商標)のパッドを通して濾過した。固体ケーキをCH3CN(120mL)で洗浄し、合わせた濾液を減圧下で濃縮した。残りの残渣をカラムクロマトグラフィーによって精製して、表題化合物80g(70g)を得た。
tert−ブチル2−(3−カルバモイル−1H−インダゾール−1−イル)アセテート80g(1.0g)をジオキサン(10mL)中の4N HClに取り、得られた反応混合物を室温で2時間撹拌した。次いで、溶媒を減圧下で除去し、残りの残渣80hを更に精製することなく直接使用した。
2−(3−カルバモイル−1H−インダゾール−1−イル)酢酸80h(5.3g、24.2mmol)、(2S,4R)−N−(2’−クロロ−2,4’,5’−トリフルオロ−[1,1’−ビフェニル]−3−イル)−4−フルオロピロリジン−2−カルボキサミドヒドロクロリド80e(9.0g、22.0mmol)のDMF(50mL)溶液にHATU(10g)を添加し、続いてDIEA(18.0mL)を室温で滴加した。混合物を室温で1時間撹拌し、揮発性物質を減圧下で除去した。残りの残渣を10%炭酸ナトリウム水溶液(50mL)で希釈し、酢酸エチルで抽出した。有機抽出物を水及びブラインで洗浄した後、MgSO4で乾燥させた。溶液を濾過し、濾液を減圧下で蒸発させた。残りの残渣をカラムクロマトグラフィーによって精製して、表題化合物80(10.0g)を得た。1H NMR(400MHz,DMSO−d6,300K):(主回転異性体) δ 2.13−2.26(m,1H)、2.45−2.57(m,1H)、3.88−4.00(m,1H)、4.18−4.27(m,1H)、4.76( t,J=8.4Hz,1H)、5.43−5.68(m,3H)、7.07−7.09(m,1H)、7.20−7.27(m,2H)、7.35−7.42(m,2H)、7.59−7.64(m,2H)、7.85−7.89(m,1H)、7.91−7.99(m,1H)、8.17(d,J=8.4Hz,1H)、10.00(s,1H)。19F NMR(376MHz,DMSO−d6,300K):(主回転異性体) δ −126.7、−135.8、−139.4、−175.9。LC(方法A):tR=2.28分。LC/MS(EI) m/z:[M+H]+ 574。
表1に、例示的な式Iの化合物を特性化データとともに示す。実施例8のアッセイを用いて化合物のIC50を決定した。他の標準D因子阻害アッセイも利用可能である。3連の***はIC50が1マイクロモル未満の化合物を表すために用い、2連の**はIC50が1マイクロモル〜10マイクロモルの化合物を示し、1連の*はIC50が10マイクロモル超の化合物を表す。
最終濃度80nMのヒトD因子(ヒト血清から精製、Complement Technology, Inc.)を50mMトリス、1M NaCl(pH7.5)中で様々な濃度の試験化合物とともに室温で5分間インキュベートする。合成基質Z−L−Lys−SBzl及びDTNB(エルマン試薬)を各々100μMの最終濃度で添加する。色の増大を、分光蛍光光度計において動態モードで30分間にわたって30秒の時点でマイクロプレートにおけるOD405nmで記録する。IC50値を、試験化合物濃度に応じた補体D因子活性の阻害率から非線形回帰によって算出する。
溶血アッセイは、G. Ruiz-Gomez, et al., J. Med. Chem. (2009) 52: 6042-6052によって以前に記載されている。アッセイでは赤色血液細胞(red blood cells)(RBC)、ウサギ赤血球(Complement Technologiesから購入)をGVBバッファー(0.1%ゼラチン、5mM Veronal、145mM NaCl、0.025%NaN3、pH7.3)+10mM最終濃度のMg−EGTAを用いて洗浄する。細胞を1×108細胞/mLの濃度で使用する。溶血アッセイの前に、ウサギ赤血球の100%の溶解を達成するのに必要とされる正常ヒト血清(NHS)の最適濃度を滴定によって決定する。NHS(Complement Technologies)を阻害剤とともに37℃で15分間インキュベートし、バッファー中のウサギ赤血球を添加し、37℃で更に30分間インキュベートした。陽性対照(100%の溶解)は血清及びRBCからなり、陰性対照(0%の溶解)はMg−EGTAバッファー及びRBCのみからなる。サンプルを2000gで5分間遠心分離し、上清を回収する。上清の光学密度を405nmでUV/可視分光光度計を用いてモニタリングする。各サンプルにおける溶解率を陽性対照(100%の溶解)に対して算出する。
Claims (20)
- 式:
R1、R2、R2’、及びR 3 はいずれの場合にも独立して水素、ハロゲン、ヒドロキシル、ニトロ、シアノ、アミノ、C1〜C6アルキル、C2〜C6アルケニル、C1〜C6アルコキシ、C2〜C6アルキニル、C2〜C6アルカノイル、C1〜C6チオアルキル、ヒドロキシC1〜C6アルキル、アミノC1〜C6アルキル、−C0〜C4アルキルNR9R10、−C(O)OR9、−OC(O)R9、−NR9C(O)R10、−C(O)NR9R10、−OC(O)NR9R10、−O(ヘテロアリール)、−NR9C(O)OR10、C1〜C2ハロアルキル、C1〜C2ハロアルコキシ、−C0〜C4アルキル(C3〜C7シクロアルキル)及び−O−C0〜C4アルキル(C3〜C7シクロアルキル)から選ばれ:
R2及びR2’はともに3員〜6員の炭素環式スピロ環を形成していてもよく、又は
R2及びR2’はともに3員〜6員の複素環式スピロ環を形成していてもよく、いずれの場合もスピロ環は非置換であるか、又は1つ若しくは複数のハロゲン又はメチル置換基で置換され、又は
R1及びR2はともに3員の炭素環を形成していてもよく、又は
R1及びR2はともに4員〜6員の炭素環、又はN、O及びSから独立して選ばれる1個若しくは2個のヘテロ原子を含有する4員〜6員の複素環を形成していてもよく、又は
R2及びR3は隣接炭素原子に結合する場合に、ともに3員〜6員の炭素環又は3員〜6員の複素環を形成していてもよく、いずれの場合も非スピロ環は非置換であるか、又はハロゲン、ヒドロキシル、シアノ、−COOH、C1〜C4アルキル、C2〜C4アルケニル、C1〜C4アルコキシ、C2〜C4アルカノイル、ヒドロキシC1〜C4アルキル、(モノ−及びジ−C1〜C4アルキルアミノ)C0〜C4アルキル、−C0〜C4アルキル(C3〜C7シクロアルキル)、−O−C0〜C4アルキル(C3〜C7シクロアルキル)、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換されていてもよく、
R9及びR10はいずれの場合にも独立して水素、C1〜C6アルキル及び(C3〜C7シクロアルキル)C0〜C4アルキルから選ばれ、
R 18 及びR 18’ は独立して水素、ハロゲン、ヒドロキシメチル及びメチルから選ばれ、
Aは
R5及びR6は独立して(o)及び(p)から選ばれ:
(o)−CHO、−C(O)NH2、−C(O)NH(CH3)又はC2〜C6アルカノイル、
(p)水素、ヒドロキシル、ハロゲン、シアノ、ニトロ、−COOH、−SO2NH 2 、−C(NH2)C1〜C3ハロアルキル、−CF(C=CH2)、−C(=NCN)C1〜C6アルキル、C1〜C6アルキル、C2〜C6アルケニル、C1〜C6アルコキシ、−C0〜C4アルキル(C3〜C7シクロアルキル)、−C(O)C0〜C4アルキル(C3〜C7シクロアルキル)、−P(O)(OR9)2、−OC(O)R9、−C(O)OR9、−C(O)N(CH2CH2R9)(R10)、−NR9C(O)R10、フェニル、又は5員若しくは6員のヘテロアリール:水素、ヒドロキシル、シアノ及び−COOH以外のR5及びR6は各々非置換であるか、又はハロゲン、ヒドロキシル、アミノ、イミノ、シアノ、シアノイミノ、C1〜C2アルキル、C1〜C4アルコキシ、−C0〜C2アルキル(モノ−及びジ−C1〜C4アルキルアミノ)、C1〜C2ハロアルキル、C1〜C2ハロアルコキシ、C(O)アルキル、C(O)シクロアルキル、C(O)アリール、C(O)複素環及びC(O)ヘテロアリールから独立して選ばれる1つ若しくは複数の置換基で置換され:
R8及びR8’は独立して水素、ハロゲン、ヒドロキシル、C1〜C6アルキル、C1〜C6アルコキシ及び(C1〜C4アルキルアミノ)C0〜C2アルキルから選ばれるか、又はR8及びR8’はともにオキソ基を形成し、
X12はCR12又はNであり、
X13はCR13又はNであり、
R12及びR13は独立して(q)、(r)及び(s)から選ばれ:
(q)水素、ハロゲン、ヒドロキシル、ニトロ、シアノ、アミノ、−COOH、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシ、
(r)C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルカノイル、C1〜C6アルコキシ、C2〜C6アルケニルオキシ、−C(O)OR9、C1〜C6チオアルキル、−C0〜C4アルキルNR9R10、−C(O)NR9R10、−SO2R9、−SO2NR9R10、−OC(O)R9及び−C(NR9)NR9R10(いずれの場合も(r)は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、アミノ、−COOH、−CONH2、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選択される1つ若しくは複数の置換基で置換され、いずれの場合も(r)はフェニル、並びにN、O及びSから独立して選ばれる1個、2個又は3個のヘテロ原子を含有する4員〜7員の複素環から選ばれる1つの置換基でも任意に置換され、そのフェニル又は4員〜7員の複素環は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルカノイル、C1〜C6アルコキシ、(モノ−及びジ−C1〜C6アルキルアミノ)C0〜C4アルキル、C1〜C6アルキルエステル、−C0〜C4アルキル)(C3〜C7シクロアルキル)、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換される)、
(s)−C(CH2)2R30、
R30は−NR9C(O)R31又はR32であり、
R31及びR32はC1〜C6アルキル、C1〜C6ハロアルキル、(C3〜C7シクロアルキル)C0〜C4アルキル、(フェニル)C0〜C4アルキル、N、O及びSから独立して選ばれる1個、2個又は3個のヘテロ原子を有する(4員〜7員のヘテロシクロアルキル)C0〜C4アルキル、並びにN、O及びSから独立して選ばれる1個、2個又は3個のヘテロ原子を有する(5員又は6員の不飽和又は芳香族複素環)C0〜C4アルキルから選択され、
いずれの場合も(s)は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、アミノ、オキソ、−B(OH)2、−Si(CH3)3、−COOH、−CONH2、−P(O)(OH)2、C1〜C6アルキル、C1〜C6アルコキシ、−C0〜C2アルキル(モノ−及びジ−C1〜C4アルキルアミノ)、C1〜C6アルキルエステル、C1〜C4アルキルアミノ、C1〜C4ヒドロキシルアルキル、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換されていてもよく、
Bは単環式若しくは二環式の炭素環若しくは炭素環式オキシ基、若しくはN、O及びSから独立して選択される1個、2個、3個若しくは4個のヘテロ原子並びに1つの環当たり4個〜7個の環原子を有する単環式、二環式若しくは三環式の複素環基であるか、又は、
BはC2〜C6アルケニル若しくはC2〜C6アルキニル基であるか、又は
Bは−(C0〜C4アルキル)(アリール)、−(C0〜C4アルキル)(ヘテロアリール)、又は−(C0〜C4アルキル)(ビフェニル)であり、
いずれの場合もBは非置換であるか、又は(w)及び(x)から独立して選ばれる1つ若しくは複数の置換基、並びに(y)及び(z)から選ばれる0若しくは1つの置換基で置換され:
(w)ハロゲン、ヒドロキシル、−COOH、シアノ、C1〜C6アルキル、C2〜C6アルカノイル、C1〜C6アルコキシ、−C0〜C4アルキルNR9R10、−SO2R9、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシ、
(x)ニトロ、C2〜C6アルケニル、C2〜C6アルキニル、C1〜C6チオアルキル、−JC3〜C7シクロアルキル、−B(OH)2、−JC(O)NR9R23、−JOSO2OR21、SR9、−C(O)(CH2)1〜4S(O)R21、−O(CH2)1〜4S(O)NR21R22、−JOP(O)(OR21)(OR22)、−JP(O)(OR21)(OR22)、−JOP(O)(OR21)R22、−JP(O)(OR21)R22、−JOP(O)R21R22、−JP(O)R21R22、−JSP(O)(OR21)(OR22)、−JSP(O)(OR21)(R22)、−JSP(O)(R21)(R22)、−JNR9P(O)(NHR21)(NHR22)、−JNR9P(O)(OR21)(NHR22)、−JNR9P(O)(OR21)(OR22)、−JC(S)R21、−JNR21SO2R22、−JNR9S(O)nNR10R22、−JSO2NR9COR22、−JSO2NR9CONR21R22、−JNR21SO2R22、−JC(O)NR21SO2R22、−JC(NH2)NR22、−JC(NH2)NS(O)2R22、−JOC(O)NR21R22、−JNR21C(O)OR22、−JNR21OC(O)R22、−(CH2)1〜4C(O)NR21R22、−JC(O)R24R25、−JNR9C(O)R21、−JC(O)R21、−JNR9C(O)NR10R22、−CCR21、−(CH2)1〜4OC(O)R21及び−JC(O)OR23(いずれの場合も(x)は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、アミノ、オキソ、−B(OH)2、−Si(CH3)3、−COOH、−CONH2、−P(O)(OH)2、C1〜C6アルキル、C1〜C6アルコキシ、−C0〜C2アルキル(モノ−及びジ−C1〜C4アルキルアミノ)、C1〜C6アルキルエステル、C1〜C4アルキルアミノ、C1〜C4ヒドロキシルアルキル、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換されていてもよい)、
(y)ナフチル、ナフチルオキシ、インダニル、N、O及びSから選ばれる1個又は2個のヘテロ原子を含有する(4員〜7員のヘテロシクロアルキル)C0〜C4アルキル、並びにN、O及びSから独立して選ばれる1個、2個又は3個のヘテロ原子を含有し、各環中に4個〜7個の環原子を含有する二環式複素環(いずれの場合も(y)は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルカノイル、C1〜C6アルコキシ、(モノ−及びジ−C1〜C6アルキルアミノ)C0〜C4アルキル、C1〜C6アルキルエステル、−C0〜C4アルキル(C3〜C7シクロアルキル)、−SO2R9、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換される)、
(z)テトラゾリル、(フェニル)C0〜C2アルキル、(フェニル)C1〜C2アルコキシ、フェノキシ、並びにN、O、B及びSから独立して選ばれる1個、2個又は3個のヘテロ原子を含有する5員又は6員のヘテロアリール(いずれの場合も(z)は非置換であるか、又はハロゲン、ヒドロキシル、ニトロ、シアノ、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルカノイル、C1〜C6アルコキシ、(モノ−及びジ−C1〜C6アルキルアミノ)C0〜C4アルキル、C1〜C6アルキルエステル、−C0〜C4アルキル(C3〜C7シクロアルキル)、−SO2R9、−OSi(CH3)2C(CH3)3、C1〜C2ハロアルキル及びC1〜C2ハロアルコキシから独立して選ばれる1つ若しくは複数の置換基で置換される)、
Jはいずれの場合にも独立して共有結合、C1〜C4アルキレン、−OC1〜C4アルキレン、C2〜C4アルケニレン及びC2〜C4アルキニレンから選ばれ、
R21及びR22はいずれの場合にも独立して水素、ヒドロキシル、シアノ、アミノ、C1〜C6アルキル、C1〜C6ハロアルキル、C1〜C6アルコキシ、(C3〜C7シクロアルキル)C0〜C4アルキル、(フェニル)C0〜C4アルキル、−C1〜C4アルキルOC(O)OC1〜C6アルキル、−C1〜C4アルキルOC(O)C1〜C6アルキル、−C1〜C4アルキルC(O)OC1〜C6アルキル、N、O及びSから独立して選ばれる1個、2個又は3個のヘテロ原子を有する(4員〜7員のヘテロシクロアルキル)C0〜C4アルキル、並びにN、O及びSから独立して選ばれる1個、2個又は3個のヘテロ原子を有する(5員又は6員の不飽和又は芳香族複素環)C0〜C4アルキルから選ばれ、
R23はいずれの場合にも独立して(C3〜C7シクロアルキル)C0〜C4アルキル、(フェニル)C0〜C4アルキル、N、O及びSから独立して選ばれる1個、2個又は3個のヘテロ原子を有する(4員〜7員のヘテロシクロアルキル)C0〜C4アルキル、並びにN、O及びSから独立して選ばれる1個、2個又は3個のヘテロ原子を有する(5員又は6員の不飽和又は芳香族複素環)C0〜C4アルキルから選ばれ、及び
R24及びR25は付着する窒素とともに4員〜7員の単環式ヘテロシクロアルキル基、又は縮合環、スピロ環若しくは架橋環を有する6員〜10員の二環式複素環基を形成する)の化合物、又はその薬学的に許容可能な塩。 - X12がCR12であり且つX13がCR13である、請求項1に記載の化合物又はその薬学的に許容可能な塩。
- R6が−CHO、−C(O)NH2、−C(O)NH(CH3)、C2−C6アルカノイル、及び水素原子から選ばれる、請求項1〜3のいずれか一項に記載の化合物又はその薬学的に許容可能な塩。
- a)R1、R2’、及びR3が全て水素であり且つR2がフッ素である、又は
b)R1及びR2が共に3員〜6員のシクロアルキルを形成し且つR2’及びR3が全て水素である、
請求項1〜4のいずれか一項に記載の化合物又はその薬学的に許容可能な塩。 - Bが塩素、臭素、ヒドロキシル、−SCF3、C1〜C2アルキル、C1〜C2アルコキシ、トリフルオロメチル、フェニル及びトリフルオロメトキシから選択される1つ、2つ、又は3つの置換基で置換されたフェニル又はピリジニルであり、塩素、臭素、ヒドロキシル及び−SCF3以外の該置換基それぞれは任意に置換されていてもよい、請求項1〜5のいずれか一項に記載の化合物又はその薬学的に許容可能な塩。
- R12及びR13が両方水素である、請求項1〜7のいずれか一項に記載の化合物又はその薬学的に許容可能な塩。
- 有効量の請求項1〜10のいずれか一項から選択される化合物又はその薬学的に許容可能な塩を含む医薬組成物。
- 薬学的に許容可能な担体を更に含む、請求項11に記載の医薬組成物。
- ヒト患者における補体D因子により媒介される障害の治療のための、請求項11又は12に記載の医薬組成物。
- 前記障害が発作性夜間血色素尿症(PNH)、多発性硬化症、関節炎、関節リウマチ、呼吸器疾患、又は心血管疾患である、請求項14に記載の医薬組成物。
- 前記障害がC3糸球体腎炎である、請求項14に記載の医薬組成物。
- 前記障害が非典型溶血性尿毒症症候群である、請求項14に記載の医薬組成物。
- 前記障害が眼障害である、請求項18に記載の医薬組成物。
- 前記障害が加齢黄斑変性(AMD)である、請求項18に記載の医薬組成物。
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JP2018526367A (ja) * | 2015-08-26 | 2018-09-13 | アキリオン ファーマシューティカルズ,インコーポレーテッド | 医学的障害の治療のためのアリール、ヘテロアリール及び複素環式化合物 |
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