JP5670325B2 - キナーゼ阻害化合物としての置換されたピリダジンカルボキサミド化合物 - Google Patents
キナーゼ阻害化合物としての置換されたピリダジンカルボキサミド化合物 Download PDFInfo
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- JP5670325B2 JP5670325B2 JP2011514617A JP2011514617A JP5670325B2 JP 5670325 B2 JP5670325 B2 JP 5670325B2 JP 2011514617 A JP2011514617 A JP 2011514617A JP 2011514617 A JP2011514617 A JP 2011514617A JP 5670325 B2 JP5670325 B2 JP 5670325B2
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- amino
- dichloro
- ethoxy
- fluorophenyl
- pyridazin
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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
- C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
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Description
本願は、2008年6月19日に出願された米国仮特許出願第61/132,505号の優先権を主張するものである。上記特許出願の開示内容全体が参照により本明細書に組み込まれる。
and Comoglio, P. Nature Rev. Cancer 2002, 2, 289-300]。
Oncogene 1999, 18, 5221-5231)。Metは、かなりの割合のヒトのがんで過剰発現しており、原発腫瘍から転移への移行期に増幅される。多くの研究において、c−Metおよび/またはHGF/SFの発現は、様々な種類のがん(肺がん、結腸がん、乳がん、前立腺がん、肝臓がん、膵臓がん、脳腫瘍、腎臓がん、卵巣がん、胃がん、皮膚がんおよび骨がんを含む)の疾患の進行状態と関連づけられている。さらに、c−MetまたはHGFの過剰発現は、肺がん、肝臓がん、胃がんおよび乳がんを含む複数の主要なヒトのがんにおける予後不良および疾患の転機に関連していることが分かっている。また、c−Metは、膵臓がん、神経膠腫および肝細胞癌(carcinoma)などのがんに直接関与しているが、成功を収めた治療計画はない。
Proc. Nat. Acad. Sci. 1997, 94, 11445-11500)。HGF/Metは、頭頸部扁平上皮癌細胞におけるアノイキス、すなわち浮遊(suspension)誘発性プログラム細胞死(アポトーシス)を阻害することが分かっている。アノイキス抵抗性または足場非依存性生存は、上皮細胞の発がん性形質転換の顕著な特徴である(Zeng, Q. et al., J. Biol. Chem. 2002, 277, 25203-25208)。
Exp. Metastasis 2000, 18, 639-649)、乳房腫瘍(Elliott, B. E. et
al., 2002, Can. J. Physiol. Pharmacol. 80, 91-102)、前立腺腫瘍(Knudsen,
B. S. et al., Urology 2002, 60, 1113-1117)、肺腫瘍(Siegfried,
J. M. et al., Ann. Thorac. Surg. 1998, 66, 1915-1918)、および胃腫瘍(Amemiya, H. et al., Oncology 2002, 63, 286-296)を含む多くの転移性腫瘍において、Met/HGFの発現の増加が見られる。また、HGF−Metシグナル伝達は、アテローム性動脈硬化症のリスクの増加(Yamamoto, Y. et al., J. Hypertens. 2001, 19, 1975-1979; Morishita, R.
et al., Endocr. J. 2002, 49, 273-284)、および肺線維症の増加(Crestani,
B. et al., Lab. Invest. 2002, 82, 1015-1022)とも関連づけられている。
Anticancer Ther. 9(3), 331-356, 2009)。
Zou et al. Cancer Res 2007; 67: 4408; 特許公開:国際公開第WO2004076412号、第WO2006021881号、第WO2006021886号)。
R1は、アリールアルキルまたはヘテロアリールアルキルであって、それぞれが場合により1〜4つの独立したZ1で置換されており、
R3は、水素、ヒドロキシル、アルコキシまたはアルキルアミノであり、
R6は、場合により置換されたアリールまたはヘテロアリール、飽和または不飽和ヘテロシクリルであり、ここで、R6は、場合によりアルキル、シクロアルキル、ヘテロシクリル、アルコキシ、ヒドロキシアルキル、−C(O)NR7R8およびZ1から独立して選択される1〜3つの基で置換されており、ここで、それぞれが場合によりさらに置換されていてもよく、
R7およびR8はそれぞれ、H、アルキル、シクロアルキル、アルケニル、アルキニル、アリール、ヘテロシクリル、ヘテロアリールから独立して選択されるか、あるいは、R7およびR8は窒素と一緒になって、ヘテロシクリルまたはヘテロアリールを形成し、
各Z1は、ハロゲン、CN、NO2、OR15、SR15、S(O)2OR15、NR15R16、C1〜C2パーフルオロアルキル、C1〜C2パーフルオロアルコキシ、1,2−メチレンジオキシ、C(O)OR15、C(O)NR15R16、OC(O)NR15R16、NR15C(O)NR15R16、C(NR16)NR15R16、NR15C(NR16)NR15R16、S(O)2NR15R16、R17、C(O)R17、NR15C(O)R17、S(O)R17、S(O)2R17、R16、オキソ、C(O)R16、C(O)(CH2)nOH、(CH2)nOR15、(CH2)nC(O)NR15R16、NR15S(O)2R17(式中、nは独立して0〜6である)であり、
各R15は独立して、水素、C1〜C4アルキルまたはC3〜C6シクロアルキルであり、
各R16は独立して、水素、アルケニル、アルキニル、C3〜C6シクロアルキル、アリール、ヘテロシクリル、ヘテロアリール、C1〜C4アルキル、あるいはC3〜C6シクロアルキル、アリール、ヘテロシクリルまたはヘテロアリールで置換されたC1〜C4アルキルであり、
各R17は独立して、C3〜C6シクロアルキル、アリール、ヘテロシクリル、ヘテロアリール、C1〜C4アルキル、あるいはC3〜C6シクロアルキル、アリール、ヘテロシクリルまたはヘテロアリールで置換されたC1〜C4アルキルである。
essentially)」は同様に米国特許法に基づく意味を有し、その用語は非限定的であり、列挙されているその基本的または新規な特性が、列挙されていないものの存在によって変更されることはないが、先行技術の実施形態を除外する限り、列挙されていないものの存在を認めるものである。
(Manfred E. Wolff ed., 5th ed)に記載されている方法などの周知の方法を用いて通常調節することができ、Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8th
ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs"も参照されたい。
J. et al. Journal of Medicinal Chemistry 1988, 31, 318-322; Bundgaard, H.
Design of Prodrugs; Elsevier: Amsterdam, 1985; pp 1-92; Bundgaard, H.; Nielsen,
N. M. Journal of Medicinal Chemistry 1987, 30, 451-454; Bundgaard, H. A
Textbook of Drug Design and Development; Harwood Academic Publ.: Switzerland,
1991 ; pp 113-191; Digenis, G. A. et al. Handbook of Experimental Pharmacology
1975, 28, 86-112; Friis, G. J.; Bundgaard, H. A Textbook of Drug Design and
Development; 2 ed.; Overseas Publ.: Amsterdam, 1996; pp 351-385; Pitman, I. H.
Medicinal Research Reviews 1981, 1, 189-214を参照されたい。
bridge)(例えば、−(CH2)X−(式中、xは1〜5である))を指し、これは1〜3個の低級アルキル基で置換されていてもよい。
好適な置換基としては、ハロゲン、CN、NO2、OR15、SR15、S(O)2OR15、NR15R16、C1〜C2パーフルオロアルキル、C1〜C2パーフルオロアルコキシ、1,2−メチレンジオキシ、C(O)OR15、C(O)NR15R16、OC(O)NR15R16、NR15C(O)NR15R16、C(NR16)NR15R16、NR15C(NR16)NR15R16、S(O)2NR15R16、R17、C(O)R17、NR15C(O)R17、S(O)R17、S(O)2R17、R16、オキソ、C(O)R16、C(O)(CH2)nOH、(CH2)nOR15、(CH2)nC(O)NR15R16、NR15S(O)2R17(式中、nは独立して0〜6である)が挙げられるが、これらに限定されない。各R15は独立して、水素、C1〜C4アルキルまたはC3〜C6シクロアルキルである。各R16は独立して、水素、アルケニル、アルキニル、C3〜C6シクロアルキル、アリール、ヘテロシクリル、ヘテロアリール、C1〜C4アルキル、あるいはC3〜C6シクロアルキル、アリール、ヘテロシクリルまたはヘテロアリールで置換されたC1〜C4アルキルである。各R17は独立して、C3〜C6シクロアルキル、アリール、ヘテロシクリル、ヘテロアリール、C1〜C4アルキル、あるいはC3〜C6シクロアルキル、アリール、ヘテロシクリルまたはヘテロアリールで置換されたC1〜C4アルキルである。各R15、R16およびR17における各C3〜C6シクロアルキル、アリール、ヘテロシクリル、ヘテロアリールおよびC1〜C4アルキルは、場合によりハロゲン、CN、C1〜C4アルキル、OH、C1〜C4アルコキシ、NH2、C1〜C4アルキルアミノ、C1〜C4ジアルキルアミノ、C1〜C2パーフルオロアルキル、C1〜C2パーフルオロアルコキシまたは1,2−メチレンジオキシで置換することができる。
一態様では、本発明は、下記式の化合物:
R1は、アリールアルキルまたはヘテロアリールアルキルであって、それぞれが場合により1〜4つの独立したZ1で置換されており、
R3は、水素、ヒドロキシル、アルコキシまたはアルキルアミノであり、
R6は、場合により置換されたアリールまたはヘテロアリール、飽和もしくは不飽和ヘテロシクリルであり、ここで、R6は、場合によりアルキル、シクロアルキル、ヘテロシクリル、アルコキシ、ヒドロキシアルキル、−C(O)NR7R8およびZ1から独立して選択される1〜3つの基で置換されており、これらのうちそれぞれが場合によりさらに置換されていてもよく、
R7およびR8はそれぞれ、H、アルキル、シクロアルキル、アルケニル、アルキニル、アリール、ヘテロシクリル、ヘテロアリールから独立して選択されるか、あるいは、R7およびR8は窒素と一緒になってヘテロシクリルまたはヘテロアリールを形成し、
各Z1は、ハロゲン、CN、NO2、OR15、SR15、S(O)2OR15、NR15R16、C1〜C2パーフルオロアルキル、C1〜C2パーフルオロアルコキシ、1,2−メチレンジオキシ、C(O)OR15、C(O)NR15R16、OC(O)NR15R16、NR15C(O)NR15R16、C(NR16)NR15R16、NR15C(NR16)NR15R16、S(O)2NR15R16、R17、C(O)R17、NR15C(O)R17、S(O)R17、S(O)2R17、R16、オキソ、C(O)R16、C(O)(CH2)nOH、(CH2)nOR15、(CH2)nC(O)NR15R16、NR15S(O)2R17(式中、nは独立して0〜6である)であり、
各R15は独立して、水素、C1〜C4アルキルまたはC3〜C6シクロアルキルであり、
各R16は独立して、水素、アルケニル、アルキニル、C3〜C6シクロアルキル、アリール、ヘテロシクリル、ヘテロアリール、C1〜C4アルキル、あるいはC3〜C6シクロアルキル、アリール、ヘテロシクリルまたはヘテロアリールで置換されたC1〜C4アルキルであり、
各R17は独立して、C3〜C6シクロアルキル、アリール、ヘテロシクリル、ヘテロアリール、C1〜C4アルキル、あるいはC3〜C6シクロアルキル、アリール、ヘテロシクリルまたはヘテロアリールで置換されたC1〜C4アルキルである。
R6は場合により置換されたアリールまたはヘテロアリール、飽和もしくは不飽和ヘテロシクリルであり、ここで、R6は、場合によりアルキル、シクロアルキル、ヘテロシクリル、アルコキシ、ヒドロキシアルキルまたは−C(O)NR7R8で置換されており、かつ
R7およびR8はそれぞれ、H、アルキル、シクロアルキル、アルケニル、アルキニル、アリール、ヘテロシクリル、ヘテロアリールから独立して選択されるか、あるいは、R7およびR8は窒素と一緒になってヘテロシクリルまたはヘテロアリールを形成する。
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−6−モルホリン−4−イル−ピリジン−3−イル−カルボキサミド(1)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−ピラゾール−4−イルカルボキサミド(2)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(1−メチルピラゾール−4−イル)カルボキサミド(3)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−イソオキサゾール−4−イルカルボキサミド(4)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−[4−(ピロリジニルカルボニル)フェニル]カルボキサミド(5)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−[4−(N−メチルカルバモイル)フェニル]カルボキサミド(6)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(6−メトキシ(3−ピリジル))カルボキサミド(7)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−[6−(N−メチルカルバモイル)(3−ピリジル)]カルボキサミド(8)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−[1−(2−ヒドロキシエチル)ピラゾール−4−イル]カルボキサミド(9)、
N−(1−(2H−3,4,5,6−テトラヒドロピラン−4−イル)ピラゾール−4−イル){6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}カルボキサミド(10)、
6−アミノ−5−(1−(2,6−ジクロロ−3−フルオロフェニル)エトキシ)−ピリダジン−3−イル−N−(ピリジン−4−イル)−カルボキサミド(11)、
6−アミノ−5−(1−(2,6−ジクロロ−3−フルオロフェニル)エトキシ)−ピリダジン−3−イル−N−(ピリジン−3−イル)−カルボキサミド(12)、
6−アミノ−5−(1−(2,6−ジクロロ−3−フルオロフェニル)エトキシ)−ピリダジン−3−イル−N−(ピリミジン−5−イル)−カルボキサミド(13)、
6−アミノ−5−[1−(2,6−ジクロロ−3−フルオロ−フェニル)−エトキシ]−ピリダジン−3−カルボン酸(テトラヒドロ−ピラン−4−イル)−アミド(14)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(4−メトキシフェニル)カルボキサミド(15)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(4−モルホリン−4−イルフェニル)カルボキサミド(16)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−ベンズアミド(17)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−[4−(2−モルホリン−4−イルエトキシ)フェニル]カルボキサミド(18)、
6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(1−メチル−6−オキソ−1,6−ジヒドロ−ピリジン−3−イル))カルボキサミド(19)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(1−メチル−6−オキソ(3−ピペリジル))カルボキサミド(20)、
6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(6−オキソ−1,6−ジヒドロピリジン−3−イル))カルボキサミド(21)、
6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(6,7−ジヒドロ−4H−ピラノ[4,3−d]1,3−チアゾール−2−イル)カルボキサミド(22)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(4,5,6,7−テトラヒドロ−1,3−チアゾロ[5,4−c]ピリジン−2−イル)カルボキサミド(23)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(1−(4−ピペリジル)ピラゾール−4−イル)カルボキサミド(24)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−{4−[(4−メチルピペラジニル)カルボニル]フェニル}カルボキサミド(25)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−[4−(ピペラジニルカルボニル)フェニル]カルボキサミド(26)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−[1−(2−メトキシエチル)−6−オキソ−1,6−ジヒドロ−ピリジン−3−イル)]カルボキサミド(27)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(1−エチル−6−オキソ−1,6−ジヒドロ−ピリジン−3−イル))カルボキサミド(28)、および
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(2−メトキシ(4−ピリジル))カルボキサミド(29)。
(1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd
Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents
for Organic Synthesis, John Wiley and Sons (1994);およびL.
Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and
Sons (1995)ならびにこれらの改訂版に記載されているものが挙げられる。
Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed.
1985)を参照されたい。
J. et al. Journal of Medicinal Chemistry 1988, 31, 318-322; Bundgaard, H.
Design of Prodrugs; Elsevier: Amsterdam, 1985; pp 1-92; Bundgaard, H.; Nielsen,
N. M. Journal of Medicinal Chemistry 1987, 30, 451-454; Bundgaard, H. A
Textbook of Drug Design and Development; Harwood Academic Publ.: Switzerland,
1991; pp 113-191; Digenis, G. A. et al. Handbook of Experimental Pharmacology
1975, 28, 86-112; Friis, G. J.; Bundgaard, H. A Textbook of Drug Design and
Development; 2 ed.; Overseas Publ.: Amsterdam, 1996; pp 351-385; Pitman, I. H.
Medicinal Research Reviews 1981, 1, 189-214を参照されたい。
(1966) Cancer Chemother Rep 50: 219に記載されている。体表面積は、患者の身長および体重から概算してもよい。例えば、Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537を参照されたい。有効量の本発明の化合物は、約0.001mg/kg〜約500mg/kg、より好ましくは0.01mg/kg〜約50mg/kg、より好ましくは0.1mg/kg〜約2.5mg/kgの範囲とすることができる。有効な投与量は、当業者によって認識されているように、治療される疾患、疾患の重症度、投与経路、患者の性別、年齢および全体的な健康状態、賦形剤の使用、他の薬剤の使用などの他の治療法の同時使用の可能性、ならびに治療している医師の判断に応じて異なるであろう。
Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia
2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif.
(2000)を参照されたく、それらの各参考文献の内容全体が参考により本明細書に組み込まれる。
別の実施形態によれば、本発明は、疾患または障害あるいはその症状(例えば、本明細書に詳述されている疾患または障害あるいはその症状)に罹患しているか罹患しやすい対象の治療方法であって、前記対象に有効量の本発明の化合物または組成物を投与する工程を含む方法を提供する。そのような疾患は当該技術分野でよく知られており、本明細書にも開示されている。
Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia
2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif.
(2000)、および他の医学書から入手し得る。しかし、第2の治療薬の最適な有効量の範囲を決定することは当業者の範囲に十分に含まれている。
工程2:A2(284g、2.19mol)のメタノール(3.5L)溶液に、NaHCO3(368.4g、4.38mol)、次いで臭素(350g、2.19mol)を室温で滴下した。その添加の完了後、この混合物を20時間撹拌し、次いで、濾過し、メタノールで数回洗浄した。濾液を濃縮し、残渣を水(2L)に溶解し、酢酸エチル(2L×3)で抽出した。一緒にした有機相を10%チオ硫酸ナトリウム水溶液(2L)、重炭酸ナトリウム飽和水溶液(2L)および塩水(2L)で洗浄し、無水硫酸マグネシウムで乾燥し、蒸発させた。残渣をカラムクロマトグラフィー(EA:PE=2:1)で精製してA3(159.8g、35%)を得た。
工程3:0℃まで冷却したA4(150g、0.72mol)のメタノール(800mL)溶液に、NaBH4(66g、1.74mol)を数回に分けて添加した。得られた混合物を室温で約1時間撹拌し、蒸発させた。pH=6になるまで、残渣に水(1L)、次いで3NのHClを0℃で添加した。得られた混合物を酢酸エチル(1L×2)で抽出した。一緒にした有機相を無水硫酸ナトリウムで乾燥し、濾過および濃縮してA5(148.6g、98%)を得た。
工程4:A5(147.6g、0.71mol)のTHF(3L)溶液に、60%のNaH(28.4g、0.71mol)を0℃で添加し、得られた混合物をその温度で30分間撹拌した後、A3(147g、0.71mmol)を素早く添加した。得られた混合物を一晩加熱還流し、蒸発させた。残渣をカラムクロマトグラフィー(PE:EA=4:1)で精製して進行段階の(advanced)中間体A6(89.3g、37.6%)を得た。
工程5:A6(97g、0.288mol)のDMF(1L)溶液に、Boc2O(113g、0.519mol)およびDMAP(7g、58mmol)を添加した。この混合物を室温で一晩撹拌し、蒸発させた。残渣をカラムクロマトグラフィー(PE:EA=10:1)で精製してA7(136g、88%)を得た。
工程6:酢酸ナトリウム(41g、0.50mol)をA7(136g、0.25mol)のエタノール/DMF[(5:1)(1200mL)]溶液に添加した。この混合物を脱気した後、Pd(dppf)Cl2・CH2Cl2(18.63g、22.5mmol)を添加した。得られた混合物を一酸化炭素雰囲気下90℃で1.5時間加熱した後、蒸発させた。残渣をカラムクロマトグラフィー(PE:EA=1:4)で精製してA8(141g、97%)を得た。
工程7:A8(141g、0.246mol)のTHF(650mL)溶液に、1NのLiOH水溶液(390mL)を添加した。得られた混合物を週末の間室温で撹拌した後、pH=5になるまで2NのHClで酸性にし、酢酸エチル(300mL×5)で抽出した。一緒にした有機相をNa2SO4で乾燥し、濾過および濃縮してA(134g、99%)を得た。
工程2:1b(300mg、1.36mmol)およびPd/C(10%、300mg)のメタノール混合溶液を雰囲気下室温で2.5時間水素化し、濾過および濃縮して1c(258mg、100%)を得た。
工程3:A(200mg、0.37mmol)のDMF(10mL)溶液に、HATU(209mg、0.55mmol)、次いでDIEA(95mg、0.73mmol)を添加した。得られた混合物を室温で30分間撹拌し、1c(105mg、0.55mmol)を添加した。室温で1.5時間撹拌した後、溶媒を蒸発させ、残渣をカラムクロマトグラフィー(PE:EA=1:2)で精製して1d(185mg、71%)を得た。
工程4:1d(185mg、0.26mmol)のDCM(3mL)溶液に、TFA(1mL)を添加し、得られた混合物を室温で1時間撹拌し、蒸発させ、pH=9になるまで飽和Na2CO3で塩基性にし、DCM(5mL×4)で抽出した。一緒にした有機層を乾燥し、蒸発させた。残渣をカラムクロマトグラフィー(DCM:メタノール=1:2)で精製し、メタノールで粉砕して1(54mg、40.7%)を得た。1H-NMR
(300MHz, CDCl3): δ=9.64 (s, 1H), 8.34 (d, 1H), 8.09 (dd, 1H), 7.39
(s, 1H), 7.31-7.36 (m, 1H), 7.06-7.12 (m, 1H), 6.65 (d, 1H), 6.23-6.26 (m, 1H),
5.34 (s, 1H), 3.81-3.84 (m, 4H), 3.44-3.48 (m, 4H), 1.89 (d, 3H). LC-MS [M+H]+:
507.0
工程2:2b〜2の手順は、1b〜1の手順と同様であり、これにより、2(6.9mg、A〜2からの収率は2.6%である)を得た。1H-NMR
(300MHz, CD3OD): δ=7.87 (d, 2H), 7.45-7.50 (m, 1H), 7.27 (t, 1H),
7.17 (s, 1H), 6.25-6.32 (m, 1H), 1.88 (d, 3H). LC-MS [M+H]+: 411.0.
工程2:3a〜3の手順は、1b〜1の手順と同様であり、これにより、3(133mg、A〜3の収率は42.7%である)を得た。1H-NMR
(300MHz, DMSO-d6): δ=10.76 (s, 1H), 8.02 (s, 1H), 7.64 (s, 1H), 7.56-7.61 (m, 1H),
7.47 (t, 1H), 7.01 (s, 1H), 6.82 (s, 2H), 6.15-6.22 (m, 1H), 3.78 (s, 3H), 1.81
(d, 3H). LC-MS [M+H]+: 424.9.
工程2:4b(200mg、1.75mmol)の濃塩酸(9mL)溶液に、SnCl2・2H2O(1.98g、8.77mmol)を添加した。この混合物を室温で1.5時間撹拌した後、pH=8〜9になるまで飽和Na2CO3で調整し、濾過した。水相をEA(30×4)で抽出し、一緒にした抽出物を無水Na2SO4で乾燥し、濾過した。50mLのHCl/Et2O溶液を濾液に添加し、30分間撹拌した後、蒸発乾固して4c(125mg、59%)を得た。
工程3:4c〜4の合成は、1cおよび1の合成と同様であり、これにより、4(99mg、44%)を得た。1H-NMR (300MHz,
DMSO): δ=11.13 (s, 1H), 9.22 (s, 1H), 8.78 (s, 1H), 7.57- 7.61 (m, 1H),
7.44-7.49 (m, 1H), 7.01 (s, 2H), 6.98(s, 1H), 6.15-6.21 (m, 1H), 1.80(d, 3H).
LC-MS [M+H]+:411.9.
工程2:5b(370mg)のMeOH溶液に10%のPd/C(200mg)を添加した。この混合物を室温で1時間水素化した。反応混合物を濾過し、濾液を蒸発させて5c(276mg、86.5%)を得た。
工程3:5c〜5の合成は、1c〜1の合成と同様であり、これにより、5(54.5mg、29%)を得た。1H-NMR (300MHz,
DMSO): δ=10.69 (s, 1H), 7.89 (s, 1H), 7.87 (s, 1H), 7.56-7.61(m, 1H), 7.44-7.50
(m, 3H), 7.02 (s, 1H), 6.98(s, 2H), 6.19-6.21 (m, 1H), 3.39-3.46 (m, 4H),
1.80-1.87 (m, 7H). LC-MS [M+H]+: 518.2.
DMSO): δ=10.69 (s, 1H), 8.35-8.39 (m, 1H), 7.90 (d, 2H), 7.79 (d, 2H),
7.57-7.61 (m, 1H), 7.47-7.50 (m, 1H), 7.01 (s, 1H), 6.99(s, 2H), 6.16-6.22 (m, 1H),
2.76 (d, 3H), 1.81 (d, 3H). LC-MS [M+H]+: 478.0.
DMSO-d6): δ=10.62 (s, 1H), 8.54 (d, 1H), 8.08-8.13 (dd, 1H), 7.56-7.61 (m, 1H),
7.44-7.49 (m, 1H), 7.02 (s, 1H), 6.94 (s, 2H), 6.78 (d, 1H), 6.16-6.22 (m, 1H),
3.81 (s, 3H), 1.81 (d, 3H). LC-MS [M+H]+:452.0
工程2:酢酸ナトリウム(373mg、4.55mol)を、8b(849mg、2.276mol)のエタノール/DMF[(5:1)(84mL)]溶液に添加した。この混合物を脱気した後、Pd(dppf)Cl2・CH2Cl2(186mg、0.228mmol)を添加した。得られた混合物を一酸化炭素雰囲気下90℃で1.5時間加熱した後、蒸発させた。残渣をカラムクロマトグラフィー(PE:EA=10:1)で精製して8c(0.7g、84%)を得た。
工程3:8c(350mg、0.956mmol)のDCM(5mL)溶液に、TFA(1.1mL、14.34mmol)を添加した。この混合物を2時間撹拌した後、蒸発乾固して8dを得た。
工程4:8d〜8eの合成は、A〜5dの合成と同様であり、これにより、8e(390mg、70.3%)を得た。
工程5:8e(390mg、0.562mmol)のTHF(4mL)溶液に、1NのLiOH水溶液(2mL)を添加した。この混合物を室温で3時間撹拌した後、溶媒のほとんどを蒸発させた。pH=3〜4になるまで残渣を酸性にし、DCM(20mL×3)で抽出し、Na2SO4で乾燥し、蒸発させて8f(330mg、88.2%)を得た。
工程6:8f〜8gの合成は、A〜5dの合成と同様であり、これにより、8g(147mg、80.3%)を得た。
工程7:8g〜8の合成は、1d〜1の合成と同様であり、これにより、8(18.5mg、18%)を得た。1H-NMR (300MHz,
DMSO-d6): δ=11.04 (s, 1H), 9.04 (d, 1H), 8.63-8.67 (m, 1H), 8.46-8.49 (dd, 1H),
7.97 (d, 1H), 7.58-7.62 (m, 1H), 7.45-7.51 (m, 1H), 7.06 (s, 3H), 6.18-6.22 (m,
1H), 2.77-2.81 (d, 3H), 1.82 (d, 3H). LC-MS [M+H]+:479.0.
工程2:9a〜9の手順は、1b〜1の手順と同様であり、これにより、9(230mg、A〜9からの収率は69%である)を得た。1H-NMR (300MHz, DMSO-d6): δ=10.77 (s, 1H), 8.06 (s, 1H), 7.66 (s, 1H),
7.57-7.62 (m, 1H), 7.47 (t, 1H), 7.01 (s, 1H), 6.86 (s, 2H), 6.17-6.20 (m, 1H),
4.84 (t, 1H), 4.08 (t, 2H), 3.66-3.72 (m, 2H), 1.81 (d, 3H). LC-MS [M+H]+:454.9.
工程2:10a〜10の手順は、1b〜1の手順と同様であり、これにより、10(18.5mg、A〜10からの収率は7.5%である)を得た。1H-NMR
(300MHz, CDCl3): δ=9.64 (s, 1H), 8.07 (s, 1H), 7.55 (s, 1H), 7.37
(s, 1H), 7.31-7.36 (m, 1H), 7.06-7.12 (m, 1H), 6.23-6.26 (m, 1H), 5.35 (s, 2H),
4.28-4.34 (m, 1H), 4.08-4.13 (m, 2H), 3.49-3.57 (m, 2H), 2.05-2.12 (m, 4H),
1.88 (d, 3H). LC-MS [M+H]+: 495.0.
δ=9.94 (s, 1H), 8.52-8.54 (d, 2H), 7.62-7.64 (dd, 2H), 7.33-7.38 (m, 2H),
7.07-7.13 (m, 1H), 6.24-6.27 (m, 1H), 5.43 (s, 2H), 1.89-1.92 (d, 3H). LC-MS
[M+H]+: 422.0.
(s, 1H), 8.79-8.80 (d, 1H), 8.36-8.38 (dd, 1H), 8.24-8.28 (m, 1H), 7.40 (s, 1H),
7.30-7.40 (m, 1H), 7.-7-7.13(q, 1H), 6.23-6.29 (q, 1H), 5.41 (s, 2H), 1.89-1.91
(d, 3H). LC-MS [M+H]+: 422.0.
2H), 8.99 (s, 1H), 7.34-7.39 (m, 2H), 7.08-7.14 (q, 1H), 6.22-6.27(q, 1H),
5.47(s, 2H), 1.89-1.92 (d, 1H). LC-MS [M+H]+: 423.0.
δ=7.30-7.35 (m, 1H), 7.06-7.13 (m, 1H), 6.79 (s, 1H), 6.13-6.19 (m, 1H), 5.16
(s, 2H), 4.16-4.26 (m, 1H), 3.48-3.78 (m, 2H), 1.83-1.85 (d, 3H), 1.60-1.60 (m,
6H). LC-MS [M+H]+: 429.1.
工程2:15b(196mg、0.30mmol)を、DCM(5mL)およびTFA(1.5mL)の混合液に溶解し、室温で2時間撹拌し、蒸発させた。残渣を飽和Na2CO3でpH=8に調整し、酢酸エチル(10mL×5)で抽出した。一緒にした有機相をMgSO4で乾燥し、濃縮した。残渣をメタノールで粉砕し、濾過して15(114mg、84%)を得た。1H-NMR
(300MHz, CDCl3): δ=1.88 (d, 3H), 3.80 (s, 3H), 5.34 (s, 2H),
6.21-6.29 (m, 1H), 6.87-6.90 (m, 2H), 7.06-7.11 (m, 1H), 7.31-7.36 (m, 1H),
7.42 (s, 1H), 7.58-7.62 (m, 2H), 9.69 (s, 1H). LC-MS [M+H]+:450.9.
δ=1.88 (d, 3H), 3.12 (t, 4H), 3.86 (t, 4H), 5.33 (s, 2H), 6.24-6.26 (m, 1H),
6.90 (d, 2H), 7.05-7.11 (m, 1H), 7.31-7.36 (m, 1H), 7.41 (s, 1H), 7.60 (d, 2H),
9.68 (s, 1H). LC-MS [M+H]+:505.9.
δ=1.90 (d, 3H), 5.34 (s, 2H), 6.23-6.29 (m, 1H), 7.06-7.15 (m, 2H), 7.32-7.38
(m, 3H), 7.43 (s, 1H), 7.68-7.71 (m, 2H), 9.79 (s, 1H). LC-MS [M+H]+:420.9.
工程2:18c(160mg、0.63mmol)のメタノール(10mL)溶液に、10%のPd/C(140mg)を添加した。この混合物を水素雰囲気で一晩水素化した。Pd/Cを濾別し、濾液を蒸発させて粗製の18d(135mg、96%)を得、これをさらに精製することなく次の工程で使用した。
工程3:18d〜18の手順は、実施例15の手順と同様であった(131mg、Aから44%)。1H-NMR (300MHz, CDCl3):
δ=1.89 (d, 3H), 2.57 (t, 4H), 2.79 (t, 2H), 3.73 (t, 4H), 4.10 (t, 2H), 5.34
(s, 2H), 6.22-6.28 (m, 1H), 6.87-6.92 (m, 2H), 7.06-7.08 (m, 1H), 7.31-7.36 (m,
1H), 7.41 (s, 1H), 7.57-7.62 (m, 2H), 9.69 (s, 1H). LC-MS [M+H]+:550.0.
工程2:還元鉄粉(129mg、2.30mmol)および2NのHCl(0.07mL)を、19b(113mg、0.33mmol)のエタノール(3mL)撹拌溶液に0℃で添加した。得られた混合物を2時間加熱還流し、濾過した。茶色の固体をエタノールで数回洗浄した。一緒にしたエタノール相を蒸発させ、残渣を酢酸エチル(15mL)に溶解し、1.5NのNa2CO3水溶液(20mL)で洗浄した。2相混合物を分離し、水相を酢酸エチル(15mL×3)で再抽出した。一緒にした有機相をMgSO4で乾燥し、濾過し、蒸発させて19c(205mg、約100%)を得た。
工程3:19c〜19の手順は、実施例15の手順と同様であった(70mg、Aから42%)。1H-NMR (300MHz, CDCl3):
δ=1.89 (d, 3H), 3.57 (s, 3H), 5.40 (s, 2H), 6.21-6.27 (m, 1H), 6.59 (d, 1H),
7.06-7.12 (m, 1H), 7.26-7.37 (m, 3H), 8.28 (d, 1H), 9.40 (s, 1H). LC-MS [M+H]+:451.9.
工程2:20a〜20の手順は、実施例15の手順と同様であった(131mg、Aから21%)。1H-NMR (300MHz, CDCl3):
δ=1.88 (d, 3H), 1.92-2.08 (m, 2H), 2.47-2.54 (m, 2H), 2.92 (d, 3H), 3.20-3.27
(m, 1H), 3.59-3.65 (m, 1H), 4.39-4.42 (m, 1H), 5.37 (s, 2H), 6.18-6.24 (m, 1H),
7.06-7.11 (m, 1H), 7.31-7.36 (m, 2H), 7.95 (d, 1H). LC-MS [M+H]+:457.1.
工程2:21a〜21の手順は、実施例15の手順と同様であった(6.8mg、39cから4.2%)。1H-NMR (300MHz, DMSO-d6): δ=1.82
(d, 3H), 6.14-6.21 (m, 1H), 6.32 (d, 1H), 6.89 (s, 2H), 6.99 (s, 1H), 7.47 (t, 1H),
7.56-7.61 (m, 1H), 7.76-7.80 (m, 1H), 7.93 (s, 1H), 10.40 (s, 1H), 11.41 (brs, 1H).
LC-MS [M+H]+:437.9.
DMSO-d6): δ=1.83 (d, 3H), 2.64-2.73 (m, 2H), 3.92 (t, 2H), 4.68 (s,
2H), 6.18-6.24 (m, 1H), 6.98-7.12 (m, 3H), 7.46 (t, 1H), 7.58-7.62 (m, 1H),
11.69 (s, 1H). LC-MS [M+H]+:484.1.
DMSO-d6): δ=1.82 (d, 3H), 1.97-2.03 (m, 1H), 2.51-2.58 (m, 2H), 2.96
(t, 2H), 3.80 (s, 2H), 6.18-6.24 (m, 1H), 6.99 (s, 1H), 7.07 (brs, 2H), 7.48
(t, 1H), 7.58-7.63 (m, 1H). LC-MS [M+H]+:482.9.
3H), 2.14-2.19 (m, 4H), 2.99-3.06 (m, 2H), 3.32-3.44 (m, 2H), 4.42-4.50 (m, 1H),
6.28-6.34 (m, 1H), 7.14 (s, 1H), 7.51 (t, 1H), 7.61-7.66 (m, 1H), 7.70 (s, 1H),
8.07 (s, 1H), 8.69 (brs, 1H), 9.16-9.18 (m, 1H), 9.39-9.42 (m, 1H), 10.93 (s, 1H).
LC-MS [M+H]+:494.0
DMSO-d6): δ=1.84 (d, 3H), 2.78 (d, 3H), 3.02-3.11 (m, 2H), 3.35-3.43
(m, 4H), 3.77-3.96 (m, 2H), 6.20-6.27 (m, 1H), 7.06 (s, 1H), 7.42-7.63 (m, 5H),
7.94 (d, 2H), 10.59 (brs, 1H), 10.75 (s, 1H). LC-MS [M+H]+:547.1.
(m, 1H), 1.90 (d, 3H), 2.88 (m, 4H), 3.56 (brs, 4H), 5.40 (s, 2H), 6.22-6.29
(m, 1H), 7.06-7.12 (m, 1H), 7.32-7.37 (m, 2H), 7.40-7.43 (m, 2H), 7.72-7.75 (m,
2H), 9.89 (s, 1H). LC-MS [M+H]+:533.0.
3H), 3.32 (s, 3H), 3.69 (t, 2H), 4.10-4.15 (m, 2H), 5.38 (s, 2H), 6.23-6.27 (m,
1H), 6.58 (d, 1H), 7.07-7.12 (m, 1H), 7.32-7.44 (m, 3H), 8.13 (d, 1H), 9.39 (s,
1H). LC-MS [M+H]+:496.0.
工程2:化合物28a(5g、29.7mmol)およびFe(6.7g、119mmol)のAcOH(5mL)、水(50mL)およびMeOH(50mL)混合溶液を30分間加熱還流した。溶媒を真空除去し、残渣をカラムクロマトグラフィーで精製して化合物28b(2.5g、60%)を得た。
工程3:化合物28b(1g、7.25mmol)のDMF(30ml)溶液に、HATU(4.13g、10.87mmol)および化合物A(20mg、163mmol)、DIEA(3.8mL、21.74mmol)を添加し、この混合物を室温で一晩撹拌した。反応混合物を水で処理し、EAで抽出した。有機層を塩水で洗浄し、MgSO4で乾燥し、減圧下で濃縮し、粗生成物をフラッシュクロマトグラフィー(DCM:MeOH=10:l)で精製して化合物28c(3.2g、66%)を得た。
工程4:化合物28c(2g、3mmol)のDCM(5mL)溶液に、TFA(3mL)を添加した。この混合物を室温で4時間撹拌し、蒸発させた。残渣をカラムクロマトグラフィー(DCM:MeOH=20:1)で精製して28(700mg、50%)を得た。1H-NMR
(300MHz, DMSO-d6): δ=10.04(s, 1H), 8.23-8.24 (d, 1H), 7.69-7.73 (dd, 1H),
7.56-7.61 (m, 1H), 7.44-7.50(t, 1H), 6.97 (s, 1H), 6.92 (s, 2H), 6.33-6.37 (d, 1H),
6.15-6.18 (q, 1H), 3.85-3.92 (q, 2H), 1.80-1.82 (d, 3H), 1.17-1.22 (t, 3H),.
LC-MS [M+H]+: 467.0.
工程2〜3:その後の合成は、実施例28の合成と同様であった(700mg、最終工程のために67%)。1H-NMR (300MHz,
DMSO-d6): δ=10.83(s, 1H), 8.00-8.02 (d, 1H), 7.57-7.61 (m, 1H), 7.44-7.50 (m,
2H), 7.35-7.36(d, 1H), 7.02(m, 3H), 6.19-6.21 (q, 1H), 3.81 (s, 3H), 1.80-1.83
(d, 3H). LC-MS [M+H]+: 453.0.
c−MetおよびALKに対する生化学アッセイ
キナーゼアッセイ。Fabian et al. (2005)
Nature Biotechnology, vol. 23, p.329およびKaraman et al.
(2008) Nature Biotechnology, vol. 26, p.127に記載されている方法でアッセイを行なった。
基本的に以下の手順に従って、当該化合物の生化学活性をアッセイした。25μlの最終反応体積で、Ron(h)(5〜10mU)を、8mMのMOPS(pH7.0)、0.2mMのEDTA、250μMのKKSRGDYMTMQIG、10mMのMgAcetateおよび[(γ−33P−ATP](具体的な活性:およそ500cpm/pmol、必要に応じて濃縮)と共にインキュベートする。MgATPミックスの添加によって反応を開始した。室温で40分間インキュベートした後、3%のリン酸溶液5μlを添加して反応を停止させた。次いで、反応液10μlをP30フィルターマットに滴下し、乾燥およびシンチレーション計数前に、5分間にわたって75mMのリン酸中で3回、メタノール中で1回洗浄した。
このアッセイではA549細胞を使用する。培養基(RPMI+10%FBS)中に40,000細胞/ウェルの密度で細胞を24ウェルプレートに播種し、付着のために37°Cで一晩培養する。細胞を飢餓培地(RPMI+1%BSA)に曝露する。試験化合物の希釈液をプレートに添加し、37℃で1時間インキュベートする。次いで、細胞を15分間室温まで冷却した後、40ng/mlのHGFで15分間刺激する。細胞を氷冷したPBSで1回洗浄した後、110ul/ウェル溶菌緩衝液(Cell Signaling社製#9803+0.2%プロテアーゼ阻害剤、Sigma社製P1860)によって4℃で1時間溶菌する。細胞溶菌液を微小遠心管に移し、4℃において10000rpmで10分間回転させ、リン酸化HGFRを、製造者の指示書に従って、Human
Phospho-HGF R/c-Met ELISAキット(R&D社製、DYC2480)によって定量化する。
本明細書において引用されている各出願および特許ならびにその各出願および特許で引用されている各文書または参考文献(各取得済特許の訴訟中を含む;「出願引用文書」)、およびこれらの出願および特許のいずれかの優先権に対応し、かつ/またはそれらの一部であるPCTおよび外国出願または特許、および各「出願引用文書」で引用または参照されている各文書は、参照により明示的に本明細書に組み込まれる。より一般的には、文書または参考文献は、参考文献の一覧または本明細書自体のいずれか一方において本明細書で引用されており、これらの各文書または参考文献(「本明細書中で引用されている参考文献」)、ならびに各「本明細書中で引用されている参考文献」で引用されている各文書または参考文献(任意の製造者の仕様書、指示書などを含む)は、参照により明示的に本明細書に組み込まれる。
Claims (9)
- 式Iの化合物:
あるいはその塩、あるいはそのカルバミン酸塩、炭酸塩、またはリン酸塩類似体、あるいはその水和物、溶媒和物または多形体(式中:
R1は、アリールアルキルまたはヘテロアリールアルキルであって、それぞれが場合により1〜4つの独立したZ1で置換されており、
R3は、水素、ヒドロキシル、アルコキシまたはアルキルアミノであり、
R6は、置換されたアリール、または場合により置換されたピリドニルであり、ここで、R6は、場合によりアルキル、シクロアルキル、ヘテロシクリル、アルコキシ、ヒドロキシアルキル、−C(O)NR7R8およびZ1から独立して選択される1〜3つの基で置換されており、これらのうちそれぞれが場合によりさらに置換されていてもよく、
R7およびR8はそれぞれ、H、アルキル、シクロアルキル、アルケニル、アルキニル、アリール、ヘテロシクリル、ヘテロアリールから独立して選択されるか、あるいは、R7およびR8は窒素と一緒になってヘテロシクリルまたはヘテロアリールを形成し、
各Z1は、ハロゲン、CN、NO2、OR15、SR15、S(O)2OR15、NR15R16、C1〜C2パーフルオロアルキル、C1〜C2パーフルオロアルコキシ、1,2−メチレンジオキシ、C(O)OR15、C(O)NR15R16、OC(O)NR15R16、NR15C(O)NR15R16、C(NR16)NR15R16、NR15C(NR16)NR15R16、S(O)2NR15R16、R17、C(O)R17、NR15C(O)R17、S(O)R17、S(O)2R17、R16、オキソ、C(O)R16、C(O)(CH2)nOH、(CH2)nOR15、(CH2)nC(O)NR15R16、NR15S(O)2R17(式中、nは独立して0〜6である)であり、
各R15は独立して、水素、C1〜C4アルキルまたはC3〜C6シクロアルキルであり、
各R16は独立して、水素、アルケニル、アルキニル、C3〜C6シクロアルキル、アリール、ヘテロシクリル、ヘテロアリール、C1〜C4アルキル、あるいはC3〜C6シクロアルキル、アリール、ヘテロシクリルまたはヘテロアリールで置換されたC1〜C4アルキルであり、かつ
各R17は独立して、C3〜C6シクロアルキル、アリール、ヘテロシクリル、ヘテロアリール、C1〜C4アルキル、あるいはC3〜C6シクロアルキル、アリール、ヘテロシクリルまたはヘテロアリールで置換されたC1〜C4アルキルである)。 - R6が置換されたアリールであり、ここで、R6がアルキル、アルコキシまたは−C(O)NR7R8で置換されている、請求項1に記載の化合物。
- R6が置換されたアリールであり、ここで、R6が−C(O)NR7R8で置換されている、請求項2に記載の化合物。
- R6が場合により置換されたピリドニルである、請求項1に記載の化合物。
- R1が場合により1〜4つの独立したZ1で置換されたアリールアルキルである、請求項1に記載の化合物。
- 各Z1は独立してハロゲンである、請求項2に記載の化合物。
- R3がHである、請求項1に記載の化合物。
- 式IIの請求項1に記載の化合物:
あるいはその塩、あるいはそのカルバミン酸塩、炭酸塩、またはリン酸塩類似体、あるいはその水和物、溶媒和物または多形体(式中:
R6は、置換されたアリール、または場合により置換されたピリドニルであり、ここで、R6は、場合によりアルキル、シクロアルキル、ヘテロシクリル、アルコキシ、ヒドロキシアルキルまたは−C(O)NR7R8で置換されており、かつ
R7およびR8はそれぞれ、H、アルキル、シクロアルキル、アルケニル、アルキニル、アリール、ヘテロシクリル、ヘテロアリールから独立して選択されるか、あるいは、R7およびR8は窒素と一緒になってヘテロシクリルまたはヘテロアリールを形成する)。 - 当該化合物が以下から選択される、請求項1に記載の化合物:
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−[4−(ピロリジニルカルボニル)フェニル]カルボキサミド(5)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−[4−(N−メチルカルバモイル)フェニル]カルボキサミド(6)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(4−メトキシフェニル)カルボキサミド(15)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(4−モルホリン−4−イルフェニル)カルボキサミド(16)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−[4−(2−モルホリン−4−イルエトキシ)フェニル]カルボキサミド(18)、
6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(1−メチル−6−オキソ−1,6−ジヒドロ−ピリジン−3−イル))カルボキサミド(19)、
6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(6−オキソ−1,6−ジヒドロピリジン−3−イル))カルボキサミド(21)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−{4−[(4−メチルピペラジニル)カルボニル]フェニル}カルボキサミド(25)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−[4−(ピペラジニルカルボニル)フェニル]カルボキサミド(26)、
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−[1−(2−メトキシエチル)−6−オキソ−1,6−ジヒドロ−ピリジン−3−イル)]カルボキサミド(27)、および
{6−アミノ−5−[(2,6−ジクロロ−3−フルオロフェニル)エトキシ]ピリダジン−3−イル}−N−(1−エチル−6−オキソ−1,6−ジヒドロ−ピリジン−3−イル))カルボキサミド(28)。
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Also Published As
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KR20110044974A (ko) | 2011-05-03 |
IL210099A (en) | 2015-11-30 |
US20110160209A1 (en) | 2011-06-30 |
US9296724B2 (en) | 2016-03-29 |
EP2303018A1 (en) | 2011-04-06 |
CN102098917A (zh) | 2011-06-15 |
EP2303018B1 (en) | 2015-10-14 |
RU2011139352A (ru) | 2013-04-10 |
CA2728408A1 (en) | 2009-12-23 |
EP2303018A4 (en) | 2012-06-20 |
MX2010014171A (es) | 2011-07-04 |
PL2303018T3 (pl) | 2016-06-30 |
US20160176900A1 (en) | 2016-06-23 |
EP3061752A1 (en) | 2016-08-31 |
ES2670665T3 (es) | 2018-05-31 |
RU2526618C2 (ru) | 2014-08-27 |
ES2551899T3 (es) | 2015-11-24 |
BRPI0914305B1 (pt) | 2021-05-11 |
US20140221376A1 (en) | 2014-08-07 |
JP2011524905A (ja) | 2011-09-08 |
US8697866B2 (en) | 2014-04-15 |
EP3061752B1 (en) | 2018-02-21 |
CA2728408C (en) | 2017-12-05 |
BRPI0914305B8 (pt) | 2021-05-25 |
AU2009260810A1 (en) | 2009-12-23 |
KR101691640B1 (ko) | 2016-12-30 |
WO2009154769A1 (en) | 2009-12-23 |
NZ590542A (en) | 2012-12-21 |
BRPI0914305A2 (pt) | 2015-08-11 |
IL210099A0 (en) | 2011-02-28 |
CN102098917B (zh) | 2016-03-16 |
AU2009260810B2 (en) | 2015-09-17 |
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