JP2020510061A - ピラゾロクロロフェニル化合物、組成物及びその使用方法 - Google Patents
ピラゾロクロロフェニル化合物、組成物及びその使用方法 Download PDFInfo
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- JP2020510061A JP2020510061A JP2019550583A JP2019550583A JP2020510061A JP 2020510061 A JP2020510061 A JP 2020510061A JP 2019550583 A JP2019550583 A JP 2019550583A JP 2019550583 A JP2019550583 A JP 2019550583A JP 2020510061 A JP2020510061 A JP 2020510061A
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- alkyl
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- FOEYMRPOKBCNCR-UHFFFAOYSA-N spiro[2.5]octane Chemical compound C1CC11CCCCC1 FOEYMRPOKBCNCR-UHFFFAOYSA-N 0.000 description 1
- CTDQAGUNKPRERK-UHFFFAOYSA-N spirodecane Chemical compound C1CCCC21CCCCC2 CTDQAGUNKPRERK-UHFFFAOYSA-N 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
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- PJFHZKIDENOSJB-JIVDDGRNSA-N symbicort inhalation aerosol Chemical compound C1=CC(OC)=CC=C1C[C@H](C)NC[C@@H](O)C1=CC=C(O)C(NC=O)=C1.C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O PJFHZKIDENOSJB-JIVDDGRNSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- XCAQIUOFDMREBA-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)OC(C)(C)C XCAQIUOFDMREBA-UHFFFAOYSA-N 0.000 description 1
- GNBBRRLXAVORAR-UHFFFAOYSA-N tert-butyl n-[5-(5-chloro-2-methoxyphenyl)-1-methylpyrazol-4-yl]carbamate Chemical compound COC1=CC=C(Cl)C=C1C1=C(NC(=O)OC(C)(C)C)C=NN1C GNBBRRLXAVORAR-UHFFFAOYSA-N 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229950002896 tetomilast Drugs 0.000 description 1
- 125000001935 tetracenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C12)* 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005888 tetrahydroindolyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000004525 thiadiazinyl group Chemical group S1NN=C(C=C1)* 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000001730 thiiranyl group Chemical group 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 239000003769 thromboxane A2 receptor blocking agent Substances 0.000 description 1
- 239000002396 thromboxane receptor blocking agent Substances 0.000 description 1
- 238000004613 tight binding model Methods 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- 229960003989 tocilizumab Drugs 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002463 transducing effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229960005204 tretoquinol Drugs 0.000 description 1
- RGVPOXRFEPSFGH-AWEZNQCLSA-N tretoquinol Chemical compound COC1=C(OC)C(OC)=CC(C[C@H]2C3=CC(O)=C(O)C=C3CCN2)=C1 RGVPOXRFEPSFGH-AWEZNQCLSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- UEUZRTVOLSCNIX-UHFFFAOYSA-N trimethyl-[2-[(4-nitropyrazol-1-yl)methoxy]ethyl]silane Chemical compound C[Si](C)(C)CCOCN1C=C([N+]([O-])=O)C=N1 UEUZRTVOLSCNIX-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- NZFCFINYMZDNDL-UHFFFAOYSA-N tripyrrolidin-1-yl(triazolo[4,5-b]pyridin-3-yloxy)phosphanium Chemical compound C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=NC=CC=C2N=N1 NZFCFINYMZDNDL-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 229960000859 tulobuterol Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000002447 tumor necrosis factor alpha converting enzyme inhibitor Substances 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 102000042286 type I cytokine receptor family Human genes 0.000 description 1
- 108091052247 type I cytokine receptor family Proteins 0.000 description 1
- 102000042287 type II cytokine receptor family Human genes 0.000 description 1
- 108091052254 type II cytokine receptor family Proteins 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960003824 ustekinumab Drugs 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229960004026 vilanterol Drugs 0.000 description 1
- KLOLZALDXGTNQE-JIDHJSLPSA-N vilanterol trifenate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)O)C1=CC=CC=C1.C1=C(O)C(CO)=CC([C@@H](O)CNCCCCCCOCCOCC=2C(=CC=CC=2Cl)Cl)=C1 KLOLZALDXGTNQE-JIDHJSLPSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 125000005863 α-amino(C1-C4)alkanoyl group Chemical group 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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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
- C07D513/04—Ortho-condensed systems
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- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
本願は、2017年3月14日に出願された国際出願第PCT/CN2017/076598号に対する優先権の利益を主張する。同出願は、その全体が参照により本明細書に組み入れられる。
本発明の分野は、ヤヌスキナーゼ、例えばJAK1の阻害剤である、式I及びその部分式(subformula)で示される化合物並びにこれらの化合物を含有する組成物、及びJAKキナーゼの阻害に応答性の状態を患っている患者の診断又は処置を含む使用方法(これらに限定されない)に属する。
サイトカイン経路は、炎症及び免疫の多くの態様を含む広い範囲の生物学的機能を媒介する。JAK1、JAK2、JAK3及びTYK2を含むヤヌスキナーゼ(JAK)は、I型及びII型サイトカインレセプターと会合し、サイトカインシグナル伝達をレギュレーションする細胞質プロテインキナーゼである。同起源レセプターとのサイトカインの結合により、レセプターに会合しているJAKの活性化がトリガーされ、これにより、シグナル伝達性転写因子(STAS)タンパク質のJAK媒介性チロシンリン酸化がもたらされ、最終的に、特定の遺伝子セットの転写活性化がもたらされる(Schindler et al., 2007, J. Biol. Chem. 282: 20059-63)。JAK1、JAK2及びTYK2は、広いパターンの遺伝子発現を示す。一方、JAK3の発現は、白血球に限定されている。サイトカインレセプターは、典型的には、ヘテロ二量体として機能性であり、その結果として、通常2つ以上の種類のJAKキナーゼが、サイトカインレセプター複合体と会合する。様々なサイトカインレセプター複合体と会合する特定のJAKが、多くの場合遺伝学的研究により決定され、他の実験的証拠により裏付けられてきた。JAK酵素阻害の例示的な治療的利益は、例えば、第WO2013/014567号で検討されている。
本発明の一態様は、式(I):
[式中、
R1は、C2〜C6アルケニル、C2〜C6アルキニル、−(C0〜C3アルキル)CN、−(C0〜C3アルキル)ORa、−(C0〜C3アルキル)Ra、−(C0〜C3アルキル)SRa、−(C0〜C3アルキル)NRaRb、−(C0〜C3アルキル)OCF3、−(C0〜C3アルキル)CF3、−(C0〜C3アルキル)NO2、−(C0〜C3アルキル)C(O)Ra、−(C0〜C3アルキル)C(O)ORa、−(C0〜C3アルキル)C(O)NRaRb、−(C0〜C3アルキル)NRaC(O)Rb、−(C0〜C3アルキル)S(O)1−2Ra、−(C0〜C3アルキル)NRaS(O)1−2Rb、−(C0〜C3アルキル)S(O)1−2NRaRb、−(C0〜C3アルキル)(5〜6−員のヘテロアリール)又は−(C0〜C3アルキル)フェニルであり、ここで、R1は、場合によりハロゲン、C1〜C3アルキル、オキソ、−CF3、−(C0〜C3アルキル)ORc又は−(C0〜C3アルキル)NRcRdにより置換されており、
各Raは、独立して水素、C1〜C6アルキル、C3〜C6シクロアルキル、3〜10員のヘテロシクリル、5〜6員のヘテロアリール、−C(O)Rc、−C(O)ORc、−C(O)NRcRd、−NRcC(O)Rd、−S(O)1−2Rc、−NRcS(O)1−2Rd及び−S(O)1−2NRcRdからなる群より選択され、ここで、Raの任意のC3〜C6シクロアルキル、3〜10員のヘテロシクリル及び5〜6員のヘテロアリールは、場合によりReにより置換されており、
各Rbは、独立して水素及びC1〜C3アルキルからなる群より選択され、ここで、前記アルキルは、場合によりハロゲン又はオキソにより置換されており、
各Rc及びRdは、独立して水素、3〜6員のヘテロシクリル、C3〜C6シクロアルキル及びC1〜C3アルキルからなる群より選択され、ここで、Rc及びRdの任意の3〜6員のヘテロシクリル、C3〜C6シクロアルキル及びC1〜C3アルキルは、場合によりハロゲン又はオキソにより置換されており、又は、Rc及びRdは、それらが結合している原子と一緒になって、場合によりハロゲン、オキソ、−CF3又はC1〜C3アルキルにより置換されている3〜6員のヘテロシクリルを形成し、
各Reは、独立してオキソ、ORf、NRfRg、ハロゲン、3〜10員のヘテロシクリル、C3〜C6シクロアルキル及びC1〜C6アルキルからなる群より選択され、ここで、Reの任意のC3〜C6シクロアルキル及びC1〜C6アルキルは、場合によりORf、NRfRg、ハロゲン、3〜10員のヘテロシクリル、オキソ又はシアノにより置換されており、ここで、Reの任意の3〜10員のヘテロシクリルは、場合によりハロゲン、オキソ、シアノ、−CF3、NRhRk、3〜6員のヘテロシクリル又はC1〜C3アルキル(場合によりハロゲン、オキソ、ORfもしくはNRhRkにより置換されている)により置換されており、
各Rf及びRgは、独立して水素、C1〜C6アルキル、3〜6員のヘテロシクリル及びC3〜C6シクロアルキルからなる群より選択され、ここで、Rf及びRgの任意のC1〜C6アルキル、3〜6員のヘテロシクリル及びC3〜C6シクロアルキルは、場合によりRmにより置換されており、
各Rh及びRkは、独立して水素及びC1〜C6アルキル(場合によりハロゲン、シアノ、3〜6員のヘテロシクリル又はオキソにより置換されている)からなる群より選択され、又は、Rh及びRkは、それらが結合している原子と一緒になって、場合によりハロゲン、シアノ、オキソ、−CF3又はC1〜C3アルキル(場合によりハロゲンもしくはオキソにより置換されている)により置換されている3〜6員のヘテロシクリルを形成し、
各Rmは、独立してハロゲン、シアノ、オキソ、C3〜C6シクロアルキル、ヒドロキシ及びNRhRkからなる群より選択され、ここで、Rmの任意のC3〜C6シクロアルキルは、場合によりハロゲン、オキソ、シアノ又はC1〜C3アルキルにより置換されており、
R2は、フェニル、5〜6員のヘテロアリール、C3〜C6シクロアルキル又は3〜10員のヘテロシクリルであり、ここで、R2は、場合により1〜5個のRnにより置換されており、
各Rnは、独立してC1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、オキソ、ハロゲン、−(C0〜C3アルキル)CN、−(C0〜C3アルキル)ORo、−(C0〜C3アルキル)SRo、−(C0〜C3アルキル)NRoRp、−(C0〜C3アルキル)OCF3、−(C0〜C3アルキル)CF3、−(C0〜C3アルキル)NO2、−(C0〜C3アルキル)C(O)Ro、−(C0〜C3アルキル)C(O)ORo、−(C0〜C3アルキル)C(O)NRoRp、−(C0〜C3アルキル)NRoC(O)Rp、−(C0〜C3アルキル)S(O)1−2Ro、−(C0〜C3アルキル)NRoS(O)1−2Rp、−(C0〜C3アルキル)S(O)1−2NRoRp、−(C0〜C3アルキル)(C3〜C6シクロアルキル)、−(C0〜C3アルキル)(3〜6員のヘテロシクリル)、−(C0〜C3アルキル)C(O)(3〜6員のヘテロシクリル)、−(C0〜C3アルキル)(5〜6員のヘテロアリール)及び−(C0〜C3アルキル)フェニルからなる群より選択され、ここで、各Rnは、独立して、場合によりハロゲン、C1〜C3アルキル、オキソ、−CF3、−(C0〜C3アルキル)ORr又は−(C0〜C3アルキル)NRrRsにより置換されており、又は、2つのRnは一緒になって、−O(CH2)1−3O−を形成し、
各Roは、独立して水素、C1〜C6アルキル、C3〜C6シクロアルキル、3〜6員のヘテロシクリル、−C(O)Rr、−C(O)ORr、−C(O)NRrRs、−NRrC(O)Rs、−S(O)1−2Rr、−NRrS(O)1−2Rs及び−S(O)1−2NRrRsからなる群より選択され、ここで、前記アルキル、シクロアルキル及びヘテロシクリルは、独立して、場合によりオキソ、C1〜C3アルキル、ORr、NRrRs又はハロゲンにより置換されており、各Rpは、独立して水素及びC1〜C3アルキルからなる群より選択され、ここで、前記アルキルは、独立して、場合によりハロゲン又はオキソにより置換されており、又は、Ro及びRpは、それらが結合している原子と一緒になって、場合によりハロゲン、オキソ、−CF3又はC1〜C3アルキルにより置換されている3〜6員のヘテロシクリルを形成し、
各Rr及びRsは、独立して水素及びC1〜C3アルキル(場合によりハロゲン又はオキソにより置換されている)からなる群より選択され、又は、Rr及びRsは、それらが結合している原子と一緒になって、場合によりハロゲン、オキソ、−CF3又はC1〜C3アルキルにより置換されている3〜6員のヘテロシクリルを形成し、
Xは、それぞれ独立してO、S及びNからなる群より選択される2又は3個の原子を含む、9〜10員の二環式ヘテロアリールであり、ここで、9〜10員の二環式ヘテロアリールは、場合によりRuにより置換されており、ただし、Xは、場合によりRuにより置換されている下記の基:
ではなく、
各Ruは、独立して水素、ハロ、C1〜C6アルキル、C3〜C6シクロアルキル、3〜6員のヘテロシクリル、−ORv、−C(O)Rv、−C(O)ORv、−C(O)NRvRw、−NRvRw、−NRvC(O)Rw、−S(O)1−2Rv、−NRvS(O)1−2Rw及び−S(O)1−2NRvRwからなる群より選択され、ここで、前記アルキル、シクロアルキル及びヘテロシクリルは、独立して、場合によりオキソ、C1〜C3アルキル、−ORv、−NRvRw又はハロゲンにより置換されており、
各Rv及びRwは、独立して水素及びC1〜C3アルキル(場合によりハロゲン又はオキソにより置換されている)からなる群より選択され、又は、Rv及びRwは、それらが結合している原子と一緒になって、場合によりハロゲン、オキソ、−CF3又はC1〜C3アルキルにより置換されている3〜6員のヘテロシクリルを形成している]
で示される化合物又はその塩を含む。
定義
「ハロゲン」又は「ハロ」は、F、Cl、Br又はIを指す。加えて、「ハロアルキル」等の用語は、モノハロアルキル及びポリハロアルキルを含むことを意味する。
は、化学構造中で波状結合が連結している原子の、分子の残り部分又は分子のフラグメントの残り部分への結合点を示す。ある実施態様では、アスタリスクを伴った矢印が、結合点を示すために、波線の要領で使用される。
また、実施例1〜15から選択される化合物及び表1における化合物、又はそれらの任意の組み合わせも提供される。
[式中、
Ru1は、H又はメチルであり、
Ru2は、メチル又はジフルオロメチルであり、
Ru3は、メチル、メトキシ、ハロ又はNH2である]
で示される化合物、又はその塩を提供する。
[式中、
R3は、H、ハロゲン、シアノ、C1〜C3アルキル、C2〜C3アルケニル、C2〜C3アルキニル又は−ORtであり、
R4は、H、ハロゲン、シアノ、C1〜C3アルキル、C2〜C3アルケニル、C2〜C3アルキニル又は−ORtであり、
R5は、H、ハロゲン、シアノ、C1〜C3アルキル、C2〜C3アルケニル、C2〜C3アルキニル又は−ORtであり、
各Rtは、独立して、H、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル又は−(C0〜C3アルキル)フェニルである]
ではない、式(I)で示される化合物を提供する。
本発明の化合物は、本明細書に記載された合成経路により合成することができる。特定の実施態様では、本明細書に含まれる説明に加えて、又はそれを踏まえ、化学分野において周知のプロセスを使用することができる。出発物質は、商業的供給源、例えばAldrich Chemicals(Milwaukee, Wis.)から一般に入手できるか、又は、当業者に周知の方法を使用して容易に調製される(例えば、Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed.) Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin(補足を含む(Beilsteinオンラインデータベースからも入手できる))又はComprehensive Heterocyclic Chemistry, Editors Katrizky and Rees, Pergamon Press, 1984に一般的に記載されている方法により調製される)。
(1)カルボン酸をアミンと反応させてアミドを形成すること。このような変換は、当業者に公知の種々の試薬を使用して達成することができるが、包括的なレビューは、Tetrahedron, 2005, 61, 10827-10852に見出すことができる。
(2)第一級又は第二級アミンと、アリールハロゲン化物又は擬ハロゲン化物、例えばトリフラートの反応(「Buchwald−Hartwigクロスカップリング」として一般に公知)は、各種の触媒、リガンド及び塩基を使用して達成することができる。これらの方法のレビューは、Comprehensive Organic Name Reactions and Reagents, 2010, 575-581に提供される。
(3)アリールハロゲン化物とビニルボロン酸又はボロナートエステルとの間でのパラジウムクロスカップリング反応。この変換は、ある種の「鈴木−宮浦クロスカップリング」であり、Chemical Reviews, 1995, 95(7), 2457-2483に十分にレビューされている分類の反応である。
(4)エステルを加水分解して、対応するカルボン酸を与えることは、当業者に周知であり、条件は、メチル及びエチルエステルについては、水性強塩基、例えば水酸化リチウム、ナトリウムもしくはカリウム、又は水性強鉱酸、例えばHClの使用を含み;tert−ブチルエステルについては、加水分解は酸、例えばジオキサン中でHCl、又はジクロロメタン(DCM)中でトリフルオロ酢酸(TFA)を使用して行われるであろう。
例示的なスキームそれぞれにおいて、反応生成物を互いに、又は出発物質から分離することが有利な場合がある。各工程、又は一連の工程の所望の生成物を、当技術分野において一般的な技術により、所望の程度の均質性に分離し又は精製する(以下、分離する)。典型的には、このような分離は、溶媒又は溶媒混合物からの多相抽出、結晶化もしくはトリチュレーション、蒸留、昇華又はクロマトグラフィーを含む。クロマトグラフィーは、例えば、逆相及び順相;サイズ排除;イオン交換;超臨界流体;高圧、中圧及び低圧液体クロマトグラフィー法及び装置;小規模分析;模擬移動床(SMB)及び調製用薄層又は厚層クロマトグラフィー並びに小規模薄層クロマトグラフィー及びフラッシュクロマトグラフィーの技術を含む任意の数の方法を含みうる。
本発明が関係する化合物は、JAKキナーゼ阻害剤、例えばJAK1阻害剤であり、幾つかの疾患、例えば炎症性疾患、例えば喘息の処置に有用である。
本発明の化合物* 24mg/キャニスター
レシチン、NF Liq.Conc. 1.2mg/キャニスター
トリクロロフルオロメタン、NF 4.025g/キャニスター
ジクロロジフルオロメタン、NF 12.15g/キャニスター
*例えば式Iで示される化合物、又は表1に示される化合物、又は実施例1〜15の化合物
局所(吸入)投与による肺への送達のための薬剤の最適化は、近年レビューされている(Cooper, A. E. et al. Curr. Drug Metab. 2012, 13, 457-473)。送達装置における限界のために、吸入された薬剤の用量は、高度に強力な分子を必要とするヒトにおいて低くなりやすい(約1mg/日未満)。乾燥粉末吸入により送達される予定の化合物については、1〜5μmのサイズに微粉化することができる、化合物の結晶形態を生成できるという要件もある。加えて化合物は、所望の持続期間の薬理学的効果を発揮できるように、所定の期間にわたって肺における十分な濃度が維持され、また全身的阻害が望ましくない薬理学的標的の場合には、全身的暴露が少なくなる必要がある。肺は本質的に、大きな分子(タンパク質、ペプチド)と、肺での短い半減期を伴う低分子の両方に対して高い透過性を有するため、化合物の1つ以上の特徴の修飾(膜透過性の最小化、溶解速度の低下、もしくはリン脂質に富む肺組織への結合を高めるための、化合物へのある程度の塩基性の導入)により、又は酸性細胞内区画、例えばリソソーム(pH5)での捕捉により、肺吸収速度を減じることが必要である。したがって、ある実施態様では、本発明の化合物は、これらの特徴の1つ以上を示す。
本発明の化合物、例えば式Iで示される化合物、又は表1に示される化合物、又は実施例1〜15の化合物は、ヤヌスキナーゼ、例えばJAK1キナーゼの活性を阻害する。例えば、本発明の化合物、例えば式Iで示される化合物、又は表1に示される化合物、又は実施例1〜15の化合物は、JAK1キナーゼによるシグナル伝達兼転写活性化因子(STAT)のリン酸化並びにSTAT媒介サイトカイン産生を阻害する。本発明の化合物、例えば式Iで示される化合物、又は表1に示される化合物、又は実施例1〜15の化合物は、サイトカイン経路、例えば、IL−6、IL−15、IL−7、IL−2、IL−4、IL−9、IL−10、IL−13、IL−21、G−CSF、IFNアルファ、IFNベータ又はIFNガンマ経路を介して、細胞におけるJAK1キナーゼ活性を阻害するのに有用である。したがって、一実施態様では、細胞を本発明の化合物、例えば式Iで示される化合物、又は表1に示される化合物、又は実施例1〜15の化合物と接触させて、細胞におけるヤヌスキナーゼ活性(例えば、JAK1活性)を阻害する方法が提供される。
本発明の化合物、例えば式Iで示される化合物、又は表1に示される化合物、又は実施例1〜15の化合物は、単独で、又は処置のための他の薬剤と組み合わせて利用することができる。医薬組成物又は投薬計画の第2の化合物は、典型的には、本発明の化合物に対して補完的な活性を有し、それらが互いに悪影響を及ぼさないようにする。このような薬剤は、適切には、意図した目的に有効な量で、組み合わされて存在する。化合物は、単一の医薬組成物中に共に又は別々に投与されてもよく、別々に投与される場合、これは同時に、又は連続的に行われうる。このような連続投与は、時間的に近くても、離れていてもよい。
別の実施態様は、ヤヌスキナーゼ、例えばJAK1キナーゼの阻害に応答性の疾患又は障害を処置するための製品(例えば、キット)を含む。該キットは、
(a)本発明の化合物、例えば式Iで示される化合物、又は表1に示される化合物、又は実施例1〜15の化合物を含む第1の医薬組成物と、
(b)使用のための説明書と、
を含むことができる。
(c)第2の医薬組成物、例えば、上記された処置のための薬剤、例えば、炎症性障害の処置のための薬剤又は化学療法剤を含む医薬組成物
を更に含む。
本発明をある程度詳細に説明し、例示してきたが、本開示は単に例としてなされたものであり、部品の組み合わせ及び配置における多数の変更が、特許請求の範囲により定義された本発明の精神及び範囲から逸脱することなく、当業者により用いられ得ると理解される。
DIPEA ジイソプロピルエチルアミン
DMF N,N−ジメチルホルムアミド
DMSO ジメチルスルホキシド
DMSO−d6 重水素化ジメチルスルホキシド
EtOAc 酢酸エチル
EtOH エタノール
g グラム
HATU (O−(7−アザベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスファート)
HCl 塩酸
HM−N Isolute HM−Nは、改変型の珪藻土である。
L リットル
MeCN アセトニトリル
MeOH メタノール
mg ミリグラム
mL ミリリットル
NaOH 水酸化ナトリウム
Pd2(dba)3 トリス(ジベンジリデンアセトン)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)、ジクロロメタンとの錯体
Pd(OAc)2 酢酸パラジウム(II)
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)
RT 周囲温度
THF テトラフルオロフラン
TFA トリフルオロ酢酸
TLC 薄層クロマトグラフィー
XantPhos 4,5−ビス(ジフェニルホスフィノ)−9,9−ジメチルキサンテン
Shim-Pack XR-ODSカラム(50×3mm、粒径2.2μm)を備えたSHIMADZU 20A HPLCにおいて、溶媒A:水+0.05% トリフルオロ酢酸;溶媒B:アセトニトリル+0.05% トリフルオロ酢酸で溶出させて、実験を行った。勾配:
勾配−時間 流速(ml/分) %A %B
0.00 1.0 95 5
2.20 1.0 0 100
3.20 1.0 0 100
3.30 1.0 95 5
検出−UV(220及び254nm)及びELSD
Shim-Pack XR-ODSカラム(50×3mm、粒径2.2μm)を備えたSHIMADZU 20A HPLCにおいて、溶媒A:水+0.05% トリフルオロ酢酸;溶媒B:アセトニトリル+0.05% トリフルオロ酢酸で溶出させて、実験を行った。勾配:
勾配−時間 流速(ml/分) %A %B
0.00 1.0 95 5
3.50 1.0 15 85
4.20 1.0 15 85
4.30 1.0 95 5
検出−UV(220及び254nm)及びELSD
Poroshell HPH-C18カラム(50×3mm、粒径2.7μm)を備えたSHIMADZU 20A HPLCにおいて、溶媒A:水/5mM NH4HCO3;溶媒B:アセトニトリルで溶出させて、実験を行った。勾配:
勾配−時間 流速(ml/分) %A %B
0.00 1.5 90 10
2.00 1.5 5 95
2.70 1.5 5 95
2.80 1.5 90 10
検出−UV(220及び254nm)及びELSD
Shim-Pack XR-ODSカラム(50×3mm、粒径2.2μm)を備えたSHIMADZU 20A HPLCにおいて、溶媒A:水+0.05% トリフルオロ酢酸;溶媒B:アセトニトリル+0.05% トリフルオロ酢酸で溶出させて、実験を行った。勾配:
勾配−時間 流速(ml/分) %A %B
0.00 1.0 95 5
1.10 1.0 0 100
1.60 1.0 0 100
1.70 1.0 95 5
検出−UV(220及び254nm)及びELSD
Shim-Pack XR-ODSカラム(50×3mm、粒径2.2μm)を備えたSHIMADZU 20A HPLCにおいて、溶媒A:水+0.05% トリフルオロ酢酸;溶媒B:アセトニトリル+0.05% トリフルオロ酢酸で溶出させて、実験を行った。勾配:
勾配−時間 流速(ml/分) %A %B
0.00 1.0 95 5
4.20 1.0 20 80
5.20 1.0 20 80
5.30 1.0 95 5
検出−UV(220及び254nm)及びELSD
Shim-Pack XR-ODSカラム(50×3mm、粒径2.2μm)を備えたSHIMADZU 20A HPLCにおいて、溶媒A:水+0.05% トリフルオロ酢酸;溶媒B:アセトニトリル+0.05% トリフルオロ酢酸で溶出させて、実験を行った。勾配:
勾配−時間 流速(ml/分) %A %B
0.00 1.0 70 30
4.20 1.0 15 85
5.20 1.0 15 85
5.30 1.0 95 5
検出−UV(220及び254nm)及びELSD
Shim-Pack XR-ODSカラム(50×3mm、粒径2.2μm)を備えたSHIMADZU 20A HPLCにおいて、溶媒A:水+0.05% トリフルオロ酢酸;溶媒B:アセトニトリル+0.05% トリフルオロ酢酸で溶出させて、実験を行った。勾配:
勾配−時間 流速(ml/分) %A %B
0.00 1.2 95 5
3.50 1.2 60 40
3.70 1.2 0 100
4.70 1.2 0 100
4.75 1.2 95 5
検出−UV(220及び254nm)及びELSD
Shim-Pack XR-ODSカラム(50×3mm、粒径2.2μm)を備えたSHIMADZU 20A HPLCにおいて、溶媒A:水+0.05% トリフルオロ酢酸;溶媒B:アセトニトリル+0.05% トリフルオロ酢酸で溶出させて、実験を行った。勾配:
勾配−時間 流速(ml/分) %A %B
0.00 1.2 95 5
2.00 1.2 5 95
2.70 1.2 5 95
2.75 1.2 95 5
検出−UV(220及び254nm)及びELSD
Acquity UPLC(バイナリポンプ/PDA検出器)+ZQ質量分析計において、イオン化源としてESIを使用して、実験を行った。LC分離には、流速0.4ml/分で、Acquity UPLC BEH C18 1.7μm、100×2.1mmカラムを使用した。溶媒Aは0.1% ギ酸を含む水であり、溶媒Bは0.1% ギ酸を含むアセトニトリルである。勾配は、5% 溶媒Bで0.4分、次いで6分まで5〜95% 溶媒B、そして6.8分まで95% B保持からなった。LCカラム温度は40℃である。UVダイオードアレイ200〜500nm及び質量スペクトルフルスキャンを全ての実験に適用した。
正及び負イオンモードで作動するエレクトロスプレー源を備え、Waters 1525 LCシステムに連結されたWaters ZMD単一四重極質量分析計において、実験を行った。検出は、UVダイオードアレイ検出器及びSedex 85蒸発光散乱検出器を使用して達成した。LCカラムは、Phenomenex Luna 3ミクロンC18(2)30×4.6mmであった。流速は2mL/分であった。最初の溶媒系は、0.1% ギ酸を含有する水(溶媒A)95%及び0.1% ギ酸を含有するアセトニトリル(溶媒B)5%で0.5分であり、次いで、次の4分間かけて5% 溶媒A及び95% 溶媒Bまでの勾配とした。最後の溶媒系を更に1分間一定に保持した。
イオン化源としてESIを使用するAgilent MSD(6140)質量分析計と連結したAgilent 1290 UHPLC(Phenomenex XB-C18、1.7μm、50×2.1mm、粒径1.7μm)において、溶媒A:水+0.1% ギ酸;溶媒B:アセトニトリル+0.1% ギ酸で溶出させて、実験を行った。勾配:
勾配−時間(分) 流速(ml/分) %A %B
0 0.4 98 2
1.5 0.4 2 98
8.5 0.4 2 98
10 0.4 2 98
11.5 0.4 98 2
検出−UV(200nm、254nm)
イオン化源としてESIを使用するAgilent MSD(6140)質量分析計と連結したAgilent 1200 HPLC(Agilent ZORBAX SB-C18、粒径1.8μm、2.1×50mm)において、溶媒A:水+0.1% ギ酸;溶媒B:アセトニトリル+0.1%ギ酸で溶出させて、実験を行った。勾配:
分 流速(ml/分) %A %B
0.0 0.4 97 3
7.0 0.4 5 95
8.5 0.4 5 95
8.7 0.4 97 3
10 0.4 97 3
検出−UV(200nm、254nm)
3−(5−クロロ−2−メトキシフェニル)−1−メチル−1H−ピラゾール−4−アミン
撹拌されている5−クロロ−2−メトキシ安息香酸(1.87g、10.0mmol)のテトラヒドロフラン(20mL)溶液に、N,N−カルボニルジイミダゾール(1.64g、10.1mmol)を加え、撹拌を20分間継続して、アシル−イミダゾールを生成した。別に、カリウムエチルマロナート(4.08g、23.99mmol)及び塩化マグネシウム(1.15g、12.10mmol)をテトラヒドロフラン(20mL)中に懸濁させた。アシル−イミダゾール溶液を塩化マグネシウム混合物に加えた。添加が完了したら、この混合物を50℃で1.5時間加熱した。この反応混合物を酢酸エチルと水の間で分配し、有機部分を硫酸マグネシウムで乾燥させ、celiteのパッドに通してろ過し、濃縮して、エチル 3−(5−クロロ−2−メトキシフェニル)−3−オキソプロパノアート(2.57g、101%)を提供した。これを更に精製することなく使用した。LC/MS(ESI):[M+H]+=257.2。
tert−ブチル 3−(5−クロロ−2−メトキシフェニル)−1−メチル−1H−ピラゾール−4−イルカルバマート(543mg、48%)。LC/MS(ESI):[M+H]+=338.3;1H NMR (400MHz, CDCl3): δ: 7.84 (s, 1H), 7.39 (d, 1H), 7.23 (s, 1H), 6.96 (d, 1H), 5.92 (s, 1H), 3.89 (m, 6H), 1.48 (s, 9H)。
tert−ブチル 5−(5−クロロ−2−メトキシフェニル)−1−メチル−1H−ピラゾール−4−イルカルバマート(774mg、68%)。LC/MS(ESI):[M+H]+=338.3;1H NMR (400MHz, CDCl3): δ: 7.84 (s, 1H), 7.59 (s, 1H), 7.29 (d, 1H), 6.93 (d, 1H), 3.89 (m, 6H), 1.48 (s, 9H)。
5−(5−クロロ−2−(ジフルオロメトキシ)フェニル)−1−((2−(トリメチルシリル)エトキシ)メチル)−1H−ピラゾール−4−アミン
2−ブロモ−4−クロロフェノール(4.98g、24.0mmol)のDMF(25mL)溶液に、クロロジフルオロ酢酸ナトリウム(8.42g、55.2mmol)、炭酸セシウム(10.97g、33.67mmol)及び水(2.5mL)を加えた。反応物を100℃で16時間撹拌した。反応混合物を酢酸エチルと水の間で分配し、有機部分をブラインで洗浄し、乾燥(MgSO4)させ、蒸発させた。粗生成物を、ヘプタン中0〜20%のEtOAcで溶出するシリカでのフラッシュクロマトグラフィーにより精製して、2−ブロモ−4−クロロ−1−(ジフルオロメトキシ)ベンゼン(2.98g、48%)を透明な無色の油状物として生成した。LCMS(ESI)m/zシグナルなし;1H NMR (400 MHz, DMSO-d6): δ7.90 (d, 1H), 7.54 (dd, 1H), 7.38 (d, 1H), 7.28 (t, 1H)。
N−(3−(5−クロロ−2−メトキシフェニル)−1−メチル−1H−ピラゾール−4−イル)−2−メチル−2H−ピラゾロ[4,3−c]ピリジン−7−カルボキサミド
4−アジド−5−ブロモニコチンアルデヒド(0.50g、2.2mmol)のTHF(10mL)溶液に、メチルアミン(THF中2M、9.0mL、18mmol)及び無水硫酸ナトリウムを加えた。混合物を室温で一晩撹拌した。固体をろ過により除去し、ろ液を蒸発させて、粗1−(4−アジド−5−ブロモピリジン−3−イル)−N−メチルメタンイミン(0.578g、定量的と推定)を与えた。イミンをトルエン(50mL)に溶解させ、還流下で4時間加熱した。冷却した反応混合物を蒸発させ、残留物をジクロロメタンと希炭酸水素ナトリウムの間で分配した。水相を更にジクロロメタンで抽出し、合わせた有機抽出物を無水硫酸ナトリウムで乾燥させ、減圧下で濃縮した。残留物を、シリカでのクロマトグラフィー(ジクロロメタン中10〜100%の酢酸エチル)により精製して、7−ブロモ−2−メチル−2H−ピラゾロ[4,3−c]ピリジン(0.18g、38%)を白色の固体として与えた。TLC:Rf=0.07;DCM/EA=1/1。
N−(3−(5−クロロ−2−メトキシフェニル)−1−メチル−1H−ピラゾール−4−イル)−1H−ピラゾロ[4,3−c]ピリジン−7−カルボキサミド
4−アジド−5−ブロモニコチンアルデヒド(0.50g、2.2mmol)のTHF(13mL)溶液に、4−メトキシベンジルアミン(0.343mL、2.64mmol)のTHF(2mL)溶液を加えた。無水硫酸ナトリウムを加え、混合物を室温で3時間撹拌した。混合物をろ過し、ろ液を蒸発させて、粗1−(4−アジド−5−ブロモピリジン−3−イル)−N−(4−メトキシベンジル)メタンイミンを与えた。このイミンをトルエン(45mL)に溶解させ、2.5時間加熱還流した。冷却した反応混合物を蒸発させ、残留物をシリカでのクロマトグラフィー(溶媒勾配:ジクロロメタン中50〜100%の酢酸エチル)により精製した。適切な画分を合わせ、蒸発させて、7−ブロモ−2−(4−メトキシベンジル)−2H−ピラゾロ[4,3−c]ピリジン(0.48g、69%)を白色の固体として与えた。1H NMR (300 MHz, CDCl3): δ 8.98 (s, 1H), 8.42 (s, 1H), 8.02 (s, 1H), 7.32 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.62 (s, 2H), 3.82 (s, 3H)。
N−(3−(5−クロロ−2−メトキシフェニル)−1H−ピラゾール−4−イル)チアゾロ[5,4−c]ピリジン−7−カルボキサミド
N,N−ジメチルアセトアミド(8.0mL)中の4−アミノ−3,5−ジブロモピリジン(643mg、2.55mmol、1当量)及びカリウムエチルキサントゲナート(495mg、3.09mmol、1.21当量)の入った密閉反応容器を、マイクロ波照射により160℃で20分間加熱した。追加のカリウムエチルキサントゲナート(0.490g、3.06mmol、1.20当量)を混合物に加え、得られた溶液をマイクロ波照射により160℃で更に20分間加熱した。反応混合物を0℃に冷却し、その後ヨードメタン(382μL、6.13mmol、2.40当量)を加えた。20分後、反応物を真空中で濃縮し、得られた残留物をフラッシュカラムクロマトグラフィー(溶媒:2:1 ヘプタン/酢酸エチル)により精製した。適切な画分を合わせ、蒸発させて、7−ブロモ−2−(メチルチオ)チアゾロ[5,4−c]ピリジン(505mg、75.7%)を黄褐色の固体として与えた。1H NMR (500 MHz, CDCl3):δ: 8.88 (s, 1H), 8.66 (s, 1H), 2.85 (s, 3H)。
N−(3−(5−クロロ−2−(ジフルオロメトキシ)フェニル)−1H−ピラゾール−4−イル)チアゾロ[5,4−c]ピリジン−7−カルボキサミド
5−[5−クロロ−2−(ジフルオロメトキシ)フェニル]−1−[[2−(トリメチルシリル)エトキシ]メチル]−1H−ピラゾール−4−アミン(2.40g、6.15mmol)のDMA(30mL)溶液に、2−(メチルスルファニル)−[1,3]チアゾロ[5,4−c]ピリジン−7−カルボン酸(920mg、4.06mmol)、PyAOP(3.20g、6.13mmol)、4−ジメチルアミノピリジン(100mg、0.819mmol)及びDIPEA(1.60g、12.3mmol)を加えた。得られた溶液を45℃で2時間撹拌した。反応混合物を室温に放冷し、水と酢酸エチルの間で分配した。有機相をブラインで洗浄し、乾燥させ、真空下で濃縮した。残留物をシリカゲルでのフラッシュクロマトグラフィー(溶媒勾配:1/2〜3/2 酢酸エチル/石油エーテル)により精製した。適切な画分を合わせ、真空下で濃縮して、N−[5−[5−クロロ−2−(ジフルオロメトキシ)フェニル]−1−[[2−(トリメチルシリル)エトキシ]−メチル]−1H−ピラゾール−4−イル]−2−(メチルスルファニル)−[1,3]チアゾロ[5,4−c]ピリジン−7−カルボキサミド(1.95g、80%)を褐色の油状物として与えた。LC/MS(方法D、ESI):[M+H]+=598.1、RT=1.30分。
2−アミノ−N−(3−(5−クロロ−2−(ジフルオロメトキシ)フェニル)−1H−ピラゾール−4−イル)チアゾロ[5,4−c]ピリジン−7−カルボキサミド
2−アミノ−N−[5−[5−クロロ−2−(ジフルオロメトキシ)フェニル]−1−[[2−(トリメチルシリル)エトキシ]−メチル]−1H−ピラゾール−4−イル]−[1,3]チアゾロ[5,4−c]ピリジン−7−カルボキサミド(100mg、0.176mmol)をHCl(2.0mL、12M)及びメタノール(4.0mL)の溶液により室温で一晩処理した。得られた混合物を真空下で濃縮した。DCM(5.0mL)及びDIPEA(0.50mL)を加えた。得られた混合物を真空下で濃縮した。残留物をシリカゲルでのフラッシュクロマトグラフィー(溶媒:10/1 ジクロロメタン/メタノール)により精製した。適切な画分を合わせ、真空下で濃縮した。粗生成物を下記条件でのPrep−HPLCにより更に精製した:カラム、XBridge Shield RP18 OBDカラム、19*150mm、5um;移動相、10mmol NH4HCO3を含む水及びMeCN(15.0% MeCNから12分間で50.0%へ);検出器、UV254nm。適切な画分を合わせ、蒸発させて、2−アミノ−N−[3−[5−クロロ−2−(ジフルオロメトキシ)フェニル]−1H−ピラゾール−4−イル]−[1,3]チアゾロ[5,4−c]ピリジン−7−カルボキサミド(27.2mg、35%)をオフホワイト色の固体として与えた。LC/MS(方法A、ESI):[M+H]+=437.1、RT=1.30分;1H NMR (300 MHz, DMSO-d6): δ 13.14 (s, 1H), 11.02 (s, 1H), 8.90 (s, 1H), 8.88 (s, 1H), 8.20 - 8.17 (m, 3H), 7.62 (d, J = 2.7 Hz, 1H), 7.53 (dd, J = 8.8, 2.7 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.05 (t, J = 73.6 Hz, 1H)。
上記実施例2に類似する方法を使用して調製した。LC/MS(方法K、ESI):[M+H]+=405.0、RT=4.27分;1H NMR (400 MHz, DMSO-d6): δ 13.63 (s, 1H), 13.30 - 13.04 (m, 1H), 10.44 - 9.98 (m, 1H), 9.22 (s, 1H), 8.86 (s, 1H), 8.39 (s, 1H), 8.19 (s, 1H), 7.69 - 7.45 (m, 2H), 7.37 - 6.86 (m, 2H)。
N−(3−(5−クロロ−2−(ジフルオロメトキシ)フェニル)−1H−ピラゾール−4−イル)イソチアゾロ[4,3−b]ピリジン−3−カルボキサミド
市販の3−ブロモ−[1,2]チアゾロ[4,3−b]ピリジン(300mg、1.39mmol)、DIPEA(300mg、2.32mmol)、Pd(dppf)Cl2.CH2Cl2(114mg、0.140mmol)のメタノール(15mL)溶液を、加圧槽反応器中、CO(10atm)下95℃で5時間撹拌した。次いで反応混合物を室温に放冷し、真空下で濃縮した。残留物をシリカゲルでのフラッシュクロマトグラフィー(溶媒:1/3 酢酸エチル/石油エーテル)により精製した。適切な画分を合わせ、真空下で濃縮して、メチル [1,2]チアゾロ[4,3−b]ピリジン−3−カルボキシラート(220mg、81%)を黄色の固体として与えた。LC/MS(方法D、ESI):[M+H]+=195.1、RT=1.13分。
N−(3−(5−クロロ−2−(ジフルオロメトキシ)フェニル)−1H−ピラゾール−4−イル)−5H−ピロロ[3,2−b]ピラジン−2−カルボキサミド
市販の2−ブロモ−5H−ピロロ[2,3−b]ピラジン(1.00g、5.05mmol)のN,N−ジメチルホルムアミド(10mL)溶液に、Cs2CO3(2.50g、7.67mmol)及び[2−(クロロメトキシ)エチル]トリメチルシラン(1.26g、7.55mmol)を加えた。この反応混合物を室温で一晩撹拌し、真空下で濃縮した。残留物をシリカゲルでのフラッシュクロマトグラフィー(溶媒:1/10 酢酸エチル/石油エーテル)により精製した。適切な画分を合わせ、蒸発させて、2−ブロモ−5−[[2−(トリメチルシリル)エトキシ]メチル]−5H−ピロロ[2,3−b]ピラジン(1.50g、90%)を黄色の固体として与えた。LC/MS(方法D、ESI):[M+H]+=328.0、RT=1.23分。
2−アミノ−N−(3−(5−クロロ−2−(ジフルオロメトキシ)フェニル)−1H−ピラゾール−4−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボキサミド
tert−ブチル N−[3−([3−[5−クロロ−2−(ジフルオロメトキシ)フェニル]−1H−ピラゾール−4−イル]カルバモイル)ピラゾロ[1,5−a]ピリミジン−2−イル]カルバマート(100mg、0.192mmol)を、ジクロロメタン(4.0mL)中、トリフルオロ酢酸(4.0mL)で処理した。得られた溶液を室温で一晩撹拌し、真空下で濃縮した。DCM(5.00mL)及びDIPEA(0.50mL)を加えた。得られた混合物を真空下で濃縮した。粗生成物を下記条件でのPrep−HPLCにより更に精製した:カラム、XBridge Shield RP18 OBDカラム、19*150mm、5um;移動相、10mmol NH4HCO3を含む水及びMeCN(15.0% MeCNから12分間で55.0%へ);検出器、UV254nm。適切な画分を合わせ、蒸発させて、2−アミノ−N−[3−[5−クロロ−2−(ジフルオロメトキシ)フェニル]−1H−ピラゾール−4−イル]ピラゾロ[1,5−a]ピリミジン−3−カルボキサミド(40.3mg、50%)を淡黄色の固体として与えた。LC/MS(方法E、ESI):[M+H]+=420.0、RT=2.76分。1H NMR (300 MHz, DMSO-d6): δ 13.03 (s, 1H), 9.54 (s, 1H), 8.94 (d, J = 6.6 Hz, 1H), 8.36 (d, J = 4.8 Hz, 1H), 8.26 (s, 1H), 7.68 - 7.61 (m, 2H), 7.46 (d, J = 8.7 Hz, 1H), 7.25 (t, J = 73.2 Hz, 1H), 7.00 (dd, J = 6.6 Hz, 4.8 Hz, 1H), 6.56 (s, 2H)。
N−(3−(5−クロロ−2−(ジフルオロメトキシ)フェニル)−1H−ピラゾール−4−イル)フロ[3,2−c]ピリジン−7−カルボキサミド
7−ブロモフロ[3,2−c]ピリジン(500mg、2.52mmol)、Pd(OAc)2(56.0mg、0.249mmol)、XantPhos(290mg、0.501mmol)及びDIPEA(1.63g、12.6mmol)のメタノール(2.0mL)及びトルエン(6.0mL)溶液を、CO(10atm)雰囲気下、100℃で一晩撹拌した。得られた混合物を室温に放冷し、真空下で濃縮した。残留物をシリカゲルでのフラッシュクロマトグラフィー(溶媒:1/1 酢酸エチル/石油エーテル)により精製した。適切な画分を合わせ、真空下で濃縮して、メチルフロ[3,2−c]ピリジン−7−カルボキシラート(260mg、58%)を黄色の固体として与えた。TLC:Rf=0.4;PE/EA=1/1。
N−(3−(5−クロロ−2−(ジフルオロメトキシ)フェニル)−1H−ピラゾール−4−イル)フロ[3,2−b]ピリジン−3−カルボキサミド
3−ブロモフロ[3,2−b]ピリジン(700mg、3.53mmol)、Pd(OAc)2(79.0mg、0.352mmol)、Xantphos(405mg、0.700mmol)及びDIPEA(2.28g、17.6mmol)のメタノール(15mL)及びトルエン(45mL)溶液を、CO(20atm)雰囲気下、100℃で48時間撹拌した。得られた混合物を室温に放冷し、真空下で濃縮した。残留物をシリカゲルでのフラッシュクロマトグラフィー(溶媒:95/5 ジクロロメタン/メタノール)により精製した。適切な画分を合わせ、真空下で濃縮して、メチル フロ[3,2−b]ピリジン−3−カルボキシラート(300mg、48%)を白色の固体として与えた。TLC:Rf=0.4、EA/Hex=1/1。
N−(3−(5−クロロ−2−(ジフルオロメトキシ)フェニル)−1H−ピラゾール−4−イル)−6−フルオロピラゾロ[1,5−a]ピリミジン−3−カルボキサミド
(2Z)−3−(ジエチルアミノ)−2−フルオロ−2−プロペナール(326mg、2.25mmol−文献:K. Funabiki, T. Ohtsuki, T. lshihara and. Yamanaka, Chem. Lett., 1994, 1075-78の手順に従って合成)及びエチル 3−アミノ−1H−ピラゾール−4−カルボキシラート(698mg、4.50mmol)の酢酸(6ml)溶液を、還流下で4時間加熱した。混合物を室温に放冷し、真空下で濃縮して、淡黄色の固体を与えた。得られた残留物を2M NaOH水溶液(15ml)で処理し、次いでDCMで抽出した。有機層を無水硫酸ナトリウムで乾燥させ、ろ過し、蒸発させた。残留物をシリカゲルでのフラッシュクロマトグラフィー(溶媒勾配:ペンタン中0〜50%の酢酸エチル)により精製した。適切な画分を合わせ、蒸発させて、エチル 6−フルオロピラゾロ[1,5−a]ピリミジン−3−カルボキシラート(24mg、5%)を淡黄色の固体として与えた。LC/MS(方法K、ESI):[M+H]+=325、RT=3.89分。1H NMR (400 MHz, CDCl3): δ 8.82 (d, J = 2.7 Hz, 1H), 8.72 (dd, J = 3.6, 2.7 Hz, 1H), 8.60 (s, 1H), 4.45 (q, J = 7.1 Hz, 2H), 4.45 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H)。
N−(3−(5−クロロ−2−(ジフルオロメトキシ)フェニル)−1H−ピラゾール−4−イル)−5−メチルピラゾロ[1,5−a]ピリミジン−3−カルボキサミド
上記実施例12に類似する方法を使用して調製した。LC/MS(方法I、ESI):[M+H]+=419.0、RT=3.80分;1H NMR (400 MHz, DMSO-d6): δ 13.05 (s, 1H), 10.44 - 9.70 (s, 1H), 9.16 (d, J = 7.0 Hz, 1H), 8.56 (s, 1H), 8.32 (s, 1H), 7.68 - 7.60 (m, 2H), 7.48 - 7.42 (m, 1H), 7.15 (d, J = Hz, 1H), 7.09 (t, J = 73.4Hz, 1H), 2.42 (s, 3H)。
N−(3−(5−クロロ−2−(ジフルオロメトキシ)フェニル)−1H−ピラゾール−4−イル)−5−メトキシピラゾロ[1,5−a]ピリミジン−3−カルボキサミド
上記実施例12に類似する方法を使用して調製した。LC/MS(方法I、ESI):[M+H]+=435.0、RT=3.84分;1H NMR (400 MHz, DMSO-d6): δ 13.05 (s, 1H), 9.05 (d, J = 7.7Hz, 1H), 8.96 (s, 1H), 8.45 (s, 1H), 8.26 (s, 1H), 7.64 - 7.57 (m, 2H), 7.38 - 7.34 (m, 1H), 7.08 (t, J = 73.4Hz, 1H), 6.72 (d, J = 7.5Hz, 1H), 3.46 (s, 3H)。
N−(3−(5−クロロ−2−(ジフルオロメトキシ)フェニル)−1H−ピラゾール−4−イル)−3H−イミダゾ[4,5−c]ピリジン−7−カルボキサミド
上記実施例12に類似する方法を使用して調製した。LC/MS(方法I、ESI):[M+H]+=405.1、RT=3.74分;1H NMR (400 MHz, DMSO-d6) δ 13.48 (s, 1H), 11.12 (s, 1H), 9.06 (s, 1H), 8.93 (s, 1H), 8.61 (s, 1H), 8.37 (s, 1H), 7.49 (dd, J = 8.8, 2.7 Hz, 1H), 7.38 (d, J = 2.7 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 3.92 (s, 3H), 3.76 (s, 3H)。
単離されたリコンビナントJAK1及びJAK2キナーゼドメインの活性を、Caliper LabChip(登録商標)技術(Caliper Life Sciences, Hopkinton, MA)を使用して、JAK3由来のペプチド(5−カルボキシフルオレセインによりN末端が蛍光ラベルされたVal−Ala−Leu−Val−Asp−Gly−Tyr−Phe−Arg−Leu−Thr−Thr)のリン酸化をモニタリングすることにより測定した。阻害定数(Ki)を決定するために、化合物をDMSOで系列希釈し、DMSO最終濃度2%で、精製酵素(1.5nM JAK1又は0.2nM JAK2)、100mM HEPES緩衝液(pH7.2)、0.015% Brij-35、1.5μM ペプチド基質、ATP(25μM)、10mM MgCl2、4mM DTTを含有するキナーゼ反応物 50μLに加えた。384ウェルのポリプロピレンマイクロタイタープレート中、反応物を22℃で30分間インキュベートし、次いでEDTA含有溶液(100mM HEPES緩衝液(pH7.2)、0.015% Brij-35、150mM EDTA)25μLの添加により停止させ、EDTAの最終濃度を50mMにした。キナーゼ反応の終了後、Caliper LabChip(登録商標)3000を製造元の仕様書に従って使用し、リン酸化生成物の割合を、総ペプチド基質の比率として決定した。次いでKi値を、ATP競合阻害用に改変されたMorrison tight bindingモデル(Morrison, J.F., Biochim. Biophys. Acta. 185:269-296 (1969);William, J.W. and Morrison, J.F., Meth. Enzymol., 63:437-467 (1979))[Ki=Ki,app/(1+[ATP]/Km,app)]を使用して決定した。
JAK1依存性のSTATリン酸化を測定するように設計された細胞系アッセイにおいて、阻害能(EC50)を決定した。上記されたように、Jak/Statシグナル伝達経路を遮断することによるIL−4、IL−13及びIL−9シグナル伝達の阻害により、肺炎前臨床モデルにおける喘息症状を緩和することができる(Mathew et al., 2001, J Exp Med 193(9): 1087-1096;Kudlacz et. al., 2008, Eur J. Pharmacol 582(1-3): 154-161)。
Claims (42)
- 式(I):
[式中、
R1は、C2〜C6アルケニル、C2〜C6アルキニル、−(C0〜C3アルキル)CN、−(C0〜C3アルキル)ORa、−(C0〜C3アルキル)Ra、−(C0〜C3アルキル)SRa、−(C0〜C3アルキル)NRaRb、−(C0〜C3アルキル)OCF3、−(C0〜C3アルキル)CF3、−(C0〜C3アルキル)NO2、−(C0〜C3アルキル)C(O)Ra、−(C0〜C3アルキル)C(O)ORa、−(C0〜C3アルキル)C(O)NRaRb、−(C0〜C3アルキル)NRaC(O)Rb、−(C0〜C3アルキル)S(O)1−2Ra、−(C0〜C3アルキル)NRaS(O)1−2Rb、−(C0〜C3アルキル)S(O)1−2NRaRb、−(C0〜C3アルキル)(5〜6−員のヘテロアリール)又は−(C0〜C3アルキル)フェニルであり、ここで、R1は、場合によりハロゲン、C1〜C3アルキル、オキソ、−CF3、−(C0〜C3アルキル)ORc又は−(C0〜C3アルキル)NRcRdにより置換されており、
各Raは、独立して水素、C1〜C6アルキル、C3〜C6シクロアルキル、3〜10員のヘテロシクリル、5〜6員のヘテロアリール、−C(O)Rc、−C(O)ORc、−C(O)NRcRd、−NRcC(O)Rd、−S(O)1−2Rc、−NRcS(O)1−2Rd及び−S(O)1−2NRcRdからなる群より選択され、ここで、Raの任意のC3〜C6シクロアルキル、3〜10員のヘテロシクリル及び5〜6員のヘテロアリールは、場合によりReにより置換されており、
各Rbは、独立して水素及びC1〜C3アルキルからなる群より選択され、ここで、前記アルキルは、場合によりハロゲン又はオキソにより置換されており、
各Rc及びRdは、独立して水素、3〜6員のヘテロシクリル、C3〜C6シクロアルキル及びC1〜C3アルキルからなる群より選択され、ここで、Rc及びRdの任意の3〜6員のヘテロシクリル、C3〜C6シクロアルキル及びC1〜C3アルキルは、場合によりハロゲン又はオキソにより置換されており、又は、Rc及びRdは、それらが結合している原子と一緒になって、場合によりハロゲン、オキソ、−CF3又はC1〜C3アルキルにより置換されている3〜6員のヘテロシクリルを形成し、
各Reは、独立してオキソ、ORf、NRfRg、ハロゲン、3〜10員のヘテロシクリル、C3〜C6シクロアルキル及びC1〜C6アルキルからなる群より選択され、ここで、Reの任意のC3〜C6シクロアルキル及びC1〜C6アルキルは、場合によりORf、NRfRg、ハロゲン、3〜10員のヘテロシクリル、オキソ又はシアノにより置換されており、ここで、Reの任意の3〜10員のヘテロシクリルは、場合によりハロゲン、オキソ、シアノ、−CF3、NRhRk、3〜6員のヘテロシクリル又はC1〜C3アルキル(ハロゲン、オキソ、ORfもしくはNRhRkにより場合により置換されている)により置換されており、
各Rf及びRgは、独立して水素、C1〜C6アルキル、3〜6員のヘテロシクリル及びC3〜C6シクロアルキルからなる群より選択され、ここで、Rf及びRgの任意のC1〜C6アルキル、3〜6員のヘテロシクリル及びC3〜C6シクロアルキルは、場合によりRmにより置換されており、
各Rh及びRkは、独立して水素及びC1〜C6アルキル(場合によりハロゲン、シアノ、3〜6員のヘテロシクリル又はオキソにより置換されている)からなる群より選択され、又は、Rh及びRkは、それらが結合している原子と一緒になって、場合によりハロゲン、シアノ、オキソ、−CF3又はC1〜C3アルキル(場合によりハロゲンもしくはオキソにより置換されている)により置換されている3〜6員のヘテロシクリルを形成し、
各Rmは、独立してハロゲン、シアノ、オキソ、C3〜C6シクロアルキル、ヒドロキシ及びNRhRkからなる群より選択され、ここで、Rmの任意のC3〜C6シクロアルキルは、場合によりハロゲン、オキソ、シアノ又はC1〜C3アルキルにより置換されており、
R2は、フェニル、5〜6員のヘテロアリール、C3〜C6シクロアルキル又は3〜10員のヘテロシクリルであり、ここで、R2は、場合により1〜5個のRnにより置換されており、
各Rnは、独立してC1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、オキソ、ハロゲン、−(C0〜C3アルキル)CN、−(C0〜C3アルキル)ORo、−(C0〜C3アルキル)SRo、−(C0〜C3アルキル)NRoRp、−(C0〜C3アルキル)OCF3、−(C0〜C3アルキル)CF3、−(C0〜C3アルキル)NO2、−(C0〜C3アルキル)C(O)Ro、−(C0〜C3アルキル)C(O)ORo、−(C0〜C3アルキル)C(O)NRoRp、−(C0〜C3アルキル)NRoC(O)Rp、−(C0〜C3アルキル)S(O)1−2Ro、−(C0〜C3アルキル)NRoS(O)1−2Rp、−(C0〜C3アルキル)S(O)1−2NRoRp、−(C0〜C3アルキル)(C3〜C6シクロアルキル)、−(C0〜C3アルキル)(3〜6員のヘテロシクリル)、−(C0〜C3アルキル)C(O)(3〜6員のヘテロシクリル)、−(C0〜C3アルキル)(5〜6員のヘテロアリール)及び−(C0〜C3アルキル)フェニルからなる群より選択され、ここで、各Rnは、独立して、場合によりハロゲン、C1〜C3アルキル、オキソ、−CF3、−(C0〜C3アルキル)ORr又は−(C0〜C3アルキル)NRrRsにより置換されており、又は、2つのRnは一緒になって、−O(CH2)1−3O−を形成し、
各Roは、独立して水素、C1〜C6アルキル、C3〜C6シクロアルキル、3〜6員のヘテロシクリル、−C(O)Rr、−C(O)ORr、−C(O)NRrRs、−NRrC(O)Rs、−S(O)1−2Rr、−NRrS(O)1−2Rs及び−S(O)1−2NRrRsからなる群より選択され、ここで、前記アルキル、シクロアルキル及びヘテロシクリルは、独立して、場合によりオキソ、C1〜C3アルキル、ORr、NRrRs又はハロゲンにより置換されており、各Rpは、独立して水素及びC1〜C3アルキルからなる群より選択され、ここで、前記アルキルは、独立して、場合によりハロゲン又はオキソにより置換されており、又は、Ro及びRpは、それらが結合している原子と一緒になって、場合によりハロゲン、オキソ、−CF3又はC1〜C3アルキルにより置換されている3〜6員のヘテロシクリルを形成し、
各Rr及びRsは、独立して水素及びC1〜C3アルキル(場合によりハロゲン又はオキソにより置換されている)からなる群より選択され、又は、Rr及びRsは、それらが結合している原子と一緒になって、場合によりハロゲン、オキソ、−CF3又はC1〜C3アルキルにより置換されている3〜6員のヘテロシクリルを形成し、
Xは、それぞれ独立してO、S及びNからなる群より選択される2又は3個の原子を含む、9〜10員の二環式ヘテロアリールであり、ここで、9〜10員の二環式ヘテロアリールは、場合によりRuにより置換されており、ただしXは、場合によりRuにより置換されている下記の基:
ではなく、
各Ruは、独立して水素、ハロ、C1〜C6アルキル、C3〜C6シクロアルキル、3〜6員のヘテロシクリル、−ORv、−C(O)Rv、−C(O)ORv、−C(O)NRvRw、−NRvRw、−NRvC(O)Rw、−S(O)1−2Rv、−NRvS(O)1−2Rw及び−S(O)1−2NRvRwからなる群より選択され、ここで、前記アルキル、シクロアルキル及びヘテロシクリルは、独立して、場合によりオキソ、C1〜C3アルキル、−ORv、−NRvRw又はハロゲンにより置換されており、
各Rv及びRwは、独立して水素及びC1〜C3アルキル(場合によりハロゲン又はオキソにより置換されている)からなる群より選択され、又は、Rv及びRwは、それらが結合している原子と共に、場合によりハロゲン、オキソ、−CF3又はC1〜C3アルキルにより置換されている3〜6員のヘテロシクリルを形成している]
で示される化合物又はその薬学的に許容し得る塩であって、
ただし、下記のもの:
又はその薬学的に許容し得る塩ではない、化合物又はその薬学的に許容し得る塩。 - R1が、−(C0〜C3アルキル)NRaRbである、請求項1記載の化合物又はその薬学的に許容し得る塩。
- R1が、H又は−(C0〜C3アルキル)Raである、請求項1記載の化合物又はその薬学的に許容し得る塩。
- R1が、−(C0〜C3アルキル)C(O)Raである、請求項1記載の化合物又はその薬学的に許容し得る塩。
- R1が、H又はメチルである、請求項1記載の化合物又はその薬学的に許容し得る塩。
- R2が、場合により1〜5個のRnにより置換されているフェニルである、請求項1〜9のいずれか一項記載の化合物又はその薬学的に許容し得る塩。
- R2が、場合により1〜2個のRnにより置換されているフェニルである、請求項1〜9のいずれか一項記載の化合物又はその薬学的に許容し得る塩。
- Xが、それぞれ独立してO、S及びNからなる群より選択される2又は3つの原子を含む9員の二環式ヘテロアリールであり、ここで、9員の二環式ヘテロアリールが、場合によりRuにより置換されている、請求項1〜14のいずれか一項記載の化合物又はその薬学的に許容し得る塩。
- Xが、それぞれ独立してO、S及びNからなる群より選択される2つの原子を含む9員の二環式ヘテロアリールであり、ここで、9員の二環式ヘテロアリールが、場合によりRuにより置換されている、請求項1〜14のいずれか一項記載の化合物又はその薬学的に許容し得る塩。
- Xが、それぞれ独立してO、S及びNからなる群より選択される3つの原子を含む9員の二環式ヘテロアリールであり、ここで、9員の二環式ヘテロアリールが、場合によりRuにより置換されている、請求項1〜14のいずれか一項記載の化合物又はその薬学的に許容し得る塩。
- Xが、少なくとも2つの窒素原子を含み、場合によりRuにより置換されている、9員の二環式ヘテロアリールである、請求項1〜14のいずれか一項記載の化合物又はその薬学的に許容し得る塩。
- Xが、少なくとも3つの窒素原子を含み、場合によりより多くのRuにより置換されている、9員の二環式ヘテロアリールである、請求項1〜14のいずれか一項記載の化合物又はその薬学的に許容し得る塩。
- Xが、それぞれ独立してO、S及びNからなる群より選択される2又は3つの原子を含む10員の二環式ヘテロアリールであり、ここで、10員の二環式ヘテロアリールが、場合によりRuにより置換されている、請求項1〜14のいずれか一項記載の化合物又はその薬学的に許容し得る塩。
- Xが、それぞれ独立してO、S及びNからなる群より選択される2つの原子を含む10員の二環式ヘテロアリールであり、ここで、10員の二環式ヘテロアリールが、場合によりRuにより置換されている、請求項1〜14のいずれか一項記載の化合物又はその薬学的に許容し得る塩。
- Xが、それぞれ独立してO、S及びNからなる群より選択される3つの原子を含む10員の二環式ヘテロアリールであり、ここで、10員の二環式ヘテロアリールが、場合によりRuにより置換されている、請求項1〜14のいずれか一項記載の化合物又はその薬学的に許容し得る塩。
- Xが、少なくとも2つの窒素原子を含み、場合によりRuにより置換されている、10員の二環式ヘテロアリールである、請求項1〜14のいずれか一項記載の化合物又はその薬学的に許容し得る塩。
- Xが、少なくとも3つの窒素原子を含み、場合によりRuにより置換されている、10員の二環式ヘテロアリールである、請求項1〜14のいずれか一項記載の化合物又はその薬学的に許容し得る塩。
- 請求項1〜32のいずれか一項記載の化合物又はその薬学的に許容し得る塩と、薬学的に許容し得る賦形剤とを含む、医薬組成物。
- 治療における、請求項1〜32のいずれか一項記載の化合物又はその薬学的に許容し得る塩の使用。
- 炎症性疾患の処置における、請求項1〜32のいずれか一項記載の化合物又はその薬学的に許容し得る塩の使用。
- 炎症性疾患の処置用の医薬の製造のための、請求項1〜32のいずれか一項記載の化合物又はその薬学的に許容し得る塩の使用。
- 炎症性疾患の処置における使用のための、請求項1〜32のいずれか一項記載の化合物又はその薬学的に許容し得る塩。
- 炎症性疾患が、喘息である、請求項35〜37のいずれか一項記載の使用又は化合物もしくはその薬学的に許容し得る塩。
- 患者におけるヤヌスキナーゼ活性の阻害に応答性の疾患又は状態を予防し、治療し又はこれらの重症度を下げる方法であって、治療上有効な量の請求項1〜32のいずれか一項記載の化合物又はその薬学的に許容し得る塩を、患者に投与する工程を含む、方法。
- 疾患又は状態が、喘息である、請求項39記載の方法。
- ヤヌスキナーゼが、JAK1である、請求項39記載の方法。
- 本明細書で上記された発明。
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