JP2018516264A - Janusキナーゼ阻害剤 - Google Patents
Janusキナーゼ阻害剤 Download PDFInfo
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- JP2018516264A JP2018516264A JP2017561893A JP2017561893A JP2018516264A JP 2018516264 A JP2018516264 A JP 2018516264A JP 2017561893 A JP2017561893 A JP 2017561893A JP 2017561893 A JP2017561893 A JP 2017561893A JP 2018516264 A JP2018516264 A JP 2018516264A
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- acid
- compound
- pharmaceutically acceptable
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- 125000005842 heteroatom Chemical group 0.000 claims description 28
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- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
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- 230000004962 physiological condition Effects 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000005495 pyridazyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000001648 tannin Substances 0.000 description 1
- 235000018553 tannin Nutrition 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 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
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/495—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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- C—CHEMISTRY; METALLURGY
- 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
-
- 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
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- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
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- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
AはC(R)又はNから選択され;
L1は、単結合、−C(=O)O−、−C(=O)−、−S(=O)−、−S(=O)2−、−C(=O)N(R)−、−N(R)C(=O)N(R)−、−N(R)−、−S(=O)N(R)−、−S(=O)2N(R)C(R)2−、−S(=O)N(R)C(R)2−から選択され;
R1は、H、CN、OH、NH2、ハロゲン、又は任意に1、2、3若しくは4個のRに置換された:C1−6アルキル基、C1−6ヘテロアルキル基、C3−6シクロアルキル基、3〜6員のヘテロシクロアルキル基から選択され;
Rは、それぞれ独立に、H、CN、OH、NH2、ハロゲン、又は任意に1、2、3若しくは4個のR’に置換された:C1−6アルキル基、C1−6ヘテロアルキル基から選択され;
R’は、ハロゲン、OH、NH2、CN、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2から選択され;
前記「ヘテロ」は、ヘテロ原子又はヘテロ原子基から選択され、N、O、S、−C(=O)O−、−C(=O)−、−S(=O)−、−S(=O)2−から選択され、前記いずれの場合においても、前記「ヘテロ」の数は、それぞれ独立に、1、2、又は3から選択される。
から選択される。
から選択される。
から選択される。
別途に説明しない限り、本明細書で使用される用語及び連語は、以下の意味を有する。一つの特定の用語又は連語は、特別に定義されていない場合、不確定又は不明瞭ではなく、普通の定義として理解されるべきである。本明細書に商品名が現れた場合、対応の商品又はその活性成分を指す。本明細書に使用される用語「薬学的に許容される」とは、信頼性のある医学判断の範囲内でヒト組織及び動物組織との接触使用のために適することができるが、高すぎる毒性、刺激性、アレルギー反応又は他の問題又は合併症を伴わず、合理的なベネフィット/リスク比を満たしている化合物、材料、組成物及び/又は剤形に向けられる。
は、シクロヘキシル基又はシクロヘキサジエンにおける任意の位置に置換されてもよいことを表す。
カラム:AD(250mm*30mm,10um)キラルカラム
移動相:A:超臨界CO2、B:B:イソプロパノール(0.1%のアンモニア水を含む)、A:B=60:40
流速:80mL/min
カラム温度:38℃
波長:220nm
射出圧力:100Bar
ノズル温度:60℃
蒸発温度:20℃
補正温度:25℃
カラム:AD(250mm*30mm,10um)キラルカラム
移動相:A:超臨界CO2、B:B:アルコール(0.1%のイソプロパノールを含む)、A:B=55:45
流速:80mL/min
カラム温度:38℃
波長:220nm
射出圧力:100Bar
ノズル温度:60℃
蒸発温度:20℃
補正温度:25℃
7−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]−5,6,7,8−テトラヒドロイミダゾ[1,2−a]ピリジン−2−カルボン酸の製造方法及び精製方法は、7−[メチル−[7Hピロロ[2,3−d]ピリミジン−4−イル]アミノ]−5,6,7,8−テトラヒドロイミダゾ[1,2−a]ピリジン−2−ホルムアミドの製造方法及び精製方法と同様である。MS(ESI)計算値はC15H16N6O2312で、測定値は313[M+H]+であった。
7−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]−5,6,7,8−テトラヒドロイミダゾ[1,2−a]ピリジン−2−カルボン酸(120mg、384.2umol)及びEDCI(184mg、960.5umol)をピリジン(5mL)に溶解させ、反応液を25℃で15分間攪拌した後、3,3−ジフルオロシクロブタナミン(49mg、461.1umol)を加えて、混合物を25℃で1時間攪拌した。LC−MSで原料が全て消耗したことが示された。反応液に水(20mL)を加えて希釈し、DCM:i−PrOH=3:1(20mL*3)で抽出した。得られた有機層を合併し、無水硫酸ナトリウムで乾燥して、ろ過し減圧で濃縮して残留物を得た。残留物を分取HPLCによって精製して(アルカリ条件)、N−(3,3−ジフルオロシクロブチル)−7−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]−5,6,7,8−テトラヒドロイミダゾ[1,2−a]ピリジン−2−ホルムアミド(WX593)を得た(30mg、収率:15.9%)。MS(ESI)計算値はC19H21F2N7O401で、測定値は402[M+H]+であった。1H NMR(400MHz, METHANOL-d4) 8.15 (s, 1H), 7.61 (s, 1H), 7.14 (d, J=3.76Hz, 1H), 6.71 (d, J=3.51Hz, 1H), 5.42-5.53 (m, 1H), 4.30-4.39 (m, 2H), 4.14-4.27 (m, 1H), 3.41 (s, 3H), 3.08-3.23 (m, 2H), 2.91-3.05 (m, 2H), 2.62-2.78 (m, 2H), 2.48 (dq, J=5.65, 12.34Hz, 1H), 2.23 (d, J=11.29Hz, 1H)
組換え体タンパク質JAK1、JAK2、JAK3プロテアーゼは、いずれもLifetechnologyから購入し、LANCE Ultra ULight(商標)−JAK−1(Tyr1023)peptide及びLANCE Eu−W1024 Anti−Phosphotyrosine(PT66)は、いずれもPerkinElmerから購入した。読み取りは、マイクロプレートリーダーEnvision(PerkinElmer)で実施した。
被験化合物を濃度勾配で3倍希釈して、最終濃度は10uM〜0.17nMにおける11個の濃度であり、各濃度で2個のウェルを設けた。測定反応におけるDMSOの含有量は1%である。
2nM JAK1プロテインキナーゼ、50nM LANCE Ultra ULight(商標)−JAK−1(Tyr1023)peptide、38uM ATP、50mM HEPES(pH7.5)、10mM MgCl2、1mM EGTA、2mM DTT、0.01% BRIJ−35。ウェルプレートはWhite Proxiplate 384−Plus plate(Perkin Elmer)で、室温で90分間反応させ、反応体系は10ulである。
0.02nM JAK2プロテインキナーゼ、50nM LANCE Ultra ULight(商標)−JAK−1(Tyr1023)peptide、12uM ATP、50mM HEPES(pH7.5)、10mM MgCl2、1mM EGTA、2mM DTT、0.01% BRIJ−35。ウェルプレートはWhite Proxiplate 384−Plus plate(Perkin Elmer)で、室温で60分間反応させ、反応体系は10ulである。
0.05nM JAK2プロテインキナーゼ、50nM LANCE Ultra ULight(商標)−JAK−1(Tyr1023)peptide、4uM ATP、50mM HEPES(pH7.5)、10mM MgCl2、1mM EGTA、2mM DTT、0.01% BRIJ−35。ウェルプレートはWhite Proxiplate 384−Plus plate(Perkin Elmer)で、室温で90分間反応させ、反応体系は10ulである。
10ulの測定試薬をウェルプレートに添加して、ここで、LANCE Eu−W1024 Anti−Phosphotyrosine(PT66)の最終濃度は2nMで、EDTAの最終濃度は10mMで、室温で60分間インキュベートした。読み取りは、Envisonで実施した。
阻害率(%)=(Min−Ratio)/(Max−Min)×100%の式でリード数を阻害率(%)に変換した。4パラメートの曲線あてはめ(Model 205 in XLFIT5、iDBS)で、IC50を測定し、詳細を表1に示す。
被験化合物を溶解させて得られた清澄な液体を、それぞれ尾静脈注射及び胃内投与によって雄DBA/1マウス体内に投与した(夜断食、7〜8週齢)。被験化合物を投与後、静脉注射群は0.083、0.25、0.5、1、2、4、8、及び24時間で、胃内投与群は0.25、0.5、1、2、4、8、及び24時間で、それぞれ下顎静脈から採血し遠心分離によって血漿を得た。LC−MS/MSを用いて血漿濃度を測定し、「WinNonlin」(商標)Version 6.3という薬物動態学的解析ソフトを用いて、ノンコンパートメントモデルの対数線形台形法で薬物動態学的パラメータを算出した。
アジュバント誘発のラット関節炎モデルを用いて、本発明に係る化合物の関節炎に対する治療効果を検証した。
コラーゲン誘発のマウス関節炎モデルを用いて、本発明に係る化合物の関節炎に対する治療効果を検証した。
Claims (12)
- 式(I)で示される化合物又はその薬学的に許容される塩:
式中、
AはC(R)又はNから選択され;
L1は、単結合、−C(=O)O−、−C(=O)−、−S(=O)−、−S(=O)2−、−C(=O)N(R)−、−N(R)C(=O)N(R)−、−N(R)−、−S(=O)N(R)−、−S(=O)2N(R)C(R)2−、−S(=O)N(R)C(R)2−から選択され;
R1は、H、CN、OH、NH2、ハロゲン、又は任意に1、2、3若しくは4個のRに置換された:C1−6アルキル基、C1−6ヘテロアルキル基、C3−6シクロアルキル基、3〜6員のヘテロシクロアルキル基から選択され;
Rは、それぞれ独立に、H、CN、OH、NH2、ハロゲン、又は任意に1、2、3若しくは4個のR’に置換された:C1−6アルキル基、C1−6ヘテロアルキル基から選択され;
R’は、ハロゲン、OH、NH2、CN、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2から選択され;
前記「ヘテロ」は、ヘテロ原子又はヘテロ原子基から選択され、N、O、S、−C(=O)O−、−C(=O)−、−S(=O)−、−S(=O)2−から選択され、前記いずれの場合においても、前記「ヘテロ」の数は、それぞれ独立に、1、2、又は3から選択される。 - 前記Rは、H、CN、OH、NH2、ハロゲン、又は任意に1、2、若しくは2個のR’に置換されたMe、Et、NHCH3、N(CH3)2、NHCH3、N(CH3)2、
から選択される、請求項1に記載の化合物又はその薬学的に許容される塩。 - 前記L1は、単結合、−C(=O)O−、−C(=O)−、−S(=O)−、−S(=O)2−、−C(=O)NH−、−NHC(=O)NH−、−NH−、−S(=O)NH−、−S(=O)2NHCH2−、−S(=O)NHCH2−から選択される、請求項1に記載の化合物又はその薬学的に許容される塩。
- 前記R1は、H、CN、OH、NH2、又は任意に1、2、3若しくは4個のRに置換された:C1−3アルキル基、C1−2アルキル基−N(C1−2アルキル基)2、C1−2アルキル基−NH−C1−2アルキル基、C1−3アルキル基−S(=O)2−C1−3アルキル基、C1−3アルキル基−S(=O)−C1−3アルキル基、C4−5シクロアルキル基、4〜5員のヘテロシクロアルキル基から選択される、請求項1又は2に記載の化合物又はその薬学的に許容される塩。
- 前記R1は、CN、又は任意に1、2、3若しくは4個のRに置換されたMe、Et、
から選択される、請求項4に記載の化合物又はその薬学的に許容される塩。 - 前記R1は、CN、Me、
から選択される、請求項5に記載の化合物又はその薬学的に許容される塩。 - 前記化合物は、
- 以下のステップを含む、請求項1に記載の式(I)で示される化合物の製造方法:
式中、
PGはアミノ保護基で、Cbz、Boc、Fmoc、Alloc、Teco、メトキシカルボニル基、エトキシカルボニル基、Pht、Tos、Tfa、Bn、PMBから選択され、
R1は、請求項1に定義される。 - 治療有効量の請求項1〜8いずれか1項に記載の化合物又はその薬学的に許容される塩、及び薬学的に許容される担体を含む、医薬組成物。
- Janusキナーゼ関連疾患を治療するための薬剤の製造における、請求項1〜8のいずれか1項に記載の化合物若しくはその薬学的に許容される塩、又は請求項9に記載の医薬組成物の使用。
- 前記疾患が関節炎である、請求項10に記載の使用。
- 前記疾患が関節リウマチである、請求項10に記載の使用。
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