JP6720225B2 - ヘテロアリール置換のアミノピリジン化合物 - Google Patents
ヘテロアリール置換のアミノピリジン化合物 Download PDFInfo
- Publication number
- JP6720225B2 JP6720225B2 JP2017566812A JP2017566812A JP6720225B2 JP 6720225 B2 JP6720225 B2 JP 6720225B2 JP 2017566812 A JP2017566812 A JP 2017566812A JP 2017566812 A JP2017566812 A JP 2017566812A JP 6720225 B2 JP6720225 B2 JP 6720225B2
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- Prior art keywords
- pyridin
- carbonitrile
- compound
- alkyl
- isopropylamino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 aminopyridine compounds Chemical class 0.000 title claims description 66
- 150000001875 compounds Chemical class 0.000 claims description 192
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 36
- 239000008194 pharmaceutical composition Substances 0.000 claims description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 20
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 19
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 18
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 15
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- 201000005569 Gout Diseases 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 12
- 125000003566 oxetanyl group Chemical group 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 9
- 125000001425 triazolyl group Chemical group 0.000 claims description 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 201000004681 Psoriasis Diseases 0.000 claims description 8
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 8
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 8
- FUCFDTKIFAGVLY-UHFFFAOYSA-N 2-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-N-propan-2-yl-5-(4-propyltriazol-1-yl)pyridin-4-amine Chemical compound ClC=1C=NC=2N(C=1)N=CC=2C1=NC=C(C(=C1)NC(C)C)N1N=NC(=C1)CCC FUCFDTKIFAGVLY-UHFFFAOYSA-N 0.000 claims description 7
- XDESSKZUXMNMMO-UHFFFAOYSA-N 3-[4-(propan-2-ylamino)-5-(4-propyltriazol-1-yl)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound C(C)(C)NC1=CC(=NC=C1N1N=NC(=C1)CCC)C1=CN=C2N1N=CC(=C2)C#N XDESSKZUXMNMMO-UHFFFAOYSA-N 0.000 claims description 7
- XOYXADDAQJVPEI-UHFFFAOYSA-N 3-[5-[1-(3-hydroxy-3-methylbutyl)pyrazol-4-yl]-4-(propan-2-ylamino)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound OC(CCN1N=CC(=C1)C=1C(=CC(=NC=1)C1=CN=C2N1N=CC(=C2)C#N)NC(C)C)(C)C XOYXADDAQJVPEI-UHFFFAOYSA-N 0.000 claims description 7
- QSRKCOCAYVQGSS-UHFFFAOYSA-N 3-[5-[4-(2-hydroxypropan-2-yl)pyrazol-1-yl]-4-(propan-2-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyrimidine-6-carbonitrile Chemical compound OC(C)(C)C=1C=NN(C=1)C=1C(=CC(=NC=1)C=1C=NN2C=1N=CC(=C2)C#N)NC(C)C QSRKCOCAYVQGSS-UHFFFAOYSA-N 0.000 claims description 7
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- 239000003085 diluting agent Substances 0.000 claims description 7
- OAQFIXDKTZYDRL-UHFFFAOYSA-N imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound N=1C=CN2N=CC(=CC2=1)C#N OAQFIXDKTZYDRL-UHFFFAOYSA-N 0.000 claims description 7
- 201000006417 multiple sclerosis Diseases 0.000 claims description 7
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
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- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 claims description 5
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- 125000002393 azetidinyl group Chemical group 0.000 claims description 5
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 5
- 125000006712 (C1-C4) deuteroalkyl group Chemical group 0.000 claims description 4
- ZACIZZRZZPYFAZ-UHFFFAOYSA-N 1-[4-[6-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-4-(propan-2-ylamino)pyridin-3-yl]pyrazol-1-yl]-2-methylpropan-2-ol Chemical compound ClC1=CC=2N(N=C1)C(=CN=2)C1=CC(=C(C=N1)C=1C=NN(C=1)CC(C)(O)C)NC(C)C ZACIZZRZZPYFAZ-UHFFFAOYSA-N 0.000 claims description 4
- DOTOFFAVTNZRLB-UHFFFAOYSA-N 2-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-N-cyclopropyl-5-(1-propyltriazol-4-yl)pyridin-4-amine Chemical compound ClC1=CC=2N(N=C1)C(=CN=2)C1=NC=C(C(=C1)NC1CC1)C=1N=NN(C=1)CCC DOTOFFAVTNZRLB-UHFFFAOYSA-N 0.000 claims description 4
- KFILYRVIDVXHNI-UHFFFAOYSA-N 2-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-N-propan-2-yl-5-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]pyridin-4-amine Chemical compound ClC1=CC=2N(N=C1)C(=CN=2)C1=NC=C(C(=C1)NC(C)C)C=1C=NN(C=1)CC(F)(F)F KFILYRVIDVXHNI-UHFFFAOYSA-N 0.000 claims description 4
- JDHXZJLBUNAELN-UHFFFAOYSA-N 3-[4-(cyclopropylamino)-5-(1-propyltriazol-4-yl)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound C1(CC1)NC1=CC(=NC=C1C=1N=NN(C=1)CCC)C1=CN=C2N1N=CC(=C2)C#N JDHXZJLBUNAELN-UHFFFAOYSA-N 0.000 claims description 4
- TWOADEWSFFZZFG-UHFFFAOYSA-N 3-[4-(propan-2-ylamino)-5-(1-propylpyrazol-4-yl)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound C(C)(C)NC1=CC(=NC=C1C=1C=NN(C=1)CCC)C1=CN=C2N1N=CC(=C2)C#N TWOADEWSFFZZFG-UHFFFAOYSA-N 0.000 claims description 4
- PRAAEKYPJNFSSE-IRXDYDNUSA-N 3-[4-[[(1S,3S)-3-fluorocyclopentyl]amino]-5-[4-(3-hydroxy-3-methylbutyl)triazol-1-yl]pyridin-2-yl]pyrazolo[1,5-a]pyrimidine-6-carbonitrile Chemical compound F[C@@H]1C[C@H](CC1)NC1=CC(=NC=C1N1N=NC(=C1)CCC(C)(C)O)C=1C=NN2C=1N=CC(=C2)C#N PRAAEKYPJNFSSE-IRXDYDNUSA-N 0.000 claims description 4
- KIFBHFOPKPWRAP-UHFFFAOYSA-N 3-[5-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-4-(propan-2-ylamino)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound OC(CN1N=CC(=C1)C=1C(=CC(=NC=1)C1=CN=C2N1N=CC(=C2)C#N)NC(C)C)(C)C KIFBHFOPKPWRAP-UHFFFAOYSA-N 0.000 claims description 4
- VGDZIORKWAXUFJ-UHFFFAOYSA-N 3-[5-[1-(oxan-4-yl)pyrazol-4-yl]-4-(propan-2-ylamino)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound C(C)(C)NC1=CC(=NC=C1C=1C=NN(C=1)C1CCOCC1)C1=CN=C2N1N=CC(=C2)C#N VGDZIORKWAXUFJ-UHFFFAOYSA-N 0.000 claims description 4
- XDSRHSZBMTXRBP-UHFFFAOYSA-N 3-[5-[1-(oxan-4-yl)triazol-4-yl]-4-(propan-2-ylamino)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound C(C)(C)NC1=CC(=NC=C1C=1N=NN(C=1)C1CCOCC1)C1=CN=C2N1N=CC(=C2)C#N XDSRHSZBMTXRBP-UHFFFAOYSA-N 0.000 claims description 4
- PYJGADHQKPQSHH-UHFFFAOYSA-N 3-[5-[4-(3-hydroxy-3-methylbutyl)triazol-1-yl]-4-(oxetan-3-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyrimidine-6-carbonitrile Chemical compound OC(CCC=1N=NN(C=1)C=1C(=CC(=NC=1)C=1C=NN2C=1N=CC(=C2)C#N)NC1COC1)(C)C PYJGADHQKPQSHH-UHFFFAOYSA-N 0.000 claims description 4
- BXPJRPWKDYCOMG-UHFFFAOYSA-N 3-[5-[4-(3-hydroxy-3-methylbutyl)triazol-1-yl]-4-(propan-2-ylamino)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound OC(CCC=1N=NN(C=1)C=1C(=CC(=NC=1)C1=CN=C2N1N=CC(=C2)C#N)NC(C)C)(C)C BXPJRPWKDYCOMG-UHFFFAOYSA-N 0.000 claims description 4
- RKHHFANTEKSOQG-UHFFFAOYSA-N 3-[5-[5-(oxan-4-yl)-1H-pyrazol-3-yl]-4-(propan-2-ylamino)pyridin-2-yl]imidazo[1,2-b]pyridazine-7-carbonitrile Chemical compound C(C)(C)NC1=CC(=NC=C1C1=NNC(=C1)C1CCOCC1)C1=CN=C2N1N=CC(=C2)C#N RKHHFANTEKSOQG-UHFFFAOYSA-N 0.000 claims description 4
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- SWYUCJNNROTAJE-UHFFFAOYSA-N 2-(7-chloroimidazo[1,2-b]pyridazin-3-yl)-N-[1-(2,2-difluoroethyl)pyrazol-4-yl]-5-(1-propylpyrazol-4-yl)pyridin-4-amine Chemical compound ClC1=CC=2N(N=C1)C(=CN=2)C1=NC=C(C(=C1)NC=1C=NN(C=1)CC(F)F)C=1C=NN(C=1)CCC SWYUCJNNROTAJE-UHFFFAOYSA-N 0.000 claims description 3
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- OVCXRBARSPBVMC-UHFFFAOYSA-N triazolopyridine Chemical compound C=1N2C(C(C)C)=NN=C2C=CC=1C=1OC=NC=1C1=CC=C(F)C=C1 OVCXRBARSPBVMC-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 201000008827 tuberculosis Diseases 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
- 230000002792 vascular Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
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Description
本願は、2015年6月24日付け出願の、インド仮特許出願番号1880/DEL/15(その内容が本明細書に組み込まれる)の利益を主張する。
本願は、一般に、IRAK−4の調整を含め、キナーゼ阻害剤として有用であるヘテロアリール置換のアミノピリジン化合物に関する。ヘテロアリール置換のアミノピリジン化合物、かかる化合物を含む組成物、およびそれらの使用方法が本明細書において提供される。本発明はさらには、キナーゼ調整と関連付けられる症状の治療に有用である少なくとも1つの本発明の化合物を含有する医薬組成物、および哺乳動物においてキナーゼ、IRAK−4を含め、その活性を阻害する方法に関する。
:750-754 (2002))。対照的に、IRAK1(Thomas, J.A.ら、J. Immunol., 163: 978-984 (1999));Swantek, J.L.ら、J. Immunol., 164: 4301-4306 (2000))またはIRAK2(Wan, Y.ら、J. Biol. CHem., 284: 10367-10375 (2009))のいずれかの欠失はシグナル伝達の部分的喪失をもたらす。さらには、IRAK4は、そのキナーゼ活性がシグナル伝達の阻害に必要とされることがわかっている、IRAKファミリーの唯一の構成員である。マウスゲノムにおいて野生型IRAK4のキナーゼ不活性変異体(KDKI)との置換は、IL−1、IL−18を、およびTLR3を除くすべてのTLRを含む、あらゆるMyD88依存性受容体を通してシグナル伝達を害する(Koziczak-Holbro, M.ら、J. Biol. CHem., 282: 13552-13560 (2007);Kawagoe, T.ら、J. Exp. Med., 204: 1013-1024 (2007);およびFraczek, J.ら、J. Biol. CHem., 283: 31697-31705 (2008))。
HETは、イミダゾ[1,2−b]ピリダジニル、およびピラゾロ[1,5−a]ピリミジニルより選択されるヘテロアリールであり、ここで該ヘテロアリールはそのヘテロアリール中にある炭素環原子によって式(I)の化合物におけるピリジニル基と結合し、そしてここで該ヘテロアリールは0ないし2個のRbで置換され;
Aはピラゾリル、イミダゾリル、またはトリアゾリルであり、各々が0または1個のRaで置換され;
R3は:
(i)−CH2CH3、−CH(CH3)2、−CH2CHF2、−CH(CH3)CH2OH、シクロプロピル、オキセタニル、またはテトラヒドロピラニルであるか;または
(ii)ピラゾリルであって、C1−3アルキル、C1−3ヒドロキシアルキル、C1−3フルオロアルキル、オキセタニル、テトラヒドロフラニル、およびテトラヒドロピラニルより独立して選択される0ないし2個の置換基で置換され;
Raは:
(i)F、Cl、−OH、−CN、C1−6アルキル、C1−4フルオロアルキル、C1−4シアノアルキル、またはC1−6ヒドロキシアルキルであるか;または
(ii)C3−6シクロアルキル、アゼチジニル、オキセタニル、テトラヒドロフラニル、テトラヒドロピラニル、ピペリジニル、ピペラジニル、ピロリル、ピロリジノイル、モルホリニル、ピロリジニル、フェニル、ピラゾリル、イミダゾリル、ピリジニル、またはピリミジニルであって、その各々は、F、−CN、−OH、−NRyRy、C1−3アルキル、C1−3フルオロアルキル、−CH(フェニル)2、−O(C1−4アルキル)、−C(O)(C1−4アルキル)、−C(O)(C1−4デューテロアルキル)、−C(O)(C3−6シクロアルキル)、−C(O)O(C1−4アルキル)、−C(O)NRyRy、−C(O)(フェニル)、−C(O)(ピリジニル)、−C(O)CH2(C3−6シクロアルキル)、−NHC(O)CH3、−NHC(O)OCH3、−NHC(O)OC(CH3)3、−S(O)2(C1−3アルキル)、および−OS(O)2(C1−3アルキル)より独立して選択される0ないし4個の置換基で置換され;
Rbは、各々、F、Cl、−CN、−NH2、−CH3、−OCH3、およびシクロプロピルより独立して選択され;および
Ryは、各々独立して、HまたはC1−3アルキルである]
で示される少なくとも1の化合物またはその塩を提供する。
本発明の特徴および利点は、以下の詳細な記載を読むことで、当業者によってさらに容易に理解されるであろう。明瞭にするのに、別個の実施態様に関連して前後に記載される本発明の特定の特徴を合わせて一の実施態様を形成してもよいことが分かるであろう。反対に、簡潔にするために、単一の実施態様に関連して記載される本発明の種々の特徴をそのサブコンビネーションを形成するのに合わせてもよい。ここで同定される実施態様は例示を意図とするものであり、制限を目的とするものではない。
a)The Practice of Medicinal Chemistry、Camille G. Wermuthら、Ch 31, (Academic Press、1996);
b)Design of Prodrugs、H. Bundgaard編, (Elsevier、1985);
c)A Textbook of Drug Design and Development、P. Krogsgaard-LarsonおよびH. Bundgaard編、Ch 5, pgs113-191(Harwood Academic Publishers、1991);および
d)Hydrolysis in Drug and Prodrug Metabolism、Bernard TestaおよびJoachim M. Mayer、(Wiley-VCH、2003)
に記載されている。
本発明の化合物は、IRAK4の調整を含め、キナーゼ活性を調整する。本発明の化合物により調整され得るキナーゼ活性の他の型は、限定されるものではないが、Pelle/IRAKファミリー、およびその変異体を包含する。
本発明の化合物は有機合成の分野の当業者に周知の多くの方法にて調製され得る。本発明の化合物は、下記の方法を、合成有機化学の分野において公知の合成方法と一緒に用いて、あるいは当業者がそれに適宜変更を加えることにより合成され得る。好ましい方法は、それに限定されるものではないが、下記の方法を包含する。本明細書中に引用されるすべての文献は出典を明示することにより本明細書に組み込まれるものとする。
この分野における合成経路を計画するにおいてもう一つ別の大きな要因が、本発明に記載の化合物に存在する反応性官能基を保護するのに使用される保護基の賢明な選別にあることも理解されよう。熟練した当業者に多くの選択肢を記載する信頼すべき説明書が、Greeneら(Protective Groups in Organic Synthesis、Third Edition、Wiley and Sons (1999))である。
本発明の化合物、本発明の化合物の調製に用いられる中間体は、以下の実施例に示される操作および関連する操作を用いて調製され得る。これらの実施例に用いられる方法および条件、ならびにこれらの実施例において調製される実際の化合物は、限定的であることを意図とするものではなく、本発明の化合物がどのように調製され得るかを説明するものである。これらの実施例において使用される出発材料および試剤は、本明細書に記載の操作により調製されない場合、通常は、商業的に入手可能であるか、または化学文献にて報告されているかのいずれかであり、あるいは化学文献に記載の操作を用いることにより調製されてもよい。発明は以下の実施例にてさらに具体的に定められる。実施例は単に例示として付与されると理解すべきである。上記の検討および実施例の記載から、当業者は、発明の精神および範囲を逸脱することなく、その本質的特性を解明することができ、発明が様々な使用および条件に適応するように種々の変化および修飾を行うことができる。結果として、本発明は本明細書にて下記に示される例示としての実施例により限定されるものではなく、むしろ添付される特許請求の範囲により限定されるものとする。
A.サンファイアー(Sunfire)C18(3x150mm)、3.5ミクロン、移動相A:95:5 水/MeCN、0.05%TFA;移動相B:95:5 MeCN/水、0.05%TFA;1mL/分、勾配:12分
3−(5−(4−(2−ヒドロキシプロパン−2−イル)−1H−ピラゾール−1−イル)−4−(イソプロピルアミノ)ピリジン−2−イル)ピラゾロ[1,5−a]ピリミジン−6−カルボニトリル
2−(1−(6−クロロ−4−(イソプロピルアミノ)ピリジン−3−イル)−1H−ピラゾール−3−イル)プロパン−2−オール(40mg、0.14ミリモル)および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)ピラゾロ[1,5−a]ピリミジン−6−カルボニトリル(73mg、0.27ミリモル)の1,4−ジオキサン(2mL)中攪拌溶液に、KOAc(40mg、0.407ミリモル)を加えた。該混合物をN2で5分間脱気処理に付し、次にテトラキストリフェニルホスフィンPd(0)(31mg、0.027ミリモル)を添加した。該混合物を5分間さらに脱気処理に付し、次にマイクロ波の照射の下で120℃で1時間加熱した。該混合物を冷却し、濾過して濃縮した。生成物を分取性TLC(5%MeOH/DCM)に付して精製し、3−(5−(4−(2−ヒドロキシプロパン−2−イル)−1H−ピラゾール−1−イル)−4−(イソプロピルアミノ)ピリジン−2−イル)ピラゾロ[1,5−a]ピリミジン−6−カルボニトリル(8mg、14%収率)を得た。1H NMR(400MHz、MeOD−d4) δ 9.70(s,1H)、8.94(s,1H)、8.85(s,1H)、8.2(s,1H)、8.00(s,1H)、7.95(s,1H)、7.81(s,1H)、3.90(m,1H)、1.61(s,6H)、1.31(s,3H)、1.25(s,3H);LCMS 403.5(M+H);HPLC rt 12.9分、条件G
2−(7−クロロイミダゾ[1,2−b]ピリダジン−3−イル)−N−イソプロピル−5−(4−(テトラヒドロ−2H−ピラン−4−イル)−1H−ピラゾール−1−イル)ピリジン−4−アミン
N−イソプロピル−5−(1−(テトラヒドロ−2H−ピラン−4−イル)−1H−ピラゾール−4−イル)−2−(トリメチルスタンニル)ピリジン−4−アミン(45mg、0.100ミリモル)および7−クロロ−3−ヨードイミダゾ[1,2−b]ピリダジン(28.0mg、0.100ミリモル)の1,4−ジオキサン(10mL)中攪拌溶液に、CuI(1.91mg、10μmol)を加えた。該混合物をN2で5分間脱気処理に供し、次にテトラキストリフェニルホスフィンPd(0)(12mg、0.00ミリモル)を加えた。該混合物を5分間さらに脱気処理に付し、次に密封した管中にて110℃で15時間加熱した。該混合物を冷却し、セライトを通して濾過し、濯いだ。濾液を濃縮し、DCMと1.5N HClとの間に分配した。水層をDCMで洗浄し、次にNaHCO3で処理した。該生成物をEtOAcに抽出し、分取性HPLCに通して精製し、2−(7−クロロイミダゾ[1,2−b]ピリダジン−3−イル)−N−イソプロピル−5−(1−(テトラヒドロ−2H−ピラン−4−イル)−1H−ピラゾール−4−イル)ピリジン−4−アミン(7mg、17%収率)を得た。1H NMR:(400MHz、DMSO−d6) δ 8.85(d,J=2.0Hz,1H)、8.56(d,J=2.5Hz,1H)、8.38(s,1H)、8.21(s,1H)、8.14(s,1H)、7.86(s,1H)、7.78(s,1H)、5.21(d,J=7.5Hz,1H)、4.48(brs.,1H)、4.00(d,J=11.5Hz,2H)、3.79(brs.,1H)、3.57−3.43(m,2H)、2.10−1.94(m,4H)、1.27(d,J=6.5Hz,6H);LCMS 438.3(M+H);HPLC rt 1.61分、条件E
2−(6−クロロピラゾロ[1,5−a]ピリミジン−3−イル)−N−イソプロピル−5−(4−プロピル−1H−1,2,3−トリアゾール−1−イル)ピリジン−4−アミン
2−クロロ−N−イソプロピル−5−(4−プロピル−1H−1,2,3−トリアゾール−1−イル)ピリジン−4−アミン(30mg、0.107ミリモル)を1,4−ジオキサン(2mL)およびDMA(0.5mL)に溶かし、次に0.2mLの水、6−クロロ−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)ピラゾロ[1,5−a]ピリミジン(59.9mg、0.214ミリモル)およびKOAc(31.6mg、0.322ミリモル)を添加した。該混合物を10分間脱気処理に付し、次にテトラキストリフェニルホスフィンPd(0)(25mg、0.021ミリモル)を添加し、5分間脱気処理に付した。該混合物をマイクロ波リアクター中100℃で2時間加熱した。該反応混合物を冷却し、濾過し、濾液を高真空下にて濃縮した。その残渣をDMFに溶かし、分取性HPLCに通して精製し、2−(6−クロロピラゾロ[1,5−a]ピリミジン−3−イル)−N−イソプロピル−5−(4−プロピル−1H−1,2,3−トリアゾール−1−イル)ピリジン−4−アミン(9.7mg、18%収率)を得た。1H NMR(500MHz、DMSO−d6) δ 9.75(s,1H)、8.99(s,1H)、8.93(s,1H)、8.43(s,1H)、8.33(s,1H)、7.90(s,1H)、7.27(brs.,1H)、3.97(d,J=6.5Hz,0.5H)、3.58(brs.,0.5H)、2.73(t,J=7.6Hz,2H)、1.72(sxt,J=7.4Hz,2H)、1.27(d,J=6.3Hz,6H)、0.99(t,J=7.3Hz,3H)
3−(4−(イソプロピルアミノ)−5−(4−プロピル−1H−1,2,3−トリアゾール−1−イル)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル
5mLのマイクロ波用管にて、N−イソプロピル−5−(4−プロピル−1H−1,2,3−トリアゾール−1−イル)−2−(トリメチルスタンニル)ピリジン−4−アミン(100mg、0.184ミリモル)、3−ブロモイミダゾ[1,2−b]ピリダジン−7−カルボニトリル(41mg、0.184ミリモル)、およびCuI(3.50mg、0.018ミリモル)のジオキサン(3mL)中混合物に窒素を5分間通気して脱気処理に供した。該混合物をテトラキス(トリフェニルホスフィン)Pd(0)(42.5mg、0.037ミリモル)で処理し、さらに5分間脱気処理に供し、次に該バイアルを密封した。反応混合物をマイクロ波リアクターに入れて150℃で20分間加熱した。反応混合物を濾過し、濾液を高真空下にて濃縮した。その残渣を分取性HPLCに通して精製し、3−(4−(イソプロピルアミノ)−5−(4−プロピル−1H−1,2,3−トリアゾール−1−イル)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル(3.4mg、5%収率)を得た。1H NMR(500MHz、DMSO−d6) δ 9.10(d,J=7.2Hz,2H)、8.71(brs,1H)、8.52−8.32(m,2H)、8.12(brs,1H)、6.57(d,J=7.2Hz,1H)、3.94−3.74(m,1H)、2.72(t,J=7.3Hz,2H)、1.78−1.64(m,2H)、1.27(d,J=6.2Hz,6H)、0.99(t,J=7.2Hz,3H);LCMS 388.3(M+H);HPLC rt 1.65分、条件C
3−(4−(イソプロピルアミノ)−5−(1−(テトラヒドロ−2H−ピラン−4−イル)−1H−1,2,3−トリアゾール−4−イル)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル
5mLのマイクロ波用管にて、N−イソプロピル−5−(1−(テトラヒドロ−2H−ピラン−4−イル)−1H−1,2,3−トリアゾール−4−イル)−2−(トリメチルスタンニル)ピリジン−4−アミン(77mg、0.17ミリモル)、3−ブロモイミダゾ[1,2−b]ピリダジン−7−カルボニトリル(45.5mg、0.204ミリモル)、およびCuI(3.24mg、0.017ミリモル)のジオキサン(1mL)中混合物に、窒素を5分間通気して脱気処理に供した。該混合物をテトラキス(トリフェニルホスフィン)Pd(0)(39.3mg、0.034ミリモル)で処理し、さらに5分間脱気処理に供し、次に該バイアルを密封した。反応混合物をマイクロ波を用いて150℃で加熱した。溶媒を蒸発させ、残渣をDMSO(2mL)に溶かした。該溶液を濾過し、分取性HPLCに付して精製し、3−(4−(イソプロピルアミノ)−5−(1−(テトラヒドロ−2H−ピラン−4−イル)−1H−1,2,3−トリアゾール−4−イル)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル(6mg、8%収率)を得た。1H NMR(500MHz、DMSO−d6) δ 9.05(brs,1H)、9.01(s,1H)、8.88(s,1H)、8.69(brs,1H)、8.66(s,1H)、8.22(d,J=6.9Hz,1H)、8.01(s,1H)、4.86(brs.,1H)、4.01(d,J=12.8Hz,2H)、2.19−2.01(m,4H)、1.33(d,J=6.2Hz,6H)
3−(5−(1−(3−ヒドロキシ−3−メチルブチル)−1H−ピラゾール−4−イル)−4−(イソプロピルアミノ)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル
4−(3−(4−(イソプロピルアミノ)−6−(トリメチルスタンニル)ピリジン−3−イル)−1H−ピラゾール−5−イル)−2−メチルブタン−2−オール(121mg、0.269ミリモル)のジオキサン(4mL)中攪拌溶液[圧力管中]に、3−ブロモイミダゾ[1,2−b]ピリダジン−7−カルボニトリル(50mg、0.224ミリモル)を添加し、その混合物をアルゴンで10分間脱気処理に付した。この混合物に、Pd(Ph3P)4(52mg、0.045ミリモル)を添加し、さらに5分間脱気処理に供した。圧力管を閉め、110℃で16時間加熱した。該反応混合物を分析用フィルターに通して濾過し、酢酸エチルで徹底的に洗浄し、濃縮して粗化合物を得た。その生成物を分取性HPLCに通して精製し、3−(5−(5−(3−ヒドロキシ−3−メチルブチル)−1H−ピラゾール−3−イル)−4−(イソプロピルアミノ)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル(13.2mg、13.5%収率)を得た。1H NMR(400MHz、DMSO−d6) δ 13.21(s,1H)、9.21−9.19(m,2H)、8.85(s,1H)、8.74(s,1H)、7.90(s,1H)、6.88(s,1H)、4.50(brs,1H)、4.12−4.07(m,1H)、2.76 −2.72(m,2H)、1.77−1.73(m,2H)、1.38(d,J= 6.4Hz,6H)、1.15(s,6H)
本発明の化合物の薬理学的特性は多数の生物学的アッセイにより確認され得る。下記の典型例としての生物学的アッセイを本発明の化合物で実施した。
該アッセイはU字底384ウェルプレートにて行われた。最終アッセイ容量は30μLであり、アッセイ緩衝液(20mM HEPES(pH7.2)、10mM MgCl2、0.015%Brij 35および4mM DTT)中に15μLの酵素と基質(蛍光ペプチドおよびATP)および試験化合物を添加して調製された。反応はIRAK4と基質および試験化合物とを合わせることで開始された。該反応混合物を室温で60分間インキュベートし、45μLの35mM EDTAを各サンプルに添加することで反応を終わらせた。その反応混合物をキャリパー(Caliper)LABCHIP(登録商標)3000(Caliper, Hopkinton, MA)で蛍光基質とリン酸化生成物の電気泳動分離により分析した。阻害データは、100%阻害としての酵素不含の対照反応と、0%阻害としてのビヒクルのみの反応とを比較することにより判断された。該アッセイにおける試剤の最終濃度は、ATP、500μM;FL−IPTSPITTTYFFFKKKペプチド、1.5μM;IRAK4、0.6nM;およびDMSO、1.6%である。
アッセイの13〜27日前、Caco−2細胞を、24ウェルのトランズウェルプレートにて1.45x105細胞/cm2の密度で、ウェル当たり約4.8x104細胞でコラーゲン被覆のポリカーボネートフィルター膜に播種した。細胞を10%ウシ胎児血清、10mM HEPES、1%非必須アミノ酸、2mM L−グルタミン、100U/mLペニシリン−G、および100μg/mLストレプトマイシンを補足したDMEMからなる培地にて成長させた。その培地を3日毎に取り換え、細胞を37℃で95%相対湿度および5%CO2の環境に維持した。アッセイの直前に、細胞を密着結合形成について評価した。試験化合物を100%DMSOに10mMまで溶解させ、アッセイ緩衝液中にて3μMに希釈した。透過性実験は、200μLのアッセイ緩衝液+/−化合物を、24ウェルのトランズウェル低結合クラスタープレートの先端トランズウェルコンパートメントに、そして600μLアッセイ緩衝液+/−化合物を側底コンパートメントに添加することで開始された。先端から側底(AからB)への透過性(吸収方向性(absorptive direction))について、化合物含有の緩衝液を先端コンパートメント(ドナーウェル)に入れ、一方で緩衝液だけを対応する側底コンパートメント(レシーバーウェル)に入れた。側底から先端(BからA)の透過性(分泌方向性(secretive direction))について、化合物含有の緩衝液を側底コンパートメント(ドナーウェル)に入れ、その一方で緩衝液だけを対応する先端コンパートメント(レシーバーウェル)に入れた。次にトランズウェルを緩やかに攪拌しながら37℃で95%相対湿度および5%CO2の環境にて2時間インキュベートした。インキュベーションの後、各先端および側底コンパートメントから100μLを取り出し、内部標体としてウェル当たり100μLの250nMのプロプラノロール、250nMのジクロフェナク、および500nMのトルブタミドを含有するアセトニトリルで予め負荷された、96ウェルの低結合プレートに移した。サンプルをその後でLC−MS/MSにより分析し、化合物の濃度を測定した。
抗凝血性ACD−Aを含有するヒト全血を384ウェルプレートに入れ(25μL/ウェル)、化合物と共に5%CO2インキュベーター中にて37℃で60分間インキュベートした。5%CO2インキュベーター中にて25μL RPMI(Gibco)中TLR2アゴニスト、10μg/mLの最終濃度のリポタイコ酸(Invivogen、San Diego、CA)でその血液を5時間刺激した。インキュベーションの終わりに、プレートを2300rpmで5分間遠心分離に付した。上澄みを採取し、フローサイトメトリービーズアッセイ(BD Biosciences、San Jose、CA)によりIL−6レベルを分析した。
末梢血単核細胞(PBMC)を抗凝血性EDTA(2.5mM)含有のヒト血液からFicoll勾配において遠心分離操作により単離した。PBMC(250000細胞/ウェル)を、5%CO2インキュベーター中37℃で30分間、アッセイ培地(10%熱不活化FCSを含むRPMI)にて化合物と共に培養した。化合物で前処理した後、細胞を5時間、10μg/mlのリポタイコ酸(Invivogen、San Diego、CA)、TLR2アゴニストで刺激した。培養の終わりに、プレートを1800rpmで10分間遠心分離に付し、細胞をペレット状にした。上澄みを採取し、ELISA(BD Biosciences、San Jose、CA)によりIL−6レベルを分析した。
Claims (15)
- 式(I):
[式中:
HETは、イミダゾ[1,2−b]ピリダジニルおよびピラゾロ[1,5−a]ピリミジニルより選択されるヘテロアリールであり、ここで該ヘテロアリールはそのヘテロアリール中にある炭素環原子によって式(I)の化合物におけるピリジニル基と結合し、そしてここで該ヘテロアリールは0ないし2個のRbで置換され;
Aは、ピラゾリル、イミダゾリル、またはトリアゾリルであり、各々が0または1個のRaで置換され;
R3は:
(i)−CH2CH3、−CH(CH3)2、−CH2CHF2、−CH(CH3)CH2OH、オキセタニル、テトラヒドロピラニル、またはC3−5シクロアルキルであって、0ないし2個のFで置換されるか;
(ii)C 1−3アルキル、C1−3ヒドロキシアルキル、C1−3フルオロアルキル、オキセタニル、テトラヒドロフラニル、およびテトラヒドロピラニルから独立して選択される0ないし2個の置換基で置換されたピラゾリルであり;
Raは:
(i)F、Cl、−OH、−CN、C1−6アルキル、C1−4フルオロアルキル、C1−4シアノアルキル、またはC1−6ヒドロキシアルキルであるか;または
(ii)C3−6シクロアルキル、アゼチジニル、オキセタニル、テトラヒドロフラニル、テトラヒドロピラニル、ピペリジニル、ピペラジニル、ピロリル、ピロリジノイル、モルホリニル、ピロリジニル、フェニル、ピラゾリル、イミダゾリル、ピリジニル、またはピリミジニルであって、その各々が、F、−CN、−OH、−NRyRy、C1−3アルキル、C1−3フルオロアルキル、−CH(フェニル)2、−O(C1−4アルキル)、−C(O)(C1−4アルキル)、−C(O)(C1−4デューテロアルキル)、−C(O)(C3−6シクロアルキル)、−C(O)O(C1−4アルキル)、−C(O)NRyRy、−C(O)(フェニル)、−C(O)(ピリジニル)、−C(O)CH2(C3−6シクロアルキル)、−NHC(O)CH3、−NHC(O)OCH3、−NHC(O)OC(CH3)3、−S(O)2(C1−3アルキル)、および−OS(O)2(C1−3アルキル)より独立して選択される0ないし4個の置換基で置換され;
Rbは、各々、F、Cl、−CN、−NH2、−CH3、−OCH3、およびシクロプロピルより独立して選択され;および
Ryは、各々独立して、HまたはC1−3アルキルである]
で示される化合物またはその塩。 - HETが、イミダゾ[1,2−b]ピリダジニル、およびピラゾロ[1,5−a]ピリミジニルより選択されるヘテロアリールであり、ここで該ヘテロアリールはそのヘテロアリール中にある炭素環原子によって式(I)の化合物におけるピリジニル基と結合し、そしてここで該ヘテロアリールは0ないし2個のRbで置換され;
Aが、ピラゾリル、イミダゾリル、またはトリアゾリルであり、各々が0または1個のRaで置換され;
R3が:
(i)−CH2CH3、−CH(CH3)2、−CH2CHF2、−CH(CH3)CH2OH、シクロプロピル、オキセタニル、またはテトラヒドロピラニルであるか;または
(ii)C 1−3アルキル、C1−3ヒドロキシアルキル、C1−3フルオロアルキル、オキセタニル、テトラヒドロフラニル、およびテトラヒドロピラニルより独立して選択される0ないし2個の置換基で置換されたピラゾリルであり;
Raが:
(i)F、Cl、−OH、−CN、C1−6アルキル、C1−4フルオロアルキル、C1−4シアノアルキル、またはC1−6ヒドロキシアルキルであるか;または
(ii)C3−6シクロアルキル、アゼチジニル、オキセタニル、テトラヒドロフラニル、テトラヒドロピラニル、ピペリジニル、ピペラジニル、ピロリル、ピロリジノイル、モルホリニル、ピロリジニル、フェニル、ピラゾリル、イミダゾリル、ピリジニル、またはピリミジニルであって、その各々は、F、−CN、−OH、−NRyRy、C1−3アルキル、C1−3フルオロアルキル、−CH(フェニル)2、−O(C1−4アルキル)、−C(O)(C1−4アルキル)、−C(O)(C1−4デューテロアルキル)、−C(O)(C3−6シクロアルキル)、−C(O)O(C1−4アルキル)、−C(O)NRyRy、−C(O)(フェニル)、−C(O)(ピリジニル)、−C(O)CH2(C3−6シクロアルキル)、−NHC(O)CH3、−NHC(O)OCH3、−NHC(O)OC(CH3)3、−S(O)2(C1−3アルキル)、および−OS(O)2(C1−3アルキル)より独立して選択される0ないし4個の置換基で置換され;
Rbが、各々、F、Cl、−CN、−NH2、−CH3、−OCH3、およびシクロプロピルより独立して選択され;および
Ryが、各々独立して、HまたはC1−3アルキルである、
請求項1に記載の化合物またはその塩。 - HETが、イミダゾ[1,2−b]ピリダジニルおよびピラゾロ[1,5−a]ピリミジニルより選択されるヘテロアリールであり、ここで該ヘテロアリールはそのヘテロアリール中にある炭素環原子によって式(I)の化合物におけるピリジニル基と結合し、そしてここで該ヘテロアリールは0ないし1個のRbで置換され;
Aが、ピラゾリル、またはトリアゾリルであり、その各々が、0または1個のRaで置換され;
R3が、−CH(CH3)2、シクロプロピル、ジフルオロシクロブチル、フルオロシクロペンチル、オキセタニル、テトラヒドロピラニル、または2,2−ジフルオロエチルピラゾリルであり;
Raが、−OH、−CH3、−CH2CH2CH3、−CH2CF3、−C(CH3)2OH、−CH2C(CH3)2OH、−CH2CH2C(CH3)2OH、テトラヒドロピラニル、アセチルアゼチジニル、または
Rbが、Clまたは−CNである、
請求項1に記載の化合物またはその塩。 - HETが、イミダゾ[1,2−b]ピリダジニルおよびピラゾロ[1,5−a]ピリミジニルより選択されるヘテロアリールであり、ここで該ヘテロアリールはそのヘテロアリール中にある炭素環原子によって式(I)の化合物におけるピリジニル基と結合し、そしてここで該ヘテロアリールは0ないし1個のRbで置換され;
Aが、ピラゾリル、またはトリアゾリルであり、その各々が0または1個のRaで置換され;
R3が、−CH(CH3)2、シクロプロピル、または2,2−ジフルオロエチルピラゾリルであり;
Raが、−OH、−CH3、−CH2CH2CH3、−CH2CF3、−C(CH3)2OH、−CH2C(CH3)2OH、−CH2CH2C(CH3)2OH、テトラヒドロピラニル、アセチルアゼチジニル、または
Rbが、Clまたは−CNである、
請求項1または2に記載の化合物またはその塩。 - Aが
- Aが
- HETが:
- HETが
R3が、−CH(CH3)2、シクロプロピル、
Rbが、Clまたは−CNである、
請求項1に記載の化合物またはその塩。 - Aがピラゾリルである、請求項1に記載の化合物またはその塩。
- Aがトリアゾリルである、請求項1に記載の化合物またはその塩。
- 化合物が:3−(5−(4−(2−ヒドロキシプロパン−2−イル)−1H−ピラゾール−1−イル)−4−(イソプロピルアミノ)ピリジン−2−イル)ピラゾロ[1,5−a]ピリミジン−6−カルボニトリル(1);2−(7−クロロイミダゾ[1,2−b]ピリダジン−3−イル)−N−イソプロピル−5−(4−(テトラヒドロ−2H−ピラン−4−イル)−1H−ピラゾール−1−イル)ピリジン−4−アミン(2);3−(4−(イソプロピルアミノ)−5−(1−(テトラヒドロ−2H−ピラン−4−イル)−1H−ピラゾール−4−イル)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル(3);1−(4−(6−(7−クロロイミダゾ[1,2−b]ピリダジン−3−イル)−4−(イソプロピルアミノ)ピリジン−3−イル)−1H−ピラゾール−1−イル)−2−メチルプロパン−2−オール(4);3−(5−(1−(2−ヒドロキシ−2−メチルプロピル)−1H−ピラゾール−4−イル)−4−(イソプロピルアミノ)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル(5);3−(4−(イソプロピルアミノ)−5−(1−プロピル−1H−ピラゾール−4−イル)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル(6);2−(7−クロロイミダゾ[1,2−b]ピリダジン−3−イル)−N−イソプロピル−5−(1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−4−イル)ピリジン−4−アミン(7);3−(4−(イソプロピルアミノ)−5−(1−(2,2,2−トリフルオロエチル)−1H−ピラゾール−4−イル)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル(8);2−(7−クロロイミダゾ[1,2−b]ピリダジン−3−イル)−N−(1−(2,2−ジフルオロエチル)−1H−ピラゾール−4−イル)−5−(1−プロピル−1H−ピラゾール−4−イル)ピリジン−4−アミン(9);3−(4−((1−(2,2−ジフルオロエチル)−1H−ピラゾール−4−イル)アミノ)−5−(1−プロピル−1H−ピラゾール−4−イル)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル(10);2−(6−クロロピラゾロ[1,5−a]ピリミジン−3−イル)−N−イソプロピル−5−(4−プロピル−1H−1,2,3−トリアゾール−1−イル)ピリジン−4−アミン(11);3−(4−(イソプロピルアミノ)−5−(4−プロピル−1H−1,2,3−トリアゾール−1−イル)ピリジン−2−イル)ピラゾロ[1,5−a]ピリミジン−6−カルボニトリル(12);4−(1−(6−(6−クロロピラゾロ[1,5−a]ピリミジン−3−イル)−4−(イソプロピルアミノ)ピリジン−3−イル)−1H−1,2,3−トリアゾール−4−イル)−2−メチルブタン−2−オール(13);4−(1−(6−(6−クロロピラゾロ[1,5−a]ピリミジン−3−イル)−4−(オキセタン−3−イルアミノ)ピリジン−3−イル)−1H−1,2,3−トリアゾール−4−イル)−2−メチルブタン−2−オール(14);3−(4−(イソプロピルアミノ)−5−(4−プロピル−1H−1,2,3−トリアゾール−1−イル)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル(15);3−(4−(イソプロピルアミノ)−5−(1−(テトラヒドロ−2H−ピラン−4−イル)−1H−1,2,3−トリアゾール−4−イル)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル(16);3−(5−(1−(1−アセチルアゼチジン−3−イル)−1H−1,2,3−トリアゾール−4−イル)−4−(イソプロピルアミノ)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル(17);3−(4−(シクロプロピルアミノ)−5−(1−プロピル−1H−1,2,3−トリアゾール−4−イル)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル(18);2−(7−クロロイミダゾ[1,2−b]ピリダジン−3−イル)−N−シクロプロピル−5−(1−プロピル−1H−1,2,3−トリアゾール−4−イル)ピリジン−4−アミン(19);2−(7−クロロイミダゾ[1,2−b]ピリダジン−3−イル)−N−イソプロピル−5−(1−プロピル−1H−1,2,3−トリアゾール−4−イル)ピリジン−4−アミン(20);(3R)−メチル 4−(4−(6−(7−クロロイミダゾ[1,2−b]ピリダジン−3−イル)−4−(シクロプロピルアミノ)ピリジン−3−イル)−1H−1,2,3−トリアゾール−1−イル)−3−ヒドロキシ−3−メチルピペリジン−1−カルボキシラート(21);3−(5−(4−(3−ヒドロキシ−3−メチルブチル)−1H−1,2,3−トリアゾール−1−イル)−4−(イソプロピルアミノ)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル(22);4−(1−(6−(6−クロロピラゾロ[1,5−a]ピリミジン−3−イル)−4−((テトラヒドロ−2H−ピラン−4−イル)アミノ)ピリジン−3−イル)−1H−1,2,3−トリアゾール−4−イル)−2−メチルブタン−2−オール(23);3−(4−((3,3−ジフルオロシクロブチル)アミノ)−5−(4−(3−ヒドロキシ−3−メチルブチル)−1H−1,2,3−トリアゾール−1−イル)ピリジン−2−イル)ピラゾロ[1,5−a]ピリミジン−6−カルボニトリル(24);3−(4−(((1S,3S)−3−フルオロシクロペンチル)アミノ)−5−(4−(3−ヒドロキシ−3−メチルブチル)−1H−1,2,3−トリアゾール−1−イル)ピリジン−2−イル)ピラゾロ[1,5−a]ピリミジン−6−カルボニトリル(25);3−(5−(4−(3−ヒドロキシ−3−メチルブチル)−1H−1,2,3−トリアゾール−1−イル)−4−(オキセタン−3−イルアミノ)ピリジン−2−イル)ピラゾロ[1,5−a]ピリミジン−6−カルボニトリル(26);3−(5−(1−(3−ヒドロキシ−3−メチルブチル)−1H−ピラゾール−4−イル)−4−(イソプロピルアミノ)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル(27);3−(4−(イソプロピルアミノ)−5−(5−(テトラヒドロ−2H−ピラン−4−イル)−1H−ピラゾール−3−イル)ピリジン−2−イル)イミダゾ[1,2−b]ピリダジン−7−カルボニトリル(28);および3−(5−(5−(3−ヒドロキシ−3−メチルブチル)−1H−ピラゾール−3−イル)−4−((テトラヒドロ−2H−ピラン−4−イル)アミノ)ピリジン−2−イル)ピラゾロ[1,5−a]ピリミジン−6−カルボニトリル(29)
より選択される、請求項1に記載の化合物またはその塩。 - 請求項1−11のいずれか一項に記載の1または複数の化合物と、医薬的に許容される担体または希釈剤とを含む、医薬組成物。
- 治療のための請求項1−11のいずれか一項に記載の化合物またはその塩を含む医薬組成物、あるいは治療のための請求項12に記載の医薬組成物。
- 炎症疾患、自己免疫疾患またはがんの治療のための請求項12または13に記載の医薬組成物。
- 疾患が、クローン病、潰瘍性結腸炎、喘息、移植片対宿主病、同種移植の拒絶反応、慢性閉塞性肺疾患、グレーブス病、関節リウマチ、全身性紅斑性狼瘡、ループス腎炎、皮膚ループス、乾癬、クリオピリン関連周期性症候群、TNF受容体関連周期性症候群、家族性地中海熱、成人発症スチル病、全身性発症若年性突発性関節炎、多発性硬化症、神経因性疼痛、痛風および痛風性関節炎より選択される、請求項14に記載の医薬組成物。
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