JP2015518894A - Egfr活性を調節するための化合物および組成物 - Google Patents
Egfr活性を調節するための化合物および組成物 Download PDFInfo
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- JP2015518894A JP2015518894A JP2015516156A JP2015516156A JP2015518894A JP 2015518894 A JP2015518894 A JP 2015518894A JP 2015516156 A JP2015516156 A JP 2015516156A JP 2015516156 A JP2015516156 A JP 2015516156A JP 2015518894 A JP2015518894 A JP 2015518894A
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- Prior art keywords
- methyl
- azepan
- enoyl
- alkyl
- benzo
- Prior art date
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- Granted
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 293
- 230000000694 effects Effects 0.000 title abstract description 21
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- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 title abstract 3
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 title abstract 3
- 239000000203 mixture Substances 0.000 title description 193
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 66
- 125000005842 heteroatom Chemical group 0.000 claims description 59
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 56
- 229910052717 sulfur Inorganic materials 0.000 claims description 55
- 229910052760 oxygen Inorganic materials 0.000 claims description 54
- 125000005843 halogen group Chemical group 0.000 claims description 44
- 150000002431 hydrogen Chemical class 0.000 claims description 41
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- 238000011282 treatment Methods 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 32
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 28
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 229910052698 phosphorus Inorganic materials 0.000 claims description 21
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- BRSYTDWQLDZUPF-UHFFFAOYSA-N 2-methylpyridine-4-carboxamide Chemical compound CC1=CC(C(N)=O)=CC=N1 BRSYTDWQLDZUPF-UHFFFAOYSA-N 0.000 claims description 10
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
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- CMGSCQBXDPYNGB-ZHMUPQBKSA-N n-[7-chloro-1-[(3r)-1-[(e)-4-(dicyclopropylamino)but-2-enoyl]azepan-3-yl]benzimidazol-2-yl]-2-methylpyridine-4-carboxamide Chemical compound C1=NC(C)=CC(C(=O)NC=2N(C3=C(Cl)C=CC=C3N=2)[C@H]2CN(CCCC2)C(=O)\C=C\CN(C2CC2)C2CC2)=C1 CMGSCQBXDPYNGB-ZHMUPQBKSA-N 0.000 claims description 4
- UQLIJVPLMFPORY-NBILRRPASA-N n-[7-chloro-1-[(3r)-1-[(e)-4-(dimethylamino)but-2-enoyl]azepan-3-yl]benzimidazol-2-yl]-2,6-dimethylpyridine-4-carboxamide Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC(C)=NC(C)=C1 UQLIJVPLMFPORY-NBILRRPASA-N 0.000 claims description 4
- MNKAISMGRLQTPA-HSZRJFAPSA-N n-[7-chloro-1-[(3r)-1-prop-2-enoylazepan-3-yl]-6-(2-pyrrolidin-1-ylethoxy)benzimidazol-2-yl]-2,6-dimethylpyridine-4-carboxamide Chemical compound CC1=NC(C)=CC(C(=O)NC=2N(C3=C(Cl)C(OCCN4CCCC4)=CC=C3N=2)[C@H]2CN(CCCC2)C(=O)C=C)=C1 MNKAISMGRLQTPA-HSZRJFAPSA-N 0.000 claims description 4
- QEDYHISEDZQKOR-OAHLLOKOSA-N n-[7-chloro-6-methoxy-1-[(3r)-1-prop-2-enoylazepan-3-yl]benzimidazol-2-yl]pyridazine-4-carboxamide Chemical compound N1([C@H]2CN(CCCC2)C(=O)C=C)C2=C(Cl)C(OC)=CC=C2N=C1NC(=O)C1=CC=NN=C1 QEDYHISEDZQKOR-OAHLLOKOSA-N 0.000 claims description 4
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- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229960004449 vismodegib Drugs 0.000 description 1
- BPQMGSKTAYIVFO-UHFFFAOYSA-N vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000008136 water-miscible vehicle Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229960000833 xylometazoline Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- 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
- A61K31/4164—1,3-Diazoles
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- 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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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Abstract
Description
本出願は、2012年6月6日に出願された、インド仮特許出願第1741/DEL/2012号;および2013年2月28日に出願された、米国仮出願第61/770,752号の利益を主張し、これらのそれぞれは、その全体が参照により本明細書に組み込まれる。
環Bは、フェニル;N、O、およびSから選択される1〜3個のヘテロ原子を含む5〜6員ヘテロアリール;またはN、O、S、およびPから選択される1〜2個のヘテロ原子を含む5〜6員ヘテロシクリルであり、場合によりオキソで置換されており;
Eは、NHまたはCH2であり;
R1、R1’およびR2は、独立して、水素;ハロ;シアノ;CN;C1〜6アルキル;C1〜6ハロアルキル;N、O、およびSから選択される1〜4個のヘテロ原子を含む5〜6員ヘテロアリール;フェニル、N、O、S、およびPから選択される1〜2個のヘテロ原子を含む5〜6員ヘテロシクリルであり、場合によりオキソ;−X1−C(O)OR3;−X1−O−C(O)R3;−X1−C(O)R3;−X1−C(O)NR4R5;−X1−C(O)NR4−X3−C(O)OR3;−X1−C(O)NR4−X3−S(O)0〜2R6;−X1−NR4R5;−X1NR4−X2−C(O)R3;−X1−NR4−X2−C(O)OR3;−X1−NR4−X2−C(O)NR4R5;−X1−NR4−X3−S(O)0〜2R6;−X1−NR4S(O)2R6;−X1−OS(O)2R6;−X1−OR3;−X1−O−X4−OR3;−X1−O−X4−S(O)0〜2R6;−X1−O−X4−NR4R5;−X1−S(O)0〜2R6;−X1−S(O)0〜2−X3−NR4R5;−X1−C(O)NR4−X3−P(O)R6aR6b;−X1−NR4−X1−P(O)R6aR6b;−X1−O−X1−P(O)R6aR6b;−X1−P(O)R6a−X1−NR4R5;−X1−P(O)R6aR6bまたは−X1−S(O)2NR4R5で置換されており;ここで、R1またはR2におけるそれぞれのフェニル、ヘテロアリール、もしくはヘテロシクリルは、置換されていないか、またはOH、ハロ、C1〜6アルキル、C1〜6ハロアルキル、およびC1〜6ハロアルコキシから選択される1〜3個の基で置換されており;
R3、R4、およびR5は、独立して、水素、C1〜6アルキルもしくはC1〜6ハロアルキルであるか;またはこの際、R4およびR5は、NR4R5におけるNと一緒になって、N、O、S、およびPから選択される1〜2個のヘテロ原子を含む4〜7員環を形成してもよく、および場合により1〜4個のR7で置換されており;
R6は、C1〜6アルキルまたはC1〜6ハロアルキルであり;
R6aおよびR6bは、独立して、ヒドロキシ、C1〜6アルキル、C1〜6ハロアルキル、C1〜6アルコキシ、C1〜6ハロアルコキシ、6〜10員単環式もしくは二環式アリール;N、O、およびSから選択される1〜4個のヘテロ原子を含む5〜10員ヘテロアリール;またはN、O、およびSから選択される1〜4個のヘテロ原子を含む4〜12員単環式もしくは二環式ヘテロシクリルであり、場合によりオキソで置換されており:
Zは、
R9およびR10は、独立して、水素、ハロ、C1〜6アルキル、C1〜6ハロアルキル、OH、シアノ、C1〜6アルキル、C1〜6ハロアルキルであり;
R11a、R11b、R11c、R11d、R11e、R11f、R11g、R11h、R11i、R11j、R11k、およびR11lは、独立して、水素、C1〜6アルキル、またはC1〜6ハロアルキルであり;
R12およびR13は、独立して、水素、ハロ、シアノ、C1〜6アルキル、またはC1〜6ハロアルキルであり;
R14およびR15は、独立して、水素、C1〜6アルキル、−L1−R23、−(CRaRb)2〜3Rc、もしくは−L2−Rdであるか;またはR14およびR15は、NR14R15におけるNと一緒になって、N、O、S、およびPから選択される1〜2個のヘテロ原子を含む4〜7員環を形成してもよく、および場合により1〜4個のR18基で置換されており;
R16およびR17は、独立して、水素もしくはC1〜6アルキルであるか、またはR16およびR17は、それらが結合している炭素と一緒になって、C3〜6シクロアルキルを形成してもよく;
X1およびX2は、独立して、結合またはC1〜6アルキルであり;
X3は、C1〜6アルキルであり;
X4は、C2〜6アルキルであり;
R19は、水素、C1〜6アルキル、COR20、COOR20、CONR20R21、またはS(O)2R20であり;
R20は、C1〜6アルキル、C1〜6ハロアルキル、またはシクロアルキルであり;
R21は、水素もしくはC1〜6アルキルであるか;またはR20およびR21は、NR20R21におけるNと一緒になって、N、O、S、Pから選択される1〜2個のヘテロ原子を含む4〜7員環を形成してもよく、および場合により1〜4個のR22基で置換されており;
R7、R18およびR22は、独立して、オキソ、ハロ、ヒドロキシ、C1〜6アルキル、C1〜6ハロアルキル、C1〜6アルコキシ、またはC1〜6ハロアルコキシであり;
R23は、独立して、C3〜7シクロアルキル、またはN、O、およびSから選択される1〜3個のヘテロ原子を含む4〜10員ヘテロシクリルであり、場合によりオキソで置換されており;およびR23は、置換されていないか、またはC1〜6アルキル、C1〜6ハロアルキル、−L3−Re、もしくは−L4−Rfで置換されており;
RcおよびReは、独立して、ハロ、シアノ、ヒドロキシ、−OR24、−NRR25、−NR−CO2R24、−NR−SO2−R26、−NR−COR26、−NR−C(O)−NRR25、−OC(O)−NRR25、またはハロ、C1〜6アルコキシ、ヒドロキシ、もしくはシアノで置換されたC1〜6アルキルであり;
RdおよびRfは、独立して、−SO2NRR25、−CONRR25、−C(O)OR24、−SO2R26、またはC(O)R26であり;
R24は、C1〜6アルキル、C1〜6ハロアルキル、−L2−R23a、または−(CRaRb)2〜3−N(RaRb)2であり;
R25は、水素、C1〜6アルキル、C1〜6ハロアルキル、−L2−R23b、または−(CR2)2〜3−N(RaRb)2であり;
R26は、C1〜6アルキル、C1〜6ハロアルキル、−L2−R23c、または−(CRaRb)1〜3−N(RaRb)2であり;
R23a、R23b、およびR23cは、R23から独立して選択され;
R、Ra、およびRbは、独立して、水素またはC1〜6アルキルであり;
L1、L2、L3、およびL4は、独立して、結合または−(CRaRb)1〜3であり;および
nおよびmは、独立して、1〜3であり;
pおよびqは、1〜4である)
またはその薬学的に許容される塩が提供される。
R1およびR1’は、独立して、水素;ハロ;シアノ;C1〜6アルキル;C1〜6ハロアルキル;−X1−NR4R5;−X1−OR3;−X1−S(O)0〜2R6;−X1−P(O)R6aR6b;置換されていないか、もしくはC1〜6アルキルで置換されているフェニル;またはN、O、およびSから選択される1〜4個のヘテロ原子を含む5〜6員ヘテロアリールであり;
R2は、水素、ハロ;シアノ;C1〜6アルキル;C1〜6ハロアルキル;−X1−C(O)OR3;−X1−C(O)R3;−X1−C(O)NR4R5;−X1−C(O)NR4−X3−C(O)OR3;−X1−C(O)NR4−X3−S(O)0〜2R6;−X1−NR4R5;−X1NR4−X2−C(O)R3;−X1−NR4−X3−S(O)0〜2R6;−X1−OR3;−X1−O−X4−OR3;−X1−S(O)0〜2R6;−X1−O−X4−NR4R5;またはN、O、およびSから選択される1〜4個のヘテロ原子を含む5〜6員ヘテロアリールから選択され、および置換されていないか、またはC1〜6アルキルで置換されており;
R3,R4、およびR5は、独立して、水素、C1〜6アルキル、もしくはC1〜6ハロアルキルであるか;またはこの際、R4およびR5は、NR4R5におけるNと一緒になって、N,O、S、およびPから選択される1〜2個のヘテロ原子を含む4〜7員環を形成してもよく、および場合により1〜4個のR7基で置換されており;
R6、R6a、およびR6bは、C1〜6アルキルであり;
Zは、
R9、R10、R11a、R11b、R11c、R11d、R11e、R11f、R11g、R11h、R11i、R11j、R11k、およびR11lは、水素であり;
R12、R13、R16、およびR17は、独立して、水素またはC1〜6アルキルであり;
R14およびR15は、独立して、水素;C1〜6アルキル;−C(O)O−(C1〜6アルキル);置換されていないか、もしくはC1〜6アルキルで置換されているC3〜7シクロアルキルであるか;またはR14およびR15は、NR14R15におけるNと一緒になって、N、O、S、およびPから選択される1〜2個のヘテロ原子を含む4〜7員環を形成してもよく、および場合により1〜4個のR18基で置換されており;
R7およびR18は、独立して、オキソ、ハロ、ヒドロキシ、C1〜6アルキル、またはC1〜6アルコキシであり;
R19は、水素、COR20、またはCOOR20であり;
R20は、C1〜6アルキルであり;
pは、1であり;
mおよびqは、独立して、1〜2であり;
環B、X1、X2、X3、およびX4、ならびにnは、本明細書で記載された実施形態のいずれかで定義されたとおりである)
が提供される。
式中、Yは、OまたはNR19であり;
R1、R1’、R2、R8、R19、A、B、Y、m、およびnは、本明細書で記載された実施形態のいずれかで定義されたとおりである。
が提供される。特定の実施形態において、W1、W2、W3、およびW4の少なくとも2個はCR1であり、その他はNである。
R1およびR1’が、独立して、水素;ハロ;シアノ;C1〜6アルキル;C1〜6ハロアルキル;−X1−NR4R5;−X1−OR3;−X1−S(O)0〜2R6;置換されていないか、もしくはC1〜6アルキルで置換されているフェニル;テトラゾリルまたはピロリルであり;
それぞれのX1が、結合またはCH2であり;
R3、R4、およびR5が、独立して、水素、C1〜6アルキル、もしくはC1〜6ハロアルキルであるか;またはこの際、R4およびR5が、NR4R5におけるNと一緒になって、ピペリジニルを形成し;
R6が、式(1)または式(2)で定義されたとおりである、
本明細書で記載されたとおりの式(1)、式(2)、式(2A)、式(2B)、式(2C)、式(2D)、式(3A)、式(3B)、式(3C)、式(4)、もしくは式(5)の化合物、またはその薬学的に許容される塩が提供される。
R1が、水素、ハロ、シアノ、C1〜6アルキル、C1〜6ハロアルキル、テトラゾリル、ピロリル、−X1−NR4R5、−X1−OR3、−X1−S(O)0〜2R6、または置換されていないか、もしくはC1〜6アルキルで置換されているフェニルであり;
R1’が、水素、ハロ、またはC1〜6アルキルであり;
R3、R4、およびR5が、独立して、水素、C1〜6アルキル、もしくは1〜6ハロアルキルであるか;またはこの際、R4およびR5が、NR4R5におけるNと一緒になって、ピペリジニルを形成し;
X1が、結合またはCH2であり;
R6が、式(1)または式(2)で定義されたとおりである、
本明細書で記載されたとおりの式(1)、式(2)、式(2A)、式(2B)、式(2C)、式(2D)、式(3A)、式(3B)、式(3C)、式(4)、もしくは式(5)の化合物、またはその薬学的に許容される塩が提供される。
第10の実施形態において、本明細書では、R1およびR1’が、独立して、水素;メチル;t−ブチル;トリフルオロメチル;メトキシ;エトキシ;トリフルオロメトキシ;ジフルオロメトキシ;フルオロ;クロロ;シアノ;ジメチルアミノ;メチルスルホニル;ジメチルホスホリル;テトラゾリル;ピロリル;置換されていないか、もしくはメチルで置換されているフェニル;またはピペリジニルである、本明細書で記載されたとおりの式(1)、式(2)、式(2A)、式(2B)、式(2C)、式(2D)、式(3A)、式(3B)、式(3C)、式(4)、もしくは式(5)の化合物、またはその薬学的に許容される塩が提供される。
R14およびR15が、独立して、水素、C1〜6アルキル、もしくはC3〜7シクロアルキルであるか;またはR14およびR15が、NR14R15におけるNと一緒になって、アゼチジニル、ピペリジル、ピロリジニル、もしくはモルホリニルを形成してもよく;この際、前記アゼチジニルまたはピロリジニルは、場合により1〜2個のハロ、メトキシ、またはヒドロキシルで置換されていることができ;
R12、R13、R16、R17、およびqが、本明細書で記載された実施形態のいずれかで定義されたとおりである、本明細書で記載されたとおりの式(1)、式(2)、式(2A)、式(2B)、式(2C)、式(2D)、式(3A)、式(3B)、式(3C)、式(4)、もしくは式(5)の化合物、またはそれらの薬学的に許容される塩が提供される。
N−{7−クロロ−1−[(3R)−1−[4−(ピロリジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−[4−(ピロリジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−[4−(3−フルオロアゼチジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−[4−(3−フルオロアゼチジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−{4−[(3R)−3−フルオロピロリジン−1−イル]ブタ−2−エノイル}アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−{4−[3−フルオロピロリジン−1−イル]ブタ−2−エノイル}アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−{4−[(3S)−3−フルオロピロリジン−1−イル]ブタ−2−エノイル}アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−{4−[3−フルオロピロリジン−1−イル]ブタ−2−エノイル}アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−[4−(3,3−ジフルオロピロリジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−[4−(3,3−ジフルオロピロリジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−{4−[(3R)−3−メトキシピロリジン−1−イル]ブタ−2−エノイル}アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−{4−[3−メトキシピロリジン−1−イル]ブタ−2−エノイル}アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−{4−[(3S)−3−メトキシピロリジン−1−イル]ブタ−2−エノイル}アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−{4−[3−メトキシピロリジン−1−イル]ブタ−2−エノイル}アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−{4−[(3R)−3−ヒドロキシピロリジン−1−イル]ブタ−2−エノイル}アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−{4−[3−ヒドロキシピロリジン−1−イル]ブタ−2−エノイル}アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−[(2E)−4−[(3S)−3−ヒドロキシピロリジン−1−イル]ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−[(2E)−4−[3−ヒドロキシピロリジン−1−イル]ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−[(2E)−4−(ピロリジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−クロロ−1−[1−[(2E)−4−(ピロリジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
2−メチル−N−{7−メチル−1−[(3R)−1−[(2E)−4−(ピロリジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−4−カルボキサミド;
2−メチル−N−{7−メチル−1−[1−[(2E)−4−(ピロリジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−[(3R)−3−フルオロピロリジン−1−イル]ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−4−[3−フルオロピロリジン−1−イル]ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−[(2E)−4−[(3R)−3−フルオロピロリジン−1−イル]ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−クロロ−1−[1−[(2E)−4−[3−フルオロピロリジン−1−イル]ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[(3R)−1−[4−(アゼチジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−7−クロロ−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{1−[1−[4−(アゼチジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−7−クロロ−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−[4−(3−ヒドロキシアゼチジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−[4−(3−ヒドロキシアゼチジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−[(2E)−4−(3−メトキシアゼチジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−[(2E)−4−(3−メトキシアゼチジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−[(2E)−4−(3,3−ジフルオロアゼチジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−[(2E)−4−(3,3−ジフルオロアゼチジン−1−イル)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{5−メチル−1−[(3S)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{5−メチル−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{7−クロロ−1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2,6−ジメチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2,6−ジメチルピリジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−(トリフルオロメチル)ピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−(トリフルオロメチル)ピリジン−4−カルボキサミド;
N−{7−クロロ−6−メトキシ−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−クロロ−6−メトキシ−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[(3R)−1−(エテンスルホニル)アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[1−(エテンスルホニル)アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−7−(ピロリジン−1−イルメチル)−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−7−(ピロリジン−1−イルメチル)−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{5−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{7−クロロ−1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−6−メトキシ−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−クロロ−1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−6−メトキシ−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−2−フルオロベンズアミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]ピペリジン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]ピペリジン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−1,3−オキサゾール−5−カルボキサミド;
N−{1−[(6R)−4−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]−1,4−オキサゼパン−6−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[4−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]−1,4−オキサゼパン−6−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[(6S)−4−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]−1,4−オキサゼパン−6−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[4−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]−1,4−オキサゼパン−6−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−イミダゾ[4,5−c]ピリジン−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{3−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−3H−イミダゾ[4,5−c]ピリジン−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ベンズアミド;
N−{1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−7−(トリフルオロメチル)−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−7−(トリフルオロメチル)−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{7−メチル−1−[4−(プロパ−2−エノイル)−1,4−オキサゼパン−6−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{7−クロロ−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−クロロ−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−クロロ−1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{7−クロロ−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[(3R)−1−(ブタ−2−イノイル)アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[1−(ブタ−2−イノイル)アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[(3R)−1−[(2E)−ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[1−[(2E)−ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−3−フルオロベンズアミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−3,5−ジフルオロベンズアミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)ピリジン−3−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)ピリダジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−4−フルオロベンズアミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−2,3−ジフルオロベンズアミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−2,4−ジフルオロベンズアミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−2,5−ジフルオロベンズアミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−3,4−ジフルオロベンズアミド;
3−クロロ−N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−2−フルオロベンズアミド;
3−クロロ−N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−2,4−ジフルオロベンズアミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−3,4,5−トリフルオロベンズアミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)ピリジン−2−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)ピリジン−4−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)ピリミジン−2−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)ピリミジン−4−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)ピラジン−2−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)ピリダジン−3−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)ベンズアミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−3−メチルベンズアミド;
3−シアノ−N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)ベンズアミド;
3−クロロ−N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)ベンズアミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−3−メトキシベンズアミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−6−メトキシピリジン−3−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−6−(トリフルオロメチル)ピリジン−3−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−6−メチルピリジン−3−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−2−メトキシピリジン−4−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−1−メチル−2−オキソ−1,2−ジヒドロピリジン−4−カルボキサミド;
2−(ジメチルアミノ)−N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)ピリジン−4−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)イミダゾ[2,1−b][1,3]チアゾール−6−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−3−メタンスルホニルベンズアミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−3−(1H−1,2,3,4−テトラゾール−1−イル)ベンズアミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−2−メチルピリミジン−4−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)イミダゾ[1,2−a]ピリジン−6−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)フラン−2−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−2−(ピペリジン−1−イル)ピリジン−4−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−2−フルオロピリジン−4−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−4,5−ジメチルフラン−2−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−2−(1H−1,2,3,4−テトラゾール−1−イル)ピリジン−4−カルボキサミド;
2−tert−ブチル−N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)ピリジン−4−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−2−メチルピリジン−3−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)イミダゾ[1,5−a]ピリジン−7−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−2−メチル−1,3−チアゾール−5−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)−2−エトキシピリジン−4−カルボキサミド;
N−(1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル)ナフタレン−2−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−5−(トリフルオロメチル)ピリジン−3−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−5−(トリフルオロメチル)ピリジン−3−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−5−メチルピリジン−3−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−5−メチルピリジン−3−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−5−フルオロピリジン−3−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−5−フルオロピリジン−3−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−5−(1H−ピロール−1−イル)ピリジン−3−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−5−(1H−ピロール−1−イル)ピリジン−3−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−メトキシピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−メトキシピリジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2,6−ジメチルピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2,6−ジメチルピリジン−4−カルボキサミド;
2−クロロ−N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−4−カルボキサミド;
2−クロロ−N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−4−カルボキサミド;
2−クロロ−N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−6−メチルピリジン−4−カルボキサミド;
2−クロロ−N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−6−メチルピリジン−4−カルボキサミド;
2−クロロ−N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−6−メトキシピリジン−4−カルボキサミド;
2−クロロ−N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−6−メトキシピリジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−フェニルピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−フェニルピリジン−4−カルボキサミド;
6−クロロ−N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−3−カルボキサミド;
6−クロロ−N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−3−カルボキサミド;
5,6−ジクロロ−N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−3−カルボキサミド;
5,6−ジクロロ−N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−3−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−5−メトキシピリジン−3−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−5−メトキシピリジン−3−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−(2−メチルフェニル)ピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−(2−メチルフェニル)ピリジン−4−カルボキサミド;
6−メチル−N−{7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
6−メチル−N−{7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−6−メチルピリダジン−4−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−6−メチルピリダジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メトキシ−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メトキシ−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−メトキシ−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−メトキシ−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−(プロパン−2−イルオキシ)−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−(プロパン−2−イルオキシ)−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−7−(プロパン−2−イルオキシ)−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−7−(プロパン−2−イルオキシ)−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[(3R)−1−[4−(ジメチルアミノ)ブタ−2−イノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[1−[4−(ジメチルアミノ)ブタ−2−イノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
(R)−N−(7−メチル−1−(1−(2−メチル−4,4−ジオキシド−5,6−ジヒドロ−1,4−オキサチイン−3−カルボニル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)ピリダジン−4−カルボキサミド;
N−(7−メチル−1−(1−(2−メチル−4,4−ジオキシド−5,6−ジヒドロ−1,4−オキサチイン−3−カルボニル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)ピリダジン−4−カルボキサミド;
N−{1−[(3R)−1−[(5,6−ジヒドロ−1,4−ジオキシン−2−イル)カルボニル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[1−[(5,6−ジヒドロ−1,4−ジオキシン−2−イル)カルボニル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−メチル−1−[(3R)−1−[2−(ピペリジン−1−イルメチル)プロパ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−メチル−1−[1−[2−(ピペリジン−1−イルメチル)プロパ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−メチル−1−[(3R)−1−[2−(ピロリジン−1−イルメチル)プロパ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−メチル−1−[1−[2−(ピロリジン−1−イルメチル)プロパ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[(3R)−1−{2−[(ジエチルアミノ)メチル]プロパ−2−エノイル}アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[1−{2−[(ジエチルアミノ)メチル]プロパ−2−エノイル}アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−メチル−1−[(3R)−1−[2−(モルホリン−4−イルメチル)プロパ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−メチル−1−[1−[2−(モルホリン−4−イルメチル)プロパ−2−エノイル]アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
メチル 1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−2−{[3−(トリフルオロメチル)ベンゼン]アミド}−1H−1,3−ベンゾジアゾール−7−カルボキシレート;
N−{5−メチル−1−[1−(プロパ−2−エノイル)ピペリジン−4−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{5−メチル−1−[1−(プロパ−2−エノイル)ピロリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{5−メチル−1−[1−(プロパ−2−エノイル)アゼチジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{5−メチル−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[1−(ブタ−2−エノイル)アゼチジン−3−イル]−5−メチル−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−(トリフルオロメトキシ)ピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−(トリフルオロメトキシ)ピリジン−4−カルボキサミド;
2−(ジフルオロメトキシ)−N−{1−[(3R)−1−[4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−4−カルボキサミド;
2−(ジフルオロメトキシ)−N−{1−[1−[4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−4−カルボキサミド;
2−クロロ−N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−6−(トリフルオロメトキシ)ピリジン−4−カルボキサミド;
2−クロロ−N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−6−(トリフルオロメトキシ)ピリジン−4−カルボキサミド;
N−{5−メチル−1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{5−メチル−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{7−メチル−1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{7−メチル−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{5−メチル−1−[1−(プロパ−2−エノイル)アゼパン−4−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{7−メチル−1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ベンズアミド;
N−{7−メチル−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ベンズアミド;
2−メチル−N−{7−メチル−1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−4−カルボキサミド;
2−メチル−N−{7−メチル−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−4−カルボキサミド;
メチル 1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−2−{[3−(トリフルオロメチル)ベンゼン]アミド}−1H−1,3−ベンゾジアゾール−5−カルボキシレート;
メチル 1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−2−{[3−(トリフルオロメチル)ベンゼン]アミド}−1H−1,3−ベンゾジアゾール−5−カルボキシレート;
N−{7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−5−(ピロリジン−1−イルメチル)−1H−1,3−ベンゾジアゾール−2−イル}ベンズアミド;
N−{7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−5−(ピロリジン−1−イルメチル)−1H−1,3−ベンゾジアゾール−2−イル}ベンズアミド;
N−[5−(モルホリン−4−イルメチル)−1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]−3−(トリフルオロメチル)ベンズアミド;
N−[5−(モルホリン−4−イルメチル)−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]−3−(トリフルオロメチル)ベンズアミド;
2,6−ジメチル−N−{7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−5−(ピロリジン−1−イルメチル)−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−4−カルボキサミド;
2,6−ジメチル−N−{7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−5−(ピロリジン−1−イルメチル)−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−4−カルボキサミド;
N−{7−[(3−ヒドロキシピロリジン−1−イル)メチル]−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ベンズアミド;
N−{7−[(3−ヒドロキシピロリジン−1−イル)メチル]−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ベンズアミド;
N−(1−(1−アクリロイルアゼパン−3−イル)−7−(1,1−ジオキシドチオモルホリン−4−カルボニル)−1H−ベンゾ[d]イミダゾール−2−イル)ベンズアミド;
N−(7−シアノ−1−{1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル}−5−(ヒドロキシメチル)−1H−1,3−ベンゾジアゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド;
N−{1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−5−(ピロリジン−1−イルメチル)−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−5−(ピロリジン−1−イルメチル)−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−[5−(ピペリジン−1−イルメチル)−1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]−3−(トリフルオロメチル)ベンズアミド;
N−[5−(ピペリジン−1−イルメチル)−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]−3−(トリフルオロメチル)ベンズアミド;
N−{5−[(N−メチルアセトアミド)メチル]−1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{5−[(N−メチルアセトアミド)メチル]−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−(5−{[(3R,4R)−3,4−ジヒドロキシピロリジン−1−イル]メチル}−1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド;
N−(5−{[3,4−ジヒドロキシピロリジン−1−イル]メチル}−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド;
N−[5−(ヒドロキシメチル)−1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]−3−(トリフルオロメチル)ベンズアミド;
N−[5−(ヒドロキシメチル)−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]−3−(トリフルオロメチル)ベンズアミド;
N−[5−(メトキシメチル)−1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]−3−(トリフルオロメチル)ベンズアミド;
N−[5−(メトキシメチル)−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]−3−(トリフルオロメチル)ベンズアミド;
N−[5−(エトキシメチル)−1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]−3−(トリフルオロメチル)ベンズアミド;
N−[5−(エトキシメチル)−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]−3−(トリフルオロメチル)ベンズアミド;
N−{5−[(2−メトキシエトキシ)メチル]−1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{5−[(2−メトキシエトキシ)メチル]−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{5−[(3,3−ジフルオロピロリジン−1−イル)メチル]−1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{5−[(3,3−ジフルオロピロリジン−1−イル)メチル]−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
2−メチル−N−{7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−5−(ピロリジン−1−イルメチル)−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−4−カルボキサミド;
2−メチル−N−{7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−5−(ピロリジン−1−イルメチル)−1H−1,3−ベンゾジアゾール−2−イル}ピリジン−4−カルボキサミド;
N−(5−{[(2−メタンスルホニルエチル) (メチル)アミノ]メチル}−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)ベンズアミド;
N−(5−{[(2−メタンスルホニルエチル) (メチル)アミノ]メチル}−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)ベンズアミド;
N−{5−[(2−メトキシエトキシ)メチル]−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ベンズアミド;
N−{5−[(2−メトキシエトキシ)メチル]−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ベンズアミド;
N−{7−[(ジメチルアミノ)メチル]−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ベンズアミド;
N−{7−[(ジメチルアミノ)メチル]−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ベンズアミド;
N−{7−[(2−メトキシエトキシ)メチル]−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ベンズアミド;
N−{7−[(2−メトキシエトキシ)メチル]−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}ベンズアミド;
N−[7−(ヒドロキシメチル)−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]ベンズアミド;
N−[7−(ヒドロキシメチル)−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]ベンズアミド;
(R)−N−(1−(1−アクリロイルアゼパン−3−イル)−7−((1,1−ジオキシドチオモルホリノ)メチル)−1H−ベンゾ[d]イミダゾール−2−イル)ベンズアミド;
N−(1−(1−アクリロイルアゼパン−3−イル)−7−((1,1−ジオキシドチオモルホリノ)メチル)−1H−ベンゾ[d]イミダゾール−2−イル)ベンズアミド;
N−(7−{[(2−メタンスルホニルエチル) (メチル)アミノ]メチル}−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)ベンズアミド;
N−(7−{[(2−メタンスルホニルエチル) (メチル)アミノ]メチル}−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)ベンズアミド;
メチル 3−({2−ベンズアミド−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−7−イル}ホルムアミド)プロパノエート;
メチル 2−({2−ベンズアミド−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−7−イル}ホルムアミド)アセテート;
3−({2−ベンズアミド−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−7−イル}ホルムアミド)プロパン酸;
2−({2−ベンズアミド−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−7−イル}ホルムアミド)酢酸;
N−[7−(3−メチル−1,2,4−オキサジアゾール−5−イル)−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]ベンズアミド;
1−(1−アクリロイルアゼパン−3−イル)−2−ベンズアミド−N−(2−(メチルスルホニル)エチル)−1H−ベンゾ[d]イミダゾール−7−カルボキサミド;
N−(7−{[(3R,4R)−3,4−ジヒドロキシピロリジン−1−イル]カルボニル}−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)ベンズアミド;
N−(7−{[3,4−ジヒドロキシピロリジン−1−イル]カルボニル}−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)ベンズアミド;
N−[7−(3−メチル−1,2,4−オキサジアゾール−5−イル)−1−[4−(プロパ−2−エノイル)−1,4−オキサゼパン−6−イル]−1H−1,3−ベンゾジアゾール−2−イル]ベンズアミド;
N−(1−{4−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]−1,4−オキサゼパン−6−イル}−7−(3−メチル−1,2,4−オキサジアゾール−5−イル)−1H−1,3−ベンゾジアゾール−2−イル)ベンズアミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]ピペリジン−3−イル]−5−(ヒドロキシメチル)−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]ピペリジン−3−イル]−5−(ヒドロキシメチル)−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
2−メチル−N−[7−メチル−5−(ピペリジン−1−イルメチル)−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]ピリジン−4−カルボキサミド;
2−メチル−N−[7−メチル−5−(ピペリジン−1−イルメチル)−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]ピリジン−4−カルボキサミド;
N−[5−(アゼチジン−1−イルメチル)−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]−2−メチルピリジン−4−カルボキサミド;
N−[5−(アゼチジン−1−イルメチル)−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル]−2−メチルピリジン−4−カルボキサミド;
N−(5−{[(3S)−3−ヒドロキシピロリジン−1−イル]メチル}−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2−メチルピリジン−4−カルボキサミド;
N−(5−{[3−ヒドロキシピロリジン−1−イル]メチル}−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2−メチルピリジン−4−カルボキサミド;
N−(5−{[(3S)−3−フルオロピロリジン−1−イル]メチル}−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2−メチルピリジン−4−カルボキサミド;
N−(5−{[3−フルオロピロリジン−1−イル]メチル}−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2−メチルピリジン−4−カルボキサミド;
N−(5−{[(3R)−3−フルオロピロリジン−1−イル]メチル}−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2−メチルピリジン−4−カルボキサミド;
N−(5−{[3−フルオロピロリジン−1−イル]メチル}−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2−メチルピリジン−4−カルボキサミド;
N−(5−{[(3S)−3−メトキシピロリジン−1−イル]メチル}−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2−メチルピリジン−4−カルボキサミド;
N−(5−{[3−メトキシピロリジン−1−イル]メチル}−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2−メチルピリジン−4−カルボキサミド;
N−(5−{[(3R)−3−メトキシピロリジン−1−イル]メチル}−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2−メチルピリジン−4−カルボキサミド;
N−(5−{[3−メトキシピロリジン−1−イル]メチル}−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2−メチルピリジン−4−カルボキサミド;
N−{5−[(3,3−ジフルオロピロリジン−1−イル)メチル]−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{5−[(3,3−ジフルオロピロリジン−1−イル)メチル]−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{5−[(3−フルオロアゼチジン−1−イル)メチル]−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{5−[(3−フルオロアゼチジン−1−イル)メチル]−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{5−[(3,3−ジフルオロアゼチジン−1−イル)メチル]−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{5−[(3,3−ジフルオロアゼチジン−1−イル)メチル]−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{5−[(3−メトキシアゼチジン−1−イル)メチル]−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{5−[(3−メトキシアゼチジン−1−イル)メチル]−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
(R)−N−(1−(1−アクリロイルアゼパン−3−イル)−5−((1,1−ジオキシドチオモルホリノ)メチル)−7−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(1−(1−アクリロイルアゼパン−3−イル)−5−((1,1−ジオキシドチオモルホリノ)メチル)−7−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(5−{[(3S)−3−メトキシピロリジン−1−イル]メチル}−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2,6−ジメチルピリジン−4−カルボキサミド;
N−(5−{[3−メトキシピロリジン−1−イル]メチル}−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2,6−ジメチルピリジン−4−カルボキサミド;
N−(5−{[(3R)−3−メトキシピロリジン−1−イル]メチル}−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2,6−ジメチルピリジン−4−カルボキサミド;
N−(5−{[3−メトキシピロリジン−1−イル]メチル}−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2,6−ジメチルピリジン−4−カルボキサミド;
N−(5−{[(3S)−3−フルオロピロリジン−1−イル]メチル}−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2,6−ジメチルピリジン−4−カルボキサミド;
N−(5−{[3−フルオロピロリジン−1−イル]メチル}−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2,6−ジメチルピリジン−4−カルボキサミド;
N−(5−{[(3R)−3−フルオロピロリジン−1−イル]メチル}−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2,6−ジメチルピリジン−4−カルボキサミド;
N−(5−{[3−フルオロピロリジン−1−イル]メチル}−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2,6−ジメチルピリジン−4−カルボキサミド;
2,3−ジフルオロ−N−(5−{[(3R)−3−メトキシピロリジン−1−イル]メチル}−7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)ベンズアミド;
2,3−ジフルオロ−N−(5−{[3−メトキシピロリジン−1−イル]メチル}−7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)ベンズアミド;
6−メチル−N−{7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−5−(ピロリジン−1−イルメチル)−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
6−メチル−N−{7−メチル−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−5−(ピロリジン−1−イルメチル)−1H−1,3−ベンゾジアゾール−2−イル}ピリダジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−ブタ−2−エノイル]アゼパン−3−イル]−5−{[(3S)−3−メトキシピロリジン−1−イル]メチル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2,6−ジメチルピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−ブタ−2−エノイル]アゼパン−3−イル]−5−{[3−メトキシピロリジン−1−イル]メチル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2,6−ジメチルピリジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−ブタ−2−エノイル]アゼパン−3−イル]−5−{[(3R)−3−メトキシピロリジン−1−イル]メチル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−ブタ−2−エノイル]アゼパン−3−イル]−5−{[3−メトキシピロリジン−1−イル]メチル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−5−(ピロリジン−1−イルメチル)−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−5−(ピロリジン−1−イルメチル)−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−ブタ−2−エノイル]アゼパン−3−イル]−5−{[(3S)−3−フルオロピロリジン−1−イル]メチル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2,6−ジメチルピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−ブタ−2−エノイル]アゼパン−3−イル]−5−{[3−フルオロピロリジン−1−イル]メチル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2,6−ジメチルピリジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−ブタ−2−エノイル]アゼパン−3−イル]−5−{[(3S)−3−フルオロピロリジン−1−イル]メチル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−ブタ−2−エノイル]アゼパン−3−イル]−5−{[3−フルオロピロリジン−1−イル]メチル}−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
メチル 1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−2−{[3−(トリフルオロメチル)ベンゼン]アミド}−1H,4H,5H,6H,7H−イミダゾ[4,5−c]ピリジン−5−カルボキシレート;
N−{5−メタンスルホニル−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H,4H,5H,6H,7H−イミダゾ[4,5−c]ピリジン−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{5−アセチル−1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−1H,4H,5H,6H,7H−イミダゾ[4,5−c]ピリジン−2−イル}−3−(トリフルオロメチル)ベンズアミド;
メチル 3−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−2−{[3−(トリフルオロメチル)ベンゼン]アミド}−3H,4H,5H,6H,7H−イミダゾ[4,5−c]ピリジン−5−カルボキシレート;
N−{5−メタンスルホニル−3−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−3H,4H,5H,6H,7H−イミダゾ[4,5−c]ピリジン−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{5−アセチル−3−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−3H,4H,5H,6H,7H−イミダゾ[4,5−c]ピリジン−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{5−メチル−3−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−3H,4H,5H,6H,7H−イミダゾ[4,5−c]ピリジン−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[(3R)−1−[(2E)−ブタ−2−エノイル]アゼパン−3−イル]−5−{[(3S)−3−メトキシピロリジン−1−イル]メチル}−1H−1,3−ベンゾジアゾール−2−イル}−2,6−ジメチルピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−ブタ−2−エノイル]アゼパン−3−イル]−5−{[(3S)−3−メトキシピロリジン−1−イル]メチル}−1H−1,3−ベンゾジアゾール−2−イル}−2,6−ジメチルピリジン−4−カルボキサミド;
N−(5−{[(3S)−3−メトキシピロリジン−1−イル]メチル}−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2,6−ジメチルピリジン−4−カルボキサミド;
N−(5−{[3−メトキシピロリジン−1−イル]メチル}−1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル)−2,6−ジメチルピリジン−4−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メトキシ−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メトキシ−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−6−メトキシ−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{7−クロロ−1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−6−メトキシ−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{6−クロロ−1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−5−メトキシ−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{6−クロロ−1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−5−メトキシ−1H−1,3−ベンゾジアゾール−2−イル}−2−メチルピリジン−4−カルボキサミド;
N−{6−クロロ−1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−5−メトキシ−1H−1,3−ベンゾジアゾール−2−イル}−2,6−ジメチルピリジン−4−カルボキサミド;
N−{6−クロロ−1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−5−メトキシ−1H−1,3−ベンゾジアゾール−2−イル}−2,6−ジメチルピリジン−4−カルボキサミド;
1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−2−{[3−(トリフルオロメチル)ベンゼン]アミド}−1H−1,3−ベンゾジアゾール−5−カルボン酸;
1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−2−{[3−(トリフルオロメチル)ベンゼン]アミド}−1H−1,3−ベンゾジアゾール−5−カルボン酸;
1−[(3R)−1−(プロパ−2−エノイル)ピペリジン−3−イル]−2−C−[3−(トリフルオロメチル)ベンゼン]−1H−1,3−ベンゾジアゾール−2,5−ジカルボキサミド;
1−[1−(プロパ−2−エノイル)ピペリジン−3−イル]−2−C−[3−(トリフルオロメチル)ベンゼン]−1H−1,3−ベンゾジアゾール−2,5−ジカルボキサミド;
1−[1−(プロパ−2−エノイル)アゼパン−3−イル]−2−{[3−(トリフルオロメチル)ベンゼン]アミド}−1H−1,3−ベンゾジアゾール−7−カルボン酸;
N−{7−メチル−1−[(6R)−4−(プロパ−2−エノイル)−1,4−オキサゼパン−6−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{7−メチル−1−[(6S)−4−(プロパ−2−エノイル)−1,4−オキサゼパン−6−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;
N−{1−[(3S)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−(トリフルオロメチル)ピリジン−4−カルボキサミド;
N−{1−[(3S)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−メチル−1,3−チアゾール−5−カルボキサミド;
N−{1−[(3R)−1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−メチル−1,3−チアゾール−5−カルボキサミド;
N−{1−[1−[(2E)−4−(ジメチルアミノ)ブタ−2−エノイル]アゼパン−3−イル]−7−メチル−1H−1,3−ベンゾジアゾール−2−イル}−2−メチル−1,3−チアゾール−5−カルボキサミド;
N−{7−メチル−1−[(3S)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;および
N−{7−メチル−1−[(3R)−1−(プロパ−2−エノイル)アゼパン−3−イル]−1H−1,3−ベンゾジアゾール−2−イル}−3−(トリフルオロメチル)ベンズアミド;またはその薬学的に許容される塩が提供される。
(R)−N−(7−クロロ−1−(1−(1−メチル−1,2,5,6−テトラヒドロピリジン−3−カルボニル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(N−(7−クロロ−1−(1−(1−メチル−1,2,5,6−テトラヒドロピリジン−3−カルボニル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R)−N−(7−クロロ−1−(1−(1−メチル−1,2,3,6−テトラヒドロピリジン−4−カルボニル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(1−メチル−1,2,3,6−テトラヒドロピリジン−4−カルボニル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R,E)−N−(7−クロロ−1−(1−(4−(ジメチルアミノ)−4−メチルペンタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ジメチルアミノ)−4−メチルペンタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
tert−ブチル 4−アクリロイル−6−(7−クロロ−2−(2−メチルイソニコチンアミド)−1H−ベンゾ[d]イミダゾール−1−イル)−1,4−ジアゼパン−1−カルボキシレート;
N−(1−(1−アクリロイル−1,4−ジアゼパン−6−イル)−7−クロロ−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(1−(1−アセチル−4−アクリロイル−1,4−ジアゼパン−6−イル)−7−クロロ−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R)−N−(1−(1−アクリロイルアゼパン−3−イル)−7−クロロ−6−(2−(ピロリジン−1−イル)エトキシ)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
N−(1−(1−アクリロイルアゼパン−3−イル)−7−クロロ−6−(2−(ピロリジン−1−イル)エトキシ)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
(R,E)−N−(7−クロロ−1−(1−(4−(ジシクロプロピルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ジシクロプロピルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R)−N−(1−(1−アクリロイルアゼパン−3−イル)−7−メチル−5−((4−メチル−3−オキソピペラジン−1−イル)メチル)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
N−(1−(1−アクリロイルアゼパン−3−イル)−7−メチル−5−((4−メチル−3−オキソピペラジン−1−イル)メチル)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
(R)−N−(5−((4−アセチルピペラジン−1−イル)メチル)−1−(1−アクリロイルアゼパン−3−イル)−7−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
N−(5−((4−アセチルピペラジン−1−イル)メチル)−1−(1−アクリロイルアゼパン−3−イル)−7−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
(E)−N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−(ジメチルホスホリル)−6−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−(ジメチルホスホリル)−6−メチルイソニコチンアミド;
(R,E)−tert−ブチル 4−(3−(7−クロロ−2−(2−メチルイソニコチンアミド)−1H−ベンゾ[d]イミダゾール−1−イル)アゼパン−1−イル)−4−オキソブタ−2−エニル(メチル)カルバメート;
tert−ブチル 4−(3−(7−クロロ−2−(2−メチルイソニコチンアミド)−1H−ベンゾ[d]イミダゾール−1−イル)アゼパン−1−イル)−4−オキソブタ−2−エニル(メチル)カルバメート;
(R,E)−N−(7−クロロ−1−(1−(4−(メチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(メチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R,E)−N−(7−クロロ−1−(1−(4−(メチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(メチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
(R,E)−N−(1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−7−(トリフルオロメチル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−7−(トリフルオロメチル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R,E)−N−(1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−7−(トリフルオロメチル)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
N−(1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−7−(トリフルオロメチル)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
(R,E)−N−(7−クロロ−1−(1−(4−(シクロプロピルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(シクロプロピルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R,E)−N−(1−(1−(4−(tert−ブチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−7−クロロ−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(1−(1−(4−(tert−ブチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−7−クロロ−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R,E)−N−(7−クロロ−1−(1−(4−(1−メチルシクロプロピルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(1−メチルシクロプロピルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R)−N−(1−(1−アクリロイルアゼパン−3−イル)−7−クロロ−6−(2−(ピロリジン−1−イル)エトキシ)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(1−(1−アクリロイルアゼパン−3−イル)−7−クロロ−6−(2−(ピロリジン−1−イル)エトキシ)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R,E)−N−(1−(1−ブタ−2−エノイルアゼパン−3−イル)−7−クロロ−6−(2−(ピロリジン−1−イル)エトキシ)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(1−(1−ブタ−2−エノイルアゼパン−3−イル)−7−クロロ−6−(2−(ピロリジン−1−イル)エトキシ)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R,E)−N−(1−(1−ブタ−2−エノイルアゼパン−3−イル)−7−クロロ−6−(2−(ピロリジン−1−イル)エトキシ)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
N−(1−(1−ブタ−2−エノイルアゼパン−3−イル)−7−クロロ−6−(2−(ピロリジン−1−イル)エトキシ)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
(S,E)−N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(S,E)−N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
(S,E)−N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−(ジメチルホスホリル)−6−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−(ジメチルホスホリル)−6−メチルイソニコチンアミド;
(R,E)−N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−(ジメチルホスホリル)−6−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−(ジメチルホスホリル)−6−メチルイソニコチンアミド;
(S,E)−N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−(ジメチルホスホリル)イソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−(ジメチルホスホリル)イソニコチンアミド;
(R,E)−N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−(ジメチルホスホリル)イソニコチンアミド;および
N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−(ジメチルホスホリル)イソニコチンアミド;
またはその薬学的に許容される塩が提供される。
特定の実施形態において、本明細書では、
(R,E)−N−(7−クロロ−1−(1−(4−(ピロリジン−1−イル)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ピロリジン−1−イル)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R,E)−N−(7−クロロ−1−(1−(4−(3−フルオロアゼチジン−1−イル)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(3−フルオロアゼチジン−1−イル)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(S)−N−(1−(1−アクリロイルピペリジン−3−イル)−5−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド;
N−(1−(1−アクリロイルピペリジン−3−イル)−5−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド;
(R,E)−N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R,E)−N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
(R,E)−N−(1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−7−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−7−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R,E)−N−(1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−7−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−2−(トリフルオロメチル)イソニコチンアミド;
N−(1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−7−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−2−(トリフルオロメチル)イソニコチンアミド;
(R)−N−(1−(1−アクリロイルアゼパン−3−イル)−7−クロロ−6−メトキシ−1H−ベンゾ[d]イミダゾール−2−イル)ピリダジン−4−カルボキサミド;
N−(1−(1−アクリロイルアゼパン−3−イル)−7−クロロ−6−メトキシ−1H−ベンゾ[d]イミダゾール−2−イル)ピリダジン−4−カルボキサミド;
N−(7−メチル−1−(1−(ビニルスルホニル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド;
N−(1−(1−アクリロイルアゼパン−3−イル)−7−(ピロリジン−1−イルメチル)−1H−ベンゾ[d]イミダゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド;
tert−ブチル 4−アクリロイル−6−(7−クロロ−2−(2−メチルイソニコチンアミド)−1H−ベンゾ[d]イミダゾール−1−イル)−1,4−ジアゼパン−1−カルボキシレート;
N−(1−(1−アクリロイル−1,4−ジアゼパン−6−イル)−7−クロロ−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(1−(1−アセチル−4−アクリロイル−1,4−ジアゼパン−6−イル)−7−クロロ−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R)−N−(1−(1−アクリロイルアゼパン−3−イル)−7−クロロ−6−(2−(ピロリジン−1−イル)エトキシ)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
N−(1−(1−アクリロイルアゼパン−3−イル)−7−クロロ−6−(2−(ピロリジン−1−イル)エトキシ)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
(R,E)−N−(7−クロロ−1−(1−(4−(ジシクロプロピルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ジシクロプロピルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R)−1−(1−アクリロイルピペリジン−3−イル)−2−(3−(トリフルオロメチル)ベンズアミド)−1H−ベンゾ[d]イミダゾール−5−カルボン酸;
1−(1−アクリロイルピペリジン−3−イル)−2−(3−(トリフルオロメチル)ベンズアミド)−1H−ベンゾ[d]イミダゾール−5−カルボン酸;
(R)−1−(1−アクリロイルピペリジン−3−イル)−2−(3−(トリフルオロメチル)ベンズアミド)−1H−ベンゾ[d]イミダゾール−5−カルボキサミド;
1−(1−アクリロイルピペリジン−3−イル)−2−(3−(トリフルオロメチル)ベンズアミド)−1H−ベンゾ[d]イミダゾール−5−カルボキサミド;および
1−(1−アクリロイルアゼパン−3−イル)−2−(3−(トリフルオロメチル)ベンズアミド)−1H−ベンゾ[d]イミダゾール−7−カルボン酸;
から選択される化合物、またはその薬学的に許容される塩形態、特に
酢酸塩、アスコルビン酸塩、アジピン酸塩、アスパラギン酸塩、安息香酸塩、ベシル酸塩、臭化物/臭化水素酸塩、重炭酸塩/炭酸塩、重硫酸塩/硫酸塩、カンファースルホン酸塩、カプリン酸塩、塩化物/塩酸塩、クロルテオフィリン酸塩(chlortheophyllonate)、クエン酸塩、エタンジスルホン酸塩、フマル酸塩、グルセプト酸塩、グルコン酸塩、グルクロン酸塩、グルタミン酸塩、グルタル酸塩、グリコール酸塩、馬尿酸塩、ヨウ化水素酸塩/ヨウ化物、イセチオン酸塩、乳酸塩、ラクトビオン酸塩、ラウリル硫酸塩、リンゴ酸塩、マレイン酸塩、マロン酸塩、マンデル酸塩、メシル酸塩、メチル硫酸塩、ムケート(mucate)、ナフトエ酸塩、ナプシル酸塩、ニコチン酸塩、硝酸塩、オクタデカン酸塩、オレイン酸塩、シュウ酸塩、パルミチン酸塩、パモン酸塩、リン酸塩/リン酸水素塩/リン酸二水素塩、ポリガラクツロン酸塩、プロピオン酸塩、セバシン酸塩、ステアリン酸塩、コハク酸塩、スルホサリチル酸塩、硫酸塩、酒石酸塩、トシル酸塩、トリフェニル酢酸塩(trifenatate)、トリフルオロ酢酸塩、またはキシナホ酸塩、なかでもメシル酸塩が提供される。
本明細書で使用される場合の「C1〜6アルキル」という用語は、1〜6個までの炭素原子を有する飽和または不飽和アルキルラジカル(このラジカルは、直鎖であるか、または1つもしくは複数の分岐で分岐されている、のいずれかである);例えば、ブチル、例えば、n−ブチル、sec−ブチル、イソブチル、tert−ブチル;プロピル、例えば、n−プロピルもしくはイソプロピル;エチルまたはメチルを意味する。特定の実施形態において、C1〜6アルキルは、飽和アルキルラジカルであり、特定される場合、置換されていなくても、または例えば、ハロ(すなわち、ハロアルキル、例えば、トリフルオロメチルなど)、ヒドロキシ(ヒドロキシアルキル、例えば、ヒドロキシメチル、ヒドロキシエチル、2−ヒドロキシ−2−プロピルなど)、もしくはシアノ(シアノアルキル、例えば、シアノメチル、シアノエチルなど)で置換されていてもよい。
本発明は、上皮成長因子受容体(EGFR)の活性を調節するための組成物および方法を提供する。1つの態様において、本発明は、EGFRの阻害剤として作用する化合物を提供する。本発明の様々な実施形態が本明細書で説明される。
環Bは、フェニル;N、O、およびSから選択される1〜3個のヘテロ原子を含む5〜6員ヘテロアリール;またはN、O、S、およびPから選択される1〜2個のヘテロ原子を含む5〜6員ヘテロシクリルであり、場合によりオキソで置換されており;
Eは、NHまたはCH2であり;
R1、R1’およびR2は、独立して、水素;ハロ;シアノ;C1〜6アルキル;C1〜6ハロアルキル;N、O、およびSから選択される1〜4個のヘテロ原子を含む5〜6員ヘテロアリール;フェニル、N、O、S、およびPから選択される1〜2個のヘテロ原子を含む5〜6員ヘテロシクリルであり、場合によりオキソ;−X1−C(O)OR3;−X1−O−C(O)R3;−X1−C(O)R3;−X1−C(O)NR4R5;−X1−C(O)NR4−X3−C(O)OR3;−X1−C(O)NR4−X3−S(O)0〜2R6;−X1−NR4R5;−X1NR4−X2−C(O)R3;−X1−NR4−X2−C(O)OR3;−X1−NR4−X2−C(O)NR4R5;−X1−NR4−X3−S(O)0〜2R6;−X1−NR4S(O)2R6;−X1−OS(O)2R6;−X1−OR3;−X1−O−X4−OR3;−X1−O−X4−S(O)0〜2R6;−X1−O−X4−NR4R5;−X1−S(O)0〜2R6;−X1−S(O)0〜2−X3−NR4R5;−X1−C(O)NR4−X3−P(O)R6aR6b;−X1−NR4−X1−P(O)R6aR6b;−X1−O−X1−P(O)R6aR6b;−X1−P(O)R6a−X1−NR4R5;−X1−P(O)R6aR6bまたは−X1−S(O)2NR4R5で置換されており;ここで、R1またはR2におけるそれぞれのフェニル、ヘテロアリール、またはヘテロシクリルは、置換されていないか、またはOH、ハロ、C1〜6アルキル、C1〜6ハロアルキル、およびC1〜6ハロアルコキシから選択される1〜3個の基で置換されており;
R3、R4、およびR5は、独立して、水素、C1〜6アルキル、もしくはC1〜6ハロアルキルであるか;またはこの際、R4およびR5は、NR4R5におけるNと一緒になって、N、O、S、およびPから選択される1〜2個のヘテロ原子を含む4〜7員環を形成してもよく、および場合により1〜4個のR7で置換されており;
R6は、C1〜6アルキルまたはC1〜6ハロアルキルであり;
R6aおよびR6bは、独立して、ヒドロキシ、C1〜6アルキル、C1〜6ハロアルキル、C1〜6アルコキシ、C1〜6ハロアルコキシ、6〜10員単環式もしくは二環式アリール;N、O、およびSから選択される1〜4個のヘテロ原子を含む5〜10員ヘテロアリール;またはN、O、およびSから選択される1〜4個のヘテロ原子を含む4〜12員単環式もしくは二環式ヘテロシクリルであり、場合によりオキソで置換されており;
Zは、
R9およびR10は、独立して、水素、ハロ、C1〜6アルキル、C1〜6ハロアルキル、OH、シアノ、C1〜6アルキル、C1〜6ハロアルキルであり;
R11a、R11b、R11c、R11d、R11e、R11f、R11g、R11h、R11i、R11j、R11k、およびR11l、は、独立して、水素、C1〜6アルキル、またはC1〜6ハロアルキルであり;
R12およびR13は、独立して、水素、ハロ、シアノ、C1〜6アルキル、またはC1〜6ハロアルキルであり;
R14およびR15は、独立して、水素、C1〜6アルキル、−L1−R19、−(CRaRb)2〜3−Rc、もしくは−L2−Rdであるか;またはR14およびR15は、NR14R15におけるNと一緒になって、N、O、S、およびPから選択される1〜2個のヘテロ原子を含む4〜7員環を形成してもよく、および場合により1〜4個のR18基で置換されおり;
R16およびR17は、独立して、水素もしくはC1〜6アルキルであるか;またはR16およびR17は、それらが結合している炭素と一緒になって、C3〜6シクロアルキルを形成してもよく;
X1およびX2は、独立して、結合またはC1〜6アルキルであり;
X3は、C1〜6アルキルであり;
X4は、C2〜6アルキルであり;
R19は、水素、C1〜6アルキル、COR20、COOR20、CONR20R21、またはS(O)2R20であり;
R20は、C1〜6アルキル、C1〜6ハロアルキル、またはシクロアルキルであり;
R21は、水素もしくはC1〜6アルキルであるか;またはR20およびR21は、NR20R21におけるNと一緒になって、N、O、S、Pから選択される1〜2個のヘテロ原子を含む4〜7員環を形成してもよく、および場合により1〜4個のR22基で置換されており;
R7、R18およびR22は、独立して、オキソ、ハロ、ヒドロキシ、C1〜6アルキル、C1〜6ハロアルキル、C1〜6アルコキシ、またはC1〜6ハロアルコキシであり;
R23は、独立して、C3〜7シクロアルキル、またはN、O、およびSから選択される1〜3個のヘテロ原子を含む4〜10員ヘテロシクリルであり、場合によりオキソで置換されており;ならびにR23は、置換されていないか、またはC1〜6アルキル、C1〜6ハロアルキル、−L3−Rc、もしくは−L4−Rfで置換されており;
RcおよびReは、独立して、ハロ、シアノ、ヒドロキシ、−OR24、−NRR25、−NR−CO2R24、−NR−SO2−R26、−NR−COR26、−NR−C(O)−NRR25、−OC(O)−NRR25、またはハロ、C1〜6アルコキシ、ヒドロキシ、もしくはシアノで置換されたC1〜6アルキルであり;
RdおよびRfは、独立して、−SO2NRR25、−CONRR25、−C(O)OR24、−SO2R26、またはC(O)R26であり;
R24は、C1〜6アルキル、C1〜6ハロアルキル、−L2−R23a、または−(CRaRb)2〜3−N(RaRb)2であり;
R25は、水素、C1〜6アルキル、C1〜6ハロアルキル、−L2−R23b、または−(CR2)2〜3−N(RaRb)2であり;
R26は、C1〜6アルキル、C1〜6ハロアルキル、−L2−R23c、または−(CRaRb)1〜3−N(RaRb)2であり;
R23a、R23b、およびR23cは、R23から独立して選択され;
R、Ra、およびRbは、独立して、水素またはC1〜6アルキルであり;
L1、L2、L3、およびL4は、独立して、結合または−(CRaRb)1〜3であり;および
nおよびmは、独立して、1〜3であり;
pおよびqは、1〜4である)、
またはその薬学的に許容される塩が提供される。
R1およびR1’は、独立して、水素;ハロ;シアノ;C1〜6アルキル;C1〜6ハロアルキル;−X1−NR4R5;−X1−OR3;−X1−S(O)0〜2R6;−X1−P(O)R6aR6b;置換されていないか、もしくはC1〜6アルキルで置換されているフェニル;またはN、O、およびSから選択される1〜4個のヘテロ原子を含む5〜6員ヘテロアリールであり;
R2は、水素、ハロ;シアノ;C1〜6アルキル;C1〜6ハロアルキル;−X1−C(O)OR3;−X1−C(O)R3;−X1−C(O)NR4R5;−X1−C(O)NR4−X3−C(O)OR3;−X1−C(O)NR4−X3−S(O)0〜2R6;−X1−NR4R5;−X1NR4−X2−C(O)R3;−X1−NR4−X3−S(O)0〜2R6;−X1−OR3;−X1−O−X4−OR3;−X1−S(O)0〜2R6;−X1−O−X4−NR4R5;またはN、O、およびSから選択される1〜4個のヘテロ原子を含む5〜6員ヘテロアリールから選択され、および置換されていないか、またはC1〜6アルキルで置換されており;
R3、R4、およびR5は、独立して、水素、C1〜6アルキル、もしくはC1〜6ハロアルキルであるか;またはこの際、R4およびR5は、NR4R5におけるNと一緒になって、N、O、S、およびPから選択される1〜2個のヘテロ原子を含む4〜7員環を形成してもよく、および場合により1〜4個のR7基で置換されており;
R6、R6a、およびR6bは、C1〜6アルキルであり;
Zは、
R9、R10、R11a、R11b、R11c、R11d、R11e、R11f、R11g、R11h、R11i、R11j、R11k、およびR11lは、水素であり;
R12、R13、R16、およびR17は、独立して、水素またはC1〜6アルキルであり;
R14およびR15は、独立して、水素;C1〜6アルキル;−C(O)O−(C1〜6アルキル);置換されていないか、もしくはC1〜6アルキルで置換されているC3〜7シクロアルキルであるか;またはR14およびR15は、NR14R15におけるNと一緒になって、N、O、S、およびPから選択される1〜2個のヘテロ原子を含む4〜7員環を形成してもよく、および場合により1〜4個のR18基で置換されており;
R7およびR18は、独立して、オキソ、ハロ、ヒドロキシ、C1〜6アルキル、またはC1〜6アルコキシであり;
R19は、水素、COR20、またはCOOR20であり;
R20は、C1〜6アルキルであり;
pは、1であり;
mおよびqは、独立して、1〜2であり;
環B、X1、X2、X3、およびX4、ならびにnは、本明細書で記載された実施形態のいずれかで定義されたとおりである)
が提供される。
式中、Yは、OまたはNR19であり;
R1、R1’、R2、R8、R19、A、B、Y、m、およびnは、本明細書で記載された実施形態のいずれかで定義されたとおりである。
が提供される。特定の実施形態において、W1、W2、W3、およびW4の少なくとも2個はCR1であり、その他はNである。
典型的には、式(1)の化合物は、以下に例証される以下のスキームのいずれか1つに従って調製することができ、式中、それぞれのN−R8部分が、N−Hで置き換えられている以外は、A、B、R1、R1’、R2、R8、E、n、およびmは、本発明の概要で定義されたとおりであり、Z*は、Zと同じである。特定の実施形態において、EはNHである。以下のスキームのいずれにおいても、定義されたとおりのラジカルは、その任意の保護基を包含することが理解される。当業者はまた、これらの方法が代表的なものであり、本発明の化合物を調製するための他の方法を制限しないことも理解する。
本発明は、上皮成長因子受容体(EGFR)の活性を調節することができる化合物および組成物を提供する。
1つの態様において、本発明は、本発明の化合物、および薬学的に許容される担体、希釈剤、または添加剤を含む、医薬組成物を提供する。医薬組成物は、経口、静脈内、皮内、筋内、腹腔内、皮下、鼻腔内、硬膜外、舌下、脳内、膣内、脳室内、髄腔内、硬膜外、経皮、直腸、吸入による、または局所投与のために製剤化され得る。
中間体の合成
中間体1
(R)−tert−ブチル3−アミノアゼパン−1−カルボキシレート
中間体2
(S,E)−4−(3−ヒドロキシピロリジン−1−イル)ブタ−2−エン酸塩酸塩
中間体16
(S)−N−(5−メチル−1−(ピペリジン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド
中間体17
tert−ブチル3−(2−アミノ−1H−イミダゾ[4,5−c]ピリジン−1−イル)ピペリジン−1−カルボキシレート
中間体18
N−(1−(ピペリジン−3−イル)−1H−イミダゾ[4,5−c]ピリジン−2−イル)−3−(トリフルオロメチル)ベンズアミド
中間体19
tert−ブチル3−(2−アミノ−3H−イミダゾ[4,5−c]ピリジン−3−イル)ピペリジン−1−カルボキシレート
中間体20
N−(3−(ピペリジン−3−イル)−3H−イミダゾ[4,5−c]ピリジン−2−イル)−3−(トリフルオロメチル)ベンズアミド
中間体21
(R)−メチル2−アミノ−1−(1−(tert−ブトキシカルボニル)ピペリジン−3−イル)−1H−ベンゾ[d]イミダゾール−5−カルボキシレート
中間体22
(R)−tert−ブチル3−(5−(ヒドロキシメチル)−2−(3−(トリフルオロメチル)ベンズアミド)−1H−ベンゾ[d]イミダゾール−1−イル)ピペリジン−1−カルボキシレート
中間体23
(R)−N−(5−(モルホリノメチル)−1−(ピペリジン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド
中間体24
tert−ブチル3−(2−アミノ−5−メチル−1H−ベンゾ[d]イミダゾール−1−イル)アゼパン−1−カルボキシレート
中間体25
N−(1−(アゼパン−3−イル)−5−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド
中間体26
(R)−tert−ブチル3−(2−アミノ−7−クロロ−1H−ベンゾ[d]イミダゾール−1−イル)アゼパン−1−カルボキシレート
中間体27
(R)−N−(1−(アゼパン−3−イル)−7−クロロ−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド塩酸塩
中間体28
(R)−tert−ブチル3−(2−アミノ−7−クロロ−6−メトキシ−1H−ベンゾ[d]イミダゾール−1−イル)アゼパン−1−カルボキシレート
中間体29
(R)−N−(1−(アゼパン−3−イル)−7−クロロ−6−メトキシ−1H−ベンゾ[d]イミダゾール−2−イル)ピリダジン−4−カルボキサミド塩酸塩
中間体30
(R)−N−(1−(アゼパン−3−イル)−7−クロロ−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド塩酸塩
中間体31
(R)−tert−ブチル3−(2−アミノ−7−メチル−1H−ベンゾ[d]イミダゾール−1−イル)アゼパン−1−カルボキシレート
中間体32
(R)−N−(1−(アゼパン−3−イル)−7−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド塩酸塩
中間体33および34
(R)−および(S)−N−(7−メチル−1−(1,4−オキサゼパン−6−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド
中間体35
(R)−tert−ブチル3−(2−アミノ−5−(ヒドロキシメチル)−7−メチル−1H−ベンゾ[d]イミダゾール−1−イル)アゼパン−1−カルボキシレート
中間体36
(R)−N−(1−(アゼパン−3−イル)−7−メチル−5−(ピロリジン−1−イルメチル)−1H−ベンゾ[d]イミダゾール−2−イル)ベンズアミド塩酸塩
中間体37
N−(1−(アゼパン−3−イル)−7−(ピロリジン−1−イルメチル)−1H−ベンゾ[d]イミダゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド塩酸塩
中間体38
(R)−N−(1−(アゼパン−3−イル)−7−メチル−5−(ピロリジン−1−イルメチル)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド塩酸塩
中間体39
N−(1−((R)−アゼパン−3−イル)−7−((3−ヒドロキシピロリジン−1−イル)メチル)−1H−ベンゾ[d]イミダゾール−2−イル)ベンズアミド
中間体40
N−(1−(アゼパン−3−イル)−7−(1,1−ジオキシドチオモルホリン−4−カルボニル)−1H−ベンゾ[d]イミダゾール−2−イル)ベンズアミド塩酸塩
中間体41
2−アミノ−1−(1−(tert−ブトキシカルボニル)アゼパン−3−イル)−7−シアノ−1H−ベンゾ[d]イミダゾール−5−カルボキシレート
中間体42
N−(1−(アゼパン−3−イル)−7−シアノ−5−(ヒドロキシメチル)−1H−ベンゾ[d]イミダゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド塩酸塩
中間体43
メチル1−(ピペリジン−3−イル)−2−(3−(トリフルオロメチル)ベンズアミド)−6,7−ジヒドロ−1H−イミダゾ[4,5−c]ピリジン−5(4H)−カルボキシレート
中間体44
(R)−N−(1−(アゼパン−3−イル)−7−クロロ−1H−ベンゾ[d]イミダゾール−2−イル)ピリダジン−4−カルボキサミド塩酸塩
中間体45
(R)−N−(1−(アゼパン−3−イル)−7−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−2−(トリフルオロメチル)イソニコチンアミド塩酸塩
中間体46
(R)−N−(1−(アゼパン−3−イル)−7−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド塩酸塩
中間体47
1−メチル−1,2,5,6−テトラヒドロピリジン−3−カルボン酸塩酸塩
中間体48
1−メチル−1,2,3,6−テトラヒドロピリジン−4−カルボン酸塩酸塩
中間体49
(E)−4−(ジメチルアミノ)−4−メチルペンタ−2−エン酸塩酸塩
中間体50
2−(ジメチルホスホリル)−6−メチルイソニコチン酸塩酸塩
中間体51
2−(ジメチルホスホリル)イソニコチン酸塩酸塩
中間体52
(R)−N−(1−(アゼパン−3−イル)−7−クロロ−1H−ベンゾ[d]イミダゾール−2−イル)−2−(ジメチルホスホリル)−6−メチルイソニコチンアミド二塩酸塩
中間体53
(R)−N−(1−(アゼパン−3−イル)−7−クロロ−1H−ベンゾ[d]イミダゾール−2−イル)−2−(ジメチルホスホリル)イソニコチンアミド二塩酸塩
中間体54
1−ベンジル4−tert−ブチル6−アミノ−1,4−ジアゼパン−1,4−ジカルボキシレート
中間体55
1−ベンジル4−tert−ブチル6−(2−アミノ−7−クロロ−1H−ベンゾ[d]イミダゾール−1−イル)−1,4−ジアゼパン−1,4−ジカルボキシレート
中間体56
tert−ブチル6−(7−クロロ−2−(2−メチルイソニコチンアミド)−1H−ベンゾ[d]イミダゾール−1−イル)−1,4−ジアゼパン−1−カルボキシレート
中間体57
(R)−tert−ブチル3−(2−アミノ−7−クロロ−6−(2−(ピロリジン−1−イル)エトキシ)−1H−ベンゾ[d]イミダゾール−1−イル)アゼパン−1−カルボキシレート
中間体58
(R)−N−(1−(アゼパン−3−イル)−7−クロロ−6−(2−(ピロリジン−1−イル)エトキシ)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド
EGFR生化学アッセイ
IC50決定。EGFR生化学アッセイはすべて、HTRF法によって行った。EGFR(L858R/T790M)酵素は、Carnaから購入した(GST−a.a.669−1210)。基質ペプチドビトチン−TK−ペプチドは、Cis−Bioから購入した。反応混合物は、最終容量10μLにおいて反応緩衝液(50mM HEPES pH7.1、10mM MgCl2、0.01%BSA、1mM TCEP、および0.1mM Na3VO4)中1μMペプチド基質、10μM ATP、および0.036nM EGFR(L858R/T790M)を含んだ。反応はすべて、白色ProxiPlate(商標)384−ウェルPlusプレート(PerkinElmer)中室温で行い、60分において5μLの0.2M EDTAによってクエンチした。5μlの検出試薬(ウェル当たり2.5ngのPT66Kおよび0.05μgのSAXL)を添加し、プレートを室温で1時間インキュベートし、次いで、EnVisionリーダーで読み取った。化合物をアッセイ混合物中に希釈し(最終DMSO0.5%)、IC50値は、上記のとおりのアッセイ条件下で2連で12点(50〜0.000282μM)阻害曲線によって決定した。非プレインキュベーション条件の場合、ATPおよびペプチドを含むアッセイ溶液に化合物を添加し、反応を酵素の添加によって開始した。プレインキュベーション条件の場合、酵素およびペプチドを含むアッセイ溶液に化合物を添加し、室温で所望の期間プレインキュベートし、次いで、反応をATPの添加によって開始した。
組織培養。ヒトEGFRを発現するNIH/3T3細胞株(WT、L858R、およびL858R/T790M)(DFCIにおけるMatthew Meyerson’s Labから得た)を、100μg/mlのPenicillin/Streptomycin(Hyclone#SV30010)および2μg/mlのPuromycinで補給した10%FBS/DMEM中で維持した。Puromycinを含まない5%FBS/DMES Pen/Strep中再懸濁させた、0.05%トリプシン/EDTA(Hyclone#SH30236.01)によって細胞を採取し、透明底を有する384−ウェル黒色プレート(Greiner#789068G)において50μlの培地中ウェル当たり9,000個細胞でプレーティングした。細胞を、37℃、5%CO2加湿組織培養インキュベータ中で一晩インキュベートさせた。12点試験化合物曲線は、384ウェル化合物プレート(Greiner#789201L)中10μM原液をDMSO中1:3に連続希釈することによって調製した。50nlのPin Head装置(perkin Elmer)を用いることによって、細胞が入っているプレートに連続希釈化合物を移し、細胞をインキュベータ中に3時間戻した。EGFR WT発現細胞だけを、50ng/mlEGF(Preprotech#AF−100−15)によって、溶解前に5分間誘導した。培地を取り除き、プロテアーゼおよびホスファターゼ阻害剤(1%Triton X−100、20mM Tris、pH7.5、1mM EDTA、1mM EGTA、150mM NaCl、1×完全カクテル阻害剤(Roche#11697498001)、1×Phosphatase阻害剤カクテルSetIIおよびSetIII(Sigma#P5726および#P0044)を含む、25μlの溶解緩衝液中で、細胞を溶解させた。プレートをホイルトップとともに最高速度で、4℃で5分間振とうした。各ウェルからの5μlのアリコートをProxiPlate(商標)384−ウェルPlusプレート(PE#6008289)に移した。プレートをホイルトップで密封し、−80℃で凍結させ、必要な場合に解凍した。
組織培養。細胞を、100μg/mlのPenicillin/Streptomycin(Hyclone#SH30236.01)で補給した10%FBS/RPMI中で維持した。0.25%トリプシン/EDTA(Hyclone#SH30042.1)によって細胞を採取し、5%FBS/DMEM Pen/Strep中に再懸濁させ、透明底を有する384ウェル黒色プレート(Greiner#789068G)において50μlの培地中ウェル当たり10,000個細胞でプレーティングした。細胞を、37℃、5%CO2加湿組織培養インキュベータ中で一晩インキュベートした。12点試験化合物曲線は、384ウェル化合物プレート(Greiner#789201L)中10μM原液をDMSO中1:3に連続希釈することによって調製した。50nlのPin Head装置(Perkin Elmer)を用いることによって、細胞が入っているプレートに連続希釈化合物を移し、細胞をインキュベータ中に戻して3時間おいた。
組織培養。ヒト新生児上皮角化細胞(Invitrogen#C−001−5C)を、成長因子(Invitrogen#S−001−5)で補給したEpiLife培地(Invitrogen#M−EPI−500−CA)中で維持した。0.05%トリプシン/EDTA(Hyclone#SH30236.01)によって細胞を採取し、5%FBS/EpiLife培地でクエンチした。50μlのEpiLife培地(成長因子なし)中7500個細胞の密度を、384ウェル黒ベタ組織培養プレート(Greiner#789168G)の各ウェルにプレーティングし、加湿組織培養インキュベータ中37℃、5%CO2で一晩インキュベートした。12点試験化合物曲線は、384ウェル化合物プレート(Greiner#789201L)中10μM原液をDMSO中1:3に連続希釈することによって調製した。50nlのPin Head装置(Perkin Elmer)を用いることによって、細胞が入っているプレートに連続希釈化合物を移し、細胞をインキュベータ中に戻して3時間おいた。EGFR自己リン酸化の刺激を、組織培養インキュベータにおいて10ng/mlのEGF(Preprotech#AF−100−15)によって5分間行った。
組織培養。HaCaT細胞を、100μg/mlのPenicillin/Streptomycin(Hyclone#SH30236.01)で補給した10%FBS/RPMI中で維持した。0.25%トリプシン/EDTA(Hyclone#SH30042.1)によって、細胞を採取し、5%FBS/DMEM Pen/Strep中に再懸濁させ、透明底を有する384ウェル黒色プレート(Greiner#789068G)において50μlの培地中ウェル当たり10,000個細胞でプレーティングした。細胞を、37℃、5%CO2加湿組織培養インキュベータ中で一晩インキュベートした。12点試験化合物曲線は、384ウェル化合物プレート(Greiner#789201L)中10μM原液をDMSO中1:3に連続希釈することによって調製した。50nlのPin Head装置(Perkin Elmer)を用いることによって、細胞が入っているプレートに連続希釈化合物を移し、細胞をインキュベータ中に戻して3時間おいた。EGFR自己リン酸化の刺激を、組織培養インキュベータにおいて、2%FBS/PBS中で調製した10ng/mlのEGF(Preproteck#AF−100−15)によって5分間行った。
表1は、上記EGFR生化学アッセイから得たIC50測定を示す。表1において、カラムAおよびカラムBは、それぞれ、90分間プレインキュベーション有無による、EGFR(L858R/T790M)から得たIC50測定を表す。本発明の代表的な化合物は、1nM未満〜10μMの範囲、より詳細には1nM未満〜1μMの範囲の阻害IC50を示す。
Claims (24)
- 式(1)を有する化合物もしくはその互変異性体:
環Bは、フェニル;N、O、およびSから選択される1〜3個のヘテロ原子を含む5〜6員ヘテロアリール;またはN、O、およびSから選択される1〜2個のヘテロ原子を含む5〜6員ヘテロシクリルであり、場合によりオキソで置換されており;
Eは、NHまたはCH2であり;
R1、R1’およびR2は、独立して、水素;ハロ;シアノ;C1〜6アルキル;C1〜6ハロアルキル;N、O、およびSから選択される1〜4個のヘテロ原子を含む5〜6員ヘテロアリール;フェニル、N、O、SおよびPから選択される1〜2個のヘテロ原子を含む5〜6員ヘテロシクリルであり、場合によりオキソ;−X1−C(O)OR3;−X1−O−C(O)R3;−X1−C(O)R3;−X1−C(O)NR4R5;−X1−C(O)NR4−X3−C(O)OR3;−X1−C(O)NR4−X3−S(O)0〜2R6;−X1−NR4R5;−X1NR4−X2−C(O)R3;−X1−NR4−X2−C(O)OR3;−X1−NR4−X2−C(O)NR4R5;−X1−NR4−X3−S(O)0〜2R6;−X1−NR4S(O)2R6;−X1−OS(O)2R6;−X1−OR3;−X1−O−X4−OR3;−X1−O−X4−S(O)0〜2R6;−X1−O−X4−NR4R5;−X1−S(O)0〜2R6;−X1−S(O)0〜2−X3−NR4R5;−X1−C(O)NR4−X3−P(O)R6aR6b;−X1−NR4−X1−P(O)R6aR6b;−X1−O−X1−P(O)R6aR6b;−X1−P(O)R6a−X1−NR4R5;−X1−P(O)R6aR6bまたは−X1−S(O)2NR4R5で置換されており;ここで、R1またはR2におけるそれぞれのフェニル、ヘテロアリール、またはヘテロシクリルは、置換されていないか、またはOH、ハロ、C1〜6アルキル、C1〜6ハロアルキル、およびC1〜6ハロアルコキシから選択される1〜3個の基で置換されており;
R3、R4、およびR5は、独立して、水素、C1〜6アルキルもしくはC1〜6ハロアルキルであるか;またはこの際、R4およびR5は、NR4R5におけるNと一緒になって、N、O、S、およびPから選択される1〜2個のヘテロ原子を含む4〜7員環を形成してもよく、および場合により1〜4個のR7で置換されており;
R6は、C1〜6アルキルまたはC1〜6ハロアルキルであり;
R6aおよびR6bは、独立して、ヒドロキシ、C1〜6アルキル、C1〜6ハロアルキル、C1〜6アルコキシ、C1〜6ハロアルコキシ、6〜10員単環式もしくは二環式アリール;N、O、およびSから選択される1〜4個のヘテロ原子を含む5〜10員ヘテロアリール;またはN、O、およびSから選択される1〜4個のヘテロ原子を含む4〜12員単環式もしくは二環式ヘテロシクリルであり、場合によりオキソで置換されており:
Zは、
R8は、
R9およびR10は、独立して、水素、ハロ、C1〜6アルキル、C1〜6ハロアルキル、OH、シアノ、C1〜6アルコキシ、C1〜6ハロアルコキシであり;
R11a、R11b、R11c、R11d、R11e、R11f、R11g、R11h、R11i、R11j、R11k、およびR11lは、独立して、水素、C1〜6アルキル、またはC1〜6ハロアルキルであり;
R12およびR13、独立して、水素、ハロ、シアノ、C1〜6アルキル、またはC1〜6ハロアルキルであり;
R14およびR15は、独立して、水素、C1〜6アルキル、−L1−R23、−(CRaRb)2〜3−Rc、もしくは−L2−Rdであるか;またはR14およびR15は、NR14R15におけるNと一緒になって、N、O、S、およびPから選択される1〜2個のヘテロ原子を含む4〜7員環を形成してもよく、および場合により1〜4個のR18基で置換されており;
R16およびR17は、独立して、水素もしくはC1〜6アルキルであるか;またはR16およびR17は、それらが結合している炭素と一緒になって、C3〜6シクロアルキルを形成してもよく;
X1およびX2は、独立して、結合またはC1〜6アルキルであり;
X3は、C1〜6アルキルであり;
X4は、C2〜6アルキルであり;
R19は、水素、C1〜6アルキル、COR20、COOR20、CONR20R21、またはS(O)2R20であり;
R20は、C1〜6アルキル、C1〜6ハロアルキル、またはシクロアルキルであり;
R21は、水素もしくはC1〜6アルキルであるか;またはR20およびR21は、NR20R21におけるNと一緒になって、N、O、S、Pから選択される1〜2個のヘテロ原子を含む4〜7員環を形成してもよく、および場合により1〜4個のR22基で置換されており;
R7、R18、およびR22は、独立して、オキソ、ハロ、ヒドロキシ、C1〜6アルキル、C1〜6ハロアルキル、C1〜6アルコキシ、またはC1〜6ハロアルコキシであり;
R23は、独立して、C3〜7シクロアルキル、またはN、O、およびSから選択される1〜3個のヘテロ原子を含む4〜10員ヘテロシクリルであり、場合によりオキソで置換されており;ならびにR23は、置換されていないか、またはC1〜6アルキル、C1〜6ハロアルキル、−L3−Re、もしくは−L4−Rfで置換されており;
RcおよびReは、独立して、ハロ、シアノ、ヒドロキシ、−OR24、−NRR25、−NR−CO2R24、−NR−SO2−R26、−NR−COR26、−NR−C(O)−NRR25、−OC(O)−NRR25、またはハロ、C1〜6アルコキシ、ヒドロキシ、もしくはシアノで置換されたC1〜6アルキルであり、
RdおよびRfは、独立して、−SO2NRR25、−CONRR25、−C(O)OR24、−SO2R26、またはC(O)R26であり;
R24は、C1〜6アルキル、C1〜6ハロアルキル、−L2−R23a、または−(CRaRb)2〜3−N(RaRb)2であり;
R25は、水素、C1〜6アルキル、C1〜6ハロアルキル、−L2−R23b、または−(CR2)2〜3−N(RaRb)2であり;
R26は、C1〜6アルキル、C1〜6ハロアルキル、−L2−R23c、または−(CRaRb)1〜3−N(RaRb)2であり;
R23a、R23b、およびR23cは、R23から独立して選択され;
R、Ra、およびRbは、独立して、水素またはC1〜6アルキルであり;
L1、L2、L3、およびL4は、独立して、結合または−(CRaRb)1〜3であり;
nおよびmは、独立して、1〜3であり、pおよびqは、1〜4である)
またはその薬学的に許容される塩。 - 前記化合物が、式(2):
R1およびR1’は、独立して、水素;ハロ;シアノ;C1〜6アルキル;C1〜6ハロアルキル;−X1−NR4R5;−X1−OR3;−X1−S(O)0〜2R6;−X1−P(O)R6aR6b;置換されていないか、もしくはC1〜6アルキルで置換されているフェニル;またはN、O、およびSから選択される1〜4個のヘテロ原子を含む5〜6員ヘテロアリールであり;
R2は、水素、ハロ;シアノ;C1〜6アルキル;C1〜6ハロアルキル;−X1−C(O)OR3;−X1−C(O)R3;−X1−C(O)NR4R5;−X1−C(O)NR4−X3−C(O)OR3;−X1−C(O)NR4−X3−S(O)0〜2R6;−X1−NR4R5;−X1NR4−X2−C(O)R3;−X1−NR4−X3−S(O)0〜2R6;−X1−OR3;−X1−O−X4−OR3;−X1−S(O)0〜2R6;−X1−O−X4−NR4R5;またはN、O、およびSから選択される1〜4個のヘテロ原子を含む5〜6員ヘテロアリールから選択され、および置換されていないか、またはC1〜6アルキルで置換されており;
R3、R4、およびR5は、独立して、水素、C1〜6アルキル、もしくはC1〜6ハロアルキルであるか;またはこの際、R4およびR5は、NR4R5におけるNと一緒になって、N、O、S、およびPから選択される1〜2個のヘテロ原子を含む4〜7員環を形成してもよく、および場合により1〜4個のR7基で置換されており;
R6、R6a、およびR6bは、C1〜6アルキルであり;
Zは、
Yは、OまたはNR19であり;
R8は、
R9、R10、R11a、R11b、R11c、R11d、R11e、R11f、R11g、R11h、R11i、R11j、R11k、およびR11lは、水素であり;
R12、R13、R16、およびR17は、独立して、水素またはC1〜6アルキルであり;
R14およびR15は、独立して、水素;C1〜6アルキル;−C(O)O−(C1〜6アルキル);置換されていないか、もしくはC1〜6アルキルで置換されているC3〜7シクロアルキルであるか;またはR14およびR15は、NR14R15におけるNと一緒になって、N、O、S、およびPから選択される1〜2個のヘテロ原子を含む4〜7員環を形成してもよく、および場合により1〜4個のR18基で置換されており;
R7およびR18は、独立して、オキソ、ハロ、ヒドロキシ、C1〜6アルキル、またはC1〜6アルコキシであり;
R19は、水素、COR20、またはCOOR20であり;
R20は、C1〜6アルキルであり;
pは、1であり;
mおよびqは、独立して、1〜2であり、
環B、X1、X2、X3、およびX4、ならびにnは、請求項1で定義されたとおりである)
のものである、請求項1に記載の化合物またはその薬学的に許容される塩。 - 環Bが、それが結合している原子と一緒になって、縮合フェニル、ピリジル、またはピペリジルを形成し、それらのそれぞれは、置換されていないか、または(R2)mで置換されており;
mおよびR2が、請求項1または2で定義されたとおりである、請求項1〜3のいずれか一項に記載の化合物またはその薬学的に許容される塩。 - 環Aが、フェニル、ピリジル、ピリミジニル、ピリダジニル、ピラジニル、ピリジン−2−オニル、オキサゾリル、フラニル、チアゾリル、イミダゾール[2,1−b]チアゾリル、イミダゾ[1,2−a]ピリジニル、イミダゾ[1,5−a]ピリジニル、またはナフチルであり、それらのそれぞれは、置換されていないか、または(R1)nおよびR1’で置換されており;
R1、R1’、およびnが、請求項1または2で定義されたとおりである、請求項1〜4のいずれか一項に記載の化合物またはその薬学的に許容される塩。 - R1およびR1’が、独立して、水素;ハロ;シアノ;C1〜6アルキル;C1〜6ハロアルキル;−X1−NR4R5;−X1−OR3;−X1−S(O)0〜2R6;置換されていないか、もしくはC1〜6アルキルで置換されているフェニル;テトラゾリル、またはピロリルであり;
各X1が、結合またはCH2であり;
R3、R4、およびR5が、独立して、水素、C1〜6アルキル、もしくはC1〜6ハロアルキルであるか;またはこの際、R4およびR5が、NR4R5におけるNと一緒になって、ピペリジニルを形成し、
R6が、請求項1または2で定義されたとおりである、請求項1〜7のいずれか一項に記載の化合物またはその薬学的に許容される塩。 - R1が、水素、ハロ、シアノ、C1〜6アルキル、C1〜6ハロアルキル、テトラゾリル、ピロリル、−X1−NR4R5、−X1−OR3、−X1−(S)0〜2R6、または置換されていないか、もしくはC1〜6アルキルで置換されているフェニルであり;
R1’が、水素、ハロ、またはC1〜6アルキルであり;
R3、R4、およびR5が、独立して、水素、C1〜6アルキル、もしくはC1〜6ハロアルキルであるか;またはこの際、R4およびR5が、NR4R5におけるNと一緒になって、ピペリジニルを形成し;
X1が、結合またはCH2であり;
R6が、請求項1または2で定義されたとおりである、請求項1〜7のいずれか一項に記載の化合物またはその薬学的に許容される塩。 - R1およびR1’が、独立して、水素;メチル;t−ブチル;トリフルオロメチル;メトキシ;エトキシ;トリフルオロメトキシ;ジフルオロメトキシ;フルオロ;クロロ;シアノ;ジメチルアミノ;メチルスルホニル;ジメチルホスホリル;テトラゾリル;ピロリル;置換されていないか、もしくはメチルで置換されているフェニル;またはピペリジニルである、請求項1〜7のいずれか一項に記載の化合物またはその薬学的に許容される塩。
- R2が、水素;クロロ;メチル;トリフルオロメチル;メトキシ;イソプロポキシ;シアノ;ヒドロキシメチル;メトキシメチル;エトキシメチル;メチルスルホニル;メチルカルボニル;カルボキシ;メトキシカルボニル;カルバモイル;ジメチルアミノメチル;置換されていないか、または1〜2個のヒドロキシ、ハロ、もしくはメトキシで置換されているピロリジニルメチル;モルホリノメチル;置換されていないか、または1〜2個のハロもしくはメトキシで置換されているアゼジチニルメチル;ピペリジニルメチル;((4−メチル−3−オキソ−ピペラジン−1−イル)メチル);((4−アセチルピペラジン−1−イル)メチル);(1,1−ジオキシドチオモルホリン−4−カルボニル);置換されていないか、または1〜2個のヒドロキシで置換されているピロリジニルカルボニル;ピロリジニルエトキシ;(1,1−ジオキシドチオモルホリノ)メチル;あるいは置換されていないか、またはC1〜6アルキルで置換されている1,2,4−オキサジアゾリルであり;
代替として、R2が、−CH2−N(CH3)−C(O)−CH3;−CH2−O−(CH2)2−OCH3;−CH2−N(CH3)−(CH2)2−SO2(CH3);−C(O)NH−(CH2)1〜2−C(O)−OCH3;−C(O)NH−(CH2)1〜2−C(O)OH;または−C(O)NH−(CH2)2−SO2(CH3)である、請求項1〜10のいずれか一項に記載の化合物またはその薬学的に許容される塩。 - 前記化合物が、
(R,E)−N−(7−クロロ−1−(1−(4−(ピロリジン−1−イル)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ピロリジン−1−イル)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R,E)−N−(7−クロロ−1−(1−(4−(3−フルオロアゼチジン−1−イル)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(3−フルオロアゼチジン−1−イル)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(S)−N−(1−(1−アクリロイルピペリジン−3−イル)−5−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド;
N−(1−(1−アクリロイルピペリジン−3−イル)−5−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド;
(R,E)−N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R,E)−N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
(R,E)−N−(1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−7−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−7−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R,E)−N−(1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−7−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−2−(トリフルオロメチル)イソニコチンアミド;
N−(1−(1−(4−(ジメチルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−7−メチル−1H−ベンゾ[d]イミダゾール−2−イル)−2−(トリフルオロメチル)イソニコチンアミド;
(R)−N−(1−(1−アクリロイルアゼパン−3−イル)−7−クロロ−6−メトキシ−1H−ベンゾ[d]イミダゾール−2−イル)ピリダジン−4−カルボキサミド;
N−(1−(1−アクリロイルアゼパン−3−イル)−7−クロロ−6−メトキシ−1H−ベンゾ[d]イミダゾール−2−イル)ピリダジン−4−カルボキサミド;
N−(7−メチル−1−(1−(ビニルスルホニル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド;
N−(1−(1−アクリロイルアゼパン−3−イル)−7−(ピロリジン−1−イルメチル)−1H−ベンゾ[d]イミダゾール−2−イル)−3−(トリフルオロメチル)ベンズアミド;
tert−ブチル 4−アクリロイル−6−(7−クロロ−2−(2−メチルイソニコチンアミド)−1H−ベンゾ[d]イミダゾール−1−イル)−1,4−ジアゼパン−1−カルボキシレート;
N−(1−(1−アクリロイル−1,4−ジアゼパン−6−イル)−7−クロロ−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(1−(1−アセチル−4−アクリロイル−1,4−ジアゼパン−6−イル)−7−クロロ−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R)−N−(1−(1−アクリロイルアゼパン−3−イル)−7−クロロ−6−(2−(ピロリジン−1−イル)エトキシ)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
N−(1−(1−アクリロイルアゼパン−3−イル)−7−クロロ−6−(2−(ピロリジン−1−イル)エトキシ)−1H−ベンゾ[d]イミダゾール−2−イル)−2,6−ジメチルイソニコチンアミド;
(R,E)−N−(7−クロロ−1−(1−(4−(ジシクロプロピルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
N−(7−クロロ−1−(1−(4−(ジシクロプロピルアミノ)ブタ−2−エノイル)アゼパン−3−イル)−1H−ベンゾ[d]イミダゾール−2−イル)−2−メチルイソニコチンアミド;
(R)−1−(1−アクリロイルピペリジン−3−イル)−2−(3−(トリフルオロメチル)ベンズアミド)−1H−ベンゾ[d]イミダゾール−5−カルボン酸;
1−(1−アクリロイルピペリジン−3−イル)−2−(3−(トリフルオロメチル)ベンズアミド)−1H−ベンゾ[d]イミダゾール−5−カルボン酸;
(R)−1−(1−アクリロイルピペリジン−3−イル)−2−(3−(トリフルオロメチル)ベンズアミド)−1H−ベンゾ[d]イミダゾール−5−カルボキサミド;
1−(1−アクリロイルピペリジン−3−イル)−2−(3−(トリフルオロメチル)ベンズアミド)−1H−ベンゾ[d]イミダゾール−5−カルボキサミド;および
1−(1−アクリロイルアゼパン−3−イル)−2−(3−(トリフルオロメチル)ベンズアミド)−1H−ベンゾ[d]イミダゾール−7−カルボン酸
から選択される、請求項1〜12のいずれか一項に記載の化合物またはその薬学的に許容される塩。 - 請求項1〜13のいずれか一項に記載の化合物またはその薬学的に許容される塩、および薬学的に許容される担体を含む、医薬組成物。
- 請求項1〜13のいずれか一項に記載の化合物またはその薬学的に許容される塩、および化学治療剤を含む、組合せ。
- 系または対象に、治療有効量の請求項1〜13のいずれか一項に記載の化合物、またはその薬学的に許容される塩を投与することを含む、上皮成長因子(EGFR)を阻害する方法。
- 上皮成長因子受容体(EGFR)によって媒介される状態を処置する方法であって、このような処置を必要としている系または対象に、有効量の請求項1〜13のいずれか一項に記載の化合物、またはその薬学的に許容される塩を投与することを含む、方法。
- 上皮成長因子受容体(EGFR)を阻害するための、請求項1〜13のいずれか一項に記載の化合物またはその薬学的に許容される塩の使用。
- 上皮成長因子受容体(EGFR)によって媒介される状態を処置するための医薬品の製造における、請求項1〜13のいずれか一項に記載の化合物またはその薬学的に許容される塩の使用。
- 上皮成長因子受容体(EGFR)によって媒介される状態を処置するための、請求項1〜13のいずれか一項に記載の化合物またはその薬学的に許容される塩の使用。
- EGFRによって媒介される状態が、非小細胞肺がん(NSCLC)、頭頸部がん、結腸直腸がん、乳がん、膵臓がん、卵巣がん、胃がん、神経膠腫、および前立腺がんから選択される、請求項17に記載の方法、または請求項20に記載の化合物もしくはその薬学的に許容される塩の使用。
- EGFRが、突然変異EGFRである、請求項16もしくは17に記載の方法、または請求項18〜20のいずれか一項に記載の化合物もしくはその薬学的に許容される塩の使用。
- 突然変異EGFRが、G719S、G719C、G719A、L858R、L861Q、エクソン19欠失突然変異、またはエクソン20挿入突然変異を含む、請求項22に記載の方法、または請求項22に記載の化合物もしくはその薬学的に許容される塩の使用。
- 突然変異EGFRが、EGFR T790M、T854A、またはD761Y抵抗性突然変異をさらに含む、請求項23に記載の方法、または請求項23に記載の化合物もしくはその薬学的に許容される塩の使用。
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JP2018531225A (ja) * | 2015-09-18 | 2018-10-25 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | Irak阻害剤としてのヘテロアリール化合物及びその使用 |
JP7083750B2 (ja) | 2015-09-18 | 2022-06-13 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | Irak阻害剤としてのヘテロアリール化合物及びその使用 |
JP2019510802A (ja) * | 2016-04-07 | 2019-04-18 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドGlaxosmithkline Intellectual Property Development Limited | タンパク質調節物質として有用な複素環アミド |
JP2021514373A (ja) * | 2018-02-21 | 2021-06-10 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Egfr阻害剤としての新たなベンズイミダゾール化合物および誘導体 |
JP7313364B2 (ja) | 2018-02-21 | 2023-07-24 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Egfr阻害剤としての新たなベンズイミダゾール化合物および誘導体 |
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