JP6495886B2 - Btk阻害剤としての複素環式芳香族化合物 - Google Patents
Btk阻害剤としての複素環式芳香族化合物 Download PDFInfo
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- JP6495886B2 JP6495886B2 JP2016502294A JP2016502294A JP6495886B2 JP 6495886 B2 JP6495886 B2 JP 6495886B2 JP 2016502294 A JP2016502294 A JP 2016502294A JP 2016502294 A JP2016502294 A JP 2016502294A JP 6495886 B2 JP6495886 B2 JP 6495886B2
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- alkyl
- alkoxy
- optionally substituted
- pharmaceutically acceptable
- acceptable salt
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- 229940124291 BTK inhibitor Drugs 0.000 title description 2
- 150000002390 heteroarenes Chemical class 0.000 title 1
- -1 R 2 —S (O) m — Chemical group 0.000 claims description 53
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- 125000000217 alkyl group Chemical group 0.000 claims description 49
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- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 201000006417 multiple sclerosis Diseases 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 7
- 229910052786 argon Inorganic materials 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
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- ISDIBDPXVWNENH-UHFFFAOYSA-N 1-[7-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]-2-azaspiro[3.5]nonan-2-yl]prop-2-en-1-one Chemical compound C1=2C(N)=NC=NC=2N(C2CCC3(CN(C3)C(=O)C=C)CC2)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 ISDIBDPXVWNENH-UHFFFAOYSA-N 0.000 claims 1
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- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 125000005046 dihydronaphthyl group Chemical group 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229950000206 estolate Drugs 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethane-1,2-disulfonate Chemical compound [O-]S(=O)(=O)CCS([O-])(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 125000000350 glycoloyl group Chemical group O=C([*])C([H])([H])O[H] 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000003519 mature b lymphocyte Anatomy 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- LRMHVVPPGGOAJQ-UHFFFAOYSA-N methyl nitrate Chemical compound CO[N+]([O-])=O LRMHVVPPGGOAJQ-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- 229950006327 napsilate Drugs 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- 125000000165 tricyclic carbocycle group Chemical group 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
1.技術分野
本発明は、BTKを阻害する新規な化合物及びそれらの医薬としての使用に関する。
ヒト酵素のプロテインキナーゼファミリーのメンバーは、リン酸基の付加を介する特定タンパク質のそれらの翻訳後修飾に起因して、多数の別個のシグナル伝達プロセスにおいて、重要な調節的役割を果たす(Hunter, Cell, 1987 50, 823-829)。ブルートンチロシンキナーゼ(BTK)は、チロシンキナーゼのTecファミリーのメンバーであり、そしてB細胞発生、活性化及び抗体産生において重大な役割を果たす。
本発明は、複素環式芳香族化合物の新規なクラス及びそれを作成し、そして使用するための方法を含む。これらの化合物は、BTKへの良好な阻害効果を示すので、自己免疫及びアレルギー性障害の処置に有用である。
第一の一般的な実施態様において、式(I):
[式中、
Cyは、炭素環、ヘテロアリール又は複素環であり、各々は、R1によって置換されており、そしてハロゲン、ハロC1−4アルキル、C1−4アルキル、オキソ及びC1−4アルコキシによって場合により置換されており;
R1は、以下:
L−Ar、C1−6アルキル、−S(O)m−R3及びC1−6アルコキシから選択され、各Ar、C1−6アルキル及びC1−6アルコキシは、ベンジル、ハロゲン、ハロC1−4アルキル、C1−4アルキル、R2−S(O)m−、−CN、−C(O)−N(R3)2又はC1−4アルコキシによって場合により置換されており;
Lは、結合、O、>C(O)、−(CH2)n−、−O−(CH2)n−、−N(R3)−、−N(R3)−(CH2)n−、−(CH2)n−N(R3)−、−C(O)−N(R3)−、−C(O)−N(R3)−(CH2)n−、−N(R3)−C(O)−N(R3)−、−N(R3)−C(O)−、−S(O)m−N(R3)−、R3−S(O)m−及び−N(R3)−S(O)m−から選択されるリンカーであり、ここで、各L中の−CH2−は、C1−3アルキルによって置き換えられている1〜2個の水素を有することができ、該C1−3アルキル基は、場合により環化してC3−6シクロアルキル環を形成することができ;
Arは、炭素環、複素環又はヘテロアリールであり;
式(I)のXは、窒素含有C6−C10スピロ環であり、各Xは、1個のR4によって置換されており、そしてハロゲン、ハロC1−4アルキル、C1−4アルキル及びC1−4アルコキシによって場合により置換されており;
R4は、
であり、
各nは、独立に1〜4であり;
各mは、独立に0〜2であり;
各R2及びR3は、独立に、水素又はC1−4アルキルから選択され;
各R5は、独立に、水素、ハロゲン、C1−4アルキル、C1−4アルコキシ、C1−4アルキルC1−4アルコキシ、C1−4アルキルヒドロキシ、−(CH2)n−複素環及び複素環から選択され、各複素環は、ハロゲン、OH又はR2−S(O)m−によって場合により置換されており;
Cy、R1−R5及びYに関して先に定義された各基は、可能であれば部分的又は完全にハロゲン化され得る]
で示される化合物又はその薬学的に許容し得る塩が提供される。
Cyは、フェニル、ピラゾリル、ピリジニル、ピロリル、イミダゾリル、チアゾリル、フラニル、オキサゾリル、イソオキサゾリル、チエニル、ピリダジニル、ピリミジニル、ピラジニル又はピラニルであり、各々は、R1によって置換されており、そしてC1−4アルキル、F、Cl又はオキソによって場合により置換されており;
R1は、以下:
L−Ar及び−S(O)m−R3から選択され、各R1は、Br、C1−4アルキル、R3−S(O)2−、−CN、−C(O)−NH(R3)及びC1−3アルコキシによって場合により置換されており;
Arは、フェニル、ピリジニル、ピリダジニル、ベンジルによって場合により置換されているピリミジニル、ピラジニル、ベンゾオキサゾリル、インドリル、イソインドリル、ベンゾフラニル、ベンゾイミダゾリル、ベンゾチアゾリル、ピペリジニル、ピペラジニル又はピロリジニルである]の化合物又はその薬学的に許容し得る塩が提供される。
Cyは、フェニル又はピリジニルであり、各々は、R1によって置換されており、そしてF、Cl、オキソ又はC1−2アルコキシによって場合により置換されており;
R1は、L−Arであり、各R1は、Br、C1−4アルキル、CH3−S(O)2−、−CN、−C(O)−NH(R3)及びC1−2アルコキシによって場合により置換されており;
Arは、フェニル、ピリジニル、ピリダジニル、ベンジルによって場合により置換されているピリミジニル、ピラジニル、ベンゾオキサゾリル、インドリル、イソインドリル、ベンゾフラニル、ベンゾイミダゾリル、ベンゾチアゾリル又はピペリジニルである]の化合物又はその薬学的に許容し得る塩が提供される。
Cyは、フェニル又はピリジニルであり、各々は、R1によって置換されており、そしてF、Cl、オキソ又はC1−2アルコキシによって場合により置換されており;
L−Arは、F、Cl、C1−4アルキル、CH3−S(O)2−、−CN、−C(O)−NH(CH3)及びC1−2アルコキシによって場合により置換されており;
Arは、フェニル又はピリミジニルである]の化合物又はその薬学的に許容し得る塩が提供される。
R4は、
であり、
各R5は、独立に、水素、C1−3アルキル、ハロC1−3アルキル、C1−3アルキルC1−3アルコキシ、−CH2−複素環及び複素環から選択され、各複素環は、F、Cl、OH及びCH3−S(O)2−によって場合により置換されており、そして各複素環は、ピロリジニル、ピペリジニル、モルホリニル、1,4−オキサゼパン及びオキシランから選択される]の化合物又はその薬学的に許容し得る塩が提供される。
ここで明確に定義されない用語は、全開示内容及び文脈全体を踏まえると当業者に明らかである意味を有する。
例えば、
などの表示において、
実線は、環系が、炭素原子1、2又は3を介して分子に結合されてもよく、したがって以下の表示:
と同等であることを意味する。
最適の反応条件及び反応時間は、使用される特定の反応物に応じて変わることもできる。特に断りない限り、溶媒、温度、圧力、及び他の反応条件は、当業者によって容易に選択されることもできる。具体的な手順は、合成例の項に提供されている。中間体及び生成物は、シリカゲルのクロマトグラフィー、再結晶化及び/又は逆相HPLC(RHPLC)によって精製されてもよい。別々のエナンチオマーは、キラルHPLCを使用したラセミ生成物の分割によって得られうる。RHPLC精製方法は、0.1% ギ酸又は0.1% TFAを含有する水中0〜100%アセトニトリルを使用し、そして以下のカラムの1つを使用した:
a)Waters Sunfire OBD C18 5μm 30x150mmカラム
b)Waters XBridge OBD C18 5μm 30x150mmカラム
c)Waters ODB C8 5μm 19x150mmカラム.
d)Waters Atlantis ODB C18 5μm 19x50mmカラム.
e)Waters Atlantis T3 OBD 5μm 30x100mmカラム
f)Phenomenex Gemini Axia C18 5μm 30x100mmカラム
式Iの化合物は、以下の一般スキームIaに示されるとおりに調製されてもよい。
スキームIaにおいて、Aを適切な試薬と反応させてBを与え(Yは、OTf、Cl、Br、Iである)、適切なパラジウム触媒系、例えばビス(ジフェニルホスフィノ)フェロセンパラジウム(II)クロリド錯体又はテトラキス(トリフェニルホスフィン)パラジウム(0)の存在下、炭酸カリウム、炭酸セシウム又はリン酸カリウムのような無機塩基の存在下、ジオキサン及び水の組合せのような適切な溶媒系中、適切なボロン酸又はピナコールエステルを使用して、BからCを調製することができる。X−LG(LGは、脱離基である)を適切な塩基で処理し、そしてCと反応させて、一般式(I)で示される化合物を与える。
スキームIbにおいて、トリフェニルホスフィン及び適切な試薬、例えばDEAD、DIAD又はDBADの存在下、THF又はトルエンのような適切な溶媒中、Bを、アルコールを含有したX−OHと反応させて、Eを与える。次に、適切なパラジウム触媒系、例えばビス(ジフェニルホスフィノ)フェロセンパラジウム(II)クロリド錯体又はテトラキス(トリフェニルホスフィン)パラジウム(0)の存在下、炭酸カリウム、炭酸セシウム又はリン酸カリウムのような無機塩基の存在下、ジオキサン及び水の組合せのような適切な溶媒系中、Eを適切なボロン酸又はピナコールエステルと反応させて、一般式(I)の化合物を与える。
中間体I−1の合成
DMF(350.0mL)中のR−1(50.0g、0.37mol)の溶液に、NIS(83.3g、0.37mol)を加える。反応混合物を、75℃に24時間加熱する。次に、混合物を室温に冷やし、そして水に注ぐ。混合物を濾過し、そして沈殿物を水で洗浄し、減圧下で乾燥させて、化合物I−1(45.0g、48%)を与える。
中間体I−2の合成
1,4−ジオキサン(650.0mL)/水(100.0mL)中のI−1(7.0g、26.8mmol)の撹拌した溶液に、(4−フェノキシフェニル)ボロン酸(7.4g、34.6mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0)(0.93g、0.85mmol)及びNa2CO3(5.6g、52.8mmol)を加える。反応混合物を90℃に60時間加熱し、そして次に室温に冷やし、そして真空下で濃縮する。残留物を、シリカゲルのCombi-flashクロマトグラフィーを介して精製して、I−2(3.5g、43.0%)を与える。
中間体I−3の合成
THF(50.0mL)中のI−1(5.0g、0.019mol)、化合物2A(4.1g、0.019mol)、Ph3P(6.0g、0.023mol)の混合溶液に、DBAD(4.6g、0.023mol)を、窒素下、室温で滴下する。添加後、反応混合物を、60℃に加熱し、そして一晩撹拌する。反応混合物を、室温に冷やし、そして真空下で濃縮する。残留物を、シリカゲルのCombi-flashクロマトグラフィーを介し、次に分取HPLCを介して精製し、化合物I−3(2.8g、33%)を与える。
中間体I−9の合成及びジアステレオマー(disastereomers)I−10及びI−11の分離
DMF(5mL)中のI−1(1.0g、3.83mmol)の撹拌した溶液に、水素化ナトリウム(0.17g、4.2mmol)を加える。5分後、I−8(1.6g、4.2mmol)を加え、そして反応混合物を、70℃に2日間加熱する。反応物を、室温に冷やし、そして飽和NH4Cl溶液(100mL)で希釈する。有機物を、酢酸エチル(4×250mL)で抽出し、ブラインで洗浄し、硫酸ナトリウムで乾燥させ、そして真空下で濃縮する。残留物を、シリカゲルのCombi-flashカラム(DCM中0〜8% MeOH)を介して精製して、I−9(1.75g、97.1%) m/z 472.28 [M+H], RT 0.72を与える。I−9を、分取HPLCによって分離して、ジアステレオマーI−10(1.6g、88.8%) m/z 472.28 [M+H], RT0.98;I−11(0.15 g, 8.3%) m/z 472.54 [M+H], RT 0.69を与える。
中間体I−12の合成
CH2Cl2中のR−3(5.0g、23mmol)の溶液を、TEA(6.5mL、47mmol)及びDMAP(0.57g、4.7mmol)で処理する。混合物を、24時間撹拌して、次に真空下で濃縮する。残留物を、EtOAcに溶解し、そして飽和塩化アンモニウム水溶液及びブラインで洗浄する。有機物を回収し、そして揮発物を真空下で除去する。粗残留物を、Et2Oでトリチュレートし、そして固体を濾過し、そして回収して、I−12(5.6g、65%) m/z 367.9 [M+]を与える。
中間体I−13の合成
DMF(3.0mL)中のI−2(0.15g、0.5mmol)の撹拌した溶液に、I−12(0.2g、0.54mmol)及びCs2CO3(0.32g、1.0mmol)を加える。反応混合物を、60℃に加熱する。18時間後、反応混合物を、真空下で濃縮し、そしてシリカゲルのCombi-flashクロマトグラフィー(CH2Cl2中5% MeOHの溶媒勾配を使用する)を介して精製して、I−13(0.18g、73%)を与える。以下の中間体を、同様のやり方で調製した:
中間体I−15の合成:
マイクロ波反応器内に、1,4−ジオキサン(0.2mL)中のI−3(0.35g、0.77mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0)(0.09g、0.077mmol)、ヘキサメチルジスタンナン(0.19mL、0.92mmol)を入れる。反応混合物を、5分間アルゴンで脱気し、そして次に115℃に1時間加熱する。反応混合物を、室温に冷やし、そしてその後、R−4(0.60g、1.84mmol)及びテトラキス(トリフェニルホスフィン)パラジウム(0)(0.09g、0.077mmol)の添加が続く。反応混合物を、5分間アルゴンで脱気し、そして次に115℃に一晩加熱する。反応混合物を室温に冷やし、そして真空下で濃縮する。残留物を、シリカゲルのCombi-flashクロマトグラフィー(CH2Cl2中0〜6% MeOHの溶媒勾配を使用する)を介して精製して、I−15(0.27g、70.7%)を与える。
実施例1の合成
CH2Cl2(5.0mL)中のR−13(0.18g、0.36mmol)の撹拌した溶液に、TFA(0.21g、1.8mmol)を、室温で加える。3時間後、反応混合物を、CH2Cl2中10% MeOHと飽和NaHCO3水溶液で分液する。有機物を回収し、MgSO4で乾燥させ、濾過し、そして真空下で濃縮して、I−20(0.12g、83.4%)を与える。
Ex 2、3、4、5
実施例11の合成
CH2Cl2中のI−15(0.27g、0.54mmol)の撹拌した溶液に、TFA(1.5g、13.1mmol)を室温で加える。1時間後、反応混合物を、真空下で濃縮する。残留物を、NaHCO3含有カラムを通過させて、I−21(0.21g、96.9%)を与える。
Ex 6、7、8、9、10、12、13、14、15、16、17
BTKアッセイ
HTRFアッセイ(Cisbio KinEASE-TK cat # 62TK0PEC)を、基質のBTK介在リン酸化を阻害する試験化合物の能力を定量化するために、実施した。アッセイを、384ウェルプレートにおいて構築し、ここで、6nMの全長ヒトHis標識したBTK(Life Technologies cat # PV3587)及び様々な濃度での試験化合物を、28℃で15分間プレインキュベートした。次に、1uMのTK基質−ビオチン及び30uM ATPを加え、そして28℃で追加の30分間インキュベートした。リン酸化を、62.5nM ストレプトアビジン−XL665及びHTRF検出緩衝液(Cisbio cat # 62SDBRDF)中に1:100希釈したTK−抗体クリプテートを加えることによって検出して、そして室温で60分間インキュベートした。プレートを、Envisionプレート読取機で読み取った。そして蛍光を、620nm(クリプテート)及び665nm(XL665)で測定する。比率を計算し(665/620)、そして対照及びブランクウェルに対するPOCに変換する。
50mM HEPES(Invitrogen #15630)、0.01% Brij−35(sigma #B4184)、10mM MgCl2(Sigma M1028)、1mM EGTA(Ambion AM9262)及び100uM オルトバナジウム酸ナトリウム(sodium orthovanedate)(Sigma S6508)、1mM DTT(Sigma D5545)及び10nM 補充酵素緩衝液(supplement enzyme buffer)(Cisbio cat# 61SEBALB)。
それらの生物学的特性に基づいて、本発明による式(I)の化合物又はそれらの互変異性体、ラセミ体、エナンチオマー、ジアステレオマー、それらの混合物及び先に述べた形態の全ての塩は、BTKへの良好な阻害効果を示すので、自己免疫及びアレルギー性障害を処置するのに適する。
Claims (10)
- 式(I):
[式中、
Cyは、炭素環、ヘテロアリール又は複素環であり、各々は、R1によって置換されており、そして、ハロゲン、ハロC1−4アルキル、C1−4アルキル、オキソ又はC1−4アルコキシによって場合により置換されており;
R1は、以下:
L−Ar、C1−6アルキル、−S(O)m−R3及びC1−6アルコキシから選択され、各Ar、C1−6アルキル及びC1−6アルコキシは、ベンジル、ハロゲン、ハロC1−4アルキル、C1−4アルキル、R2−S(O)m−、−CN、−C(O)−N(R3)2又はC1−4アルコキシによって場合により置換されており;
Lは、結合、−O−、−C(O)−、−(CH2)n−、−O−(CH2)n−、−N(R3)−、−N(R3)−(CH2)n−、−(CH2)n−N(R3)−、−C(O)−N(R3)−、−C(O)−N(R3)−(CH2)n−、−N(R3)−C(O)−N(R3)−、−N(R3)−C(O)−、−S(O)m−N(R3)−、R3−S(O)m−及び−N(R3)−S(O)m−から選択されるリンカーであり、ここで、各L中の−CH2−は、C1−3アルキルによって置き換えられている1〜2個の水素を有することができ、該C1−3アルキル基は、場合により環化してC3−6シクロアルキル環を形成することができ;
Arは、炭素環、複素環又はヘテロアリールであり;
Xは、
であり、各Xは、ハロゲン、ハロC1−4アルキル、C1−4アルキル又はC1−4アルコキシによって場合により置換されており;
R4は、
であり、
各nは、独立に1〜4であり;
各mは、独立に0〜2であり;
各R2及びR3は、独立に、水素及びC1−4アルキルから選択され;
各R5は、独立に、水素、ハロゲン、C1−4アルキル、C1−4アルコキシ、C1−4アルキルC1−4アルコキシ、C1−4アルキルヒドロキシ、−(CH2)n−複素環及び複素環から選択され、各複素環は、ハロゲン、OH又はR2−S(O)m−によって場合により置換されており;
Cy、R1−R5及びYに関して先に定義された各基は、可能であれば部分的又は完全にハロゲン化されていてもよい]
で示される化合物(但し
(1−(6−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−2−アザスピロ[3.3]ヘプタン−2−イル)−2−プロペン−1−オン)、
(1−(2−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−7−アザスピロ[3.5]ノナン−7−イル)−2−プロペン−1−オン)、
(1−(7−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−2−アザスピロ[3.5]ノナン−2−イル)−2−プロペン−1−オン)、及び
(1−(2−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−6−アザスピロ[3.5]ノナン−6−イル)−2−プロペン−1−オン)を除く)、又はその薬学的に許容し得る塩。 - Cyが、フェニル、ピラゾリル、ピリジニル、ピロリル、イミダゾリル、チアゾリル、フラニル、オキサゾリル、イソオキサゾリル、チエニル、ピリダジニル、ピリミジニル、ピラジニル又はピラニルであり、各々が、R1によって置換されており、そして、C1−4アルキル、F、Cl又はオキソによって場合により置換されており;
R1が、以下:
L−Ar及び−S(O)m−R3から選択され、各R1が、Br、C1−4アルキル、R3−S(O)2−、−CN、−C(O)−NH(R3)及びC1−3アルコキシによって場合により置換されており;
Arが、フェニル、ピリジニル、ピリダジニル、ベンジルによって場合により置換されているピリミジニル、ピラジニル、ベンゾオキサゾリル、インドリル、イソインドリル、ベンゾフラニル、ベンゾイミダゾリル、ベンゾチアゾリル、ピペリジニル、ピペラジニル又はピロリジニルである、
請求項1記載の化合物、又はその薬学的に許容し得る塩。 - Cyが、フェニル又はピリジニルであり、各々が、R1によって置換されており、そして、F、Cl、オキソ又はC1−2アルコキシによって場合により置換されており;
R1が、L−Arであり、各R1が、Br、C1−4アルキル、CH3−S(O)2−、−CN、−C(O)−NH(R3)及びC1−2アルコキシによって場合により置換されており;
Arが、フェニル、ピリジニル、ピリダジニル、ベンジルによって場合により置換されているピリミジニル、ピラジニル、ベンゾオキサゾリル、インドリル、イソインドリル、ベンゾフラニル、ベンゾイミダゾリル、ベンゾチアゾリル又はピペリジニルである、
請求項1記載の化合物、又はその薬学的に許容し得る塩。 - Cyが、フェニル又はピリジニルであり、各々が、R1によって置換されており、そして、F、Cl、オキソ又はC1−2アルコキシによって場合により置換されており;
L−Arが、F、Cl、C1−4アルキル、CH3−S(O)2−、−CN、−C(O)−NH(CH3)及びC1−2アルコキシによって場合により置換されており;
Arが、フェニル又はピリミジニルである、
請求項1記載の化合物、又はその薬学的に許容し得る塩。 - 請求項1〜8のいずれか一項記載の化合物又はその薬学的に許容し得る塩を含む、医薬組成物。
- 関節リウマチ、全身性エリテマトーデス(systemic lupus erythromatosis)、強皮症、喘息、アレルギー性鼻炎、アレルギー性湿疹、B細胞リンパ腫、多発性硬化症、若年性関節リウマチ、若年性特発性関節炎、炎症性腸疾患、移植片対宿主病、乾癬性関節炎、強直性脊椎炎及びブドウ膜炎から選択される疾患を処置するための、請求項9記載の医薬組成物。
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