ES2997111T3 - Pyridazinyl amino derivatives as alk5 inhibitors - Google Patents
Pyridazinyl amino derivatives as alk5 inhibitors Download PDFInfo
- Publication number
- ES2997111T3 ES2997111T3 ES21743186T ES21743186T ES2997111T3 ES 2997111 T3 ES2997111 T3 ES 2997111T3 ES 21743186 T ES21743186 T ES 21743186T ES 21743186 T ES21743186 T ES 21743186T ES 2997111 T3 ES2997111 T3 ES 2997111T3
- Authority
- ES
- Spain
- Prior art keywords
- fluorophenyl
- amino
- chloro
- ethyl
- pyridazin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 Pyridazinyl amino Chemical class 0.000 title claims description 122
- 239000003112 inhibitor Substances 0.000 title description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 400
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 36
- 201000010099 disease Diseases 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- 230000019491 signal transduction Effects 0.000 claims abstract description 8
- 241000124008 Mammalia Species 0.000 claims abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 192
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 124
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 123
- 125000000217 alkyl group Chemical group 0.000 claims description 114
- 125000002947 alkylene group Chemical group 0.000 claims description 87
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 87
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 58
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 37
- 206010016654 Fibrosis Diseases 0.000 claims description 32
- 230000004761 fibrosis Effects 0.000 claims description 32
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 21
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 21
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 20
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 16
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 15
- 208000035475 disorder Diseases 0.000 claims description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 230000002265 prevention Effects 0.000 claims description 11
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- FQYRLEXKXQRZDH-UHFFFAOYSA-N 4-aminoquinoline Chemical compound C1=CC=C2C(N)=CC=NC2=C1 FQYRLEXKXQRZDH-UHFFFAOYSA-N 0.000 claims description 8
- 125000001188 haloalkyl group Chemical group 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 6
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 5
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 230000009787 cardiac fibrosis Effects 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 3
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 3
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 3
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 2
- RAYIKMXTWRUOPJ-UHFFFAOYSA-N 2-(4-ethylpiperazin-1-ium-1-yl)-2-methylpropanoate Chemical compound CCN1CCN(C(C)(C)C(O)=O)CC1 RAYIKMXTWRUOPJ-UHFFFAOYSA-N 0.000 claims description 2
- 206010054793 Arterial fibrosis Diseases 0.000 claims description 2
- QUROZZCLSDCQAM-UHFFFAOYSA-N CC(N=NC(C(C=C(C=C1)Cl)=C1F)=C1)=C1NC1=CC(NC(CCN2CCN(C)CC2)=O)=NC=C1 Chemical compound CC(N=NC(C(C=C(C=C1)Cl)=C1F)=C1)=C1NC1=CC(NC(CCN2CCN(C)CC2)=O)=NC=C1 QUROZZCLSDCQAM-UHFFFAOYSA-N 0.000 claims description 2
- YMXZVWVKOSDVNG-UHFFFAOYSA-N CC(N=NC(C(C=C(C=C1)Cl)=C1F)=C1)=C1NC1=CC(NC(CCN2CCNCC2)=O)=NC=C1 Chemical compound CC(N=NC(C(C=C(C=C1)Cl)=C1F)=C1)=C1NC1=CC(NC(CCN2CCNCC2)=O)=NC=C1 YMXZVWVKOSDVNG-UHFFFAOYSA-N 0.000 claims description 2
- QCHNVBJCBOIATR-UHFFFAOYSA-N FC(C=CC(Cl)=C1)=C1C1=CC(NC2=CC=NC3=CC(OCCN4CCNCC4)=CC=C23)=CN=N1 Chemical compound FC(C=CC(Cl)=C1)=C1C1=CC(NC2=CC=NC3=CC(OCCN4CCNCC4)=CC=C23)=CN=N1 QCHNVBJCBOIATR-UHFFFAOYSA-N 0.000 claims description 2
- GWVNCZJGEFOPIX-UHFFFAOYSA-N FC(C=CC(Cl)=C1)=C1C1=CC(NC2=CC=NC3=CC(OCCN4CCOCC4)=CC=C23)=CN=N1 Chemical compound FC(C=CC(Cl)=C1)=C1C1=CC(NC2=CC=NC3=CC(OCCN4CCOCC4)=CC=C23)=CN=N1 GWVNCZJGEFOPIX-UHFFFAOYSA-N 0.000 claims description 2
- OXWFDIJHMAHNFI-UHFFFAOYSA-N O=C(C1=CC=C(C(NC2=CN=NC(C(C=C(C=C3)Cl)=C3F)=C2)=CC=N2)C2=C1)NCCN1CCOCC1 Chemical compound O=C(C1=CC=C(C(NC2=CN=NC(C(C=C(C=C3)Cl)=C3F)=C2)=CC=N2)C2=C1)NCCN1CCOCC1 OXWFDIJHMAHNFI-UHFFFAOYSA-N 0.000 claims description 2
- ALQSHHUCVQOPAS-UHFFFAOYSA-N Pentane-1,5-diol Chemical compound OCCCCCO ALQSHHUCVQOPAS-UHFFFAOYSA-N 0.000 claims description 2
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 2
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 2
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 2
- VQXJLGJJFHNUHC-UHFFFAOYSA-N n-[2-(4-ethylpiperazin-1-yl)ethyl]acetamide Chemical compound CCN1CCN(CCNC(C)=O)CC1 VQXJLGJJFHNUHC-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 1
- CKQFWQCSMNUSRI-UHFFFAOYSA-N 1,1-dimethylpiperazin-1-ium Chemical compound C[N+]1(C)CCNCC1 CKQFWQCSMNUSRI-UHFFFAOYSA-N 0.000 claims 1
- IFFLKGMDBKQMAH-UHFFFAOYSA-N 2,4-diaminopyridine Chemical compound NC1=CC=NC(N)=C1 IFFLKGMDBKQMAH-UHFFFAOYSA-N 0.000 claims 1
- XLMAXIQHOIAZSH-UHFFFAOYSA-N 3-pyrrolidin-1-ylazetidine-1-carboxylic acid Chemical compound C1N(C(=O)O)CC1N1CCCC1 XLMAXIQHOIAZSH-UHFFFAOYSA-N 0.000 claims 1
- SQIQQEFNYTXCJY-UHFFFAOYSA-N 4-(2-hydroxyethyl)piperazine-1-carboxylic acid Chemical compound OCCN1CCN(C(O)=O)CC1 SQIQQEFNYTXCJY-UHFFFAOYSA-N 0.000 claims 1
- ITCRFAHFEBMUGW-UHFFFAOYSA-N 4-[2-(dimethylamino)ethyl]piperazine-1-carboxylic acid Chemical compound CN(C)CCN1CCN(C(O)=O)CC1 ITCRFAHFEBMUGW-UHFFFAOYSA-N 0.000 claims 1
- OEYWMVKCMARLOK-UHFFFAOYSA-N CC(C)C(C=C1)=CC(C2=CC(NC3=CC=NC4=CC(OCCN5CCN(C)CC5)=CC=C34)=CN=N2)=C1F Chemical compound CC(C)C(C=C1)=CC(C2=CC(NC3=CC=NC4=CC(OCCN5CCN(C)CC5)=CC=C34)=CN=N2)=C1F OEYWMVKCMARLOK-UHFFFAOYSA-N 0.000 claims 1
- CBRDAYRXLUOQFR-UHFFFAOYSA-N CC(C)N(CCN(CCC(NC1=NC=CC(NC2=C(C)N=NC(C(C=C(C=C3)Cl)=C3F)=C2)=C1)=O)C1)C1C(OC)=O Chemical compound CC(C)N(CCN(CCC(NC1=NC=CC(NC2=C(C)N=NC(C(C=C(C=C3)Cl)=C3F)=C2)=C1)=O)C1)C1C(OC)=O CBRDAYRXLUOQFR-UHFFFAOYSA-N 0.000 claims 1
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- TYGVMIBEPIKLRD-UHFFFAOYSA-N methyl 2-[4-[3-[(4-bromopyridin-2-yl)amino]-3-oxopropyl]-1-methylpiperazin-2-yl]acetate Chemical compound CN1C(CC(OC)=O)CN(CCC(NC2=NC=CC(Br)=C2)=O)CC1 TYGVMIBEPIKLRD-UHFFFAOYSA-N 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- MZEVRGMQXLNKEZ-UHFFFAOYSA-N methyl 4,6-dichloropyridazine-3-carboxylate Chemical compound COC(=O)C1=NN=C(Cl)C=C1Cl MZEVRGMQXLNKEZ-UHFFFAOYSA-N 0.000 description 1
- MTXSNKJIYCCGKL-UHFFFAOYSA-N methyl 4-[3-[(4-bromopyridin-2-yl)amino]-3-oxopropyl]-1-methylpiperazine-2-carboxylate Chemical compound CN(CCN(CCC(NC1=NC=CC(Br)=C1)=O)C1)C1C(OC)=O MTXSNKJIYCCGKL-UHFFFAOYSA-N 0.000 description 1
- CPNMUJAOYRRWCQ-UHFFFAOYSA-N methyl 4-bromo-1h-pyrrolo[2,3-b]pyridine-3-carboxylate Chemical compound C1=CC(Br)=C2C(C(=O)OC)=CNC2=N1 CPNMUJAOYRRWCQ-UHFFFAOYSA-N 0.000 description 1
- ROTWWLOBDCESBP-UHFFFAOYSA-N methyl 4-bromoquinoline-6-carboxylate Chemical compound N1=CC=C(Br)C2=CC(C(=O)OC)=CC=C21 ROTWWLOBDCESBP-UHFFFAOYSA-N 0.000 description 1
- JPDTUYYBALHQGC-UHFFFAOYSA-N methyl 4-chloro-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C1=CN=C2NC(C(=O)OC)=CC2=C1Cl JPDTUYYBALHQGC-UHFFFAOYSA-N 0.000 description 1
- DDDSGYZATMCUDW-UHFFFAOYSA-N methyl 4-chloro-7-methoxyquinoline-6-carboxylate Chemical compound C1=CN=C2C=C(OC)C(C(=O)OC)=CC2=C1Cl DDDSGYZATMCUDW-UHFFFAOYSA-N 0.000 description 1
- QUCTXYQKZCLAPW-UHFFFAOYSA-N methyl 4-chloroquinoline-7-carboxylate Chemical compound ClC1=CC=NC2=CC(C(=O)OC)=CC=C21 QUCTXYQKZCLAPW-UHFFFAOYSA-N 0.000 description 1
- QIVLVAMUANGXOQ-UHFFFAOYSA-N methyl 4-ethyl-1-methylpiperazine-2-carboxylate Chemical compound CCN1CC(C(OC)=O)N(C)CC1 QIVLVAMUANGXOQ-UHFFFAOYSA-N 0.000 description 1
- GJCGETJITKWKRS-UHFFFAOYSA-N methyl 4-ethylpiperazine-2-carboxylate Chemical compound CCN1CCNC(C1)C(=O)OC GJCGETJITKWKRS-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- IBMRTYCHDPMBFN-UHFFFAOYSA-N monomethyl glutaric acid Chemical compound COC(=O)CCCC(O)=O IBMRTYCHDPMBFN-UHFFFAOYSA-N 0.000 description 1
- JDRMYOQETPMYQX-UHFFFAOYSA-N monomethyl succinate Chemical compound COC(=O)CCC(O)=O JDRMYOQETPMYQX-UHFFFAOYSA-N 0.000 description 1
- 210000000651 myofibroblast Anatomy 0.000 description 1
- FCCDHFPUGHJSMW-UHFFFAOYSA-N n-(4-aminopyridin-2-yl)cyclopropanecarboxamide Chemical compound NC1=CC=NC(NC(=O)C2CC2)=C1 FCCDHFPUGHJSMW-UHFFFAOYSA-N 0.000 description 1
- KBXDYISZXRQXMW-UHFFFAOYSA-N n-(4-bromopyridin-2-yl)cyclopropanecarboxamide Chemical compound BrC1=CC=NC(NC(=O)C2CC2)=C1 KBXDYISZXRQXMW-UHFFFAOYSA-N 0.000 description 1
- DOSLAIHYFXFJGY-UHFFFAOYSA-N n-(4-nitropyridin-2-yl)cyclopropanecarboxamide Chemical compound [O-][N+](=O)C1=CC=NC(NC(=O)C2CC2)=C1 DOSLAIHYFXFJGY-UHFFFAOYSA-N 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- YXEAFYVYABSWIX-UHFFFAOYSA-N n-benzyl-n'-tritylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CNCCNC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 YXEAFYVYABSWIX-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- JUIXJPRSYHSLHK-UHFFFAOYSA-N n-methyloxetan-3-amine Chemical compound CNC1COC1 JUIXJPRSYHSLHK-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-M nicotinate Chemical compound [O-]C(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-M 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
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- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- QUBQYFYWUJJAAK-UHFFFAOYSA-N oxymethurea Chemical compound OCNC(=O)NCO QUBQYFYWUJJAAK-UHFFFAOYSA-N 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 239000011941 photocatalyst Substances 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
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- 208000023504 respiratory system disease Diseases 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 229910052895 riebeckite Inorganic materials 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000001384 succinic acid Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- HWLNKJXLGQVMJH-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC21CCNCC2 HWLNKJXLGQVMJH-UHFFFAOYSA-N 0.000 description 1
- NRADOPGBTAJXKB-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC11CNC1 NRADOPGBTAJXKB-UHFFFAOYSA-N 0.000 description 1
- MGHFVXFMQGQAKJ-UHFFFAOYSA-N tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC11CNCC1 MGHFVXFMQGQAKJ-UHFFFAOYSA-N 0.000 description 1
- OUFBVDKNEWUFHP-UHFFFAOYSA-N tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)C1CNC2 OUFBVDKNEWUFHP-UHFFFAOYSA-N 0.000 description 1
- VLMVFRLASKOYKX-UHFFFAOYSA-N tert-butyl 3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate Chemical compound COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1 VLMVFRLASKOYKX-UHFFFAOYSA-N 0.000 description 1
- ZFMZQYSBINYTHP-UHFFFAOYSA-N tert-butyl 3-(hydroxymethyl)-4-methylpiperazine-1-carboxylate Chemical compound CN1CCN(C(=O)OC(C)(C)C)CC1CO ZFMZQYSBINYTHP-UHFFFAOYSA-N 0.000 description 1
- QSYTWBKZNNEKPN-UHFFFAOYSA-N tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(CCN)CC1 QSYTWBKZNNEKPN-UHFFFAOYSA-N 0.000 description 1
- VRXIOAYUQIITBU-UHFFFAOYSA-N tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(CCO)CC1 VRXIOAYUQIITBU-UHFFFAOYSA-N 0.000 description 1
- CTEDVGRUGMPBHE-UHFFFAOYSA-N tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CO)CC1 CTEDVGRUGMPBHE-UHFFFAOYSA-N 0.000 description 1
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 1
- MYPAWHOIUKGJIE-UHFFFAOYSA-N tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC21OCCNC2 MYPAWHOIUKGJIE-UHFFFAOYSA-N 0.000 description 1
- QISVDZAPJGYHOO-UHFFFAOYSA-N tert-butyl N-[3-(3-hydroxypropylamino)propyl]-N-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)CCCNCCCO QISVDZAPJGYHOO-UHFFFAOYSA-N 0.000 description 1
- RFDSJHHLGFFVHD-UHFFFAOYSA-N tert-butyl n-(2-hydroxyethyl)-n-methylcarbamate Chemical compound OCCN(C)C(=O)OC(C)(C)C RFDSJHHLGFFVHD-UHFFFAOYSA-N 0.000 description 1
- ACNRTYKOPZDRCO-UHFFFAOYSA-N tert-butyl n-(2-oxoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC=O ACNRTYKOPZDRCO-UHFFFAOYSA-N 0.000 description 1
- UURMRXVNPHJYPC-UHFFFAOYSA-N tert-butyl n-(3-acetamidopropyl)carbamate Chemical compound CC(=O)NCCCNC(=O)OC(C)(C)C UURMRXVNPHJYPC-UHFFFAOYSA-N 0.000 description 1
- GJGLBUZZTLPCOT-UHFFFAOYSA-N tert-butyl n-(3-hydroxypropyl)-n-methylcarbamate Chemical compound OCCCN(C)C(=O)OC(C)(C)C GJGLBUZZTLPCOT-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- 229940062627 tribasic potassium phosphate Drugs 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- SFEBPWPPVGRFOA-UHFFFAOYSA-N trifluoromethanesulfinic acid Chemical class OS(=O)C(F)(F)F SFEBPWPPVGRFOA-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- C07D487/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Hydrogenated Pyridines (AREA)
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| EP20185890 | 2020-07-15 | ||
| PCT/EP2021/069649 WO2022013307A1 (en) | 2020-07-15 | 2021-07-14 | Pyridazinyl amino derivatives as alk5 inhibitors |
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| PT (1) | PT4182308T (https=) |
| SI (1) | SI4182308T1 (https=) |
| WO (1) | WO2022013307A1 (https=) |
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| JP7702205B2 (ja) * | 2021-09-15 | 2025-07-03 | 株式会社東芝 | 新規アミン化合物、酸性ガス吸収剤、酸性ガスの除去方法及び酸性ガス除去 |
| CN114957331A (zh) * | 2022-04-22 | 2022-08-30 | 北京康辰药业股份有限公司 | 磷酸酯取代的环丙酰胺衍生喹唑啉类化合物的制备方法 |
| WO2024180206A1 (en) | 2023-03-02 | 2024-09-06 | Chiesi Farmaceutici S.P.A. | Pyridazinyl amino derivatives as alk5 inhibitors |
| WO2024180207A1 (en) | 2023-03-02 | 2024-09-06 | Chiesi Farmaceutici S.P.A. | Pyridazinyl amino derivatives as alk5 inhibitors |
| KR20240159754A (ko) * | 2023-04-28 | 2024-11-06 | 한국원자력의학원 | N-메틸피페라진 에탄올 카바메이트(N-methylpiperazine ethanol carbamate) 구조를 포함하는 신규 화합물 및 이의 용도 |
| WO2025132458A1 (en) | 2023-12-18 | 2025-06-26 | Chiesi Farmaceutici S.P.A. | Pyridazinyl amino derivatives as alk5 inhibitors |
| WO2025132460A1 (en) | 2023-12-18 | 2025-06-26 | Chiesi Farmaceutici S.P.A. | Pyridazinyl amino derivatives as alk5 inhibitors |
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| DE60001229T2 (de) | 1999-04-09 | 2003-10-30 | Smithkline Beecham Corp., Philadelphia | Triarylimidazole |
| AR029803A1 (es) | 2000-02-21 | 2003-07-16 | Smithkline Beecham Plc | Imidazoles sustituidos con piridilo y composiciones farmaceuticas que las comprenden |
| GB0007405D0 (en) | 2000-03-27 | 2000-05-17 | Smithkline Beecham Corp | Compounds |
| EP1317450B1 (en) * | 2000-09-15 | 2006-11-22 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
| CA2423050A1 (en) | 2000-09-20 | 2002-03-28 | Ortho-Mcneil Pharmaceutical, Inc. | Pyrazine derivatives as modulators of tyrosine kinases |
| AR039241A1 (es) | 2002-04-04 | 2005-02-16 | Biogen Inc | Heteroarilos trisustituidos y metodos para su produccion y uso de los mismos |
| JP2006503043A (ja) * | 2002-09-10 | 2006-01-26 | サイオス インク． | ＴＧＦβ阻害剤 |
| AU2004278382B2 (en) * | 2003-09-30 | 2008-09-18 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
| BRPI0714409A2 (pt) | 2006-07-14 | 2013-03-12 | Novartis Ag | derivados de pirimidina como inibidores de alk-5 |
| ES2375425T3 (es) | 2007-07-26 | 2012-02-29 | Novartis Ag | Compuestos org�?nicos. |
| BRPI0817434A2 (pt) | 2007-10-17 | 2015-06-16 | Novartis Ag | Composto orgânicos |
| AR070127A1 (es) | 2008-01-11 | 2010-03-17 | Novartis Ag | Pirrolo - pirimidinas y pirrolo -piridinas |
| MX2010007604A (es) | 2008-01-11 | 2010-08-02 | Novartis Ag | Pirimidinas como inhibidores de cinasa. |
| US8343966B2 (en) | 2008-01-11 | 2013-01-01 | Novartis Ag | Organic compounds |
| EA201001687A1 (ru) | 2008-04-29 | 2011-06-30 | Новартис Аг | Производные имидазопиридина в качестве ингибиторов активиноподобной рецепторной киназы ( alk-4 или alk-5 ) |
| CN102596200A (zh) * | 2009-11-07 | 2012-07-18 | 默克专利有限公司 | 作为TGF-β受体激酶抑制剂的杂芳基氨基喹啉类 |
| DK2731949T3 (en) | 2011-07-13 | 2018-06-14 | Tiumbio Co Ltd | 2-PYRIDYL-SUBSTITUTED IMIDAZOLS AS ALK5 AND / OR ALK4 INHIBITORS |
| HRP20201384T1 (hr) * | 2014-01-01 | 2020-11-27 | Medivation Technologies Llc | Spojevi i postupci njihove upotrebe |
| US20200247812A1 (en) * | 2018-07-10 | 2020-08-06 | Integral Biosciences Private Limited | Heterocyclic compounds and methods of use |
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- 2021-07-14 FI FIEP21743186.5T patent/FI4182308T3/fi active
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- 2021-07-14 PL PL21743186.5T patent/PL4182308T3/pl unknown
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- 2021-07-14 AU AU2021307559A patent/AU2021307559A1/en active Pending
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| BR112023000588A2 (pt) | 2023-01-31 |
| AR122986A1 (es) | 2022-10-19 |
| TW202216677A (zh) | 2022-05-01 |
| HRP20241617T1 (hr) | 2025-01-31 |
| CA3184990A1 (en) | 2022-01-20 |
| WO2022013307A1 (en) | 2022-01-20 |
| PT4182308T (pt) | 2024-12-04 |
| AU2021307559A1 (en) | 2023-02-16 |
| JP2023533849A (ja) | 2023-08-04 |
| KR20230051500A (ko) | 2023-04-18 |
| US12479826B2 (en) | 2025-11-25 |
| BR112023000588A8 (pt) | 2023-05-09 |
| JP7686741B2 (ja) | 2025-06-02 |
| EP4182308A1 (en) | 2023-05-24 |
| US20240018122A1 (en) | 2024-01-18 |
| CN116096719A (zh) | 2023-05-09 |
| SI4182308T1 (sl) | 2025-04-30 |
| FI4182308T3 (fi) | 2024-12-07 |
| HUE069150T2 (hu) | 2025-02-28 |
| PL4182308T3 (pl) | 2025-01-07 |
| EP4182308B1 (en) | 2024-09-04 |
| CN116096719B (zh) | 2025-09-30 |
| MX2023000521A (es) | 2023-02-13 |
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