TW201831481A - 作為Rho激酶抑制劑之酪胺酸醯胺衍生物 - Google Patents
作為Rho激酶抑制劑之酪胺酸醯胺衍生物 Download PDFInfo
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- TW201831481A TW201831481A TW107102944A TW107102944A TW201831481A TW 201831481 A TW201831481 A TW 201831481A TW 107102944 A TW107102944 A TW 107102944A TW 107102944 A TW107102944 A TW 107102944A TW 201831481 A TW201831481 A TW 201831481A
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- Prior art keywords
- phenyl
- pyrrolo
- methyl
- oxy
- amino
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- 239000003590 rho kinase inhibitor Substances 0.000 title description 7
- PQFMNVGMJJMLAE-QMMMGPOBSA-N L-tyrosinamide Chemical class NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 PQFMNVGMJJMLAE-QMMMGPOBSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 135
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims abstract description 21
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims abstract description 21
- 208000006673 asthma Diseases 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 11
- 208000019693 Lung disease Diseases 0.000 claims abstract description 9
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 8
- -1 -NR 7 R 8 Chemical group 0.000 claims description 509
- 241000009298 Trigla lyra Species 0.000 claims description 77
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 71
- 239000000203 mixture Substances 0.000 claims description 58
- 125000003118 aryl group Chemical group 0.000 claims description 56
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 49
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 claims description 46
- 125000001072 heteroaryl group Chemical group 0.000 claims description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 32
- 125000005843 halogen group Chemical group 0.000 claims description 30
- 239000003112 inhibitor Substances 0.000 claims description 30
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims description 29
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 25
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 24
- 150000001412 amines Chemical class 0.000 claims description 21
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 claims description 20
- 238000006467 substitution reaction Methods 0.000 claims description 19
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 17
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
- 229920006395 saturated elastomer Polymers 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000004122 cyclic group Chemical group 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 12
- 230000005764 inhibitory process Effects 0.000 claims description 12
- 238000009472 formulation Methods 0.000 claims description 11
- 125000005016 hydroxyalkynyl group Chemical group 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 238000010828 elution Methods 0.000 claims description 9
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000012453 solvate Substances 0.000 claims description 9
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 8
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- 239000003380 propellant Substances 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 6
- 125000003003 spiro group Chemical group 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 5
- 125000006709 (C5-C7) cycloalkenyl group Chemical group 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 125000002431 aminoalkoxy group Chemical group 0.000 claims description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 5
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 5
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 claims description 4
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 claims description 4
- 102100026476 Prostacyclin receptor Human genes 0.000 claims description 4
- 239000012190 activator Substances 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 4
- 239000000443 aerosol Substances 0.000 claims description 4
- 239000005557 antagonist Substances 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 210000004369 blood Anatomy 0.000 claims description 4
- 239000008280 blood Substances 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 229940043355 kinase inhibitor Drugs 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 4
- 125000006661 (C4-C6) heterocyclic group Chemical group 0.000 claims description 3
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 108091006335 Prostaglandin I receptors Proteins 0.000 claims description 3
- 239000003242 anti bacterial agent Substances 0.000 claims description 3
- 229940088710 antibiotic agent Drugs 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000004639 dihydroindenyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 3
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 230000026731 phosphorylation Effects 0.000 claims description 3
- 238000006366 phosphorylation reaction Methods 0.000 claims description 3
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 claims description 3
- RONWGALEIBILOG-VMJVVOMYSA-N quinine sulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 RONWGALEIBILOG-VMJVVOMYSA-N 0.000 claims description 3
- 230000019491 signal transduction Effects 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- ZBIWOALTDQQQTG-UHFFFAOYSA-N (1-methylpiperazin-2-yl)methanol Chemical compound CN1CCNCC1CO ZBIWOALTDQQQTG-UHFFFAOYSA-N 0.000 claims description 2
- CHCWOCCOJMAGFK-SFHVURJKSA-N (2S)-2-amino-N-cyclohexyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]propanamide Chemical compound N1=CN=C(C2=C1NC=C2)OC1=CC=C(C=C1)C[C@@H](C(=O)NC1CCCCC1)N CHCWOCCOJMAGFK-SFHVURJKSA-N 0.000 claims description 2
- BNPHYNQCHNBJEL-UHFFFAOYSA-N 1-benzyl-2,6-dimethylpiperazine Chemical compound CC1CNCC(C)N1CC1=CC=CC=C1 BNPHYNQCHNBJEL-UHFFFAOYSA-N 0.000 claims description 2
- OENSKTBBCGEQNS-UHFFFAOYSA-N 2-amino-N-cyclohexyl-2-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]propanamide Chemical compound N1C=CC=2C1=NC=CC=2OC1=CC=C(C=C1)CC(C(=O)NC1CCCCC1)(C)N OENSKTBBCGEQNS-UHFFFAOYSA-N 0.000 claims description 2
- 102100034134 Activin receptor type-1B Human genes 0.000 claims description 2
- XMLUZISWZHXARX-UHFFFAOYSA-N C=1N=CN2C=1C=CCC2 Chemical compound C=1N=CN2C=1C=CCC2 XMLUZISWZHXARX-UHFFFAOYSA-N 0.000 claims description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
- 101000894568 Catharanthus roseus Catharanthine synthase Proteins 0.000 claims description 2
- 102000009410 Chemokine receptor Human genes 0.000 claims description 2
- 108050000299 Chemokine receptor Proteins 0.000 claims description 2
- 108010053770 Deoxyribonucleases Proteins 0.000 claims description 2
- 102000016911 Deoxyribonucleases Human genes 0.000 claims description 2
- 108010073099 Epoprostenol Receptors Proteins 0.000 claims description 2
- 101000799189 Homo sapiens Activin receptor type-1B Proteins 0.000 claims description 2
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 claims description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 2
- 102100025751 Mothers against decapentaplegic homolog 2 Human genes 0.000 claims description 2
- 101710143123 Mothers against decapentaplegic homolog 2 Proteins 0.000 claims description 2
- 102100025748 Mothers against decapentaplegic homolog 3 Human genes 0.000 claims description 2
- 101710143111 Mothers against decapentaplegic homolog 3 Proteins 0.000 claims description 2
- 102000007451 Steroid Receptors Human genes 0.000 claims description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 229940125715 antihistaminic agent Drugs 0.000 claims description 2
- 239000000739 antihistaminic agent Substances 0.000 claims description 2
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 claims description 2
- 229940124630 bronchodilator Drugs 0.000 claims description 2
- 239000000168 bronchodilator agent Substances 0.000 claims description 2
- 125000006378 chloropyridyl group Chemical group 0.000 claims description 2
- 125000006639 cyclohexyl carbonyl group Chemical group 0.000 claims description 2
- 229940112141 dry powder inhaler Drugs 0.000 claims description 2
- 239000002713 epithelial sodium channel blocking agent Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000004175 fluorobenzyl group Chemical group 0.000 claims description 2
- 102000052502 human ELANE Human genes 0.000 claims description 2
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 239000003591 leukocyte elastase inhibitor Substances 0.000 claims description 2
- 230000002934 lysing effect Effects 0.000 claims description 2
- 229940071648 metered dose inhaler Drugs 0.000 claims description 2
- 125000006178 methyl benzyl group Chemical group 0.000 claims description 2
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 229940082615 organic nitrates used in cardiac disease Drugs 0.000 claims description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 2
- 229960003910 promethazine Drugs 0.000 claims description 2
- 150000003815 prostacyclins Chemical class 0.000 claims description 2
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 2
- 229940044601 receptor agonist Drugs 0.000 claims description 2
- 239000000018 receptor agonist Substances 0.000 claims description 2
- LAXAZNKQIFIYLK-UHFFFAOYSA-N 2-amino-1-(4-benzylpiperazin-1-yl)-3-[3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]propan-1-one Chemical compound NC(C(=O)N1CCN(CC1)CC1=CC=CC=C1)CC1=CC(=C(C=C1)OC1=C2C(=NC=C1)NC=C2C)F LAXAZNKQIFIYLK-UHFFFAOYSA-N 0.000 claims 2
- FJCXTPNZOVBNQZ-UHFFFAOYSA-N 2-amino-3-[3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]-1-(2-phenylpyrrolidin-1-yl)propan-1-one Chemical compound NC(C(=O)N1C(CCC1)C1=CC=CC=C1)CC1=CC(=C(C=C1)OC1=C2C(=NC=C1)NC=C2C)F FJCXTPNZOVBNQZ-UHFFFAOYSA-N 0.000 claims 2
- NCNVPWCTEBODPS-UHFFFAOYSA-N 4-cyclopropylpiperidine Chemical compound C1CC1C1CCNCC1 NCNVPWCTEBODPS-UHFFFAOYSA-N 0.000 claims 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 claims 2
- UQHBDVXYDKLPMP-LJQANCHMSA-N (2R)-2-amino-3-[4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]-N-phenylpropanamide Chemical compound N[C@@H](C(=O)NC1=CC=CC=C1)CC1=CC=C(C=C1)OC1=C2C(=NC=C1)NC=C2C UQHBDVXYDKLPMP-LJQANCHMSA-N 0.000 claims 1
- FAEDBLAWSZOIJI-OAQYLSRUSA-N (2R)-2-amino-N-benzyl-N-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]propanamide Chemical compound N1C=CC=2C1=NC=CC=2OC1=CC=C(C=C1)C[C@H](C(=O)N(C)CC1=CC=CC=C1)N FAEDBLAWSZOIJI-OAQYLSRUSA-N 0.000 claims 1
- XJEKLXVZUBIEGO-LJQANCHMSA-N (2R)-2-amino-N-cyclohexyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]propanamide Chemical compound N1C=CC=2C1=NC=CC=2OC1=CC=C(C=C1)C[C@H](C(=O)NC1CCCCC1)N XJEKLXVZUBIEGO-LJQANCHMSA-N 0.000 claims 1
- WWYISOYNLADYJT-SCTDSRPQSA-N (2S)-1-[(3aR,6aS)-2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-2-amino-3-[3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]propan-1-one Chemical compound N[C@H](C(=O)N1C[C@@H]2CN(C[C@@H]2C1)C)CC1=CC(=C(C=C1)OC1=C2C(=NC=C1)NC=C2C)F WWYISOYNLADYJT-SCTDSRPQSA-N 0.000 claims 1
- QWWAYCFHDKIEKU-JZXOWHBKSA-N (2S)-1-[(3aS,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl]-2-amino-3-[3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]propan-1-one Chemical compound N[C@H](C(=O)N1C[C@@H]2CNC[C@@H]2C1)CC1=CC(=C(C=C1)OC1=C2C(=NC=C1)NC=C2C)F QWWAYCFHDKIEKU-JZXOWHBKSA-N 0.000 claims 1
- YTFZREGNRCKJMS-QHCPKHFHSA-N (2S)-2-amino-1-(4-benzyl-4-hydroxypiperidin-1-yl)-3-[3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]propan-1-one Chemical compound N[C@H](C(=O)N1CCC(CC1)(O)CC1=CC=CC=C1)CC1=CC(=C(C=C1)OC1=C2C(=NC=C1)NC=C2C)F YTFZREGNRCKJMS-QHCPKHFHSA-N 0.000 claims 1
- IGZMPNQURJPTEV-QFIPXVFZSA-N (2S)-2-amino-1-(4-benzyl-4-hydroxypiperidin-1-yl)-3-[3-fluoro-4-[(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]phenyl]propan-1-one Chemical compound N[C@H](C(=O)N1CCC(CC1)(O)CC1=CC=CC=C1)CC1=CC(=C(C=C1)OC=1C2=C(N=CN=1)NC=C2C)F IGZMPNQURJPTEV-QFIPXVFZSA-N 0.000 claims 1
- XEYFDVMDBYDZQA-DEOSSOPVSA-N (2S)-2-amino-1-(4-benzylpiperazin-1-yl)-3-[3-fluoro-4-[(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]propan-1-one Chemical compound N[C@H](C(=O)N1CCN(CC1)CC1=CC=CC=C1)CC1=CC(=C(C=C1)OC1=C2C(=NC=C1)NC(=C2)C)F XEYFDVMDBYDZQA-DEOSSOPVSA-N 0.000 claims 1
- WYYIPGZLXLNLFX-QFIPXVFZSA-N (2S)-2-amino-1-(4-benzylpiperazin-1-yl)-3-[3-fluoro-4-[(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]phenyl]propan-1-one Chemical compound N[C@H](C(=O)N1CCN(CC1)CC1=CC=CC=C1)CC1=CC(=C(C=C1)OC=1C2=C(N=CN=1)NC=C2C)F WYYIPGZLXLNLFX-QFIPXVFZSA-N 0.000 claims 1
- MVSOWGILPYPLPF-QHCPKHFHSA-N (2S)-2-amino-1-(4-benzylpiperazin-1-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]propan-1-one Chemical compound N1=CN=C(C2=C1NC=C2)OC1=CC=C(C=C1)C[C@@H](C(=O)N1CCN(CC1)CC1=CC=CC=C1)N MVSOWGILPYPLPF-QHCPKHFHSA-N 0.000 claims 1
- FQSBFOHBSBSPOE-QHCPKHFHSA-N (2S)-2-amino-1-(4-benzylpiperazin-1-yl)-3-[4-[(3-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]propan-1-one Chemical compound N[C@H](C(=O)N1CCN(CC1)CC1=CC=CC=C1)CC1=CC=C(C=C1)OC1=C2C(=NC=C1)NC=C2F FQSBFOHBSBSPOE-QHCPKHFHSA-N 0.000 claims 1
- YVUJXMGIWMVKMG-QHCPKHFHSA-N (2S)-2-amino-1-(4-benzylpiperazin-1-yl)-3-[5-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)pyridin-2-yl]propan-1-one Chemical compound N1C=CC=2C1=NC=CC=2OC=1C=CC(=NC=1)C[C@@H](C(=O)N1CCN(CC1)CC1=CC=CC=C1)N YVUJXMGIWMVKMG-QHCPKHFHSA-N 0.000 claims 1
- NVMAVBONYSCHRF-DEOSSOPVSA-N (2S)-2-amino-1-(4-benzylpiperidin-1-yl)-3-[3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]propan-1-one Chemical compound N[C@H](C(=O)N1CCC(CC1)CC1=CC=CC=C1)CC1=CC(=C(C=C1)OC1=C2C(=NC=C1)NC=C2C)F NVMAVBONYSCHRF-DEOSSOPVSA-N 0.000 claims 1
- YVBSMKHLIZMWGH-SFHVURJKSA-N (2S)-2-amino-1-(7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-3-[3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]propan-1-one Chemical compound N[C@H](C(=O)N1CC2=C(N=CN=C2)CC1)CC1=CC(=C(C=C1)OC1=C2C(=NC=C1)NC=C2C)F YVBSMKHLIZMWGH-SFHVURJKSA-N 0.000 claims 1
- GGRAYLAJNWSEEO-AEFFLSMTSA-N (2S)-2-amino-1-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-3-[3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]propan-1-one Chemical compound N[C@H](C(=O)N1C[C@@H](CC1)N(C)C)CC1=CC(=C(C=C1)OC1=C2C(=NC=C1)NC=C2C)F GGRAYLAJNWSEEO-AEFFLSMTSA-N 0.000 claims 1
- GGRAYLAJNWSEEO-WMZOPIPTSA-N (2S)-2-amino-1-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-3-[3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]propan-1-one Chemical compound N[C@H](C(=O)N1C[C@H](CC1)N(C)C)CC1=CC(=C(C=C1)OC1=C2C(=NC=C1)NC=C2C)F GGRAYLAJNWSEEO-WMZOPIPTSA-N 0.000 claims 1
- FFJBSUYOVLOYHT-BKSPAHHJSA-N (2S)-2-amino-1-[(3S,5R)-4-benzyl-3,5-dimethylpiperazin-1-yl]-3-[3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]propan-1-one Chemical compound N[C@H](C(=O)N1C[C@@H](N([C@@H](C1)C)CC1=CC=CC=C1)C)CC1=CC(=C(C=C1)OC1=C2C(=NC=C1)NC=C2C)F FFJBSUYOVLOYHT-BKSPAHHJSA-N 0.000 claims 1
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Abstract
本發明係有關於屬於雙環二氫嘧啶-羧醯胺衍生物的Rho激酶抑制作用的式I化合物,此等化合物之製備方法,含有該等化合物之醫藥組成物及其治療用途。
特別地,本發明之化合物用於許多ROCK酶機轉相關聯的病症之治療上可能有用,諸如肺臟疾病包括氣喘、慢性阻塞性肺病(COPD)、特發性肺纖維化(IPF)及肺動脈高壓(PAH)。
Description
本發明係有關於Rho激酶的抑制性化合物(後文稱作ROCK抑制劑);特別地,本發明係有關於酪胺酸醯胺衍生物,此等化合物之製備方法,含有其之醫藥組成物,及其治療用途。
更明確言之,本發明之化合物為Rho-相關聯的雙螺旋生成性蛋白質激酶(ROCK)之ROCK-I及/或ROCK-II同功異形體之活性或功能的抑制劑。
因此,本發明之化合物用於與ROCK酶機轉相關聯的許多病症之治療上是有用的,諸如肺臟疾病包括氣喘、慢性阻塞性肺病(COPD)、特發性肺纖維化(IPF)及肺動脈高壓(PAH)。
Rho-相關聯的雙螺旋生成性蛋白質激酶(ROCK)屬於絲胺酸-蘇胺酸激酶的AGC(PKA/PKG/PKC)家族。已描述兩種ROCK之人類同功異形體,ROCK-I(又稱p160 ROCK或ROKβ)及ROCK-II(ROKα)為約160kDa蛋白質,其含有N端Ser/Thr激酶功能域,其後接著雙螺旋結構,普列克基蛋白(pleckstrin)同源功能域,及在C端的富含半胱胺酸區(Riento,K.;Ridley,A.J.Rocks:multifunctional kinases in cell behaviour.Nat.Rev.Mol.Cell Biol.2003,4,446-456)。
ROCK-II及ROCK-I兩者在許多人類組織及齧齒類組織表現,包括心、胰、肺、肝、骨骼肌、腎及腦(Riento and Ridley,2003)。ROCK已被識別為RhoA之效應物分子,且涉及多項細胞功能,包括肌動蛋白組織、細胞黏附、細胞遷移、及胞質分裂(Riento and Ridley,2003;Feng Y,LoGrasso PV,Defert O,Li R.Rho Kinase(ROCK)Inhibitors and Their Therapeutic Potential.J Med Chem.2016;59(6):2269-300)。其也涉及透過效應物(諸如肌球蛋白輕鏈磷酸酶(MLC))之磷酸化而調節平滑肌收縮。確實,ROCK在藉由數種在血管及/或呼吸道調節平滑肌細胞收縮的作用劑,包括血清素、血管緊張素II、內皮素I、血小板衍生生長因子(PDGF)、及尿加壓素(urotensin)II,所引發的信號轉導中扮演要角(Li Q,Xu Y,Li X,Guo Y,Liu G.Inhibition of Rho-kinase ameliorates myocardial remodeling and fibrosis in pressure overload and myocardial infarction:role of TGF-β1-TAK1.Toxicol Lett.2012;211(2):91-7;Shi J,Wei L.Rho kinases in cardiovascular physiology and pathophysiology:the effect fo fasudil.J Cardiovasc Pharmacol.2013;62(4):341-54)。至今只有兩種ROCK抑制劑已經於日本及/或中國核准供臨床使用:Fasudil(Suzuki Y,Shibuya M,Satoh S,Sugiyama H,Seto M,Takakura K.Safety and efficacy of fasudil monotherapy and fasudil-ozagrel combination therapy in patients with subarachnoid hemorrhage:sub-analysis of the post-marketing surveillance study.Neurol Med Chir(Tokyo).2008;48(6):241-7)於1995年被核准用於腦血管痙攣之治療;及ripasudil(Tanihara H,Inoue T,Yamamoto T,Kuwayama Y,Abe H,Fukushima A,Suganami H,Araie M;K-115 Clinical Study Group.One-year clinical evaluation of 0.4% ripasudil(K-115)in patients with open-angle glaucoma and ocular hypertension.Acta Ophthalmol.2016;94(1):e26-34)於2014年被核准用於青光眼之治療。
ROCK媒介血管收縮及媒介內皮功能異常,此乃數種心血管病的兩項關鍵組成因子,包括高血壓性心臟病、冠狀動脈病、動脈粥狀硬化、血管再狹窄、雷諾氏現象、中風、及青光眼(Hartmann S,Ridley AJ,Lutz S.The Function of Rho-Associated Kinases ROCK1 and ROCK2 in the Pathogenesis of Cardiovascular Disease.Front Pharmacol.2015 Nov 20;6:276)。特別地,得自臨床試驗之藥理資料顯示:ROCK抑制劑於青光眼病人降低眼內壓,及驗證有利效果(Inoue T,Tanihara H.Rho-associated kinase inhibitors:a novel glaucoma therapy.Prog Retin Eye Res.2013;37:1-12)。比較對照組,於患肺高壓病人體,ROCK活性於肺組織中及於循環嗜中性細胞中顯著地增高(Duong-Quy S,Bei Y,Liu Z,Dinh-Xuan AT.Role of Rho-kinase and its inhibitors in pulmonary hypertension.Pharmacol Ther.2013;137(3):352-64)。已確立嗜中性細胞ROCK活性與肺高壓的嚴重程度及持續時間間有顯著交互關係(Duong-Quy et al.,2013)。ROCK也促成心纖維化、心肥大、及隨後心衰竭的發展。晚近使用ROCK抑制劑諸如fasudil的實驗研究,已經顯示ROCK抑制作用於心臟組織重建的效果(Li et al.,2012)。缺乏各種ROCK同功異形體的小鼠,於多個心臟組織重建的病理模型中,也呈現心肌纖維化的減少(Shimizu Tl,Liao JK.Rho Kinases and Cardiac Remodeling.Circ J.2016;80(7):1491-8)。
ROCK用於腦血管病症之治療上也極有前景。確實,臨床前期研究指出:Rho激酶抑制作用可能減少顱內血管瘤及腦海綿狀畸形的生成/生長/破裂(Bond LM,Sellers JR,McKerracher L.Rho kinase as a target for cerebral vascular disorders.Future Med Chem.2015;7(8):1039-53)。
RhoA-ROCK傳訊在維持陰莖弛軟狀態上重要,及ROCK傳訊之藥理抑制作用以NO不相干方式強化了平滑肌鬆弛,提示ROCK為用於治療勃起功能異常的新穎治療標靶(Sopko NA,Hannan JL,Bivalacqua TJ.Understanding and targeting the Rho kinase pathway in erectile dysfunction.Nat Rev Urol.2014;11(11):622-8)。
ROCK活性乃白血球-血小板-內皮交互作用、白血球外滲作用及水腫的重要傳訊機轉。於內皮細胞中,Rho激酶的過度活化,藉由有利於發炎細胞補充增員的干擾細胞-細胞接合而造成滲漏。組合在一起考量,此等證據指出ROCK於與急性及慢性發炎病以及自體免疫病相關聯的病理狀況上扮演某種角色。特別地,ROCK對自體免疫及自體免疫病的促成作用的研究正在進行中(Zanin-Zhorov A,Flynn R,Waksal SD,Blazar BR.Isoform-specific targeting of ROCK proteins in immune cells.Small GTPases.2016;7(3):173-177)。此點由ROCK傳訊T細胞的發展與功能(包括黏著、趨化反應、及抗原相依性活化)上扮演某種角色獲得驗證,以及ROCK抑制於類風濕性關節炎及狼瘡之實驗模型中之有利功效獲得證實(LoGrasso,P.;Feng,Y.Rho kinase inhibitors and their application to inflammatory disorders.Curr.Top.Med.Chem.2009; 9,704-723;Yoshimi,E.;Kumakura,F.;Hatori,C.;Hamachi,E.;Iwashita,A.;Ishii,N.;Terasawa,T.;Shimizu,Y.;Takeshita,N.Antinociceptive effects of AS1892802,a novel rho kinase inhibitor,in rat models of inflammatory and noninflammatory arthritis.J.Pharmacol.Exp.Ther.2010,334,955-963;Stirzaker RA,Biswas PS,Gupta S,Song L,Bhagat G,Pernis AB.Administration of fasudil,a ROCK inhibitor,attenuates disease in lupus-prone NZB/W F1 female mice.Lupus.2012 May;21(6):656-61)。法舒地爾(Fasudil)於T細胞遷移上的抑制效果可能使得其臨床應用擴大成為多發性硬化的新穎療法(Yu JZ,Ding J,Ma CG,Sun CH,Sun YF,Lu CZ,Xiao BG.Therapeutic potential of experimental autoimmune encephalomyelitis by Fasudil,a Rho kinase inhibitor.J Neurosci Res.2010;88(8):1664-72)。累積的證據也驗證ROCK於調節發炎性腸病(IBD)病因的下列三項重大因子上扮演關鍵角色:腸障壁干擾;管腔內容物暴露於黏膜免疫細胞;及免疫反應異常(Huang Y,Xiao S,and Jiang Q.Role of Rho kinase signal pathway in inflammatory bowel disease Int J Clin Exp Med.2015;8(3):3089-3097)。臨床上,也在監視下將ROCK抑制劑使用於乾癬(Yiu ZZ,Warren RB.Novel Oral Therapies for Psoriasis and Psoriatic Arthritis.Am J Clin Dermatol.2016;17(3):191-200)。
有數條證據顯示ROCK在糖尿病病理上扮演某種角色。確實,ROCK1 KO小鼠具有胰島素抗性,葡萄糖誘發胰島素的分泌顯著地增加,結果導致高胰島素血症(Lee D.H.,Shi J.,Jeoung N.H.,Kim M.S.,Zabolotny J.M.,Lee S.W.,et al.Targeted disruption of ROCK1 causes insulin resistance in vivo.J.Biol.Chem.2009;284,11776-11780)。此外,於第一型及第二型糖尿病模型的研究中,已指出ROCKi用於糖尿病性腎病的非血壓依賴型腎臟保護作用(Komers R.Rho kinase inhibition in diabetic kidney disease.Br J Clin Pharmacol.2013;76(4):551-9)。
現在已有實質證據證實ROCK涉及促成數種急性及慢性肺病相關聯的病理路徑中之許多路徑,包括氣喘、COPD、支氣管擴張、及ARDS/ALI。指定ROCK的生物功效,ROCK選擇性抑制劑有治療多種呼吸系疾病的病理機轉的潛力,諸如平滑肌過度反應性、支氣管縮窄、氣道發炎及氣道組織重建、神經調節、及因呼吸道病毒性感染所致之惡化(Fernandes LB,Henry PJ,Goldie RG.Rho kinase as a therapeutic target in the treatment of asthma and chronic obstructive pulmonary disease.Ther Adv Respir Dis.2007 Oct;1(1):25-33)。確實,Rho激酶抑制劑Y-27632造成支氣管弛張,及減少肺嗜伊紅細胞增多及減輕氣道過度反應(Gosens,R.;Schaafsma,D.;Nelemans,S.A.;Halayko,A.J.Rhokinase as a drug target for the treatment of airway hyperresponsiveness in asthma.Mini-Rev.Med.Chem.2006,6,339-348)。已經於患有特發性肺纖維化(IPF)的人體及此種疾病的動物模型中驗證肺ROCK活化作用。於此等研究模型中,ROCK抑制劑可預防纖維化,及更要緊地,誘使已確立的纖維化退行,如此指示ROCK抑制劑乃用來中止肺纖維化進行的潛在有力藥理作用劑(Jiang,C.;Huang,H.;Liu,J.;Wang,Y.;Lu,Z.;Xu,Z.Fasudil,a rho-kinase inhibitor,attenuates bleomycin-induced pulmonary fibrosis in mice.Int.J.Mol.Sci.2012, 13,8293-8307)。
累積的證據證實:ROCK透過調節惡性病相關聯的多種關鍵細胞功能,而在腫瘤發展與進行上扮演要角的構想,包括腫瘤發生、腫瘤生長、腫瘤轉移、血管新生、腫瘤細胞凋亡/存活、及化學品抗性(Wei L,Surma M,Shi S,Lambert-Cheatham N,Shi J.Novel Insights into the Roles of Rho Kinase in Cancer.Arch Immunol Ther Exp(Warsz).2016;64(4):259-78)。如此,指出ROCK抑制劑也是用於癌症的潛在有力藥理作用劑。
投予口服ROCK抑制劑,有效地改善了移植物對宿主病(GVHD)的實驗模型的臨床表徵(Biol Blood Marrow Transplant.2014;20(8):1104-11;Blood.2016;127(17):2144-54)。進一步發現強調了Rho激酶可於進行性核上麻痺(PSP)及皮質基底核退化症(CBD)中對抗τ堆積,因而可作為合理的治療標靶(Gentry et al.,J Neurosci.2016;36(4):1316-23)。
多種中樞神經系統病症出現Rho/ROCK路徑的異常活化。ROCK在成人腦部及脊索受傷時被活化,及在脊索受傷之後,ROCK之抑制導致再生加速與功能復原的提升(Kubo T,Hata K,Yamaguchi A,Yamashita T.Rho-ROCK inhibitors as emerging strategies to promote nerve regeneration.Curr Pharm Des.2007;13(24):2493-9)。也已證實Rho/ROCK路徑的抑制,用於中風、發炎疾病及脫髓鞘病、阿茲海默氏病、及神經病變性疼痛的動物模型中有效(由Mueller,B.K.;Mack,H.;Teusch,N.Rho kinase,a promising drug target for neurological disorders.Nat.Rev.Drug Discovery 2005,4,387-398綜論)。
考文獻中已描述多種化合物為Rho激酶抑制劑。例如參考WO2004/039796;WO2006/009889;WO2010/032875;WO2009/079008;WO2014/118133。
許多治療領域中仍然有待發展新穎的且藥理上改良的ROCK抑制劑,諸如:心血管病及呼吸系統病、勃起功能障礙、纖維化疾病、胰島素抗性、腎衰竭、中樞神經系統病症、自體免疫病、及腫瘤學。
有鑑於多種病理反應係由ROCK酶媒介,故仍然持續需要有用於許多病症之治療上有用的此等ROCK酶之抑制劑。本發明係有關於新穎化合物,其為Rho-相關聯的雙螺旋生成性蛋白質激酶(ROCK)之ROCK-I及/或ROCK-II同功異形體的抑制劑,其具有治療上期望的特性,用於許多肺臟疾病特別具有前景,包括氣喘、慢性阻塞性肺病(COPD)、特發性肺纖維化(IPF)及肺高壓(PH),及特別是肺動脈高壓(PAH)。
本發明係有關於式(I)化合物
其中X1、X2、R、R0、R1、R2、R3、R4、R5、R6及p係如後文於 本發明之詳細說明部分中報告,作為ROCK抑制劑,其製備方法,與一個或多個醫藥上可接受之載劑混合的或為單獨使用的或為與一個或多個活性成分組合的包含該等化合物之醫藥組成物。
於一個態樣中,本發明提供本發明之化合物用於製造藥物之用途。
於又一個態樣中,本發明提供本發明之化合物用於製造任何以ROCK酶的活性異常為特徵之疾病的治療用藥物之用途,及/或於該疾病中,期望抑制ROCK酶活性,特別地,比較其它激酶,係透過對ROCK酶同功異形體之選擇性抑制而發揮作用。
再者,本發明提供其中期望抑制ROCK酶活性的任何疾病之預防及/或治療方法,該方法包含對有此等治療需要之病人投予治療上有效量之本發明之化合物。
特別地,本發明之化合物單獨或與其它活性成分組合,可被投予用於肺臟疾病之預防及/或治療,該等疾病包括氣喘、慢性阻塞性肺病(COPD)、特發性肺纖維化(IPF)及肺高壓(PH),且尤其是肺動脈高壓(PAH)。
本發明係有關於作為Rho激酶(ROCK)抑制劑的化合物類別。
該類化合物抑制ROCK酶之活性或功能,及更明確言之,其乃Rho-相關聯的雙螺旋生成性蛋白質激酶(ROCK)之ROCK-I及ROCK-II同功異形體之抑制劑。本發明係有關於式(I)化合物
其中X1及X2於各次出現時係獨立地為CH基或氮原子;p為0或1至3之整數;當存在時,各個R為鹵原子;R0及R1係獨立地選自於由下列所組成之組群:-H,鹵原子,-NR7R8,-CN,(C1-C6)烷基,(C1-C6)鹵烷基,(C1-C6)羥基烷基,(C1-C6)胺基烷基,(C1-C6)烷氧基-(C1-C6)烷基,(C3-C10)環烷基,(C2-C6)烯基,(C5-C7)環烯基,(C2-C6)炔基, (C2-C6)羥基炔基,芳基、雜芳基及(C3-C6)雜環烷基,該等芳基、雜芳基及(C3-C6)雜環烷基中之各者個別任選地及獨立地經以選自於下列中之一個或多個基團取代:鹵原子,-OH,-CN,-NR7R8,-CH2NR7R8,(C1-C6)烷基,(C1-C6)鹵烷基,(C1-C6)羥基烷基,(C2-C6)烯基,(C2-C6)炔基,(C2-C6)羥基炔基;R2及R3為相同或相異且係選自於由下列所組成之組群:-H,(C1-C6)烷基,(C1-C6)鹵烷基,(C1-C6)羥基烷基,(C1-C6)胺基烷基,(C1-C6)烷氧基(C1-C6)烷基,(C3-C10)環烷基(C3-C8)雜環烷基, 芳基,雜芳基,芳基(C1-C6)烷基,雜芳基(C1-C6)烷基,(C3-C8)環烷基(C1-C6)烷基,(C3-C8)雜環烷基-(C1-C6)烷基,該等芳基、雜芳基、環烷基、雜環烷基中之各者係進一步任選地經以獨立地選自於下列中之一個或多個基團取代:鹵原子、-CN、-OH、(C1-C8)烷基、(C1-C6)鹵烷基、(C1-C10)烷氧基、芳基、芳基(C1-C6)烷基、胺基甲醯基、(C1-C6)胺基烷基、(C1-C6)羥基烷基;或替代地,R2及R3與其鍵聯之氮原子一起,生成一環系或二環系飽和的或部分飽和的雜環系基團,較佳地4至6員一環系基團,於該雜環系基團中之至少又一個環碳原子係任選地由獨立地選自於N、S或O中之至少又一個雜原子置換,及/或可帶有-側氧基(=O)取代基,該雜環系基團係進一步任選地包括螺環二取代,以及在兩相毗鄰或鄰近原子上的取代生成額外5至6員環系或雜環系飽和環、部分飽和環或芳香環;該雜環系基團個別任選地進一步經以選自於由下列所組成之組群中之一個或多個基團取代:鹵原子,羥基,-NR7R8,-CH2NR7R8, (C1-C6)烷基,(C1-C6)鹵烷基,(C1-C6)羥基烷基,(C2-C6)烯基,(C2-C6)炔基,(C2-C6)羥基炔基,(C1-C6)烷氧基(C1-C6)烷基,(C1-C6)烷醯基,胺基甲醯基,(C3-C6)環烷基-羰基,(C3-C6)雜環烷基-羰基,芳基(C1-C6)烷基,芳基烷醯基,芳基磺醯基,雜芳基(C1-C6)烷基,雜芳基-羰基,雜芳基氧基,(C3-C6)環烷基,(C3-C8)環烷基(C1-C6)烷基,(C3-C6)雜環烷基-(C1-C6)烷基,芳基及雜芳基,該等環烷基、芳基及雜芳基中之各者係進一步任選地經以鹵原子、(C1-C8)烷基、(C1-C10)烷氧基、(C1-C6)烷基硫基、(C1-C6)胺基烷基、(C1-C6)胺基烷氧基、胺基甲醯基、(C1-C6)烷基-磺醯基取代; R4及R5於各次出現時係獨立地選自於由下列所組成之組群:H,(C1-C6)烷基,(C1-C6)鹵烷基,(C1-C6)羥基烷基,(C1-C6)胺基烷基,(C1-C6)烷氧基,(C1-C6)烷氧基-(C1-C6)烷基,(C3-C6)環烷基-(C1-C6)烷基,(C3-C6)雜環烷基-(C1-C6)烷基,(C3-C6)環烷基-羰基,(C3-C6)雜環烷基-羰基,芳基、雜芳基及(C3-C6)雜環烷基;其中該等(C3-C6)環烷基、芳基、雜芳基及(C3-C6)雜環烷基中之任一者個別任選地及獨立地經以選自於下列中之一個或多個基團取代:鹵原子,-OH,(C1-C6)烷基;R6係選自於由-H、(C1-C6)烷基、(C1-C6)鹵烷基所組成的組群;R7及R8於各次出現時係獨立地選自於由下列所組成之組群:H,(C1-C6)烷基,(C1-C6)鹵烷基, (C1-C6)羥基烷基,(C1-C6)胺基烷基,(C1-C6)烷氧基,(C1-C6)烷氧基-(C1-C6)烷基,(C3-C6)雜環烷基-(C1-C6)烷基,芳基、雜芳基及(C3-C6)雜環烷基;其中該等芳基、雜芳基及(C3-C6)雜環烷基中之任一者個別任選地及獨立地經以選自於下列中之一個或多個基團取代:鹵原子,-OH,(C1-C6)烷基;或R7及R8與其鍵聯之氮原子一起生成4至6員雜環系基團,其中於該雜環系基團中之至少又一個環碳原子可由選自於N、S或O中之至少一個基團置換;該雜環系基團可進一步任選地經以選自於下列中之基團取代:H,-CN,鹵原子,-側氧基,-NR7R8,(C1-C6)烷基,(C1-C6)鹵烷基,(C1-C6)羥基烷基,(C1-C6)胺基烷基, (C1-C6)烷氧基,(C1-C6)烷氧基-(C1-C6)烷基,烷醯基;及其醫藥上可接受之鹽及其溶劑合物。
如於本文中使用,術語「醫藥上可接受之鹽」係指式(I)化合物之衍生物,其中親代化合物係藉由使用習知意圖為醫藥上可接受之任何鹼或酸,將自由態酸基或鹼基(若存在時)轉換成對應的加成鹽而合宜地經修飾。
如此,鹽類之合宜實例可包括鹼性殘基(諸如胺基)之無機或有機酸加成鹽,以及酸殘基(諸如羧酸基)之無機或有機鹼加成鹽。
於本發明中,可被合宜地使用來製備鹽類之無機鹼陽離子包含鹼金屬之離子或鹼土金屬之離子,諸如鉀、鈉、鈣或鎂。
經由作為鹼功能的主化合物與無機酸或有機酸反應而生成鹽所獲得者包含,例如,鹽酸、氫溴酸、硫酸、磷酸、甲烷磺酸、樟腦磺酸、乙酸、草酸、順丁烯二酸、反丁烯二酸、丁二酸、及檸檬酸等之鹽類。
如於本文中使用,術語「鹵素」或「鹵原子」包括氟、氯、溴、及碘原子,較佳地為氯或氟;表示氟、氯、溴、碘作為取代基。
術語「(C1-C6)烷基」係指直鏈或分支烷基,其中組成碳原子之數目係於1至6之範圍。特定烷基為甲基、乙基、正丙基、異丙基、及第三丁基。
表示法「(C1-C6)鹵烷基」係指如上定義的「(C1-C6)烷基」其中一個或多個氫原子經以一個或多個鹵原子置換,該等鹵原子可彼此相同或相異。
如此,(C1-C6)鹵烷基之實例可包括鹵化烷基、多鹵化烷基、及全鹵化烷基其中全部氫原子皆被鹵原子置換,例如,三氟甲基或二氟甲基。
以類似方式,術語「(C1-C6)羥基烷基」或「(C1-C6)胺基烷基」係指如上定義的「(C1-C6)烷基」其中一個或多個氫原子分別地經以一個或多個羥基(OH)或胺基置換。非限制性實例個別地為羥基甲基及胺基甲基及其類。
於本文描述中,除非另行界定,否則胺基烷基之定義涵蓋經以一個或多個胺基(NR7R8)取代的烷基(亦即「(C1-C6)烷基」)。如此,胺基烷基之實例為一-胺基烷基,諸如R7R8N-(C1-C6)烷基。
至於如上文及下文中定義的取代基R7及R8,本文中進一步解釋當R7及R8與其鍵聯之氮原子一起生成4至6員雜環系基團時,於該雜環系基團中之至少又一個環碳原子可由至少一個雜原子(例如,N、S或O)任選地置換及/或可載有-側氧基(=O)取代基。須瞭解雜環系基團可在環中任何可用的點上,亦即,碳原子上或可供取代的任何雜原子上,進一步任選地經取代。碳原子上的取代包括螺二取代,以及在兩相鄰碳原子上的取代,於兩種情況下,如此生成了一個額外5至6員雜環系環。如此,雜環基團之實例為1-吡咯啶基、1-哌啶基、1-哌基、4-啉基、哌-4-基-2-酮、4-甲基哌-1-基、4-甲基哌-1-基-2-酮、7-甲基-2,7-二吖螺[3.5]壬烷-2- 基、2-甲基-2,9-二吖螺[5.5]十一烷-9-基、9-甲基-3,9-二吖螺[5.5]十一烷-3-基、及(3aR,6aS)-5-甲基-八氫吡咯并[3,4-c]吡咯-2-基、8-甲基-2,8-二吖螺[4.5]癸烷-2-基、5-甲基-八氫吡咯并[3,4-c]吡咯-2-基、1,1-二氧化物噻啉-4-基。
術語「(C3-C10)環烷基」及同樣地「(C3-C6)環烷基」係指含有指定數目環碳原子之飽和環系烴基。實例包括環丙基、環丁基、環戊基、環己基、及環庚基,及多環系諸如金剛烷基。
術語「(C2-C6)烯基」係指具有呈順式或反式組態之一個或多個雙鍵(共軛或非共軛)的直鏈或分支碳鏈,其中之原子數目係於2至6之範圍。
以類似方式,術語「(C5-C7)環烯基」係指含有5至7個環碳原子及一或二個雙鍵之環系烴基。
術語「(C2-C6)炔基」係指具有一個或多個三鍵的直鏈或分支碳鏈,其中之原子數目係於2至6之範圍。
術語「(C2-C6)羥基炔基」係指如上定義的「(C1-C6)炔基」其中一個或多個氫原子經以一個或多個羥基(OH)置換。
術語「(C2-C6)胺基炔基」係指如上定義的「(C1-C6)炔基」其中一個或多個氫原子經以一個或多個(-NR7R8)基置換。
表示法「芳基」係指含6至20個環原子之,較佳地含6至15個環原子之一-、二-或三-環碳環系,其中至少一個環為芳香環。表示法「雜芳基」係指含5至20個環原子之,較佳地5至15個環原子之一-、二-或三-環的環系,其中至少一個環為芳香環,且其中至少一個環原子為雜原子(例如,N、S或O)。
合宜的芳基或雜芳基一環系之實例包括例如,苯基、 噻吩基、吡咯基、吡唑基、咪唑基、異唑基、唑基、異噻唑基、噻唑基、吡啶基、嘧啶基、吡基、三基、呋喃基及其類。
合宜的芳基或雜芳基二環系之實例包括萘基、聯苯基、嘌呤基、喋啶基、吡唑并嘧啶基、苯并三唑基、苯并咪唑基、喹啉基、異喹啉基、吲哚基、異吲哚基、苯并噻吩基、苯并二基、二氫苯并二基、茚基、二氫茚基、二氫苯并[1,4]二基、苯并噻唑-2-基、二氫苯并二呯基、苯并基及其類。
合宜的芳基或雜芳基三環系之實例包括芴基,以及前述雜芳基二環系之苯并稠合衍生物。
以類似方式,表示法「伸芳基」及「伸雜芳基」係指二價基,諸如伸苯基、伸聯苯基、及伸噻吩基。此等基團也俗稱為「芳烴二基」及「雜芳烴二基」。舉例言之,鄰-伸苯基又名苯-1,2-二基。伸噻吩基又稱噻吩二基。
衍生表示法「(C3-C6)雜環烷基」係指飽和或部分不飽和一環系(C3-C6)環烷基,其中至少一個環碳原子係由至少一個雜原子(例如,N、S或O)置換或可載有-側氧基(=O)取代基。該雜環烷基(亦即,雜環系基團或雜環系基)可在環中任何可用的點上,亦即碳原子上進一步任選地經取代,或在可供取代的雜原子或雜基上進一步任選地經取代。碳原子上的取代包括螺二取代,以及在兩相鄰碳原子上的取代,於兩種情況下,如此生成了額外稠合5至6員雜環系環。(C3-C6)雜環烷基之實例係以下列為代表:吡咯啶基、咪唑啶基、噻唑啶基、哌基、哌啶基、啉基、噻啉基、二氫吡啶基或四氫吡啶基、四氫吡喃基、吡喃基、2H-吡喃基或4H-吡喃基、二氫呋喃基或四氫呋喃基、二氫異唑基、吡咯啶-2-酮-基、二氫 吡咯基及其類。
該等雜環基團之特定實例為1-吡咯啶基、1-甲基-2-吡咯啶基、1-哌啶基、1-哌基、4-啉基、哌-4-基-2-酮、4-甲基哌-1-基、1-甲基哌啶-4-基、4-甲基哌-1-基-2-酮、7-甲基-2,7-二吖螺[3.5]壬烷-2-基、2-甲基-2,9-二吖螺[5.5]十一烷-9-基、9-甲基-3,9-二吖螺[5.5]十一烷-3-基、及(3aR,6aS)-5-甲基-八氫吡咯并[3,4-c]吡咯-2-基。
術語「芳基(C1-C6)烷基」係指芳基環鍵聯至直鏈或分支烷基其中組成碳原子之數目係於1至6之範圍,例如,苯基甲基(亦即,苄基)、苯基乙基、或苯基丙基。
同樣地,術語「雜芳基(C1-C6)烷基」係指雜芳基環鍵聯至直鏈或分支烷基其中組成碳原子之數目係於1至6之範圍,例如,呋喃基甲基。
術語「烷醯基」係指HC(O)-或烷基羰基(例如,(C1-C6)烷基C(O)-)其中該「烷基」具有如上界定之意義。實例包括甲醯基、乙醯基、丙醯基、丁醯基。
同樣地,「(C1-C6)烷基-磺醯基」係指(C1-C6)烷基-S(O)2基其中該烷基具有如上定義之意義。(C1-C6)烷基-磺醯基之實例為甲基磺醯基。
術語「胺基甲醯基」係指胺基羰基衍生基-C(O)NR7R8,其中R7及R8係如上於胺基烷基中之定義界定,且包括經取代之(較佳地,胺基烷基經取代之)及螺環經取代之衍生物。此等胺基甲醯基之實例為胺基羰基、哌-1-羰基、啉-N-羰基、啉-N-羰基及N-(2-(二甲基胺基)乙基)胺基羰基、N-(2-(二甲基胺基) 乙基)-N-甲基胺基羰基、N-(3-(二甲基胺基)丙基)-N-甲基胺基羰基、4-甲基哌-1-甲羰基、4-(二甲基胺基)哌啶-1-羰基、N-(2-(4-甲基哌-1-基)乙基)胺基羰基、(2-啉基-乙基)胺基羰基、N-甲基-N-(2-啉基-乙基)胺基羰基、N-(2-(哌啶-1-基)乙基)胺基羰基、N-甲基-N-(2-(哌啶-1-基)乙基)胺基羰基、N-(1-甲基哌啶-4-基-甲基)胺基羰基、N-甲基-N-(1-甲基哌啶-4-基)胺基羰基、N-甲基-N-(1-甲基哌啶-4-基)胺基羰基、5-甲基八氫吡咯并[3,4-c]吡咯-2-羰基。
術語「羥基羰基」係指端基HOC(O)-。
術語「(C1-C10)烷氧」或「(C1-C10)烷氧基」,同樣地「(C1-C6)烷氧」或「(C1-C6)烷氧基」係指透過氧橋附接的具有所示碳數的直鏈烴或分支烴。同樣地,術語「(C1-C6)烷基硫基」係指透過硫橋附接的如上烴。
衍生表示法「(C1-C6)鹵烷氧」或「(C1-C6)鹵烷氧基」係指透過氧橋附接的如上定義之鹵烷基。(C1-C6)鹵烷氧基之實例為三氟甲氧基。
類似地,衍生表示法「(C3-C6)雜環烷基氧基」及「(C3-C6)雜環烷基(C1-C6)烷氧基」分別係指透過氧橋附接的雜環烷基,及鏈接雜環烷基-烷氧基。此等(C3-C6)雜環烷基氧基及(C3-C6)雜環烷基(C1-C6)烷氧基之實例分別地為(哌啶-4-基)氧基、1-甲基哌啶-4-基)氧基、2-(哌啶-4-基)乙氧基、2-(1-甲基哌啶-4-基)乙氧基、及2-(4-啉基)乙氧基。
衍生表示法「芳基氧基」及「芳基(C1-C6)烷氧基」,同樣地「雜芳基氧基」及「雜芳基(C1-C6)烷氧基」係指透過氧橋附接的芳基或雜芳基,及鏈接芳基-烷氧基或雜芳基-烷氧基。此等基 團之實例分別地為苯基氧基及苄基氧基及吡啶基氧基。
同樣地,衍生表示法「(C3-C6)雜環烷基-(C1-C6)烷基」及「(C3-C6)環烷基-(C1-C6)烷基」係指透過具有指示的碳原子數之烷基附接至分子其餘部分的如上定義之雜環烷基及環烷基。實例為哌啶-4-基-甲基、環己基乙基。
衍生表示法「(C1-C6)烷氧基-(C1-C6)烷基」係指透過具有指示的碳原子數之烷基附接至分子其餘部分的如上定義之烷氧基。實例為甲氧基甲基。
衍生表示法「(C1-C6)烷氧基羰基」係指透過羰基附接至分子其餘部分的如上定義之烷氧基。實例為乙氧基羰基。
又復,衍生表示法例如「(C1-C6)烷氧基羰基-胺基」係指透過羰基附接至分子其餘部分的如上定義之烷氧基,隨後接著胺基(-NR7-)。(C1-C6)烷氧基羰基-胺基之實例為第三丁氧基-羰基-胺基。
如此,「(C1-C6)烷氧基羰基(C3-C6)雜環烷基(C1-C6)烷基」係指順序地鏈接且透過具有指示的碳原子數之烷基附接至分子其餘部分的烷氧基羰基雜環烷基取代基。實例為(第三丁基哌啶-1-羧酸酯)-4-基-甲基。
衍生表示法「(C1-C6)胺基烷氧基」係指透過氧橋附接的如上定義之(C1-C6)胺基烷基,例如(2-(二甲基胺基)乙氧基。
表示法「(C1-C6)羥基烷氧基」係指透過氧橋附接至分子其餘部分的如上定義之羥基烷基,例如羥基乙氧基。
衍生表示法「(C1-C6)胺基烷基甲醯基」係指經以(C1-C6)胺基烷基取代之「胺基甲醯基」,如上定義(亦即, -C(O)NR7R8,其中R8為(C1-C6)胺基烷基)。實例為2-(二甲基胺基)乙基胺基甲醯基。
術語「芳基烷醯基」係指芳基C(O)基或芳基烷基羰基[例如芳基(C1-C6)烷基C(O)-],其中芳基及烷基具有如上定義之意義。實例以苄醯基、苯基乙醯基、苯基丙醯基、或苯基丁醯基為代表。同樣地,「芳基磺醯基」係指芳基S(O)2基,其中芳基具有如上定義之意義。實例為苯基磺醯基。
又同樣地,類似於如上提供之定義中,鏈接取代基自組成片段而衍生其定義,諸如「(C3-C6)環烷基-羰基」、「(C3-C6)雜環烷基-羰基」、「雜芳基-羰基」係如透過羰基附接至分子的其餘部分的如上定義的片段。此等基團之實例為環丙烷羰基、吡咯啶-3-羰基、(吡啶-3-基)羰基。
表示法「飽和、部分不飽和或芳香族5或6員環烷-二基、芳烴-二基、或雜環-二基」係指含有五個成員之或六個成員之合宜的二取代之環烷或雜環或芳香族殘基,包括1,2-、1,3-或1,4-苯-二基;2,3-、3,4-、4,5-或5,6-吡啶-二基;3,4-、4,5-或5,6-嗒-二基;4,5-或5,6-嘧啶-二基;2,3-吡二基;2,3-、3,4-或4,5-噻吩-二基/呋喃-二基/吡咯-二基;4,5-咪唑-二基/唑-二基/噻唑-二基;3,4-或4,5-吡唑-二基/異唑-二基/異噻唑-二基;其飽和或部分不飽和類似物及其類。也包括其它非相鄰二取代殘基(二基),諸如4,6-嘧啶-二基。
如於本文中使用,表示法「環系」係指一環系、二環系、或多環系,其可以是飽和、部分不飽和或不飽和,諸如芳基、(C3-C10)環烷基、(C3-C6)雜環烷基或雜芳基。
如於本文中使用,術語「基」、「基團」、或「片段」或「取代基」乃同義詞,且意圖指示可附接至鍵結或其它片段或分子的官能基或分子片段。如此,舉個實例,於本文中「雜環系基團」係指一環系或二環系飽和的或部分飽和的雜環系部分(基、基團),較佳地4至6員一環系基團,於該雜環系基團中之至少又一個環碳原子係任選地由獨立地選自於N、S或O中之至少又一個雜原子置換,及/或可帶有-側氧基(=O)取代基,該雜環系基團係進一步任選地包括螺環二取代,以及在兩相毗鄰或鄰近原子上的取代生成額外5至6員環系或雜環系飽和的、部分飽和的或芳香環。如此,該等雜環系基團之實例為1-吡咯啶基、1-哌啶基、1-哌基、4-啉基、哌-4-基-2-酮、4-甲基哌-1-基、4-甲基哌-1-基-2-酮、7-甲基-2,7-二吖螺[3.5]壬烷-2-基、2-甲基-2,9-二吖螺[5.5]十一烷-9-基、9-甲基-3,9-二吖螺[5.5]十一烷-3-基、及(3aR,6aS)-5-甲基-八氫吡咯并[3,4-c]吡咯-2-基及其類。
不在兩個字母或兩個符號間之連接號(「-」)意圖表示取代基的附接點。當以圖解表示時,環系官能基中之附接點係以位在可用環原子中之一者的一點(「.」)指示,於該處,該官能基係可附接至鍵結或其它分子片段。
如於本文中使用,作為其它常用表示法的替代方案,例如(=O),側氧基部分係以(O)表示。如此,就通式而言,作為其它常用表示法,例如-CO-、-(CO)-或-C(=O)-的替代方案,於本文中羰基較佳地表示為-C(O)-。通常,括弧基為旁出基(未涵括於鏈中),及當視為有用時,括弧係用來輔助釐清線性化學式;例如,磺醯基-SO2-也可表示為-S(O)2-,以與亞磺醯基-S(O)O-區分。
當使用數字索引時,例如於陳述「p為0或1至3之整數」中,陳述(數值)「p為0」表示取代基R為不存在,換言之,環上沒有取代基R。
每當鹼性胺基或第四銨基存在於式I化合物中時,可能存在有選自於下列中之生理上可接受之陰離子:氯陰離子、溴陰離子、碘陰離子、三氟乙酸根、甲酸根、硫酸根、磷酸根、甲烷磺酸根、硝酸根、順丁烯二酸根、乙酸根、檸檬酸根、反丁烯二酸根、酒石酸根、草酸根、丁二酸根、苯甲酸根、對-甲苯磺酸根、帕莫酸根、及萘二磺酸根。同樣地,於酸性基諸如COOH基之存在下,也可存在有對應的生理上可接受之陽離子鹽,例如包括鹼金屬離子或鹼土金屬離子。
熟諳技藝人士顯然易知當含有一個或多個立體產生中心時,式(I)化合物可呈光學立體異構物存在。
當依據本發明之化合物具有至少一個立體產生中心時,其因而可呈對映異構物存在。當依據本發明之化合物具有二個或多個立體產生中心時,其可額外地呈非對映異構物存在。須瞭解全部此等單一對映異構物、非對映異構物、及其呈任何比例之混合物皆係涵蓋於本發明之範圍內。載有立體產生中心的碳之絕對組態(R)或(S)係基於基團的順位,而根據嵌-英-普(Cahn-Ingold-Prelog)命名法則指定。
阻轉異構物(atropisomer)係來自於阻止以單鍵為中心旋轉的結果,其中對旋轉的立體應變位障為够高而使得能達成構象異構體的分離(Bringmann G et al,Angew.Chemie Int.Ed.44(34),5384-5427,2005.doi:10.1002/anie.200462661)。
Oki定義阻轉異構物為於指定溫度具有大於1000秒之半生期的交互轉換的構象異構體(Oki M,Topics in Stereochemistry 14,1-82,1983)。
阻轉異構物與其它對掌化合物之差異在於,於多種情況下,其可熱平衡,而對掌性異構現象之其它形式通常只可能化學平衡。
藉對掌光學分割方法,諸如選擇性結晶化,阻轉異構物之分離為可能。於阻轉對映異構選擇性合成或阻轉異構選擇性合成中,一種阻轉異構物係犧牲另一種阻轉異構物而予生成。阻轉異構選擇性合成可使用對掌性輔助進行,例如柯巴許(Corey Bakshi Shibata(CBS))催化劑,此乃衍生自脯胺酸之非對稱性催化劑;或比較另一種阻轉異構物,當異構化反應有利於一種阻轉異構物時,藉基於熱力學平衡之方法進行。
式(I)化合物之外消旋形式,以及個別阻轉異構物(實質上不含其對應之對映異構物),及富含立體異構物之阻轉異構物混合物係涵括於本發明之範圍內。
本發明進一步係有關涵括於本發明之範圍內之式(I)化合物的對應氘衍生物。
須瞭解前文中及後文中對式I化合物描述的全部較佳基團或具體例可彼此組合且比照適用。
於一較佳具體例中,本發明係有關於如前文定義之式(I)化合物,其中X1及X2各自為CH;其係由式Ia表示:
於第二較佳具體例中,本發明係有關於如前文定義之式(I)化合物,其中R2及R3與其鍵聯之氮原子一起,生成一環系飽和雜環系基團,其為哌環;以式Ib表示:
其中R9係選自於由下列所組成之組群:(C1-C6)烷基,(C1-C6)烷氧基(C1-C6)烷基,(C1-C6)烷醯基,胺基甲醯基,(C3-C6)環烷基-羰基,(C3-C6)雜環烷基-羰基,芳基(C1-C6)烷基,芳基烷醯基,芳基磺醯基, 雜芳基(C1-C6)烷基,雜芳基-羰基,雜芳基氧基,(C3-C6)環烷基,(C3-C8)環烷基(C1-C6)烷基,(C3-C6)雜環烷基-(C1-C6)烷基,芳基及雜芳基,該等環烷基、雜環烷基、芳基及雜芳基中之各者係進一步任選地經以一個或多個鹵原子、(C1-C8)烷基、(C1-C10)烷氧基、(C1-C6)烷基硫基、(C1-C6)胺基烷基、(C1-C6)胺基烷氧基、胺基甲醯基、(C1-C6)烷基-磺醯基取代;及其中該哌環係進一步任選地經以選自於由(C1-C6)烷基、(C1-C6)羥基烷基、及芳基所組成的組群中之一個或多個取代基R10取代;全部其它變數係如前文定義。
於第三較佳具體例中,本發明係有關於如前文定義之式(I)化合物,
其中X1及X2兩者皆為CH基; p為0或1至3之整數;當存在時,各個R為鹵原子;R0為-H,及R1係獨立地選自於由下列所組成之組群:-CN,(C1-C6)烷基,(C1-C6)羥基烷基,R2為-H,及R3係選自於由下列所組成之組群:(C3-C10)環烷基,(C3-C8)雜環烷基,雜芳基(C1-C6)烷基;雜芳基、環烷基、雜環烷基中之各者係進一步任選地經以一個或多個(C1-C8)烷基或(C1-C6)羥基烷基取代;R4及R5兩者皆為H;R6為-H;及其醫藥上可接受之鹽及其溶劑合物。
依據本發明之化合物的較佳組群為式(I)化合物其中X1及X2於各次出現時係獨立地為CH基或氮原子;p為0或1至3之整數;當存在時,各個R為氟;R0為-H或(C1-C6)烷基其為甲基,及R1係獨立地選自於由下列所組成之組群: -H,鹵原子其為溴、氯、碘、氟,-NR7R8,-CN,(C1-C6)烷基其為甲基,(C1-C6)鹵烷基,(C1-C6)羥基烷基其為羥基甲基、羥基乙基,(C1-C6)胺基烷基,(C1-C6)烷氧基-(C1-C6)烷基其為甲氧基甲基,(C3-C10)環烷基其為環丙基,(C2-C6)烯基,(C5-C7)環烯基,(C2-C6)炔基,(C2-C6)羥基炔基其為羥基丙炔基,芳基其為苯基、羥基苯基,雜芳基其為異唑基、N-甲基咪唑基、吡啶基、噻唑基、N-乙基吡唑基、噻吩基-甲腈,及(C3-C6)雜環烷基其為二氫吡咯基、二氫呋喃基,R2為-H或(C1-C6)烷基其為甲基,及R3係獨立地選自於由下列所組成之組群:(C1-C6)烷基其為甲基,(C1-C6)鹵烷基,(C1-C6)羥基烷基,(C1-C6)胺基烷基其為二甲基胺基乙基、二甲基胺基丙基, (C1-C6)烷氧基(C1-C6)烷基其為甲氧基丙基,(C3-C10)環烷基其為環己基、羥基甲基環己基、羥基乙基環己基、氰基-環己基、4-胺基羰基-環己烷-4-基、4-二甲基胺基甲基-環己烷-4-基,(C3-C8)雜環烷基其為N-甲基哌啶基、(羥基甲基)-N-甲基哌啶基、N-苄基哌啶基、N-甲基吖呾-3-基、四氫吡喃基、4-羥基甲基-四氫吡喃-4-基、啶基,芳基其為苯基、三氟甲基苯基、二氫茚基,雜芳基其為噻唑基、吡啶基、氯吡啶基、異喹啉基,芳基(C1-C6)烷基其為苄基、鄰-、間-、對-羥基甲基苄基、苯乙基,雜芳基(C1-C6)烷基其為(吡啶基)乙基、(噻吩基)甲基、(N-苯基-吡唑基)乙基,(C3-C8)環烷基(C1-C6)烷基其為環己基甲基,(C3-C8)雜環烷基-(C1-C6)烷基其為(哌啶-4-基)甲基、(N-苄基哌啶基)甲基、(N-甲基哌啶-4-基)甲基、N-甲基吖呾-3-基-甲基、啉基丙基;或替代地,R2及R3與其鍵聯之氮原子一起,生成一環系基團其為哌-N-基、甲基哌-N-基、苯基-N-甲基哌-N-基、N-苯基-哌-N-基、三甲基哌-N-基、4-苄基-3,5-二甲基哌-N-基、(羥基甲基)-N-甲基哌-N-基、乙醯基(哌-N-基)、苯基乙醯基(哌-N-基)、苄醯基(哌-N-基)、4-(((二甲基胺基)甲基)苄醯基)哌-1-基、環丙基(哌-N-基)、環丙基甲基(哌-N-基)、環丙烷羰基(哌-N-基)、環己烷羰基(哌-N-基)、N-甲基哌啶-4-羰基(哌-N-基)、4-(吡啶-3-羰基)哌-N-基、4-(1-甲基-1H-吡唑-4-羰基)哌-N-基、4-(1- 甲基-1H-咪唑-4-羰基)哌-N-基、4-(1H-噻唑-4-羰基)哌-N-基、4-二甲基胺基羰基(哌-N-基)、(苯基磺醯基)哌-N-基、(吡啶基)哌-N-基、(吡啶基甲基)哌-N-基、(甲氧基乙基)哌-N-基、(苄基)哌-N-基、(甲氧基苄基)哌-N-基、(3-(二甲基胺基丙氧基)苄基)哌-N-基、(氟苄基)哌-N-基、(甲基苄基)哌-N-基、N-(((甲基胺基羰基)苯基)甲基)哌-N-基、N-(((甲基胺基羰基)呋喃基)甲基)哌-N-基、(苯乙基)哌-N-基、(嘧啶基甲基)哌-N-基、(2-(甲基硫基)嘧啶基甲基)哌-N-基、(((甲基磺醯基)哌啶-4-基)甲基)哌-N-基、((N-甲基-咪唑-5-基)甲基)哌-N-基、((1-甲基-1H-咪唑-2-基)甲基)哌-N-基、((甲基噻唑基)甲基)哌-N-基、((吡-2-基)甲基)哌-N-基、((1-甲基-1H-吡唑-4-基)甲基)哌-N-基、苯并[d][1,3]二呃-5-基甲基)哌-N-基、(喹啉-2-基甲基)哌-N-基、((1,2,3-噻二唑-4-基)甲基)哌-N-基、(嗒-4-基甲基)哌-N-基、吡咯啶-N-基、苯基吡咯啶-N-基、(吡啶基)吡咯啶-N-基、哌啶-N-基、(二甲基胺基)哌啶-N-基、4-((二甲基胺基)甲基)哌啶-N-基、苄基哌啶-N-基、苄基羥基哌啶-N-基、吡啶基哌啶-N-基、吡啶基氧基哌啶-N-基、(苯基磺醯基)哌啶-N-基、4-苯基-5,6-二氫吡啶-1(2H)-基、苯基啉-N-基、3-(二甲基胺基)吖呾-N-基、3-(二甲基胺基)甲基-吖呾-N-基、3-(二甲基胺基)吡咯啶-N-基、3-(3-甲基-1,2,4-二唑-5-基)吡咯啶-N-基、3-(二甲基胺基)哌啶-N-基,或生成二環系基團其為5,6-二氫咪唑并[1,5-a]吡-7(8H)-基、3,4-二氫-2,7-啶-2(1H)-基、1H-吡咯并[3,4-c]吡啶-2(3H)-基、六氫吡并[2,1-c][1,4]-8(1H)-基、3,4-二氫異喹啉-2(1H)-基、5-甲基-2,5-二吖二環[2.2.1]庚烷-2-基、5-苄基-2,5-二吖二環[2.2.1]庚烷 -2-基、7,8-二氫吡啶并[4,3-d]嘧啶-6(5H)-基、2,6-二吖螺環[3.3]庚烷-2-基、6-甲基-2,6-二吖螺環[3.3]庚烷-2-基、7-甲基-2,7-二吖螺環[3.5]壬烷-2-基、2-甲基-2,9-二吖螺環[5.5]十一碳烷-9-基、9-甲基-3,9-二吖螺環[5.5]十一碳烷-3-基、八氫吡咯并[3,4-c]吡咯-2-基或5-甲基-八氫吡咯并[3,4-c]吡咯-2-基;R4係選自於由下列所組成之組群:H,(C1-C6)烷基其為甲基,(C3-C6)環烷基-(C1-C6)烷基其為環己基甲基,及(C3-C6)環烷基-羰基其為環己基羰基或(吡咯啶-3-基)羰基;及R5係獨立地選自於由下列所組成之組群:H,(C1-C6)烷基其為甲基;R6係選自於由下列所組成之組群:-H,及(C1-C6)烷基其為甲基;及其醫藥上可接受之鹽及其溶劑合物。
本發明也提供醫藥組成物其包含式I化合物或其醫藥上可接受之鹽與一個或多個醫藥上可接受之載劑或賦形劑混合,或單獨使用或組合一個或多個其它活性成分。
於一個態樣中,本發明提供式(I)化合物作為藥物使用。
於又一個態樣中,本發明提供式(I)化合物或其醫藥上可接受之鹽用於治療與ROCK酶機轉相關聯的病症之藥物,特別地用於諸如肺臟疾病等病症之治療用藥物之製造上的用途。
特別地,本發明提供式(I)化合物,其係用於選自於由下列所組成之組群中之肺臟疾病之預防及/或治療:氣喘、慢性阻塞性肺病(COPD)、特發性肺纖維化(IPF)、肺高壓(PH),及特別是肺動脈高壓(PAH)。
再者,本發明提供與ROCK酶機轉相關聯的病症之預防及/或治療方法,該方法包含對有此種治療需要之病人投予治療上有效量之本發明之化合物。
特別地,本發明提供預防及/或治療方法,其中該病症為氣喘、慢性阻塞性肺病(COPD)、特發性肺纖維化(IPF)、肺高壓(PH),及特別是肺動脈高壓(PAH)。
依據特定具體例,本發明提供下表中列舉的化合物及其醫藥上可接受之鹽。
本發明之化合物,包括前文列舉的全部化合物,可運用如下通用方法及程序,或藉使用熟諳技藝人士方便易得的略經修改方法,而從易得的起始物料製備。雖然於本文中已經顯示或描述本發明之特定具體例,但熟諳技藝人士將瞭解全部本發明之具體例或態樣可運用本文中描述的方法或使用其它已知方法、試劑及起始物料製備。除非另行陳述,否則當指定典型的或較佳的製程條件(亦即,反應溫度、時間、反應物之莫耳比、溶劑、壓力等)時,也可使用其它製程條件。雖然最佳反應條件可取決於使用的特定反應物或溶劑而改變,但此等條件方便地由熟諳技藝人士藉例行性優化程序決定。
因此,如下描述的且於如下反應式中報告的製備程序不應被視為限制可供應用於本發明之化合物之製備的可用合成方法的範圍。
於某些情況下,根據通用化學原理,需要有一步驟來遮罩或保護敏感性部分或反應性部分,可採用一般已知之保護基(PG)(Protective group in organic syntheses,3rd ed.T.W.Greene,P. G.M.Wuts)。
式I化合物,包括以上列舉的全部化合物,通常可根據如下反應式中顯示之程序製備。當特定細節或步驟與通用反應式不同時,其已於特定實例及/或於額外反應式中詳加說明。
式I化合物含有至少一個立體產生中心,如於下圖中以星號*標記。
利用對映異構上純質起始物料及中間產物,對映異構上純質化合物可根據如下描述之反應製備。在攜載NR4R5(於上圖中以星號*標記)的碳上之式I對映異構上純質化合物之製備,可運用於如下反應式中所見對映異構上純質中間產物IV及XII達成。此等中間產物可以是市售可購得或方便地易由熟諳技藝人士自商業來源產製。
於另一辦法中,對映異構上純質化合物可利用對掌層析術而自對應外消旋物製備。每當式I化合物中有兩個或多個立體產生中心時,則結構式係藉不同的立體異構物加以特徵化。立體化學上純質化合物可藉對掌性分離而自非對映立體異構混合物獲得,或藉非對映立體異構物之層析分離,接著藉進一步對掌性分離成單一立體異構物而逐步地獲得。
式I化合物其中R5為H可如後文描述根據反應式1製備。反應式1針對實施例1至151及實施例225至229之製備提供了至少一個非限制性合成途徑。
用於保護二環系中間產物II之5員環的NH之典型保護基(PG1)可以是2-[(三甲基矽烷基)乙氧基]甲基(SEM)、4-甲苯磺醯基(Ts)、及對-甲氧基苄基(PMB),及無論如何絕不限制其它保護基的使用。中間產物III可以製自對應中間產物II及用於導入PG1的合宜試劑,例如Ts-Cl(甲苯磺醯氯)、SEM-Cl([2-(三甲基矽烷基)乙氧基]甲基氯)、或PMB-Br(對-甲氧基苄基溴)。該等組成分間之反應可於室溫或更低溫,於強鹼諸如NaH之存在下,於極性有機溶劑諸如DMF或DCM中進行。
中間產物IV之羧酸可以PG2合宜地保護為酯(例如,甲酯),及胺基可以PG3(例如,Boc基)保護為胺基甲酸酯。此等轉換可始於未經保護的似酪胺酸衍生物,藉由使用一般眾所周知之方法達成。
中間產物V可透過鈀催化O-芳基化而得自中間產物III及IV。舉例言之,反應之進行方式可經由於無機鹼諸如碳酸鉀存在下,於合宜有機溶劑諸如甲苯或THF中,芳基鹵中間產物III及酚衍生物IV,與合宜鈀催化系統諸如Pd2dba3/XPhos或另一種以鈀源/膦為基礎的配位基,於高溫(約100℃)反應歷時數小時進行。
於不同辦法中,中間產物V可始於中間產物VIII以二步驟式合成獲得。中間產物VIII之硝基藉中間產物IV之酚Ipso-取代而獲得中間產物VII,可於等於或高於100℃之溫度,及於無機鹼諸如碳酸鉀存在下,於高沸有機溶劑諸如DMSO中進行。經由 利用非同源鈀催化的氫化,藉去除氯原子,中間產物VII可被轉換成中間產物V,其係藉由於Pd/C及有機鹼諸如TEA存在下,於氫環境下反應VII進行。類似中間產物III,中間產物VIII可如前文描述而自對應未經保護之雜環製備。
自中間產物V去除PG2(當PG2為甲基時)而獲得中間產物VI,同時不影響其它保護(PG1:SEM、Ts、或PMB及PG3:Boc),使用無機鹼諸如LiOH於甲醇/水之混合物,通常於室溫及歷時1小時至隔夜之時間可藉水解進行。於某些情況下,為了合成方便,水解可於等於或高於50℃之溫度進行,且可能同時導致PG1裂解而獲得中間產物VIa。中間產物VIa可以中間產物VI之類似方式使用。
中間產物VI(或VIa)與中間產物IX間之反應而獲得中間產物X(或Xa)可於合宜的醯胺偶合反應條件下進行。舉例言之,於合宜有機溶劑諸如DCM或DMF,通常於約為室溫之溫度歷時數小時至隔夜之時間,中間產物VI(或VIa)及中間產物IX可於活化劑諸如COMU或HATU存在下,與有機鹼諸如DIPEA或TEA反應進行。
另外地,中間產物X可以前文針對製備中間產物V之相似方式,透過鈀催化O-芳基化而自中間產物XI及中間產物III製備。中間產物XI可以前文針對製備中間產物X之相似方式,藉中間產物XII與中間產物IX之醯胺偶合獲得。
從中間產物X(或Xa,其只帶有PG3)去除PG1及PG3以獲得式I化合物(其中R5為H)可根據使用的裂解條件逐步地或同時達成(Protective group in organie syntheses,3rd ed.T.W.Greene,P.G.M.Wuts)。舉例言之,使用TFA混合物於有機溶劑諸如DCM之 酸性裂解,可脫保護Boc及PMB兩者;而SEM可能要求於濃甲醇系氨或LiOH中的額外處理。甲苯磺醯基(Ts)可於無機鹼諸如LiOH於水/甲醇之溶液中,於等於或高於50℃之溫度水解。
於另一具體例中,式I化合物(其中R5為H,及R2及R3與其鍵聯之氮原子一起形成哌環,任選地於第二氮以R9取代)可根據反應式2製備,針對實施例152至177之製備提供了至少一個非限制性合成途徑。
中間產物Xb指示式X化合物其中R2及R3與其鍵聯之氮原子一起形成哌環,於其中第二氮係由保護基(指示為PG4)保護,該保護基可正交於PG1及PG3。合宜的PG4基可以羧基苄基氧基(Cbz)為代表。於有機溶劑諸如甲醇或乙醇中及於約為室溫之溫度,於Pd/C催化劑之存在下藉催化氫化,中間產物Xb(PG4為Cbz)可被轉換成中間產物XIIIa。
如於反應式1中針對中間產物X之描述,經由去除PG3及PG1,式I化合物(其中R5為H,及R2及R3與其鍵聯之氮原子一起形成哌環)可從中間產物XIIIa製備。
利用醯胺偶合或還原胺化,經由導入R9基(如前文載明),中間產物XIIIb可從中間產物XIIIa製備。至於醯胺偶合,中間產物XIIIa及合宜羧酸可使用針對中間產物VI與中間產物IX之偶合,於反應式1中已描述的相似條件反應。還原胺化可使用還原劑諸如NaBH(OAc)3、NaBH3CN或NaBH4,及於合宜有機溶劑諸如DCE、DCM、THF或甲醇中,藉由反應中間產物XIIIa與合宜醛進行。反應於室溫歷經數小時時間順利進行。在添加還原劑之前,胺與醛反應以預先生成亞胺可能有用。
採用針對中間產物X,於反應式1中已描述的相同裂解條件,經由去除PG1及PG3,式I化合物(如前述,其中R5為H,及R2及R3與其鍵聯之氮原子一起形成哌環)可從中間產物XIIIb 製備。熟諳技藝人士顯然易知,在PG1及PG3之脫保護前,中間產物XIIIb的R9取代基可進一步經後續處理以獲得式I化合物。舉例言之,若R9為3-(甲氧基羰基)苯基)甲基或甲氧基羰基雜芳基甲基(例如,5-(甲氧基羰基)-2-呋喃基甲基),則可以包括甲酯水解及醯胺偶合之二步驟式方法輕易地轉變成對應醯胺。
於本發明之另一具體例中,式I化合物可根據反應式3製備。反應式3針對實施例178至185之製備提供了至少一個非限制性合成途徑。
藉由去除PG3,中間產物V(其中R4為H)可被轉變成中間產物XIV。舉例言之,當PG1為Ts及PG3為Boc時,藉由使用TFA與有機溶劑諸如DCM之混合物的酸性裂解,可達成PG3之選擇性去除。然後使用醯胺偶合或還原胺化,藉由導入R4及/或R5,中間產物XIV可被轉變成中間產物XV。使用類似於反應式1中針對中間產物VI與中間產物IX之偶合已描述的條件,經由中間產物 XIV與合宜羧酸反應可進行醯胺偶合。以類似針對反應式2之中間產物XIIIa所述方式,經由中間產物XIV與合宜醛反應可進行還原胺化。另外地,中間產物XIV上之還原胺化可於催化劑諸如Pd/C之存在下及於醇系溶劑諸如甲醇或乙醇中,藉由原地產生的亞胺之催化氫化進行。
藉由使用類似針對PG2及PG1之去除已描述的條件,中間產物XV可被轉變成中間產物XVI或XVIa,或使用選擇性脫保護條件而只去除PG2而被轉變成XVIa。
採用反應式1中已描述的條件,式I化合物可得自中間產物XVI(或XVIa)及IX之醯胺偶合。如於反應式1中已述,當中間產物XVIa使用於醯胺偶合時,將需要去除PG1。
另外地,以類似反應式1中描述之方式,透過與合宜羧酸之醯胺偶合,經由轉換對應化合物(其中R4=H),可獲得式I化合物(其中R4為醯基部分,例如,雜環烷基羰基或環烷基羰基)。
於本發明之另一具體例中,式I化合物(其中R5=H,R1為鹵原子,X=Cl、Br、I、或CN或例如芳基、雜芳基、羥基炔基、環烷基及環雜烷基,及進一步任選地經取代)可根據反應式4製備,其針對實施例186至206及實施例217至224之製備提供了至少一個非限制性合成途徑。
中間產物VII(其中R1為H)可使用對應NXS(N-鹵丁二醯亞胺,X:Cl、Br或I)藉親電子鹵化而被轉換成中間產物XVII,該反應係於有機溶劑諸如MeCN中及於約室溫之溫度歷時數小時進行。中間產物XVII可於二步驟式合成中轉換成中間產物XVIII。首先,移除PG2及然後於醯胺偶合條件下,所得羧酸中間產物與胺IX偶合。PG2之移除及醯胺偶合兩者可使用於反應式1中已描述的類似條件進行。
於不同辦法中,以類似前文針對VII轉變成XVII已述之方式,中間產物XVIII可藉鹵化而得自中間產物X(其中R1為H)。
中間產物XVIII轉變成中間產物Xc(其中R1為CN)可藉金屬催化的氰化進行。舉例言之,於鈀催化劑之存在下,諸如Pd2(dba)3/1,1’-鐵茂(ferrocene)二基貳(二苯基膦),於有機溶劑諸如DMF中,及於高於100℃之溫度歷時長達隔夜或更長,中間產物XVIII可與氰化鋅反應而獲得中間產物Xc。
藉後述參考文獻中描述的鈀催化之交叉偶合反應,諸如Sonogashira、Suzuki或其它,經由導入R1基(芳基、雜芳基、羥基炔基、環烷基、或環雜烷基),中間產物XVIII另可被轉變成中間產物Xd(Strategic application of named reactions in organic synthesis,L.Kurti,B.Czako,Ed.2005)。舉例言之,Sonogashira偶合之進行方式可經由於鈀催化劑諸如PdCl2(dppf)2 DCM加合物或肆三苯基膦鈀(0)之存在下,於碘化銅(I)及鹼諸如三甲基胺之存在下,於有機溶劑諸如THF中,於約90℃或以上之溫度及歷時長達隔夜或更長,加熱中間產物XVIII及合宜的第一炔進行。Suzuki偶 合之進行方式可經由於鈀催化劑諸如PdCl2(dppf)2 DCM加合物之存在下,帶有無機鹼諸如強鹼碳酸鹽中,於約90℃或以上之溫度及歷時長達隔夜或更長,加熱中間產物XVIII及合宜的二羥硼酸或皮納可(pinacolate)衍生物於水/有機溶劑諸如DME或THF之混合物進行。
藉由使用於反應式1中針對PG1及PG3之移除已描述的類似方法,中間產物XVIII、Xc、及Xd可被轉變成式I化合物,其中個別地R1為鹵原子(Cl、Br或I),或氰基(CN),或芳基、雜芳基、羥基炔基、環烷基、或環雜烷基。
於本發明之另一具體例中,式I化合物(其中R1為-CH2OH或-CH2CH2OH)可遵照反應式5製備。反應式5針對實施例207至216及實施例225至229之製備提供了至少一個非限制性合成途徑。
以如針對中間產物X(反應式1)描述的相同方式,式I化合物(其中R1為-CH2OH或-CH2CH2OH)可藉由PG1及PG3之去除自中間產物XXIa及/或XXIb製備。以中間產物XXIb為例,其帶有保護基PG5,該保護基可於與PG1及PG3之相同條件下裂解。
以如針對中間產物X(反應式1)描述的相同方式,中間產物XXIa可經由中間產物XX及中間產物IX之醯胺偶合獲得。使用鈀催化的O-芳基化,中間產物XX可始於中間產物IV及中間產物XIX(其中Y為CHO)製備,其後為如於反應式1中描述的PG2之去除。所得醛中間產物可經還原而獲得中間產物XX,例如,藉硼氫化鈉於有機溶劑諸如DCM/MeOH之混合物於室溫歷時長達隔夜或更長。
遵照針對將III及IV變換成X(反應式1)描述的相同合成順序,中間產物XXIb可從中間產物IV及XXII製備,包括XXII使用IV之O-芳基化,其後接著PG2之脫保護,及與IX的醯胺偶合。中間產物XXII可藉二步驟式合成而從中間產物XIX製備。含括於Y中之甲醯基部分的還原可如於本反應式中針對中間產物XX描述的相同方式進行。藉使用通用方法,所得醇中間產物可以PG5(例如,TBDMS)保護而獲得中間產物XXII。
中間產物XIX可以中間產物III(反應式1)之相似方式製備。
本發明之化合物為激酶活性抑制劑,特別為Rho激酶活性抑制劑。概略言之,屬於ROCK抑制劑之化合物用於ROCK酶機轉相關聯的許多病症之治療上是有用的。
於一個具體例中,可藉本發明之化合物治療的病症包括青光眼、發炎性腸病(IBD)、及選自於下列之肺病:氣喘、慢性阻塞性肺病(COPD)、間質性肺病,諸如特發性肺纖維化(IPF)及肺動脈高壓(PAH)。
於另一個具體例中,可藉本發明之化合物治療的病症係選自於由下列所組成之組群:氣喘、慢性阻塞性肺病(COPD)、及間質性肺病,諸如特發性肺纖維化(IPF)及肺動脈高壓(PAH)。
於又一個具體例中,該病症係選自於特發性肺纖維化(IPF)及肺動脈高壓(PAH)。
本發明之治療方法包含對有需要的病人投予安全有效量之式(I)化合物或其醫藥上可接受之鹽。如於本文中使用,當述及式(I)化合物或其醫藥上可接受之鹽或其它醫藥活性劑時,「安全及有效量」係指足够治療病人的病況,但又够低而可避免嚴重不良效應的化合物用量,雖言如此,其可由熟諳技藝人士例示地決定。式(I)化合物或其醫藥上可接受之鹽可一次投予,或根據投藥計畫投予,其中歷經一段指定的時間,多個劑量可於不等的時間間隔投予。典型每日劑量可取決於選用的特定投藥途徑而予改變。
本發明也提供式(I)化合物混合一個或多個醫藥上可接受之載劑或賦形劑的醫藥組成物,例如於Remington’s Pharmaceutical Sciences Handbook,XVII Ed.,Mack Pub.,N.Y.,U.S.A.中描述者。
本發明之化合物及其醫藥組成物之投予可根據病人的需要完成,例如,經口、經鼻、經腸道外(皮下、靜脈、肌肉、 胸骨內及藉輸注)、藉吸入、經直腸、經陰道、經外用、經局部、經皮、及經眼投予。
各種固體口服劑型可被使用來投予本發明之化合物,包括錠劑、明膠膠囊、膠囊劑、膠囊型錠劑、粒劑、喉片、及散裝粉劑等固體劑型。本發明之化合物可單獨使用或組合各種醫藥上可接受之載劑、稀釋劑(諸如蔗糖、甘露糖醇、乳糖、澱粉)及已知之賦形劑投予,包括懸浮劑、增溶劑、緩衝劑、黏結劑、崩散劑、保藏劑、著色劑、矯味劑、潤滑劑及其類。定時釋放膠囊劑、錠劑、及膠漿劑也優異地用於投予本發明之化合物。
各種液體口服劑型也可被使用來投予本發明之化合物,包括水性及非水性溶液劑、乳液劑、懸浮液劑、糖漿劑及酏劑。此等劑型也可含有合宜的已知惰性稀釋劑諸如水,及合宜的已知賦形劑諸如保藏劑、保濕劑、甜味劑、矯味劑,以及用於乳化及/或懸浮本發明之化合物的化學作用劑。本發明之化合物例如可呈等張無菌溶液劑型注射,例如靜脈注射。其它製劑亦屬可能。
經直腸投予本發明之化合物的栓劑可經由該化合物與合宜賦形劑(諸如可可脂、水楊酸酯類、及聚乙二醇類)混合製備。
也已知經陰道投藥用配方,其可呈乳膏劑、膠漿劑、糊膏劑、發泡劑、或噴霧劑配方劑型,其除了活性成分之外含有諸如合宜載劑。
為了供外用投藥,醫藥組成物可呈適合投予皮膚、眼、耳或鼻的乳膏劑、軟膏劑、硬膏劑、擦劑、乳液劑、懸浮液劑、膠漿劑、溶液劑、糊膏劑、散劑、噴霧劑及滴劑劑型。外用投藥也涉及透過諸如經皮貼片等裝置而經皮投予。
為了用於呼吸道疾病之治療,式(I)化合物較佳地係藉吸入投予。
吸入性製劑包括可吸入粉劑、含推進劑之計量氣霧劑、或不含推進劑之可吸入配方。
為了呈乾粉投予,可運用先前技術已知之單劑或多劑吸入器。於該種情況下,粉劑可填充於明膠、塑性或其它膠囊內、卡匣內或泡胞罩板包裝內或貯器內。
通常為無毒性且對本發明之化合物為化學惰性之稀釋劑或載劑,例如,乳糖或適用於改良可吸入分量的任何其它添加劑皆可添加至本發明之粉狀化合物。
含推進劑氣體諸如氫氟烷類的吸入性氣霧劑可含有呈溶液形式或分散形式的本發明之化合物。推進劑驅動配方也可含有其它成分,諸如共溶劑、安定劑及任選的其它賦形劑。
包含本發明之化合物的不含推進劑之可吸入配方可呈於水性、醇性或水醇性介質的溶液或懸浮液劑型,而該可吸入配方可藉先前技術已知之噴射霧化器或超音波霧化器,或藉軟霧霧化器諸如Respimat®遞送。
本發明之化合物可作為唯一活性劑投予,或與選自於下列的其它醫藥活性成分組合投予(亦即,呈固定劑量組合作為共治療劑投予,或呈分開配方之活性成分的組合療法投予):有機硝酸鹽及NO給予體;吸入性NO;可溶性鳥苷酸環化酶(sGC)激活劑;前列環素類似物PGI2及前列環素受體促效劑;抑制環狀鳥苷一磷酸(cGMP)及/或環狀腺苷一磷酸(cAMP)降解之化合物,諸如磷酸二酯酶(PDE)1、2、3、4及/或5之抑制劑,尤其是PDE 5抑制劑; 人類嗜中性彈力蛋白酶抑制劑;抑制信號轉導串級之化合物,諸如酪胺酸激酶及/或絲胺酸/蘇胺酸激酶抑制劑;抗血栓劑,例如血小板凝集抑制劑、抗凝血劑或血纖維蛋白原溶解物質;降低血壓之活性物質,例如,鈣拮抗劑、血管緊張素II拮抗劑、ACE抑制劑、內皮素拮抗劑、腎素抑制劑、醛固酮合成酶抑制劑、α受體阻斷劑、β受體阻斷劑、礦物皮質激素受體拮抗劑;中性肽鏈內切酶抑制劑;滲透劑;ENaC阻斷劑;抗發炎劑包括皮質類固醇及趨化激素受體之拮抗劑;支氣管擴張劑,例如,β2促效劑及蕈毒鹼拮抗劑;抗組織胺藥;止咳藥;抗生素諸如巨環類抗生素及DNase藥物及選擇性裂解劑,諸如重組人類去氧核糖核酸酶I(rhDNase);Smad2及Smad3之ALK5及/或ALK4磷酸化抑制劑;色胺酸水解酶1(TPH1)抑制劑;及多重激酶抑制劑。
於一較佳具體例中,本發明之化合物係下列成分組合一起投藥:磷酸二酯酶V,諸如西地那非(sildenafil)、伐地那非(vardenafil)及他達拉非(tadalafil);有機硝酸鹽及NO給予體(例如,硝基氫氰酸鹽、硝化甘油、異山梨糖醇一硝酸酯、異山梨糖醇二硝酸酯、脈導敏(molsidomine)或SIN-1、及吸入性NO);合成前列環素類似物PGI2,諸如伊洛前列素(iloprost)、曲前列尼爾(treprostinil)、前列環素(epoprostenol)及貝前列素(beraprost);前列環素受體之促效劑,諸如西里哌格(selexipag)及WO 2012/007539之化合物;可溶性鳥苷酸環化酶(sGC)激活劑,例如利奧西呱(riociguat);及酪胺酸激酶,例如伊馬替尼(imatinib)、索拉非尼(sorafenib)及尼羅替尼(nilotinib);及內皮素拮抗劑(例如,馬西替坦 (macitentan)、普勝騰(bosentan)、西他生坦(sitaxentan)及安立生坦(ambrisentan))。
本發明之化合物之劑量取決於多項因素,包括欲治療的特定疾病、症狀之嚴重度、投藥途徑、劑量間隔之頻率、使用的特定化合物、化合物之功效、毒理學側寫、及藥力學側寫。
優異地,式(I)化合物例如可以0.001至1000毫克/日,較佳地0.1至500毫克/日之劑量投予。
當式(I)化合物係藉吸入途徑投予時,其較佳地係以0.001至500毫克/日,較佳地0.1至100毫克/日之劑量投予。
適用於藉吸入投予的包含本發明之化合物的醫藥組成物,諸如可吸入粉劑、含推進劑之計量氣霧劑、或不含推進劑之可吸入配方。
本發明也係有關於包含本發明之化合物的醫藥組成物,其可以是單劑或多劑乾粉吸入器、定量劑量吸入器及軟霧霧化器。
下列實施例以進一步細節例示本發明。
除非另行載明,否則反應係惰性環境下進行,及全部溶劑及商業製劑係如接收的狀況使用。
藉層析術純化係指使用CombiFlash® Companion純化系統或Biotage SP1純化系統純化。當產物係使用Isolute® SPE Si II卡匣純化時,「Isolute SPE Si卡匣」係指具有50微米平均粒徑及標稱60埃孔隙度的不規則粒子之含未經黏結的活性二氧化矽之 預填充聚丙烯管柱。含有要求產物之洗提分(藉TLC分析及/或LCMS分析識別)經滙集及於減壓下濃縮。當使用SCX-2卡匣時,「SCX-2卡匣」係指含有未經封端的經丙烯磺酸官能化之二氧化矽強力陽離子交換吸附劑之Isolute®預填充聚丙烯管柱。當HPLC被使用於純化(藉MDAP純化)時,含有要求產物之洗提分(藉TLC分析及/或LCMS分析識別)經滙集,及使用Biotage EV10蒸發器去除溶劑。另外地,滙集之產物洗提分經凍乾。
NMR光譜係在Varian Unity Inova 400光譜儀上使用於400MHz操作的5毫米反相偵測三重共振探針,或在Bruker Avance DRX 400光譜儀上使用於400MHz操作的5毫米反相偵測三重共振TXI探針,或在Bruker Avance DPX 300光譜儀上使用於300MHz操作的標準5毫米雙頻探針,或在Bruker傅立葉300光譜儀上使用於300MHz操作的5毫米雙頻探針獲得。移位係以相對於四甲基矽烷的ppm表示。
實施例及中間產物使用的化學名係以Structure To Name Enterprise 12.0 CambridgeSoft(Perkin Elmer)產生。
後續處理中使用的常用無機鹽溶液為水性溶液。鹽水係指氯化鈉飽和水性溶液。除非另行載明。
Waters Micromass ZQ2000質譜儀具有維持於40℃的C18-反相管柱(100×2.1毫米Acquity BEH具有1.7微米粒徑),使用A:水+0.1%甲酸;B:MeCN+0.1%甲酸洗提。
梯度: 梯度-時間 流速(毫升/分鐘)%A %B
檢測-MS、UV PDA
MS離子化方法-電噴灑(正離子/負離子)
Waters Micromass ZQ2000質譜儀具有維持於40℃的C18-反相管柱(100×2.1毫米Acquity BEH具有1.7微米粒徑),使用A:水+0.1%甲酸;B:MeCN+0.1%甲酸洗提。
梯度:
檢測-MS、UV PDA
MS離子化方法-電噴灑(正離子/負離子)
Quattro Micro Mass Spectrometer具有維持於40℃的C18-反相管柱(100×2.1毫米Acquity BEH具有1.7微米粒徑),使用A:水+0.1%甲酸;B:MeCN+0.1%甲酸洗提。
梯度:
檢測-MS、UV PDA
MS離子化方法-電噴灑(正離子/負離子)
QDa Mass Spectrometer具有維持於40℃的C18-反相管柱(50×2.1毫米Acquity CSH具有1.7微米粒徑),使用A:水+0.1%甲酸;B:MeCN+0.1%甲酸洗提。
梯度:
檢測-MS、UV PDA
MS離子化方法-電噴灑(正離子/負離子)
QDa Mass Spectrometer具有維持於40℃的C18-反相管柱(50×2.1毫米Acquity BEH具有1.7微米粒徑),使用A:水+0.1%甲酸;B:MeCN+0.1%甲酸洗提。
梯度:
檢測-MS、UV PDA
MS離子化方法-電噴灑(正離子/負離子)
QDa Mass Spectrometer具有維持於50℃的C18-反相管柱(50×2.1毫米Acquity BEH具有1.7微米粒徑),使用A:水+0.1%甲酸;B:MeCN+0.1%甲酸洗提。
梯度:
檢測-MS、UV PDA
MS離子化方法-電噴灑(正離子/負離子)
Waters Platform LC具有C18-反相管柱(30×4.6毫米Phenomenex Luna具有3微米粒徑),使用A:水+0.1%甲酸;B:乙腈+0.1%甲酸洗提。
梯度:
檢測-MS、ELS、UV(使用在線UV檢測器100微升平分至MS)
MS離子化方法-電噴灑(正離子/負離子)
QDa Mass Spectrometer具有維持於50℃的C18-反相管柱(50×2.1毫米Acquity BEH具有1.7微米粒徑),使用A:水+0.1%甲酸;B:MeCN+0.1%甲酸洗提。
梯度:
檢測-MS、UV PDA
MS離子化方法-電噴灑(正離子/負離子)
QZ Mass Spectrometer具有C18-反相管柱(30×4.6毫米Phenomenex Luna具有3微米粒徑),使用A:水+0.1%甲酸;B:MeCN+0.1%甲酸洗提。
梯度:
檢測-MS、UV PDA
MS離子化方法-電噴灑(正離子/負離子)
Agilent Technologies 1260 Infinity純化系統具有維持於室溫的XSELECT CSH Prep C18管柱(19×250毫米,5微米OBD)
動相A:0.1%水性甲酸
動相B:0.1%甲酸於乙腈
流速:20毫升/分鐘
梯度計畫:10%-95%,22分鐘,取中於特定聚焦梯度
樣本:注入20-60毫克/毫升於DMSO之溶液(+任選的甲酸及水)MDAP方法(鹼性)
Agilent Technologies 1260 Infinity純化系統具有維持於室溫的XBridge Prep C18 OBD管柱(19×250毫米,5微米OBD)
動相A:0.1%水性氨
動相B:0.1%氨於乙腈
流速:20毫升/分鐘
梯度計畫:10%-95%,22分鐘,取中於特定聚焦梯度
樣本:注入20-60毫克/毫升於DMSO之溶液(+任選的甲酸及水)SFC方法
超臨界流體層析術(SFC)係使用Waters Thar Prep100製備性SFC系統(P200 CO2泵浦,2545改性劑泵浦,2998 UV/VIS偵測器,2767帶有堆疊注射模組的液體處理器)或Waters Thar Investigator半製備性系統(Waters流體輸送模組,2998 UV/VIS偵測器,Waters液分收集模組)進行。使用的管柱及等梯度法係針對各化合物指示,單一對映異構物係使用指定方法分析。若干化合物已通過第二純化處理以達成要求的% ee純度。
當化合物係藉HPLC純化時,其係於C18-反相管柱(250×21.2毫米Phenomenex Kinetex具有5微米粒徑)上進行。描述 特定洗提混合物,除非另行載明,否則峰值係藉UV(254奈米)檢測。含有純質產物之洗提分通常經組合及凍乾而獲得固體。
當化合物係藉HPLC純化時,其係於C18-反相管柱(250×21.2毫米Phenomenex Kinetex EVO具有5微米粒徑)上進行。描述特定洗提混合物,除非另行載明,否則峰值係藉UV(254奈米)檢測。含有純質產物之洗提分通常經組合及凍乾而獲得固體。
對映異構物係藉對掌性HPLC分離,其係使用Chiralpak IC管柱(21×250毫米,5μM)及以15%乙醇於庚烷(帶有0.5% DEA)於18毫升/分鐘之流速洗提。
實驗章節中使用的縮寫:
COMU 六氟磷酸(1-氰基-2-乙氧基-2-側氧基亞乙基胺基氧基)二甲基胺基-啉基-碳烯陽離子
DCE 1,2-二氯乙烷
DCM 二氯甲烷
DEA 二乙基胺
DIPEA 二異丙基乙基胺
DME 1,2-二甲氧基乙烷
DMF N,N-二甲基甲醯胺
DMSO 二甲亞碸
h 小時
HATU (1-[貳(二甲基胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸酯)
HPLC 高效液相層析術
IMS 工業用變性酒精
LCMS 液相層析術-質譜術
MDAP 質量導向自動純化
MeCN 乙腈
NBS N-溴丁二醯亞胺
NCS N-氯丁二醯亞胺
NIS N-碘丁二醯亞胺
Pd2(dba)3 參(二亞苄基丙酮)二鈀(0)
Pd2(dppf)2 [1,1’-貳(二苯基膦基)鐵茂]二氯鈀(II)
Rt 滯留時間
RT 室溫
SFC 超臨界流體層析術
SM 起始物料
TEA 三乙基胺
TFA 三氟乙酸
THF 四氫呋喃
XPhos 2-二環己基膦基-2’,4’,6’-三異丙基聯苯
於如下程序中,部分起始物料係透過「中間產物」或「實施例」編號帶有步驟編號上的指示加以識別。此點係僅供用於輔助技藝精湛的化學師。
如熟諳技藝人士將瞭解,當述及「相似的」或「類似的」程序之使用時,此種程序可能涉及次要變化,例如,反應溫度、試劑/溶劑用量、反應時間、後續處理條件、或層析純化條件。
當指示時,實施例中之化合物的立體化學已基於下述假設而被指定,於任何隨後反應條件期間皆維持於起始物料的經光學分割之立體產生中心之絕對組態。
ee%(對映異構上過量)係藉針對實施例8、55、57、91及132描述的對掌性LC或SFC方法量測。此等方法考慮為欲使用於測定ee%用的分析方法實例。
除非另行陳述,否則當絕對組態(R)或(S)係以化合物名稱報告時,ee%須視為等於或大於90%。至於具有ee%之測量值小於90的該等實施例,則報告確切數值。其中未測定ee%之測量值時,標示為n.d.(未測定)。
步驟A
(S)-2-胺基-3-(3-氟-4-羥基苯基)丙酸甲酯(中間產物1A-a)
3-氟-L-酪胺酸(6.0g,30.12mmol)懸浮於甲醇(120ml),及混合物於冰浴中冷卻。逐滴添加亞磺醯氯(11ml,150.6mmol)。讓混合物溫熱至室溫及然後攪拌隔夜。蒸發去除溶劑及殘餘物溶解於水(50ml)。使用飽和水性碳酸氫鈉鹼化混合物之後,產物萃取入乙酸乙酯(4×40ml)。組合有機萃取物經脫水(Na2SO4)及蒸發而獲得期望產物呈嗶嘰色固體(4.55g)。
LCMS(方法4):Rt=0.65min,m/z 214.1[M+H]+
步驟B
(S)-2-((第三丁氧基羰基)胺基)-3-(3-氟-4-羥基苯基)丙酸甲酯(中間產物1B-a)
中間產物1A-a(4.55g,21.34mmol)懸浮於DCM(153ml)與THF(77ml)之混合物。混合物於冰浴中冷卻及添加二碳酸二第三丁酯(5.12g,23.47mmol)。讓反應混合物溫熱至室溫及然後攪拌4小時。於減壓下蒸發去除溶劑,及粗產物於120克Si卡匣上層析以0-10% 2M甲醇性氨於DCM洗提。獲得中間產物1B-a呈黃色膠狀物(5.96g)。
LCMS(方法4):Rt=1.29min,m/z 336.2[M+Na]+
步驟C
4-溴-3-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(中間產物1C-a)
4-溴-3-甲基-7-吖吲哚(4.0g,18.95mmol)溶解於DMF(37ml),及溶液於冰浴中冷卻。加入氫化鈉(60%於礦油上,1.14g,28.43mmol),及混合物於氮氣流下攪拌1小時。逐滴添加2-(三甲基矽烷基)乙氧基甲基氯(4.0ml,22.74mmol),及然後攪拌反應混合物又歷時30分鐘。以水(20ml)淬熄之後,產物萃取入乙酸乙酯(3×20ml)。組合萃取物經脫水(Na2SO4)及蒸發。殘餘物於120克Si卡匣上層析以0-25%乙酸乙酯於環己烷洗提而獲得中間產物1C-a,呈無色油(3.78g)。
LCMS(方法6):Rt=1.90min,m/z 341.1/343.0[M+H]+
步驟D
(S)-2-((第三丁氧基羰基)胺基)-3-(3-氟-4-((3-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物1D-a)
中間產物1B-a(5.96g,19.02mmol)及中間產物1C-a(6.09g,17.84mmol),Pd2(dba)3(0.82g,0.89mmol),XPhos(0.85g,1.78mmol),及碳酸鉀(5.42g,39.25mmol)於甲苯(224ml)之混合物於氬氣環境下音振處理5分鐘。混合物於100℃加熱3小時,及然後在通過矽藻土(Celite®)過濾之前讓其冷卻至室溫。蒸發去除溶劑及殘餘物溶解於水(40ml),及以乙酸乙酯(3×30ml)萃取。組合有機萃取物以鹽水洗滌(30ml),脫水(Na2SO4)及蒸發。粗產物於300克Si卡匣上層析以0-50%乙酸乙酯於環己烷洗提。獲得產物呈嗶嘰色固體(4.85g)。
LCMS(方法4):Rt=1.88min,m/z 574.4[M+H]+
步驟E
(S)-2-((第三丁氧基羰基)胺基)-3-(3-氟-4-((3-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸(中間產物1E-a)
中間產物1D-a(4.85g,8.45mmol)溶解於甲醇(42ml)、水(42ml)及THF(21ml)之混合物。添加氫氧化鋰水合物(1.06g,25.35mmol)及反應混合物於室溫攪拌10分鐘。溶劑經縮減及產物萃取入乙酸乙酯(3×20ml)。組合有機萃取物以鹽水洗滌(30ml),脫水(Na2SO4)及蒸發,獲得嗶嘰色固體(4.74g)。
LCMS(方法6):Rt=1.79min,m/z 560.4[M+H]+
步驟F
(S)-3-(3-氟-4-((3-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-((1-甲基哌啶-4-基)胺基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物1F-a)
中間產物1E-a(500mg,0.89mmol),1-甲基哌啶-4-胺(112mg,0.98mmol),及COMU(457mg,1.07mmol)溶解於DCM(15ml),及添加DIPEA(0.35ml,1.96mmol)。反應於室溫攪拌2.5小時,及然後又添加額外量之4-胺基-1-甲基哌啶(55mg,0.49mmol)。又持續攪拌2小時。加水(15ml)及分離DCM層。水層進一步以DCM(2×10ml)萃取,及組合有機萃取物經脫水(Na2SO4)及蒸發。產物於40克Si卡匣上層析以0-10% 2M甲醇性氨於DCM洗提。獲得中間產物1F-a呈黃色固體(418mg)。
LCMS(方法4):Rt=1.27min,m/z 656.3[M+H]+
步驟G
(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(1-甲基哌啶-4-基)丙醯胺(實施例1)
中間產物1F-a(418mg,0.64mmol)溶解於DCM(7.1ml)及TFA(7.1ml)之混合物,及反應於室溫攪拌4小時。混合物以甲醇稀釋及通過10g SCX-2卡匣以甲醇及然後以2M甲醇性氨洗提。靜置18小時之後,氨溶液經蒸發獲得殘餘物,其藉HPLC純化,以10-98%乙腈於水(添加0.1% NH4OH)之梯度洗提。獲得實施例1呈白色固體(111mg)。
LCMS(方法1):Rt=1.69min,m/z 425.9[M+H]+
1H NMR(400MHz,d6-DMSO)δ 11.38(s,1H),7.97(d,J=5.4Hz,1H),7.64(d,J=7.8Hz,1H),7.28-7.20(m,2H),7.13(d,J=1.6Hz,1H),7.08(dd,J=1.3,8.3Hz,1H),6.16(d,J=4.8Hz,1H),3.53-3.42(m,1H),3.41-3.35(m,1H),2.87(dd,J=5.9,13.3Hz,1H),2.74-2.54(m,3H),2.38(d,J=1.0Hz,3H),2.12(s,3H),1.97-1.86(m,2H),1.79-1.69(s,2H),1.68-1.57(m,2H),1.43-1.26(m,2H).
下列實施例係藉於各步驟以適當起始物料置換,而以實施例1之類似方式製備。
下列中間產物係藉以指示的起始物料置換實施例1之步驟A中之酪胺酸,而以中間產物1B-a之類似方式製備。
下列中間產物係以中間產物1C-a之類似方式而自指示的起始物料製備。
下列中間產物係以中間產物1D-a之類似方式而自指示的起始物料製備。
下列中間產物係以中間產物1E-a之類似方式而自指示的起始物料製備。
下列實施例係藉於步驟F中以下表中指示的中間產物1E及胺起始物料置換,遵照相同的合成順序而以實施例1之類似方式製備。
步驟A
4-溴-1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶(中間產物131A-a)
4-溴-7-吖吲哚(5.0g,28.90mmol)溶解於DMF(40ml),及溶液於氮氣流下於室溫攪拌。逐份添加氫化鈉(60%於礦油上,1.50g,37.58mmol)及反應攪拌30分鐘。歷經10分鐘時間逐滴添加4-甲苯磺醯氯(5.77g,30.37mmol)於DMF(10ml)之溶液, 及然後反應又攪拌2小時。反應混合物審慎地傾倒入冷水(100ml)中及攪拌30分鐘。所得沈澱藉過濾收集及真空乾燥。獲得產物呈灰白色固體(9.12g)。
LCMS(方法6):Rt=1.59min,m/z 351.1/353.1[M+H]+
步驟B
(S)-2-((第三丁氧基羰基)胺基)-3-(4-((第三丁基二甲基矽烷基)氧基)苯基)丙酸甲酯(中間產物131B)
中間產物1B-c(500mg,1.69mmol),第三丁基二甲基矽烷基氯(306mg,2.03mmol)及咪唑(288mg,5.25mmol)於DMF(10ml)之溶液於室溫攪拌18小時。反應混合物分溶於乙酸乙酯(15ml)與水(15ml)間,及分離有機層,以水洗滌(2×10ml),脫水(Na2SO4)及蒸發,獲得期望產物呈無色油(769mg)。
LCMS(方法6):Rt=1.89min,m/z 432.4[M+H]+
步驟C
(S)-2-((第三丁氧基羰基)(甲基)胺基)-3-(4-((第三丁基二甲基矽烷基)氧基)苯基)丙酸甲酯(中間產物131C)
氫化鈉(72mg,1.80mmol)添加至中間產物131B(692mg,1.69mmol)於THF(10ml)及DMF(1ml)之混合物的溶液內。 攪拌10分鐘之後,加入甲基碘(316mg,5.08mmol)及持續攪拌24小時。反應混合物分溶於乙酸乙酯(5ml)與水(5ml)間,及分離有機層,以水洗滌(2×10ml),脫水(Na2SO4)及蒸發。產物於Si卡匣(25g)上純化以0-25%乙酸乙酯於環己烷洗提,獲得期望產物呈黃色油(436mg)。
LCMS(方法6):Rt=1.95min,m/z 424.3[M+H]+
步驟D
N-(第三丁氧基羰基)-N-甲基-L-酪胺酸甲酯(中間產物131D)
中間產物131C(436mg,1.03mmol)於乙酸(4.45ml)、THF(1.5ml)及水(1.5ml)之混合物的溶液於室溫攪拌18小時,及然後於40℃攪拌18小時,及於75℃攪拌18小時。反應混合物於減壓下濃縮,及藉審慎地添加固體碳酸鉀將pH調整至pH 10。產物萃取入乙酸乙酯(15ml),及有機層經脫水(Na2SO4)及蒸發。產物於Si卡匣(25g)上純化以0-25%乙酸乙酯於環己烷洗提,獲得期望產物呈無色油,其於靜置時結晶(110mg)。
LCMS(方法9):Rt=2.95min,m/z 332.2[M+Na]+
步驟E
(S)-2-((第三丁氧基羰基)(甲基)胺基)-3-(4-((1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物131E-a)
中間產物131E-a係使用類似於實施例1步驟D中使用的程序而自中間產物131A-a及中間產物131D製備。
LCMS(方法9):Rt=4.18min,m/z 580.1[M+H]+
步驟F
(S)-2-((第三丁氧基羰基)(甲基)胺基)-3-(4-((1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸(中間產物131F-a)
中間產物131F-a係使用類似於實施例1步驟E中使用的程序而自中間產物131E-a製備。
LCMS(方法9):Rt=3.77min,m/z 566.1[M+H]+
步驟G
(S)-(1-(環己基胺基)-1-側氧-3-(4-((1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙烷-2-基)(甲基)胺基甲酸第三丁酯(中間產物131G-a)
中間產物131G-a係使用類似於實施例1步驟F中使用的程序而自中間產物131F-a及環己基甲胺製備。
LCMS(方法9):Rt=4.39min,m/z 647.2[M+H]+
步驟H
(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-環己基-2-(甲基胺基)丙醯胺(實施例131)
中間產物131G-a(118mg,0.182mmol)溶解於DCM(4ml)及TFA(4ml)之混合物內,及溶液於室溫攪拌1小時。混合物傾倒至SCX-2卡匣(10g)上。以甲醇沖洗之後,產物以2M甲醇性氨洗提,及蒸發去除揮發物。殘餘物溶解於二(4ml)內及添加4M氫氧化鈉(4ml)。混合物於80℃攪拌4小時。反應混合物以DCM/IPA(10:1)(10ml)稀釋及以鹽水洗滌。水層又以DCM(3×10ml)萃取,及組合萃取物經脫水(Na2SO4)及蒸發。產物藉HPLC純化 以0-80%乙腈於水(添加0.1%NH4OH)之梯度洗提而獲得白色固體(27mg)。
Rt=2.47min,m/z 393.3[M+H]+(方法1)
1H NMR(400MHz,d6-DMSO)δ 11.72(s,1H),8.05(d,J=5.4Hz,1H),7.58(d,J=8.1Hz,1H),7.34(dd,J=2.6,3.3Hz,1H),7.25(d,J=8.6Hz,2H),7.06(d,J=8.6Hz,2H),6.36(d,J=5.4Hz,1H),6.21(dd,J=1.9,3.5Hz,1H),3.57-3.47(m,1H),3.10(t,J=6.9Hz,1H),2.76(d,J=6.9Hz,2H),2.18(s,3H),1.87(s,1H),1.69-1.48(m,4H),1.29-0.99(m,6H).
ee%=38%
下列實施例係藉於各步驟以合宜的起始物料置換,而以實施例131之類似方式製備。
中間產物131A-b之製備
如下中間產物係以中間產物131A-a之類似方式而自指示的起始物料製備。
中間產物131E-b至131E-e之製備
下列中間產物係以中間產物131E-a之類似方式,根據實施例1步驟D中使用的方法而自指示的起始物料製備。
中間產物131F-b至131F-e之製備
下列中間產物係根據實施例1步驟E中使用的方法而自指示的起始物料製備。
下列實施例係藉於步驟G中以指示的中間產物131F及胺置換,使用實施例131相同的合成順序製備。
步驟A
(S)-(3-(3-氟-4-羥基苯基)-1-側氧基-1-(苯基胺基)丙烷-2-基)胺基甲酸第三丁酯(中間產物145A-a)
中間產物145A-a係使用類似針對實施例1步驟F使用的程序而從(S)-2-((第三丁氧基羰基)胺基)-3-(3-氟-4-羥基苯基)丙酸及苯胺製備。
LCMS(方法6):Rt=1.36min,m/z 373.1[M-H]-
步驟B
(S)-(3-(3-氟-4-((3-甲基-1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-側氧基-1-(苯基胺基)丙烷-2-基)胺基甲酸第三丁酯(中間產物145B-a)
中間產物145B-a係使用類似針對實施例1步驟D使用的程序而從中間產物145A-a及131A-b製備。
LCMS(方法6):Rt=1.80min,m/z 659.3[M+H]+
步驟C
(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-苯基丙醯胺(實施例145)
中間產物145B-a(180mg,0.274mmol)溶解於DCM(5ml)內及加入TFA(1ml)。於室溫攪拌90分鐘後,蒸發去除揮發物,及殘餘物溶解於甲醇。液載荷至SCX-2卡匣(5g)上。以DCM及甲醇沖洗之後,自由態鹼以2M甲醇性氨洗提。蒸發獲得殘餘物,其再度溶解於甲醇(5ml)。加入氫氧化鋰水合物(22mg,0.516mmol)於水(2ml),及反應於室溫攪拌18小時,然後於50℃攪拌2小時。 甲醇經蒸發去除及水性混合物以DCM(12ml)萃取。有機層經脫水(Na2SO4)及蒸發。產物藉HPLC純化以10-98%乙腈於水(添加0.1%NH4OH)之梯度洗提,獲得白色固體(14mg)。
Rt=2.62min,m/z 405.2[M+H]+(方法1)
1H NMR(400MHz,d6-DMSO)δ 11.38(s,1H),9.84(s,1H),7.94(d,J=5.4Hz,1H),7.60(d,J=7.5Hz,2H),7.36-7.12(m,6H),7.05(t,J=7.4Hz,1H),6.08(d,J=4.9Hz,1H),3.60(dd,J=5.7,7.9Hz,1H),3.01(dd,J=5.5,13.4Hz,1H),2.79(dd,J=8.1,13.4Hz,1H),2.37(d,J=1.0Hz,3H),2.00(s,2H).
下列實施例係藉於各步驟以合宜的起始物料置換,而以實施例145之類似方式製備。
中間產物145A-b至145A-d之製備
下列中間產物係以中間產物145A-a之類似方式,經由以指示的胺置換實施例145步驟A中之酪胺酸製備。
中間產物145B-b至145B-e之製備
下列中間產物係以中間產物145B-a之類似方式而自指示的起始物料製備。
下列實施例係藉於步驟C中以下表中指示的中間產物置換,遵照相同的合成順序而以實施例145之類似方式製備。
步驟A
2-((第三丁氧基羰基)胺基)-3-(4-羥基苯基)-2-甲基丙酸甲酯(中間產物150A)
中間產物150A係使用類似實施例1步驟A及步驟B使用的程序而自2-胺基-3-(4-羥基苯基)-2-甲基丙酸製備。
LCMS(方法6):Rt=1.27min,m/z 332.1[M+Na]+
步驟B
2-((第三丁氧基羰基)胺基)-2-甲基-3-(4-((1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物150B)
中間產物150B係使用類似實施例1步驟D使用的程序而自中間產物150A及中間產物131A-a製備。
LCMS(方法6):Rt=1.73min,m/z 580.2[M+H]+
步驟C
3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-((第三丁氧基羰基)胺基)-2-甲基丙酸(中間產物150C)
中間產物150B(1.0g,1.73mmol)溶解於甲醇(10ml)內,及加入2M氫氧化鋰(1ml)。反應於60℃攪拌3小時。加入又一部分2M氫氧化鋰(1ml),及持續加熱歷時4小時。於室溫又攪拌18小時後,反應混合物經蒸發,以1M鹽酸(20ml)處理,及產物以DCM(30ml)萃取。有機萃取物經脫水(Na2SO4)及蒸發,獲得產物呈膠狀物(861mg)。
LCMS(方法6):Rt=1.13min,m/z 412.3[M+H]+
步驟D
(3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(環己基胺基)-2-甲基-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物150D)
中間產物150D係使用類似實施例1步驟F中使用的程序而自中間產物150C及環己胺製備。
LCMS(方法6):Rt=1.45min,m/z 493.2[M+H]+(方法1)
步驟D
3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-環己基-2-甲基丙醯胺(實施例150)
實施例150係使用類似實施例1步驟G中使用的方法而從中間產物150D製備。
LCMS(方法1):Rt=2.47min,m/z 393.3[M+H]+
1H NMR(400MHz,d6-DMSO)δ 11.71(s,1H),8.05(d,J=5.4Hz,1H),7.47(d,J=8.3Hz,1H),7.35-7.32(m,1H),7.23(d,J=8.6Hz,2H),7.06(d,J=8.6Hz,2H),6.37(d,J=5.4Hz,1H),6.19(dd,J=2.0,3.5Hz,1H),3.51-3.43(m,1H),3.05(d,J=12.8Hz,1H),2.63(d,J=12.8Hz,1H),1.80(s,2H),1.70-1.47(m,5H),1.34-1.22(m,2H),1.21(s,3H),1.19-0.98(m,3H).
實施例151係藉於步驟D中以下表中指示的胺起始物料置換,遵照相同的合成順序而以實施例150之類似方式而自中間產物150C製備。
步驟A
(S)-4-(2-((第三丁氧基羰基)胺基)-3-(3-氟-4-((3-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯基)哌-1-羧酸苄酯(中間產物152A)
中間產物152A係使用類似實施例1步驟F中使用的程序而自中間產物1E-a及哌-1-羧酸苄酯製備。
LCMS(方法6):Rt=1.89min,m/z 762.2[M+H]+
步驟B
(S)-(3-(3-氟-4-((3-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-側氧基-1-(哌-1-基)丙烷-2-基)胺基甲酸第三丁酯(中間產物152B)
中間產物152A(1.50g,1.97mmol)溶解於IMS(44.6ml)內及加入10%鈀/碳(187mg)。混合物於氣球提供的氫氣環境下攪拌。18小時後,混合物通過矽藻土過濾,及於減壓下蒸發去除溶劑。殘餘物於40g Si卡匣上層析,以0-10% 2M氨於甲醇於DCM洗提。獲得產物呈白色固體(951mg)。
LCMS(方法6):Rt=1.39min,m/z 628.2[M+H]+
步驟C
(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(哌-1-基)丙-1-酮(實施例152)
中間產物152B(66mg,0.11mmol)溶解於DCM(1.2ml)及加入TFA(1.2ml)。溶液於室溫攪拌3小時。反應混合物以甲醇稀釋及通過5g SCX-2卡匣。以甲醇沖洗後,產物以2M氨於甲醇洗提。蒸發獲得殘餘物,其溶解於THF(1.2ml)。添加4M水性氫氧化鈉(1.2ml),及反應於室溫攪拌1小時。以水(8ml)稀釋後, 產物以乙酸乙酯(3×10ml)萃取。組合有機萃取物經脫水(Na2SO4)及蒸發。產物藉HPLC純化以10-98%乙腈於水(添加0.1%NH4OH)之梯度洗提。獲得期望產物呈嗶嘰色固體(23mg)。
LCMS(方法1):Rt=1.57min,m/z 398.2[M+H]+
1H NMR(400MHz,d6-DMSO)δ 11.39(s,1H),8.00-7.96(m,1H),7.34-7.20(m,2H),7.15-7.08(m,2H),6.16-6.10(m,1H),3.96-3.89(m,1H),3.50-3.30(m,8H),2.80(dd,J=6.2,13.2Hz,1H),2.72-2.63(m,2H),2.55-2.52(m,1H),2.38-2.36(m,4H).
ee%(n.d.)
步驟A
(S)-(3-(3-氟-4-((3-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-側氧基-1-(4-(嗒-4-基甲基)哌-1-基)丙烷-2-基)胺基甲酸第三丁酯(中間產物153A)
中間產物152B(150mg,0.24mmol),嗒-4-甲醛(39mg,0.36mmol),及乙酸(0.05ml)於DCE(3ml)之溶液於4埃(Å)分子篩上於室溫攪拌2.5小時。添加三乙醯氧基硼氫化鈉(127mg,0.60mmol)及又持續攪拌歷時1小時。混合物以甲醇稀釋及通過10g SCX-2卡匣。以甲醇沖洗後,產物以2M氨於甲醇洗提。蒸發獲得期望產物(168mg),其未經進一步純化即供使用。
LCMS(方法6):Rt=1.69min,m/z 720.3[M+H]+
步驟B
(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(嗒-4-基甲基)哌-1-基)丙-1-酮(實施例153)
實施例153係使用類似實施例1步驟G中使用的方法而從中間產物153A製備。
LCMS(方法1):Rt=2.07min,m/z 490.1[M+H]+
1H NMR(400MHz,d6-DMSO)δ 11.40(s,1H),9.18-9.15(m,2H),7.99(d,J=5.4Hz,1H),7.59(dd,J=2.4,5.1Hz,1H),7.32(dd,J=1.9,11.8Hz,1H),7.24(dd,J=8.4,8.4Hz,1H),7.14(s,1H),7.11(dd,J=1.3,8.3Hz,1H),6.17(d,J=5.4Hz,1H),3.93(dd,J=6.8,6.8Hz,1H),3.55(s,2H),3.53-3.36(m,4H),2.80(dd,J=6.2,13.2Hz,1H),2.67(dd,J=7.5,13.2Hz,1H),2.43-2.22(m,6H),2.18-2.10(m,1H),1.63-1.83(s,2H).
下列實施例係藉於步驟A中以下表中指示的對應醛置換,而以實施例153之類似方式製備。
步驟A
(S)-3-((4-(2-((第三丁氧基羰基)胺基)-3-(3-氟-4-((3-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯基)哌-1-基)甲基)苯甲酸甲酯(中間產物165A)
中間產物165A係使用類似實施例153步驟A中使用的程序而自中間產物152B及3-甲醯基苯甲酸甲酯製備。
LCMS(方法4):Rt=1.51min,m/z 776.4[M+H]+
步驟B
(S)-3-((4-(2-((第三丁氧基羰基)胺基)-3-(3-氟-4-((3-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯基)哌-1-基)甲基)苯甲酸(中間產物165B)
中間產物165B係使用類似實施例1步驟E中使用的方法而自中間產物165A製備。
LCMS(方法4):Rt=1.42min,m/z 762.5[M+H]+
步驟C
(S)-(3-(3-氟-4-((3-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(3-(甲基胺基甲醯基)苄基)哌-1-基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物165C)
中間產物165C係使用類似實施例1步驟F中使用的方法而自中間產物165B及甲胺製備。
LCMS(方法4):Rt=1.37min,m/z 775.5[M+H]+
步驟D
(S)-3-((4-(2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯基)哌-1-基)甲基)-N-甲基苄醯胺(實施例165)
實施例165係使用類似實施例1步驟G中使用的方法而自中間產物165C製備。
LCMS(方法1):Rt=1.93min,m/z 545.2[M+H]+
1H NMR(400MHz,DMSO)11.41(s,1H),8.42-8.38(m,1H),7.98(d,J=5.4Hz,1H),7.75(s,1H),7.73-7.69(m,1H),7.41(d,J=6.5Hz,2H),7.31(dd,J=2.1,12.0Hz,1H),7.24(dd,J=8.4,8.4Hz,1H),7.14-7.08(m,2H),6.16(d,J=5.4Hz,1H),3.93(dd,J=6.6,6.6Hz,1H),3.49(s,3H),3.46-3.41(m,3H),2.84-2.76(m,4H),2.67(dd,J=7.4,13.1Hz,1H),2.38(s,3H),2.37-2.30(m,2H),2.23-2.18(m,1H),2.06(dd,J=7.4,7.4Hz,1H),1.70(s,2H).
如下實施例係藉於步驟A中以下表中指示的醛置換,而以實施例165之類似方式製備。
步驟A
(S)-(1-(4-苄醯基哌-1-基)-3-(3-氟-4-((3-甲基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物167A)
中間產物167A係使用類似實施例1步驟F中使用的條件而自中間產物152B及苯甲酸製備。
LCMS(方法6):Rt=1.81min,m/z 732.3[M+H]+
步驟B
(S)-2-胺基-1-(4-苄醯基哌-1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮(實施例167)
實施例167係使用類似實施例1步驟G中使用的方法而自中間產物167A製備。
LCMS(方法2):Rt=3.51min,m/z 502.0[M+H]+
1H NMR(400MHz,d6-DMSO)δ 11.40(s,1H),7.96(d,J=5.4Hz,1H),7.47-7.38(m,5H),7.35(d,J=11.8Hz,1H),7.24(t,J=8.4Hz,1H),7.14-7.10(m,2H),6.13(d,J=5.4Hz,1H),3.94-3.94(m,1H),3.71-3.37(m,7H),3.26-3.01(m,1H),2.84(dd,J=5.8,13.2Hz,1H),2.72-2.65(m,1H),2.38(s,3H),1.75(s,2H).
下列實施例係藉於步驟A中以下表中指示的對應羧酸置換,而以實施例167之類似方式製備。
步驟A
3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(二甲基胺基)-1-側氧基丙烷-2-基)胺基甲醯基)吡咯啶-1-羧酸第三丁酯(中間產物178A)
實施例113(45mg,0.139mmol),外消旋1-(第三丁氧基羰基)吡咯啶-3-羧酸(33mg,0.153mmol)及DIPEA(72μl,0.419mmol)溶解於DMF(2ml)與DCM(5ml)之混合物內。加入HATU(63mg,0.166mmol)及反應於室溫攪拌隔夜。蒸發獲得殘餘物,其未經進一步純化即供使用(82mg)。
LCMS(方法6):Rt=1.08及1.09min,m/z 522.3[M+H]+
步驟B
N-(3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(二甲基胺基)-1-側氧基丙烷-2-基)吡咯啶-3-羧醯胺(實施例178)
中間產物178A(72mg,粗產物)溶解於DCM(3ml)內及加入TFA(1ml)。反應於室溫攪拌隔夜及然後蒸發去除揮發物。殘餘物溶解於甲醇及載荷至已經以甲醇調理的2g SCX-2上。以甲醇沖洗之後,產物以2M氨於甲醇洗提。蒸發去除溶劑之後,殘餘物藉HPLC純化以10-98%乙腈於水(添加0.1%甲酸)之梯度洗提。獲得期望產物呈灰白色固體(24mg)。
LCMS(方法3):Rt=1.93min,m/z 422.3[M+H]+
1H NMR(400MHz,d6-DMSO)δ 11.72(s,1H),8.45(d,J=8.4Hz,1H),8.33(s,1H),8.07(d,J=5.4Hz,1H),7.33-7.30 (m,3H),7.10-7.07(m,2H),6.36(d,J=5.4Hz,1H),6.14(d,J=2.9Hz,1H),4.96-4.88(m,1H),3.07-2.96(m,2H),2.95(s,3H),2.93-2.88(m,2H),2.87-2.77(m,2H),2.82(s,3H),2.74(dd,J=6.5,10.5Hz,1H),1.97-1.73(m,2H).
下列實施例係藉以如於下表中指示的適當起始物料置換,而以實施例178之類似方式製備。
中間產物179A至180A之製備
下列中間產物係藉以於下表中指示的對應起始物料置換步驟1中之中間產物1E-a及胺,而以實施例1之類似方式製備。
下列實施例係藉於步驟A中以下表中指示的起始物料置換,而以實施例178之類似方式製備。
步驟A
2-((第三丁氧基羰基)胺基)-3-(4-((1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物181A)
中間產物181A係使用類似實施例1步驟D中使用的方法而自中間產物131A-a及(第三丁氧基甲醯基)酪胺酸甲酯製備。
LCMS(方法6):Rt=1.69min,m/z 566.2[M+H]+
步驟B
2-胺基-3-(4-((1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物181B)
中間產物181A(2.31g,4.09mmol)溶解於DCM(10ml)內及加入TFA(2ml)。反應於室溫攪拌6小時及然後蒸發去除揮發物。殘餘物於24g Si卡匣上層析,以0-10%甲醇於DCM洗提獲得產物呈嗶嘰色固體(2.03g)。
LCMS(方法6):Rt=1.07min,m/z 466.2[M+H]+
步驟C
2-(環己烷羧醯胺基)-3-(4-((1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物181C)
中間產物181B(250mg,0.538mmol)溶解於DCM(10ml)內,及加入DIPEA(140μl,0.806mmol)及環己烷甲醯氯(87μl,0.646mmol)。反應於室溫攪拌18小時及然後以DCM(20ml)稀釋。溶液以飽和氯化銨溶液(10ml)及鹽水(10ml)洗滌,脫水(Na2SO4)及蒸發。獲得產物呈固體(290mg)。
LCMS(方法5):Rt=1.64min,m/z 576.3[M+H]+
步驟D
2-(環己烷羧醯胺基)-3-(4-((1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸(中間產物181D)
中間產物181C(290mg,0.504mmol)溶解於甲醇(5ml)內,及加入氫氧化鋰水合物(32mg,0.762mmol)於水(1ml)之溶液。反應於室溫攪拌隔夜。甲醇經蒸發去除,及水層藉添加1N HCl調整至pH 5。產物萃取入DCM(10ml),及溶液經脫水(Na2SO4)及蒸發,獲得產物呈固體(248mg)。
LCMS(方法5):Rt=1.56min,m/z 562.2[M+H]+
步驟E
N-(1-((2-(二甲基胺基)乙基)胺基)-1-側氧基-3-(4-((1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙烷-2-基)環己烷羧醯胺(中間產物181E)
中間產物181E係使用類似實施例1步驟F中使用的方法而自中間產物181D及N,N-二甲基乙烷-1,2-二胺製備。
LCMS(方法6):Rt=1.19min,m/z 632.4[M+H]+
步驟F
N-(3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-((2-(二甲基胺基)乙基)胺基)-1-側氧基丙烷-2-基)環己烷羧醯胺(實施例181)
中間產物181E(153mg,0.267mmol)溶解於甲醇(5ml)內,及加入氫氧化鋰水合物(22mg,0.533mmol)於水(1.5ml)之溶液。反應於室溫攪拌1小時,及然後添加THF(3ml)。於50℃持續攪拌2小時。蒸發去除溶劑,及粗產物混合物藉HPLC純化以10-98%乙腈於水(添加0.1%NH4OH)之梯度洗提。獲得實施例181呈白色固體(30mg)。
LCMS(方法1):Rt=2.49min,m/z 478.3[M+H]+
1H NMR(400MHz,DMSO)δ 11.71(s,1H),8.05-8.03(m,1H),7.89(d,J=8.7Hz,1H),7.82(dd,J=5.4,5.4Hz,1H),7.33-7.28(m,3H),7.07(d,J=8.6Hz,2H),6.34(d,J=5.4Hz,1H),6.16(d,J=3.5Hz,1H),4.53-4.45(m,1H),3.18-3.10(m,2H),3.01(dd,J=4.7,13.5Hz,1H),2.75(dd,J=10.1,13.6Hz,1H),2.28-2.22(m,2H),2.14-2.13(m,6H),1.70-1.54(m,4H),1.50-1.46(m,1H),1,29-1.11(m,6H).
步驟A
2-(二甲基胺基)-3-(4-((1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物182A)
中間產物181B(475mg,1.022mmol)溶解於IMS(10ml)內,及溶液添加至含有10%鈀/碳(50mg)之燒瓶內。加入水性三聚甲醛(37%,0.61ml,8.18mmol),及容器抽真空及以氫氣回填充。反應於氫氣環境下於室溫攪拌18小時。混合物通過矽藻土過濾,及蒸發去除溶劑獲得期望產物,其未經進一步純化即供使用(603mg粗產物)。
LCMS(方法6):Rt=1.13min,m/z 494.2[M+H]+
步驟B
3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-(二甲基胺基)丙酸(中間產物182B)
中間產物182A(504mg,1.02mmol)溶解於甲醇(10ml)內,及加入氫氧化鋰水合物(86mg,2.04mmol)於水(2ml)之溶液。反應於50℃攪拌4小時及然後於室溫攪拌隔夜。於減壓下蒸發去除溶劑,及粗產物未經進一步純化即用於次一步驟。
LCMS(方法6):Rt=0.59min,m/z 326.2[M+H]+
步驟C
3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-(二甲基胺基)-N-(四氫-2H-吡喃-4-基)丙醯胺(實施例182)
實施例182係使用類似實施例1步驟F中使用的方法而從中間產物182B及四氫-2H-吡喃-4-胺製備。
LCMS(方法1):Rt=1.95min,m/z 409.3[M+H]+
1H NMR(400MHz,d6-DMSO)δ 11.71(s,1H),8.05(d,J=5.4Hz,1H),7.72(d,J=7.8Hz,1H),7.33(d,J=3.5Hz,1H),7.26(d,J=8.6Hz,2H),7.06(d,J=8.6Hz,2H),6.35(d,J=5.4Hz,1H),6.17(d,J=3.4Hz,1H),3.82-3.70(m,3H),3.30-3.24(m,1H),3.19-3.12(m,2H),2.96(dd,J=9.6,13.0Hz,1H),2.80(dd,J=5.0,13.1Hz,1H),2.27(s,6H),1.66-1.59(m,1H),1.50-1.18(m,3H).
如下實施例係藉以下表中指示的置換步驟C中之胺,而以實施例182之類似方式製備。
步驟A
(S)-2-胺基-3-(4-((3-甲基-1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物184A)
中間產物184A係使用類似實施例1步驟G中之方法而自中間產物131E-c製備。
LCMS(方法8):Rt=1.18min,m/z 480.2[M+H]+
步驟B
(S)-2-(二甲基胺基)-3-(4-((3-甲基-1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物184B)
中間產物184B係使用類似針對中間產物182A使用的方法而自中間產物184A製備。
LCMS(方法6):Rt=1.17min,m/z 508.4[M+H]+
步驟C
(S)-2-(二甲基胺基)-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸(中間產物184C)
中間產物184C係使用類似針對中間產物182B使用的方法而自中間產物184B製備。
LCMS(方法6):Rt=0.71min,m/z 340.3[M+H]+
步驟D
(S)-N-環己基-2-(二甲基胺基)-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺(實施例184)
實施例184係使用類似實施例1步驟F中使用於醯胺偶合的方法而從中間產物184C及環己胺製備。
LCMS(方法1):Rt=2.59min,m/z 421.3[M+H]+
1H NMR(400MHz,d6-DMSO)11.35(s,1H),7.98-7.96(m,1H),7.54(d,J=8.1Hz,1H),7.24(d,J=8.6Hz,2H),7.12(s,1H),7.02(d,J=8.5Hz,2H),6.19(d,J=5.4Hz,1H),3.55-3.46(m,1H),3.17-3.11(m,1H),2.94(dd,J=9.6,13.0Hz,1H),2.76(dd,J=5.1,13.0Hz,1H),2.31(d,J=1.0Hz,3H),2.26(s,6H),1.71-1.46(m,5H),1.29-0.93(m,5H).
(ee%=75%)
步驟A
2-((環己基甲基)胺基)-3-(4-((1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物185A)
中間產物181B(250mg,0.538mmol)及環己烷甲醛(72μl,0.589mmol)溶解於DCM(5ml)內,及加入三乙醯氧基硼氫化鈉(228mg,1.08mmol)。反應於室溫攪拌1小時。反應混合物以 飽和水性氯化銨(5ml)及鹽水(5ml)洗滌,脫水(Na2SO4)及蒸發。產物未經進一步純化即用於次一反應(255mg)。
LCMS(方法5):Rt=1.26min,m/z 562.3[M+H]+
步驟B
2-((環己基甲基)胺基)-3-(4-((1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸(中間產物185B)
中間產物185B係使用類似實施例1步驟E中使用的程序而自中間產物185A製備。
LCMS(方法5):Rt=1.31min,m/z 548.2[M+H]+
步驟C
2-((環己基甲基)胺基)-N-甲基-3-(4-((1-甲苯磺醯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺(中間產物185C)
中間產物185C係使用類似實施例1步驟F中使用的程序而自中間產物185B及甲基胺(2M於THF)製備。
LCMS(方法6):Rt=1.19min,m/z 561.3[M+H]+
步驟D
3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-((環己基甲基)胺基)-N-甲基丙醯胺(實施例185)
實施例185係使用類似實施例182步驟B使用的程序而從中間產物185C製備。
LCMS(方法1):Rt=2.43min,m/z 407.3[M+H]+
1H NMR(400MHz,d6-DMSO)δ 11.71(s,1H),8.06(d,J=5.4Hz,1H),7.77-7.70(m,1H),7.32(d,J=3.5Hz,1H),7.27(d,J=8.4Hz,2H),7.08(d,J=8.5Hz,2H),6.37(d,J=5.4Hz,1H),6.14(d,J=3.4Hz,1H),3.18-3.10(m,1H),2.84(dd,J=6,0,13.4Hz,1H),2.70(dd,J=7.9,13.4Hz,1H),2.57(d,J=4.7Hz,3H),2.34-2.21(m,1H),2.17-2.09(m,1H),1.68-1.56(m,6H),1.32-1.20(m,1H),1.19-1.05(m,3H),0.84-0.73(m,2H).
步驟A
(S)-(1-(環己基胺基)-3-(3-氟-4-羥基苯基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物186A)
中間產物186A係使用類似實施例1步驟F的程序而自(S)-2-((第三丁氧基羰基)胺基)-3-(3-氟-4-羥基苯基)丙酸及環己胺製備。
LCMS(方法6):Rt=1.35min,m/z 403.3[M+Na]+
步驟B
(S)-(1-(環己基胺基)-3-(3-氟-4-((1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物186B)
中間產物186B係使用類似實施例1步驟D中使用的方法而自中間產物186A及中間產物1C-c製備。
LCMS(方法6):Rt=1.84min,m/z 627.4[M+H]+
步驟C
(S)-(3-(4-((3-溴-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯基)-1-(環己基胺基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物186C)
中間產物186B(580mg,0.927mmol)溶解於乙腈(15ml)內,及溶液於0℃攪拌。添加NBS(173mg,0.972mmol),及反應於0℃攪拌30分鐘。於室溫持續攪拌1小時,及然後添加1M硫代硫酸鈉(15ml)。產物萃取入乙酸乙酯(3×10ml),及組合萃取物經脫水(Na2SO4)及蒸發。殘餘物於12克Si卡匣上層析以0-30%乙酸乙酯於環己烷洗提。獲得純質產物呈奶油色固體(351mg)。
LCMS(方法6):Rt=1.91min,m/z 705.3/707.3[M+H]+
步驟D
(S)-2-胺基-3-(4-((3-溴-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯基)-N-環己基丙醯胺(實施例186)
實施例186係使用類似實施例1步驟G中使用的程序而從中間產物186C製備。
LCMS(方法1):Rt=3.08min,m/z 475.1/477.1[M+H]+
1H NMR(400MHz,d6-DMSO)δ 12.16(s,1H),8.08(d,J=5.5Hz,1H),7.62-7.60(m,2H),7.30-7.23(m,2H),7.09(d,J=8.3Hz,1H),6.27-6.24(m,1H),3.55-3.47(m,1H),3.40-3.35(m,1H),2.88(dd,J=5.8,13.2Hz,1H),2.71(dd,J=7.4,13.2Hz,1H),1.82(s,2H),1.69-1.49(m,5H),1.32-1.02(m,5H).
步驟A
(S)-(1-(4-苄基哌-1-基)-3-(3-氟-4-羥基苯基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物187A)
中間產物187A係使用類似實施例1步驟F中使用的方法而自N-Boc-3-氟-L-酪胺酸及1-苄基哌製備。
LCMS(方法6):Rt=0.94min,m/z 458.3[M+H]+
步驟B
(S)-(1-(4-苄基哌-1-基)-3-(3-氟-4-((1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物187B)
中間產物187B係使用類似實施例1步驟D中使用的程序而自中間產物187A及中間產物1C-c製備。
LCMS(方法6):Rt=1.42min,m/z 704.4[M+H]+
步驟C
(S)-(1-(4-苄基哌-1-基)-(3-(4-((3-溴-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物187C)
中間產物187C係使用類似針對中間產物186C使用的程序而自中間產物187B製備。
LCMS(方法6):Rt=1.49min,m/z 782.3/784.3[M+H]+
步驟D
(S)-2-胺基-1-(4-苄基哌-1-基)-3-(4-((3-溴-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯基)丙-1-酮(實施例187)
實施例187係使用類似實施例1步驟G中使用的程序而自中間產物187C製備。
LCMS(方法1):Rt=2.42min,m/z 552.2[M+H]+
1H NMR(400MHz,DMSO)12.17(s,1H),8.09(d,J=5.4Hz,1H),7.63(s,1H),7.35-7.24(m,6H),7.12(d,J=8.3Hz,1H),6.27-6.25(m,1H),3.94(t,J=6.9Hz,1H),3.55-3.38(m,5H),2.80(dd,J=6.4,13.1Hz,1H),2.68(dd,J=7.3,13.3Hz,1H),2.34-2.33(m,2H),2.20-2.16(m,1H),2.04(m,1H),1.78-1.78(m,2H).
步驟A
(S)-3-(4-((3-溴-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-((第三丁氧基羰基)胺基)丙酸甲酯(中間產物188A)
中間產物188A係使用類似中間產物186C的程序而自中間產物1D-e製備。
LCMS(方法6):Rt=1.88min,m/z 620.2/622.2[M+H]+
步驟B
(S)-3-(4-((3-溴-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-((第三丁氧基羰基)胺基)丙酸(中間產物188B)
中間產物188B係使用類似實施例1步驟E中使用的程序而自中間產物188A製備。
LCMS(方法6):Rt=1.79min,m/z 606.2/608.2[M+H]+
步驟C
(S)-(3-(4-((3-溴-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(環己基胺基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物188C)
中間產物188C係使用類似實施例1步驟F中使用的程序而自中間產物188B及環己胺製備。
LCMS(方法6):Rt=1.91min,m/z 687.3/689.3[M+H]+
步驟D
(S)-2-胺基-3-(4-((3-溴-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-環己基丙醯胺(實施例188)
實施例188係使用類似實施例1步驟G中使用的程序而自中間產物188C製備。
LCMS(方法1):Rt=3.01min,m/z 457.1/459.1[M+H]+
1H NMR(400MHz,d6-DMSO)12.11(s,1H),8.07(d,J=5.4Hz,1H),7.60-7.58(m,2H),7.28(d,J=8.6Hz,2H),7.10-7.07(m,2H),6.29(d,J=5.4Hz,1H),3.55-3.46(m,1H),3.39-3.35(m,1H),2.87(dd,J=5.8,13.2Hz,1H),2.68(dd,J=7.4,13.3Hz,1H),1.76-1.75(m,2H),1.69-1.54(m,4H),1.29-1.16(m,3H),1.16-1.02(m,3H).
步驟A
(S)-(3-(4-((3-溴-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-側氧基-1-((四氫-2H-吡喃-4-基)胺基)丙烷-2-基)胺基甲酸第三丁酯(中間產物189A)
中間產物189A係使用類似實施例1步驟F中使用的程序而自中間產物188B及四氫-2H-吡喃-4-胺製備。
LCMS(方法8):Rt=1.76min,m/z 689.3/691.3[M+H]+
步驟B
(S)-2-胺基-3-(4-((3-溴-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(四氫-2H-吡喃-4-基)丙醯胺(實施例189)
實施例189係使用類似實施例1步驟G使用於脫保護的程序而自中間產物189A製備。
LCMS(方法1):Rt=2.49min,m/z 459.1/461.1
1H NMR(400MHz,d6-DMSO)12.12(s,1H),8.08(d,J=5.4Hz,1H),7.73-7.69(m,1H),7.59(s,1H),7.28(d,J=8.6Hz,2H),7.09(d,J=8.5Hz,2H),6.30(d,J=5.4Hz,1H),3.83-3.70(m,3H),3.40-3.34(m,3H),2.87(dd,J=5.9,13.2Hz,1H),2.69(dd,J=7.4,13.2Hz,1H),1.82(s,2H),1.66-1.55(m, 2H),1.43-1.26(m,2H).
(S)-2-胺基-N-環己基-3-(4-((3-碘-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺(實施例190)
實施例190係經由於步驟C中以NIS取代NBS而以實施例186之方式製備。
LCMS(方法1):Rt=3.03min,m/z 505.1[M+H]+
1H NMR(400MHz,d6-DMSO)12.13(s,1H),8.06(d,J=5.4Hz,1H),7.60(s,1H),7.58(d,J=8.3Hz,1H),7.28(d,J=8.5Hz,2H),7.07(d,J=8.5Hz,2H),6.29(d,J=5.4Hz,1H),3.55-3.46(m,1H),3.39-3.34(m,1H),2.87(dd,J=5.8,13.2Hz,1H),2.67(dd,J=7.5,13.2Hz,1H),1.72-1.52(m,6H),1.30-1.02(m,6H).
(S)-2-胺基-3-(4-((3-氯-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-環己基丙醯胺(實施例191)
實施例191係經由於步驟C中以NCS取代NBS而以實施例186之方式製備。
LCMS(方法1):Rt=2.96min,m/z 413.2[M+H]+
1H NMR(400MHz,d6-DMSO)12.03(s,1H),8.08(d,J=5.4Hz,1H),7.60-7.55(m,2H),7.28(d,J=8.6Hz,2H),7.09(d,J=8.6Hz,2H),6.29(d,J=5.5Hz,1H),3.55-3.46(m,1H),3.39-3.34(m,1H),2.87(dd,J=5.8,13.2Hz,1H),2.68(dd,J=7.4,13.3Hz,1H),1.76(s,1H),1.70-1.52(m,5H),1.29-1.05(m,6H).
步驟A
(S)-2-((第三丁氧基羰基)胺基)-3-(4-((3-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物192A)
中間產物192A係使用NIS替代NBS,以類似中間產物186C之方式而自中間產物1D-e製備。
LCMS(方法4):Rt=1.91min,m/z 668.0[M+H]+
步驟B
(S)-2-((第三丁氧基羰基)胺基)-3-(4-((3-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸(中間產物192B)
中間產物192B係使用類似實施例1步驟E之方式而自中間產物192A製備。
LCMS(方法4):Rt=1.83min,m/z 654.0[M+H]+
步驟C
(S)-(1-(4-苄基哌-1-基)-(3-(4-((3-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物192C)
中間產物192C係使用實施例1步驟F中使用的相同條件而自中間產物192B及1-苄基哌製備。
LCMS(方法4):Rt=2.64min,m/z 812.1[M+H]+
步驟D
(S)-2-胺基-1-(4-苄基哌-1-基)-3-(4-((3-(吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮(實施例192)
中間產物192C(200mg,0.247mmol),吡啶-4-二羥硼酸(61mg,0.496mmol),PdCl2(dppf)2.CH2Cl2(10mg,0.012 mmol),及碳酸鉀(75mg,0.543mmol)於DME(3ml)及水(1ml)之混合物以氬氣通氣歷時5分鐘。混合物於90℃攪拌18小時及然後讓其冷卻至室溫。混合物施加至5g SCX-2卡匣,其然後以DCM及甲醇沖洗。產物以2M氨於甲醇洗提,及蒸發,獲得殘餘物,其攝取入DMC(5ml)中。加入TFA(2ml),及溶液於室溫攪拌隔夜。於減壓下去除揮發成分後,產物藉HPLC純化以10-98%乙腈於水(添加0.1%NH4OH)之梯度洗提。獲得期望化合物呈白色固體(53mg)。
LCMS(方法1):Rt=1.69min,m/z 533.1[M+H]+
1H NMR(400MHz,d6-DMSO)12.25(s,1H),8.47-8.45(m,2H),8.11(d,J=5.5Hz,1H),7.92(s,1H),7.74-7.71(m,2H),7.32-7.24(m,6H),7.14(d,J=8.5Hz,2H),6.34(d,J=5.4Hz,1H),3.91(dd,J=6.9,6.9Hz,1H),3.57(s,3H),3.43-3.38(m,5H),2.77(dd,J=6.7,13.1Hz,1H),2.70-2.62(m,1H),2.35-2.17(m,3H),2.06-2.02(m,1H),1.71(s,1H).
(ee% n.d.)
下列實施例係藉以下表中指示的置換步驟D中之二羥硼酸或二羥硼酸酯,而以實施例192之類似方式製備。
(S)-2-胺基-N-環己基-3-(4-((3-環丙基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺(實施例203)
實施例203係使用類似實施例192步驟D中使用的方法而從中間產物188C及環丙基二羥硼酸製備。
LCMS(方法1):Rt=2.75min,m/z 419.3[M+H]+
1H NMR(400MHz,d6-DMSO)δ 11.37(s,1H),7.99(d,J=5.4Hz,1H),7.57(d,J=8.1Hz,1H),7.25(d,J=8.6Hz,2H),7.05(d,J=8.6Hz,2H),7.02(d,J=2.0Hz,1H),6.26(d,J=5.4Hz,1H),3.54-3.45(m,1H),3.38-3.34(m,1H),2.85(dd,J=5.9,13.2Hz,1H),2.67(dd,J=7.5,13.1Hz,1H),2.08-2.02(m,1H),1.72-1.61(m,5H),1.55-1.51(m,1H),1.28-1.01(m,6H),0.77-0.71(m,2H),0.60-0.55(m,2H).
ee%=82%
步驟A
(S)-2-((第三丁氧基羰基)胺基)-3-(3-氟-4-((1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物204A)
中間產物204A係使用類似實施例1步驟D中使用的方法而自中間產物1C-c及中間產物1A-a製備。
LCMS(方法6):Rt=1.99min,m/z 560.3[M+H]+
步驟B
(S)-2-((第三丁氧基羰基)胺基)-3-(3-氟-4-((3-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-丙酸甲酯(中間產物204B)
中間產物204B係使用類似用於中間產物186C之程序但以NIS替代NBS,而自中間產物204A製備。
LCMS(方法4):Rt=2.09min,m/z 686.3[M+H]+
步驟C
(S)-2-((第三丁氧基羰基)胺基)-3-(3-氟-4-((3-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸(中間產物204C)
中間產物204C係使用類似實施例1步驟E中使用的方法而自中間產物204B製備。
LCMS(方法9):Rt=2.70min,m/z 672.1[M+H]+
步驟D
(S)-(3-(3-氟-4-((3-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-((1-甲基哌啶-4-基)胺基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物204D)
中間產物204D係使用類似實施例1步驟F中使用的方法而自中間產物204C及1-甲基哌啶-4-胺製備。
LCMS(方法4):Rt=1.51min,m/z 768.3[M+H]+
步驟E
(S)-(3-(3-氟-4-((3-苯基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-((1-甲基哌啶-4-基)胺基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物204E)
中間產物204D(500mg,0.651mmol),4,4,5,5-四甲基-2-苯基-1,3,2-二戊硼環(266mg,1.30mmol),Pd2Cl2(dppf).CH2Cl2(27mg,0.033mmol),碳酸鉀(198mg,1.43mmol),DME(4ml)及水(0.4ml)之混合物於95℃加熱19小時。冷卻之後,混合物通過矽藻土過濾。溶液以乙酸乙酯(20ml)稀釋,以水洗滌(10ml)及脫水(Na2SO4)。蒸發獲得粗產物,其於Si卡匣(24g)上層析以0-100%乙酸乙酯於環己烷洗提,然後以0-10%甲醇於DCM洗提。獲得純質產物呈無色泡沫體(180mg)。
LCMS(方法4):Rt=1.35min,m/z 718.5[M+H]+
步驟F
(S)-2-胺基-3-(3-氟-4-((3-苯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(1-甲基哌啶-4-基)丙醯胺(實施例204)
實施例204係使用類似實施例1步驟G中使用的方法而自中間產物204E製備。
LCMS(方法1):Rt=2.21min,m/z 488.2[M+H]+
1H NMR(400MHz,DMSO)δ 12.04(s,1H),8.07(d,J=5.4Hz,1H),7.70-7.60(m,4H),7.36-7.18(m,5H),7.07(dd,J=1.3,8.4Hz,1H),6.24(d,J=5.2Hz,1H),3.51-3.43(m,1H),3.37(t, J=6.7Hz,1H),2.85(dd,J=6.1,13.2Hz,1H),2.73-2.54(m,3H),2.12(s,3H),1.94-1.87(m,2H),1.75(s,2H),1.62-1.54(m,2H),1.42-1.24(m,2H).
以下實施例係藉由置換於步驟E中指定的二羥硼酸酯,使用實施例204所使用的類似程序而從中間產物204D及二羥硼酸酯製備。
步驟A
4-溴-1-(4-甲氧基苄基)-1H-吡咯并[2,3-b]吡啶(中間產物206A)
4-溴-7-吖吲哚(2.5g,12.69mmol)溶解於DMF(20ml)內,及溶液於氮氣流下於冰浴中冷卻。加入氫化鈉(60%於礦油,635mg,15.88mmol),及混合物攪拌30分鐘。然後添加4-甲氧基苄基溴(2.81g,13.96mmol),及反應於室溫攪拌2小時。於該時間之後,藉小心加水(30ml)淬熄混合物,及產物萃取入乙酸乙酯(3×20ml)。組合萃取物經脫水(Na2SO4)及蒸發。粗產物於80克Si卡匣上層析以0-30%乙酸乙酯於環己烷洗提。獲得純質產物呈奶油色固體(3.62g)。
LCMS(方法4):Rt=1.61min,m/z 316.9/318.9[M+H]+
步驟B
(S)-2-((第三丁氧基羰基)胺基)-3-(4-((1-(4-甲氧基苄基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物206B)
中間產物206B係根據類似實施例1步驟D中使用的程序而自中間產物206A及中間產物1B-c製備。
LCMS(方法4):Rt=1.65min,m/z 532.1[M+H]+
步驟C
(S)-2-((第三丁氧基羰基)胺基)-3-(4-((3-碘-1-(4-甲氧基苄基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物206C)
中間產物206C係使用類似用於中間產物186C之程序但以NIS置換NBS,而自中間產物206B及NIS製備。
LCMS(方法4):Rt=1.75min,m/z 658.0[M+H]+
步驟D
(S)-2-((第三丁氧基羰基)胺基)-3-(4-((3-碘-1-(4-甲氧基苄基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸(中間產物206D)
中間產物206D係使用類似實施例1步驟E中使用的程序而自中間產物206C製備。
LCMS(方法4):Rt=1.68min,m/z 644.0[M+H]+
步驟E
(S)-(3-(4-((3-碘-1-(4-甲氧基苄基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-側氧基-1-((2-(哌啶-4-基)乙基)胺基)丙烷-2-基)胺基甲酸第三丁酯(中間產物206E)
中間產物206E係使用類似實施例1步驟F中使用的程序而自中間產物206D及2-(哌啶-4-基)乙-1-胺製備。
LCMS(方法4):Rt=1.27min,m/z 748.0[M+H]+
步驟F
(S)-2-胺基-3-(4-((3-(4-羥基苯基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(2-(吡啶-4-基)乙基)丙醯胺(實施例206)
中間產物206E(170mg,0.228mmol),(4-((第三丁基二甲基矽烷基)氧基)苯基)二羥硼酸(115mg,0.456mmol),Pd2Cl2(dppf).CH2Cl2(9mg,mmol),碳酸鉀(69mg,mmol),DME(3ml)及水(1ml)之混合物於90℃加熱19小時。蒸發獲得粗產物, 其於Si卡匣(24g)上層析以0-10%甲醇於DCM洗提。產物溶解於TFA(2ml)內及於90℃攪拌18小時。加入三氟甲烷磺酸(34mg,0.288mmol)及於65℃持續加熱3小時。讓反應冷卻及傾倒至SCX-2卡匣(5g)上。以DCM及甲醇沖洗之後,產物以2M甲醇性氨洗提。蒸發獲得粗產物,其藉HPLC純化以10-98%乙腈於水(添加0.1%NH4OH)之梯度洗提,獲得白色固體(7mg)。
LCMS(方法1):Rt=1.74min,m/z 494.1[M+H]+
1H NMR(400MHz,d6-DMSO)δ 11.82(s,1H),9.24(s,1H),8.46-8.43(m,2H),8.02(d,J=5.5Hz,1H),7.95(dd,J=5.8,5.8Hz,1H),7.45-7.40(m,3H),7.26-7.19(m,4H),7.06(d,J=8.6Hz,2H),6.71-6.68(m,2H),6.25(d,J=5.4Hz,1H),3.39-3.27(m,3H),2.88(dd,J=5.1,13.3Hz,1H),2.70(dd,J=7.1,7.1Hz,2H),2.60(q,J=7.4Hz,1H),1.69(s,2H).
ee%(n.d.)
步驟A
4-溴-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-甲醛(中間產物207A)
中間產物207A係使用類似用於製備中間產物1C-a之程序而從3-甲醯基-4-溴-7-吖吲哚製備。
LCMS(方法4):Rt=1.91min,m/z 355.1/357.1[M+H]+
步驟B
(S)-2-((第三丁氧基羰基)胺基)-3-(3-氟-4-((3-甲醯基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物207B)
中間產物207B係根據類似實施例1步驟D中之程序而自中間產物207A及中間產物1B-a製備。
LCMS(方法6):Rt=1.76min,m/z 588.4[M+H]+
步驟C
(S)-2-((第三丁氧基羰基)胺基)-3-(3-氟-4-((3-甲醯基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸(中間產物207C)
中間產物207C係使用類似實施例1步驟E之程序而自中間產物207B製備。
LCMS(方法6):Rt=1.69min,m/z 574.3[M+H]+
步驟D
(S)-2-((第三丁氧基羰基)胺基)-3-(3-氟-4-((3-(羥基甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸(中間產物207D)
中間產物207C(386mg,0.674mmol)溶解於DCM(10ml)與甲醇(1ml)之混合物中,及加入硼氫化鈉(26mg,0.684mmol)。反應於室溫攪拌隔夜。加入又一部分硼氫化鈉(52mg,1.37mmol),及持續加熱歷時2小時。反應混合物以水洗滌(10ml),脫水(Na2SO4)及蒸發。獲得產物呈奶油色固體(346mg)。
LCMS(方法6):Rt=1.59min,m/z 576.3[M+H]+
步驟E
(S)-(1-(4-苄基哌-1-基)-3-(3-氟-4-((3-(羥基甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物207E)
中間產物207E係使用類似實施例1步驟F中使用的程序而自中間產物207D及1-苄基哌製備。
LCMS(方法6):Rt=1.30min,m/z 734.5[M+H]+
步驟F
(S)-2-胺基-1-(4-苄基哌-1-基)-3-(3-氟-4-((3-(羥基甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮(實施例207)
實施例207係使用類似實施例1步驟G中使用的程序而從中間產物207E製備。
LCMS(方法2):Rt=3.23min,m/z 504.4[M+H]+
1H NMR(400MHz,d6-DMSO)δ 11.55(s,1H),8.00(d,J=5.5Hz,1H),7.34-7.22(m,9H),7.11(dd,J=1.3,8.3Hz,1H),6.17(d,J=5.4Hz,1H),4.79-4.76(m,3H),3.94(t,J=6.8Hz,1H),3.46-3.42(m,5H),2.80(dd,J=6.3,13.1Hz,1H),2.67(dd,J=7.4,13.1Hz,1H),2.39-2.29(m,2H),2.25-2.14(m,1H),2.11-2.01(m,1H),1.72-1.71(m,2H).
下列實施例係藉於步驟E中以如下顯示的胺置換1-苄基哌,而以實施例207之類似方式製備。
步驟A
(4-溴-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)甲醇(中間產物213A)
中間產物213A係使用類似用於製備中間產物207D的程序而自中間產物207A製備。
LCMS(方法4):Rt=1.58min,m/z 357.1/359.1[M+H]+
步驟B
4-溴-3-(((第三丁基二甲基矽烷基)氧基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(中間產物213B)
中間產物213A(204mg,0.57mmol)於DCM(6.5ml)以咪唑(78mg,1.14mmol)處理。加入第三丁基二甲基矽烷基氯(102mg,0.68mmol),及反應於室溫攪拌隔夜。反應混合物以水(10ml)稀釋,及分離DCM層。水層進一步以DCM(10ml)萃取,及組合萃取物經脫水(Na2SO4)及蒸發。殘餘物粗產物於25g Si卡匣上層析以0-30%乙酸乙酯於環己烷洗提,獲得期望產物呈無色油(240mg)。
LCMS(方法4):Rt=2.19min,m/z 471.2/473.2[M+H]+
步驟C
(S)-2-((第三丁氧基羰基)胺基)-3-(4-((3-(((第三丁基二甲基矽烷基)氧基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯基)丙酸甲酯(中間產物213C)
中間產物213C係根據實施例1步驟D中之程序而自中間產物213B及中間產物1B-a製備。
LCMS(方法4):Rt=4.55min,m/z 704.5[M+H]+
步驟D
(S)-2-((第三丁氧基羰基)胺基)-3-(4-((3-(((第三丁基二甲基矽烷基)氧基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯基)丙酸(中間產物213D)
中間產物213D係使用實施例1步驟E中之程序而自中間產物213C製備。
LCMS(方法4):Rt=4.39min,m/z 690[M+H]+
步驟E
(S)-3-(4-((3-(((第三丁基二甲基矽烷基)氧基)甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯 基)-1-側氧基-1-(4-(吡啶-2-基甲基)哌-1-基)丙烷-2-基)胺基甲酸第三丁酯(中間產物213E)
中間產物213E係使用類似實施例1步驟F中使用的程序而自中間產物213D及1-(吡啶-2-基甲基)哌製備。
LCMS(方法4):Rt=3.33min,m/z 849.5[M+H]+
步驟F
(S)-2-胺基-3-(3-氟-4-((3-(羥基甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(吡啶-2-基甲基)哌-1-基)丙-1-酮(實施例213)
實施例213係使用類似實施例1步驟G中使用的程序而從中間產物213E製備。
LCMS(方法1):Rt=1.57min,m/z 505.2[M+H]+
1H NMR(400MHz,d6-DMSO)δ 11.56-11.56(m,1H),8.49(dd,J=0.9,4.9Hz,1H),8.01(d,J=5.4Hz,1H),7.79-7.74(m,1H),7.44(d,J=7.8Hz,1H),7.34-7.22(m,4H),7.11(dd,J=1.3,8.3Hz,1H),6.19-6.17(m,1H),4.82-4.74(m,3H),3.94(dd,J=6.9,6.9Hz,1H),3.58(s,2H),3.54-3.37(m,4H),2.80(dd,J=6.4,13.2Hz,1H),2.71-2.64(m,1H),2.42-2.23(m,3H),2.18-2.07(m,1H),1.79-1.75(m,2H).
步驟A
2-(4-溴-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)乙酸甲酯(中間產物216A)
中間產物216A係使用類似用於中間產物1C-a的方法而自2-(4-溴-1H-吡咯并[2,3-b]吡啶-3-基)乙酸甲酯製備。
LCMS(方法4):Rt=1.70min,m/z 399.1/401.1[M+H]+
步驟B
2-(4-溴-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-3-基)乙-1-醇(中間產物216B)
中間產物216B係使用類似用於中間產物207D之製備的方法而自中間產物216A製備。
LCMS(方法4):Rt=1.64min,m/z 371.0/373.0[M+H]+
步驟C
4-溴-3-(2-((第三丁基二甲基矽烷基)氧基)乙基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(中間產物216C)
中間產物216C係使用類似用於中間產物213B之製備的方法而自中間產物216B製備。
LCMS(方法4):Rt=2.27min,m/z 485.0/487.0[M+H]+
步驟D
(S)-2-((第三丁氧基羰基)胺基)-3-(4-((3-(2-((第三丁基二甲基矽烷基)氧基)乙基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸甲酯(中間產物216D)
中間產物216D係使用類似實施例1步驟D的程序而自中間產物216C及中間產物1B-c製備。
LCMS(方法4):Rt=2.11min,m/z 700.5[M+H]+
步驟E
(S)-2-((第三丁氧基羰基)胺基)-3-(4-((3-(2-((第三丁基二甲基矽烷基)氧基)乙基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙酸(中間產物216E)
中間產物216E係使用類似實施例1步驟E中使用的程序而自中間產物216D製備。
LCMS(方法4):Rt=2.08min,m/z 686.5[M+H]+
步驟F
(S)-(1-(4-苄基哌-1-基)-3-(4-((3-(2-羥基乙基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物216F)
中間產物216F係使用類似實施例1步驟D的方法而自中間產物216E及1-苄基哌製備。
LCMS(方法4):Rt=2.29min,m/z 730.7[M+H]+
步驟G
(S)-2-胺基-1-(4-苄基哌-1-基)-3-(4-((3-(2-羥基乙基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮(實施例216)
實施例216係如針對實施例1步驟G之描述而自中間產物216F合成。
LCMS(方法1):Rt=1.71min,m/z 500.2[M+H]+
1H NMR(400MHz,DMSO)δ 11.42(s,1H),7.98(d,J=5.4Hz,1H),7.33-7.24(m,7H),7.16(d,J=2.2Hz,1H),7.08(d,J=8.5Hz,2H),6.21(d,J=5.4Hz,1H),4.53(dd,J=5.2,5.2Hz,1H),3.91(dd,J=6,8,6.8Hz,1H),3.71-3.63(m,2H),3.45-3.42(m,6H),2.95-2.89(m,2H),2.78(dd,J=6.8,13.1Hz,1H),2.66(dd,J=6.6,12.7Hz,1H),2.35-2.29(m,2H),2.22-2.17(m,1H), 2.03(s,1H),1.77(s,2H).
步驟A
(S)-(1-(環己基胺基)-1-側氧基-3-(4-((1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙烷-2-基)胺基甲酸第三丁酯(中間產物217A)
中間產物217A係使用如同實施例1步驟F的相同程序而自中間產物1E-e及環己胺製備。
LCMS(方法5):Rt=1.91min,m/z 609.4[M+H]+
步驟B
(S)-(1-(環己基胺基)-3-(4-((3-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物217B)
中間產物217B係使用如同用於中間產物186C的相同程序經由以NIS替代NBS而自中間產物217A製備。
LCMS(方法4):Rt=2.27min,m/z 735.4[M+H]+
步驟C
(S)-(3-(4-((3-(3-((第三丁基二甲基矽烷基)氧基)丙-1-炔-1-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(環己基胺基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物217C)
中間產物217B(390mg,0.531mmol),第三丁基二甲基(丙-2-炔-1-基氧基)矽烷(181mg,1.06mmol),PdCl2(dppf)2.CH2Cl2(22mg,0.027mmol),碘化銅(I)(10mg,0.053mmol)及三甲基胺(739ml,5.32mmol)於THF(10ml)密封於反應管內,及容器以氬氣掃除歷時5分鐘。混合物於90℃加熱隔夜,及然後讓其冷卻至室溫。混合物於減壓下濃縮,及於24克Si卡匣上層析以0-30%乙酸乙酯於環己烷洗提。獲得產物呈奶油色固體(410mg)。
LCMS(方法6):Rt=2.18min,m/z 777.6[M+H]+
步驟D
(S)-2-胺基-N-環己基-3-(4-((3-(3-羥基丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺(實施例217)
實施例217係使用類似實施例1步驟G中使用的程序而從中間產物217C製備。
LCMS(方法2):Rt=3.25min,m/z 433.1[M+H]+
1H NMR(400MHz,d6-DMSO)δ d 12.09(s,1H),8.07(d,J=5.5Hz,1H),7.69(s,1H),7.59(d,J=8.1Hz,1H),7.27(d,J=8.6Hz,2H),7.07(d,J=8.5Hz,2H),6.32(d,J=5.4Hz,1H),5.16(s,1H),4.20(s,2H),3.55-3.47(m,1H),3.36(dd,J=5.8,7.4Hz,1H),2.87(dd,J=5.7,13.3Hz,1H),2.67(dd,J=7.8,13.2Hz,1H),1.84(s,2H),1.72-1.48(m,4H),1.29-1.05(m,6H).實施例218
步驟A
(S)-(3-(4-((3-氰基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-側氧基-1-((四氫-2H-吡喃-4-基)胺基)丙烷-2-基)胺基甲酸第三丁酯(中間產物218A)
中間產物189A(122mg,0.177mmol),氰化鋅(13mg,0.111mmol),Pd2(dba)3(8mg,0.009mmol),1,1’-鐵茂二基貳(二苯基膦)(12mg,0.022mmol),及水(5滴)於DMF(3ml)於125℃加熱隔夜。讓混合物冷卻至室溫,及然後分溶於乙酸乙酯(10ml)與鹽水(8ml)間。有機層經分離,脫水(Na2SO4)及蒸發。粗產物(160mg)未經進一步純化即用於次一步驟。
LCMS(方法8):Rt=1.65min,m/z 636.4[M+H]+
步驟B
(S)-2-胺基-3-(4-((3-氰基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(四氫-2H-吡喃-4-基)丙醯胺(實施例218)
實施例218係使用類似實施例1步驟G中使用的程序而從中間產物218A製備。
LCMS(方法1):Rt=2.26min,m/z 406.2[M+H]+
1H NMR(400MHz,DMSO)d 8.38(s,1H),8.19(d,J=5.5Hz,1H),7.72(d,J=7.8Hz,1H),7.32(d,J=8.6Hz,2H),7.16(d,J=8.6Hz,2H),6.40(d,J=5.5Hz,1H),3.83-3.71(m,3H),3.41-3.36(m,3H),2.89(dd,J=5.8,13.2Hz,1H),2.72(dd,J=7.6,13.2Hz,1H),1.67-1.55(m,2H),1.43-1.27(m,2H).
下列實施例係以類似實施例218之方式,以二步驟式合成而自所顯示的起始物料製備。
中間產物223A至224B之製備
下列中間產物係以實施例1步驟F報告的相似方式而自中間產物204C及所指示的胺製備。
下列實施例係以類似實施例218之方式,以二步驟式合成而自所顯示的起始物料製備。
步驟A
4-溴-7-甲苯磺醯基-7H-吡咯并[2,3-b]嘧啶(中間產物225A)
中間產物225A係使用類似中間產物131A-a之方式而自4-溴-7H-吡咯并[2,3-b]嘧啶製備。
LCMS(方法7):Rt=3.82min,m/z 351.9/353.9[M+H]+
步驟B
(S)-2-((第三丁氧基羰基)胺基)-3-(4-((7-甲苯磺醯基-7H-吡咯并[2,3-b]嘧啶-4-基)氧基)苯基)丙酸甲酯(中間產物225B)
中間產物225B係使用類似實施例1步驟D中使用的方法而自中間產物225A及中間產物1B-c製備。
LCMS(方法5):Rt=1.73min,m/z 567.3[M+H]+
步驟C
(S)-2-第三丁氧基羰基胺基-3-{4-[7-(甲苯-4-磺醯基)-7H-吡咯并[2,3-b]嘧啶-4-基氧基]苯基}丙酸(中間產物225C)
中間產物225B(406mg,1.02mmol)溶解於甲醇內,及加入2M氫氧化鋰溶液。反應於室溫攪拌隔夜。甲醇於減壓下蒸發及所得水性溶液藉加入1N HCl酸化至pH 5。產物萃取入DCM(3 ×8ml),及組合萃取物經脫水(Na2SO4)及蒸發。獲得產物呈奶油色固體(299mg)。
LCMS(方法5):Rt=1.29min,m/z 399.2[M+H]+
步驟D
(S)-(3-(4-((7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-1-(環己基胺基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(中間產物225D)
中間產物225D係使用類似實施例1步驟F中使用的程序而自中間產物225C及環己胺製備。
LCMS(方法6):Rt=1.43min,m/z 480.4[M+H]+
步驟E
(S)-3-(4-((7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-2-胺基-N-環己基丙醯胺(實施例225)
實施例225係使用類似實施例1步驟G中使用的程序而自中間產物225D製備。
LCMS(方法6):Rt=2.82min,m/z 380.2[M+H]+
1H NMR(400MHz,d6-DMSO)δ 12.19(s,1H),8.28(s,1H),7.63(d,J=8.1Hz,1H),7.44(d,J=3.5Hz,1H),7.27(d,J=8.6Hz,2H),7.14(d,J=8.6Hz,2H),6.41(d,J=3.5Hz,1H),3.57-3.47 (m,1H),3.40-3.35(m,1H),2.90(dd,J=5.5,13.3Hz,1H),2.66(dd,J=7.8,13.3Hz,1H),1.72-1.62(m,5H),1.54(dd,J=3.6,8.9Hz,1H),1.29-1.05(m,6H).
下列實施例係藉以下表中指示之胺置換於步驟D中之胺而以實施例225之類似方式製備。
步驟A
(S)-2-((第三丁氧基羰基)胺基)-3-(5-羥基吡啶-2-基)丙酸甲酯(中間產物227A)
中間產物227A係使用類似實施例1步驟B中使用的方法而自(S)-2-胺基-3-(5-羥基吡啶-2-基)丙酸甲酯鹽酸鹽製備。
LCMS(方法6):Rt=0.86min,m/z 297.1[M+H]+
步驟B
6-氯-4-硝基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶(中間產物227B)
中間產物227B係使用類似實施例1步驟C中使用的方法而自6-氯-4-硝基-1H-吡咯并[2,3-b]吡啶製備。
LCMS(方法6):Rt=4.71min
1H NMR(400MHz,DMSO)δ 7.99(s,1H),7.68(d,J=3.5Hz,1H),7.24(d,J=3.5Hz,1H),5.75(s,2H),3.60(m,2H),0.98(m,2H),0.00(s,9H).
步驟C
(S)-2-((第三丁氧基羰基)胺基)-3-(5-((6-氯-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)吡啶-2-基)丙酸甲酯(中間產物227C)
中間產物227B(302mg,0.924mmol),中間產物227A(273mg,0.922mmol),及碳酸鉀(382mg,2.77mmol)於120℃於DMSO(5ml)加熱2小時。讓反應混合物冷卻及然後傾倒入水(15ml)中。產物萃取入乙酸乙酯(3×10ml),及組合萃取物經脫水(Na2SO4)及蒸發。藉於Si卡匣(24g)上層析以0-40%乙酸乙酯於環己烷洗提,獲得純質產物。產物為奶油色固體(320mg)。
LCMS(方法6):Rt=1.85min,m/z 577.3[M+H]+
步驟D
(S)-2-((第三丁氧基羰基)胺基)-3-(5-((1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)吡啶-2-基)丙酸甲酯(中間產物227D)
中間產物227C(320mg,0.556mmol)及三甲基胺(93μl,0.663mmol)於IMS(20ml)之溶液於氫氣環境下於10%鈀/碳(32mg)上攪拌。於室溫攪拌18小時後,混合物通過矽藻土過濾,及溶劑經蒸發去除,獲得期望產物呈奶油色固體(309mg)。
LCMS(方法4):Rt=1.96min,m/z 543.3[M+H]+
步驟E
(S)-2-((第三丁氧基羰基)胺基)-3-(5-((1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)吡啶-2-基)丙酸(中間產物227E)
中間產物227E係根據實施例1步驟E中描述的程序而自中間產物227D製備。
LCMS(方法6):Rt=1.65min,m/z 529.3[M+H]+
步驟F
(S)-(1-(環己基胺基)-1-側氧基-3-(5-((1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)吡啶-2-基)丙烷-2-基)胺基甲酸第三丁酯(中間產物227F)
中間產物227F係使用類似實施例1步驟F中使用的程序而自中間產物227E及環己胺製備。
LCMS(方法6):Rt=1.79min,m/z 610.4[M+H]+
步驟G
(S)-3-(5-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)吡啶-2-基)-2-胺基-N-環己基丙醯胺(實施例227)
實施例227係使用類似實施例1步驟G中使用的方法而自中間產物227F製備。
LCMS(方法1):Rt=2.36min,m/z 380.2[M+H]+
1H NMR(400MHz,DMSO)δ 11.80(s,1H),8.42(d,J=2.7Hz,1H),8.09(d,J=5.4Hz,1H),7.67(d,J=8.1Hz,1H),7.56(dd,J=2.9,8.5Hz,1H),7.38(d,J=3.6Hz,1H),7.33(d,J=8.5Hz,1H),6.43(d,J=5.4Hz,1H),6.24(d,J=3.5Hz,1H),3.57-3.47(m,2H),3.05(dd,J=5.3,13.4Hz,1H),2.83(dd,J=8.2,13.4Hz,1H),1.83(s,2H),1.72-1.59(m,3H),1.58-1.49(m,1H),1.28-1.06(m,6H).
下列實施例係藉以表中指示之胺置換步驟F中之胺而以實施例227之類似方式製備。
步驟A
(R)-(1-(環己基胺基)-3-(3,5-二氟-4-羥基苯基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(實施例229A)
(R)-2-((第三丁氧基羰基)胺基)-3-(3,5-二氟-4-羥基苯基)丙酸(500mg,1.58mmol)及環己胺(172mg,1.74mmol),DIPEA(822μl,4.74mmol)及HATU(719mg,1.90mmol)於室溫於DMF(2ml)及DCM(10ml)之混合物中攪拌。3小時後,反應混合物於減壓下濃縮,及殘餘物分溶於DCM(20ml)及飽和碳酸氫鈉溶液(15ml)間。分離有機層,以鹽水洗滌,脫水(Na2SO4)及蒸發。粗產物於Si卡匣(40g)上層析以0-100%乙酸乙酯於環己烷洗提獲得奶油色泡沫體(468mg)。
LCMS(方法6):Rt=1.40min,m/z 397.1[M-H]-
步驟B
(R)-(3-(4-((6-氯-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3,5-二氟苯基)-1-(環己基胺基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(實施例229B)
中間產物229B係使用類似用於中間產物227C之程序而自中間產物229A及中間產物227B製備。
LCMS(方法6):Rt=1.97min,m/z 679.3[M+H]+
步驟C
(R)-(1-(環己基胺基)-3-(3,5-二氟-4-((1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-側氧基丙烷-2-基)胺基甲酸第三丁酯(實施例229C)
中間產物229C係使用類似用於中間產物227D之程序而自中間產物229B製備。
LCMS(方法6):Rt=1.87min,m/z 645.4[M+H]+
步驟D
(R)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3,5-二氟苯基)-2-胺基-N-環己基丙醯胺(實施例229)
中間產物229C(216mg,0.336mmol)溶解於DCM(5ml)內及加入TFA(1ml)。於室溫攪拌1小時後,蒸發去除揮發物,及殘餘物溶解於甲醇(10ml)。添加2M氫氧化鋰(2ml)及反應於室溫攪拌18小時。甲醇經蒸發及水性混合物以DCM(12ml)萃取。有機層經脫水(Na2SO4)及蒸發。產物藉HPLC純化以10-98%乙腈於水(添加0.1%甲酸)之梯度洗提獲得白色固體(67mg)。
LCMS(方法1):Rt=2.86min,m/z 415.2[M+H]+
1H NMR(400MHz,DMSO)δ 11.85(s,1H),8.07(d,J=5.4Hz,1H),7.71(d,J=8.0Hz,1H),7.41(dd,J=2.5,3.4Hz,1H),7.18(d,J=9.0Hz,2H),6.36(d,J=5.5Hz,1H),6.34(dd,J=1.9,3.4Hz,1H),3.58-3.49(m,1H),3.47(t,J=6.7Hz,1H),2.91(dd,J=6.1,13.2Hz,1H),2.77(dd,J=7.5,13.3Hz,1H),1.73-1.49(m,6H),1.32-1.03(m,6H).
下列外消旋實施例係使用如下指定的條件進行光學分割而獲得純質對映異構物。
本發明之化合物抑制Rho激酶活性的功效可使用ADP-Glo套組(Promega)於含有40mM Tris pH7.5,20mM MgCl2,0.1mg/ml BSA,50μM DTT及2.5μM肽酶基質(髓鞘鹼性蛋白)的10微升分析試驗中測定。於分析試驗中,化合物溶解於DMSO使 得DMSO之終濃度為1%。全部反應/培養係於25℃進行。化合物(2微升)及Rho激酶1或Rho激酶2(4微升)經混合及培養30分鐘。藉添加ATP(4微升)引發反應,使得於分析試驗中之ATP終濃度為10μM。培養1小時後添加10微升ADP-Glo試劑,及又經45分鐘培養後,添加20微升激酶檢測緩衝液,及混合物又經培養30分鐘。以光度計量測發光信號。對照組由不含化合物之分析試驗孔組成,使用未添加酶的分析試驗孔測量得背景值。化合物係以劑量-反應格式試驗,及計算於各種化合物之濃度的激酶活性之抑制。為了測定IC50(抑制50%酶活性所需化合物之濃度),使用反曲擬合(sigmoidal fit),資料擬合至%抑制相對於Log10化合物濃度作圖,具有可變斜率及匹配最大值至100%及最小值至0%。為了測定Ki值,利用Cheng-Prusoff方程式(Ki=IC50/(1+[S]/Km))。
式(I)化合物顯示低於5μM之Ki值,及對於大部分本發明之化合物Ki甚至低於500nM。
個別化合物的結果提供如下於表1中且係以活性範圍表示。
其中化合物係根據如下分類標準,就其對ROCK-I及ROCK-II同功異形體的抑制活性之強度加以分類:
+++:Ki<3nM
++:Ki於3-30nM之範圍
+:Ki>30nM
Claims (12)
- 一種式(I)化合物
- 如請求項1之化合物,其中,X 1及X 2中之各者為CH基,全部其它變數係如請求項1中定義;或其醫藥上可接受之鹽及其溶劑合物。
- 如請求項1之化合物,其中,R 2及R 3與其鍵聯之氮原子一起,生成一環系飽和雜環系基團,其為哌 環;該化合物係由式Ib表示:
- 如請求項1之化台物,其中,X 1及X 2兩者皆為CH基;p為0或1至3之整數;當存在時,各個R為鹵原子;R 0為-H,及 R 1係獨立地選自於由下列所組成之組群:-CN,(C 1-C 6)烷基,(C 1-C 6)羥基烷基,R 2為-H,及R 3係選自於由下列所組成之組群:(C 3-C 10)環烷基,(C 3-C 8)雜環烷基,雜芳基(C 1-C 6)烷基;雜芳基、環烷基、雜環烷基中之各者係進一步任選地經以一個或多個(C 1-C 8)烷基或(C 1-C 6)羥基烷基取代;R 4及R 5兩者皆為H;R 6為-H;或其醫藥上可接受之鹽及其溶劑合物。
- 如請求項1之化合物,其中,X 1及X 2於各次出現時係獨立地為CH基或氮原子;p為0或1至3之整數;當存在時,各個R為氟;R 0為-H或(C 1-C 6)烷基其為甲基,及R 1係獨立地選自於由下列所組成之組群:-H,鹵原子其為溴、氯、碘、氟,-NR 7R 8,-CN, (C 1-C 6)烷基其為甲基,(C 1-C 6)鹵烷基,(C 1-C 6)羥基烷基其為羥基甲基、羥基乙基,(C 1-C 6)胺基烷基,(C 1-C 6)烷氧基-(C 1-C 6)烷基其為甲氧基甲基,(C 3-C 10)環烷基其為環丙基,(C 2-C 6)烯基,(C 5-C 7)環烯基,(C 2-C 6)炔基,(C 2-C 6)羥基炔基其為羥基丙炔基,芳基其為苯基、羥基苯基,雜芳基其為異 唑基、N-甲基咪唑基、吡啶基、噻唑基、N-乙基吡唑基、噻吩基-甲腈,及(C 3-C 6)雜環烷基其為二氫吡咯基、二氫呋喃基,R 2為-H或(C 1-C 6)烷基其為甲基,及R 3係獨立地選自於由下列所組成之組群:(C 1-C 6)烷基其為甲基,(C 1-C 6)鹵烷基,(C 1-C 6)羥基烷基,(C 1-C 6)胺基烷基其為二甲基胺基乙基、二甲基胺基丙基,(C 1-C 6)烷氧基(C 1-C 6)烷基其為甲氧基丙基,(C 3-C 10)環烷基其為環己基、羥基甲基環己基、羥基乙基環己基、氰基-環己基、4-胺基羰基-環己烷-4-基、4-二甲基胺基甲基-環己烷-4-基, (C 3-C 8)雜環烷基其為N-甲基哌啶基、(羥基甲基)-N-甲基哌啶基、N-苄基哌啶基、N-甲基吖呾-3-基、四氫吡喃基、4-羥基甲基-四氫吡喃-4-基、 啶基,芳基其為苯基、三氟甲基苯基、二氫茚基,雜芳基其為噻唑基、吡啶基、氯吡啶基、異喹啉基,芳基(C 1-C 6)烷基其為苄基、鄰-、間-、對-羥基甲基苄基、苯乙基,雜芳基(C 1-C 6)烷基其為(吡啶基)乙基、(噻吩基)甲基、(N-苯基-吡唑基)乙基,(C 3-C 8)環烷基(C 1-C 6)烷基其為環己基甲基,(C 3-C 8)雜環烷基-(C 1-C 6)烷基其為(哌啶-4-基)甲基、(N-苄基哌啶基)甲基、(N-甲基哌啶-4-基)甲基、N-甲基吖呾-3-基-甲基、 啉基丙基;或替代地,R 2及R 3與其鍵聯之氮原子一起,生成一環系基團其為哌 -N-基、甲基哌 -N-基、苯基-N-甲基哌 -N-基、N-苯基-哌 -N-基、三甲基哌 -N-基、4-苄基-3,5-二甲基哌 -N-基、(羥基甲基)-N-甲基哌 -N-基、乙醯基(哌 -N-基)、苯基乙醯基(哌 -N-基)、苄醯基(哌 -N-基)、4-(((二甲基胺基)甲基)苄醯基)哌 -1-基、環丙基(哌 -N-基)、環丙基甲基(哌 -N-基)、環丙烷羰基(哌 -N-基)、環己烷羰基(哌 -N-基)、N-甲基哌啶-4-羰基(哌 -N-基)、4-(吡啶-3-羰基)哌 -N-基、4-(1-甲基-1H-吡唑-4-羰基)哌 -N-基、4-(1-甲基-1H-咪唑-4-羰基)哌 -N-基、4-(1H-噻唑-4-羰基)哌 -N-基、4-二甲基胺基羰基(哌 -N-基)、(苯基磺醯基)哌 -N-基、(吡啶基)哌 -N-基、(吡啶基甲基)哌 -N-基、(甲氧基乙基)哌 -N-基、(苄基)哌 -N-基、(甲氧基苄基)哌 -N-基、(3-(二甲基胺基丙氧基)苄基)哌 -N- 基、(氟苄基)哌 -N-基、(甲基苄基)哌 -N-基、N-(((甲基胺基羰基)苯基)甲基)哌 -N-基、N-(((甲基胺基羰基)呋喃基)甲基)哌 -N-基、(苯乙基)哌 -N-基、(嘧啶基甲基)哌 -N-基、(2-(甲基硫基)嘧啶基甲基)哌 -N-基、(((甲基磺醯基)哌啶-4-基)甲基)哌 -N-基、((N-甲基-咪唑-5-基)甲基)哌 -N-基、((1-甲基-1H-咪唑-2-基)甲基)哌 -N-基、((甲基噻唑基)甲基)哌 -N-基、((吡 -2-基)甲基)哌 -N-基、((1-甲基-1H-吡唑-4-基)甲基)哌 -N-基、苯并[d][1,3]二 呃-5-基甲基)哌 -N-基、(喹 啉-2-基甲基)哌 -N-基、((1,2,3-噻二唑-4-基)甲基)哌 -N-基、(嗒 -4-基甲基)哌 -N-基、吡咯啶-N-基、苯基吡咯啶-N-基、(吡啶基)吡咯啶-N-基、哌啶-N-基、(二甲基胺基)哌啶-N-基、4-((二甲基胺基)甲基)哌啶-N-基、苄基哌啶-N-基、苄基羥基哌啶-N-基、吡啶基哌啶-N-基、吡啶基氧基哌啶-N-基、(苯基磺醯基)哌啶-N-基、4-苯基-5,6-二氫吡啶-1(2H)-基、苯基 啉-N-基、3-(二甲基胺基)吖呾-N-基、3-(二甲基胺基)甲基-吖呾-N-基、3-(二甲基胺基)吡咯啶-N-基、3-(3-甲基-1,2,4- 二唑-5-基)吡咯啶-N-基、3-(二甲基胺基)哌啶-N-基,或生成二環系基團其為5,6-二氫咪唑并[1,5-a]吡 -7(8H)-基、3,4-二氫-2,7- 啶-2(1H)-基、1H-吡咯并[3,4-c]吡啶-2(3H)-基、六氫吡 并[2,1-c][1,4] -8(1H)-基、3,4-二氫異喹啉-2(1H)-基、5-甲基-2,5-二吖二環[2.2.1]庚烷-2-基、5-苄基-2,5-二吖二環[2.2.1]庚烷-2-基、7,8-二氫吡啶并[4,3-d]嘧啶-6(5H)-基、2,6-二吖螺環[3.3]庚烷-2-基、6-甲基-2,6-二吖螺環[3.3]庚烷-2-基、7-甲基-2,7-二吖螺環[3.5]壬烷-2-基、2-甲基-2,9-二吖螺環[5.5]十一碳烷-9-基、9-甲基-3,9-二吖螺環[5.5]十一碳烷-3-基、八氫吡咯并[3,4-c]吡咯-2-基或5-甲基 -八氫吡咯并[3,4-c]吡咯-2-基;R 4係選自於由下列所組成之組群:H,(C 1-C 6)烷基其為甲基,(C 3-C 6)環烷基-(C 1-C 6)烷基其為環己基甲基,及(C 3-C 6)環烷基-羰基其為環己基羰基或(吡咯啶-3-基)甲醯基;及R 5係獨立地選自於由下列所組成之組群:H,(C 1-C 6)烷基其為甲基;R 6係選自於由下列所組成之組群:-H,及(C 1-C 6)烷基其為甲基;或其醫藥上可接受之鹽及其溶劑合物。
- 如請求項1之化合物,其中,該化合物係選自於:(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(1-甲基哌啶-4-基)丙醯胺;(S)-2-胺基-1-(7,8-二氫吡啶并[4,3-d]嘧啶-6(5H)-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(6-甲基-2,6-二吖螺環[3.3]庚烷-2-基)丙-1-酮;(2S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(2-苯基 啉基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-苯基哌 -1-基)丙-1-酮;(2S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-甲基-3-苯基哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(苯基磺醯基)哌啶-1-基)丙-1-酮;(2S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基) 苯基)-1-(3-(3-甲基-1,2,4- 二唑-5-基)吡咯啶-1-基)丙-1-酮;(S)-2-胺基-1-(4-苄基-4-羥基哌啶-1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-(3,4-二氫異喹啉-2(1H)-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(吡啶-3-基氧基)哌啶-1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(吡啶-4-基)哌啶-1-基)丙-1-酮;(S)-2-胺基-1-(4-苄基哌啶-1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-(4-(二甲基胺基)哌啶-1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-N-(3-(二甲基胺基)丙基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(2S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(六氫吡 并[2,1-c][1,4] -8(1H)-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-((3S,5R)-3,4,5-三甲基哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(3,3,4-三甲基哌 -1-基)丙-1-酮;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(2-甲氧基乙基)哌 -1-基)丙-1-酮;(S)-2-胺基-N-環己基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶 -4-基)氧基)苯基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-苯基-5,6-二氫吡啶-1(2H)-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(苯基磺醯基)哌 -1-基)丙-1-酮;(S)-4-(2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯基)-N,N-二甲基哌 -1-羧醯胺;(S)-2-胺基-1-((1S,4S)-5-苄基-2,5-二吖二環[2.2.1]庚烷-2-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-((1S,4S)-5-甲基-2,5-二吖二環[2.2.1]庚烷-2-基)丙-1-酮;(S)-2-胺基-1-((3S,5R)-4-苄基-3,5-二甲基哌 -1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(吡啶-2-基甲基)哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(吡啶-3-基甲基)哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(2,6-二吖螺環[3.3]庚烷-2-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-((3aR,6aS)-5-甲基六氫吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基) 苯基)-1-((3aR,6aS)-六氫吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(1-(羥基甲基)環己基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(4-(羥基甲基)四氫-2H-吡喃-4-基)丙醯胺;(S)-2-胺基-N-(1-氰基環己基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(S)-1-(2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺基)環己烷羧醯胺;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(1-(2-羥基乙基)環己基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(4-(羥基甲基)-1-甲基哌啶-4-基)丙醯胺;(S)-2-胺基-N-(1-((二甲基胺基)甲基)環己基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-甲基-N-((1-甲基哌啶-4-基)甲基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-((1-甲基哌啶-4-基)甲基)丙醯胺;(S)-2-胺基-1-(3-(二甲基胺基)吖呾-1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(1-甲基吖呾-3-基)丙醯胺;(S)-2-胺基-1-((R)-3-(二甲基胺基)吡咯啶-1-基)-3-(3-氟-4-((3-甲 基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-甲基-N-(1-甲基哌啶-4-基)丙醯胺;(S)-2-胺基-1-(4-((二甲基胺基)甲基)哌啶-1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-((R)- 啶-3-基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-((1-甲基吖呾-3-基)甲基)丙醯胺;(S)-2-胺基-1-(3-((二甲基胺基)甲基)吖呾-1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-((S)-3-(二甲基胺基)吡咯啶-1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-((R)-3-(二甲基胺基)哌啶-1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(吡啶-4-基甲基)哌 -1-基)丙-1-酮;2-胺基-1-(4-(苯并[d][1,3]二 呃-5-基甲基)哌 -1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-苯乙基哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(四氫-2H-吡喃-4-基)丙醯胺;(R)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基) 苯基)-N-(四氫-2H-吡喃-4-基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(2-(1-苯基-1H-吡唑-4-基)乙基)丙醯胺;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(2-(吡啶-4-基)乙基)丙醯胺;2-胺基-1-(4-(環丙基甲基)哌 -1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-甲基哌 -1-基)丙-1-酮;2-胺基-1-(4-環丙基哌 -1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(噻吩-2-基甲基)丙醯胺;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(4-(羥基甲基)苄基)丙醯胺;2-胺基-N-(2,3-二氫-1H-茚-2-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(2-(羥基甲基)-4-甲基哌 -1-基)丙-1-酮;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(1H-吡咯并[3,4-c]吡啶-2(3H)-基)丙-1-酮;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(3-(吡啶-4-基)吡咯啶-1-基)丙-1-酮;2-胺基-1-(3,4-二氫-2,7- 啶-2(1H)-基)-3-(3-氟-4-((3-甲基-1H-吡 咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(3-甲氧基丙基)丙醯胺;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(2-(吡啶-2-基)乙基)丙醯胺;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(吡啶-3-基)丙醯胺;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(吡啶-4-基)丙醯胺;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(4-甲基苄基)哌 -1-基)丙-1-酮;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(3-甲基苄基)哌 -1-基)丙-1-酮;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(4-氟苄基)哌 -1-基)丙-1-酮;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(4-甲氧基苄基)哌 -1-基)丙-1-酮;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-苯乙基丙醯胺;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(哌啶-1-基)丙-1-酮;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(異喹啉-5-基)丙醯胺;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯 基)-N-(3- 啉基丙基)丙醯胺;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(吡啶-2-基)哌 -1-基)丙-1-酮;2-胺基-1-(5,6-二氫咪唑并[1,5-a]吡 -7(8H)-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;2-胺基-N-((1-苄基哌啶-4-基)甲基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;2-胺基-N-(1-苄基哌啶-4-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(2-苯基吡咯啶-1-基)丙-1-酮之第一洗提外消旋非對映異構物;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(2-苯基吡咯啶-1-基)丙-1-酮之第二洗提外消旋非對映異構物;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(3-氟-4-((2-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-N-(3-甲氧基丙基)-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(2-(吡啶-4-基)乙基)丙醯胺(S)-2-胺基-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(四氫-2H-吡喃-4-基)丙醯胺;3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(4-(三氟 甲基)苯基)丙醯胺;(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(環己基甲基)-N-甲基丙醯胺;(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-苄基-N-甲基丙醯胺;(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(6-氯吡啶-3-基)丙醯胺;(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(2-(二甲基胺基)乙基)丙醯胺;(R)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(2-(二甲基胺基)乙基)丙醯胺;(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-苄基丙醯胺;(R)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-苄基丙醯胺;(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(四氫-2H-吡喃-4-基)丙醯胺;(R)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(四氫-2H-吡喃-4-基)丙醯胺;(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-環己基-N-甲基丙醯胺;(R)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-環己基-N-甲基丙醯胺;(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(1-甲 基哌啶-4-基)丙醯胺;(R)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(1-甲基哌啶-4-基)丙醯胺;(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(噻唑-2-基)丙醯胺;(R)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(噻唑-2-基)丙醯胺;(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(環己基甲基)丙醯胺;(R)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(環己基甲基)丙醯胺;(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-苯基丙醯胺;(R)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-苯基丙醯胺;(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-環己基丙醯胺;(R)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-環己基丙醯胺;3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N,N-二甲基丙醯胺;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(4-((3-氟-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(3-氟-4-((5-甲基-7H-吡咯并 [2,3-d]嘧啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-N-(3-(二甲基胺基)丙基)-3-(3-氟-4-((5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-N-(1-甲基哌啶-4-基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-1-(4-甲基哌 -1-基)丙-1-酮;(S)-2-胺基-1-(4-環丙基哌 -1-基)-3-(3-氟-4-((5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-1-(4-(吡啶-2-基甲基)哌 -1-基)丙-1-酮;2-胺基-3-(3-氟-4-((5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-1-((1S,4S)-5-甲基-2,5-二吖二環[2.2.1]庚烷-2-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-1-(4-(吡啶-4-基)哌啶-1-基)丙-1-酮;(S)-2-胺基-1-(4-苄基-4-羥基哌啶-1-基)-3-(3-氟-4-((5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-(3,4-二氫異喹啉-2(1H)-基)-3-(3-氟-4-((5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-N-(四氫-2H-吡喃-4-基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-1-(4-(吡啶-3-基氧基)哌啶-1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基) 苯基)-1-(4-(苯基磺醯基)哌啶-1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-N-(2-(吡啶-4-基)乙基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((5-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-1-((3S,5R)-3,4,5-三甲基哌 -1-基)丙-1-酮;(S)-4-(4-(2-胺基-3-(4-苄基哌 -1-基)-3-側氧基丙基)-2-氟苯氧基)-7H-吡咯并[2,3-d]嘧啶-5-甲腈;(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-環己基-2-(甲基胺基)丙醯胺;2-胺基-1-(4-苄基哌 -1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;1-(4-乙醯基哌 -1-基)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-N-環己基-N-甲基-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(S)-2-胺基-N-苄基-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(R)-2-胺基-N-苄基-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(S)-2-胺基-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-苯基丙醯胺;(R)-2-胺基-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-苯基丙醯胺;(S)-2-胺基-N-(環己基甲基)-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶 -4-基)氧基)苯基)丙醯胺;(R)-2-胺基-N-(環己基甲基)-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(S)-2-胺基-N-環己基-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(R)-2-胺基-N-環己基-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(R)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(環己基甲基)-N-甲基丙醯胺;(R)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-苄基-N-甲基丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-苯基丙醯胺;(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯基)-2-胺基-N-環己基丙醯胺;(S)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯基)-2-胺基-N-苯基丙醯胺;(R)-2-胺基-N-環己基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(R)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-苯基丙醯胺;3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-環己基-2-甲基丙醯胺;3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-2-甲基 -N-(四氫-2H-吡喃-4-基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(嗒 -4-基甲基)哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-((2-(甲基硫基)嘧啶-4-基)甲基)哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(吡 -2-基甲基)哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-((1-甲基-1H-咪唑-2-基)甲基)哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-((2-甲基噻唑-4-基)甲基)哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-((1-甲基-1H-咪唑-5-基)甲基)哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(喹 啉-2-基甲基)哌 -1-基)丙-1-酮;(S)-2-胺基-1-(4-(4-(3-(二甲基胺基)丙氧基)苄基)哌 -1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-((1-(甲基磺醯基)哌啶-4-基)甲基)哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(嘧啶-5-基甲基)哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基) 苯基)-1-(4-((1-甲基-1H-吡唑-4-基)甲基)哌 -1-基)丙-1-酮;(S)-1-(4-((1,2,3-噻二唑-4-基)甲基)哌 -1-基)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-3-((4-(2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯基)哌 -1-基)甲基)-N-甲基苄醯胺;(S)-5-((4-(2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯基)哌 -1-基)甲基)-N-甲基呋喃-2-羧醯胺;(S)-2-胺基-1-(4-苄醯基哌 -1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-(4-(環己烷羰基)哌 -1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(2-苯基乙醯基)哌 -1-基)丙-1-酮;(S)-2-胺基-1-(4-(環丙烷羰基)哌 -1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(1-甲基哌啶-4-羰基)哌 -1-基)丙-1-酮;(S)-2-胺基-1-(4-(4-((二甲基胺基)甲基)苄醯基)哌 -1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-(4-(3-((二甲基胺基)甲基)苄醯基)哌 -1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-菸鹼醯基哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基) 苯基)-1-(4-(1-甲基-1H-吡唑-4-羰基)哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(1-甲基-1H-咪唑-4-羰基)哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(噻唑-2-羰基)哌 -1-基)丙-1-酮;N-(3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(二甲基胺基)-1-側氧基丙烷-2-基)吡咯啶-3-羧醯胺;N-(3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-側氧基-1-(苯基胺基)丙烷-2-基)吡咯啶-3-羧醯胺;N-(3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(環己基胺基)-1-側氧基丙烷-2-基)吡咯啶-3-羧醯胺;N-(3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-((2-(二甲基胺基)乙基)胺基)-1-側氧基丙烷-2-基)環己烷羧醯胺;3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-(二甲基胺基)-N-(四氫-2H-吡喃-4-基)丙醯胺;3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-環己基-2-(二甲基胺基)丙醯胺;(S)-N-環己基-2-(二甲基胺基)-3-(4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-((環己基甲基)胺基)-N-甲基丙醯胺;(S)-2-胺基-3-(4-((3-溴-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯基)-N-環己基丙醯胺;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(4-((3-溴-1H-吡咯并[2,3-b]吡 啶-4-基)氧基)-3-氟苯基)丙-1-酮;(S)-2-胺基-3-(4-((3-溴-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-環己基丙醯胺;(S)-2-胺基-3-(4-((3-溴-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(四氫-2H-吡喃-4-基)丙醯胺;(S)-2-胺基-N-環己基-3-(4-((3-碘-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(S)-2-胺基-3-(4-((3-氯-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-環己基丙醯胺;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(4-((3-(吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(4-((3-(1-乙基-1H-吡唑-5-基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(4-((3-(吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-5-(4-(4-(2-胺基-3-(4-苄基哌 -1-基)-3-側氧基丙基)苯氧基)-1H-吡咯并[2,3-b]吡啶-3-基)噻吩-2-甲腈;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(4-((3-(噻唑-5-基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(4-((3-(1-甲基-1H-咪唑-5-基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(4-((3-(異 唑-4-基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(4-((3-苯基-1H-吡咯并[2,3-b] 吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(4-((3-(4-羥基苯基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(4-((3-(2,5-二氫呋喃-3-基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(4-((3-(2,5-二氫-1H-吡咯-3-基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-N-環己基-3-(4-((3-環丙基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-苯基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(1-甲基哌啶-4-基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-(噻唑-5-基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(1-甲基哌啶-4-基)丙醯胺;(S)-2-胺基-3-(4-((3-(4-羥基苯基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(2-(吡啶-4-基)乙基)丙醯胺;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(3-氟-4-((3-(羥基甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-N-環己基-3-(3-氟-4-((3-(羥基甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-(羥基甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(四氫-2H-吡喃-4-基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-(羥基甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(1-甲基哌啶-4-基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-(羥基甲基)-1H-吡咯并[2,3-b]吡啶-4-基) 氧基)苯基)-1-((1S,4S)-5-甲基-2,5-二吖二環[2.2.1]庚烷-2-基)丙-1-酮;(S)-2-胺基-N-(3-(二甲基胺基)丙基)-3-(3-氟-4-((3-(羥基甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-(羥基甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-(吡啶-2-基甲基)哌 -1-基)丙-1-酮;(S)-2-胺基-3-(3-氟-4-((3-(甲氧基甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(四氫-2H-吡喃-4-基)丙醯胺;(S)-2-胺基-3-(3-氟-4-((3-(甲氧基甲基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(4-甲基哌 -1-基)丙-1-酮;(S)-2-胺基-1-(4-苄基哌 -1-基)-3-(4-((3-(2-羥基乙基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮;(S)-2-胺基-N-環己基-3-(4-((3-(3-羥基丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙醯胺;(S)-2-胺基-3-(4-((3-氰基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(四氫-2H-吡喃-4-基)丙醯胺;(S)-2-胺基-3-(4-((3-氰基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-環己基丙醯胺;(S)-4-(4-(2-胺基-3-(4-苄基哌 -1-基)-3-側氧基丙基)-2-氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-甲腈;(S)-2-胺基-3-(4-((3-氰基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯基)-N-環己基丙醯胺;(S)-2-胺基-3-(4-((3-氰基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3-氟苯基)-N-(1-甲基哌啶-4-基)丙醯胺; 4-(4-((S)-2-胺基-3-((1S,4S)-5-甲基-2,5-二吖二環[2.2.1]庚烷-2-基)-3-側氧基丙基)-2-氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-甲腈;(S)-4-(4-(2-胺基-3-側氧基-3-(4-(吡啶-2-基甲基)哌 -1-基)丙基)-2-氟苯氧基)-1H-吡咯并[2,3-b]吡啶-3-甲腈;(S)-3-(4-((7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-2-胺基-N-環己基丙醯胺;(S)-3-(4-((7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-2-胺基-1-(4-苄基哌 -1-基)丙-1-酮;(S)-3-(5-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)吡啶-2-基)-2-胺基-N-環己基丙醯胺;(S)-3-(5-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)吡啶-2-基)-2-胺基-1-(4-苄基哌 -1-基)丙-1-酮;(R)-3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)-3,5-二氟苯基)-2-胺基-N-環己基丙醯胺;2-胺基-1-(4-苄基哌 -1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮之第一洗提單一對映異構物;2-胺基-1-(4-苄基哌 -1-基)-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)丙-1-酮之第二洗提單一對映異構物;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(3-(3-甲基-1,2,4- 二唑-5-基)吡咯啶-1-基)丙-1-酮之第一洗提非對映異構物;(S)-2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-1-(3-(3-甲基-1,2,4- 二唑-5-基)吡咯啶-1-基)丙-1-酮之第二洗提非對映異構物; 3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(4-(三氟甲基)苯基)丙醯胺之第一洗提對映異構物;3-(4-((1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-2-胺基-N-(4-(三氟甲基)苯基)丙醯胺之第二洗提對映異構物;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(2-(吡啶-4-基)乙基)丙醯胺之第一洗提對映異構物;2-胺基-3-(3-氟-4-((3-甲基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)苯基)-N-(2-(吡啶-4-基)乙基)丙醯胺之第二洗提對映異構物;或其醫藥上可接受之鹽及其溶劑合物。
- 一種醫藥組成物,其包含請求項1至6中任一項定義之化合物或其醫藥上可接受之鹽,其係單獨使用或組合另一種或另多種活性成分,與一或多種醫藥上可接受之載劑或賦形劑混合。
- 如請求項7之醫藥組成物,其係適用於藉吸入投藥,諸如可吸入粉劑、含推進劑之計量氣霧劑或不含推進劑之可吸入配方。
- 如請求項1至6中任一項之化合物,其係用作為藥物。
- 如請求項1至6中任一項之化合物,其係用於預防及/或治療選自於由下列所組成之組群中之肺臟疾病:氣喘、慢性阻塞性肺病(COPD)、特發性肺纖維化(IPF)、肺高壓(PH),及特別是肺動脈高壓(PAH)。
- 一種組合,其係由請求項1至6中任一項之化合物與選自於由下列所組成之類別中之一或多種活性成分組成:有機硝酸鹽及NO給予體;吸入性NO;可溶性鳥苷酸環化酶(sGC)激活劑;前列環素類似物PGI2及前列環素受體促效劑;抑制環狀鳥苷一磷酸(cGMP)及/或環狀腺苷一磷酸(cAMP)降解之化合物;人類嗜中性彈力蛋白 酶抑制劑;抑制信號轉導串級之化合物;降低血壓之活性物質;中性肽鏈內切酶抑制劑;滲透劑;ENaC阻斷劑;抗發炎劑包括皮質類固醇及趨化激素受體之拮抗劑;支氣管擴張劑;抗組織胺藥;止咳藥;抗生素及DNase藥物及選擇性裂解劑;Smad2及Smad3之ALK5及/或ALK4磷酸化抑制劑;色胺酸水解酶1(TPH1)抑制劑;及多重激酶抑制劑。
- 一種裝置,其包含請求項7之醫藥組成物,其可以是單劑或多劑乾粉吸入器、定量劑量吸入器及軟霧霧化器。
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MA51285A (fr) | 2017-12-18 | 2021-04-28 | Chiesi Farm Spa | Dérivés d'azaindole comme inhibiteurs de rho-kinase |
AR114926A1 (es) * | 2018-06-13 | 2020-10-28 | Chiesi Farm Spa | Derivados de azaindol como inhibidores de rho-quinasa |
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KR20210082186A (ko) * | 2018-10-19 | 2021-07-02 | 오하이오 스테이트 이노베이션 파운데이션 | 폐 염증 요법을 위한 나노담체 |
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CA2503646C (en) | 2002-10-28 | 2011-09-27 | Bayer Healthcare Ag | Heteroaryloxy-substituted phenylaminopyrimidines as rho-kinase inhibitors |
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EP1756092A4 (en) * | 2004-06-17 | 2009-12-02 | Smithkline Beecham Corp | NEW INHIBITORS OF RHO-KINASEN |
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